EDITION
6 Pathophysiology of Heart Disease A COLLA BORATI V E P ROJ ECT OF MED ICA L S TU D EN TS A N D FACU LTY
EDITION
6 Pathophysiology of Heart Disease A COLLA BORATIV E P ROJ ECT OF MED ICA L S TU D EN TS A N D FACU LTY EDITOR Leonard S. Lilly, MD Professor of Medicine Harvard Medical School Chief, Brigham and Women’s/ Faulkner Cardiology Brigham and Women’s Hospital Boston, Massachusetts
Senior Acquisitions Editor: Crystal Taylor Product Development Editor: Amy Weintraub Editorial Assistant: Brooks Phelps Marketing Director: Lisa Zoks Production Project Manager: Marian Bellus Design Coordinator: Holly McLaughlin Creative Director: Larry Pezzato Manufacturing Coordinator: Margie Orzech Prepress Vendor: SPi Global Copyright © 2016 Wolters Kluwer. Copyright ©2011, 2007, 2003, 1998, 1993 Lippincott Williams & Wilkins, a Wolters Kluwer business. All rights reserved. This book is protected by copyright. No part o this book may be reproduced or transmitted in any orm or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any in ormation storage and retrieval system without written permission rom the copyright owner, except or brie quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part o their o f cial duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at
[email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China Library of Congress Cataloging-in-Publication Data Pathophysiology o heart disease (Lilly) Pathophysiology o heart disease : a collaborative project o medical students and aculty / editor, Leonard S. Lilly. — Sixth edition. p. ; cm. Includes bibliographical re erences and index. ISBN 978-1-4511-9275-9 (alk. paper) I. Lilly, Leonard S., editor. II. Harvard Medical School. III. Title. [DNLM: 1. Heart Diseases—physiopathology. WG 210] RC682.9 616.1' 207—dc23 2015008633 This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency o the content o this work. This work is no substitute or individual patient assessment based upon healthcare pro essionals’ examination o each patient and consideration o , among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data and other actors unique to the patient. The publisher does not provide medical advice or guidance and this work is merely a re erence tool. Healthcare pro essionals, and not the publisher, are solely responsible or the use o this work including all medical judgments and or any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health in ormation, independent pro essional verif cation o medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and healthcare pro essionals should consult a variety o sources. When prescribing medication, healthcare pro essionals are advised to consult the product in ormation sheet (the manu acturer’s package insert) accompanying each drug to veri y, among other things, conditions o use, warnings and side e ects and identi y any changes in dosage schedule or contraindications, particularly i the medication to be administered is new, in requently used or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher or any injury and/ or damage to persons or property, as a matter o products liability, negligence law or otherwise, or rom any re erence to or use by any person o this work. LWW.com
Dedicated to
Carolyn, Jonathan, Rebecca, Douglas, Deborah, Norma and David Lilly
List of Contributors STUDENT CONTRIBUTORS Andrey V. Dolinko (MD 2016) Joshua Drago (MD 2015) David B. Fischer (MD 2016) P. Connor Johnson (MD 2015) Zena L. Knight (MD 2015) Michael T. Kuntz (MD 2015) Jacob E. Lemieux, D.Phil. (MD 2015) Diana M. López (MD 2016) David Miranda (MD 2016) Morgan J. Prust (MD 2015)
Patricia Challender Come, MD Associate Professor of Medicine Harvard Medical School Cardiologist, Harvard Vanguard Medical Associates Boston, Massachusetts Mark A. Creager, MD Professor of Medicine Geisel School of Medicine at Dartmouth Director, Heart and Vascular Center Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire
Sruthi Renati (MD 2015)
Jayme Wilder (MD 2015)
G. William Dec, MD Roman W. DeSanctis Professor of Medicine Harvard Medical School
FACULTY CONTRIBUTORS
Chief (Emeritus), Cardiology Division Massachusetts General Hospital Boston, Massachusetts
Elizabeth Ryznar, MSc (MD 2015) Sarrah Shahaw y (MD 2016)
Elliott M. Antman, MD Professor of Medicine Harvard Medical School Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Eugene Braunwald, MD (Foreword) Distinguished Hersey Professor of Medicine Harvard Medical School Founding Chairman, TIMI Study Group
Director, Harvard–MIT Biomedical Engineering Center Professor of Medicine Harvard Medical School Boston, Massachusetts
Brigham and Women’s Hospital Boston, Massachusetts
Michael A. Fifer, MD Professor of Medicine Harvard Medical School
David W. Brow n, MD Associate Professor of Pediatrics Harvard Medical School
Director, Cardiac Catheterization Laboratory
Cardiology Division Children’s Hospital Boston, Massachusetts
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Elazer R. Edelman, MD, PhD Thomas D. and Virginia W. Cabot Professor of Health Sciences and Technology Massachusetts Institute of Technology
Director, Hypertrophic Cardiomyopathy Program Massachusetts General Hospital Boston, Massachusetts
List of Contributors Gregory D. Lew is, MD Assistant Professor of Medicine Harvard Medical School
William G. Stevenson, MD Professor of Medicine Harvard Medical School
Director, Cardiology Intensive Care Unit Massachusetts General Hospital Boston, Massachusetts
Director, Clinical Cardiac Electrophysiology Program Brigham and Women’s Hospital Boston, Massachusetts
Peter Libby, MD Mallinckrodt Professor of Medicine Harvard Medical School Senior Physician Brigham and Women’s Hospital Boston, Massachusetts Leonard S. Lilly, MD Professor of Medicine Harvard Medical School
Gary R. Strichartz, PhD Professor of Anesthesia (Pharmacology) Harvard Medical School Director, Pain Research Center Vice Chairman of Research, Department of Anesthesia Brigham and Women’s Hospital Boston, Massachusetts
Chief, Brigham and Women’s/ Faulkner Cardiology Brigham and Women’s Hospital Boston, Massachusetts
Gordon H. Williams, MD Professor of Medicine Harvard Medical School
Patrick T. O’Gara, MD Professor of Medicine Harvard Medical School
Director, Center for Clinical Investigation Brigham and Women’s Hospital Boston, Massachusetts
Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts Marc S. Sabatine, MD, MPH Professor of Medicine Harvard Medical School Chairman, TIMI Study Group Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts
Director, Specialized Center of Research in Hypertension
vii
Foreword It is axiomatic that when designing any product or service, the needs o the prospective user must receive primary consideration. Regrettably, this is rarely the case with medical textbooks, which play a vital role in the education o students, residents, ellows, practicing physicians, and paramedical pro essionals. Most books are written or a wide audience so as to attract as many readers (and buyers) as possible. Most medical textbooks are tomes written either or the specialist or advanced trainee or they are technical “how to” manuals. Medical educators appreciate that the needs o medical students exposed to a subject or the f rst time di er importantly rom those o practicing physicians who wish to review an area learned previously or to be updated on new developments in a f eld with which they already have some amiliarity. The lack o textbooks designed specif cally or students leads aculty at schools around the country to spend countless hours preparing and duplicating voluminous lecture notes, and providing students with custom-designed “camels” (a camel is a cow created by a committee!). Pathophysiology o Heart Disease: A Collaborative Project o Medical Students and Faculty represents a re reshing and innovative departure in the preparation o a medical text. Students—the intended user—dissatisf ed with currently available textbooks on cardiology, made their needs clear. They need to understand the pathophysiology o cardiovascular disorders, and how the pathophysiology leads to key clinical and laboratory f ndings and to the rationale or management. Fortunately, their pleas ell on receptive ears. Dr. Leonard Lilly, a Pro essor o Medicine at Harvard Medical School, who is a brilliant teacher and a respected cardiologist at the Brigham and Women’s and Faulkner Hospitals, has served as the senior editor o this project. He has brought together a group o talented Harvard medical students and aculty who have collaborated closely to produce this superb introductory text specif cally designed to meet the needs o medical students during their initial encounters with patients with heart disease. Dr. Lilly, who was a co-author o most o the chapters made certain that there were no repetitions or major gaps, as so o ten occurs with multi-authored texts. While Pathophysiology o Heart Disease is not meant to be encyclopedic or all inclusive, it is remarkably thorough. The f rst f ve editions o this f ne book were received enthusiastically, and Pathophysiology o Heart Disease is now a required or recommended text at many medical schools not only in the United States and Canada, but in other countries as well. It has been translated into several languages, has received two awards o excellence rom the American Medical Writers Association, and has inspired other student– aculty collaborative book projects at Harvard and at other medical schools. This sixth edition is completely updated, as is required by a f eld as dynamic as cardiology. The f gures have been upgraded, are now in ull color, and they display complex concepts in uncomplicated ways. This edition will prove to be even more valuable than its predecessors. Dr. Lilly and his colleagues—both aculty and students—have made a signif cant and unique contribution in preparing this important book. Future generations o medical educators and students, and ultimately the patients that they serve, will be indebted to them or this important contribution. Eugene Braunwald, MD Distinguished Hersey Pro essor o Medicine Harvard Medical School Boston, Massachusetts
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Preface This textbook is a comprehensive introduction to diseases o the cardiovascular system. Although excellent cardiology re erence books are available, their encyclopedic content can overwhelm the beginning student. There ore, this text was created to serve as a simplif ed bridge between courses in basic physiology and the care o patients in clinical settings. It is intended to help medical students and physicians-in-training orm a solid oundation o knowledge o diseases o the heart and circulation and is designed to be read in its entirety during standard courses in cardiovascular pathophysiology. Emphasis has been placed on the basic mechanisms by which cardiac illnesses develop, in order to acilitate subsequent indepth study o clinical diagnosis and therapy. The original motivation or writing this book was the need or such a text voiced by our medical students, as well as their desire to participate in its creation and direction. Consequently, the book’s development is unusual in that it represents a close collaboration between Harvard medical students and cardiology aculty, who shared in the writing and editing o the manuscript. The goal o this pairing was to ocus the subject matter on the needs o the student, while providing the expertise o our aculty members. In this updated and rewritten sixth edition o Pathophysiology of Heart Disease, the collaborative e ort has continued between a new generation o medical students and our cardiovascular aculty. The introductory chapters o the book review basic cardiac anatomy and physiology and describe the tools needed or understanding clinical aspects o subsequently presented material. The remainder o the text addresses the major groups o cardiovascular diseases. The chapters are designed and edited to be read in sequence but are su f ciently cross-re erenced so that they can also be used out o order. The f nal chapter describes the major classes o cardiovascular drugs and explains the physiologic rationale or their uses. It has been a great privilege or me to collaborate with the 106 talented and creative medical students who have contributed to the six editions o this book. Their intelligence enthusiasm, energy, and dedication have made the production o each manuscript enjoyable and intellectually stimulating. I particularly recognize David Fischer, who stepped orward as the main student author liaison or this edition and was instrumental in acilitating organization o this project. I am indebted to my aculty colleague coauthors or their time, their expertise, and their continued commitment to this book. I especially acknowledge Pro essor Gary Strichartz, who has been an essential contributor to this project since 1996, and whose input into uture editions I will greatly miss as he transitions to retirement and new pursuits. I sincerely appreciate the thought ul and constructive comments received rom aculty and students around the globe pertaining to previous editions o this book. These communications have been very help ul in directing the current revision, and the many warm remarks and have been an important source o encouragement. I also acknowledge with gratitude several individuals who provided material, detailed comments and reviews, or other support to this edition: Suhny Abbara, Lauren Bayer, Marcelo DiCarli, Sharmila Dorbala, Marie Gerhard-Herman, Andetta Hunsaker, Raymond Kwong, Gillian Lieberman, Robert Padera, Helmut Rennke, Frank Rybicki, Christian Sampson, Frederick Schoen, Pinak Shah, Benjamin Smith, Michael Steigner, and Scott Streckenbach. It has been a pleasure to work with the editorial and production sta s o our publisher, Lippincott Williams & Wilkins. In particular, I thank Amy Weintraub, Crystal Taylor, Marian Bellus, Holly McLaughlin, and Leslie Jebaraj or their skill and pro essionalism in bringing this edition to completion.
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x Preface Finally, a project of this magnitude could not be undertaken without the support and patience of my family, and for that, I am very grateful. On behalf of the contributors, I hope that this book enhances your understanding of cardiovascular diseases and provides a solid foundation for further learning and clinical care of your patients. Leonard S. Lilly, MD Boston, Massachusetts
Table of Contents List of Contributors Foreword viii Prefa ce ix
vi
Chapt e r 1 0 The Cardiomyopathies
249
P. Connor Johnson, G. William Dec, and Leonard S. Lilly
Chapt e r 1 Normal Cardiac Structure and Function 1 Jacob E. Lemieux, Elazer R. Edelman, Gary R. Strichartz, and Leonard S. Lilly
Chapt e r 2 The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs 26 David B. Fischer and Leonard S. Lilly
Chapt e r 3 Cardiac Imaging and Catheterization
Chapt e r 1 1 Mechanisms of Cardiac Arrhythmias 268 Morgan J. Prust, William G. Stevenson, Gary R. Strichartz, and Leonard S. Lilly
Chapt e r 1 2 Clinical Aspects of Cardiac Arrhythmias 287 Morgan J. Prust, William G. Stevenson, and Leonard S. Lilly
43
Chapt e r 1 3 Hypertension
Diana M. López and Patricia Challender Come
Chapt e r 4 The Electrocardiogram
310
Joshua Drago, Gordon H. Williams, and Leonard S. Lilly
74
David B. Fischer and Leonard S. Lilly
Chapt e r 1 4 Diseases of the Pericardium
334
Leonard S. Lilly
Chapt e r 5 Atherosclerosis
112
Sarrah Shahawy and Peter Libby
Chapt e r 1 5 Diseases of the Peripheral Vasculature 350
Chapt e r 6 Ischemic Heart Disease
Sruthi Renati and Mark A. Creager
134
Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly
Chapt e r 1 6 Congenital Heart Disease
373
Zena L. Knight and David W. Brown
Chapt e r 7 Acute Coronary Syndromes
162
Jayme Wilder, Marc S. Sabatine, and Leonard S. Lilly
Chapt e r 8 Valvular Heart Disease
400
Andrey V. Dolinko, Michael T. Kuntz, Elliott M. Antman, Gary R. Strichartz, and Leonard S. Lilly
192
Elizabeth Ryznar, Patrick T. O’Gara, and Leonard S. Lilly
Chapt e r 9 Heart Failure
Chapt e r 1 7 Cardiovascular Drugs
Index
456
220
David Miranda, Gregory D. Lewis, and Michael A. Fifer
xi
Normal Cardiac Structure and Function
1
Ja cob E. Lemieux Ela zer R. Edelma n Ga ry R. Stricha rtz Leona rd S. Lilly
Ch a p t e r O u t l i n e Cardiac Anatomy and Histology Pericardium Sur ace Anatomy o the Heart Internal Structure o the Heart Impulse-Conducting System Cardiac Innervation Cardiac Vessels Histology o Ventricular Myocardial Cells Basic Electrophysiology Ion Movement and Channels Resting Potential Action Potential Re ractory Periods Impulse Conduction Normal Sequence o Cardiac Depolarization Excitation–Contraction Coupling Contractile Proteins in the Myocyte Calcium-Induced Calcium Release and the Contractile Cycle Introduction to Cardiac Signaling Systems β-Adrenergic and Cholinergic Signaling
K
nowledge o normal structure and unction o the heart is crucial to understanding diseases that a f ict the cardiovascular system. The purpose o this chapter is to describe the heart’s basic anatomy, its electrical system, and the cellular and molecular mechanisms o contraction that allow the heart to serve its critical unctions.
CARDIAC ANATOMY AND HISTOLOGY Although the study o cardiac anatomy dates back to ancient times, interest in this eld has recently gained momentum. The application o sophisticated cardiac imaging techniques such as coronary angiography, echocardiography, computed tomography, and magnetic resonance imaging requires an intimate knowledge o the spatial relationships o cardiac structures. Such in ormation also proves helpul in understanding the pathophysiology o heart disease. This section emphasizes the aspects o cardiac anatomy that are important to the clinician—that is, the “ unctional” anatomy.
Pericardium The heart and roots o the great vessels are enclosed by a broserous sac called the pericardium (Fig. 1-1). This structure consists o two layers: a strong outer brous layer and an inner serosal layer. The inner serosal layer adheres to the external wall o the heart and is called the visceral pericardium. The visceral pericardium ref ects back on itsel and lines the outer brous layer, orming the parietal pericardium. The space between the visceral and parietal layers contains a thin lm o pericardial f uid that allows the heart to beat in a minimal- riction environment.
1
2
Chapter 1 The pericardium is attached to the sternum and the mediastinal portions o the right and le t pleurae. Its many connections to the surrounding structures keep the pericardial sac rmly anchored within the thorax and thereby help to maintain the heart in its normal position. Emanating rom the pericardium in a superior direction are the aorta, the pulmonary artery, and the superior vena cava (see Fig. 1-1). The in erior vena cava projects through the pericardium in eriorly.
Surface Anatomy of the Heart
S upe rior ve na cava
Aorta
Pulmona ry a rte ry
He a rt within pe rica rdium Infe rior ve na cava
Dia phra gm
FIGURE 1-1. The position of the heart in the chest. The superior vena cava, aorta, and pulmonary artery exit superiorly, whereas the inferior vena cava projects inferiorly.
The heart is shaped roughly like a cone and consists o our muscular chambers. The right and le t ventricles are the main pumping chambers. The less muscular right and le t atria deliver blood to their respective ventricles. Several terms are used to describe the heart’s sur aces and borders (Fig. 1-2). The apex is ormed by the tip o the le t ventricle, which points in eriorly, anteriorly, and to the le t. The base or posterior sur ace o the heart is ormed by the atria, mainly the le t, and lies between the lung hila. The anterior sur ace o the heart is shaped by the right atrium and ventricle. Because the le t atrium and ventricle lie more posteriorly, they orm only a small strip o this anterior sur ace. The inferior sur ace o the heart is ormed by both ventricles, primarily the le t. This sur ace o the heart lies along the diaphragm; hence, it is also re erred to as the diaphragmatic sur ace. Observing the chest rom an anteroposterior view (as on a chest radiograph; see Chapter 3), our recognized borders o the heart are apparent. The right border is established by the right atrium and is almost in line with the superior and in erior venae cavae. The in erior border is nearly horizontal and is ormed mainly by the right ventricle, with a slight contribution rom the le t ventricle near the apex. The le t ventricle and a portion o the le t atrium make up the le t border o the heart, whereas the superior border is shaped by both atria. From this description o the sur ace o the heart emerges two basic “rules” o normal cardiac anatomy: (1) right-sided structures lie mostly anterior to their le t-sided counterparts and (2) atrial chambers are located mostly to the right o their corresponding ventricles.
Internal Structure of the Heart Four major valves in the normal heart direct blood f ow in a orward direction and prevent backward leakage. The atrioventricular (AV) valves (tricuspid and mitral) separate the atria and ventricles, whereas the semilunar valves (pulmonic and aortic) separate the ventricles rom the great arteries (Fig. 1-3). All our heart valves are attached to the brous cardiac skeleton, which is composed o dense connective tissue. The cardiac skeleton also serves as a site o attachment or the ventricular and atrial muscles. The sur ace o the heart valves and the interior sur ace o the chambers are lined by a single layer o endothelial cells, termed the endocardium. The subendocardial tissue contains broblasts, elastic and collagenous bers, veins, nerves, and branches o the conducting system and is continuous with the connective tissue o the heart muscle layer, the myocardium. The myocardium is the thickest layer o the heart and consists o bundles o
Normal Cardiac Structure and Function
Bra chioce pha lic a rte ry
Le ft common ca rotid a rte ry
S upe rior ve na cava
Le ft s ubclavia n a rte ry
As ce nding a orta
Le ft pulmona ry a rte ry
Right s upe rior pulmona ry a rte ry Right infe rior pulmona ry a rte ry
Le ft pulmona ry ve ins
Right pulmona ry ve ins
Pulmona ry trunk
Le ft a tria l a ppe nda ge Right a tria l a ppe nda ge
Le ft ve ntricle
Right a trium Infe rior ve na cava Right ve ntricle
A
Apex of he a rt
Infe rior he a rt borde r
Le ft common ca rotid a rte ry
Bra chioce pha lic a rte ry
Le ft s ubclavia n a rte ry
Arch of a orta
Le ft pulmona ry a rte ry S upe rior ve na cava Le ft s upe rior pulmona ry ve in
Right pulmona ry a rte ry
Le ft infe rior pulmona ry ve in
Right s upe rior pulmona ry ve in
Le ft a trium
Right infe rior pulmona ry ve in Right a trium
Corona ry s ulcus
Infe rior ve na cava
Le ft ve ntricle
Corona ry s inus
B
Right ve ntricle
Infe rior he a rt borde r
FIGURE 1-2. The heart and great vessels. A. The anterior view. B. The posterior aspect (or base), as viewed from the back. (From Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:137–138.)
3
4
Chapter 1 Ante rio r
Pulmonic va lve Aortic va lve Tricus pid va lve Mitra l va lve Annulus fibros us Annulus fibros us
Po s te rio r
FIGURE 1-3. The four heart valves viewed from above with atria removed. The f gure depicts the period o ventricular f lling (diastole) during which the tricuspid and mitral valves are open and the semilunar valves (pulmonic and aortic) are closed. Each annulus f brosus surrounding the mitral and tricuspid valves is thicker than those surrounding the pulmonic and aortic valves; all our contribute to the heart’s f brous skeleton, which is composed o dense connective tissue.
cardiac muscle cells, the histology o which is described later in the chapter. External to the myocardium is a layer o connective tissue and adipose tissue through which pass the larger blood vessels and nerves that supply the heart muscle. The epicardium is the outermost layer o the heart and is identical to, and just another term or, the visceral pericardium previously described.
Right Atrium and Ventricle Opening into the right atrium are the superior and in erior venae cavae and the coronary sinus (Fig. 1-4). The venae cavae return deoxygenated blood rom the systemic veins into the right atrium, whereas the coronary sinus carries venous return rom the coronary arteries. The interatrial septum orms the posteromedial wall o the right atrium and separates it rom the le t atrium. The tricuspid valve is located in the f oor o the atrium and opens into the right ventricle. The right ventricle (see Fig. 1-4) is roughly triangular in shape, and its superior aspect orms a cone-shaped outf ow tract, which leads to the pulmonary artery. Although the inner wall o the outf ow tract is smooth, the rest o the ventricle is covered by a number o irregular bridges (termed trabeculae carneae) that give the right ventricular wall a spongelike appearance. A large trabecula that crosses the ventricular cavity is called the moderator band. It carries a component o the right bundle branch o the conducting system to the ventricular muscle. The right ventricle contains three papillary muscles, which project into the chamber and via their thin, stringlike chordae tendineae attach to the edges o the tricuspid valve leaf ets. The leaf ets, in turn, are attached to the brous ring that supports the valve between the right atrium and ventricle. Contraction o the papillary muscles prior to other regions o the ventricle tightens the chordae tendineae, helping to align and restrain the leaf ets o the tricuspid valve as they are orced closed. This action prevents blood rom regurgitating into the right atrium during ventricular contraction. At the apex o the right ventricular outf ow tract is the pulmonic valve, which leads to the pulmonary artery. This valve consists o three cusps attached to a brous ring. During relaxation o the ventricle, elastic recoil o the pulmonary arteries orces blood back toward the
Normal Cardiac Structure and Function
5
Pulmona ry a rte ry Aorta Pulmonic va lve
S upe rior ve na cava Inte rve ntricula r s e ptum Right a trium Mode ra tor ba nd Tra be cula e ca rne a e Infe rior ve na cava
Corona ry s inus Tricus pid va lve
Right ve ntricle
Pa pilla ry mus cle s
FIGURE 1-4. Interior structures of the right atrium and right ventricle. (Modif ed rom Goss CM. Gray’s Anatomy. 29th ed. Philadelphia, PA: Lea & Febiger; 1973:547.)
heart, distending the valve cusps toward one another. This action closes the pulmonic valve and prevents regurgitation o blood back into the right ventricle.
Left Atrium and Ventricle Entering the posterior hal o the left atrium are the our pulmonary veins (Fig. 1-5). The wall o the le t atrium is about 2 mm thick, being slightly greater than that o the right atrium. The mitral valve opens into the le t ventricle through the in erior wall o the le t atrium. The cavity o the left ventricle is approximately cone shaped and longer than that o the right ventricle. In a healthy adult heart, the wall thickness is 9 to 11 mm, roughly three times that o the right ventricle. The aortic vestibule is a smooth-walled part o the le t ventricular cavity located just in erior to the aortic valve. In erior to this region, most o the ventricle is covered by trabeculae carneae, which are ner and more numerous than those in the right ventricle. The le t ventricular chamber (see Fig. 1-5B) contains two large papillary muscles. These are larger than their counterparts in the right ventricle, and their chordae tendineae are thicker but less numerous. The chordae tendineae o each papillary muscle distribute to both leaf ets o the mitral valve. Similar to the case in the right ventricle, tensing o the chordae tendineae during le t ventricular contraction helps restrain and align the mitral leaf ets, enabling them to close properly and preventing the backward leakage o blood. The aortic valve separates the le t ventricle rom the aorta. Surrounding the aortic valve opening is a brous ring to which is attached the three cusps o the valve. Just above the right and le t aortic valve cusps in the aortic wall are the origins o the right and le t coronary arteries (see Fig. 1-5B).
Interventricular Septum The interventricular septum is the thick wall between the le t and right ventricles. It is composed o a muscular and a membranous part (see Fig. 1-5B). The margins o this septum can be traced on the sur ace o the heart by ollowing the anterior and posterior interventricular grooves. Owing to the greater hydrostatic pressure within the le t ventricle, the large
6
Chapter 1 Pulmona ry ve ins
Le ft a trium Le ft a tria l a ppe nda ge Fibrous ring of le ft AV orifice Chorda e te ndine a e
Le ft ve ntricle
Pa pilla ry mus cle s
Ante rior cus p of mitra l va lve To a ortic ve s tibule
A Orifice of right corona ry a rte ry
As ce nding a orta Pos te rior cus p of a ortic va lve
Pulmona ry a rte ry Right a ortic s inus Right cus p of a ortic va lve
Orifice of le ft corona ry a rte ry Le ft cus p of a ortic va lve
Inte rve ntricula r s e ptum, me mbra nous pa rt
Chorda e te ndine a e Inte rve ntricula r s e ptum, mus cula r pa rt Right ve ntricle
Ante rior cus p of mitra l va lve Ante rior pa pilla ry mus cle
Pos te rior pa pilla ry mus cle Tra be cula e ca rne a e
B FIGURE 1-5. Interior structures of the left atrium and left ventricle. A. The le t atrium and le t ventricular (LV) in ow region. B. Interior structures o the LV cavity. (Modif ed rom Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy, 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:142–143.)
Normal Cardiac Structure and Function
7
muscular portion o the septum bulges toward the right ventricle. The small, oval-shaped membranous part o the septum is thin and located just in erior to the cusps o the aortic valve. To summarize the unctional anatomic points presented in this section, the ollowing is a review o the path o blood f ow: deoxygenated blood is delivered to the heart through the in erior and superior venae cavae, which enter into the right atrium. Flow continues through the tricuspid valve ori ce into the right ventricle. Contraction o the right ventricle propels the blood across the pulmonic valve to the pulmonary artery and lungs, where carbon dioxide is released and oxygen is absorbed. The oxygen-rich blood returns to the heart through the pulmonary veins to the le t atrium and then passes across the mitral valve into the le t ventricle. Contraction o the le t ventricle pumps the oxygenated blood across the aortic valve into the aorta, rom which it is distributed to all other tissues o the body.
Impulse-Conducting System The impulse-conducting system (Fig. 1-6) consists o specialized cells that initiate the heartbeat and electrically coordinate contractions o the heart chambers. The sinoatrial (SA) node is a small mass o specialized cardiac muscle bers in the wall o the right atrium. It is located to the right o the superior vena cava entrance and normally initiates the electrical impulse or contraction. The atrioventricular (AV) node lies beneath the endocardium in the in eroposterior part o the interatrial septum. Distal to the AV node is the bundle of His, which per orates the interventricular septum posteriorly. Within the septum, the bundle o His bi urcates into a compact, cablelike structure on the right side, known as the right bundle branch, and a broad sheet o bers that continues over the le t side o the septum, the left bundle branch. The right bundle branch is thick and deeply buried in the muscle o the interventricular septum and continues toward the apex. Near the junction o the interventricular septum and the anterior wall o the right ventricle, the right bundle branch becomes subendocardial
S inoa tria l node Mitra l va lve
Corona ry s inus
Me mbra nous pa rt of IV s e ptum Bifurca tion of bundle of His
Atriove ntricula r node Bundle of His Right bundle bra nch
Mus cula r pa rt of IV s e ptum Le ft bundle bra nch Purkinje fibe rs unde r e ndoca rdium of pa pilla ry mus cle
Mode ra tor ba nd
FIGURE 1-6. Main components of the cardiac conduction system. This system includes the sinoatrial node, atrioventricular node, bundle o His, right and le t bundle branches, and the Purkinje f bers. The moderator band carries a large portion o the right bundle. (IV, interventricular).
8
Chapter 1 and bi urcates. One branch travels across the right ventricular cavity in the moderator band, whereas the other continues toward the tip o the ventricle. These branches eventually arborize into a nely divided anastomosing plexus that travels throughout the right ventricle. Functionally, the le t bundle branch is divided into an anterior and a posterior ascicle and a small branch to the septum. The anterior ascicle runs anteriorly toward the apex, orming a subendocardial plexus in the area o the anterior papillary muscle. The posterior ascicle travels to the area o the posterior papillary muscle; it then divides into a subendocardial plexus and spreads to the rest o the le t ventricle. The subendocardial plexuses o both ventricles send distributing Purkinje bers to the ventricular muscle. Impulses within the His–Purkinje system are transmitted rst to the papillary muscles and then throughout the walls o the ventricles, allowing papillary muscle contraction to precede that o the ventricles. This coordination prevents regurgitation o blood f ow through the AV valves, as discussed earlier.
Cardiac Innervation The heart is innervated by both parasympathetic and sympathetic a erent and e erent nerves. Preganglionic sympathetic neurons, with cell bodies located within the upper ve to six thoracic levels o the spinal cord, synapse with second-order neurons in the cervical sympathetic ganglia. Traveling within the cardiac nerves, these bers terminate in the heart and great vessels. Preganglionic parasympathetic bers originate in the dorsal motor nucleus o the medulla and pass as branches o the vagus nerve to the heart and great vessels. Here, the bers synapse with second-order neurons located in ganglia within these structures. A rich supply o vagal a erents rom the in erior and posterior aspects o the ventricles mediates important cardiac ref exes, whereas the abundant vagal e erent bers to the SA and AV nodes are active in modulating electrical impulse initiation and conduction.
Cardiac Vessels The cardiac vessels consist o the coronary arteries and veins and the lymphatics. The largest components o these structures lie within the loose connective tissue in the epicardial at.
Coronary Arteries The heart muscle is supplied with oxygen and nutrients by the right and le t coronary arteries, which arise rom the root o the aorta just above the aortic valve cusps (Fig. 1-7; see also Fig. 1-5B). A ter their origin, these vessels pass anteriorly, one on each side o the pulmonary artery (see Fig. 1-7). The large le t main coronary artery passes between the le t atrium and the pulmonary trunk to reach the AV groove. There it divides into the le t anterior descending (LAD) coronary artery and the circumf ex artery. The LAD travels within the anterior interventricular groove toward the cardiac apex. During its descent on the anterior sur ace, the LAD gives o septal branches that supply the anterior two thirds o the interventricular septum and the apical portion o the anterior papillary muscle. The LAD also gives o diagonal branches that supply the anterior sur ace o the le t ventricle. The circumf ex artery continues within the le t AV groove and passes around the le t border o the heart to reach the posterior sur ace. It gives o large obtuse marginal branches that supply the lateral and posterior wall o the le t ventricle. The right coronary artery (RCA) travels in the right AV groove, passing posteriorly between the right atrium and ventricle. It supplies blood to the right ventricle via acute marginal branches. In most people, the distal RCA gives rise to a large branch, the posterior descending artery (see Fig. 1-7C). This vessel travels rom the in eroposterior aspect o the
Normal Cardiac Structure and Function
9
Pulmona ry a rte ry Le ft ma in corona ry a rte ry
Aorta
Le ft circumflex corona ry a rte ry
Le ft a nte rior de s ce nding corona ry a rte ry
Right corona ry a rte ry
A
Le ft circumflex corona ry a rte ry Le ft a nte rior de s ce nding corona ry a rte ry
Right corona ry a rte ry
Dia gona l bra nch
Le ft circumflex corona ry a rte ry
Obtus e ma rgina l bra nche s
Acute ma rgina l bra nch
B
C
Right corona ry a rte ry
Pos te rior de s ce nding corona ry a rte ry
FIGURE 1-7. Coronary artery anatomy. A. Schematic representation o the right and le t coronary arteries demonstrates their orientation to one another. The le t main artery bi urcates into the circumf ex artery, which per uses the lateral and posterior regions o the le t ventricle (LV), and the anterior descending artery, which per uses the LV anterior wall, the anterior portion o the intraventricular septum, and a portion o the anterior right ventricular (RV) wall. The right coronary artery (RCA) per uses the right ventricle and variable portions o the posterior le t ventricle through its terminal branches. The posterior descending artery most o ten arises rom the RCA. B. Anterior view o the heart demonstrating the coronary arteries and their major branches. C. Posterior view o the heart demonstrating the terminal portions o the right and circumf ex coronary arteries and their branches.
heart to the apex and supplies blood to the in erior and posterior walls o the ventricles and the posterior one third o the interventricular septum. Just be ore giving o the posterior descending branch, the RCA usually gives o the AV nodal artery. The posterior descending and AV nodal arteries arise rom the RCA in 85% o the population, and in such people, the coronary circulation is termed right dominant. In approximately 8% , the posterior descending artery arises rom the circumf ex artery instead, resulting in a left dominant circulation. In the remaining population, the heart’s posterior blood supply is contributed to rom branches o both the RCA and the circumf ex, orming a codominant circulation.
10
Chapter 1 The blood supply to the SA node is also most o ten (70% o the time) derived rom the RCA. However, in 25% o normal hearts, the SA nodal artery arises rom the circumf ex artery, and in 5% o cases, both the RCA and the circumf ex artery contribute to this vessel. From their epicardial locations, the coronary arteries send per orating branches into the ventricular muscle, which orm a richly branching and anastomosing vasculature in the walls o all the cardiac chambers. From this plexus arise a massive number o capillaries that orm an elaborate network surrounding each cardiac muscle ber. The muscle bers located just beneath the endocardium, particularly those o the papillary muscles and the thick le t ventricle, are supplied either by the terminal branches o the coronary arteries or directly rom the ventricular cavity through tiny vascular channels, known as thebesian veins. Collateral connections, usually less than 200 µm in diameter, exist at the subarteriolar level between the coronary arteries. In the normal heart, ew o these collateral vessels are visible. However, they may become larger and unctional when atherosclerotic disease obstructs a coronary artery, thereby providing blood f ow to distal portions o the vessel rom a nonobstructed neighbor.
Coronary Veins The coronary veins ollow a distribution similar to that o the major coronary arteries. These vessels return blood rom the myocardial capillaries to the right atrium predominantly via the coronary sinus. The major veins lie in the epicardial at, usually super cial to their arterial counterparts. The thebesian veins, described earlier, provide an additional potential route or a small amount o direct blood return to the cardiac chambers.
Lymphatic Vessels The heart lymph is drained by an extensive plexus o valved vessels located in the subendocardial connective tissue o all our chambers. This lymph drains into an epicardial plexus rom which are derived several larger lymphatic vessels that ollow the distribution o the coronary arteries and veins. Each o these larger vessels then combines in the AV groove to orm a single lymphatic conduit, which exits the heart to reach the mediastinal lymphatic plexus and ultimately the thoracic duct.
Histology of Ventricular Myocardial Cells The mature myocardial cell (also termed the myocyte) measures up to 25 µm in diameter and 100 µm in length. The cell shows a cross-striated banding pattern similar to that o the skeletal muscle. However, unlike the multinucleated skeletal myo bers, myocardial cells contain only one or two centrally located nuclei. Surrounding each myocardial cell is connective tissue with a rich capillary network. Each myocardial cell contains numerous myof brils, which are long chains o individual sarcomeres, the undamental contractile units o the cell (Fig. 1-8). Each sarcomere is made up o two groups o overlapping laments o contractile proteins. Biochemical and biophysical interactions occurring between these myo laments produce muscle contraction. Their structure and unction are described later in the chapter. Within each myocardial cell, the neighboring sarcomeres are all in register, producing the characteristic cross-striated banding pattern seen by light microscopy. The relative densities o the cross bands identi y the location o the contractile proteins. Under physiologic conditions, the overall sarcomere length (Z-to-Z distance) varies between 2.2 and 1.5 µm during the cardiac cycle. The larger dimension ref ects the ber stretch during ventricular lling, whereas the smaller dimension represents the extent o ber shortening during contraction.
Normal Cardiac Structure and Function
Myofibril
Sa rcopla s mic re ticulum
Sa rcole mma
11
T tubule
Mitochondrion
FIGURE 1-8. Myocardial cell. Top. Schematic representation o the ultrastructure o the myocardial cell. The cell consists o multiple parallel myof brils surrounded by mitochondria. The T tubules are invaginations o the cell membrane (the sarcolemma) that increase the sur ace area or ion transport and transmission o electrical impulses. The intracellular sarcoplasmic reticulum houses most o the intracellular calcium and abuts the T tubules. (Modif ed rom Katz AM. Physiology of the Heart. 2nd ed. New York, NY: Raven Press; 1992:21). Bottom. Expanded view o a sarcomere, the basic unit o contraction. Each myof bril consists o serially connected sarcomeres that extend rom one Z line to the next. The sarcomere is composed o alternating thin (actin) and thick (myosin) myof laments. Titin is a protein that tethers myosin to the Z line and provides elasticity.
Z
Actin
Myos in
Titin Z
Sa rcome re
The myocardial cell membrane is named the sarcolemma. A specialized region o the membrane is the intercalated disk, a distinct characteristic o cardiac muscle tissue. Intercalated disks are seen on light microscopic study as darkly staining transverse lines that cross chains o cardiac cells at irregular intervals. They represent the gap junction complexes at the inter ace o adjacent cardiac f bers and establish structural and electrical continuity between the myocardial cells. Another unctional eature o the cell membrane is the transverse tubular system (or T tubules). This complex system is characterized by deep, f ngerlike invaginations o the sarcolemma (Fig. 1-9; see also Fig. 1-8). Similar to the intercalated disks, transverse tubular membranes establish pathways or rapid transmission o the excitatory electrical impulses that initiate contraction. The T tubule system increases the sur ace area o the sarcolemma
T tubule
Sa rcole mma
Ca ++
Ca ++ Ca ++
FIGURE 1-9. Schematic view of the tubular systems of the myocardial cell. The T tubules, invaginations o the sarcolemma, abut the sarcoplasmic reticulum at right angles at the terminal cisternae sacs. This relationship is important in linking membrane excitation with intracellular release o calcium rom the sarcoplasmic reticulum.
Ca ++ Ca ++
Ca ++
Sa rcopla s mic re ticulum ATPa s e Ca ++
Ca ++
Ca ++ Ca ++
Te rmina l cis te rna e
Ca ++
12
Chapter 1 in contact with the extracellular environment, allowing the transmembrane ion transport accompanying excitation and relaxation to occur quickly and synchronously. The sarcoplasmic reticulum (SR, the myocyte analog o the endoplasmic reticulum) is an extensive intracellular tubular membrane network that complements the T tubule system both structurally and unctionally. The SR abuts the T tubules at right angles in lateral sacs, called the terminal cisternae (see Fig. 1-9). These sacs house most o intracellular calcium stores; the release o these stores is important in linking membrane excitation with activation o the contractile apparatus. Lateral sacs also abut the intercalated disks and the sarcolemma, providing each with a complete system or excitation–contraction coupling. To serve the tremendous metabolic demand placed on the heart and the need or a constant supply o high-energy phosphates, the myocardial cell has an abundant concentration o mitochondria. These organelles are located between the individual myo brils and constitute approximately 35% o cell volume (see Fig. 1-8).
BASIC ELECTROPHYSIOLOGY Rhythmic contraction o the heart relies on the organized propagation o electrical impulses along its conduction pathway. The marker o electrical stimulation, the action potential, is created by a sequence o ion f uxes through speci c channels in the sarcolemma. To provide a basis or understanding how electrical impulses lead to cardiac contraction, the process o cellular depolarization and repolarization is reviewed here. This material serves as an important oundation or topics addressed later in the book, including electrocardiography (see Chapter 4), cardiac arrhythmias (see Chapters 11 and 12), and the actions o antiarrhythmic drugs (see Chapter 17). Cardiac cells capable o electrical excitation are o three electrophysiologic types, the properties o which have been studied by intracellular microelectrode and patch-clamp recordings: 1. Pacemaker cells (e.g., SA node, AV node) 2. Specialized rapidly conducting tissues (e.g., Purkinje bers) 3. Ventricular and atrial muscle cells The sarcolemma o each o these cardiac cell types is a phospholipid bilayer that, by itsel , is largely impermeable to ions. There are specialized proteins interspersed throughout the membrane that serve as ion channels, passive cotransporters, and active transporters (Fig. 1-10). These help to maintain ionic concentration gradients and charge di erentials between the inside and the outside o the cardiac cells. Note that normally the Na + and Ca + + concentrations are much higher outside the cell, and the K+ concentration is much higher inside.
Ion Movement and Channels The movement o speci c ions across the cell membrane serves as the basis o the action potential. Passive ion movement depends on two major actors: (1) the energetic avorability and (2) the permeability o the membrane or the ion.
Energetics The two major orces that drive the direction o passive ion f ux are the concentration gradient and the transmembrane potential (voltage). Molecules di use rom areas o high concentration to areas o lower concentration, and the gradient between these values is a determinant o the rate o ion f ow. For example, the extracellular Na + concentration is normally 145 mM, while the concentration inside the myocyte is 15 mM. As a result, a strong di usive orce tends to drive Na + into the cell, down its concentration gradient. The transmembrane potential o cells exerts an electrical orce on ions (i.e., like charges repel one another, and opposite charges attract). The transmembrane potential o a myocyte
Normal Cardiac Structure and Function Na +
13
Ca ++
A
B
C K+ Ca ++
GAP J UNCTION
G
Inte rna l [Na +] [K+] [Cl– ] [Ca ++]
ATP Ca ++
Na +
D Na +
E
15 mM 150 mM 5 mM 10 –7 M
Ca ++
ATP
Ca ++
F
ATP
Exte rna l K+
[Na +] [K+] [Cl– ] [Ca ++]
145 5 120 2
mM mM mM mM
FIGURE 1-10. Ion channels, cotransporters, and active transporters of the myocyte. A. Sodium entry through the ast sodium channel is responsible or the rapid upstroke (phase 0) o the action potential (AP) in nonpacemaker cells. B. Calcium enters the cell through calcium channel during phase 2 o the Purkinje f ber and muscle cell AP and is the main channel responsible or depolarization o pacemaker cells. C. Potassium exits through a number o di erent potassium channels to repolarize the cell, and open potassium channels contribute to the resting potential (phase 4) o nonpacemaker cells. D. Sodium–calcium exchanger helps maintain the low intracellular calcium concentration. E. Sodium–potassium ATPase maintains concentration gradients or these ions. F, G. Active calcium transporters aid removal o calcium to the external environment and into the sarcoplasmic reticulum, respectively.
at rest is about − 90 mV (the inside o the cell is negative relative to the outside). Extracellular Na + , a positively charged ion, is there ore attracted to the relatively negatively charged interior o the cell. Thus, there is a strong tendency or Na + to enter the cell and remain there, because o the steep concentration gradient and the electrical attraction.
Permeability I there is such a strong orce driving Na + into the cell, what keeps this ion rom actually moving inside? The membrane o the cell at its resting potential is not permeable to sodium. The phospholipid bilayer o the cell membrane is composed o a hydrophobic core that does not allow simple passage o charged, hydrophilic particles. Instead, permeability o the membrane is dependent on the opening o specif c ion channels, specialized proteins that span the cell membrane and contain hydrophilic pores through which certain charged atoms can pass under specif c circumstances. Typically, one cell’s sarcolemma contains a million or more such channels. Each type o channel is normally selective or a specif c ion, which is a mani estation o the size and structure o its pore. For example, in cardiac cells, some channels permit the passage o sodium ions, some are specif c or potassium, and others allow only calcium to transit through. Ions can pass through their specif c channels only at certain times. That is, ion channels are gated—at any given moment, a channel is either open or closed. The more time a channel is in its open state, the larger the number o ions that can pass through it and there ore, the greater the transmembrane current. The voltage across the membrane determines what
Chapter 1 raction o channels is open at a given time. There ore, the gating o channels is said to be voltage sensitive. As the membrane voltage changes during depolarization and repolarization o the cell, speci c channels open and close, with corresponding alterations in the ion f uxes across the sarcolemma. An example o voltage-sensitive gating is apparent in the cardiac channel known as the fast sodium channel. The transmembrane protein that orms this channel assumes various conormations depending on the cell’s membrane potential (Fig. 1-11). At a voltage o − 90 mV
CHANNEL CLOS ED (RESTING) Ac tiva tion ga te
Ra p id d e p ola riza tion Na +
III
IV Outs ide
CHANNEL OP EN
++++
II ++++
––––
––––
––––
––––
++++
++++
Ce ll me mbra ne
Ins ide
Ina c tiva tion ga te
A
B Na + R e p
s
o
p
o
n
n
o ti
ta
n
e
za ri
o
u
la
S
14
CHANNEL CLOS ED (INACTIVE) Na +
––––
––––
++++
++++
C FIGURE 1-11. Schematic representation of gating of fast sodium channels. A. Four covalently linked transmembrane domains (I, II, III, and IV) form the sodium channel, which is guarded by activation and inactivation gates. (Here, domain I is cut away to show the transmembrane pore.) In the resting membrane, most channels are in a closed state. Even though the inactivation gate is open, Na+ ions cannot easily pass through because the activation gate is closed. B. A rapid depolarization changes the cell membrane voltage and forces the activation gate to open, presumably mediated by translocation of the charged portions of a segment in each domain. With the channel in this conformation (in which both the activation and inactivation gates are open), Na+ ions permeate into the cell. C. As the inactivation gate spontaneously closes, the sodium current ceases. The inactivation gating function is thought to be achieved by a peptide loop that connects domains III and IV, which translocates into the intracellular opening of the channel pore (black arrow). The channel cannot reopen directly from this closed, inactive state. Cellular repolarization returns the channel to the resting condition ( A) . During repolarization, as high negative membrane voltages are reachieved, the activation gate closes and the inactivation gate reopens.
Normal Cardiac Structure and Function
15
(the typical resting voltage o a ventricular muscle cell), the channels are predominantly in a closed, resting state, such that Na + ions cannot pass through (Fig. 1-11A). In this resting state, the channels are available or conversion to the open con guration. A rapid wave o depolarization renders the membrane potential less negative, and this activates the resting channels to change con ormation to the open state (see Fig. 1-11B). Na + ions readily permeate through the open channels, constituting an inward Na + current that urther depolarizes the cell. However, the activated channels remain open or only a brie time, a ew thousandths o a second, and then spontaneously close to an inactive state (see Fig. 1-11C). Channels in the inactivated con ormation cannot be directly converted back to the open state. The inactivated state persists until the membrane voltage has been repolarized nearly back to its original resting level. Until then, the inactivated channel con ormation maintains a closed pore that prevents any f ow o sodium ions. Thus, during normal cellular depolarization, the voltage-dependent ast sodium channels conduct or a short period and then inactivate, unable to conduct current again until the cell membrane has nearly ully repolarized, and the channels recover rom the inactivated to the closed resting state. Another important attribute o cardiac ast sodium channels should be noted. I the transmembrane voltage o a cardiac cell is slowly depolarized and maintained chronically at levels less negative than the usual resting potential, inactivation o channels occurs without initial opening and current f ow. Furthermore, as long as this partial depolarization exists, the closed, inactive channels cannot recover to the resting state. Thus, the ast sodium channels in such a cell are persistently unable to conduct Na + ions. This is the typical case in cardiac pacemaker cells (e.g., the SA and AV nodes) in which the membrane voltage is generally less negative than − 70 mV throughout the cardiac cycle. As a result, the ast sodium channels in pacemaker cells are persistently inactivated and do not play a role in the generation o the action potential in these cells. Calcium and potassium channels in cardiac cells also act in voltage-dependent ashions, but they behave di erently than the sodium channels, as described later.
Resting Potential In nonpacemaker cardiac cells at rest, prior to excitation, the electrical charge di erential between the inside and outside o a cell corresponds to the resting potential. The magnitude o the resting potential o a cell depends on two main properties: (1) the concentration gradients or all the di erent ions between the inside and outside o the cell and (2) the relative permeabilities o ion channels that are open at rest. As in other tissues such as nerve cells and skeletal muscle, the potassium concentration is much greater inside cardiac cells compared with outside. This is attributed mainly to the cell membrane transporter Na + K+ -ATPase (see Fig. 1-10). This protein “pump” actively extrudes 3 Na + ions out o the cell in exchange or the inward movement o 2 K+ ions in an ATP-dependent process. This acts to maintain intracellular Na + at low levels and intracellular K+ at high levels. Cardiac myocytes contain a set o potassium channels (termed inward rectif er potassium channels) that are open in the resting state, at a time when other ionic channels (e.g., sodium and calcium) are closed. There ore, the resting cell membrane is much more permeable to potassium than to other ions. As a result, K+ f ows in an outward direction down its concentration gradient, removing positive charges rom the cell. As potassium ions exit the cell, negatively charged anions that are impermeant to passage are le t behind, causing the interior o the cell to become electrically negative with respect to the outside. As the interior o the cell becomes more negatively charged by the outward f ux o potassium, the positively charged K+ ions are attracted back by the electrical potential toward the cellular interior, slowing their net exit rom the cell. Thus, the K+ concentration gradient and the electrostatic orce oppose each other (Fig. 1-12). At equilibrium, these orces are
16
Chapter 1 Ope n pota s s ium cha nne ls Ins ide ce ll
CONCENTRATION [K+] out (5 mM) GRADIENT ELECTRICAL FORCE
K+
[K+] in (150 mM) + – + – + – + –
Equilibrium (Ne rns t) pote ntia l = –26.7 ln ([K+] in /[K+] out) = –91mV
FIGURE 1-12. The resting potential of a cardiac muscle cell is determined by the balance between the concentration gradient and electrostatic forces for potassium, because only potassium channels are open at rest. The concentration gradient avors outward movement o K+ , whereas the electrical orce attracts the positively charged K+ ions inward. The resting potential is approximated by the Nernst equation or potassium, as shown here.
balanced, and there is zero net movement o K+ across the membrane. The electrical potential at which that occurs is known as the potassium equilibrium potential and in ventricular myocytes is − 91 mV, as calculated by the Nernst equation, shown in Figure 1-12. Since at rest the membrane is almost exclusively permeable to potassium ions alone, this value closely approximates the cell’s resting potential. The permeability o the cardiac myocyte cellular membrane or sodium is minimal in the resting state because the channels that conduct that ion are essentially closed. However, there is a slight leak o sodium ions into the cell at rest. This small inward current o positively charged ions explains why the actual resting potential is slightly less negative (− 90 mV) than would be predicted i the cell membrane were truly only permeable to potassium. The sodium ions that slowly leak into the myocyte at rest (and the much larger amount that enters during the action potential) are continuously removed rom the cell and returned to the extracellular environment by Na + K+ -ATPase, as previously described.
Action Potential When the cell membrane’s voltage is altered, its permeability to specif c ions changes because o the voltage-gating characteristics o the ion channels. Each type o channel has a characteristic pattern o activation and inactivation that determines the progression o the electrical signal. The ionic currents that pass through the channels discussed in this chapter are listed in Table 1-1. This description begins by ollowing the development o the action potential in a typical cardiac muscle cell (Fig. 1-13). The unique characteristics o action potentials in cardiac pacemaker cells are described therea ter.
TABLE 1-1
Transmembrane Cardiac Ionic Currents Described in This Chapter
Current
Description
I I Na ICa.L
Pacemaker current; responsible or phase 4 depolarization in pacemaker cells Na+ + current; responsible or phase 0 rapid depolarization in nonpacemaker cells Slow, long-lasting Ca+ + current; responsible or phase 0 depolarization in pacemaker cells, and major contributor to inward current during phase 2 o nonpacemaker cells Maintains resting potential; current o the inward recti ying potassium channel Transient outward potassium current; responsible or phase 1 o action potential Delayed rectif er potassium currents o slow (I Ks) and rapid (I Kr) types; repolarizing currents that are active during phases 2 and 3 o action potential
I K1 Ito I Ks, I Kr
Normal Cardiac Structure and Function
Cardiac Muscle Cell
Ca ++ inwa rd a nd K+ outwa rd
1 l
Until stimulated, the resting potential o a cardiac muscle cell remains stable, at approximately − 90 mV. This resting state be ore depolarization is known as phase 4 o the action potential. Following phase 4, our additional phases characterize depolarization and repolarization o the cell (see Fig. 1-13).
i
a
0
t
17
)
p
o
t
e
n
2 3
–50 Na + inwa rd
M
e
m
b
r
a
(
n
m
e
V
0
K+ outwa rd
4 –100 0
C
u
r
r
e
INa
I
n
w
a
r
d
0 ICa.L
s
IK1
+
Ito
r
d
K
C
u
r
r
e
n
t
0
t
w
a
0
u O
At the resting membrane voltage, sodium and calcium channels are closed. Any process that makes the membrane potential less negative than the resting value causes some sodium channels to open. As these channels open, sodium ions rapidly enter the cell, f owing down their concentration gradient toward the negatively charged cellular interior. The entry o Na + ions into the cell causes the transmembrane potential to become progressively less negative, which in turn causes more sodium channels to open and promotes urther sodium entry into the cell. When the membrane voltage approaches the threshold potential (approximately − 70 mV in cardiac muscle cells), enough o these ast Na + channels have opened to generate a sel -sustaining inward Na + current (termed INa ). The entry o positively charged Na + ions at and beyond threshold exceeds the exit o K+ ions through the open inward recti er channels, such that the cell continues to depolarize, transiently to a net positive potential. The prominent inf ux o sodium ions is responsible or the rapid upstroke, or phase 0, o the action potential. However, the Na + channels remain open or only a ew thousandths o a second and are then quickly inactivated, preventing urther inf ux (see Fig. 1-13). Thus, while activation o these ast Na + channels causes the rapid early depolarization o the cell, the rapid inactivation makes tial short lived.
n
t
s
Phase 0
IKr
IKs IKr
IKs 0
FIGURE 1-13. Schematic representation of a myocyte action potential ( AP) and major ionic currents. The resting potential is represented by phase 4 o the AP. During depolarization, Na+ in ux (I Na) results in the rapid upstroke o phase 0; a transient outward potassium current (Ito) is responsible or partial repolarization during phase 1; slow Ca+ + in ux (ICa.L) balanced by K+ e ux (I Ks and I Kr) results in the plateau o phase 2; and f nal rapid repolarization results largely rom urther K+ e ux during phase 3. The resting potential o phase 4 is maintained primarily by the current IK1 through inward rectif er potassium channels.
their major contribution to the action poten-
Phase 1 Following rapid phase 0 depolarization into the positive voltage range, a brie current o repolarization during phase 1 returns the membrane potential to approximately 0 mV.
18
Chapter 1 The responsible current (termed Ito) is carried by the outward f ow o K+ ions through a type o transiently activated potassium channel.
Phase 2 This relatively long “plateau” phase o the action potential is mediated by the balance o outward K+ currents (known as IKs and IKr) carried through voltage-gated delayed rectif er K+ channels, in competition with an inward Ca + + current, which f ows through speci c L-type calcium channels. The latter channels begin to open during phase 0, when the membrane voltage reaches approximately − 40 mV, allowing Ca + + ions to f ow down their concentration gradient into the cell (this current is termed Ica.L). Ca + + entry proceeds in a more gradual ashion than the initial inf ux o sodium, because with calcium channels, activation is slower and the channels remain open much longer compared with sodium channels (see Fig. 1-13). During this phase, the near equality o current rom inward Ca + + inf ux and outward K+ e f ux results in nearly zero net current, and the membrane voltage does not change or a prolonged period, which accounts or the f at plateau portion o the action potential curve. Calcium ions that enter the cell during this phase play a critical role in triggering additional internal calcium release rom the SR, which is important in initiating myocyte contraction, as discussed later in this chapter. As the Ca + + channels gradually inactivate and the charge e f ux o K+ begins to exceed the charge inf ux o calcium, phase 3 begins.
Phase 3 This is the nal phase o repolarization that returns the transmembrane voltage back to the resting potential o approximately − 90 mV. A continued outward potassium current exceeds the low inward current o other cations and is thus responsible or this period o rapid repolarization. Phase 3 completes the action potential cycle, with a return to resting phase 4, preparing the cell or the next stimulus or depolarization. To preserve normal transmembrane ionic concentration gradients, sodium and calcium ions that enter the cell during depolarization must be returned to the extracellular environment, and potassium ions must return to the cell interior. As shown in Figure 1-10, Ca + + ions are removed by the sarcolemmal Na + –Ca + + exchanger and to a lesser extent by the ATPenergized calcium pump (sarcolemmal Ca + + -ATPase). The corrective exchange o Na + and K+ across the cell membrane is mediated by Na + K+ -ATPase, as described earlier.
Specialized Conduction System The process described in the previous sections applies to the action potential o cardiac muscle cells. The cells o the specialized conduction system (e.g., Purkinje bers) behave similarly, although the resting potential is slightly more negative and the upstroke o phase 0 is even more rapid, due to a greater presence o Na + channels in these tissues.
Pacemaker Cells The upstroke o the action potential o cardiac muscle cells does not normally occur spontaneously. Rather, when a wave o depolarization reaches the myocyte through the electrical junctions with neighboring cells, its membrane potential becomes less negative and an action potential is triggered. Conversely, certain heart cells do not require external provocation to initiate their action potential. Rather, they are capable o sel -initiated depolarization in a rhythmic ashion and are known as pacemaker cells. They are endowed with the property o automaticity, by which the cells undergo spontaneous depolarization during phase 4. When the threshold voltage is reached in such cells, an action potential upstroke is triggered (Fig. 1-14).
0
m
V
19
n
t
i
a
l
(
Ca ++ influx (ICa .L) –40 4 lf
e
m
b
r
a
n
e
p
o
t
e
0
K+ e fflux (IKs a nd IKr)
M
Cells that display pacemaker behavior include the SA node (the “natural pacemaker” o the heart) and the AV node. Although atrial and ventricular muscle cells do not normally display automaticity, they may do so under disease conditions such as ischemia. The shape o the action potential o a pacemaker cell is di erent rom that o a ventricular muscle cell in three ways:
)
Normal Cardiac Structure and Function
–80 1. The maximum negative voltage o pacemaker Time cells is approximately − 60 mV, substantially less negative than the resting potential o ven- FIGURE 1-14. Action potential of a tricular muscle cells (− 90 mV). The persistently pacemaker cell. Phase 4 is characterized by less negative membrane voltage of pacemaker gradual, spontaneous depolarization owing to cells causes the fast sodium channels within the pacemaker current (I ). When the threshold potential is reached, at about − 40 mV, the these cells to remain inactivated. upstroke o the action potential ollows. 2. Unlike that o cardiac muscle cells, phase 4 o The upstroke o phase 0 is less rapid than the pacemaker cell action potential is not f at in nonpacemaker cells because the current but has an upward slope, representing sponta- represents Ca+ + inf ux through the relatively neous gradual depolarization. This spontane- slow calcium channels (Ica.L). Repolarization ous depolarization is the result o an ionic f ux occurs with inactivation o the calcium channels + known as the pacemaker current (denoted by and K e f ux rom the cell through potassium channels (I Ks and I Kr). If; see Table 1-1). The pacemaker current is carried predominantly by Na + ions. The ion channel through which the pacemaker current passes is di erent rom the ast sodium channel responsible or phase 0 o the action potential. Importantly, this pacemaker channel opens in the very negative voltage ranges reached during repolarization o the cell. The inf ux o positively charged Na + ions through the pacemaker channel causes the membrane potential to become progressively less negative during phase 4, ultimately depolarizing the cell to its threshold voltage (see Fig. 1-14). 3. The phase 0 upstroke o the pacemaker cell action potential is less rapid and reaches a lower amplitude than that o a cardiac muscle cell. These characteristics result rom the ast sodium channels o the pacemaker cells being inactivated and the upstroke o the action potential relying solely on Ca + + inf ux through the relatively slow calcium channels.
Repolarization o pacemaker cells occurs in a ashion similar to that o ventricular muscle cells and relies on inactivation o the calcium channels and increased activation o potassium channels with enhanced K+ e f ux rom the cell.
Refractory Periods Compared with electrical impulses in nerves and skeletal muscle, the cardiac action potential is much longer in duration, supporting prolonged Ca + + entry and muscle contraction during systole. This results in a prolonged period o channel inactivation during which the muscle is re ractory (unresponsive) to restimulation. Such a long period is physiologically necessary because it allows the ventricles su cient time to relax and re ll be ore the next contraction. There are di erent levels o re ractoriness during the action potential o a myocyte, as illustrated in Figure 1-15. The degree o re ractoriness primarily ref ects the percentage o ast Na + channels that have recovered rom their inactive state and are capable o reopening. As phase 3 o the action potential progresses, an increasing number o Na + channels recover rom inactivated to resting states and can then open in response to the next depolarization. This, in turn, corresponds to an increasing probability that a stimulus will trigger an action potential and result in a propagated impulse.
Chapter 1
0
1
n
t
i
a
l
(
m
V
)
20
–50
Abs olute RP
3
M
e
m
b
r
a
n
e
p
o
t
e
2
–100
Effe ctive RP
Re la tive RP
S upra norma l pe riod
FIGURE 1-15. Refractory periods ( RPs) of the myocyte. During the absolute refractory period (ARP), the cell is unexcitable to stimulation. The effective refractory period includes a brief time beyond the ARP during which stimulation produces a localized depolarization that does not propagate (curve 1). During the relative refractory period, stimulation produces a weak action potential (AP) that propagates, but more slowly than usual (curve 2). During the supranormal period, a weaker-than-normal stimulus can trigger an AP (curve 3).
The absolute re ractory period re ers to the time during which the cell is completely unexcitable to any new stimulation. The effective re ractory period includes the absolute re ractory period but extends beyond it to include a short interval o phase 3, during which stimulation produces a localized action potential that is not strong enough to propagate urther. The relative re ractory period is the interval during which stimulation triggers an action potential that is conducted, but the rate o rise o the action potential is lower during this period because some o the Na + channels are inactivated and some o the delayed recti er K+ channels remain activated, thus reducing the available net inward current. Following the relative re ractory period, a short “supranormal” period is present in which a less-than-normal stimulus can trigger an action potential. The re ractory period o atrial cells is shorter than that o ventricular muscle cells, such that atrial rates can generally exceed ventricular rates during rapid arrhythmias (see Chapter 11).
Impulse Conduction During depolarization, the electrical impulse spreads along each cardiac cell, and rapidly rom cell to cell because each myocyte is connected to its neighbors through low-resistance gap junctions. Gap junctions are a special type o ion channel that provide electrical and biochemical coupling between cardiac myocytes, allowing the action potential to spread rapidly through the myocardium. The speed o tissue depolarization (phase 0) and the conduction velocity along the cell depend on the net inward current (which is largely dependent on the number o sodium channels), on the value o the resting potential (which sets the degree o Na+ channel inactivation), and on the resistance to current f ow between cells though the gap junctions. Tissues with a high concentration o Na + channels, such as Purkinje bers, have a large, ast inward current, which spreads quickly within and between cells to support rapid conduction. However, the less negative the resting potential, the greater the raction o ast sodium channels that are in the inactivated state and the less rapid the upstroke velocity (Fig. 1-16). Thus, alterations in the resting potential signi cantly impact the upstroke and conduction velocity o the action potential.
Normal Sequence of Cardiac Depolarization Electrical activation o the heartbeat is normally initiated at the SA node (see Fig. 1-6). The impulse spreads to the surrounding atrial muscle through the intercellular gap junctions, providing electrical continuity between the cells. Ordinary atrial muscle bers participate in the propagation o the impulse rom the SA to the AV node, although in certain regions the bers are more densely arranged, lowering intercellular resistance and thus acilitating conduction. Fibrous tissue surrounds the tricuspid and mitral valves, such that there is no direct electrical connection between the atrial and ventricular chambers other than through the AV
21
0
a
l
(
m
V
)
Normal Cardiac Structure and Function
e t o p e n r
a
–50
m
b
B
e
A
M
FIGURE 1-16. Dependence of speed of depolarization on resting potential. A. Normal resting potential (RP) and rapid rise of phase 0. B. Less negative RP results in slower rise of phase 0 and lower maximum amplitude of the action potential.
n
t
i
P ha s e 0
–100
node. As the electrical impulse reaches the AV node, a delay in conduction (approximately 0.1 seconds) is encountered. This delay occurs because the small-diameter f bers in this region conduct slowly, and the action potential is o the “slow” pacemaker type (recall that the ast sodium channels are permanently inactivated in pacemaker tissues, such that the upstroke velocity relies on the slower calcium channels). The pause in conduction at the AV node is actually benef cial because it allows the atria time to contract and ully empty their contents be ore ventricular stimulation. In addition, the delay allows the AV node to serve as a “gatekeeper” o conduction rom atria to ventricles, which is critical or limiting the rate o ventricular stimulation during abnormally rapid atrial rhythms. A ter traversing the AV node, the cardiac action potential spreads into the rapidly conducting bundle o His and Purkinje f bers, which distribute the electrical impulses to the bulk o the ventricular muscle cells, in a spatially synchronized manner. This allows or precisely timed stimulation and organized contraction o the ventricular myocytes, optimizing the volume o blood ejected by the heart.
EXCITATION–CONTRACTION COUPLING This section reviews how the electrical action potential leads to physical contraction o cardiac muscle cells, a process known as excitation–contraction coupling. During this process, chemical energy in the orm o high-energy phosphate compounds is translated into the mechanical energy o myocyte contraction.
Contractile Proteins in the Myocyte Several distinct proteins are responsible or cardiac muscle cell contraction (Fig. 1-17). O the major proteins, actin and myosin are the chie contractile elements. Two other proteins, tropomyosin and troponin, serve regulatory unctions. Myosin is arranged in thick f laments, each composed o lengthwise stacks o approximately 300 molecules. The myosin f lament exhibits globular heads that are evenly spaced
TnC Actin
TnI
TnT
Tropomyos in
Myos in he a ds
FIGURE 1-17. Schematic diagram of the main contractile proteins of the myocyte, actin, and myosin. Tropomyosin and troponin (components TnI, TnC, and TnT) are regulatory proteins.
Myos in thick fila me nt
22
Chapter 1 along its length and contain myosin ATPase, an enzyme that is necessary or contraction to occur. Actin, a smaller molecule, is arranged in thin laments as an α-helix consisting o two strands that interdigitate between the thick myosin laments (see Fig. 1-8). Titin (also termed connectin) is a very large protein that helps tether myosin to the Z line o the sarcomere and provides elasticity to the contractile process. Tropomyosin is a double helix that lies in the grooves between the actin laments and, in the resting state, inhibits the interaction between myosin heads and actin, thus preventing contraction. Troponin sits at regular intervals along the actin strands and is composed o three subunits. The troponin T (TnT) subunit links the troponin complex to the actin and tropomyosin molecules. The troponin I (TnI) subunit inhibits the ATPase activity o the actin– myosin interaction. The troponin C (TnC) subunit is responsible or binding calcium ions that regulate the contractile process.
Calcium-Induced Calcium Release and the Contractile Cycle The sensitivity o TnC to calcium establishes a crucial role or intracellular Ca + + ions in cellular contraction. The cycling o calcium in and out o the cytosol during each action potential e ectively couples electrical excitation to physical contraction. Recall that during phase 2 o the action potential, activation o L-type Ca + + channels results in an inf ux o Ca + + ions into the myocyte. The small amount o calcium that enters the cell in this ashion is not su cient to cause contraction o the myo brils, but it triggers a much greater Ca + + release rom the SR, as ollows: The T tubule invaginations o the sarcolemmal membrane bring the L-type channels into close apposition with specialized Ca + + release receptors in the SR, known as ryanodine receptors (Fig. 1-18). When calcium enters the cell and binds to the ryanodine receptor, the receptor changes to an open con ormation, which results in a much greater release o Ca + + into the cytosol rom the abundant stores in the terminal cisternae o the SR. Thus, the initial L-type Ca + + channel inf ux is ampli ed by this mechanism, known as calcium-induced calcium release (CICR), and the cytosolic calcium concentration dramatically increases.
Na +
Ca ++
Outs ide ce ll
ATP Ins ide ce ll Rya nodine re ce ptor
Sa rcopla s mic re ticulum
Ca ++ +
Binds to TnC
Ca ++
Contra ction PL Ca ++
ATP S ERCA
Ca ++
Ca ++
FIGURE 1-18. Calcium ion movements during excitation and contraction in cardiac muscle cells. Ca+ + enters the cell through calcium channels during phase 2 of the action potential, triggering a much larger calcium release from the sarcoplasmic reticulum (SR) via the ryanodine receptor complex. The binding of cytosolic Ca+ + to troponin C (TnC) allows contraction to ensue. Relaxation occurs as Ca+ + is returned to the SR by sarco(endo)plasmic reticulum calcium ATPase (SERCA). Phospholamban (PL) is a major regulator of this pump, inhibiting Ca+ + uptake in its dephosphorylated state. Excess intracellular calcium is returned to the extracellular environment by sodium– calcium exchange and to a smaller degree by the sarcolemmal Ca+ + -ATPase.
Normal Cardiac Structure and Function
23
As calcium ions bind to TnC, the activity o TnI is inhibited, which induces a con ormational change in tropomyosin. The latter event exposes the active site between actin and myosin, enabling contraction to proceed. Contraction ensues as myosin heads bind to actin laments and “f ex,” thus causing the interdigitating thick and thin laments to move past each other in an ATP-dependent reaction (Fig. 1-19). The rst step in this process is activation o the myosin head by hydrolysis o ATP, ollowing which the myosin head binds to actin and orms a cross bridge. The interaction between the myosin head and actin results in a con ormational change in the head, causing it to pull the actin lament inward. Next, while the myosin head and actin are still attached, ADP is released, and a new molecule o ATP then binds to the myosin head, causing it to release the actin lament. The cycle can then repeat. Progressive coupling and uncoupling o actin and myosin cause the muscle ber to shorten by increasing the overlap between the myo laments within each sarcomere. In the presence o ATP, this process continues or as long as the cytosolic calcium concentration remains su ciently high to inhibit the troponin–tropomyosin blocking action. Myocyte relaxation, like contraction, is synchronized with the electrical activity o the cell. Toward the end o phase 2 o the action potential, L-type channels inactivate, arresting the inf ux o Ca + + into the cell and abolishing the trigger or CICR. Concurrently, calcium is pumped back into the SR and out o the cell. Calcium is sequestered back into the SR primarily by sarco(endo)plasmic reticulum Ca+ + ATPase (SERCA), as shown in Figure 1-18. The small amount o Ca + + that entered the cell through L-type calcium channels is removed via Actin
ATP Myos in
ADP
-ATP
A. Activa tion of myos in he a d by ATP hydrolys is
D. ADP re le a s e, ATP binding, a ctin fila me nt re le a s e
-ADP
C. P hos pha te re le a s e
-ADP-P i
B. Cros s -bridge forma tion be twe e n myos in he a d a nd a ctin fila me nt
a nd powe r s troke
Pi -ADP-P i
FIGURE 1-19. The contractile process. A. Myosin head is activated by hydrolysis o ATP. B. During cellular depolarization, cytoplasmic calcium concentration increases and removes the troponin–tropomyosin inhibition, such that a cross bridge is ormed between actin and myosin. C. Inorganic phosphate (Pi) is released and a con ormational change in the myosin head draws the actin f lament inward. D. ADP is released and replaced by ATP, causing the myosin head to dissociate rom the actin f lament. As the process repeats, the muscle f ber shortens. The cycle continues until cytosolic calcium concentration decreases at the end o phase 2 o the action potential.
24
Chapter 1 the sarcolemmal Na + –Ca + + exchanger and to a lesser extent by the ATP-consuming calcium pump, sarcolemmal Ca + + -ATPase (see Fig. 1-10). As cytosolic Ca + + concentrations all and calcium ions dissociate rom TnC, tropomyosin once again inhibits the actin–myosin interaction, leading to relaxation o the contracted cell. The contraction–relaxation cycle can then repeat with the next action potential.
INTRODUCTION TO CARDIAC SIGNALING SYSTEMS β-Adrenergic and Cholinergic Signaling There is substantial evidence that the concentration o Ca + + within the cytosol is the major determinant o the orce o cardiac contraction with each heartbeat. Mechanisms that raise intracellular Ca + + concentration enhance orce development, whereas actors that lower Ca + + concentration reduce the contractile orce. β-Adrenergic stimulation is one mechanism that enhances calcium f uxes in the myocyte and thereby strengthens the orce o ventricular contraction (Fig. 1-20). Catecholamines (e.g., norepinephrine) bind to the myocyte β1-adrenergic receptor, which is coupled to and activates the G protein system (Gs) attached to the inner sur ace o the cell membrane. Gs in turn stimulates membrane-bound adenylate cyclase to produce cyclic AMP (cAMP) rom ATP. cAMP then activates speci c intracellular protein kinases (PKAs), which phosphorylate cellular
Nore pine phrine
β 1 -a dre ne rgic re ce ptor
Ace tylcholine
Mus ca rinic Ca ++ re ce ptor
Ade nyla te cycla s e +
– +
G s prote in
G i prote in
ATP cAMP Ina ctive prote in kina s e s
Ca ++
Active prote in kina s e s
PL Ca ++
+
ATP Sa rcopla s mic re ticulum
FIGURE 1-20. Effects of β-adrenergic and cholinergic stimulation on cardiac cellular signaling and calcium ion movement. The binding of a ligand (e.g., norepinephrine) to the β1-adrenergic receptor induces G protein– mediated stimulation of adenylate cyclase and formation of cyclic AMP (cAMP). The latter activates protein kinases, which phosphorylate cellular proteins, including ion channels. Phosphorylation of the slow Ca+ + channel enhances calcium movement into the cell and therefore strengthens the force of contraction. Protein kinases also phosphorylate phospholamban (PL), reducing the latter’s inhibition of Ca+ + uptake by the sarcoplasmic reticulum. The enhanced removal of Ca+ + from the cytosol facilitates relaxation of the myocyte. Cholinergic signaling, triggered by acetylcholine binding to the muscarinic receptor, activates inhibitory G proteins that reduce adenylate cyclase activity and cAMP production, thus antagonizing the effects of β-adrenergic stimulation.
Normal Cardiac Structure and Function
25
proteins, including the L-type calcium channels within the cell membrane. Phosphorylation o the calcium channel augments Ca + + inf ux, which triggers a corresponding increase in Ca + + release rom the SR, thereby enhancing the orce o contraction. β-Adrenergic stimulation o the myocyte also enhances myocyte relaxation. The return o Ca + + rom the cytosol to the SR is regulated by phospholamban (PL), a low molecular weight protein in the SR membrane. In its dephosphorylated state, PL inhibits Ca + + uptake by SERCA (see Fig. 1-18). However, β-adrenergic activation o PKAs causes PL to become phosphorylated, an action that blunts PL’s inhibitory e ect (see Fig. 1-20). The subsequently greater uptake o calcium ions by the SR hastens Ca + + removal rom the cytosol, promoting myocyte relaxation. The increased cAMP activity also results in phosphorylation o TnI, an action that inhibits actin–myosin interactions and there ore urther enhances relaxation o the cell. Cholinergic signaling via parasympathetic inputs (mainly rom the vagus nerve) opposes the e ects o β-adrenergic stimulation (see Fig. 1-20). Acetylcholine released rom parasympathetic nerve terminals binds to the muscarinic M2 receptor on cardiac cells. This receptor also activates G proteins, but in distinction to the β-adrenergic receptor, it is coupled to Gi, an inhibitory G protein system. Gi associated with cholinergic stimulation inhibits adenylate cyclase activity and reduces cAMP ormation. At the sinus node, these actions o cholinergic stimulation serve to reduce heart rate. In the myocardium, the e ect is to counteract the orce o contraction induced by β-adrenergic stimulation. It should be noted that ventricular cells are much less sensitive to this cholinergic e ect than atrial cells, likely ref ecting di erent degrees o G protein coupling. Thus, physiologic or pharmacologic catecholamine stimulation o the myocyte β1-adrenergic receptor enhances contraction o the cell, while cholinergic stimulation opposes that enhancement. We will return to these important properties in later chapters.
SUMMARY • This chapter has reviewed basic cardiac anatomy and cellular composition, the cardiac conduction system, excitation–contraction coupling, and cardiac signaling systems. The physiology o myocyte contraction will be described in Chapter 9. Each o these complex pieces integrate together to orm an organ system that unctions in a organized ashion, is robust to errors, and operates reliably over many years. As a result, the heart is capable o purpose ul stimulation billions o times during the li e span o a normal person. With each contraction cycle, the heart receives and propagates blood through the circulation to provide nutrients to and remove waste products rom the body’s tissues. • The ollowing chapters explore what can go wrong with this remarkable system.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Ken Young Lin, MD; Vivek Iyer, MD; Kirsten Greineder, MD; Stephanie Harper, MD; Scott Hyver, MD; Paul Kim, MD; Rajeev Malhotra, MD; Laurence Rhines, MD; and James D. Marsh, MD.
Ad d i t i o n a l Rea d i n g Bers DM. Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol. 2008;70:23–49. Christo els VM, Smits GJ, Kispert A, Moorman AFM. Development o pacemaker tissues o the heart. Circ Res. 2010;106:240–254. Courneya C, Parker MJ. Cardiovascular Physiology. A Clinical Approach. Baltimore, MD: Lippincott Williams & Wilkins; 2011. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2:185–194. Katz AM. Physiology of the Heart. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010.
Saucerman JJ, McCulloch AD. Cardiac beta-adrenergic signaling: rom subcellular microdomains to heart ailure. Ann N Y Acad Sci. 2006;1080:348–361. Smyth JW, Shaw RM. Forward tra cking o ion channels: What the clinician needs to know. Heart Rhythm. 2010;7:1135–1140. Wilcox BR, Cook AC, Anderson RH. Surgical Anatomy of the Heart. 4th ed. Cambridge, MA: Cambridge University Press; 2013. Zipes DP, Jali e J, eds. Cardiac Electrophysiology: From Cell to Bedside. 6th ed. Philadelphia, PA: Elsevier Saunders; 2013.
The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs
2
Da vid B. Fischer Leona rd S. Lilly
Ch a p t e r O u t l i n e Cardiac Cycle Heart Sounds First Heart Sound (S1) Second Heart Sound (S2) Extra Systolic Heart Sounds Extra Diastolic Heart Sounds Murmurs Systolic Murmurs Diastolic Murmurs Continuous Murmurs
C
ardiac diseases o ten cause abnormal ndings on physical examination, including pathologic heart sounds and murmurs. These ndings are clues to the underlying pathophysiology, and proper interpretation is essential or success ul diagnosis and disease management. This chapter rst describes heart sounds in the context o normal cardiac physiology and then ocuses on the origins o pathologic heart sounds and murmurs. Many cardiac diseases are mentioned brief y in this chapter as examples o abnormal heart sounds and murmurs. Each o these conditions is described in greater detail later in the book, so it is not necessary or desirable to memorize all o the examples presented here. Rather, the goal o this chapter is to explain the mechanisms by which the abnormal sounds are produced, so that their descriptions will make sense in later chapters.
CARDIAC CYCLE The cardiac cycle consists o precisely timed electrical and mechanical events that are responsible or rhythmic atrial and ventricular contractions. Figure 2-1 displays the pressure relationships between the le t-sided cardiac chambers during the normal cardiac cycle and serves as a plat orm or describing key events. Mechanical systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ventricular relaxation and f lling. Throughout the cardiac cycle, the right and le t atria accept blood returning to the heart rom the systemic veins and rom the pulmonary veins, respectively. During diastole, blood passes rom the atria into the ventricles across the open tricuspid and mitral valves, causing a gradual increase in ventricular diastolic pressures. In late diastole, atrial contraction propels a f nal bolus o blood into each ventricle, an action that produces a brie urther rise in atrial and ventricle pressures, termed the a wave (see Fig. 2-1).
26
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
27
Contraction o the ventricles ollows, signaling the onset o mechanical systole. As the ventricles start to contract, the pressures within them rapidly exceed AV c los e s atrial pressures. This results in the orced closure o AV op e ns the tricuspid and mitral valves, which produces the 100 rst heart sound, termed S1. This sound has two nearly Ao rta superimposed components: the mitral component slightly precedes that o the tricuspid valve because o the earlier electrical activation o the le t ventricle (as LV described in Chapter 4). 50 As the right and le t ventricular pressures rapidly MV op e ns rise urther, they soon exceed the diastolic pressures MV c los e s within the pulmonary artery and aorta, orcing the pulmonic and aortic valves to open, and blood is LA v c a ejected into the pulmonary and systemic circulations. Time The ventricular pressures continue to increase during the initial portion o this ejection phase, and then decline as ventricular relaxation commences. Since the pulmonic and aortic valves are open during this S1 S2 phase, the aortic and pulmonary artery pressures DIASTOLE SYSTOLE DIASTOLE rise and all in parallel to those o the corresponding ventricles. FIGURE 2-1. The normal cardiac cycle, showing At the conclusion o ventricular ejection, the venpressure relationships between the left-sided heart chambers. During diastole, the mitral valve (MV) is tricular pressures decline below those o the pulmoopen, so that the le t atrial (LA) and le t ventricular nary artery and aorta (the pulmonary artery and aorta (LV) pressures are equal. In late diastole, LA are elastic structures that dissipate pressure more contraction causes a small rise in pressure in both the gradually than do the ventricles), such that the pulLA and LV (the a wave). During systolic contraction, monic and aortic valves are orced to close, producthe LV pressure rises; when it exceeds the LA pressure, ing the second heart sound, S2. Like the rst heart the MV closes, contributing to the rst heart sound sound (S1), this sound consists o two parts: the aortic (S1). As LV pressure rises above the aortic pressure, the aortic valve (AV) opens, which is a silent event. (A2) component normally precedes the pulmonic (P2) As the ventricle begins to relax and its pressure alls because the diastolic pressure gradient between the below that o the aorta, the AV closes, contributing aorta and le t ventricle is greater than that between to the second heart sound (S2). As LV pressure alls the pulmonary artery and the right ventricle, orcing urther, below that o the LA, the MV opens, which is the aortic valve to shut more readily. The ventricular silent in the normal heart. In addition to the a wave, pressures all rapidly during the subsequent relaxation the LA pressure curve displays two other positive phase. As they drop below the pressures in the right def ections: the c wave represents a small rise in LA pressure as the MV closes and bulges into the atrium, and le t atria, the tricuspid and mitral valves open, and the v wave is the result o passive lling o the ollowed by diastolic ventricular lling and then repLA rom the pulmonary veins during systole, when the etition o this cycle. MV is closed. Notice in Figure 2-1 that in addition to the a wave, the atrial pressure curve (in red color) displays two other positive def ections during the cardiac cycle: the c wave represents a small rise in atrial pressure as the tricuspid and mitral valves close and bulge into their respective atria. The v wave is the result o passive lling o the atria rom the systemic and pulmonary veins during systole, a period during which blood accumulates in the atria because the tricuspid and mitral valves are closed. At the bedside, systole can be approximated as the period rom S1 to S2, and diastole rom S2 to the next S1. Although the duration o systole remains constant rom beat to beat, the length o diastole varies with the heart rate: the aster the heart rate, the shorter the diastolic phase. P
r
e
s
s
u
r
e
(
m
m
H
g
)
ECG
28
Chapter 2 The main sounds, S1 and S2, provide a framework from which all other heart sounds and murmurs can be timed. The pressure relationships and events depicted in Figure 2-1 are those that occur in the left side of the heart. Equivalent events occur simultaneously in the right side of the heart in the right atrium, right ventricle, and pulmonary artery. At the bedside, clues to right heart function can be ascertained by examining the jugular venous pulse, which is representative of the right atrial pressure (see Box 2-1).
BOX 2-1
Jugular Venous Pulsations and Assessment of Right Heart Function
Bedside observation o jugular venous pulsations in the neck is a vital part o the cardiovascular examination. With no structures impeding blood f ow between the internal jugular (IJ) veins and the superior vena cava and right atrium a (RA), the height o the IJ venous column (termed the “jugular venous pressure” or v JVP) is an accurate representation o the c RA pressure. Thus, the JVP provides an y easily obtainable measure o right heart x unction. Typical f uctuations in the jugular venous pulse during the cardiac cycle, mani ested by oscillations in the overlying skin, are shown in the gure (notice the similarity to the atrial pressure tracing in Fig. 2-1). There are two major upward components, the a and v waves, ollowed by two descents, termed x and y. The x descent, which represents the pressure decline ollowing the a wave, may be interrupted by a small upward def ection (the c wave) at the time o tricuspid valve closure, but that is o ten not distinguishable in the JVP. The a wave represents transient venous distension caused by back pressure rom RA contraction. The v wave corresponds to passive lling o the RA rom the systemic veins during systole, when the tricuspid valve is closed. Opening o the tricuspid valve in early diastole allows blood to rapidly empty rom the RA into the right ventricle; that all in RA pressure corresponds to the y descent. Conditions that abnormally raise right-sided cardiac pressures (e.g., heart ailure, tricuspid valve disease, pulmonic stenosis, pericardial diseases) elevate the JVP, while reduced intravascular volume (e.g., dehydration) decreases it. In addition, speci c disease states can inf uence the individual components o the JVP, examples o which are listed here or re erence and explained in subsequent chapters: Prominent a: right ventricular hypertrophy, tricuspid stenosis Prominent v: tricuspid regurgitation Prominent y: constrictive pericarditis
Technique of Measurement The JVP is measured as the maximum vertical height o the internal jugular vein (in cm) above the center o the right atrium, and in a normal person is ≤ 9 cm. Because the sternal angle is located approximately 5 cm above the center o the RA, the JVP is calculated at the bedside by adding 5 cm to the vertical height o the top o the IJ venous column above the sternal angle. The right-sided IJ vein is usually the easiest to evaluate because it extends directly upward rom the RA and superior vena cava. First, observe the pulsations in the skin overlying the IJ with the patient supine and the head o the bed at about a 45-degree angle. Shining a light obliquely across the neck helps to visualize the pulsations. Be sure to examine the IJ, not the external jugular vein. The ormer is medial to, or behind, the sternocleidomastoid muscle, whereas the external jugular is usually more lateral. Although the external jugular is typically easier to see, it does not always accurately ref ect RA pressure because it contains valves that inter ere with venous return to the heart.
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
BOX 2-1
29
Jugular Venous Pulsations and Assessment of Right Heart Function ( continued)
I the top o the IJ column is not visible at 45 degrees, the column o blood is either too low (below the clavicle) or too high (above the jaw) to be measured in that position. In such situations, the head o the bed must be lowered or raised, respectively, so that the top o the column becomes visible. As long as the top can be ascertained, the vertical height o the JVP above or below the sternal angle will accurately ref ect RA pressure, no matter the angle o the head o the bed. Sometimes it can be di cult to distinguish the jugular venous pulsations rom the neighboring carotid artery. Unlike the carotid, the JVP is usually not pulsatile to palpation, it has a double (or triple) upstroke rather than a single one, and it declines in most patients by assuming the seated position or during inspiration.
HEART SOUNDS Commonly used stethoscopes contain two chest pieces or auscultation o the heart. The concave “bell” chest piece, meant to be applied lightly to the skin, accentuates lowrequency sounds. Conversely, the f at “diaphragm” chest piece is designed to be pressed rmly against the skin to eliminate low requencies and there ore accentuate high- requency sounds and murmurs. Some modern stethoscopes incorporate both the bell and diaphragm unctions into a single chest piece; in these models, placing the piece lightly on the skin brings out the low- requency sounds, while rm pressure accentuates the high- requency ones. The sections below describe when, and where on the chest, to listen or high- versus low- requency sounds.
First Heart Sound ( S1 ) S1 is produced by the closu re o the m itral an d tricuspid valves in early systole an d is lou dest near the apex o the heart (Fig. 2-2). It is a high- requency sound, best heard with the diaphragm o the stethoscope. Although mitral closure usually precedes tricuspid closure, they are separated by only about 0.01 seconds, such that the human ear appreciates only a single sound. An exception occurs in patients Pulmo nic are a Ao rtic are a with right bundle branch block (see Chapter 4), (2nd–3rd le ft (2nd–3rd right in whom these components ma y be audibly split inte rs pa ce ) inte rs pa ce ) because o delayed right ventricular contraction and late closure o the tricuspid valve. Three actors determine the intensity o S1: (1) the distance separating the leaf ets o the open valves at the onset o ventricular contraction, (2) the mobility o the mitral and tricuspid leaf ets (normal, or rigid because o stenosis), and (3) the rate o rise o ventricular pressure Tric us pid are a (Table 2-1). (le ft lowe r Mitral are a s te rna l borde r) The distance between the open valve leaf ets at (a pe x) the onset o ventricular contraction relates to the electrocardiographic PR interval (see Chapter 4), the period between the onset o atrial and ventricular FIGURE 2-2. Standard positions of stethoscope activation. Atrial contraction at the end o diastole placement for cardiac auscultation. The mitral area orces the tricuspid and mitral valve leaf ets apart. localizes to the cardiac apex while the aortic and pulmonic regions represent the cardiac base. They start to passively dri t back together, but once
30
Chapter 2
TABLE 2-1 Causes o Altered Intensity o the First Heart Sound ( S1 ) Accent uat ed S1 1. Shortened PR interval 2. Mild mitral stenosis 3. High cardiac output states or tachycardia ( e.g., exercise) Diminished S1 1. Lengthened PR interval: f rst-degree AV nodal block 2. Mitral regurgitation 3. Severe mitral stenosis 4. “Sti ” le t ventricle ( e.g., le t ventricular hypertrophy due to systemic hypertension)
ventricular contraction causes the ventricular pressure to exceed that in the atrium, the leaf ets are orced to close rom whatever positions they occupy at that moment. An a ccen tua ted S1 results when the PR interval is shorter than normal, because the valve leaf ets have less time to dri t back together and are there ore orced shut rom a relatively wide distance. Similarly, in mild mitral stenosis (see Chapter 8), impeded f ow through the mitral valve causes a prolonged diastolic pressure gradient between the le t atrium and ventricle, which keeps the mobile portions o the mitral leaf ets arther apart than normal during late diastole. Because the leaf ets are relatively wide apart at the onset o systole, they are orced shut loudly when the le t ventricle contracts. S1 may also be accentuated when the heart rate is more rapid than normal (i.e., tachycardia) because diastole is shortened and the leaf ets have less time to dri t back together be ore the ventricles contract. Conditions that reduce the intensity o S1 are also listed in Table 2-1. In rst-degree atrioventricular (AV) block (see Chapter 12), a diminished S1 results rom an abnormally prolonged PR interval, which delays the onset o ventricular contraction. Consequently, ollowing atrial contraction, the mitral and tricuspid valves have a ddition al time to f oat back together so that the leaf ets are orced closed rom only a small distance apart and the sound is so tened. In patients with mitral regurgitation (see Chapter 8), S1 is o ten diminished in intensity because the mitral leaf ets may not come into ull contact with one another as they close. In severe mitral stenosis, the leaf ets are nearly xed in position throughout the cardiac cycle, and that reduced movement lessens the intensity o S1. In patients with a “sti ened” le t ventricle (e.g., a hypertrophied chamber), atrial contraction generates a higher-than-normal ventricular pressure at the end o diastole. This greater pressure causes the mitral leaf ets to dri t together more rapidly, so that they are orced closed rom a smaller-than-normal distance when ventricular contraction begins, thus reducing the intensity o S1.
Second Heart Sound ( S2 ) The second heart sound results rom the closure o the aortic and pulmonic valves and thereore has aortic (A2) and pulmonic (P2) components. Unlike S1, which is usually heard only as a single sound, the components o S2 vary with the respiratory cycle: they are normally used as one sound during expiration but become audibly separated during inspiration, a situation termed normal or physiologic splitting (Fig. 2-3). One explanation or normal splitting o S2 is as ollows. Expansion o the chest during inspiration causes the intrathoracic pressure to become more negative. The negative pressure
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
31
Expira tion P hys iologic (norma l) s plitting
S1
A2 P 2
In expira tion, A2 a nd P 2 fus e a s one s ound
Ins pira tion
Co mmo n c aus e s
Expira tion Wide ne d s plitting
S1
A2 P 2
• Right bundle bra nch block • Pulmona ry s te nos is
S1
A2 P 2
• Atria l s e pta l de fe ct
S1
P 2 A2
Ins pira tion
Expira tion
Fixe d s plitting Ins pira tion
Expira tion
Pa ra doxica l s plitting (Note reve rs e d pos ition of A2 a nd P 2 )
• Le ft bundle bra nch block • Adva nce d a ortic s te nos is
Ins pira tion
FIGURE 2-3. Splitting patterns of the second heart sound ( S2). A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound.
transiently increases the capacitance (and reduces the impedance) of the intrathoracic pulmonary vessels. As a result, there is a temporary delay in the diastolic “back pressure” in the pulmonary artery responsible for the closure of the pulmonic valve. Thus, P 2 is delayed; that is, it occurs later during inspiration than during expiration. Inspiration has the opposite effect on aortic valve closure. Because the capacitance of the intrathoracic pulmonary veins is increased by the negative pressure generated by inspiration,
32
Chapter 2 the venous return to the le t atrium and ventricle temporarily decreases. Reduced lling o the LV diminishes the stroke volume during the next systolic contraction and there ore shortens the time required or LV emptying. There ore, aortic valve closure (A2) occurs slightly earlier in inspiration than during expiration. The combination o an earlier A2 and delayed P2 during inspiration causes audible separation o the two components. Since these components are high- requency sounds, they are best heard with the diaphragm o the stethoscope, and splitting o S2 is usually most easily appreciated near the second le t intercostal space next to the sternum (see the pulmonic area in Fig. 2-2). Abnormalities o S2 include alterations in its intensity and changes in the pattern o splitting. The intensity o S2 depends on the velocity o blood coursing back toward the valves rom the aorta and pulmonary artery a ter the completion o ventricular contraction, and the suddenness with which that motion is arrested by the closing valves. In systemic hypertension or pulmonary arterial hypertension, the diastolic pressure in the respective great artery is higher than normal, such that the velocity o the blood surging toward the valve is augmented and S2 is accentuated. Conversely, in severe aortic or pulmonic valve stenosis, the valve commissures are nearly xed in position, such that the contribution o the stenotic valve to S2 is diminished. There are three types o abnormal splitting patterns o S2: widened, xed, and paradoxical. Widened splitting o S2 re ers to an increase in the time interval between A2 and P2, such that the two components are audibly separated even during expiration and become more widely separated in inspiration (see Fig. 2-3). This pattern is usually the result o delayed closure o the pulmonic valve, which occurs in right bundle branch block (described in Chapter 4) and sometimes in pulmonic valve stenosis (see Chapter 16). Fixed splitting o S2 is an abnormally widened interval between A2 and P 2 that persists unchanged through the respiratory cycle (see Fig. 2-3). The most common abnormality that causes xed splitting o S2 is an atrial septal de ect (see Chapter 16). In that condition, chronic volume overload o the right-sided circulation results in a high-capacitance, low-resistance pulmonary vascular system. This alteration in pulmonary artery hemodynamics delays the back pressure responsible or the closure o the pulmonic valve. Thus, P 2 occurs later than normal, even during expiration, such that there is wider-than-normal separation o A2 and P 2. The pattern o splitting does not change (i.e., it is xed) during the respiratory cycle because (1) inspiration does not substantially increase urther the already elevated pulmonary vascular capacitance and (2) augmented lling o the right atrium rom the systemic veins during inspiration is counterbalanced by a reciprocal decrease in the le t-to-right transatrial shunt, eliminating respiratory variations in right ventricular lling. Paradoxical splitting (also termed “reversed” splitting) re ers to audible separation o A2 and P2 during expiration that uses into a single sound on inspiration, the opposite o the normal situation. It ref ects an abnormal delay in the closure o the aortic valve such that P2 precedes A2. In adults, the most common cause is le t bundle branch block (LBBB). In LBBB, described in Chapter 4, the spread o electrical activity through the le t ventricle is impaired, resulting in delayed ventricular contraction and late closure o the aortic valve, causing A2 to abnormally ollow P2 with wide separation between them. Then, during inspiration, as in the normal case, the pulmonic valve closure sound becomes delayed and the aortic valve closure sound moves earlier. This results in narrowing, and o ten superimposition, o the two sounds; thus, there is no apparent split at the height o inspiration (see Fig. 2-3). In addition to LBBB, paradoxical splitting may be observed under circumstances in which le t ventricular ejection is greatly prolonged, such as aortic stenosis.
Extra Systolic Heart Sounds Extra systolic heart sounds may occur in early-, mid-, or late systole.
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
Early Extra Systolic Heart Sounds Abnormal early systolic sounds, or ejection clicks, occur shortly a ter S1 and coincide with the opening o the aortic or pulmonic valves (Fig. 2-4). These sounds have a sharp, high-pitched quality, so they are heard best with the diaphragm o the stethoscope placed over the aortic and pulmonic areas (see Fig. 2-2). Ejection clicks indicate the presence o aortic or pulmonic valve stenosis or dilatation o the pulmonary artery or aorta. In stenosis o the aortic or pulmonic valve, the sound occurs as the de ormed valve lea lets reach their maximal level o ascent into the great artery, just prior to blood ejection. At that moment, the rapidly ascending valve reaches its elastic limit and decelerates abruptly, an action thought to result in the sound generation. In dilatation o the root o the aorta or pulmonary artery, the sound is associated with sudden tensing o the aortic or pulmonic root with the onset o blood f ow into the vessel. The a ortic ejection click is heard at both the base (represented by the aortic and pulmonary regions in Fig. 2-2) and the apex o the heart and does not vary with respiration. In contrast, the pulmon ic ejection click is heard only at the base, and its intensity diminishes during inspiration (see Chapter 16).
Mid- or Late Extra Systolic Heart Sounds Clicks occurring in mid- or late systole are usually the result o systolic prolapse o the mitral or tricuspid valves, in which the leaf ets bulge abnormally rom the ventricular side o the AV junction into the atrium during ventricular contraction, o ten accompanied by valvular regurgitation (described in Chapter 8). They are loudest over the mitral or tricuspid auscultatory regions, respectively.
33
ECG
Ao rta
LV
MV op e ns
LA
S4 S1 Eje ction click
S2 OS
S3
FIGURE 2-4. Timing of extra systolic and diastolic heart sounds. S4 is produced by atrial contraction into a “sti ” le t ventricle (LV). An ejection click ollows the opening o the aortic or pulmonic valve in cases o valve stenosis or dilatation o the corresponding great artery. S3 occurs during the period o rapid ventricular f lling; it is normal in young people, but its presence in adults implies LV contractile dys unction. The timing o an opening snap (OS) in a patient with mitral stenosis is placed or comparison. It is not likely that more than one or two o these extra sounds would appear in the same person. LA, le t atrium; MV, mitral valve.
Extra Diastolic Heart Sounds Extra heart sounds in diastole include the opening snap (OS), the third heart sound (S3), the ourth heart sound (S4), and the pericardial knock.
Opening Snap Opening o the mitral and tricuspid valves is normally silent, but mitral or tricuspid valvular stenosis (usually the result o rheumatic heart disease; see Chapter 8) produces a sound, termed as sn ap, when the a ected valve opens. It is a sharp, high-pitched sound, and its timing does not vary signi cantly with respiration. In mitral stenosis (which is much more common than is tricuspid valve stenosis), the OS is heard best between the apex and the le t sternal border, just a ter the aortic closure sound (A2), when the le t ventricular pressure alls below that o the le t atrium (see Fig. 2-4).
34
Chapter 2
Expira tion
OS S1
S2
OS
Ins pira tion P A2 2
FIGURE 2-5. Timing of the opening snap ( OS) in mitral stenosis does not change with respiration. On inspiration, normal splitting o the second heart sound (S2) is observed so that three sounds are heard. A2, aortic component; P2, pulmonic component o S2; S1, f rst heart sound.
Because o its proximity to A2, the A2–OS sequence can be con used with a widely split second heart sound. However, careul auscultation at the pulmonic area during inspiration reveals three sounds occurring in rapid succession (Fig. 2-5), which correspond to aortic closure (A2), pulmonic closure (P 2), and then the OS. The three sounds become two on expiration when A2 and P 2 normally use. The severity o mitral stenosis can be approximated by the time interval between A2 and the OS: the more advanced the stenosis, the shorter the interval. This occurs because the degree o le t atrial pressure elevation corresponds to the severity o mitral stenosis. When the ventricle relaxes in diastole, the greater the le t atrial pressure, the earlier the mitral valve opens. Compared with severe stenosis, mild disease is marked by a less elevated le t atrial pressure, lengthening the time it takes or the le t ventricular pressure to all below that o the atrium. There ore, in mild mitral stenosis, the OS is widely separated rom A2, whereas in more severe stenosis, the A2–OS interval is narrower.
Third Heart Sound ( S3 ) When present, an S3 occurs in early diastole, ollowing the opening o the AV valves, during the ventricular rapid lling phase (see Fig. 2-4). It is a dull, low-pitched sound best heard with the bell o the stethoscope. A le t-sided S3 is typically loudest over the cardiac apex while the patient lies in the le t lateral decubitus position. A right-sided S3 is better appreciated at the lower le t sternal border. Production o the S3 appears to result rom tensing o the chordae tendineae during rapid lling and expansion o the ventricle. An S3 is a normal nding in children and young adults. In these groups, an S3 implies the presence o a supple ventricle capable o normal rapid expansion in early diastole. Conversely, when heard in middle-aged or older adults, an S3 is a sign o disease resulting rom a dilated ventricle (e.g., a patient with heart ailure due to impaired systolic contraction, as described in Chapter 9) or rom the increased transvalvular f ow that accompanies advanced mitral or tricuspid regurgitation (described in Chapter 8). A pathologic S3 is sometimes re erred to as a ventricular gallop.
Fourth Heart Sound ( S4 ) When an S4 is present, it occurs in late diastole and coincides with contraction o the atria (see Fig. 2-4). This sound is generated by the le t (or right) atrium ejecting blood into a sti ened ventricle. Thus, an S4 usually indicates the presence o cardiac disease—speci cally, a decrease in ventricular compliance typically resulting rom ventricular hypertrophy or myocardial ischemia. Like an S3, the S4 is a dull, low-pitched sound and is best heard with the bell o the stethoscope. In the case o the more common le t-sided S4, the sound is loudest at the apex, with the patient lying in the le t lateral decubitus position. S4 is sometimes re erred to as an atrial gallop.
Quadruple Rhythm or Summation Gallop In a patient with both an S3 and S4, those sounds, in conjunction with S1 and S2, produce a quadruple beat. I a patient with a quadruple rhythm develops tachycardia, diastole becomes shorter in duration, the S3 and S4 coalesce, and a summation gallop results. The summation o S3 and S4 is heard as a long middiastolic, low-pitched sound, o ten louder than S1 and S2.
The Cardiac Cycle: Mechanisms of Heart Sounds and Murmurs
35
Pericardial Knock A pericardial knock is an uncommon, high-pitched sound that occurs in patients with severe constrictive pericarditis (see Chapter 14). It appears early in diastole soon a ter S2 and can be con used with an OS or an S3. However, the knock appears slightly later in diastole than the timing o an OS and is louder and occurs earlier than does a ventricular gallop. It results rom the abrupt cessation o ventricular lling that occurs when the expanding ventricle meets a rigid pericardium in early diastole, which is the hallmark o constrictive pericarditis.
MURMURS A murmur is the sound generated by turbulent blood f ow. Under normal conditions, the movement o blood through the vascular bed is laminar, smooth, and silent. However, as a result o hemodynamic and/ or structural changes, laminar f ow can become disturbed and produce an audible noise. Murmurs result rom any o the ollowing mechanisms: 1. Flow across a partial obstruction (e.g., aortic stenosis) 2. Increased f ow through normal structures (e.g., aortic systolic murmur associated with a high-output state, such as anemia) 3. Ejection into a dilated chamber (e.g., aortic systolic murmur associated with aneurysmal dilatation o the aorta) 4. Regurgitant f ow across an incompetent valve (e.g., mitral regurgitation) 5. Abnormal shunting o blood rom one vascular chamber to a lower-pressure chamber (e.g., ventricular septal de ect [VSD]) Murmurs are described by their timing, intensity, pitch, shape, location, radiation, and response to maneuvers. Timing re ers to whether the murmur occurs during systole or diastole, or is continuous (i.e., begins in systole and continues into diastole). The intensity o the murmur is typically quanti ed by a grading system. In the case o systolic murmurs: Grade Grade Grade Grade Grade Grade
1/ 6 2/ 6 3/ 6 4/ 6 5/ 6 6/ 6
(or I/ VI): (or II/ VI): (or III/ VI): (or IV/ VI): (or V/ VI): (or VI/ VI):
Barely audible (i.e., medical students may not hear it!) Faint but immediately audible Easily heard Easily heard and associated with a palpable thrill Very loud; heard with the stethoscope lightly on the chest Audible without the stethoscope directly on the chest wall
And in the case o diastolic murmurs: Grade Grade Grade Grade
1/ 4 2/ 4 3/ 4 4/ 4
(or I/ IV): (or II/ IV): (or III/ IV): (or IV/ IV):
Barely audible Faint but immediately audible Easily heard Very loud
Pitch re ers to the requency o the murmur, ranging rom high to low. High- requency murmurs are caused by large pressure gradients between chambers (e.g., aortic stenosis) and are best appreciated using the diaphragm chest piece o the stethoscope. Low- requency murmurs imply less o a pressure gradient between chambers (e.g., mitral stenosis) and are best heard using the stethoscope’s bell piece.
36
Chapter 2 Shape describes how the murmur changes in intensity rom its onset to its completion. For example, a crescen do–decrescen do (or “diamond-shaped”) murmur rst rises and then alls o in intensity. Other shapes include decrescen do (i.e., the murmur begins at its maximum intensity then becomes so ter) and uniform (the intensity o the murmur does not change). Location re ers to the murmur’s region o maximum intensity and is usually described in terms o speci c auscultatory areas (see Fig. 2-2): Aortic area: Pulmonic area: Tricuspid area: Mitral area:
Second to third right intercostal spaces, next to the sternum Second to third le t intercostal spaces, next to the sternum Lower le t sternal border Cardiac apex
From their primary locations, murmurs are o ten heard to radiate to other areas o the chest, and such patterns o transmission relate to the direction o the turbulent f ow. Finally, similar types o murmurs can be distinguished rom one another by simple bedside maneuvers, such as standing upright, Valsalva ( orce ul expiration against a closed airway), or clenching o the sts, each o which alters the heart’s loading conditions and can a ect the intensity o many murmurs. Examples o the e ects o maneuvers on speci c murmurs are presented in Chapter 8. When reporting a murmur, some or all o these descriptors are mentioned. For example, you might describe a particular patient’s murmur o aortic stenosis as “A grade III/ VI highpitched, crescendo–decrescendo systolic murmur, loudest at the upper right sternal border, with radiation toward the neck.”
Systolic Murmurs Systolic murmurs are subdivided into systolic ejection murmurs, pansystolic murmurs, and late systolic murmurs (Fig. 2-6). A systolic ejection murmur is typical o aortic or pulmonic valve stenosis. It begins a ter the rst heart sound and terminates be ore or during S2, depending on its severity and whether the obstruction is o the aortic or pulmonic valve. The shape o the murmur is o the crescendo–decrescendo type (i.e., its intensity rises and then alls).
Example s
A. Eje ction type
• Aortic s te nos is • P ulmona ry s te nos is S1
S2 • Mitra l re gurgita tion • Tricus pid re gurgita tion • Ve ntricula r s e pta l de fe ct
B. P a ns ys tolic (holos ys tolic) S1
S2
C. La te s ys tolic
• Mitra l va lve prola ps e S 1 Click S 2
FIGURE 2-6. Classif cation o systolic murmurs. Ejection murmurs are crescendo– decrescendo in conf guration (A), whereas pansystolic murmurs are uni orm throughout systole (B). A late systolic murmur o ten ollows a midsystolic click and suggests mitral (or tricuspid) valve prolapse (C).
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
37
The ejection murmur o aortic stenosis begins in systole a ter S1, rom which it is separated by a short audible gap (Fig. 2-7). This gap corresponds to the period o isovolumetric contraction o the le t ventricle Ao rta (the period a ter the mitral valve has closed but be ore the aortic valve has opened). The murmur becomes more intense as f ow increases across the aortic valve during the rise in le t ventricular pressure (crescendo). Then, as the ventricle relaxes, orward f ow decreases and the murmur lessens in intensity (decrescendo) and LV nally ends prior to the aortic component o S2. The murmur may be immediately preceded by an ejection click, especially in mild orms o aortic stenosis. Although the intensity o the murmur does not correlate well with the severity o aortic stenosis, other eatures do. For example, the more severe the stenosis, the longer it takes to orce blood across the valve, and the later the murmur peaks in systole (Fig. 2-8). Also, as shown in Figure 2-8, as the severity o stenosis S1 S2 increases, the aortic component o S2 so tens because the leaf ets become more rigidly xed in place. Aortic stenosis causes a high- requency murmur, FIGURE 2-7. Systolic ejection murmur of aortic ref ecting the sizable pressure gradient across the stenosis. There is a short delay between the f rst valve. It is best heard in the “aortic area” at the second heart sound (S1) and the onset o the murmur (f rst and third right intercostal spaces close to the sternum dashed line). LV, le t ventricle; S2, second heart sound. (see Fig. 2-2). The murmur typically radiates toward the neck (the direction o turbulent blood f ow) but o ten can be heard in a wide distribution, including the cardiac apex. The murmur o pulmonic stenosis also begins a ter S1. It may be preceded by an ejection click, but unlike aortic stenosis, it may extend beyond the A2 sound. That is, i the stenosis is severe, it will result in a very prolonged right ventricular ejection time, elongating the murmur, which will continue beyond the closure o the aortic valve and end just be ore the closure o the pulmonic valve (P2). Pulmonic stenosis is usually loudest at the second to third le t intercostal spaces close to the sternum. It does not radiate as widely as aortic stenosis, but sometimes it is transmitted to the neck or le t shoulder. Young adults o ten have benign systolic ejection murmurs (also termed “innocent murmurs”) resulting rom increased systolic f ow across normal aortic and pulmonic valves. This type o murmur o ten becomes so ter or disappears when the patient sits upright. Pansystolic (also termed holosystolic) murmurs are caused by regurgitation o blood across an incompetent mitral or tricuspid valve or through a ventricular septal de ect (see Chapter 16). These murmurs are characterized by a uni orm intensity throughout systole (Fig. 2-6). In mitral and tricuspid valve regurgitation, as soon as ventricular systolic pressure exceeds atrial pressure (i.e., when S1 occurs), there is immediate retrograde f ow across the regurgitant valve. Thus, there is no gap between S1 and the onset o these pansystolic murmurs, in contrast to the systolic ejection murmurs discussed earlier. Similarly, there is no signi cant gap between S1 and the onset o the systolic murmur o a VSD, because le t ventricular systolic pressure exceeds right ventricular systolic pressure (and f ow occurs) quickly a ter the onset o contraction. The pansystolic murmur o advanced mitral regurgitation continues through the aortic closure sound because le t ventricular pressure remains greater than that in the le t atrium at the time o aortic closure. The murmur is heard best at the apex, is high pitched and “blowing” in quality, and o ten radiates toward the le t axilla; its intensity does not change with respiration. Aortic valve ope ns
38
Chapter 2 Tricuspid valve regurgitation is best heard along the le t lower sternal border. It generally radiates to the right o the sternum and is high pitched and blowing in quality. The intensity o the murmur increases with inspiration because the negative intrathoracic pressure induced during inspiration enhances venous return to the heart. The latter augments right ventricular stroke volume, thereby increasing the amount o regurgitated blood. The murmur o a VSD is heard best at the ourth to sixth le t intercostal spaces, is high pitched, and may be associated with a palpable thrill. The intensity o the murmur does not increase with inspiration, nor does it radiate to the axilla, which helps distinguish it rom tricuspid and mitral regurgitation, respectively. O note, the smaller the VSD, the greater the turbulence o blood f ow between the le t and right ventricles and the louder the murmur. Some o the loudest murmurs ever heard are those associated with small VSDs. Late systolic murmurs begin in mid-to-late systole and continue to the end o systole (see Fig. 2-6). The most common example is mitral regurgitation caused by mitral valve prolapse—bowing o abnormally redundant and elongated valve leaf ets into the le t atrium during ventricular contraction. This murmur is usually preceded by a midsystolic click and is described in Chapter 8.
Diastolic Murmurs
A. Mild A2 P 2
S1 EJ
B. Mode ra te S1
A2 P 2
C. S eve re S1
P2
FIGURE 2-8. The severity of aortic stenosis affects the shape of the systolic murmur and the heart sounds. A. In mild stenosis, an ejection click (EJ) is o ten present, ollowed by an early peaking crescendo–decrescendo murmur and a normal aortic component o S2 (A2). B. As stenosis becomes more severe, the peak o the murmur becomes more delayed in systole and the intensity o A2 lessens. The prolonged ventricular ejection time delays A2 so that it merges with or occurs a ter the pulmonic component o S2 (P2); the ejection click may not be heard. C. In severe stenosis, the murmur peaks very late in systole, and A2 is usually absent because o immobility o the valve leaf ets. S1, rst heart sound; S2, second heart sound.
Diastolic murmurs are divided into early decrescendo murmurs and mid-to-late rumbling murmurs (Fig. 2-9). Early diastolic murmurs result rom regurgitant f ow through either the aortic or pulmonic valve, with the ormer being much more common in adults. I produced by a ortic valve regurgitation , the murmur begins at A2, has a decrescendo shape, and terminates be ore the next S1. Because diastolic relaxation o the le t ventricle is rapid, a pressure gradient develops immediately between the aorta and lower-pressured le t ventricle in patients with aortic regurgitation, and the murmur there ore displays its maximum intensity at its onset. Therea ter in diastole, as the aortic pressure alls and the LV pressure increases (as blood regurgitates into the ventricle), the gradient between the two chambers diminishes and the murmur decreases in intensity. Aortic regurgitation is a high-pitched murmur, best heard using the diaphragm o the stethoscope along the le t sternal border with the patient sitting, leaning orward, and exhaling. Pulmonic regurgitation in adults is usually due to pulmonary arterial hypertension. It is an early diastolic decrescendo murmur similar to that o aortic regurgitation, but it is best heard in the pulmonic area (Fig. 2-2), and its intensity may increase with inspiration. Mid-to-late diastolic murmurs result rom either turbulent f ow across a stenotic mitral or tricuspid valve or less commonly rom abnormally increased f ow across a normal mitral or tricuspid valve (see Fig. 2-9). I resulting rom stenosis, the murmur begins a ter S2 and is
The Cardiac Cycle: Mechanisms o Heart Sounds and Murmurs
39
• Aortic re gurgita tion • Pulmonic re gurgita tion
A. Ea rly de cre s ce ndo S1
S2
S1
B. Mid-to-la te
• Mild mitra l or tricus pid s te nos is S1
S2
S1 OS
C. P rolonge d mid-to-la te
• S eve re mitra l or tricus pid s te nos is S1
S2 OS
S1
FIGURE 2-9. Classif cation o diastolic murmurs. A. An early diastolic decrescendo murmur is typical o aortic or pulmonic valve regurgitation. B. Mid-to-late low- requency rumbling murmurs are usually the result o mitral or tricuspid valve stenosis and ollow a sharp opening snap (OS). Presystolic accentuation o the murmur occurs in patients in normal sinus rhythm because o the transient rise in atrial pressure during atrial contraction. C. In more severe mitral or tricuspid valve stenosis, the opening snap and diastolic murmur commence earlier, and the murmur is prolonged. S1, f rst heart sound; S2, second heart sound.
preceded by an opening snap. The shape o this murmur is unique. Following valvular opening (and the OS), the murmur is at its loudest because the pressure gradient between the atrium and ventricle is at its maximum. The murmur then decrescendos or disappears totally during diastole as the transvalvular gradient decreases. The degree to which the murmur ades depends on the severity o the stenosis. I the stenosis is severe, the murmur is prolonged; i the stenosis is mild, the murmur disappears in mid-to-late diastole. Whether the stenosis is mild or severe, the murmur intensi es at the end o diastole in patients in normal sinus rhythm, when atrial contraction augments f ow (and turbulence) across the valve (see Fig. 2-9). Since the pressure gradient across a stenotic mitral valve tends to be airly low, the murmur o mitral stenosis is low pitched and is heard best with the bell o the stethoscope at the apex, while the patient lies in the le t lateral decubitus position. The much less common murmur o tricuspid stenosis is better auscultated at the lower sternum, near the xiphoid process. Hyperdynamic states such as ever, anemia, hyperthyroidism, and exercise cause increased f ow across the normal tricuspid and mitral valves and can there ore result in a diastolic murmur. Similarly, in patients with advanced mitral regurgitation, the expected systolic murmur can be accompanied by an additional diastolic murmur owing to the increased volume o blood that must return across the valve to the le t ventricle in diastole. Likewise, patients with either tricuspid regurgitation or an atrial septal de ect (see Chapter 16) have increased f ow across the tricuspid valve, and may there ore display a diastolic f ow murmur rom that site.
Continuous Murmurs Continuous murmurs are heard throughout the cardiac cycle. Such murmurs result rom conditions in which there is a persistent pressure gradient between two structures during both systole and diastole. An example is the murmur o patent ductus arteriosus, in which there is an abnormal congenital communication between the aorta and the pulmonary artery (see Chapter 16). During systole, blood f ows rom the high-pressure ascending aorta through the ductus into the
40
Chapter 2
• Pa te nt ductus a rte rios us
Continuous S1
S2
S1
• Aortic s te nos is a nd re gurgita tion • Pulmonic s te nos is a nd re gurgita tion
To-a nd-fro S1
S2
S1
FIGURE 2-10. A continuous murmur peaks at, and extends through, the second heart sound ( S2 ) . A to-and- ro murmur is not continuous; rather, there is a systolic component and a distinct diastolic component, separated by S2. S1, f rst heart sound.
lower-pressure pulmonary artery. During diastole, the aortic pressure remains greater than that in the pulmonary artery and the f ow continues across the ductus. This murmur begins in early systole, crescendos to its maximum at S2, then decrescendos until the next S1 (Fig. 2-10). The “to-and- ro” combined murmur in a patient with both aortic stenosis and aortic regurgitation could be mistaken or a continuous murmur (see Fig. 2-10). During systole, there is a diamond-shaped ejection murmur, and during diastole, a decrescendo murmur. However, in the case o a to-and- ro murmur, the sound does not extend through S2 because it has discrete systolic and diastolic components.
SUMMARY • Cardiac diseases o ten result in abnormal heart sounds and murmurs, which are clues to the underlying pathophysiology. • Systole re ers to the phase o ventricular contraction, and diastole re ers to the phase o ventricular relaxation and lling. • The normal cardiac cycle proceeds as ollows: (1) during diastole, the mitral valve (MV) is open, so that the le t atrial (LA) and le t ventricular (LV) pressures are equal; (2) in late diastole, LA contraction causes a small rise in pressure in both the LA and LV; (3) a ter a short delay, ventricular contraction causes the LV pressure to rise, and when the LV pressure exceeds the LA pressure, the MV closes, contributing to the rst heart sound (S1); (4) as LV pressure rises above the aortic pressure, the aortic valve (AV) opens, a silent event in a normal heart; (5) a ter contraction, as the ventricle relaxes and its pressure alls below that o the aorta, the AV closes, contributing to the second heart sound (S2); (6) when the LV pressure declines below that o the le t atrium, the mitral valve opens, and the cycle repeats. • Extra systolic sounds include ejection clicks, indicating aortic or pulmonic stenosis or dilatation o the aortic root or pulmonary artery, and mid-to-late clicks, indicating mitral or tricuspid valve prolapse. • Extra diastolic sounds include the opening snap (signi ying mitral stenosis), the S3 sound (indicating heart ailure or a volume overload state in older adults; an S3 is a normal sound in children and young adults), and the S4 sound (indicating reduced ventricular compliance). • Common murmurs include systolic ejection murmurs rom aortic or pulmonic stenosis, pansystolic murmurs rom mitral or tricuspid regurgitation, late systolic murmurs rom mitral valve prolapse, early diastolic murmurs rom aortic or pulmonic regurgitation, and mid-tolate diastolic murmurs rom mitral stenosis. • Tables 2-2 and 2-3 and Figure 2-11 summarize eatures o the heart sounds and murmurs described in this chapter.
TABLE 2-2 Common Heart Sounds Sound
Location
Pitch
Signif cance
S1 S2
Apex Base
High High
Normal closure of mitral and tricuspid valves Normal closure of aortic (A2) and pulmonic (P2) valves
Extra systolic sounds Ejection clicks Aortic: apex and base Pulmonic: base Mid-to-late click Mitral: apex Tricuspid: LLSB Extra diastolic sounds Opening snap Apex S3 Left-sided: apex
High High High High
Aortic or pulmonic stenosis, or dilatation of aortic root or pulmonary artery
High Low
S4
Low
Mitral stenosis Normal in children Abnormal in adults: indicates heart failure or volume overload state Reduced ventricular compliance
Left-sided: apex
Mitral or tricuspid valve prolapse
LLSB, lower left sternal border.
TABLE 2-3 Common Murmurs Murmur Type
Example
Location and Radiation
Systolic ejection
Aortic stenosis
Second right intercostal space → neck (but may radiate widely) Second to third left intercostal spaces
Pulmonic stenosis
S1
S2
Pansystolic
S1
Apex → axilla
Aortic regurgitation Pulmonic regurgitation
Along left side of the sternum Upper left side of the sternum
Mitral stenosis
Apex
S1
Mid-to-late diastolic
S2
Mitral valve prolapse
S2
Early diastolic
S2
Apex → axilla Left lower sternal border → right lower sternal border
S2
Late systolic
S2
Mitral regurgitation Tricuspid regurgitation
S1
42
Chapter 2 Ao rtic are a Eje c tion-typ e murmur • Aortic s te nos is • Flow murmur
Pulmo nic are a Eje c tion-typ e murmur • P ulmonic s te nos is • Flow murmur
Le ft s te rnal bo rde r Ea rly d ia s tolic murmur • Aortic re gurgita tion • P ulmonic re gurgita tion Tric us pid are a P a ns ys tolic murmur • Tricus pid re gurgita tion • Ve ntricula r s e pta l de fe ct Mid -to-la te d ia s tolic murmur • Tricus pid s te nos is • Atria l s e pta l de fe ct
FIGURE 2-11.
Mitral are a P a ns ys tolic murmur • Mitra l re gurgita tion Mid -to-la te d ia s tolic murmur • Mitra l s te nos is
Locations of maximum intensity of common murmurs.
Ack n ow le d gm en t s Contributors to previous editions of this chapter were Henry Jung, MD; Nicole Martin, MD; Oscar Benavidez, MD; Bradley S. Marino, MD; and Allan Goldblatt, MD.
Ad d i t i o n a l Rea d i n g Bickley LS. Bates’ Guide to Physical Examination and History Taking. 11th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013. Constant J. Essentials of Bedside Cardiology. 2nd ed. Totowa, NJ: Humana Press; 2003. LeBlond RF, DeGowin RL, Brown DD. DeGowin’s Diagnostic Examination. 9th ed. New York, NY: McGraw-Hill; 2008.
Orient JM. Sapira’s Art and Science of Bedside Diagnosis. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010. Simel DL, Rennie D. The Rational Clinical Examination: Evidence-Based Clinical Diagnosis. New York, NY: McGrawHill; 2009.
Cardiac Imaging and Catheterization
3
Dia na M. López Pa tricia Cha llender Come
Ch a p t e r O u t l i n e Cardiac Radiography Cardiac Silhouette Pulmonary Mani estations o Heart Disease Echocardiography Ventricular Assessment Valvular Lesions Coronary Artery Disease Cardiomyopathy Pericardial Disease Cardiac Catheterization Measurement o Pressure Measurement o Blood Flow Calculation o Vascular Resistance Contrast Angiography Nuclear Imaging Assessment o Myocardial Per usion Radionuclide Ventriculography Assessment o Myocardial Metabolism Computed Tomography Magnetic Resonance Imaging Integration
I
maging plays a central role in the assessment o cardiac unction and pathology. Traditional modalities such as chest radiography, echocardiography (echo), cardiac catheterization with angiography, and nuclear imaging are undamental in the diagnosis and management o cardiovascular diseases. These procedures are increasingly supplemented by newer techniques, including computed tomography (CT) and magnetic resonance imaging (MRI). This chapter presents an overview o imaging studies as they are used to assess the cardiovascular disorders described later in this book. On f rst reading, it would be benef cial to amiliarize yoursel with the in ormation but not to memorize the details. This chapter is meant as a re erence or diagnosis o conditions that will be explained in more detail in subsequent chapters.
CARDIAC RADIOGRAPHY The extent o penetration o x-rays through the body is inversely proportional to tissue density. Air-f lled tissues, such as the lung, absorb ew x-rays and expose the underlying f lm (or electronic recording sensor), causing it to appear black. In contrast, dense materials, such as bone, absorb more radiation and appear white or radiopaque. For a boundary to show between two structures, they must di er in density. Myocardium, valves, and other intracardiac structures have densities similar to that o adjacent blood; consequently, radiography cannot delineate these structures unless they happen to be calcif ed. Conversely, heart borders adjacent to a lung are depicted clearly because the heart and an air-f lled lung have di erent densities.
43
44
Chapter 3 Frontal and lateral radiographs are routinely used to assess the heart and lungs (Fig. 3-1). The frontal view is usually a posterior–anterior image in which the x-rays are transmitted rom behind (i.e., posterior to) the patient, pass through the body, and are then captured by the lm (or electronic sensor) placed against the anterior chest. This positioning places the heart close to the x-ray recording lm plate so that its image is only minimally distorted, allowing or an accurate assessment o size. In the standard lateral view, the patient’s le t side is placed against the lm plate and the x-rays pass through the body rom right to le t. The rontal radiograph is use ul or assessing the size o the le t ventricle, le t atrial appendage, pulmonary artery, aorta, and superior vena cava; the lateral view evaluates right ventricular size, posterior borders o the le t atrium and ventricle, and the anteroposterior diameter o the thorax.
AV AO LAA LA
RA RV
TV
LV
IVC
B
A
MPA
RPA
LPA
AO AA LA
RA MV RV
TV LV IVC
C
Cardiac Silhouette
MPA
SVC
D
FIGURE 3-1. Posteroanterior ( A and B) and lateral ( C and D) chest radiographs of a person without cardiopulmonary disease, illustrating cardiac chambers and valves. AO, aorta; AV, azygos vein; IVC, inferior vena cava; LA, left atrium; LAA, left atrial appendage; LPA, left pulmonary artery; LV, left ventricle; MPA, main pulmonary artery; MV, mitral valve; RA, right atrium; RPA, right pulmonary artery; RV, right ventricle; SVC, superior vena cava; TV, tricuspid valve. (Reprinted from Come PC, ed. Diagnostic Cardiology: Noninvasive Imaging Techniques. Philadelphia, PA: J.B. Lippincott; 1985, with permission.)
Chest radiograph s are use u l to evalu ate th e size o h eart ch am bers an d th e pu lm onary con sequen ces o cardiac disease. Alteration s in ch am ber size are re lected by ch an ges in th e cardiac silh ou ette. In th e ron tal view o adu lts, an en larged h eart is iden ti ied by a cardiothoracic ratio (th e m axim u m w idth o the h eart divided by th e m axim u m in tern al diam eter o th e th oracic cage) o greater th an 50% . In certain situations, the cardiac silhouette inaccurately ref ects heart size. For example, an elevated diaphragm, or narrow chest anteroposterior diameter, may cause the silhouette to expand transversely such that the heart appears larger than its actual dimensions. There ore, the chest anteroposterior diameter should be assessed on the lateral view be ore concluding the heart is truly enlarged. The presence o a pericardial e usion around the heart can also widen the cardiac silhouette because f uid and myocardial tissue a ect x-ray penetration similarly. Radiographs can depict dilatation o individual cardiac chambers. O note, concentric ventricular hypertrophy alone (i.e., without dilatation) may not result in radiographic abnormalities, because it generally occurs at the expense o the cavity’s internal volume and produces little or no change in overall cardiac size. Major causes o chamber and great vessel dilatation include heart ailure, valvular lesions, abnormal intracardiac and extracardiac communications (shunts), and certain pulmonary disorders. Because dilatation takes time to
Cardiac Imaging and Catheterization
45
FIGURE 3-2. Posteroanterior chest radiograph of a patient with severe mitral stenosis and secondary pulmonary vascular congestion. The radiograph shows a prominent left atrial appendage (arrowheads) with consequent straightening of the left heart border and suggestion of a double density right cardiac border (arrows) produced by the enlarged left atrium. The aortic silhouette is small, which suggests chronic low cardiac output. Radiographic signs of pulmonary vascular congestion include increased caliber of upper-zone pulmonary vessel markings and decreased caliber of lower-zone vessels.
develop, recent lesions, such as acute mitral valve insu ciency, may present without apparent cardiac enlargement. The pattern o chamber enlargement may suggest speci c disease entities. For example, dilatation o the le t atrium and right ventricle, accompanied by signs o pulmonary hypertension, suggests mitral stenosis (Fig. 3-2). In contrast, dilatation o the pulmonary artery and right heart chambers, but without enlargement o the le t-sided heart dimensions, can be seen in patients with pulmonary vascular obstruction, in those with increased pulmonary artery blood f ow (e.g., due to an atrial septal de ect), or in those with pulmonary hypertension o diverse causes (Fig. 3-3). Chest radiographs can also detect dilatation o the aorta. Causes o aortic enlargement include aneurysm, dissection, and aortic valve disease (Fig. 3-4). Normal aging and atherosclerosis may also cause the aorta to become dilated and tortuous.
Pulmonary Manifestations of Heart Disease The appearance o the pulmonary vasculature ref ects abnormalities o pulmonary arterial and venous pressures and pulmonary blood f ow. Increased pulmonary venous pressure, as occurs in le t heart ailure, causes increased vascular markings, redistribution o blood f ow rom the bases to the apices o the lungs (termed cepha liza tion o vessels), interstitial edema, and alveolar edema (Fig. 3-5). Cephalization appears as an increase in the number or width o vascular markings at the apex (Fig. 3-5A). Interstitial edema occurs as pulmonary congestion progresses, and the connective tissue spaces become thickened with f uid (Fig. 3-5B). Kerley B lines (short horizontal parallel lines at the periphery o the lungs adjacent to the pleura, most o ten at the lung bases) depict f uid in interlobular spaces that results rom interstitial edema (Fig. 3-5C). When f uid accumulates in the air spaces, alveolar orms o pulmonary edema produce opacity radiating rom the hilar
46
Chapter 3
FIGURE 3-3. Posteroanterior chest radiograph o a patient with pulmonary hypertension secondary to an atrial septal de ect. Radiographic signs of pulmonary hypertension include pulmonary artery dilatation (black arrows; compare with the appearance of left atrial appendage dilatation in Fig. 3-2) and large central pulmonary arteries (white arrows) associated with small peripheral vessels (a pattern known as peripheral pruning).
region bilaterally (known as a “butterf y” pattern) and air bronchograms may be seen (Fig. 3-5D). Fluid accumulation in the pleural spaces in heart ailure (i.e., pleural e usions) is mani est by blunting o the costophrenic angles (the angle between the ribs and the diaphragm).
FIGURE 3-4. Posteroanterior chest radiograph o a patient with aortic stenosis and insu f ciency secondary to a bicuspid aortic valve. In addition to poststenotic dilatation of the ascending aorta (black arrows), the transverse aorta (white arrow) is prominent.
Cardiac Imaging and Catheterization
A
B
C
D
47
FIGURE 3-5. Posteroanterior radiographs of patients with heart failure ( HF) . A. Early mani estations o HF include upper zone redistribution (cephalization) o vessels (green arrows); cardiomegaly is present. B. More pronounced mani estations o HF include interstitial edema with pulmonary vascular markings throughout the lung f elds owing to edematous interlobular septae. Fluid-associated thickening o bronchial walls is visualized as peribronchiolar cu f ng (red arrow). C. Enlarged view o Kerley B lines (yellow arrows) at the periphery o the lower le t lung f eld. D. Severe HF mani est by di use alveolar edema. Air bronchograms (blue arrows) occur when the radiolucent bronchial tree is contrasted with opaque edematous tissue. Patients with HF o ten have a combination o interstitial and alveolar edema. (Courtesy o Gillian Lieberman, MD, Beth Israel Deaconess Medical Center, Boston, MA.)
Changes in pulmonary blood f ow may also alter the appearance o the pulmonary vessels. For example, ocal oligemia (reduction in the size o blood vessels due to decreased blood f ow) is occasionally observed distal to a pulmonary embolism (termed the Westermark sign). The nding o enlarged central pulmonary arteries, but small peripheral vessels (termed peripheral pruning), suggests pulmonary hypertension (see Fig. 3-3). Table 3-1 summarizes the major radiographic ndings in common orms o cardiac disease.
48
Chapter 3
TABLE 3-1 Chest Radiography of Common Cardiac Disorders Disorder
Findings
Congestive heart failure
• • • • • • • • • • • • •
Pulmonic valve stenosis Aortic valve stenosis Aortic regurgitation Mitral stenosis Mitral regurgitation
Cephalization o vessels Interstitial edema (peribronchial cu f ng, Kerley B lines) Alveolar edema (air bronchograms) Pleural e usions Poststenotic dilatation o pulmonary artery Poststenotic dilatation o ascending aorta Le t ventricular dilatation Dilated aorta Le t atrial dilatation Signs o pulmonary venous congestion Le t atrial dilatation Le t ventricular dilatation Signs o pulmonary venous congestion in acute MR (see Chapter 8)
ECHOCARDIOGRAPHY Echocardiography plays an essential role in the diagnosis and serial evaluation o many cardiac disorders. It is sa e, noninvasive, and relatively inexpensive. High- requency (ultrasonic) waves generated by a piezoelectric element travel through the body and are ref ected at interaces where there are di erences in the acoustic impedance o adjacent tissues. The ref ected waves return to the transducer and are recorded. The machine measures the time elapsed between the initiation and reception o the sound waves, allowing it to calculate the distance between the transducer and each anatomic ref ecting sur ace. Images are then constructed rom these calculations. Three types o imaging are routinely per ormed during an echocardiographic examination: M-mode, two-dimensional (2D), and Doppler. Each type o imaging can be per ormed rom various body locations. Most commonly, transthoracic studies are per ormed, in which images are obtained by placing the transducer on the sur ace o the chest. When greater structural detail is required, transesophageal imaging is per ormed. M-mode echocardiography, the oldest orm o cardiac ultrasonography, provides data rom only one ultrasonic beam and is now rarely used by itsel . It supplements the other modalities to provide accurate measurements o wall thicknesses and timing o valve movements. In 2D echocardiography, multiple ultrasonic beams are transmitted rom the transducer through a wide arc. The returning signals are integrated to produce 2D images o the heart on a video monitor. As a result, this technique depicts anatomic relationships and de nes the movement o cardiac structures relative to one another. Wall and valve motion abnormalities, and many types o intracardiac masses (e.g., vegetations, thrombi, tumors), can be depicted. Each 2D plane (Fig. 3-6) delineates only part o a given cardiac structure. Optimal evaluation o the entire heart is achieved by using combinations o views. In transthoracic echocardiography (TTE), in which the transducer is placed against the patient’s skin, these include the parasternal long axis, parasternal short axis, apical views, and subcostal views. The parasternal long-axis view is recorded with the transducer in the third or ourth intercostal space to the le t o the sternum. This view is particularly use ul or evaluation o the le t atrium, mitral valve, le t ventricle, and le t ventricular outf ow tract (LVOT), which includes the aortic valve and adjacent interventricular septum. To obtain parasternal short-axis views, the transducer is rotated 90 degrees rom its position or the long-axis view. The short-axis images
Cardiac Imaging and Catheterization
49
Inte rve ntricula r s e ptum RV Ao Aortic va lve
LV
LA Mitra l va lve
A
LV pos te rior wa ll
RV LV
FIGURE 3-6. Transthoracic twodimensional echocardiographic views. A. Parasternal long-axis view. B. Parasternal short-axis view. Notice that the le t ventricle appears circular in this view, while the right ventricle is crescent shaped. C. Apical our-chamber view. Ao, aorta; LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle. (Modif ed rom Sahn DJ, Anderson F. Two-Dimensional Anatomy of the Heart. New York, NY: John Wiley & Sons; 1982.)
B
RV
LV Mitra l va lve
Tricus pid va lve RA
LA
C
depict transverse planes o the heart. Several di erent levels are imaged to assess the aortic valve, mitral valve, and le t ventricular wall motion. Apical TTE views are produced when the transducer is placed at the point o maximal apical impulse. The apical four-chamber view evaluates the mitral and tricuspid valves as well as the atrial and ventricular chambers, including the motion o the lateral, septal, and apical le t ventricular walls. The apical two-chamber view shows only the le t side o the heart, and it depicts movement o the anterior, in erior, and apical walls. In some patients, such as those with obstructive airways disease, the parasternal and apical views do not adequately show cardiac structures because the excessive underlying air attenuates the acoustic signal. In such patients, the subcostal view, in which the transducer is placed in erior to the rib cage, may provide a better ultrasonic window. Doppler imaging depicts blood f ow direction and velocity and identi es regions o vascular turbulence. Additionally, it permits estimation o pressure gradients within the heart and great vessels. Doppler studies are based on the physical principle that waves ref ected rom a moving object undergo a requency shi t according to the moving object’s velocity relative to the source o the waves. Color f ow mapping converts the Doppler signals to a scale o colors that represent direction, velocity, and turbulence o blood f ow in a semiquantitative way. The colors are superimposed on 2D images and show the location o stenotic and regurgitant valvular lesions and o abnormal communications within the heart and great vessels. For example, Doppler echocardiography in a patient with mitral regurgitation shows a jet o retrograde f ow into the le t atrium during systole (Fig. 3-7).
50
Chapter 3 Sound requency shi ts are converted by the echo machine into blood f ow velocity measurements by the ollowing relationship: v=
LV
fs c 2fO (cos θ )
RV
in which v equals the blood f ow velocity (m/ sec); fs, the Doppler requency shi t (kHz); c, the velocity o sound in body tissue (m/ sec); fO, the requency o the sound pulse emitted rom the transducer (MHz); RA and θ, the angle between the transmitted sound pulse and the mean LA axis o the blood f ow being assessed. Transesophageal echocardiography (TEE) uses a miniaturized transducer mounted at the end o a modi ed endoscope to transmit and receive ultrasound waves rom within the esophagus, thus producing very clear images o the neighboring cardiac structures FIGURE 3-7. Doppler color f ow (Fig. 3-8) and much o the thoracic aorta. Modern probes permit mapping o mitral regurgitation multiplanar imaging and Doppler interrogation. TEE is particularly ( MR) . The color Doppler help ul in the assessment o aortic and atrial abnormalities, conimage, recorded in systole, is ditions that are less well visualized by conventional transthoracic superimposed on an apical ourchamber view. The color Doppler echo imaging. For example, TEE is more sensitive than transthoracic signal lling the le t atrium (LA) echo or the detection o thrombus within the le t atrial appendindicates retrograde f ow o MR age (Fig. 3-9). The proximity o the esophagus to the heart makes rom the le t ventricle (LV) across TEE imaging particularly advantageous in patients or whom transthe mitral valve (arrow). RA, right thoracic echo images are unsatis actory (e.g., those with chronic atrium; RV, right ventricle. obstructive lung disease). TEE is also advantageous in the evaluation o patients with prosthetic heart valves. During standard transthoracic imaging, arti cial mechanical valves ref ect a large portion o ultrasound waves, thus inter ering with visualization o more posterior structures (termed acoustic shadowing). TEE aids visualization in such patients and is there ore the most sensitive noninvasive technique or evaluating perivalvular leaks. In addition, TEE is
A. Cros s -s e ctiona l view of a ortic va lve
LA
Es opha gus RA
N L R RV
A
C. S hort a xis view of le ft ve nticle
B LV
RV RA LA C LV RV
B. Long a xis view of ca rdia c cha mbe rs
FIGURE 3-8. Transesophageal echocardiographic views. LA, le t atrium; LV, le t ventricle; RA, right atrium; RV, right ventricle; N, noncoronary cusp o aortic valve; L, le t coronary cusp o aortic valve; R, right coronary cusp o aortic valve.
Cardiac Imaging and Catheterization
51
LA
LAA Thrombus
A
B
FIGURE 3-9. Echocardiographic imaging of an intracardiac thrombus. A. Transesophageal echocardiographic image demonstrates thrombus within the left atrial appendage. (Courtesy of Scott Streckenbach, MD, Massachusetts General Hospital, Boston, MA.) B. Schematic drawing of same image. LA, left atrium; LAA, left atrial appendage.
more sensitive than TTE or detecting eatures o endocarditis, such as vegetations and myocardial abscesses. TEE is commonly used to evaluate patients with cerebral ischemic events (i.e., strokes) o unexplained etiology, because it can identi y cardiovascular sources o embolism with high sensitivity. These etiologies include intracardiac thrombi or tumors, atherosclerotic debris within the aorta, and valvular vegetations. TEE is also highly sensitive and speci c or the detection o aortic dissection. In the operating room, TEE permits immediate evaluation a ter surgical repair o cardiac lesions. In addition, imaging o ventricular wall motion can identi y periods o myocardial ischemia during surgery. New ultrasound modalities include 3D echocardiography and intracardiac echocardiography. The spatial reconstructions a orded by 3D echo are o particular bene t in the assessment o valvular de ects, intracardiac masses, and congenital mal ormations. Intracardiac echo utilizes a transducer mounted on a catheter to provide imaging during interventional procedures in the cardiac catheterization laboratory. Contrast echocardiography is sometimes used to supplement standard imaging to evaluate or abnormal intracardiac shunts. In this technique, o ten called a “bubble study,” an echocardiographic contrast agent (e.g., agitated saline) is rapidly injected into a peripheral vein. Using standard imaging, the contrast can be visualized passing through the cardiac chambers. Normally, there is rapid opaci cation o the right-sided chambers, but because the contrast is ltered out (harmlessly) in the lungs, it does not reach the le t-sided chambers. However, in the presence o an intracardiac shunt with abnormal right-to-le t heart blood f ow, or in the presence o an intrapulmonary shunt, bubbles o contrast will appear in the le t-sided chambers as well. Newer perf uorocarbon-based contrast agents have been developed with su ciently small particle size to intentionally pass through the pulmonary circulation. These agents are used to opaci y the le t ventricular cavity and, via the coronary arteries, the myocardium, enabling superior assessment o LV contraction and myocardial per usion. Echocardiographic techniques can identi y valvular lesions, complications o coronary artery disease (CAD), septal de ects, intracardiac masses, cardiomyopathy, ventricular hypertrophy, pericardial disease, aortic disease, and congenital heart disease.
52
Chapter 3
S LV
LV LVOT
LA
LA P
P
A
B
FIGURE 3-10. Le t ventricular outf ow tract ( LVOT) obstruction in hypertrophic cardiomyopathy— parasternal long-axis view. Notice that the interventricular septum (S) is thicker and more echogenic than the posterior wall (P). A. Be ore ventricular contraction, the LVOT is only slightly narrowed. B. During contraction, the rapidly f owing blood through the LVOT incites a Venturi e ect and abnormally draws the mitral valve anteriorly toward the hypertrophied septum (arrow), creating a unctional obstruction. LA, le t atrium; LV, le t ventricle.
Typical evaluation includes assessment o cardiac chamber sizes, wall thicknesses, wall motion, valvular unction, blood f ow, and intracardiac hemodynamics. A ew o these topics are highlighted here.
Ventricular Assessment Echocardiography allows measurement o ventricular wall thickness and mass (Fig. 3-10) and calculation o the ejection fraction, a measure o contractile unction (see Chapter 9). Furthermore, 2D echocardiography depicts regional ventricular wall motion abnormalities, a sign o CAD, and displays right ventricular unction qualitatively. Diastolic dys unction (e.g., caused by ischemic disease, ventricular hypertrophy, or restrictive cardiomyopathy; see Chapter 9) can be evaluated by Doppler techniques. For example, Doppler tissue imaging is a modality that can readily record the maximum velocity o mitral annular movement in early diastole, an indicator o the le t ventricle’s ability to relax normally. Doppler measurement o f ow velocity across the mitral valve in early, compared with late, diastole also provides in ormation about diastolic unction.
Valvular Lesions Echocardiography can determine underlying causes o valvular abnormalities, and Doppler imaging quantitates the degree o valvular stenosis and regurgitation. The pressure gradient across a stenotic valve can be calculated rom the maximum blood f ow velocity (v) measured distal to the valve, using the simpli ed Bernoulli equation: Pressure gradient = 4 × v 2
Cardiac Imaging and Catheterization 1
2
V2
V1
A1
A2 A1 x V1 = A2 x V2
FIGURE 3-11. The continuity equation. Within a closed f ow stream, the volume rate o f ow at any point (calculated as the cross-sectional area at that site multiplied by the f ow velocity at the same location) is equal to the volume rate o f ow at sequential points. Thus, cross-sectional area and velocity at any location are inversely proportional to one another. Here, location 2 is narrower than location 1. There ore, the velocity at location 2 must be greater or the same volume to pass per unit time.
53
As an example, i the peak velocity recorded distal to a stenotic aortic valve is 5 m/ sec, then the calculated peak pressure gradient across the valve = 4 × 5 2 = 100 mm Hg. Other calculations permit noninvasive determination o the cross-sectional area o stenotic valves. The continuity equation is o ten used to calculate aortic valve area. This equation assumes that blood f ow (F, expressed in cc/ sec) is the same at the aortic valve ori ce (AV) as at a neighboring position along the f ow stream (e.g., in the LVOT): FLVOT = FAV As shown in Figure 3-11, blood f ow at any position along a f ow stream can also be expressed as the product o the Doppler velocity (V, in cm/ sec) and cross-sectional area (A, in cm 2) at that level. I location 1 in Figure 3-11 represents a position in the LVOT and location 2 represents the aortic valve, then ALVOT × VLVOT = AAV × VAV
The cross-sectional area o the LVOT (ALVOT) is calculated simply as π(d/ 2) 2, where d represents the LVOT diameter, measured rom the parasternal long-axis view. The velocities (VLVOT and VAV) are measured by Doppler interrogation, rom the apical our-chamber view. The equation can then be solved or the aortic valve area (AAV): AAV =
ALVOT × VLVOT VAV
Color Doppler analysis provides a qualitative assessment o the severity o regurgitant valve lesions. In mitral regurgitation (see Fig. 3-7), or example, the ratio o the regurgitant jet color Doppler area to the entire le t atrial area has traditionally been used to classi y the regurgitation as mild, moderate, or severe. More quantitative evaluation o mitral regurgitation can now be per ormed by what is known as the proximal isovelocity sur ace area (PISA) method. This technique uses advanced color Doppler techniques to calculate the regurgitant volume and e ective regurgitant ori ce area, two values that predict clinical outcomes in patients with chronic mitral regurgitation.
Coronary Artery Disease Echocardiography demonstrates ventricular wall motion abnormalities associated with in arcted or ischemic myocardium. The location and degree o abnormal systolic contraction and decreased systolic wall thickening indicate the extent o an in arction and implicate the responsible coronary artery. Echocardiography also detects complications o in arction including thrombus ormation, papillary muscle rupture, ventricular septal rupture, and aneurysm. Although echocardiography can depict those consequences o CAD, transthoracic echo resolution in adults is insu cient to satis actorily image the coronary arteries themselves. However, stress echocardiography is a technique that aids in the diagnosis o CAD. This technique visualizes le t ventricular regional wall motion abnormalities that are induced by exercise, or the in usion o speci c pharmacologic agents (e.g., dobutamine), as a sign o myocardial ischemia (see Chapter 6).
54
Chapter 3
Cardiomyopathy Cardiomyopathies are heart muscle disorders that include dilated, hypertrophic, and restrictive orms (see Chapter 10). Echocardiography can distinguish these and permits assessment o the severity o systolic and diastolic dys unction. For example, Figure 3-10 depicts asymmetrically thickened ventricular walls in a patient with hypertrophic cardiomyopathy.
Pericardial Disease Two-dimensional echocardiography can identi y abnormalities in the pericardial cavity (e.g., excessive pericardial f uid and tumor). Tamponade and constrictive pericarditis, the main complications o pericardial disease (see Chapter 14), are associated with particular echocardiographic abnormalities. In tamponade, the increased intrapericardial pressure compresses the cardiac chambers and results in diastolic “collapse” o the right atrium and right ventricle (Fig. 3-12). Constrictive pericarditis is associated with increased thickness o the pericardial echo, abnormal patterns o diastolic le t ventricular wall motion, alterations in pulmonary and hepatic venous f ow patterns, and exaggerated changes in mitral and tricuspid valve inf ow velocities during respiration. Table 3-2 summarizes the echocardiographic eatures o common cardiac diseases.
A
B
C
D
FIGURE 3-12. Echocardiogram of a patient with a pericardial effusion causing cardiac tamponade. A. Parasternal long-axis image showing a large pericardial effusion (PE) surrounding the heart. This frame was obtained in systole and shows normal appearance of the left (LV) and right (RV) ventricles during that phase. B. Same image as ( A) , but this frame was obtained in early diastole and shows collapse of the RV free wall (arrow) due to compression by the effusion. C. Subcostal view, obtained in systole, demonstrating the PE surrounding the right atrium (RA), RV, left atrium (LA), and LV. D. Same image as ( C) , obtained during diastole, showing inward collapse of the RA (arrow).
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TABLE 3-2 Echocardiography in Common Cardiac Disorders Disorder
Findings
Valvular lesions Mitral stenosis
Mitral regurgitation
Aortic stenosis
Aortic regurgitation Left ventricular function Myocardial in arction and complications
Cardiomyopathies Dilated Hypertrophic
Restrictive
• • • • • • • • • • • •
Enlarged le t atrium Thickened mitral valve leaf ets Decreased movement and separation o mitral valve leaf ets Decreased mitral valve ori ce Enlarged le t atrium (i chronic) Enlarged le t ventricle (i chronic) Systolic f ow rom le t ventricle into le t atrium by Doppler Thickened aortic valve cusps Decreased valve ori ce Increased le t ventricular wall thickness Enlarged le t ventricle Abnormalities o aortic valve or aortic root
• • • • •
Abnormal regional ventricular wall motion Thrombus within le t ventricle Aneurysm o ventricular wall Septal rupture (abnormal Doppler f ow) Papillary muscle rupture
• • • • • • • • • •
Enlarged ventricular chamber sizes Decreased systolic contraction Normal or decreased ventricular chamber sizes Increased ventricular wall thickness Diastolic dys unction (assessed by Doppler) Normal or decreased ventricular chamber sizes Increased ventricular wall thickness Ventricular contractile unction may be abnormal Diastolic dys unction (assessed by Doppler) Enlarged atria (o ten markedly so)
CARDIAC CATHETERIZATION To diagnose many cardiovascular abnormalities, intravascular catheters are inserted to measure pressures in the heart chambers, to determine cardiac output and vascular resistances, and to inject radiopaque material to examine heart structures and blood f ow. In 1929, Werner Forssmann per ormed the rst cardiac catheterization, on himself, thus ushering in the era o invasive cardiology. Much o what is known about the pathophysiology o valvular heart disease and congestive heart ailure comes rom decades o subsequent hemodynamic research in the cardiac catheterization laboratory.
Measurement of Pressure Be ore catheterization o an artery or vein, the patient is mildly sedated, and a local anesthetic is used to numb the skin site o catheter entry. The catheter, attached to a pressure transducer outside the body, is then introduced into the appropriate blood vessel. To measure pressures in the right atrium, right ventricle, and pulmonary artery, a catheter is
Chapter 3
Ao rta PCW 2–10
100–140 60–90
LA 2–10
PA RA
15–30 4–12
LV
2–8
100–140 3–12
RV 15–30 2–8
PA 15–30 4–12
Lung s
LA
PCW 2–10
2–10
LV 100–140 3–12
Ao rta 100–140 60–90
FIGURE 3-13. Diagrams indicating normal pressures in the cardiac chambers and great vessels. The top f gure shows the normal anatomic relationship o the cardiac chambers and great vessels, whereas the f gure on the bottom shows a simplif ed schematic to clari y the pressure relationships. Numbers indicate pressures in mm Hg. LA, le t atrial mean pressure; LV, le t ventricular pressure; PA, pulmonary artery pressure; PCW, pulmonary capillary wedge mean pressure; RA, right atrial mean pressure; RV, right ventricular pressure.
inserted into a emoral, brachial, or jugular vein. Pressures in the aorta and le t ventricle are measured via catheters inserted into a radial, brachial, or emoral artery. Once in the blood vessel, the catheter is guided by f uoroscopy (continuous x-ray images) to the area o study, where pressure measurements are made. Figure 3-13 depicts normal intracardiac and intravascular pressures. The measurement o right heart pressures is per ormed with a specialized balloon-tipped catheter (a common version o which is known as the Swan–Ganz catheter) that is advanced through the right side o the heart with the aid o normal blood f ow, and into the pulmonary artery. As it travels through the right side o the heart, recorded pressure measurements identi y the catheter tip’s position (see Box 3-1).
BOX 3-1
Intracardiac Pressure Tracings
When a catheter is inserted into a systemic vein and advanced into the right side o the heart, each cardiac chamber produces a characteristic pressure curve. It is important to distinguish these recordings rom one another to localize the position o the catheter tip and to derive appropriate physiologic in ormation. ECG P ulmona ry a rte ry
m
H
g
)
Right ve ntricle 20
P ulmona ry ca pilla ry we dge a v
(m re u s s
2–8
RV 15–30 2–8
re
RA
P
56
10 Right a trium a c v x y Time
Cardiac Imaging and Catheterization
BOX 3-1
Intracardiac Pressure Tracings
57
( continued)
The normal right atrial (RA) pressure demonstrates three positive def ections (see the gure in Box 2.1 or an enlarged view): the a wave ref ects RA contraction at the end o diastole, the c wave results rom bulging o the tricuspid valve toward the right atrium as it closes in early systole, and the v wave represents passive lling o the right atrium rom the systemic veins during systole, when the tricuspid valve is closed. The downward def ection that ollows the c wave is known as the x descent, and the downward def ection a ter the v wave is called the y descent. O ten the a and c waves merge so that only two major positive def ections are seen. In patients with atrial brillation, the a wave is absent because there is no organized le t atrial contraction. As the catheter is advanced into the right ventricle (RV), a dramatic increase in systolic pressure is seen. The RV systolic wave orm is characterized by a rapid upstroke and downstroke. In diastole, there is a gradual continuous increase in RV pressure as the chamber lls with blood. As the catheter is moved orward into the pulmonary artery (PA), the systolic pressure remains the same as that in the RV (as long as there is no obstruction to RV outf ow, such as pulmonic valve stenosis). However, three characteristics o the recording indicate entry into the pulmonary artery: (1) the PA diastolic pressure is higher than that o the RV; (2) the descending systolic portion o the PA tracing inscribes a dicrotic wave, a small transient pressure increase that occurs a ter the systolic peak and is related to pulmonic valve closure; and (3) the diastolic portion o the PA tracing is downsloping compared with the upsloping RV diastolic pressure. Further advancement o the catheter into a branch o the pulmonary artery results in the pulmonary capillary wedge (PCW) tracing, which ref ects the le t atrial pressure (Fig. 3-14). Its characteristic shape is similar to the RA tracing, but the pressure values are usually higher, and the tracing is o ten less clear (with the c wave not observed) because o damped transmission through the capillary vessels.
Right Atrial Pressure Right atrial pressure is equal to the central venous pressure (estimated by the jugular venous pressure on physical examination) because no obstructing valves impede blood return rom the central veins into the right atrium. Similarly, right atrial pressure normally equals right ventricular pressure during diastole because the right heart unctions as a “common chamber” when the tricuspid valve is open. The mean right atrial pressure is reduced when there is intravascular volume depletion. It is elevated in right ventricular ailure, right-sided valvular disease, and cardiac tamponade (in which the cardiac chambers are surrounded by highpressure pericardial f uid; see Chapter 14). Certain abnormalities cause characteristic changes in individual components o the right atrial (and there ore jugular venous) pressure (Table 3-3). For example, a prominent a wave is seen in tricuspid stenosis and right ventricular hypertrophy. In these conditions, the right atrium contracts vigorously against the obstructing tricuspid valve or sti ened right ventricle, respectively, generating a prominent pressure wave. Similarly, ampli ed “cannon” a waves may be produced by conditions o atrioventricular dissociation (see Chapter 12), when the right atrium contracts against a closed tricuspid valve. A prominent v wave is observed in tricuspid regurgitation because normal right atrial lling is augmented by the regurgitated blood in systole.
Right Ventricular Pressure Right ventricular systolic pressure is increased by pulmonic valve stenosis or pulmonary hypertension. Right ventricular diastolic pressure increases when the right ventricle is subjected to pressure or volume overload and may be a sign o right heart ailure.
58
Chapter 3
TABLE 3-3 Causes of Increased Intracardiac Pressures Chamber and Measurement
Causes
Right atrial pressure
• • • • • •
Right ventricular ailure Cardiac tamponade Tricuspid stenosis Right ventricular hypertrophy Atrioventricular dissociation Tricuspid regurgitation
• • • • •
Pulmonic stenosis Pulmonary hypertension Right ventricular ailure Cardiac tamponade Right ventricular hypertrophy
a wave
v wave Right ventricular pressure Systolic Diastolic
Pulmonary artery pressure Systolic and diastolic
Systolic only Pulmonary artery wedge pressure
a wave v wave
• Pulmonary hypertension • Le t-sided heart ailure • Chronic lung disease • Pulmonary vascular disease • Increased f ow (le t-to-right shunt) • Le t-sided heart ailure • Mitral stenosis or regurgitation • Cardiac tamponade • Le t ventricular hypertrophy • Mitral regurgitation • Ventricular septal de ect
Pulmonary Artery Pressure Elevation o systolic and diastolic pulmonary artery pressures occurs in three conditions: (1) leftsided heart ailure, (2) parenchymal lung disease (e.g., chronic bronchitis or end-stage emphysema), and (3) pulmonary vascular disease (e.g., pulmonary embolism, primary pulmonary hypertension, or acute respiratory distress syndrome). Normally, the pulmonary artery diastolic pressure is equivalent to the le t atrial pressure because o the low resistance o the pulmonary vasculature that separates them. I the le t atrial pressure rises because o le t-sided heart ailure, both systolic and diastolic pulmonary artery pressures increase in an obligatory manner to maintain orward f ow through the lungs. This situation leads to “passive” pulmonary hypertension. In certain conditions, however, pulmonary vascular resistance becomes abnormally high, causing pulmonary artery diastolic pressure to be elevated compared with le t atrial pressure. For example, pulmonary vascular obstructive disease may develop as a complication o a chronic le t-to-right cardiac shunt, such as an atrial or ventricular septal de ect (see Chapter 16).
Pulmonary Artery Wedge Pressure I a catheter is advanced into the right or le t pulmonary artery, its tip will ultimately reach one o the small pulmonary artery branches and temporarily occlude orward blood f ow beyond it. During that time, a column o stagnant blood stands between the catheter tip and the portions o the pulmonary capillary and pulmonary venous segments distal to it (Fig. 3-14). That column o blood acts as an extension o the catheter, and the pressure recorded through the catheter ref ects that o the downstream chamber—namely, the le t atrium. Such a pressure measurement is termed the pulmonary artery wedge pressure or pulmonary capillary wedge pressure
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PA LA Pulmona ry a rte ry ca the te r
A pulmona ry ve in
Ca the te r tip occlude s bra nch of pulmona ry a rte ry
This a re a re pre s e nts “column of blood” be twe e n ca the te r tip a nd LA Pulmona ry ca pilla rie s
FIGURE 3-14. Diagram of a pulmonary artery catheter inserted into a branch of the pulmonary artery ( PA) . Flow is occluded in the arterial, arteriolar, and capillary vessels beyond the catheter; thus, these vessels act as a conduit that transmits the left atrial (LA) pressure to the catheter tip.
(PCW) and closely matches the le t atrial pressure in most individuals. Furthermore, while the mitral valve is open during diastole, the pulmonary venous bed, le t atrium, and le t ventricle normally share the same pressures. Thus, the PCW can be used to estimate the le t ventricular diastolic pressure, a measurement o ventricular preload (see Chapter 9). As a result, measurement o PCW may be use ul in managing certain critically ill patients in the intensive care unit. Elevation o the mean PCW is seen in le t-sided heart ailure and in mitral stenosis or regurgitation. The individual components o the PCW tracing can also become abnormally high. The a wave may be increased in conditions o decreased le t ventricular compliance, such as le t ventricular hypertrophy or acute myocardial ischemia, and in mitral stenosis. The v wave is greater than normal when there is increased le t atrial lling during ventricular contraction, as in mitral regurgitation.
Measurement of Blood Flow Cardiac output is measured by either the thermodilution method or the Fick technique. In the thermodilution method, saline o a known temperature is injected rapidly through a catheter side port into the right side o the heart, at a speci c distance rom the distal tip o the catheter. The catheter tip, positioned in the pulmonary artery, contains a thermistor that registers the change in temperature induced by the injected saline. The cardiac output is proportional to the rate o the temperature change and is automatically calculated by the equipment. The Fick method relies on the principle that the quantity o oxygen consumed by tissues is related to the amount o O2 content removed rom blood as it f ows through the tissue capillary bed: O2 consumption = O2 content removed mL O2 min
mL O2 mL blood
×
Flow mL blood min
Or, in more applicable terms: O2 consumption = AVO2 di erence × Cardiac output where the arteriovenous O2 (AVO2) di erence equals the di erence in oxygen content between the arterial and venous compartments. Total body oxygen consumption can be determined by analyzing expired air rom the lungs, and arterial and venous O2 content is measured in blood samples. By rearranging the terms, the cardiac output can be calculated: Cardiac output =
O2 consumption AVO2 di erence
60
Chapter 3 For example, i the arterial blood in a normal adult contains 190 mL o O2 per liter and the venous blood contains 150 mL o O2 per liter, the arteriovenous di erence is 40 mL o O2 per liter. I this patient has a measured O2 consumption o 200 mL/ min, the calculated cardiac output is 5 L/ min. In many orms o heart disease, the cardiac output is lower than normal. In that situation, the total body oxygen consumption does not change signi cantly; however, a greater percentage o O2 is extracted per volume o circulating blood by the metabolizing tissues. The result is a lower-than-normal venous O2 content and there ore an increased AVO2 di erence. In our example, i the patient’s venous blood O2 content ell to 100 mL/ L, the AVO2 di erence would increase to 90 mL/ L and the calculated cardiac output would be reduced to 2.2 L/ min. Because the normal range o cardiac output varies with a patient’s size, it is common to report the cardiac index, which is equal to the cardiac output divided by the patient’s body sur ace area (normal range o cardiac index = 2.6 – 4.2 L/ min/ m 2).
Calculation of Vascular Resistance Once pressures and cardiac output have been determined, pulmonary and systemic vascular resistances can be calculated, based on the principle that the pressure di erence across a vascular bed is proportional to the product o f ow and resistance. The calculations are: PVR =
MPAP − LAP × 80 CO
PVR, pulmonary vascular resistance (dynes-sec-cm − 5) MPAP, mean pulmonary artery pressure (mm Hg) LAP, mean le t atrial pressure (mm Hg) CO, cardiac output (L/ min) SVR =
MAP − RAP × 80 CO
SVR, systemic vascular resistance (dynes-sec-cm − 5) MAP, mean arterial pressure (mm Hg) RAP, mean right atrial pressure (mm Hg) CO, cardiac output (L/ min) The normal PVR ranges rom 20 to 130 dynes-sec-cm − 5. The normal SVR is 700 to 1,600 dynes-sec-cm − 5.
Contrast Angiography This technique uses radiopaque contrast to visualize regions o the cardiovascular system. A catheter is introduced into an appropriate vessel and guided under f uoroscopy to the site o injection. Following administration o the contrast agent, x-rays are transmitted through the area o interest. A continuous series o x-ray exposures is recorded to produce a motion picture cineangiogram (o ten simply called a “cine” or “angiogram”). Selective injection o contrast into speci c heart chambers can be used to identi y valvular insu ciency, intracardiac shunts, thrombi within the heart, congenital mal ormations, and to measure ventricular contractile unction (Fig. 3-15). However, the noninvasive techniques described in this chapter (e.g., echocardiography) have largely supplanted the need or invasive contrast angiography or these purposes.
Cardiac Imaging and Catheterization
A
61
B
FIGURE 3-15. Left ventriculogram, in diastole ( A) and systole ( B) in the right anterior oblique projection, from a patient with normal ventricular contractility. A catheter (black arrow) is used to inject contrast into the le t ventricle (LV). The catheter can also be seen in the descending aorta (white arrowhead). AO, aortic root.
An important and widespread application of contrast injection is coronary artery angiography, to examine the location and severity of coronary atherosclerotic lesions. To maximize the test’s sensitivity and reproducibility, each patient is imaged in several standard views. When necessary, angioplasty and stent placement can be performed (Figs. 3-16 and 3-17; see Chapter 6).
LCX
LM LM
LAD LAD
Diag o nal branc h
S e ptal pe rfo rato rs
A
B
FIGURE 3-16. Cardiac catheterization and stenting of a proximal left anterior descending artery ( LAD) stenosis, shown in an anteroposterior cranial projection. A. When contrast agent is injected into the le t main coronary artery (LM), the le t circumf ex artery (LCX) lls normally, but the LAD is almost completely occluded at its origin (white arrow). B. A ter the stenosis is success ully stented, the LAD and its branches ll robustly.
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Chapter 3
A
B
FIGURE 3-17. Cardiac catheterization and stenting o right coronary artery ( RCA) stenoses. Both images are obtained in the le t anterior oblique (LAO) projection. A. The stenotic segment is located between the white arrows. B. A ter stenting, the caliber o the vessel and f ow have improved.
A small risk is associated with catheterization and contrast angiography. Complications are uncommon but include myocardial per oration by the catheter, precipitation o arrhythmias and conduction blocks, damage to vessel walls, hemorrhage, dislodgement o atherosclerotic plaques, pericardial tamponade (see Chapter 14), and in ection. The contrast medium itsel can cause anaphylaxis and renal toxicity. Table 3-4 summarizes the catheterization ndings in common cardiac abnormalities. Therapeutic interventional catheterization techniques are described in Chapter 6.
NUCLEAR IMAGING Heart unction can be evaluated using injected, radioactively labeled tracers and γ-camera detectors. The resulting images ref ect the distribution o the tracers within the cardiovascular system. Nuclear techniques are used to assess myocardial per usion, to image blood passing through the heart and great vessels, to localize and quanti y myocardial ischemia and in arction, and to assess myocardial metabolism.
TABLE 3-4 Cardiac Catheterization and Angiography in Cardiac Disorders Disorder
Finding
Coronary artery disease Mitral regurgitation Mitral stenosis
• Identi cation o atherosclerotic lesions • Large systolic v wave in le t atrial pressure tracing • Abnormally high pressure gradient between the le t atrium and le t ventricle in diastole • Large systolic v wave in the right atrial pressure tracing • Systolic pressure gradient between the le t ventricle and aorta • Reduced ejection raction (see Chapter 9) i systolic dys unction • Elevated diastolic pressure with normal ejection raction i diastolic dys unction
Tricuspid insu f ciency Aortic stenosis Heart ailure
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Assessment of Myocardial Perfusion Ischemia and infarction resulting from CAD can be detected by myocardial perfusion imaging using various radioisotopes, including compounds labeled with thallium-201 ( 201Tl) and technetium-99m ( 99m Tc). Of the latter, currently, 99m Tc-sestamibi and 99m Tc-tetrofosmin are used. Both 201Tl- and 99m Tc-labeled compounds are sensitive for the detection of ischemic or scarred myocardium, but each has distinct advantages. For example, the 99m Tc-labeled agents provide better image quality and are superior for detailed single photon emission computed tomography (SPECT, as in Fig. 3-18). Conversely, enhanced detection of myocardial cellular viability is possible with 201Tl imaging. In the case of 201Tl imaging, the radioisotope is injected intravenously while the patient exercises on a treadmill or stationary bicycle. Because thallium is a potassium analogue, it enters normal myocytes, a process thought to be partially governed by sodium–potassium ATPase. The intracellular concentration of thallium, estimated by the density of the image, depends on vascular supply (perfusion) and membrane function (tissue viability). In the normal heart, the radionuclide scan shows a homogenous distribution of thallium in the S HORT AXIS Ante rior STRES S
Sep
La t Infe rior
REST
B
STRES S
HORIZONTAL LONG AXIS
Sep
A REST
C FIGURE 3-18. Stress and rest myocardial perfusion single photon emission computed tomography images ( using 99mTc-tetrofosmin) of a patient with a high-grade stenosis within the proximal left anterior descending coronary artery. A. Miniaturized reproduction of the complete scan showing tomographic images in each of the three views (from top to bottom: short axis, vertical long axis, and horizontal long axis). The f rst, third, and f th rows demonstrate images during stress, and the second, ourth, and sixth rows are matching images acquired at rest. B, C. Enlarged selected panels from ( A) showing stress and rest images in the short-axis and horizontal long-axis views. The arrows indicate regions of decreased perfusion during stress but normal perfusion on the matching resting scans, consistent with inducible ischemia. Lat, lateral wall of the LV; Sep, septal wall. (Courtesy of Marcelo Di Carli, MD, Brigham and Women’s Hospital, Boston, MA.)
La t
64
Chapter 3 myocardial tissue. Conversely, myocardial regions that are scarred (by previous in arction) or have reduced per usion during exercise (i.e., transient myocardial ischemia) do not accumulate as much thallium as normal heart muscle. Consequently, these areas will appear on the thallium scan as light or “cold” spots. When evaluating or myocardial ischemia, an initial set o images is taken right a ter exercise and 201Tl injection. Well-per used myocardium will take up more tracer than ischemic or in arcted myocardium at this time. Delayed images are acquired several hours later, because 201 Tl accumulation does not remain xed in myocytes. Rather, continuous redistribution o the isotope occurs across the cell membrane. A ter 3 to 4 hours o redistribution, when additional images are obtained, all viable myocytes will have equal concentrations o 201Tl. Consequently, any uptake abnormalities on the initial exercise scan that were caused by myocardial ischemia will have resolved (i.e., lled in) on the delayed scan (and are there ore termed “reversible” de ects), and those representing infarcted or scarred myocardium will persist as cold spots (“ xed” de ects). O note, some myocardial segments that demonstrate persistent 201Tl de ects on both stress and redistribution imaging are alsely characterized as nonviable, scarred tissue. Sometimes, these areas represent ischemic, noncontractile, but metabolically, active areas that have the potential to regain unction i an adequate blood supply is restored. For example, such areas may represent hibernating myocardium, segments that demonstrate diminished contractile unction owing to chronic reduction o coronary blood f ow (see Chapter 6). This viable state (in which the a ected cells can be predicted to regain unction ollowing coronary revascularization) can o ten be di erentiated rom irreversibly scarred myocardium by repeat imaging at rest a ter the injection o additional 201Tl to enhance uptake by viable cells. 99m Tc-sestamibi (commonly re erred to as MIBI) is an example o a widely used 99m Tclabeled compound. This agent is a large lipophilic molecule that, like thallium, is taken up in the myocardium in proportion to blood f ow. The uptake mechanism di ers in that the compound crosses the myocyte membrane passively, driven by the negative membrane potential. Once inside the cell, it urther accumulates in mitochondria, driven by that organelle’s even more negative membrane potential. The myocardial distribution o MIBI ref ects per usion at the moment o injection, and in contrast to thallium, it remains xed intracellularly, that is, it redistributes only minimally over time. Consequently, per orming a MIBI procedure is more f exible, as images can be obtained up to 4 to 6 hours a ter injection and repeated as necessary. A MIBI study is usually per ormed as a 1-day protocol in which an initial injection o a small tracer dose and imaging are per ormed at rest. Later, a larger tracer dose is given a ter exercise, and imaging is repeated. Stress nuclear imaging studies with either 201Tl- or 99m Tc-labeled compounds have greater sensitivity and speci city than standard exercise electrocardiography or the detection o ischemia but are more expensive and should be ordered judiciously. Nuclear imaging is particularly appropriate or patients with certain baseline electrocardiogram (ECG) abnormalities o the ST segment that preclude accurate interpretation o a standard exercise test. Examples include patients with electronic pacemaker rhythms, those with le t bundle branch block, those with ST abnormalities due to le t ventricular hypertrophy, and those who take certain medications that alter the ST segment, such as digoxin. Nuclear scans also provide more accurate anatomic localization o the ischemic segment(s) and quanti cation o the extent o ischemia compared with standard exercise testing. In addition, electronic synchronizing (gating) o nuclear images to the ECG cycle permits wall motion analysis. Patients with orthopedic or neurologic conditions, as well as those with severe physical deconditioning or chronic lung disease, may be unable to per orm an adequate exercise test on a treadmill or bicycle. In such patients, stress images can be obtained instead by administering pharmacologic agents, such as adenosine or dipyridamole. These agents induce di use
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65
coronary vasodilation, augmenting blood f ow to myocardium per used by healthy coronary arteries. Since ischemic regions are already maximally dilated (because o local metabolite accumulation), the drug-induced vasodilation causes a “steal” phenomenon, reducing isotope uptake in regions distal to signi cant coronary stenoses (see Chapter 6). Alternatively, dobutamine (see Chapter 17) can be in used intravenously to increase myocardial oxygen demand as a means to assess or ischemia.
Radionuclide Ventriculography Radionuclide ventriculography (RVG, also known as blood pool imaging) is occasionally used to analyze right and le t ventricular unction. A radioisotope (usually 99m Tc) is bound to red blood cells or to human serum albumin and then injected as a bolus. Nuclear images are obtained at xed time intervals as the labeled material passes through the heart and great vessels. Multiple images are displayed sequentially to produce a dynamic picture o blood f ow. Calculations, such as determination o the ejection raction, are based on the di erence between radioactive counts present in the ventricle at the end o diastole and at the end o systole. There ore, measurements are largely independent o any assumptions o ventricular geometry and are highly reproducible. Studies suggest that RVG and echocardiography provide similar le t ventricular ejection raction values. RVG has been used historically to assess baseline cardiac unction in patients scheduled to undergo potentially cardiotoxic chemotherapy (e.g., doxorubicin) and to ollow cardiac unction over time in such patients. However, echocardiography is usually easier to per orm, does not expose the patient to ionizing radiation, and now commonly serves this role.
Assessment of Myocardial Metabolism Positron emission tomography (PET) is a specialized nuclear imaging technique used to assess myocardial per usion and viability. PET imaging employs positron-emitting isotopes (e.g., rubidium-82, nitrogen-13, and f uorine-18) attached to metabolic or f ow tracers. Sensitive detectors measure positron emission rom the tracer molecules. Myocardial perfusion is commonly assessed using nitrogen-13–labeled ammonia or rubidium-82. Both are taken up by myocytes in proportion to blood f ow. Myocardial viability can be determined by PET by studying glucose utilization in myocardial tissue. In normal myocardium under asting conditions, glucose is used or approximately 20% o energy production, with ree atty acids providing the remaining 80% . In ischemic conditions, however, metabolism shi ts toward glucose use, and the more ischemic the myocardial tissue, the stronger the reliance on glucose. Fluoro-18 deoxyglucose ( 18FDG), created by substituting f uorine-18 or hydrogen in 2-deoxyglucose, is used to study glucose uptake. This substance competes with glucose both or transport into myocytes and or subsequent phosphorylation. Unlike glucose, however, 18FDG is not metabolized and becomes trapped within the myocyte. Combined evaluation o per usion and 18FDG metabolism allows assessment o both regional blood f ow and glucose uptake, respectively. PET scanning thus helps determine whether areas o ventricular contractile dys unction with decreased f ow represent irreversibly damaged scar tissue or whether the region is still viable (e.g., hibernating myocardium). In scar tissue, both blood f ow to the a ected area and 18FDG uptake are decreased. Because the myocytes in this region are permanently damaged, such tissue is not likely to bene t rom revascularization. Hibernating myocardium, in contrast, shows decreased blood f ow but normal or elevated 18FDG uptake. Such tissue may bene t rom revascularization procedures (see Chapter 6). Table 3-5 summarizes the radionuclide imaging abnormalities associated with common cardiac conditions.
66
Chapter 3
TABLE 3-5 Nuclear Imaging in Cardiac Disorders Disorder
Findings
Myocardial ischemia Stress-delayed reinjection
201
Tl
Rest–stress 99mTc-labeled compounds PET (N-13 ammonia/ 18FDG) Myocardial infarction Stress-delayed reinjection 201Tl Rest–stress 99mTc-labeled compounds PET (N-13 ammonia/ 18FDG) Hibernating myocardium Rest-delayed 201Tl PET (N-13 ammonia/ 18FDG) 18
• Low uptake during stress with complete or partial ll-in with delayed or reinjection images • Normal uptake at rest with decreased uptake during stress • Decreased f ow with normal or increased 18FDG uptake during stress • Low uptake during stress and low uptake a ter reinjection • Low uptake in rest and stress images • Decreased f ow and decreased 18FDG uptake at rest • Complete or partial ll-in o de ects a ter reinjection • Decreased f ow and normal or increased 18FDG uptake at rest
FDG, f uoro-18 deoxyglucose; N-13, nitrogen-13; PET, positron emission tomography;
99m
Tc, technetium-99m;
201
Tl, thallium-201.
COMPUTED TOMOGRAPHY CT uses thin x-ray beams to obtain a large series o axial plane images. An x-ray tube is programmed to rotate around the body, and the generated beams are partially absorbed by body tissues. The remaining beams emerge and are captured by electronic detectors, which relay in ormation to a computer or image composition. CT scanning typically requires administration o an intravenous contrast agent to distinguish intravascular contents (i.e., blood) rom neighboring so t tissue structures (e.g., myocardium). Applications o CT in cardiac imaging include assessment o the great vessels, pericardium, myocardium, and coronary arteries. CT is used to diagnose aortic dissections and aneurysms (Fig. 3-19). It can identi y abnormal pericardial f uid, thickening, and calci cation. Myocardial abnormalities, such as regional hypertrophy or ventricular aneurysms, and intracardiac thrombus ormation can be distinctly visualized by CT. A limitation o conventional CT techniques is the arti act generated by patient motion (i.e., breathing) during image acquisition. Modern spiral CT (also called helical CT) imaging allows more rapid image acquisition, o ten during a single breath-hold, at relatively lower radiation doses than conventional CT. Spiral CT is particularly important in the diagnosis o pulmonary embolism. When an intravenous iodine-based contrast agent is administered, emboli create the appearance o “ lling de ects” in otherwise contrast-enhanced pulmonary vessels (Fig. 3-20). Electron beam computed tomography (EBCT) uses a direct electron beam to acquire images in a matter o milliseconds. Rapid succession o images depicts cardiac structures at multiple times during a single cardiac cycle. Displaying these images in a cine ormat can provide estimates o le t ventricular volumes and ejection raction. Capable o detecting coronary artery calci cation, EBCT has been used primarily to screen or CAD. Because calci ed coronary artery plaques have a radiodensity similar to that o bone, they appear attenuated (white) on CT. The Agatston score, a measure o total coronary artery calcium, correlates well with atherosclerotic plaque burden and predicts the risk o coronary events, independently o other cardiac risk actors. Newer CT technology can characterize atherosclerotic stenoses in great detail. Current multidetector row CT scanners acquire as many as 320 anatomic sections with each rotation, providing excellent spatial resolution. Administration o intravenous contrast and computer re ormatting allows visualization o the arterial lumen and regions o coronary
AA
PA
AA
AA
A
RK Live r
RK LK LK RCl
LCl LCl LEI
B
C
D
FIGURE 3-19. Computed tomography ( CT) imaging of aortic dissection. A,B. Axial images demonstrate an intimal f ap (blue arrowheads) separating the true and alse lumens o the descending thoracic and abdominal aorta. C. CT angiography (CTA) with three-dimensional reconstructions. In this le t anterior oblique view, the origin o the dissection (blue arrowhead) is apparent in the distal portion o the aortic arch. The dissection continues to the level o the renal arteries (white arrowhead) and beyond. D. In this CTA le t posterior oblique view, the dissection extends to the in rarenal aorta (white arrowhead) and involves the le t common and external iliac arteries (blue arrowhead). AA, ascending aorta; LCI, le t common iliac artery; LEI, le t external iliac artery; LK, le t kidney; PA, main pulmonary artery; RCI, right common iliac artery; RK, right kidney. (Courtesy o Suhny Abbara, MD, Massachusetts General Hospital, Boston, MA.)
FIGURE 3-20. Spiral ( helical) computed tomography image demonstrating a massive pulmonary embolism. The white arrows point to a large thrombus within the right pulmonary artery. It appears as a lling de ect within the otherwise contrast-enhanced pulmonary vasculature. AA, ascending aorta; DA, descending aorta; LPA, le t pulmonary artery; PA, main pulmonary artery; RPA, right pulmonary artery; SVC, superior vena cava.
68
Chapter 3
Ao Ao
RCA
Ao
RA LA
PA
LCX LM
LM RCA
LA LAD
RV
PA LAD
LCX LAD
RV LV
A
LV
B
C
FIGURE 3-21. Computed tomography ( CT) coronary angiography. A ter a patient is imaged in a highresolution axial CT scanner, three-dimensional reconstructions (termed volume renderings) are generated by a computer. A. Volume rendering o a normal CT angiogram. B. Volume rendering o a CT angiogram that demonstrates di use coronary artery disease. Notice that the caliber o each vessel is irregular along its length. C. This curved re ormat o the le t anterior descending artery (LAD) depicts the entire course o the vessel in a single, f at image, making it easier to detect stenoses. None are present here. Ao, aorta; LA, le t atrium; LCX, le t circumf ex artery; LM, le t main coronary artery; LV, le t ventricle; PA, pulmonary artery; RA, right atrium; RCA, right coronary artery; RV, right ventricle. (Courtesy o Suhny Abbara, MD, Massachusetts General Hospital, Boston, MA.)
narrowings (Fig. 3-21). Because image acquisition is timed with the cardiac cycle, a relatively low heart rate is desirable, such that a β-blocker is o ten administered prior to scanning. CT is not as sensitive as conventional angiography or the detection o coronary lesions, and it cannot adequately evaluate stenosis within coronary artery stents. In addition, this technique results in signi cant radiation exposure. However, CT is rapid, relatively inexpensive, and signi cantly less invasive than conventional angiography. Its role in assessing patients with symptoms suggestive o CAD and or ollowing the progression o known coronary disease is under active evaluation.
MAGNETIC RESONANCE IMAGING MRI uses a power ul magnetic eld to obtain detailed images o internal structures. This technique is based on the magnetic polarity o hydrogen nuclei, which align themselves with an applied magnetic eld. Radio requency excitation causes the nuclei to move out o alignment momentarily. As they return to their resting states, the nuclei emit the absorbed energy into signals that are translated into computer-generated images. There ore, unlike CT imaging, MRI requires no ionized radiation. Among all the imaging modalities, MRI is best at di erentiating tissue contrasts (blood, f uid, at, and myocardium) and can o ten do so even without the use o contrast agents. The addition o gadolinium-based contrast allows urther characterization o cardiac structures and tissues. The detail o so t tissue structures is o ten exquisitely demonstrated in magnetic resonance images (Fig. 3-22). Cardiac MRI (CMR) has an established role in evaluating congenital anomalies, such as shunts, and diseases o the aorta, including aneurysm and dissection. It is also used to assess le t and right ventricular mass and volume, intravascular thrombus,
Cardiac Imaging and Catheterization
69
A
B FIGURE 3-22. Cardiac magnetic resonance images of a normal person. A. Three-chamber long-axis view of the heart in diastole and systole showing the left ventricle (LV), right ventricle (RV), and left atrium (LA). The mitral valve (MV), aortic valve (AV), ascending aorta (AAO), and descending aorta (DA) are also imaged. B. Midventricular short-axis view demonstrating the LV, RV, and left ventricular papillary muscles (PMs). PW, posterior wall; S, septum. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.)
cardiomyopathies, and neoplastic disease (Fig. 3-23). ECG-gated and cine MRI techniques capture images at discrete times in the cardiac cycle, allowing or the evaluation o valvular and ventricular unction. Two applications o CMR deserve special mention. Coronary magnetic resonance angiography (coronary MRA) is a noninvasive, contrast- ree angiographic imaging modality. Laminar blood f ow appears as bright signal intensity, whereas turbulent blood f ow, at the site o stenosis, results in less bright or absent signal intensity. This technique has shown high sensitivity and accuracy or the detection o important CAD in the le t main coronary artery and in the proximal and midportions o the three major coronary vessels. Coronary MRA is also use ul in delineating coronary artery congenital anomalies. In contrast-enhanced MRI, a gadolinium-based agent is administered intravenously to identi y in arcted (irreversibly damaged) myocardium and to di erentiate it rom impaired (but viable) muscle segments. This technique is based on the act that gadolinium is excluded rom viable cells with intact cell membranes but can permeate and concentrate in in arcted zones, producing “hyperenhancement” on the image (Fig. 3-24). Owing to the high spatial resolution o this technique, the transmural extent o myocardial scar can be depicted, and the pattern o in arcting tissue can be di erentiated rom that o acute myocarditis, a condition that may present with similar clinical eatures. The use o late-enhancing gadolinium imaging also allows or the identi cation o poorly contractile “hibernating” myocardium (described in Chapter 6), tissue that is chronically ischemic, but would be expected to recover unction i adequate blood per usion is restored.
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Chapter 3
LV
LV
RV
RV
RA
RA
LA
LA
A
B
FIGURE 3-23. Magnetic resonance imaging of an intracardiac mass. Both images are apical four-chamber views. A. Before a gadolinium-based contrast agent is administered, an abnormal left atrial mass (indicated by the oval) demonstrates diminished signal relative to the surrounding tissue. In this respect, it resembles a nonvascular thrombus. B. After contrast injection, the mass enhances similar to the surrounding tissue, indicating that it is vascularized. Biopsy revealed a spindle cell carcinoma. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.)
RV
A
LV RV
LV
B
FIGURE 3-24. Gadolinium-enhanced magnetic resonance images demonstrating a region of nonviable myocardium. Both images are short-axis views. A. Imaging before administration of gadolinium demonstrates thinning of the anterior and anteroseptal myocardium (blue arrow) suggestive of infarcted tissue (compare to short-axis view of healthy myocardial wall in Fig. 3.22-B). B. After contrast injection, the subendocardial regions of the anterior and anteroseptal segments of the left ventricle selectively enhance (white arrows), indicating that scar tissue is present. Because more than half the thickness of the ventricular wall is scarred, coronary revascularization would have a low likelihood of improving contractile function of these myocardial segments. LV, left ventricle; RV, right ventricle. (Courtesy of Raymond Y. Kwong, MD, Brigham and Women’s Hospital, Boston, MA.)
Cardiac Imaging and Catheterization
71
INTEGRATION This chapter has presented an overview o imaging and catheterization techniques available to assess cardiac structure and unction. Many o these tools are expensive and yield similar in ormation. For example, estimates o ventricular contractile unction can be made by echocardiography, nuclear imaging, contrast angiography, gated CT, or MRI. Myocardial viability can be assessed using nuclear imaging studies, gadolinium MRI, or dobutamine echocardiography. Determining the single best test or any given patient depends on a number o actors. One is the ease by which images may be obtained. In a critically ill patient, bedside echocardiography provides a readily acquired measure o le t ventricular systolic unction. Conversely, obtaining similar in ormation rom a nuclear or magnetic resonance study would require a trip to the respective scanner. Other actors to consider include the magnitude o radiation exposure and the invasiveness o a given imaging technique. Expense, available equipment, and institutional expertise also play roles in selecting an imaging approach. When used appropriately, each o these tools can provide important in ormation to guide the diagnosis and management o cardiovascular disorders.
SUMMARY • Imaging and catheterization techniques provide important in ormation to guide the diagnosis and management o cardiovascular disorders; key uses are summarized here and in Table 3-6. • Chest radiography can detect chamber dilatation and visualize pulmonary signs o heart ailure. • Transthoracic echocardiography can assess ventricular systolic and diastolic dys unction, identi y valvular abnormalities and vegetations, diagnose consequences o myocardial in arction, and demonstrate pericardial and congenital abnormalities. • Transesophageal echocardiography is used to visualize intracardiac thrombus, evaluate prosthetic valve dys unction, identi y valvular vegetations and myocardial abscess in endocarditis, and diagnose aortic dissection. • Diagnostic cardiac catheterization is the “gold standard” to assess intracardiac pressures and to identi y and grade coronary artery stenoses. • Nuclear imaging can diagnose myocardial ischemia and distinguish viable myocardium rom scar tissue. • Positron emission tomography is used to assess or ischemia and can distinguish viable myocardium rom scar tissue. • Computed tomography is sensitive or the diagnosis o aortic dissection and pulmonary embolism, can assess pericardial conditions and detect coronary artery calcif cation and stenoses. • Magnetic resonance imaging demonstrates great detail o so t tissue structures and is used to def ne the specif c conditions listed in Table 3-6.
Ack n ow le d gm en t s The authors are grate ul to Marcelo Di Carli, MD; Raymond Y. Kwong, MD; and Gillian Lieberman, MD or their help ul suggestions. Contributors to previous editions o this chapter were Henry Jung, MD; Ken Young Lin, MD; Nicole Martin, MD; Deborah Bucino, MD; Sharon Horesh, MD; Shona Pendse, MD; Albert S. Tu, MD; and Patrick Yachimski, MD.
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Chapter 3
TABLE 3-6 Summary of Cardiac Imaging Techniques Imaging Technique
Findings
Examples of Clinical Uses
Chest radiography
• Cardiac and mediastinal contours • Pulmonary vascular markings • Wall thickness, chamber dimensions • Anatomic relationships and motion o cardiac structures • Flow direction, turbulence, and velocity measurements • Echo contrast studies • Stress echocardiography • Similar to TTE but higher resolution
• Detect chamber dilatation • Identi y consequences o stenotic and regurgitant valve lesions and intracardiac shunts • Visualize pulmonary signs o heart ailure • Assess global and segmental ventricular contraction • Identi y valvular abnormalities and vegetations • Diagnose consequences o myocardial in arction (e.g., ventricular aneurysm, papillary muscle rupture, intraventricular thrombus) • Identi y myocardial, pericardial, and congenital abnormalities
Transthoracic echocardiography (TTE)
Transesophageal echocardiography (TEE)
Cardiac catheterization
• Pressure measurement • Contrast angiography
Nuclear SPECT imaging (using 99mTclabeled compounds or 201Tl)
• Regional myocardial per usion • Myocardial viability
Radionuclide ventriculography Positron emission tomography (PET) Computed tomography (CT)
• Ventricular contractile unction • Myocardial per usion and metabolism • Anatomy and structural relationships
Magnetic resonance imaging (MRI)
• Detailed so t tissue anatomy
• Visualize intracardiac thrombus • Evaluate prosthetic valves and perivalvular leaks • Identi y valvular vegetations and myocardial abscess in endocarditis • Diagnose aortic dissection • Evaluate intracardiac pressures (e.g., in valvular disease, heart ailure, pericardial disease) • Visualize ventricular contractile unction, regurgitant valve lesions • Identi y coronary anatomy and severity o stenoses • Detect, quanti y, and localize myocardial ischemia • Per orm stress testing in patients with baseline ECG abnormalities • Distinguish viable myocardium rom scar tissue • Calculate ventricular ejection raction and quantitate intracardiac shunts • Evaluate contractile unction • Distinguish viable myocardium rom scar tissue • Diagnose disease o the great vessels (aortic dissection, pulmonary embolism) • Assess pericardial disease and myocardial abnormalities • Detect coronary artery calcif cation and stenoses • Assess myocardial structure and unction (e.g., ventricular mass and volume, neoplastic disease, intracardiac thrombus, cardiomyopathies) • Diagnose aortic and pericardial disease • Detect areas o ischemic vs. in arcted myocardium
ECG, electrocardiogram; SPECT, single photon emission computed tomography;
99m
Tc, technetium-99m;
201
Tl, thallium-201.
Cardiac Imaging and Catheterization
73
Ad d i t i o n a l Rea d i n g Bengel FM, Higuchi T, Javadi MS, et al. Cardiac positron emission tomography. J Am Coll Cardiol. 2009;54:1–15. Douglas PS, Garcia MJ, Haines DE, et al. ACCF/ ASE/ AHA/ ASNC/ HFSA/ HRS/ SCAI/ SCCM/ SCCT/ SCMR 2011 appropriate use criteria for echocardiography. J Am Coll Cardiol. 2011;57:1126–1166. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ AHA/ ACP/ AATS/ PCNA/ SCAI/ STS Guideline for the diagnosis and management of patients with stable ischemic heart disease. J Am Coll Cardiol. 2012;60:e44–e164. Kern MJ, Samady H. Current concepts of integrated coronary physiology in the catheterization laboratory. J Am Coll Cardiol. 2010;55:173–185. Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic resonance in patients with myocardial infarction: current and emerging applications. J Am Coll Cardiol. 2010;55:1–16.
Maganti K, Rigolin VH, Sarano EM, et al. Valvular heart disease: diagnosis and management. Mayo Clin Proc. 2010;85:483–500. Min JK, Shaw LJ, Berman DS. The present state of coronary computed tomographic angiography. J Am Coll Cardiol. 2010;55:957–965. Moscucci M, Grossman W. Grossman’s Cardiac Catheterization, Angiography and Intervention. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013. Otto CM. Textbook of Clinical Echocardiography. 5th ed. Philadelphia, PA: Elsevier Saunders; 2013. Pennell DJ. Cardiovascular magnetic resonance. Circulation. 2010;121:692–705. Perrino AC, Reeves ST. A Practical Approach to Transesophageal Echocardiography. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013.
The Electrocardiogram Da vid B. Fischer Leona rd S. Lilly
Ch a p t e r O u t l i n e Electrical Measurement—SingleCell Model Electrocardiographic Lead Reference System Sequence of Normal Cardiac Activation Interpretation of the Electrocardiogram Calibration Heart Rhythm Heart Rate Intervals (PR, QRS, QT) Mean QRS Axis Abnormalities o the P Wave Abnormalities o the QRS Complex ST-Segment and T-Wave Abnormalities
74
4
C
ardiac contraction relies on the organized f ow o electrical impulses through the heart. The electrocardiogram (ECG) is an easily obtained recording o that activity and provides a wealth o in ormation about cardiac structure and unction. This chapter presents the electrical basis o the ECG in health and disease and leads the reader through the basics o interpretation. To practice using these principles and to become skill ul at interpreting ECG tracings o your patients, you should also consult one o the complete electrocardiographic manuals listed at the end o this chapter.
ELECTRICAL MEASUREMENT—SINGLECELL MODEL This section begins by observing the propagation of an electrical impulse along a single cardiac muscle cell, illustrated in Figure 4-1. On the right side of the diagram, a voltmeter records the electrical potential at the cell’s surface on graph paper. In the resting state, the cell is polarized; that is, the entire outside of the cell is electrically positive with respect to the inside, because of the ionic distribution across the cell membrane, as described in Chapter 1. In this resting state, the voltmeter electrodes, which are placed on opposite outside surfaces of the cell, do not record any electrical activity, because there is no electrical potential difference between them (the myocyte surface is homogeneously charged). This equilibrium is disturbed, however, when the cell is stimulated (see Fig. 4-1B). During the action potential, cations rush across the sarcolemma into the cell and the polarity at the stimulated region transiently reverses such that the outside becomes negatively charged with respect to the inside; that is, the region depolarizes. At that moment, an electrical potential is created on the cell surface between the
The Electrocardiogram 75 + –
+ –
+ –
Voltme te r –
–
+
+ –
– +
– +
– +
– +
– +
–
–
– +
A
– +
De p ola riza tion Curre nt + –
+ –
+ –
+ –
+ –
– –
–
+
+
–
+
+
(+)
B
+ –
– +
– +
– +
– +
– +
– +
– +
– +
+ –
+ –
+ –
– –
–
+
+
–
+
+
(+)
+ –
+ –
– +
– +
– +
– +
– +
– +
– +
– +
– + – –
+ –
+ –
+ –
+ –
– +
– +
– +
– +
– +
– + –
–
E
(–)
+
–
+
+ –
–
(+)
+ –
+
D
(+)
+
–
+
–
+
+ –
+
C
+
FIGURE 4-1. Depolarization of a single cardiac muscle cell. A. In the resting state, the sur ace o the cell is positively charged relative to the inside. Because the sur ace is homogeneously charged, the voltmeter electrodes outside the cell do not record any electrical potential di erence (“f at line” recording). B. Stimulation o the cell initiates depolarization (blue shaded area); the outside o the depolarized region becomes negatively charged relative to the inside. Because the current o depolarization is directed toward the (+ ) electrode o the voltmeter, an upward def ection is recorded. C. Depolarization spreads, creating a greater upward def ection by the recording electrode. D. The cell has become ully depolarized. The sur ace o the cell is now completely negatively charged compared with the inside. Because the sur ace is again homogeneously charged, a f at line is recorded by the voltmeter. E. Notice that i the position o the voltmeter electrodes had been reversed, the electrical current would have been directed away rom the (+ ) electrode, causing the def ection to be downward.
(+)
+
CARDIAC MUS CLE CELL
+
(–)
+ –
+
+ –
+ –
+ –
+ –
+ –
+ –
+ –
depolarized area (negatively charged sur ace) and the still-polarized (positively charged sur ace) portions o the cell. As a result, an electrical current begins to f ow between these two regions. By convention, the direction o an electrical current is said to f ow rom areas that are negatively charged to those that are positively charged. When a depolarization current is directed toward the (+ ) electrode o the voltmeter, an upward def ection is recorded. Conversely, i it is directed away rom the (+ ) electrode, a downward def ection is recorded. Because the depolarization current in this example proceeds rom le t to right—that is, toward the (+ ) electrode—an upward def ection is recorded by the voltmeter. As the wave o depolarization propagates rightward along the cell, additional electrical orces directed toward the (+ ) electrode record an even greater upward def ection (see Fig. 4-1C). Once the cell has become ully depolarized (see Fig. 4-1D), its outside is completely negatively charged with respect to the inside, the opposite o the initial resting condition. However, because the sur ace charge is homogeneous once again, the external electrodes measure a potential di erence o zero and the voltmeter records a neutral “f at line” at this time. Note that in Figure 4-1E, i the voltmeter electrode positions had been reversed, such that the (+ ) pole was placed to the left o the cell, then as the wave o depolarization proceeds toward the right, the current would be directed away rom the (+ ) electrode and the recorded def ection would be downward. This relationship should be kept in mind when the polarity o ECG leads is described below. Depolarization initiates myocyte contraction and is then ollowed by repolarization, the process by which the cellular charges return to the resting state. In Figure 4-2, as the le t side
76
Chapter 4
–
– +
+
–
–
+ –
+
A
(+)
+
+ –
– Dire–c tion– of Curre – nt– + + + + +
+ –
+ –
+ –
+ –
+ –
De pola rize d portion Re pola rize d portion
+ –
+ –
– +
– +
– +
+ –
+ –
+ –
–
– +
+ –
+ –
+ –
+ –
+ –
+ –
C
D
–
– +
– +
– +
– +
– +
–
– +
+
–
+
–
+
– +
+
–
–
+ –
+
– +
+
B
(+)
+
+ –
(+)
FIGURE 4-2. Sequence of repolarization of a single cardiac muscle cell. A. As repolarization commences, the sur ace o the cell at that site becomes positively charged and a current is generated rom the still negatively charged sur ace areas to the repolarized region (blue arrows). Because the current is directed away rom the (+ ) electrode o the voltmeter, a downward de ection is recorded. B. Repolarization progresses. C. Repolarization has completed, and the outside sur ace o the cell is once again homogeneously charged, so that no urther electrical potential is detected ( at line once again). D. Sequence o cardiac depolarization and repolarization as measured by an ECG machine at the skin sur ace. As described in the text, repolarization actually proceeds in the direction opposite to that o depolarization in the intact heart, such that the de ections o repolarization are inverted compared to the schematics presented in parts A–C o this f gure. There ore, the def ections o depolarization and repolarization o the normal heart are oriented in the same direction. Note that the wave o repolarization is more prolonged and o lower amplitude than that o depolarization.
o the cardiac muscle cell in our example begins to repolarize, its sur ace charge becomes positive once again. An electrical potential is there ore generated, and current ows rom the still negatively charged sur ace toward the positively charged region. Since this current is directed away rom the voltmeter’s (+ ) electrode, a downward de ection is recorded, opposite to that which was observed during the process o depolarization. Repolarization is a slower process than depolarization, so the inscribed de ection o repolarization is usually wider and o lower magnitude. Once the cell has returned to the resting state, the sur ace charges are once again homogeneous and no urther electrical potential is detected, resulting in a neutral at line on the voltmeter recording (Fig. 4-2C). The depolarization and repolarization o a single cardiac muscle cell have been considered here. As a wave o depolarization spreads through the entire heart, each cell generates electrical orces, and it is the sum o these orces, measured at the skin’s sur ace, that is recorded by the ECG machine. It is important to note that in the intact heart, the sequence by which regions repolarize is actually opposite to that o their depolarization. This occurs because myocardial action potential durations are more prolonged in cells near the inner endocardium (the f rst cells stimulated by Purkinje f bers) than in myocytes near the outer epicardium (the last cells to depolarize). Thus, the cells close to the endocardium are the f rst to depolarize but are the last to repolarize. As a result, the direction o repolarization recorded by the ECG machine is usually the in verse o what was presented in the single-cell example in Figure 4-2. That is, unlike the single-cell model, the electrical de ections o depolarization and repolarization in the intact heart are usually oriented in the sa me direction on the ECG tracing (see Fig. 4-2D). The direction and magnitude o the de ections on an ECG recording depend on how the generated electrical orces are aligned to a set o specif c re erence axes, known as ECG leads, as described in the next section.
The Electrocardiogram 77
Right a rm e le ctrode
Le ft a rm e le ctrode Che s t e le ctrode s
V1 V2
FIGURE 4-3. Placement of electrocardiogram ( ECG) electrodes. A. Standard positions. B. Close-up view of chest electrode placement, at the standard positions listed in Table 4-1.
Right le g e le ctrode
V3
Le ft le g e le ctrode
A
V6 V5 V4
B
ELECTROCARDIOGRAPHIC LEAD REFERENCE SYSTEM When the f rst device to produce an ECG was invented over a century ago, the recording was made by dunking the patient’s arms and legs into large buckets o electrolyte solution that were wired to the machine. That process was likely airly messy and ortunately is no longer necessary. Instead, wire electrodes are placed directly on the skin, held in place by adhesive tabs, on each o the our limbs and on the chest in the standard arrangement as shown in Figure 4-3. The right-leg electrode is not used or the measurement but serves as an electrical ground. Table 4-1 lists the standard locations o the chest electrodes. A complete ECG (termed a “12-lead ECG”) is produced by recording electrical activity between the electrodes in specif c patterns. This results in six re erence axes in the body’s rontal plane (termed limb leads) plus six in the transverse plane (termed chest leads). Figure 4-4 demonstrates the orientation o the six limb leads, which are electronically constructed as described in the ollowing paragraphs. The ECG machine records lead aVR by selecting the right-arm electrode as the (+ ) pole with respect to the other electrodes. This is known as a unipolar lead, because though there is a (+ ) pole, there is no single (− ) pole; rather, the other limb electrodes are averaged to create a composite (− ) re erence. When the instantaneous electrical activity o the heart points in the direction o the right arm, an upward de ection is recorded in lead aVR. Conversely, when electrical orces are directed away rom the right arm, the ECG inscribes a downward de ection in aVR. Similarly, lead aVF is recorded by setting the le t leg as the (+ ) pole, such that a positive de ection is recorded when orces are directed toward the eet. Lead aVL is selected when the le t-arm electrode is made the (+ ) pole, and it records an upward de ection when electrical activity is aimed in that direction. In addition to these three unipolar leads, three bipolar limb leads are part o the standard ECG recording (Fig. 4-4). Bipolar indicates that one limb electrode is the (+ ) pole and another single electrode provides the (− ) re erence. In this case, the ECG machine inscribes an upward
TABLE 4-1 Positions of ECG Chest Electrodes V1 V2 V3 V4 V5 V6
4th ICS, 2 cm to the right of the sternum 4th ICS, 2 cm to the left of the sternum Midway between V2 and V4 5th ICS, left midclavicular line Same level as V4, left anterior axillary line Same level as V4, left midaxillary line
ICS, intercostal space.
78
Chapter 4 Unipo lar Limb Le ads (+)
(+)
(+)
a VR
a VF
a VL
Bipo lar Limb Le ads (–)
(+)
(–)
(–)
(+)
I
II
(+)
III
FIGURE 4-4. The six limb leads are derived from the electrodes placed on the arms and left leg. Top, each unipolar lead has a single (+ ) designated electrode; the (− ) pole is an average o the other electrodes. Bottom, each bipolar lead has specif c (− ) and (+ ) designated electrodes. Although these illustrations show outstretched arms to depict the location o the electrodes, such positioning is not necessary when acquiring a patient’s ECG recording. Even in the natural position o the arms by the patient’s sides, directionality o the leads is maintained.
def ection i electrical orces are heading toward the (+ ) electrode and records a downward def ection i the orces are heading toward the (− ) electrode. A simple mnemonic to remember the orientation o the bipolar leads is that the lead name indicates the number o l’s in the placement sites. For example, lead I connects the le t arm to the right arm, lead II connects the right arm to the le t leg, and lead III connects the le t arm to the le t leg. Table 4-2 summarizes how the six limb leads are derived.
TABLE 4-2 Limb Leads Lead Bipolar leads I II III Unipolar leads aVR aVL aVF a
( + ) Electrode
( − ) Electrode
LA LL LL
RA RA LA
RA LA
a
LL
a
Indicates the (− ) electrode or this lead is constructed by combining the other limb electrodes. LA, le t arm; LL, le t leg; RA, right arm.
a
The Electrocardiogram 79 By overlaying these six limb leads, an axial re erence system is established (Fig. 4-5). In the f gure, each lead is presented with its (+ ) pole designated by an arrowhead and the (− ) aspect by dashed lines. Note that each 30-degree sector o the circle alls along the (+ ) or (− ) pole o one o the standard six ECG limb leads. Also note that the (+ ) pole o lead I points to 0 degrees and that, by convention, measurement o the angles proceeds clockwise rom 0 degrees as + 30 degrees, + 60 degrees, and so orth. The complete ECG recording provides a simultaneous “snapshot” o the heart’s electrical activity, taken rom the perspective o each o these lead re erence axes. Figure 4-6 demonstrates how the magnitude and direction o electrical activity are represented by the ECG recording in each lead. This f gure should be studied until the ollowing our points are clear:
–90° –120°
–60°
–150° aVR
–30° aVL
+180°
I 0°
+30°
+150° III +120°
aVF +90°
II +60°
FIGURE 4-5. The axial reference system is created by combining the six limb leads shown in Figure 4-4. Each lead has a (+ ) region indicated by the arrowhead and a (− ) region indicated by the dashed line.
Le a d I (–)
Le a d I (+)
(+)
(–)
ECG
A
B
Le a d I (–)
C
Le a d I (+)
(–)
(+)
D
FIGURE 4-6. Relationship of the magnitude and direction of electrical activity to the ECG lead. This example uses lead I, but the same principles apply to all leads. A. The electrical vector is oriented parallel to lead I and is directed toward the (+ ) electrode; there ore, a tall upward def ection is recorded by the lead. B. The vector is still oriented toward the (+ ) electrode o lead I but not parallel to the lead, so that only a component o the orce is recorded. Thus, the recorded def ection is still upward but o lower amplitude compared with that shown in ( A) . C. The electrical vector is perpendicular to lead I so that no def ection is generated. D. The vector is directed toward the (− ) region o lead I, causing the ECG to record a downward def ection.
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Chapter 4
V6 V5
LV RV
A
B
V1
V4 V2
V3
FIGURE 4-7. The chest ( precordial) leads. A. The cross-sectional plane of the chest. B. Arrangement of the six chest electrodes shown in the cross-sectional plane. Note that the right ventricle is anterior to the left ventricle.
1. An electrical orce directed toward the (+ ) pole o a lead results in an upward de ection on the ECG recording o that lead. 2. Forces that head away rom the (+ ) electrode result in a downward de ection in that lead. 3. The magnitude o the de ection, either upward or downward, re ects how parallel the electrical orce is to the axis o the lead being examined. The more parallel the electrical orce is to the lead, the greater the magnitude o the de ection. 4. An electrical orce directed perpendicular to an electrocardiographic lead does not register any activity by that lead (a at line on the recording). The six standard limb leads examine the electrical orces in the rontal plane o the body. However, because electrical activity travels in three dimensions, recordings rom a perpendicular plane are also essential (Fig. 4-7). This is accomplished by the use o the six electrodes placed on the anterior and le t lateral aspect o the chest (see Fig. 4-3B), creating the chest (also termed “precordial”) leads. The orientation o these leads around the heart in the cross-sectional plane is shown in Figure 4-7B. These are unipolar leads and, as with the unipolar limb leads, electrical orces directed toward these individual (+ ) electrodes result in an upward de ection on the recording o that lead, and orces heading away record a downward de ection. A complete ECG records samples rom each o the six limb leads and each o the six chest leads in a standard order, examples o which are presented later in this chapter (see Figs. 4-28 to 4-36).
SEQUENCE OF NORMAL CARDIAC ACTIVATION Conduction o electrical impulses through the heart is an orderly process. The normal beat begins at the sinoatrial node, located at the junction o the right atrium and the superior vena cava (Fig. 4-8). The wave o depolarization spreads rapidly through the right and le t atria and then reaches the atrioventricular (AV) node, where it encounters an expected delay. The impulse then travels rapidly through the bundle o His and into the right and le t bundle branches. The latter divide into the Purkinje f bers, which radiate toward the myocardial f bers, stimulating them to depolarize and contract. Each heartbeat is represented on the ECG by three major de ections that record the sequence o electrical propagation (see Fig. 4-8B). The P w ave represents depolarization o the atria. Following the P wave, the tracing returns to its baseline as a result o the conduction delay at the AV node. The second de ection o the ECG, the QRS complex, represents depolarization o the ventricular muscle cells. A ter the QRS complex, the tracing returns to baseline once again, and a ter a brie delay, repolarization o the ventricular cells is signaled by the T wave. Occasionally, an additional small de ection ollows the T wave (the U wave), which is believed to represent late phases o ventricular repolarization.
The Electrocardiogram 81 AV node
Bundle of His SA node 1
2 3
FIGURE 4-8. Cardiac conduction pathway. A. The electrical impulse begins at the sinoatrial (SA) node (1) then traverses the atria (2). A ter a delay at the AV node (3), conduction continues through the bundle o His and into the right and le t bundle branches (4). The latter divide into Purkinje f bers, which stimulate contraction o the myocardial cells. B. Corresponding wave orms on the ECG recording: (1) the SA node discharges (too small to generate any de ection on ECG), (2) P wave inscribed by depolarization o the atria, (3) delay at the AV node, and (4) depolarization o the ventricles (QRS complex). The T wave represents ventricular repolarization.
Right bundle bra nch
4
4
Le ft bundle bra nch
A QRS
P
B
T
12 3 4
The QRS complex may take one o several shapes but can always be subdivided into individual components (Fig. 4-9). I the f rst de ection o the QRS complex is downward, it is known as a Q wave. However, i the initial de ection is upward, then that particular complex does not have a Q wave. The R wave is def ned as the f rst upward de ection, whether or not a Q wave is present. Any downward de ection following the R wave is known as an S wave. Figure 4-9 demonstrates several common variations o the QRS complex. In certain pathologic states, such as bundle branch blocks, additional de ections may be inscribed, as shown in the f gure. Please study Figure 4-9 until you can conf dently di erentiate a Q rom an S wave. Figure 4-10 illustrates the course o normal ventricular depolarization as it is recorded in the rontal plane by two o the ECG leads: aVF and aVL. The recording in aVF represents electrical activity rom the perspective o the in erior (i.e., underside) aspect o the heart,
A
B
C
D
E
FIGURE 4-9. Examples of QRS complexes. A. The f rst de ection is downward (Q wave), ollowed by an upward de ection (R wave), and then another downward wave (S wave). B. Because the f rst de ection is upward, this complex does not have a Q wave; rather, the downward de ection after the R wave is an S wave. C. A QRS complex without downward de ections lacks Q and S waves. D. QRS composed o only a downward de ection; this is simply a Q wave but is o ten re erred to as a QS complex. E. A second upward de ection (seen in bundle branch blocks) is re erred to as R′.
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Chapter 4
+
– + S e ptum – – + + +– – + +– + + – – + – +–+ +–– +– – + + + +– +– – + + + – – + +– + – – + + –+ – + – + – ++ – – + – –+ – + Right – – – + + ve ntricle +
a VL (+)
Le ft ve ntricle
a VF (+)
A
a VL
a VL
+ – – ++ – –+ – + + –– + – ++ + – – + + + – – –
+– + –
a VF
B
a VF
C
–
+ –+– –+ + – – +– – + + – –+ – – + + – + + – – + – + –
D
a VL –+ + – + – – + + – – + +– – + +– – + – –– + – + + + – + + – –
+ –+– –+ + – – +– – + + – –+ – – + + – + + – – + – + –
+ – – a VL –+ + + – + – – + + – – + +– – + +– – + – –– + – + + + – + + – –
a VF
a VF
E
FIGURE 4-10. Normal ventricular depolarization in the frontal plane as recorded by leads aVL and aVF. A. In the resting state, the sur ace is homogeneously charged so that the leads do not record any electrical potential. B. The f rst area to depolarize is the le t side o the ventricular septum. This results in orces heading away rom aVL (downward de ection on aVL recording) but toward the (+ ) region o aVF, such that an upward de ection is recorded by that lead. C, D. Depolarization continues; the orces rom the thickerwalled le t ventricle outweigh those o the right, such that the electrical vector swings le tward and posteriorly toward aVL (upward de ection) and away rom aVF. E. At the completion o depolarization, the sur ace is again homogeneously charged, and no urther electrical orces are recorded.
The Electrocardiogram 83 and aVL records rom the perspective o the le t lateral side. Recall that in the resting state, the sur aces o myocardial cells are homogeneously charged such that no electrical activity is detected by the external ECG leads and the machine records zero voltage. The initial portion o ventricular myocardium that is stimulated to depolarize with each cardiac cycle is the midportion o the interventricular septum, on the le t side. Because depolarization reverses the cellular charge, the sur ace o that region becomes negative with respect to the inside, and an electrical potential is generated (see Fig. 4-10B, arrow). The initial current is directed toward the right ventricle and in eriorly. Because the orce is directed away rom the (+ ) pole region o lead aVL, an initial downward de ection is recorded in that lead. At the same time, the electrical orce is directed toward the (+ ) pole region o lead aVF, causing an initial upward de ection to be recorded there. As the wave o depolarization spreads through the ventricular myocardium, the progression o net electrical vectors is depicted by the series o arrows in Figure 4-10. As the lateral walls o the ventricles are depolarized, the electrical orces o the thicker le t side outweigh those o the right. There ore, the arrow’s orientation is increasingly directed toward the le t ventricle (le tward and posteriorly). At the completion o depolarization, the myocytes are again homogeneously charged, no urther net electrical orce is generated, and the ECG voltage recording returns to baseline in both leads. Thus, in this example o depolarization in a normal heart, lead aVL inscribes an initial small Q wave ollowed by a tall R wave. Conversely, in lead aVF, there is an initial upward de ection (R wave) ollowed by a downward S wave. The sequence o ventricular depolarization can similarly be examined in the transverse (horizontal) plane o the body rom the six chest (precordial) leads (Fig. 4-11). Once again, recall that the f rst region to depolarize is the midportion o the interventricular septum on the le t side. Depolarization proceeds rom there toward the right ventricle (which is anterior to the le t ventricle), then toward the cardiac apex, and f nally around the lateral walls o both ventricles. Because the initial orces are directed anteriorly—that is, toward the (+ ) pole o V1—the initial de ection recorded by lead V1 is upward. These same initial orces are directed away rom V6 (which overlies the lateral wall o the le t ventricle), so an initial downward de ection is recorded there. As the wave o depolarization spreads, the electrical orces o the le t ventricle outweigh those o the right, and the vector swings posteriorly toward the bulk o the le t ventricular muscle. As the orces swing away rom lead V1, the de ection there becomes down wa rd, whereas it becomes more upright in lead V6. Leads V2 through V5 record intermediate steps in this process, such that the R wave becomes progressively taller rom lead V1 through lead V6 (see Fig. 4-11E), a pattern known as “R-wave progression.” Typically, the height o the R wave becomes greater than the depth o the S wave in lead V3 or V4; the lead in which this occurs is termed the “transition” lead.
INTERPRETATION OF THE ELECTROCARDIOGRAM From a technical standpoint, the ECG is recorded on a special grid divided into lines spaced 1 mm apart in both the horizontal and the vertical directions. Each f th line is made heavier to acilitate measurement. On the vertical axis, voltage is measured in millivolts (mV), and in the standard case, each 1-mm line separation represents 0.1 mV. The horizontal axis represents time. Because the standard recording speed is 25 mm/ sec, each 1 mm division represents 0.04 seconds and each heavy line (5 mm) represents 0.2 seconds (Fig. 4-12). Many cardiac disorders alter the ECG recording in a diagnostically use ul way, and it is important to interpret each tracing in a standard ashion to avoid missing subtle
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Chapter 4
V6
V6
LV
RV
A
V1
V1
B
V6
V6
V1
V1
C
D
V6 V5
LV
RV
V4 V3
V1
E
V2
FIGURE 4-11. Sequence of depolarization in the transverse ( horizontal) plane recorded by the chest ( precordial) leads. A–D. Depolarization begins at the le t side o the septum. The electrical vector then progresses posteriorly toward the thick-walled le t ventricle. Thus, V1, which is an anterior lead, records an initial upward def ection ollowed by a downward wave, whereas V6, a posterior lead, inscribes the opposite. E. In the normal pattern o the QRS rom V1 to V6, the R wave becomes progressively taller and the S wave less deep.
abnormalities. Here is a commonly followed sequence of analysis, followed by a description of each: 1. Check voltage calibration 2. Heart rhythm 3. Heart rate 4. Intervals (PR, QRS, QT) 5. Mean QRS axis 6. Abnormalities of the P wave 7. Abnormalities of the QRS (hypertrophy, bundle branch block, infarction) 8. Abnormalities of the ST segment and T wave
The Electrocardiogram 85 Pa pe r S pe e d: 25 mm/s e c
PR
QT
5 mm = 0.5 mV 1 mm = 0.1 mV
QRS 5 mm = 0.2 s e c (1 mm = 1 s ma ll box = 0.04 s e c)
FIGURE 4-12. Enlarged view of an ECG strip. A standard ECG is recorded at 25 mm/ sec, so that each 1 mm on the horizontal axis represents 0.04 seconds. Each 1 mm on the vertical axis represents 0.1 mV. Measurements in this example are as follows: PR interval (from the beginning of the P wave to the beginning of the QRS) = 4 small boxes = 0.16 seconds; QRS duration (from the beginning to the end of the QRS complex) = 1.75 small boxes = 0.07 seconds; and QT interval (from the beginning of the QRS to the end of QT the T wave) = 8 small boxes = 0.32 seconds. The corrected QT interval = . Because the R–R interval = 15 R− R 0.32 = 0.41 seconds . small boxes (0.6 seconds), the corrected QT interval = 0.6
Calibration ECG machines routinely inscribe a 1.0-mV vertical signal at the beginning or end o each 12-lead tracing to document the voltage calibration o the machine. In the normal case, each 1-mm vertical box on the ECG paper represents 0.1 mV, so that the calibration signal records a 10-mm de ection (e.g., as shown later in Fig. 4-28). However, in patients with markedly increased voltage o the QRS complex (e.g., some patients with le t ventricular hypertrophy or bundle branch blocks), the very large de ections do not f t on the standard tracing. To acilitate interpretation in such a case, the recording is o ten purposely made at hal the standard voltage (i.e., each 1-mm box = 0.2 mV), and this is indicated on the ECG tracing by a change in the height o the 1.0-mV calibration signal (at hal the standard voltage, the signal would be 5 mm tall). It is important to check the height o the calibration signal on each ECG to ensure that the voltage criteria used to def ne specif c abnormalities are applicable.
Heart Rhythm The normal cardiac rhythm, initiated by depolarization o the sinus node, is known as sinus rhythm. An ECG tracing shows sinus rhythm i the ollowing criteria are met: (1) each P wave is ollowed by a QRS; (2) each QRS is preceded by a P wave; (3) the P wave is upright in leads I, II, and III; and (4) the PR interval is greater than 0.12 seconds (three small boxes). I the heart rate in sinus rhythm is between 60 and 100 bpm, then normal sinus rhythm is present. I less than 60 bpm, the rhythm is sinus bradycardia; i greater than 100 bpm, the rhythm is sinus tachycardia. Other abnormal rhythms (termed arrhythmias or dysrhythmias) are described in Chapters 11 and 12.
86
Chapter 4
Heart Rate The standard ECG recording paper speed is 25 mm/ sec. There ore, Heart rate ( beats per minute ) =
25 mm/ sec × 60 sec/ min Number o mm betw e en beats
or more simply, as shown in Figure 4-13: Heart rate =
1, 500 Number o small boxes between two consecutive beat s
It is rarely necessary, however, to determine the exact heart rate, and a more rapid determination can be made with just a bit o memorization. Simply “count o ” the number o large boxes between two consecutive QRS complexes, using the sequence 300 — 150 — 100 — 75 — 60 — 50 which corresponds to the heart rate in beats per minute, as illustrated in Figure 4-13 (method 2). When the rhythm is irregular, these estimates cannot be easily applied, so the heart rate in such a case may be better approximated by counting the number o complexes during 6 seconds o the recording and multiplying that number by 10. ECG paper usually has time markers, spaced 3 seconds apart, printed at the top or bottom o the tracing that acilitates this measurement (see Fig. 4-13, method 3).
Intervals ( PR, QRS, QT) The PR interval, QRS interval, and QT interval are measured as demonstrated in Figure 4-12. For each o these, it is appropriate to take the measurement in the lead in which the interval is the longest in duration (the intervals can vary a bit in each lead). The PR interval is measured rom the onset o the P wave to the onset o the QRS. The QRS interval is measured rom the beginning to the end o the QRS complex. The QT interval is measured rom the beginning o the QRS to the end o the T wave. The normal ranges o the intervals are listed in Table 4-3, along with conditions associated with abnormal values. Because the QT interval varies with heart rate (the aster the heart rate, the shorter the QT), the corrected QT interval is determined by dividing the measured QT by the square root o the RR interval (see Fig. 4-12). When the heart rate is in the normal range (60 to 100 bpm), a rapid rule can be applied: i the QT interval is visually less than hal the interval between two consecutive QRS complexes, then the QT interval is within the normal range.
Mean QRS Axis The mean QRS axis represents the average o the instantaneous electrical orces generated during the sequence o ventricular depolarization as measured in the rontal plane. The normal value is between − 30 degrees and + 90 degrees (Fig. 4-14). A mean axis that is more negative than − 30 degrees implies left axis deviation, whereas an axis greater than + 90 degrees represents right axis deviation. The mean axis can be determined precisely by plotting the QRS complexes o di erent leads on the axial re erence diagram or the limb leads (see Fig. 4-5), but this is tedious and is rarely necessary. The ollowing rapid approach to axis determination generally provides su f cient accuracy. First, recall rom Figure 4-5 that each ECG lead has a (+ ) region and a (− ) region. Electrical activity directed toward the (+ ) hal results in an upward de ection, whereas activity toward the (− ) hal results in a downward de ection on the ECG recording o that
The Electrocardiogram 87 Me thod 1
Firs t, count the numbe r of s ma ll boxe s (1 mm e a ch) be twe e n two a dja ce nt QRS complexe s (i.e ., be twe e n 2 “be a ts ”). The n, s ince the s ta nda rd pa pe r s pe e d is 25 mm/s e c: He art Rate (be a ts /min)
Numbe r of mm be twe e n be a ts
1,500 numbe r of mm be twe e n be a ts
In this exa mple, the re a re 23 mm be twe e n the firs t 2 be a ts. 23 mm be twe e n be a ts
1,500 23
Me thod 2
65 bpm
The “count-off” me thod re quire s me morizing the s e que nce : 300—150—100—75—60—50 The n us e this s e que nce to count the numbe r of la rge boxe s be twe e n two cons e cutive be a ts : 300
S ta rt he re
100 150
60 75
50
The s e cond QRS fa lls be twe e n 75 a nd 60 bpm; the re fore , the he a rt ra te is a pproxima te ly midway be twe e n the m ~67 bpm. Knowing tha t the he a rt ra te is a pproxima te ly 60–70 bpm is ce rta inly clos e e nough. Me thod 3
ECG re cording pa pe r ofte n indica te s 3-s e c time ma rke rs a t the top or bottom of the tra cing: ma rke r
ma rke r 3 sec
FIGURE 4-13. Methods to calculate heart rate.
88
Chapter 4
TABLE 4-3 Electrocardiographic Intervals Interval
Normal
Decreased Interval
Increased Interval
PR
0.12–0.20 sec (3–5 small boxes) ≤ 0.10 sec (≤ 2.5 small boxes)
• Preexcitation syndrome • Junctional rhythm
• First-degree AV block
Corrected QTa ≤ 0.44 sec
• Hypercalcemia • Tachycardia
QRS
QT
a
• Bundle branch blocks • Ventricular ectopic beat • Toxic drug e ect (e.g., certain antiarrhythmic drugs—see Chapter 17) • Severe hyperkalemia • Hypocalcemia • Hypokalemia (↑ QU interval owing to ↑ U wave) • Hypomagnesemia • Myocardial ischemia • Congenital prolongation o QT • Toxic drug e ect
QT . R−R
Corrected QT =
lead. To determine whether the axis is normal or abnormal, examine the QRS complexes in limb leads I and II. As illustrated in Figure 4-15, i the QRS is primarily positive in both o these leads (i.e., the upward def ection is greater than the downward def ection in each o them), then the mean vector alls within the normal range and no urther calculation is necessary. However, i the QRS in either lead I or II is not primarily upward, then the axis is abn orma l, and the approximate axis should then be determined by the more precise method
Le ft a
xis de vi a
–150° aVR
–30° aVL
+180°
Le ft axis de viatio n • Infe rior wa ll myoca rdia l infa rction • Le ft a nte rior fa s cicula r block • Le ft ve ntricula r hype rtrophy (s ome time s )
I 0°
+30°
+150°
R
n
–60°
–120°
ti
o
–90°
ig h
III +120° ta
xis
de v
aVF +90°
Rig ht axis de viatio n • Right ve ntricula r hype rtrophy • Acute right he a rt s tra in (e.g., massive pulmonary embolism) • Le ft pos te rior fa s cicula r block
II +60°
ia tio n
FIGURE 4-14. A normal mean QRS axis falls within the shaded area ( between − 30 degrees and + 90 degrees) . A mean axis more negative than − 30 degrees is termed left axis deviation, whereas an axis more positive than + 90 degrees is right axis deviation. The f gure shows common conditions that result in axis deviation.
The Electrocardiogram 89 S imila rly, if the QRS is pre domina ntly upwa rd in limb le a d II, the n the me a n a xis fa lls within the “+” ha lf of le a d II, s hown a s the re d ha lf he re .
If the QRS complex is ma inly upwa rd (pos itive ) in limb le a d I, the n the me a n a xis fa lls within the “+” re gion of tha t le a d, s hown a s the blue ha lf of the circle be low. –90
–
+ –30
– + I 0
+150 II +60
+90
If the QRS is pre domina ntly upright in bo th le a ds I a nd II, the n the me a n a xis mus t fa ll within the ir common “+” re gions : be twe e n –30 a nd +90.
–30
Norma l Axis
+90
FIGURE 4-15. The mean axis is within the normal range if the QRS complex is predominantly upright in limb leads I and II.
described in the ollowing paragraphs. Please be aware that some ECG teaching resources recommend examining leads I and aVF, rather than leads I and II, to determine whether the mean axis alls in the normal range. However, using leads I and aVF or this purpose would erroneously classi y a mean axis between 0 degrees and − 30 degrees as being abnormal, as aVF would record a primarily downward de ection in that case. Examining leads I and II instead avoids that error. In order to determine the mean axis with greater precision when necessary, f rst consider the special example demonstrated in Figure 4-16. The sequence o a ventricular depolarization is represented in this f gure by vectors a through e, along with the corresponding de ections on the ECG recording o lead I. The initial de ection (representing le t septal depolarization) points to the patient’s right side. Because it is directed completely away rom the (+ ) pole o lead I, a strong downward de ection is recorded by the lead. As depolarization continues, the arrow swings downward and to the le t, resulting in less negative de ections in lead I. A ter arrow c, the electrical vector swings into the positive region o lead I, so that upward de ections are recorded.
90
Chapter 4
In this special example, in which electrical orces begin exactly opposite lead I’s (+ ) electrode and termie d nate when pointed directly at that electrode, note that Le ad I e a (–) (+) the mean electrical vector points straight downward c b d (in the direction o arrow c), perpendicular to the lead b c a I axis. Also note the conf guration o the inscribed QRS complex in lead I. There is a downward de ection, ollowed by an upward de ection o equal magnitude (when the upward and downward de ections o a Me an QRS are o equal magnitude, it is termed an isoelecaxis tric complex). Thus, when an ECG limb lead inscribes (+) an isoelectric QRS complex, it indicates that the mean Le ad aVF electrical axis of the ventricles is perpendicular to that particular lead. FIGURE 4-16. Sequence of ventricular There ore, an easy way to determine the mean QRS depolarization when the mean axis is + 90 degrees. axis is to glance at the six limb lead recordings and Because the mean axis is perpendicular to limb lead observe which one has the most isoelectric-appearing I, an isoelectric QRS complex (height o upward complex: the mean axis is simply perpendicular to it. def ection = height o downward def ection) is One step remains. When the mean axis is perpendicular recorded by that lead (see text or details). to a lead, it could be perpendicular in either a clockwise or a counterclockwise direction. In the example o Figure 4-16, the isoelectric complex appears in lead I, such that the mean vector could be at + 90 degrees or it could be at − 90 degrees, because both are perpendicular. To determine which o these is correct requires inspecting the recording o the ECG lead that is perpendicular to the one inscribing the isoelectric complex (and is there ore parallel to the mean axis). I the QRS is predominantly upright in that perpendicular lead, then the mean vector points toward the (+ ) pole o that lead. I it is predominantly negative, then it points away rom the lead’s (+ ) pole. In the example, the isoelectric complex appears in lead I; there ore, the next step is to inspect the perpendicular lead, which is aVF (see Fig. 4-5 i this relationship is not clear). Because the QRS complex in aVF is primarily upward, the mean axis points toward its (+ ) pole, which is in act located at + 90 degrees. To summarize, the mean QRS axis is calculated as ollows: 1. Inspect limb leads I and II. I the QRS is primarily upward in both, then the axis is normal and you are done. I not, then proceed to the next step. 2. Inspect the six limb leads and determine which one contains the QRS that is most isoelectric. The mean axis is perpendicular to that lead. 3. Inspect the lead that is perpendicular to the lead containing the isoelectric complex. I the QRS in that perpendicular lead is primarily upward, then the mean axis points to the (+ ) pole o that lead. I primarily negative, then the mean QRS points to the (− ) pole o that lead. Conditions that result in le t or right axis deviation are listed in Figure 4-14. In addition, the vertical position o the heart in many normal children and adolescents may result in a mean axis that is slightly rightward (greater than + 90 degrees). In some patients, isoelectric complexes are inscribed in all the limb leads. That situation arises when the heart is tilted, so that the mean QRS points straight orward or back rom the rontal plane, as it may be in patients with chronic obstructive lung disease; in such a case, the mean axis is said to be indeterminate.
Abnormalities of the P Wave The P wave represents depolarization o the right atrium ollowed quickly by the depolarization o the le t atrium; the two components are nearly superimposed on one another (Fig. 4-17). The P wave is usually best visualized in lead II, the lead that is most parallel to
The Electrocardiogram 91 Le ad II
Le ad V1
RA No rmal
LA Combine d
FIGURE 4-17. The P wave represents superimposition of right atrial ( RA) and left atrial ( LA) depolarization. RA depolarization occurs slightly earlier than LA depolarization, because o the proximity o the RA to the sinoatrial node. In RA enlargement, the initial component o the P wave is prominent (> 2.5 mm tall) in lead II. In LA enlargement, there is a large terminal downward def ection in lead V1 (> 1 mm wide and > 1 mm deep).
RA e nlarg e me nt (P he ight > 2.5 mm in le a d II)
LA e nlarg e me nt (Ne ga tive P in V1 > 1 mm wide a nd > 1 mm de e p)
RA
LA
RA
LA RA
LA
RA
LA
the ow o electrical current through the atria rom the sinoatrial to the AV node. When the right atrium is enlarged, the initial component o the P wave is larger than normal (the P is taller than 2.5 mm in lead II). Left atrial enlargement is best observed in lead V1. Normally, V1 inscribes a P wave with an initial positive de ection re ecting right atrial depolarization (directed anteriorly), ollowed by a negative de ection, owing to the le t atrial orces oriented posteriorly (see Fig. 1-2 or anatomic relationships). Le t atrial enlargement is there ore mani ested by a greater-thannormal negative de ection (at least 1 mm wide and 1 mm deep) in lead V1 (see Fig. 4-17).
Abnormalities of the QRS Complex Ventricular Hypertrophy Hypertrophy o the le t or right ventricle causes the a ected chamber to generate greaterthan-normal electrical activity. Ordinarily, the thicker-walled le t ventricle produces orces that are more prominent than those o the right. However, in right ventricular hypertrophy (RVH), the augmented right-sided orces may outweigh those o the le t. There ore, chest leads V1 and V2, which overlie the right ventricle, record greater-than-normal upward de ections: the R wave becomes taller than the S wave in those leads, the opposite o the normal situation (Fig. 4-18). In addition, the increased right ventricular mass shi ts the mean axis o the heart, resulting in right axis deviation (mean axis greater than + 90 degrees). In left ventricular hypertrophy, greater-than-normal orces are generated by that chamber, which simply exaggerates the normal situation. Leads that directly overlie the le t ventricle (chest leads V5 and V6 and limb leads I and aVL) show taller-than-normal R waves. Leads on the other side o the heart (V1 and V2) demonstrate the opposite: deeper-than-normal S waves. Many di erent criteria are used or the diagnosis o le t ventricular hypertrophy by ECG. Three o the most help ul criteria are listed in Figure 4-18.
Bundle Branch Blocks Interruption o conduction through the right or le t bundle branches may develop rom ischemic or degenerative damage. As a result, the a ected ventricle does not depolarize in the normal sequence. Rather than rapid uni orm stimulation by the Purkinje f bers, the cells o that ventricle must rely on relatively slow myocyte-to-myocyte spread o electrical
92
Chapter 4 V6 RIGHT VENTRICULAR HYP ERTROP HY
LV
RV
• R > S in le a d V1 • Right a xis devia tion
1 4
2 3 V1
A
V6 3
LEFT VENTRICULAR HYP ERTROP HY • S in V1 p lus R in V5 or V6 ≥ 35 mm or • R in a VL > 11 mm or • R in le a d I > 15 mm
1 2
V1
B FIGURE 4-18. Ventricular hypertrophy. The arrows indicate the sequence of average electrical forces during ventricular depolarization. A. Right ventricular (RV) hypertrophy. The RV forces outweigh those of the left, resulting in tall R waves in leads V1 and V2 and a deep S wave in lead V6 (compare to normal QRS complexes in Fig. 4-11E). B. Left ventricular (LV) hypertrophy exaggerates the normal pattern of depolarization, with greater-than-normal forces directed toward the LV, resulting in a tall R wave in V6 and a deep S wave in lead V1.
activity traveling rom the una ected ventricle. This delayed process prolongs depolarization and widens the QRS complex. A normal QRS duration is less than or equal to 0.10 seconds (≤ 2.5 small boxes). When a bundle branch block widens the QRS duration to 0.10 to 0.12 seconds (2.5 to 3.0 small boxes), an in complete bundle branch block is present. I the QRS duration is greater than 0.12 seconds (3.0 small boxes), complete bundle branch block is identif ed. In right bundle branch block (RBBB) (Fig. 4-19; see also Fig. 4-29), normal depolarization o the right ventricle is interrupted. In this case, initial depolarization o the ventricular septum (which is stimulated by a branch o the le t bundle) is una ected so that the normal small R wave in lead V1 and small Q wave in lead V6 are recorded. As the wave o depolarization spreads down the septum and into the le t ventricular ree wall, the sequence o depolarization is indistinguishable rom normal, because le t ventricular orces normally outweigh those o the right. However, by the time the le t ventricle has almost ully depolarized, slow cell-to-cell spread has f nally reached the “blocked” right ventricle and depolarization o that chamber begins, unopposed by le t ventricular activity (because that chamber has nearly ully depolarized). This prolonged depolarization process widens the QRS complex and produces a late depolarization current in the direction o the anteriorly situated right ventricle. Since the terminal portion o the QRS complex in RBBB represents these right ventricular orces acting
The Electrocardiogram 93 Rig ht Bundle Branc h Blo ck
A
V6
Le ft Bundle Branc h Blo ck
B
V6
LV
1 RV
V1
V1
V6
V6
2
V1
V1
V6
V6
3
V1
• Wide ne d QRS • RS R' in V1 (ra bbit e a rs ) • Promine nt S in V6
V1
• Wide ne d QRS • Broa d, notche d R in V6 • Abs e nt R a nd promine nt S in V1
FIGURE 4-19. Bundle branch blocks. Schematic view o the ventricles in the horizontal plane showing that interruption o conduction through the right or le t bundles results in delayed, slowed activation o the respective ventricle and widening o the QRS complex. The blue color shows progressive depolarization o the ventricles, and the red arrows show the sequence o electrical vectors that result. A. In right bundle branch block, normal initial activation o the septum (1) is ollowed by depolarization o the le t ventricle (2). Slow cell-to-cell spread activates the right ventricle (RV) after the le t ventricle (LV) has nearly ully depolarized (3), so that the late orces generated by the RV are unopposed. There ore, V1 records an abnormal terminal upward de ection (R′), and V6 records an abnormal, terminal deep S wave, as shown in panel 3. B. In left bundle branch block, the initial septal depolarization is blocked, such that the f rst orces are oriented rom right to le t. Thus, the normal initial R wave in V1 and Q wave in V6 are absent (1). A ter the RV depolarizes (2), late, slow activation o the LV results in a terminal upward de ection in V6 and downward de ection in V1 (3).
94
Chapter 4 alone, the ECG records an abnormal terminal upward de ection (known as an R′ wave) over the right ventricle in lead V1 and a downward de ection (S wave) in V6 on the opposite side o the heart. The appearance o the QRS complex in lead V1 in RBBB (upward R, downward S, then upward R′) is o ten described as having the appearance o “rabbit ears.” Left bundle branch block (LBBB) produces even more prominent QRS abnormalities. In this situation, normal initial depolarization o the le t septum does not occur; rather, the right side o the ventricular septum is f rst to depolarize, through branches o the right bundle. Thus, the initial orces o depolarization are directed toward the le t ventricle instead o the right (see Fig. 4-19B; see also Fig. 4-30). There ore, an initial downward de ection is recorded in V1, and the normal small Q wave in V6 is absent. Only a ter depolarization o the right ventricle does slow cell-to-cell spread reach the le t ventricular myocytes. These slowly conducted orces inscribe a widened QRS complex with abnormal terminally upward de ections in the leads overlying the le t ventricle (e.g., V5 and V6), as shown in Figure 4-19B.
Fascicular Blocks Recall rom Chapter 1 that the le t bundle branch subdivides into two main divisions, termed ascicles: the le t anterior ascicle and the le t posterior ascicle. Although LBBB implies that conduction is blocked in the entire le t bundle branch, impairment can also occur in just one o the two ascicles, resulting in le t anterior or le t posterior ascicular blocks (also termed hemiblocks). The main signif cance o ascicular blocks in ECG interpretation is that they can markedly alter the mean QRS axis. Anatomically, the anterior ascicle o the le t bundle runs along the ront o the le t ventricle toward the anterior papillary muscle (which is located in the anterior and superior portion o the chamber), whereas the posterior ascicle travels to the posterior papillary muscle (which is located in the posterior, in erior, and medial aspect o the le t ventricle). Under normal conditions, conduction via the le t anterior and le t posterior ascicles proceeds simultaneously, such that electrical activation o the le t ventricle is uni orm, spreading outward rom the bases o the two papillary muscles. However, i conduction is blocked in one o the two divisions, then initial LV depolarization arises exclusively rom the una ected ascicle (Fig. 4-20). In the case o left anterior fascicular block (LAFB), le t ventricular activation begins via the le t posterior ascicle alone, at the posterior papillary muscle, and then spreads to the rest o the ventricle. Because the le t posterior ascicle f rst activates the posterior, in erior, medial region o the le t ventricle, the initial impulses are directed downward (i.e., toward the eet) and toward the patient’s right side (see Fig. 4-20). This results in a positive de ection (initial small R wave) in the in erior leads (leads II, III, and aVF) and a negative de ection (small Q wave) in the le t lateral leads, I and aVL. As depolarization then spreads upward and to the le t, toward the “blocked” anterior, superior, and lateral regions o the le t ventricle, a positive de ection (R wave) is inscribed in leads I and aVL, while a negative de ection (S wave) develops in the in erior leads. The predominance o these le tward orces, resulting rom the abnormal activation o the anterior superior le t ventricular wall, results in left axis deviation (generally more negative than − 45 degrees). A complete 12-lead ECG demonstrating the pattern o LAFB is shown later (see Fig. 4-34). Left posterior fascicular block (LPFB) is less common than LAFB. In LPFB, ventricular activation begins via the le t anterior ascicle alone at the base o the anterior papillary muscle (see Fig. 4-20). As that anterosuperior le t ventricular region depolarizes, the initial orces are directed upward and to the patient’s le t (creating a positive R wave in leads I and aVL and a negative Q wave in the in erior leads). As the impulse then spreads downward and to the right toward the initially blocked region, an S wave is inscribed in leads I and aVL, while an R wave is recorded in leads II, III, and aVF. Because the bulk o these delayed orces head toward the patient’s right side, right axis deviation o the QRS mean axis occurs (see Fig. 4-36).
MV
A LV P
Le ft Ante rio r Fas c ic ular Blo ck
Le ft Po s te rio r Fas c ic ular Blo ck
a VL
a VL
X 1
X a VF
a VF a VL
a VL
2
a VF
a VF a VL
a VL
3
a VF • Le ft a xis devia tion • S ma ll Q in le a ds a VL a nd I • S ma ll R in infe rior le a ds (II, III, a VF)
a VF • Right a xis devia tion • S ma ll R in le a ds a VL a nd I • S ma ll Q in infe rior le a ds (II, III, a VF)
FIGURE 4-20. Le t anterior and le t posterior ascicular blocks and their patterns in the ECG limb leads. The schematic at the top o the f gure shows the le t ventricle (LV) in the rontal plane. The mitral valve (MV) chordae tendineae insert into the anterior (A) and posterior (P) papillary muscles, which are important landmarks: the anterior ascicle o the le t bundle branch courses toward the anterior papillary muscle, whereas the posterior ascicle travels to the posterior papillary muscle (the ascicles are not shown). Notice that the anterior papillary muscle is superior to the posterior papillary muscle. Le t side o the f gure: In le t anterior ascicular block, activation begins solely in the region o the posterior papillary muscle (1) because initial conduction to the anterior papillary muscle is blocked (denoted by the X). As a result, the initial orces o depolarization are directed downward toward the eet, producing an initial positive de ection (R wave) in lead aVF and a negative de ection (Q wave) in lead aVL. As the wave o depolarization spreads toward the le t side and superiorly, aVF begins to register a negative de ection and aVL starts to record a positive de ection (2). Panel 3 shows the complete QRS complexes at the end o depolarization. Right side o the f gure: In le t posterior ascicular block (denoted by the X), LV activation begins solely in the region o the anterior papillary muscle (1). Thus, the initial orces are directed upward and toward the patient’s le t side, producing an initial R wave in aVL and a Q wave in aVF. Panels 2 and 3 show how the spread o depolarization travels in the direction opposite that o LAFB.
96
Chapter 4 In contrast to RBBBs and LBBBs, LAFB and LPFB do not result in signif cant widening o the QRS because rapidly conducting Purkinje f bers bridge the territories served by the anterior and posterior ascicles. There ore, although the sequence o conduction is altered, the total time required or depolarization is usually only slightly prolonged. Also note that although LBBBs and RBBBs are most easily recognized by analyzing the patterns o depolarization in the precordial (chest) leads, in the case o LAFB and LPFB, it is the recordings in the limb leads (as in Fig. 4-20) that are most help ul.
Pathologic Q waves in Myocardial Infarction
A
Norma l Q Wave s
B
Pa thologic Q Wave s
As you will learn in Chapter 7, sudden complete occlusion o a FIGURE 4-21. Normal coronary artery typically results in a syndrome known as acute versus pathologic Q waves. ST-segment elevation myocardial infarction (STEMI). When this Compared with the small occurs, a sequence o abnormalities o the ST segment and T wave Q waves generated during evolves over a period o hours, as described in the next section. normal depolarization (A, blue arrow), pathologic Q Unless reper usion o the occluded artery is quickly achieved, irrewaves are more prominent versible necrosis o the heart muscle served by that vessel ensues with a width ≥ 1 mm (1 small and is marked by the ormation o pathologic Q waves as part o box) or depth greater than the electrocardiographic QRS complex. 25% o the height o the QRS Recall that it is normal or small initial Q waves to appear in complex (B, green arrow). some o the ECG leads. For example, initial septal depolarization routinely inscribes small Q waves in leads V6 and aVL. Such physiologic Q waves are o short duration (≤ 0.04 seconds or 1 small box) and o low magnitude (less than 25% o the QRS total height). In distinction, pathologic Q waves are more prominent (Fig. 4-21; also see Fig. 4-29), typically having a width greater than or equal to 1 small box in duration or a depth greater than 25% o the total height o the QRS. The ECG lead groupings in which pathologic Q waves appear re ect the anatomic site o the in arction (Table 4-4; also see Fig. 4-23). Pathologic Q waves develop in the leads overlying in arcted tissue because necrotic muscle does not generate electrical orces (Fig. 4-22). This results in an imbalance whereby electrical orces generated by other regions o healthy myocardium become abnormally unopposed. Thus, the ECG electrode over the in arcted region detects electrical currents rom the healthy tissue on opposite regions o the ventricle, which are directed away rom the in arct and the recording electrode, thus inscribing the downward de ection. Q waves are permanent evidence o an ST-elevation type o myocardial in arction; only rarely do they disappear over time. Notice in Table 4-4 that in the case o a posterior wall myocardial in arction (see Fig. 4-23A), it is not pathologic Q waves that are evident on the ECG. Because standard electrodes are
TABLE 4-4 Localization of Myocardial Infarction Anatomic Site In erior Anteroseptal Anteroapical Anterolateral Posterior a
Leads with Abnormal ECG Complexes a
Coronary Artery Most Often Responsible
II, III, aVF V1–V2 V3–V4 V5–V6, I, aVL V1–V2 (tall R wave, not Q wave)
RCA LAD LAD (distal) CFX RCA
Pathologic Q waves in all o leads V1–V6 implies an “extensive anterior MI” usually associated with a proximal le t coronary artery occlusion. CFX, le t circumf ex coronary artery; LAD, le t anterior descending coronary artery; RCA, right coronary artery.
The Electrocardiogram 97 not typically placed on the patient’s back overlying the posterior wall, other leads must be relied on to indirectly identify the presence of such an infarction. Chest leads V1 and V2, which are directly opposite the posterior wall, record the inverse of what leads placed on the back would demonstrate. Therefore, taller-than-normal R waves in leads V1 and V2 are the equivalent of pathologic Q waves in the diagnosis of a posterior wall MI. It may be recalled that RVH also produces tall R waves in leads V1 and V2. These conditions can be distinguished, however, as RVH causes right axis deviation, which is not a feature of posterior wall MI. It is important to note that if a Q wave appears in only a single ECG lead, it is not diagnostic of an infarction. True pathologic Q waves should appear in the groupings listed in Table 4-4 and Figure 4-23. For example, if a pathologic Q wave is present in lead III but not in II or aVF, it likely does not indicate an infarction. Also, Q waves are disregarded in lead aVR because electrical forces are normally directed away from the right arm. Finally, in the presence of LBBB, Q waves are usually not helpful in the diagnosis of MI because of the markedly abnormal pattern of depolarization in that condition.
a VL LV RV
1
a VL
2
a VL
3
ST-Segment and T-Wave Abnormalities Transient Myocardial Ischemia Among the most important abnormalities of the ST segments and T waves are those related to coronary artery disease. Because ventricular repolarization is very sensitive to myocardial perfusion, reversible deviations of the ST segments and T waves (usually depression of the ST segment and/ or inversion of the T wave) are common during transient episodes of myocardial ischemia, as will be explained in Chapter 6.
Acute ST-Segment Elevation MI As described in the previous section, pathologic Q waves are associated with one major type of myocardial infarction (STEMI) but do not differentiate between an acute event and an MI that occurred weeks or years earlier. However, an acute STEMI results in a temporal sequence of ST and T-wave abnormalities that permits this distinction (Fig. 4-24). The initial abnormality is elevation of the ST segment, often with a peaked
a VL
4 Pa thologic Q wave
FIGURE 4-22. Sequence of depolarization recorded by lead aVL, overlying a lateral wall infarction ( dark shaded region) . A pathologic Q wave is recorded because the necrotic muscle does not generate electrical orces; rather, at the time when the lateral wall should be depolarizing (panel 3), the activation o the healthy muscle on the opposite side o the heart is unopposed, such that net orces are directed away rom aVL. The terminal R wave recorded by aVL ref ects depolarization o the remaining viable myocardium beyond the in arct.
98
Chapter 4
Ante rola te ra l (V5 –V6 ,I, a VL)
Ante ros e pta l (V1 –V2 )
Ante ros e pta l (V1 –V2 )
P os te rior (Ta ll R in V1 –V2 ) Infe rior (II, III, a VF)
Ante roa pica l (V3 –V4 )
A Ante ros e pta l
Ante roa pica l
I
aVR
V1
V4
I
aVR
V1
V4
II
aVL
V2
V5
II
aVL
V2
V5
III
aVF
V3
V6
III
aVF
V3
V6
Ante rola te ra l
Infe rior
I
aVR
V1
V4
I
aVR
V1
V4
II
aVL
V2
V5
II
aVL
V2
V5
III
aVF
V3
V6
III
aVF
V3
V6
B FIGURE 4-23. Relationship between ECG leads and cardiac anatomic regions. A. The lead groupings listed in parentheses represent each region. B. Miniaturized 12-lead ECG schematic drawings showing the standard orientation of printed samples from each lead. The major anatomic groupings are colored and labeled in each drawing. While the presence of pathologic Q waves in leads V1 and V2 are indicative of anteroseptal infarction, be aware that tall initial R waves in those leads can indicate a posterior wall infarction (not shown in part B), as described in the text.
appearance o the T wave. At this early stage, myocardial cells are still viable and Q waves have not yet developed. In patients who achieve success ul acute coronary reper usion (by f brinolytic therapy or percutaneous coronary intervention, as described in Chapter 7), the ST segments return to baseline and the sequence o changes described in the next paragraph do not occur. In patients who do not achieve success ul acute reper usion, within several hours myocyte death leads to loss o the amplitude o the R wave and pathologic Q waves begin to be inscribed by the ECG leads positioned over the in arction territory. During the f rst 1 to 2 days ollowing in arction, the ST segments remain elevated, the T wave inverts, and the Q wave deepens (see Fig. 4-24). Several days later, the ST-segment elevation returns to baseline, but the T waves remain inverted. Weeks or months ollowing the in arct, the ST segment and T waves have usually returned to normal, but the pathologic Q waves persist, a permanent
The Electrocardiogram 99 Norma l
Acute
• ST e leva tion
Hours
Day 1–2
Days la te r
We e ks la te r
• ST e leva tion • T wave inve rs ion • ST norma lize s • ST & T norma l • R Wave • Q wave de e pe r • T wave inve rte d • Q wave pe rs is ts • Q wave be gins
FIGURE 4-24. ECG evolution during acute ST-elevation myocardial infarction. However, as described in Chapter 7, if successful early reperfusion of the coronary occlusion is achieved, the initially elevated ST segment returns to baseline without subsequent T-wave inversion or Q-wave development.
marker o the MI. I the ST segment remains elevated several weeks later, it is likely that a bulging f brotic scar (ventricular aneurysm) has developed at the site o in arction. These evolutionary changes o the QRS, ST, and T waves are recorded by the leads overlying the zone o in arction (see Table 4-4 and Fig. 4-23). Typically, reciprocal changes are observed in leads opposite that site. For example, in acute anteroseptal MI, ST-segment elevation is expected in chest leads V1 and V2; simultaneously, however, reciprocal changes (ST depression) may be inscribed by the leads overlying the opposite (in erior) region, namely in leads II, III, and aVF. An example o reciprocal ST changes is shown later in Figure 4-32. The mechanism by which ST-segment deviations develop during acute MI has not been established with certainty. It is believed, however, that the abnormality results rom injured myocardial cells immediately adjacent to the in arct zone producing abnormal diastolic or systolic currents. One explanation, the diastolic current theory, contends that these damaged cells are capable o depolarization but are abnormally “leaky,” allowing ionic ow that prevents the cells rom ully repolarizing (Fig. 4-25). Because the sur ace o such partially depolarized cells in the resting state would be relatively negatively charged compared with normal ully repolarized zones, an electrical current is generated between the two regions. This current is directed away rom the more negatively charged ischemic area, causing the baseline o the ECG leads overlying that region to shift down ward. Because the ECG machine records only relative position, rather than absolute voltages, the downward deviation o the baseline is not apparent. Following ventricular depolarization (indicated by the QRS complex), a ter all the myocardial cells have ully depolarized (including those o the injured zone), the net electrical potential surrounding the heart is true zero. However, compared with the abnormally displaced downward baseline, the ST segment appears elevated (see Fig. 4-25). As the myocytes then repolarize, the injured cells return to the abnormal state o diastolic ion leak, and the ECG again inscribes the abnormally depressed baseline. Thus, ST elevation in acute STEMI may in part re ect an abnormal shi t o the recording baseline. The systolic current theory o ST segment shi ts contends that in addition to altering the resting membrane potential, ischemic injury shortens the action potential duration o a ected cells. As a result, the ischemic cells repolarize aster than neighboring normal myocytes. Since the positive sur ace charge o the damaged myocytes is restored earlier than that o the normal cells, a voltage gradient develops between the two zones, creating an electrical current directed toward the ischemic area. This gradient occurs during the ST interval o the ECG, resulting in ST elevation in the leads overlying the ischemic region (Fig. 4-26).
Acute Non–ST-Segment Elevation MI As described in Chapter 7, not all acute myocardial in arctions result in ST-segment elevation and potential Q-wave development. A more limited type o in arction, known as acute non– ST-elevation MI, typically results rom an acute partially occlusive coronary thrombus. In such
100
Chapter 4 ST-s e g me nt Elevatio n MI
Norma l ba s e line
Injure d s e gme nt is pa rtia lly de pola rize d prio r to s timula tion
Re cording e le ctrode
He a rt fully de pola rize d
Ba s e line s hifte d downwa rd
No n–ST-s e g me nt Elevatio n MI
Ba s e line s hifte d upwa rd
Injure d s e gme nt is pa rtia lly de pola rize d prio r to s timula tion
Re cording e le ctrode
He a rt fully de pola rize d
Norma l ba s e line
FIGURE 4-25. ST deviations in acute MI: diastolic injury current. Top, ionic leak results in partial depolarization of injured myocardium in diastole, prior to electrical stimulation, which produces forces heading away from that site and shifts the ECG baseline downward. This is not noticeable on the ECG because only relative, not absolute, voltages are recorded. Following stimulation, when the entire myocardium has fully depolarized, the voltage is true zero but gives the appearance of ST elevation compared with the abnormally depressed baseline. Bottom, in non–ST-segment elevation MI, the process is similar, but the ionic leak typically arises from the subendocardial tissue. As a result, the partial depolarization before stimulation results in electrical forces directed toward the recording electrode; hence, the baseline is shifted upward. When fully depolarized, the voltage is true zero, but the ST segment appears depressed compared with the shifted baseline.
Is che mic –90 mV
A
Norma l Is c he mic c e lls re p ola rize more ra p id ly tha n norma l
+
B
+
+
ST e leva tion
Re cording e le ctrode
FIGURE 4-26. ST deviation in acute ST-segment elevation MI: systolic injury current. A. Compared with normal myocytes (solid line), ischemic myocytes (dashed line) display a reduced resting membrane potential and repolarize more rapidly. B. More rapid repolarization causes the surface of the ischemic zone to be relatively positively charged at the time the ST segment is inscribed. The associated electrical current (arrows) is directed toward the recording electrode overlying that site, so that the ST segment is abnormally elevated.
The Electrocardiogram 101
Norma l
Digoxin the ra py
• ST “s coope d” de pre s s ion • Mild P R prolonga tion
Hype rka le mia
• Ta ll “pe a ke d” T wave
S eve re hype rka le mia
• Fla tte ne d P • Wide ne d QRS
Hypoka le mia
FIGURE 4-27. Conditions that alter repolarization of myocytes and therefore result in ST-segment and T-wave abnormalities.
T U
• ST de pre s s ion, fla tte ne d T • Promine nt U wave
Hype rca lce mia
• S horte ne d QT inte rva l
Hypoca lce mia
• Prolonge d QT inte rva l
in arctions, it is ST-segment depression and/ or T-wave inversion, rather than ST elevation, that appears in the leads overlying the in arcting myocardium. The extent o myocardial damage with this orm o in arction is less than in STEMI, o ten involving only the subendocardial layers o the myocardium. As a result, pathologic Q waves do not develop, because the remaining viable cells are able to generate some electrical activity. In non–ST-elevation MI, the diastolic current theory maintains that diastolic ionic leak o injured cells adjacent to the subendocardial in arct zone generates electrical orces directed rom the inner endocardium to the outer epicardium and there ore toward the overlying ECG electrode. Thus, the baseline o the ECG is shi ted upward (see Fig. 4-25, bottom). Following ull cardiac depolarization, the electrical potential o the heart returns to true zero but, relative to the abnormal baseline, gives the appearance o ST-segment depression. In addition to myocardial ischemia and in arction, there are several other causes o ST-segment and T-wave abnormalities that result rom alterations in myocyte repolarization. The most commonly encountered o these are illustrated in Figure 4-27.
SUMMARY • The electrocardiogram (ECG) depicts the sequence o electrical impulses through the heart. • A complete ECG (12-lead ECG) is produced by recording electrical activity between the electrodes in specif c patterns, which results in six re erence axes in the body’s rontal plane (limb leads) plus six in the transverse plane (chest leads). • Each heartbeat is represented on the ECG by three major de ections that record the sequence o electrical propagation: (1) the P wave represents depolarization o the atria,
102
Chapter 4 (2) the QRS complex records depolarization o the ventricular muscle cells, and (3) the T wave indicates repolarization o the ventricular cells. • Many cardiac disorders alter the ECG recording in a diagnostically use ul way, and it is important to interpret each tracing in a consistent ashion to avoid missing subtle abnormalities: (1) check voltage calibration, (2) heart rhythm, (3) heart rate, (4) intervals (PR, QRS, QT), (5) mean QRS axis, (6) abnormalities o the P wave, (7) abnormalities o the QRS (hypertrophy, bundle branch block, pathologic Q waves), and (8) abnormalities o the ST segment and T wave (Table 4-5). • Examples o normal and abnormal ECGs are presented in Figures 4-28 to 4-36; to practice interpreting clinical tracings in greater depth, the reader should re er to any o the complete ECG texts listed under “Additional Reading.” • Disturbances o the cardiac rhythm are identif ed by electrocardiography and are described in Chapters 11 and 12.
TABLE 4-5 Summary of Sequence of ECG Interpretation 1. Calibration • Check 1.0-mV vertical box inscription (normal standard = 10 mm) 2. Rhythm • Sinus rhythm is present if • Each P wave is followed by a QRS complex • Each QRS is preceded by a P wave • P wave is upright in leads I, II, and III • PR interval is > 0.12 sec (3 small boxes) • If these criteria are not met, determine type of arrhythmia (see Chapter 12) 3. Heart rate • Use one of three methods: • 1,500/ (number of mm between beats) • Count-off method: 300—150—100—75—60—50 • Number of beats in 6 sec × 10 • Normal rate = 60–100 bpm (bradycardia < 60, tachycardia > 100) 4. Intervals • Normal PR = 0.12–0.20 sec (3–5 small boxes) • Normal QRS ≤ 0.10 sec (≤ 2.5 small boxes) • Normal QT ≤ half the RR interval, if heart rate is normal 5. Mean QRS axis • Normal if QRS is primarily upright in leads I and II (+ 90 degrees to − 30 degrees) • Otherwise, determine axis by isoelectric/ perpendicular method 6. P-wave abnormalities • Inspect P in leads II and V1 for left and right atrial enlargement 7. QRS wave abnormalities • Inspect for left and right ventricular hypertrophy • Inspect for bundle branch blocks • Inspect for pathologic Q waves: What anatomic distribution? 8. ST-segment or T-wave abnormalities • Inspect for ST elevations: • ST-segment elevation MI • Pericarditis (see Chapter 14) • Inspect for ST depressions or T-wave inversions: • Myocardial ischemia or non–ST-elevation MI • Typically accompany ventricular hypertrophy or bundle branch blocks • Metabolic or chemical abnormalities (see Fig. 4-27) 9. Compare with patient’s previous ECGs
.
E
R
U
bpm
G
0
I
F
7
2
nt
-
I
4
:
2
s
l
1
a
v
.
r
8
e
l
,
G
C
15;
E
0.
d
a
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e
P
-
(
l
)
.
08;
a
0.
m
r
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110 Chapter 4
The Electrocardiogram 111
I
a VR
V1
V4
II
a VL
V2
V5
III
a VF
V3
V6
FIGURE 4-36. 12-lead ECG ( abnormal) . Rhythm: normal sinus. Rate: 62 bpm. Intervals: PR, 0.14; QRS, 0.10; QT, 0.52 (corrected QT, 0.53, which is prolonged). Axis: + 95 degrees (right axis deviation [RAD]). QRS: pattern of left posterior fascicular block (LPFB), with small R wave in leads I and aVL, small Q wave in leads II, III, and aVF, and RAD (see Fig. 4-20 for further description of LPFB). The prolonged QT interval in this patient is the result of antiarrhythmic medication.
Ack n ow le d gm en t s Contributors to previous editions of this chapter were Stephen R. Pomedli, MD; Lilit Garibyan, MD; Kyle Low, MD; and Price Kerfoot, MD.
Ad d i t i o n a l Rea d i n g Goldberger AL, Goldberger ZD, Shvilkin A. Goldberger’s Clinical Electrocardiography: A Simplif ed Approach. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. O’Keefe JH Jr, Hammill SC, Freed MS, et al. The Complete Guide to ECGs. 3rd ed. Sudbury, MA: Jones and Bartlett Publishers; 2008. Surawicz B, Knilans TK. Chou’s Electrocardiography in Clin ical Practice. 6th ed. Philadelphia, PA: Saunders Elsevier; 2008.
Surawicz B, Childers R, Deal BJ, et al. AHA/ ACC/ HRS recommendations for the standardization and interpretation of the electrocardiogram (Parts I–VI). J Am Coll Cardiol. 2007;49:1109-1135 and 2009;53:976–1011. Thaler MS. The Only EKG Book You’ll Ever Need. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Wagner GS, Strauss DG. Marriott’s Practical Electrocardiography. 12th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2014.
Atherosclerosis Sa rra h Sha ha wy Peter Libby
Ch a p t e r O u t l i n e Vascular Biology of Atherosclerosis Normal Arterial Wall Atherosclerotic Arterial Wall Complications o Atherosclerosis Atherosclerosis Risk Factors Genetics Traditional Risk Factors Biomarkers o Cardiovascular Risk Outlook
5
A
therosclerosis is the leading cause o mortality and morbidity in developed nations. Through its major maniestations o myocardial in arction and stroke, it has also become a major cause o death in the developing world. Commonly known as “hardening o the arteries,” atherosclerosis derives its name rom the Greek roots athere-, meaning “gruel,” and -skleros, meaning “hardness.” Recent evidence has demonstrated that chronic in ammation drives the atherosclerotic process and transduces traditional risk actors (such as hypercholesterolemia) into altered behavior o vascular wall cells, contributing to the disease and its thrombotic complications. The course o atherogenesis can smolder throughout adulthood, punctuated by acute cardiovascular events. This chapter consists o two sections. The f rst part describes the normal arterial wall, the pathogenesis o atherosclerotic plaque ormation, and the complications that lead to clinical mani estations o the disease. The second section describes f ndings rom population studies that have identif ed specif c risk actors or atherosclerotic events, thereby o ering opportunities or prevention and treatment.
VASCULAR BIOLOGY OF ATHEROSCLEROSIS Normal Arterial Wall The arterial wall consists of three layers (Fig. 5-1): the intima, closest to the arterial lumen and therefore most “intimate” with the blood; the middle layer, known as the media; and the outer layer, the adventitia. A single layer of endothelial cells covers the intimal surface and provides a metabolically active barrier between circulating blood and the vessel wall. The media is the thickest layer of the normal artery. Boundaries of elastin, known as the internal and external elastic laminae,
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Atherosclerosis Inte rna l e la s tic la mina
FIGURE 5-1. Schematic diagram of the arterial wall. The intima, the innermost layer, overlies the muscular media demarcated by the internal elastic lamina. The external elastic lamina separates the media rom the outer layer, the adventitia. (Modif ed rom Lieberman M. Marks’ Basic Medical Biochemistry: A Clinical Approach. 4th ed. Philadelphia, PA: Wolters Kluwer Health; 2013:649.)
Adve ntitia
Me dia (S mooth mus cle ce lls )
113
Exte rna l e la s tic la mina
Endothe lia l ce lls
Lume n
Intima
separate this middle layer rom the intima and adventitia, respectively. The media consists o smooth muscle cells (SMCs) and extracellular matrix and serves the contractile and elastic unctions o the vessel. The elastic component, more prominent in large arteries (e.g., the aorta and its primary branches), stretches during the high pressure o systole and then recoils during diastole, propelling blood orward. The muscular component, more prominent in smaller arteries such as arterioles, constricts or relaxes to alter vessel resistance and there ore luminal blood ow ( ow = pressure/ resistance; see Chapter 6). The adventitia contains nerves, lymphatics, and blood vessels (vasa vasorum) that nourish the cells o the arterial wall. Far rom an inert conduit, the living arterial wall hosts dynamic interchanges between its cellular components—most importantly, endothelial cells, vascular SMC, and their surrounding extracellular matrix. An understanding o the dys unction that leads to atherosclerosis requires knowledge o the normal unction o these components.
Endothelial Cells In a healthy artery, the endothelium per orms structural, metabolic, and signaling unctions that maintain homeostasis o the vessel wall. The tightly adjoined endothelial cells orm a barrier that contains blood within the lumen o the vessel and controls the passage o large molecules rom the circulation into the subendothelial space. As blood traverses the vascular tree, it encounters antithrombotic molecules produced by the normal endothelium that prevent it rom clotting or that promote f brinolysis (the breakdown o f brin clots). Some o these molecules reside on the endothelial sur ace (e.g., heparan sul ate, thrombomodulin, and plasminogen activators; see Chapter 7), while other antithrombotic products o the endothelium enter the circulation (e.g., prostacyclin and nitric oxide [NO]; see Chapter 6). Although a net anticoagulant state normally prevails, the endothelium can also produce prothrombotic and antif brinolytic molecules when subjected to various stressors. Furthermore, endothelial cells secrete substances that modulate contraction o SMC in the underlying medial layer. These substances include vasodilators (e.g., NO and prostacyclin) and vasoconstrictors (e.g., endothelin) that alter the arteriolar resistance and there ore luminal blood ow. In a normal artery, the predominance o vasodilator substances results in net smooth muscle relaxation. Endothelial cells can also modulate the immune response. In the absence o pathologic stimulation, healthy arterial endothelial cells resist leukocyte adhesion and thereby oppose local in ammation. However, endothelial cells respond to local injury or in ection by expressing cell sur ace adhesion molecules, which attach mononuclear cells to the endothelium, and chemokines—substances that acilitate leukocyte recruitment to the site o
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Chapter 5 NORMAL
ACTIVATED
ENDOTHELIAL CELLS • • • • •
Impe rme a ble to la rge mole cule s Anti-infla mma tory Re s is t le ukocyte a dhe s ion Promote va s odila tion Re s is t thrombos is
Pe rme a bility Infla mma tory cytokine s Le ukocyte a dhe s ion mole cule s Va s odila tory mole cule s Antithrombotic mole cule s
ARTERIAL S MOOTH MUS CLE CELLS • Norma l contra ctile function • Ma inta in extra ce llula r ma trix • Mos t conta ine d in me dia l laye r
Infla mma tory cytokine s Extra ce llula r ma trix synthe s is Migra tion into intima a nd prolife ra tion
FIGURE 5-2. Endothelial and smooth muscle cell activation by inf ammation. Normal endothelial and SMC maintain the integrity and elasticity o the normal arterial wall while limiting immune cell inf ltration. In ammatory activation o these vascular cells corrupts their normal unctions and avors proatherogenic mechanisms that drive plaque development.
injury. These e ects result in part by activation o the transcription actor nuclear actor kappa B (NFκB.) In summary, the normal endothelium provides a protective, nonthrombogenic sur ace with homeostatic vasodilatory and anti-in ammatory properties (Fig. 5-2).
Vascular Smooth Muscle Cells SMC within the medial layer o normal muscular arteries have both contractile and synthetic capabilities. Various vasoactive substances modulate the contractile unction, resulting in vasoconstriction or vasodilation. Such agonists include circulating molecules (e.g., angiotensin II), those released rom local nerve terminals (e.g., acetylcholine), and others originating rom the overlying endothelium (e.g., endothelin and NO). SMC also synthesize the collagen, elastin, and proteoglycans that orm the bulk o the vascular extracellular matrix (see Fig. 5-2). In addition, SMC produce vasoactive and in ammatory mediators, including interleukin-6 (IL6) and tumor necrosis actor (TNF). In normal arteries, most SMC reside in the medial layer, although human arteries also contain some SMC in the intima, particularly in sites predisposed to atherosclerosis. During atherogenesis, medial SMC can migrate into the intima, proli erate, and augment synthesis o extracellular matrix macromolecules while they dampen contractile protein content.
Extracellular Matrix In healthy arteries, f brillar collagen, elastin, and proteoglycans make up most o the extracellular matrix in the medial layer. Interstitial collagen f brils, constructed rom intertwining helical proteins, possess great biomechanical strength, while elastin provides exibility. Together these components maintain the structural integrity o the vessel, despite the high pressure within the lumen. The extracellular matrix also regulates the growth o its resident cells. Native f brillar collagen, in particular, can inhibit SMC proli eration in vitro. Furthermore, the matrix in uences cellular responses to stimuli—matrix-bound cells respond in a specif c manner to growth actors and resist apoptosis (programmed cell death).
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Atherosclerotic Arterial Wall The arterial wall is a dynamic and regulated structure, but certain stimuli can disturb normal homeostasis and pave the way or atherogenesis. For example, as described later, vascular endothelial cells, as well as SMC, react readily to in ammatory mediators, such as IL-1 and TNF, and can produce them as well. With the recognition that vascular wall cells respond to, and produce, proin ammatory agents, investigations into the role o “activated” endothelial and SMC in atherogenesis burgeoned. As a consequence, vascular endothelium and SMC joined classical in ammatory cells, such as mononuclear phagocytes and T lymphocytes, as key players in early atheroma ormation and in advanced plaque progression. This undamental research has identif ed several key components that contribute to the atherosclerotic in ammatory process, including endothelial dys unction, accumulation o lipids within the intima, recruitment o leukocytes and SMC to the vessel wall, ormation o oam cells, and deposition o extracellular matrix (Fig. 5-3), as described in the ollowing sections. Rather than ollow a sequential path, the cells o atherosclerotic lesions continuously interact and modi y each other’s behavior, shaping the plaque over decades into one o many possible prof les. This section categorizes these mechanisms into three pathologic stages: the atty streak, plaque progression, and plaque disruption (Fig. 5-4). In the arterial tree, lesions o all three stages can coexist, o ten side by side.
Fatty Streak Fatty streaks represent the earliest visible lesions o atherosclerosis. On gross inspection, they appear as areas o yellow discoloration on the artery’s inner sur ace, but they neither protrude substantially into the arterial lumen nor impede blood ow. Surprisingly, atty streaks exist in the aorta and coronary arteries o most people by age 20. They do not cause symptoms, and in some locations in the vasculature, they may regress over time. Although the precise initiation o atty streak development is not known, observations in animals suggest that various stressors cause early endothelial dys unction, as described in the next section.
Foa m ce ll 8
1 LDL
Monocyte s 4
Ce ll a dhe s ion mole cule
Va s cula r e ndothe lium
IL-1 MCP-1 2
Ce ll a poptos is 7
Oxidize d LDL Inte rna l e la s tic la mina
Ma cropha ge
5 3
S cave nge r re ce ptor
6
S mooth mus cle mitoge ns S mooth mus cle prolife ra tion S mooth mus cle migra tion
FIGURE 5-3. Schematic diagram of the evolution of atherosclerotic plaque. (1) Accumulation o lipoprotein particles in the intima. The darker color depicts modif cation o the lipoproteins (e.g., by oxidation or glycation). (2) Oxidative stress, including constituents o modif ed LDL, induces local cytokine elaboration. (3) These cytokines promote increased expression o adhesion molecules that bind leukocytes and o chemoattractant molecules (e.g., monocyte chemoattractant protein-1 [MCP-1]) that direct leukocyte migration into the intima. (4) A ter entering the artery wall in response to chemoattractants, blood monocytes encounter stimuli such as macrophage colony–stimulating actor (M-CSF) that augment their expression o scavenger receptors. (5) Scavenger receptors mediate the uptake o modif ed lipoprotein particles and promote the development o oam cells. Macrophage oam cells are a source o additional cytokines and e ector molecules such as superoxide anion (O2−) and matrix metalloproteinases. (6) SMC migrate into the intima rom the media. Note the increasing intimal thickness. (7) Intimal SMC divide and elaborate extracellular matrix, promoting matrix accumulation in the growing atherosclerotic plaque. In this manner, the atty streak evolves into a f bro atty lesion. (8) In later stages, calcif cation can occur (not depicted) and f brosis continues, sometimes accompanied by smooth muscle cell death (including programmed cell death or apoptosis), yielding a relatively acellular f brous capsule surrounding a lipid-rich core that may also contain dying or dead cells. IL-1, interleukin 1; LDL, low-density lipoprotein. (Modif ed rom Mann DL, Zipes D, Libby P, Bonow RO,eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 10th ed. Philadelphia, PA: Elsevier Saunders; 2015.)
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FATTY STREAK
P LAQUE P ROGRES S ION
P LAQUE DIS RUP TION
Endothe lia l dys function Lipoprote in e ntry a nd modifica tion Le ukocyte re cruitme nt Foa m ce ll forma tion
S mooth mus cle ce ll migra tion Alte re d ma trix synthe s is a nd de gra da tion Lipid core forma tion
Dis rupte d pla que inte grity Thrombus forma tion
A
B
C
FIGURE 5-4. Stages of plaque development. A. The atty streak develops as a result o endothelial dys unction, lipoprotein entry and modif cation, leukocyte recruitment, and oam cell ormation. B. Plaque progression involves migration o SMC into the intima, where they divide and elaborate extracellular matrix. The f brous cap contains a lipid core. C. Hemodynamic stresses and degradation o extracellular matrix increase the susceptibility o the f brous cap to rupture, allowing superimposed thrombus ormation. (Modif ed rom Libby P, Ridker PM, Maseri A. In ammation and atherosclerosis. Circulation. 2002;105:1136.)
Such dys unction allows entry and modif cation o lipids within the subendothelial space, where they serve as proin ammatory mediators that initiate leukocyte recruitment and oam cell ormation—the pathologic hallmarks o the atty streak (Fig. 5-3).
Endothelial Dys unction Injury to the arterial endothelium represents a primary event in atherogenesis. Such injury can result rom exposure to diverse agents, including physical orces and chemical irritants. The predisposition o certain regions o arteries (e.g., branch points) to develop atheromata supports the role o hydrodynamic stress. In straight sections o arteries, the normal laminar (i.e., smooth) shear orces avor the endothelial production o NO, which is an endogenous vasodilator, an inhibitor o platelet aggregation, and an anti-in ammatory substance (see Chapter 6). Moreover, laminar ow and high shear stress activates transcription actors such as Krüppel-like actor 2 (KLF2) that evokes an “atheroprotective” panel o endothelial unctions and accentuates expression o the antioxidant enzyme superoxide dismutase, which protects against reactive oxygen species. Conversely, disturbed ow occurs near arterial branch points, causing low shear stress, which impairs these locally atheroprotective endothelial unctions. Accordingly, arteries with ew branches (e.g., the internal mammary artery) show relative resistance to atherosclerosis, whereas bi urcated vessels (e.g., the common carotid and le t coronary arteries) contain common sites or atheroma ormation. Endothelial dys unction may also result rom exposure to a “toxic” chemical environment. For example, tobacco smoking, abnormal circulating lipid levels, and diabetes—all known risk actors or atherosclerosis—can promote endothelial dys unction. Each o these stimuli increases endothelial production o reactive oxygen species—notably, superoxide anion—that interact with other intracellular molecules to in uence the metabolic and synthetic unctions o the endothelium. In such an environment, the cells promote local in ammation. When physical and chemical stressors interrupt normal endothelial homeostasis, an activated state ensues, mani ested by impairment o the endothelium’s role as a permeability barrier, the release o in ammatory cytokines, increased production o cell sur ace adhesion molecules that recruit leukocytes, altered release o vasoactive substances (e.g., prostacyclin and NO), and inter erence with normal antithrombotic properties. These undesired e ects o
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dys unctional endothelium lay the groundwork or subsequent events in the development o atherosclerosis (see Figs. 5-2 and 5-3).
Lipoprotein Entry and Modif cation The activated endothelium no longer serves as an e ective barrier to the passage o circulating lipoproteins into the arterial wall. Increased endothelial permeability allows the entry o low-density lipoprotein (LDL) into the intima, a process acilitated by an elevated circulating LDL concentration in patients with hypercholesterolemia. In addition to high LDL concentrations in part rom diet, several monogenic causes o elevated LDL exist, including mutations o the LDL receptor, o apolipoprotein B, and o PCSK9, a protease involved in regulation o the LDL receptor. Once within the intima, LDL accumulates in the subendothelial space by binding to proteoglycans in the extracellular matrix. This “trapping” increases the residence time o LDL within the vessel wall, where the lipoprotein may undergo chemical modif cations that can promote the development o atherosclerotic lesions. Hypertension, a major risk actor or atherosclerosis, may urther promote retention o lipoproteins in the intima by accentuating the production o LDL-binding proteoglycans by SMC. Oxidation is one type o modif cation that be alls LDL trapped in the subendothelial space. It can result rom the local action o reactive oxygen species and prooxidant enzymes derived rom activated endothelial or SMC, or rom macrophages that penetrate the vessel wall. In addition, the microenvironment o the subendothelial space sequesters oxidized LDL rom antioxidants in the plasma. In diabetic patients with sustained hyperglycemia, glycation o LDL can occur—a modif cation that may ultimately render LDL antigenic and proin ammatory. These biochemical alterations o LDL act early and contribute to the in ammatory mechanisms initiated by endothelial dys unction, and they may continue to promote in ammation throughout the li e span o the plaque. In the atty streak, and likely throughout plaque development, modif ed LDL (mLDL) promotes leukocyte recruitment and oam cell ormation.
Leukocyte Recruitment Recruitment o leukocytes (primarily monocytes and T lymphocytes) to the vessel wall is a key step in atherogenesis. The process depends on the expression o leukocyte adhesion molecules (LAMs) on the normally nonadherent endothelial luminal sur ace and on chemoattractant signals (e.g., monocyte chemotactic protein-1 [MCP-1]) that direct diapedesis (passage o cells through the intact endothelial layer) into the subintimal space. Two major subsets o LAM persist in the in amed atherosclerotic plaque: the immunoglobulin gene super amily (especially vascular cell adhesion molecule-1 [VCAM-1] and intercellular adhesion molecule-1 [ICAM-1]) and the selectins (particularly, E- and P-selectin). These LAMs and chemoattractant signals direct mainly monocytes to the orming lesion. Hypercholesterolemia avors accumulation in blood o a subset o monocytes that is characterized by expression o high levels o proin ammatory cytokines (e.g., IL-1 and TNF), distinguished in mice by expression o the cell sur ace marker Ly6c. Although outnumbered by monocytes, T lymphocytes also localize within plaques and direct the adaptive immune response. mLDL and proin ammatory cytokines can induce LAM and chemoattractant cytokine (chemokine) expression independently, but mLDL may also stimulate endothelial and SMC to produce proin ammatory cytokines, thereby rein orcing the direct action. This dual ability o mLDL to promote leukocyte recruitment and in ammation directly and indirectly persists throughout atherogenesis.
Foam Cell Formation A ter monocytes adhere to and penetrate the intima, they di erentiate into macrophages and imbibe lipoproteins to orm oam cells. Foam cells do not arise rom uptake o LDL cholesterol by classic cell sur ace LDL receptor–mediated endocytosis as described in Box 5-1
Chapter 5
BOX 5-1
The Lipoprotein Transport System
Lipoproteins erry water-insoluble ats through the bloodstream. These particles consist o a lipid core surrounded by more hydrophilic phospholipid, ree cholesterol, and apolipoproteins (also called apoproteins). The apoproteins present on various classes o lipoprotein molecules serve as the “conductors” o the system, directing the lipoproteins to specif c tissue receptors and mediating enzymatic reactions. Five major classes o lipoproteins exist, distinguished by their densities, lipid constituents, and associated apoproteins. In order o increasing density, they are chylomicrons, very-low-density lipoproteins ( VLDL) , intermediate-density lipoproteins ( IDL) , low-density lipoproteins ( LDL) , and high-density lipoproteins ( HDL) . The major steps in the lipoprotein pathways are labeled in the f gure below and described as ollows. The key apoproteins (apo) at each stage are indicated in the f gure in parentheses. Exo g e no us Pathway Die ta ry fa t
Endo g e no us Pathway
5 Nonhe pa tic ce lls
Bile a cids a nd chole s te rol
1
10
LDL (Apo B-100)
Live r Inte s tine
9 4
8
T
,
P
)
E
VLDL (Apo B-100, C, E)
IDL (Apo B-100, E)
Lip op rote in lip a s e
E
7
LP L HL
A
(
p
C
o
E , C o p
2
3 Lip op rote in lip a s e
6
C
Chylomicron re mna nts (Apo B-48, E)
Chylomicrons (Apo B-48, A,C, E)
A
118
FFA HDL
FFA HDL
Mus cle
Adipos e tis s ue
Mus cle
Adipos e tis s ue
Exogenous ( Intestinal) Pathway 1. Dietary ats are absorbed by the small intestine and repackaged as chylomicrons, accompanied by apo B-48. Chylomicrons are large particles, particularly rich in triglycerides, that enter the circulation via the lymphatic system. 2. Apo E and subtypes o apo C are trans erred to chylomicrons rom HDL particles in the bloodstream. 3. Apo C (subtype CII) enhances interactions o chylomicrons with lipoprotein lipase (LPL) on the endothelial sur ace o adipose and muscle tissue. This reaction hydrolyzes the triglycerides within chylomicrons into ree atty acids (FFAs), which are stored by adipose tissue or used or energy in cardiac and skeletal muscle. 4. Chylomicron remnants are removed rom the circulation by the liver, mediated by apo E. 5. One ate o cholesterol in the liver is incorporation into bile acids, which are exported to the intestine, completing the exogenous pathway cycle.
Endogenous ( Hepatic) Pathway Because dietary at availability is not constant, the endogenous pathway provides a reliable supply o triglycerides or tissue energy needs:
6. The liver packages cholesterol and triglycerides into VLDL particles, accompanied by apo B-100 and phospholipid. The triglyceride content o VLDL is much higher than that o cholesterol, but this is the main means by which the liver releases cholesterol into the circulation.
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BOX 5-1
119
The Lipoprotein Transport System ( continued)
7. VLDL is catabolized by LPL (similar to chylomicrons, as described in step 3), releasing atty acids to muscle and adipose tissue. During this process, VLDL also interacts with HDL, exchanging some o its triglyceride or apo C subtypes, apo E, and cholesteryl ester rom HDL. The latter exchange (important in reverse cholesterol transport, as described in the next section) is mediated by cholesteryl ester trans er protein (CETP). 8. Approximately 50% o the VLDL remnants (termed intermediate-density lipoproteins [IDL]) are then cleared in the liver by hepatic receptors that recognize apo E. 9. The remaining IDL is catabolized urther by LPL and hepatic lipase (HL), which remove additional triglyceride, apo E, and apo C, orming LDL particles. 10. Plasma clearance o LDL occurs primarily via LDL receptor–mediated endocytosis in the liver and peripheral cells, directed by LDL’s apo B-100 and apo E.
Cholesterol Homeostasis and Reverse Cholesterol Transport Intracellular cholesterol content is tightly maintained by de novo synthesis, cellular uptake, storage, and e ux rom the cell. The enzyme HMG-CoA reductase is the rate-limiting element o cholesterol biosynthesis, and cellular uptake o cholesterol is controlled by receptor-mediated endocytosis o circulating LDL (see step 10). When intracellular cholesterol levels are low, the transcription actor sterol regulatory element–binding protein (SREBP) is released rom the endoplasmic reticulum. The active ragment o SREBP enters the nucleus to increase transcription o HMG-CoA reductase and the LDL receptor—which, through their subsequent actions, tend to normalize the intracellular cholesterol content. a po AI
Fre e a po AI
Inte rna lize d chole s te ryl e s te r Na s ce nt HDL
ABCAI
LCAT
ABCGI Pe riphe ral c e lls
S R-BI re c e p tor
Ma ture HDL
Upta ke by live r a nd s te roid hormone producing tis s ue s
CETP
Tra ns fe r of chole s te rol to VLDL, IDL, LDL for tra ns port to live r
Exce s s chole s te rol
Under conditions o intracellular cholesterol excess (as in the f gure above), peripheral cells increase the transcription o the ATP-binding cassette A1 and G1 genes (ABCA1 and ABCG1, respectively). The ABCA1 gene codes or a transmembrane protein transporter that initiates e ux o cholesterol rom the cell to lipid-poor circulating apo AI (which is synthesized by the liver and intestine), thus orming nascent (immature) HDL particles. ABCG1 acilitates urther e ux o cholesterol to orm more mature HDL particles. As ree cholesterol is acquired by circulating HDL, it is esterif ed by lecithin cholesterol acyltransferase (LCAT), an enzyme activated by apo AI. The hydrophobic cholesteryl esters move into the particle’s core. Most cholesteryl esters in HDL can then be exchanged or triglycerides in the circulation (via the enzyme CETP) with any o the apo B–containing lipoproteins (i.e., VLDL, IDL, LDL), which deliver the cholesterol back to the liver. HDL can also transport cholesterol to the liver and steroid hormone–producing tissues via the SR-B1 scavenger receptor.
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Chapter 5 (e.g., as occurs in normal hepatocytes), because the high cholesterol content in these cells suppresses expression o that receptor. Furthermore, the classic LDL receptor does not recognize modif ed LDL particles. Rather, macrophages rely on a amily o “scavenger” receptors that pre erentially bind and internalize mLDL. Unlike uptake via the classic LDL receptor, mLDL ingestion by scavenger receptors evades negative eedback inhibition and permits engorgement o the macrophages with cholesterol and cholesteryl ester, resulting in the typical appearance o oam cells. Although such uptake may initially provide benef t by sequestering potentially damaging mLDL particles, the impaired e ux o these cells as compared to the rate o in ux, as well as local proli eration, leads to their accumulation in the plaque. This mitigates their protective role by ueling oam cell apoptosis and the release o proin ammatory cytokines that promote atherosclerotic plaque progression. During atherogenesis, the clearance o dead oam cells can become ine f cient, thus promoting the accumulation o cellular debris and extracellular lipids, orming the lipid-rich center o a plaque (o ten termed the n ecrotic core).
Plaque Progression Whereas endothelial cells play a central role in the ormation o the atty streak, SMC in the intima promote plaque progression by producing extracellular matrix that traps lipoproteins and adds to the bulk o the lesion. During decades o development, the typical atherosclerotic plaque acquires a distinct thrombogenic lipid core that underlies a protective f brous cap. Not all atty streaks progress into f bro atty lesions, and it is unknown why some evolve and others do not. Early plaque growth typically involves a compensatory outward remodeling o the arterial wall that preserves the diameter o the lumen and permits plaque accumulation without limitation o blood ow, hence producing no ischemic symptoms. Lesions at this stage can thus evade detection by angiography. Later plaque growth, however, can outstrip the compensatory arterial enlargement, restrict the vessel lumen, and impede per usion. Such ow-limiting plaques can result in tissue ischemia, causing symptoms such as angina pectoris (see Chapter 6) or intermittent claudication o the extremities (see Chapter 15). Many acute coronary syndromes (acute myocardial in arction and unstable angina pectoris) result when the f brous cap o an atherosclerotic plaque ruptures, exposing prothrombotic molecules within the lipid core and precipitating an acute thrombus that suddenly occludes the arterial lumen. As described in this section, the extracellular matrix plays a pivotal role in orti ying the f brous cap, isolating the thrombogenic plaque interior rom coagulation substrates in the circulation.
Smooth Muscle Cell Migration The transition rom atty streak to f brous atheromatous plaque involves the migration o SMC rom the arterial media into the intima, proli eration o the SMC within the intima, and secretion o extracellular matrix macromolecules by the SMC. Foam cells, activated platelets entering through microf ssures in the plaque sur ace, and endothelial cells can all elaborate substances that signal SMC migration and proli eration (Fig. 5-5). Foam cells produce several actors that contribute to SMC recruitment. For example, they release platelet-derived growth actor (PDGF)—also released by platelets and endothelial cells—which likely stimulates the migration o SMC across the internal elastic lamina and into the subintimal space, where they subsequently replicate. PDGF additionally stimulates the growth o resident SMC in the intima. Foam cells also release cytokines and growth actors (e.g., TNF, IL-1, f broblast growth actor, and trans orming growth actor-β [TGF-β]) that urther incite SMC proli eration and/ or the synthesis o extracellular matrix proteins. Furthermore, these stimulatory cytokines induce SMC and leukocyte activation, promoting urther cytokine release, thus rein orcing and maintaining in ammation in the lesion.
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Foa m Ce lls in Fa tty S tre a k
Endothe lia l Dys function
Cytokine s • TNF • IL-1 • TGF-β
P DGF
NO P GI2
Tis s ue fa ctor
Thrombos is a nd pla te le t a ctiva tion
• Thrombin • P DGF • TGF-β
FIGURE 5-5. Progression from the fatty streak involves the migration and proliferation of SMC. Substances released from foam cells, dysfunctional endothelial cells, and platelets contribute to this process. IL-1, interleukin-1; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostacyclin; TGF-β, transforming growth factor-β; TNF, tumor necrosis factor.
S mooth mus cle ce lls migra te to intima , prolife ra te , a nd produce extra ce llula r ma trix Fibrous P la que
According to the traditional concept, plaques grow gradually and continuously, but current evidence suggests that this progression may be punctuated by subclinical events with bursts o smooth muscle replication. For example, morphologic evidence o resolved intraplaque hemorrhages indicates that breaches in plaque integrity can occur without clinical symptoms or signs. Such plaque disruptions expose tissue actor rom oam cells to blood, which activates coagulation and microthrombus ormation. Activated platelets within such microthrombi release additional potent actors—including PDGF—that can spur a local wave o SMC migration and proli eration. Activated T cells also contribute to plaque evolution. Cells o the T helper 1 subtype (Th1) produce proin ammatory cytokines that promote plaque progression and instability, while lymphocytes o the T helper 2 subtype (Th2) and regulatory T cells (Treg) produce actors, including TGF-β and IL-10, which can inhibit SMC proli eration and potentially mitigate plaque growth.
Extracellular Matrix Metabolism As the predominant collagen-synthesizing cell type, SMC avor ortif cation o the f brous cap. Net matrix deposition depends on the balance o its synthesis by SMC and its degradation, mediated in part by a class o proteolytic enzymes known as matrix metalloproteinases (MMP). While PDGF and TGF-β stimulate production o interstitial collagens by SMC, the Th1-derived cytokine inter eron-γ (IFN-γ) inhibits SMC collagen synthesis. Furthermore, in ammatory cytokines stimulate local oam cells to secrete collagen- and elastin-degrading MMP, thereby weakening the f brous cap and predisposing it to rupture (Fig. 5-6).
Plaque Disruption Plaque Integrity The tug-o -war between matrix synthesis and degradation continues over decades but not without consequences. Death o smooth muscle and oam cells, either owing to excess in ammatory stimulation or by contact activation o apoptosis pathways, liberates cellular contents, contributing imbibed lipids and cellular debris to the growing lipid core. The size o the lipid
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Chapter 5
S
De g ra d a
e s is h t yn
ti o
n
Lume n
Colla g e n a nd e la s tin
MMP Fibro us Cap
S mooth mus cle ce ll + P DGF TGF-β
– IFN-γ T lymphocyte
+ CD40L
Foa m ce ll
+ IL-1 TNF MCP-1
Lipid core
FIGURE 5-6. Matrix metabolism underlies f brous cap integrity. The net deposition o extracellular matrix is the result o competing synthesis and degradation reactions. Smooth muscle cells synthesize the bulk o the f brous cap constituents, such as collagen and elastin. Foam cells elaborate destructive proteolytic enzymes, such as the collagen-degrading matrix metalloproteinases (MMP) and the elastolytic cathepsins. T-lymphocyte– derived actors avor destruction o the f brous cap. All plaque residents, however, contribute to the cytokine milieu o the plaque, providing multiple activating and inhibitory stimuli as shown. IFN-γ, inter eron-γ; IL-1, interleukin-1; MCP-1, monocyte chemoattractant protein-1; PDGF, platelet-derived growth actor; TGF-β, trans orming growth actor-β; TNF, tumor necrosis actor. (Modif ed rom Libby P. The molecular bases o acute coronary syndromes. Circulation. 1995;91:2844–2850; Young JL, Libby P, Schönbeck U. Cytokines in the pathogenesis o atherosclerosis. Thromb Haemost. 2002;88:554–567.)
core has biomechanical implications or the stability o the plaque. With increasing size and protrusion into the arterial lumen, mechanical stress ocuses on the plaque border abutting normal tissue, called the shoulder region. The structure o the f brous cap contributes to plaque integrity. Whereas lesions with thick f brous caps may cause pronounced arterial narrowing, they have less propensity to rupture. Conversely, plaques that have thinner caps (and o ten appear less obstructive by angiography) tend to be ragile and more likely to rupture and incite thrombosis. Current clinical terminology describes the extreme spectrums o integrity as “stable plaques” (marked by a thick f brous cap and small lipid core) or “vulnerable plaques” (marked by a thin f brous cap, rich lipid core, extensive macrophage inf ltrate, and a paucity o SMC; Fig. 5-7). Despite the common use o these terms, this distinction vastly oversimplif es the heterogeneity o plaques and may overestimate the ability to oresee a plaque’s “clinical uture” based on structural in ormation. Most plaques with the so-called “vulnerable” morphology do not actually cause clinical events; hence, attempts to specif cally identi y such plaques may not direct therapy in an e ective manner. Moreover, a substantial minority o atal thrombi in coronary arteries arise rom matrix-rich plaques with intact f brous caps, a morphology that may arise rom superf cial erosion o the lesion by mechanisms that are not well understood.
Thrombogenic Potential Rupture o atherosclerotic plaque does not inevitably cause major clinical events such as myocardial in arction or stroke. As described in the previous section, small nonocclusive thrombi may incorporate into the plaque, stimulating urther smooth muscle growth and extracellular matrix deposition (see Fig. 5-7). The balance between the thrombogenic
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Norma l a rte ry
Ea rly a the roma
“Vulne ra ble” pla que • La rge lipid pool • Thin fibrous ca p • Ma ny infla mma tory ce lls
“S ta ble” pla que • S ma ll lipid pool • Thick fibrous ca p • Pre s e rve d lume n
Rupture d pla que with thrombus forma tion
He a le d rupture • Na rrowe d lume n • Fibrous intima
Acute myoca rdia l infa rction
FIGURE 5-7. Stable versus vulnerable plaques. Stable plaque is characterized by a small lipid core and a thick f brous cap, whereas vulnerable plaque tends to have a large lipid core and a relatively thin f brous cap. The latter is subject to rupture, resulting in thrombosis. A resulting occlusive clot can cause an acute cardiac event, such as myocardial in arction. A lesser thrombus may resorb, but the wound-healing response stimulates smooth muscle cell proli eration and collagen production, thereby thickening the f brous cap and narrowing the vessel lumen urther. (Modif ed rom Libby P. In ammation in atherosclerosis. Nature. 2002;420:868–874.)
and f brinolytic potential o the plaque, and the uid phase o blood, determines whether disruption o the f brous cap leads to a transient, nonobstructive mural thrombus or to a completely occlusive clot. The probability o a major thrombotic event re ects the balance between the competing processes o clot ormation and dissolution by f brinolysis. In ammatory stimuli ound in the plaque microenvironment (e.g., CD40L) elicit tissue actor, the initiator o the extrinsic coagulation pathway, rom many plaque components including SMC, endothelial cells,
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Chapter 5 Favo r Oc c lus ive Thro mbus
Re s is t Thro mbus Ac c umulatio n
P roc oa g ula nt Tis s ue fa ctor
Antic oa g ula nts Thrombomodulin He pa rin-like mole cule s
Antifib rinolytic PAI-1
P rofib rinolytic tPA
FIGURE 5-8. Competing factors in thrombosis. The clinical mani estations o plaque disruption rely not only on the stability o the f brous cap but also on the thrombogenic potential o the plaque core. The balance o physiologic mediators dictates the prominence o the thrombus, resulting in either luminal occlusion or resorption into the plaque. PAI-1, plasminogen activator inhibitor-1; tPA, tissue plasminogen activator.
and macrophage-derived oam cells. Beyond enhancing expression o the potent procoagulant tissue actor, in ammatory stimuli urther support thrombosis by avoring the expression o antif brinolytics (e.g., plasminogen activator inhibitor-1) over the expression o anticoagulants (e.g., thrombomodulin, heparin-like molecules) and prof brinolytic mediators (e.g., t issue plasminogen activator; Fig. 5-8). Moreover, as described earlier, the activated endothelium also promotes thrombin ormation, coagulation, and f brin deposition at the vascular wall. A person’s propensity toward coagulation may be enhanced by genetics, comorbid conditions (e.g., diabetes), and/ or li estyle actors (e.g., smoking, visceral obesity). Consequently, the concept o the “vulnerable plaque” has expanded to that o the “vulnerable patient,” to acknowledge other contributors to a person’s vascular risk.
Complications of Atherosclerosis Atherosclerotic plaques do not distribute homogeneously throughout the vasculature. They usually develop f rst in the dorsal aspect o the abdominal aorta and proximal coronary arteries, ollowed by the popliteal arteries, descending thoracic aorta, internal carotid arteries, and renal arteries. There ore, the regions per used by these vessels most commonly su er the consequences o atherosclerosis. Complications o atherosclerotic plaques—including calcif cation, rupture, hemorrhage, and embolization—can have dire clinical consequences due to acute restriction o blood ow or alterations in vessel wall integrity. These complications, which are discussed in greater detail in later chapters, include the ollowing: • Calcif cation o atherosclerotic plaque, which may increase its ragility. • Rupture or ulceration o atherosclerotic plaque, which exposes procoagulants within the plaque to circulating blood, causing a thrombus to orm at that site. Such thrombosis can occlude the vessel and result in in arction o the involved organ. Alternatively, the thrombus can organize, incorporate into the lesion, and add to the bulk o the plaque. • Hemorrhage into the plaque owing to rupture o the f brous cap or o the microvessels that orm within the lesion. The resulting intramural hematoma may urther narrow the vessel lumen. • Embolization o ragments o disrupted atheroma to distal vascular sites. • Weakening o the vessel wall: the f brous plaque subjects the neighboring medial layer to increased pressure, which may provoke atrophy and loss o elastic tissue with subsequent expansion o the artery, orming an aneurysm. • Microvessel growth within plaques, providing a source or intraplaque hemorrhage and urther leukocyte tra f cking.
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The complications o atherosclerotic plaque may result in specif c clinical consequences in di erent organ systems (Fig. 5-9). When lesion growth eventually outstrips the compensatory outward enlargement o the plaque, the lesion can narrow the vessel lumen and, in the case o the coronary arteries, cause intermittent chest discom ort on exertion (angina pectoris). In contrast, plaque that does not compromise the vessel lumen but has characteristics o vulnerability (e.g., a thin f brous cap, a large lipid core, spotty calcif cations) can rupture, leading to acute thrombosis and myocardial in arction (see Chapter 7). Such nonstenotic plaques are o ten numerous and dispersed throughout the arterial tree, and because they do not limit arterial ow, they do not produce symptoms and o ten evade detection by exercise testing or angiography. The description presented here o atherogenesis and its complications can explain the limitations o widely employed treatments. For example, percutaneous intervention (angioplasty and stent placement) o symptomatic coronary stenoses e ectively relieves angina pectoris, but does not necessarily prevent uture myocardial in arction or prolong li e, with the exception o patients in the early phase o an acute ST-elevation myocardial in arction, as described in Chapter 7. This disparity likely re ects the multiplicity o nonocclusive plaques at risk o precipitating thrombotic events. It ollows that li estyle modif cations and drug therapies that curb the risk actors or plaque ormation, and lessen eatures associated with “vulnerability,” provide a critical oundation or preventing progression and complications o atherosclerosis.
S tro ke • Embolic s troke
4
• Thrombotic s troke
2
3
Co ro nary arte ry dis e as e 1
• Myoca rdia l is che mia • Uns ta ble a ngina
2
3
• Myoca rdia l infa rction 2 Re nal arte ry dis e as e • Athe roe mbolic re na l dis e a s e • Re na l a rte ry s te nos is 1
4
Ane urys ms 5
Pe riphe ral arte ry dis e as e • Limb cla udica tion 1 1
Na rrowing of ve s s e l by fibrous pla que
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P la que ulce ra tion or rupture
3
Intra pla que he morrha ge
4
Pe riphe ra l e mboli
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We a ke ning of ve s s e l wa ll
• Limb is che mia 1
FIGURE 5-9. Clinical sequelae of atherosclerosis. Complications o atherosclerosis arise rom the mechanisms listed in the f gure.
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3
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Chapter 5
ATHEROSCLEROSIS RISK FACTORS In the early 20th century, most viewed atherosclerosis as an inevitable process o aging. But in 1948, the landmark Framingham Heart Study began to examine the relationship between specif c attributes and cardiovascular disease, establishing the concept o atherosclerotic risk actors. Among later studies, the Multiple Risk Factor Intervention Trial (MRFIT) screened more than 325,000 men, o ering an opportunity to correlate risk actors with subsequent cardiovascular disease and mortality. O the major risk actors, those that are not correctable include advanced age, male gender, and heredity—that is, a history o coronary heart disease among f rst-degree relatives at a young age (be ore age 55 or a male relative or be ore age 65 or a emale relative). Risk actors or atherosclerosis amenable to modif cation include undesirable concentrations and composition o circulating lipids (dyslipidemia), tobacco smoking, hypertension, diabetes mellitus, and lack o physical activity and obesity (Table 5-1). In addition to these standard predictors, certain biologic markers associated with the development o cardiovascular events have been undergoing rigorous evaluation as “novel” risk markers. These include elevated circulating levels o the special lipoprotein particle Lp(a) and certain markers o in ammation, including the acute-phase reactant C-reactive protein (CRP). Furthermore, recent genome-wide association studies (GWAS) have sought to identi y variants in genetic loci associated with increased cardiovascular risk. The ollowing sections address these risk actors and biologic markers.
Genetics Genetic predisposition, as re ected by amily history, comprises a major risk actor or atherosclerosis. While directly causative genes remain elusive, recent GWAS have identif ed a number o loci associated with atherosclerotic disease. The strongest connection with CAD and myocardial in arction localizes to chromosome 9p21.3. This region contains genes that code or two cyclin-dependent kinase inhibitors that can regulate the cell cycle and may participate in TGF-β inhibitory pathways. Other associations with CAD include SORT-1 that encodes a molecule implicated in lipoprotein tra f cking. Such f ndings promise eventually to enhance identif cation, prevention, and treatment o atherosclerotic disease. Genetic studies have also shown that loss o unction mutations in the gene that encodes the enzyme PCSK9 (proprotein convertase subtilisin/ kexin type 9) augment LDL receptor levels on cell sur aces, boosting LDL clearance, and yielding lower LDL concentrations in blood. Individuals with loss o unction variants in PCSK9, thus exposed to lower levels o LDL rom childhood than those with the typical genotype, appear protected rom atherosclerotic events. This observation has spurred the ongoing development o biological agents that limit PCSK9 action.
TABLE 5-1 Common Cardiovascular Risk Factors Modif able risk actors Dyslipidemia (elevated LDL, decreased HDL) Tobacco smoking Hypertension Diabetes mellitus, metabolic syndrome Lack of physical activity Nonmodif able risk actors Advanced age Male sex Heredity
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Traditional Risk Factors Dyslipidemia A large and consistent body o evidence establishes abnormal circulating lipid levels as a major risk actor or atherosclerosis. Observational studies have shown that societies with high consumption o saturated at and prevalent hypercholesterolemia have greater mortality rom coronary disease than countries with traditionally low saturated at intake and low serum cholesterol levels (e.g., rural Japan and certain Mediterranean nations). Similarly, data rom the Framingham Heart Study and other cohorts have shown that the risk o ischemic heart disease increases with higher total serum cholesterol levels. The coronary risk is approximately twice as high or a person with a total cholesterol level o 240 mg/ dL compared with a person whose cholesterol level is 200 mg/ dL. In particular, elevated levels o circulating LDL correlate with an increased incidence o atherosclerosis and coronary artery disease. When present in excess, LDL can accumulate in the subendothelial space and undergo the chemical modif cations that urther damage the intima, as described earlier, initiating and perpetuating the development o atherosclerotic lesions. Thus, LDL is commonly known as “bad cholesterol.” Conversely, elevated HDL particles (o ten called “good cholesterol”) associate with protection against atherosclerosis, o ten attributed to HDL’s ability to transport cholesterol away rom the peripheral tissues back to the liver or disposal (termed “reverse cholesterol transport”) and its putative antioxidative and anti-in ammatory properties. Elevated serum LDL may persist or many reasons, including a high- at diet or abnormalities in the LDL receptor clearance mechanism. Patients with genetic de ects in the LDL receptor, which leads to a condition known as familial hypercholesterolemia, cannot remove LDL rom the circulation e f ciently. Heterozygotes with this condition have one normal and one de ective gene coding or the receptor. They display high plasma LDL levels and develop premature atherosclerosis. Homozygotes who completely lack unctional LDL receptors may experience vascular events, such as acute myocardial in arction, as early as the f rst decade o li e. Increasing evidence also implicates triglyceride-rich lipoproteins, such as VLDL and IDL, in the development o atherosclerosis. However, it remains undetermined whether these particles participate directly in the disease or simply keep company with low levels o HDL cholesterol. O note, poorly controlled type 2 diabetes mellitus commonly associates with the combination o hypertriglyceridemia and low HDL levels.
Lipid-Altering Therapy Strategies that improve abnormal lipid levels can limit the consequences o atherosclerosis. Many large studies o patients with coronary disease show that dietary or pharmacologic reduction o serum cholesterol can prevent cardiovascular events. Li estyle modif cations that may be benef cial include avoidance o tobacco, maintenance o healthy diet and weight, and augmented physical activity. Yet, even intensive li estyle modif cation may not be su f cient to prevent cardiovascular events in individuals with long established atherosclerotic risk actors. Hence, many individuals require pharmacologic agents to optimize cardiovascular outcomes. The major groups o lipid-altering agents (see Chapter 17) include HMG-CoA reductase inhibitors (also known as “statins”), niacin, f bric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid–binding agents. O these, the statins have emerged as the key LDL-lowering drugs that reduce cardiovascular events in broad categories o patients. These agents inhibit the rate-limiting enzyme responsible or cholesterol biosynthesis. The resulting reduction in intracellular cholesterol concentration promotes increased LDL receptor expression and thus augments clearance o LDL particles rom the bloodstream. Statins also lower the rate o VLDL synthesis by the liver (thus lowering circulating triglyceride levels) and raise HDL by an unknown mechanism.
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Chapter 5 Major clinical trials evaluating statin therapy have demonstrated reductions in ischemic cardiac events, the occurrence o ischemic strokes, and mortality rates in individuals both with and without a history o prior atherosclerotic cardiovascular events. Based on previous guideline recommendations, many clinicians use specif c serum LDL targets to adjust the dose o statin therapy. However, in 2013, the American College o Cardiology and American Heart Association issued updated guidelines that advocate a di erent approach. Based on evidence rom multiple randomized controlled clinical trials, the new recommendations ocus therapy on groups o patients most likely to benef t rom lipid-lowering therapy (Table 5-2) and recommends dosages o statins that were employed in such trials, rather than titrating dosages based on serum lipoprotein levels. In particular, such studies have a f rmed that more intense doses o statins improve outcomes in acute and chronic coronary heart disease more than lower-dose regimens. The clinical benef ts o statins likely derive rom several mechanisms. Lowering LDL can limit lipid accumulation in atherosclerotic plaques and orestall the biological consequences detailed earlier in this chapter. Other potentially benef cial actions (so-called “pleiotropic e ects”) include reduced in ammation, a driver o atherosclerosis and its complications. These pleiotropic e ects likely result rom activation o the transcription actor KLF2 and inter erence with prenylation o small G proteins implicated in the regulation o in ammatory unctions o vascular cells and leukocytes. Clinical trials have provided data that support an anti-in ammatory action o statins by showing reductions in plasma levels o CRP, a serum marker o in ammation described later. Such analyses cannot separate the LDL-lowering e ect o statins rom their anti-in ammatory mechanisms because o the prominent role o LDL in initiating in ammatory cascades. Nonetheless, accumulating clinical and experimental data suggest that at least part o the benef t o statins derives rom mechanisms other than LDL lowering. Other classes o drugs that lower LDL (e.g., niacin, f brates, inhibitors o bile acid, or cholesterol absorption rom the gut) do not share the e f cacy o statins in reducing clinical events. These agents are now primarily prescribed to patients who do not tolerate statins or when LDL cholesterol reduction is not adequate on statin therapy alone.
TABLE 5-2
American College of Cardiology/ American Heart Association Recommended Groups for Statin Therapy
Patient Type
Recommendation
Clinical atherosclerotic cardiovascular disease (ASCVD) already present (i.e., history of CAD, stroke, or peripheral vascular disease) LDL cholesterol ≥ 190 mg/ dL Diabetics (age 40–75 with LDL 70–189 mg/ dL) and 10-year cardiac riskc ≥ 7.5% 10-year cardiac riskc < 7.5% without clinical ASCVD Nondiabetics (age 40–75 with LDL 70–189 mg/ dL) without clinical ASCVD but with 10-year cardiac riskc ≥ 7.5%
High-intensity statina
High-intensity statina High-intensity statina Moderate-intensity statinb Moderate-to-high intensity statina,b
High-intensity statin is intended to lower LDL cholesterol ≥ 50% (e.g., atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily); for patients aged ≥ 75, or if at risk of statin adverse effect, consider moderate-intensity statin instead. b Moderate-intensity statin is intended to lower LDL cholesterol 30%–50% (e.g., atorvastatin 10–20 mg daily, rosuvastatin 5–10 mg daily, or simvastatin 20–40 mg daily). c The 10-year ASCVD risk for fatal or nonfatal myocardial infarction or stroke can be estimated using the online calculator at http:/ / my.americanheart.org/ cvriskcalculator CAD, coronary artery disease. a
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While elevated serum HDL appears to protect against atherosclerosis, recent clinical trials have ailed to show clinical benef t o pharmacologically raising HDL in contemporary treated patients. For example, the prospective placebo-controlled AIM-HIGH and HPS2THRIVE studies demonstrated that niacin (the most e ective available agent to raise serum HDL) did not reduce cardiac event rates in patients who had already achieved desirable LDL levels on statin therapy. In addition, recent clinical studies o two experimental drugs that greatly raise HDL cholesterol (known as cholesteryl ester trans er protein [CETP] inhibitors) showed no clinical benef t. Similarly, clinical trials o drug therapies that reduce elevated triglyceride levels (i.e., using f brates or omega-3 supplements) have not shown signif cant improvement in cardiovascular event rates. Such drugs are now used primarily to reduce severely elevated levels o serum triglycerides to prevent the associated complication o pancreatitis.
Tobacco Smoking Numerous studies have shown that tobacco smoking predisposes to atherosclerosis and ischemic heart disease. Even low level smoking leads to adverse outcomes, but the heaviest smokers have the greatest risk o cardiovascular events. Tobacco smoking could promote atherosclerotic disease in several ways, including enhanced oxidative modif cation o LDL, decreased circulating HDL levels, endothelial dys unction owing to tissue hypoxia and increased oxidant stress, increased platelet adhesiveness, increased expression o soluble LAMs, inappropriate stimulation o the sympathetic nervous system by nicotine, and displacement o oxygen by carbon monoxide rom hemoglobin. Extrapolation rom animal experiments suggests that smoking not only accelerates atherogenesis but also increases the propensity or thrombosis—both components o the “vulnerable patient.” Fortunately, smoking cessation can reverse some o the adverse outcomes. People who stop smoking greatly reduce their likelihood o coronary heart disease, compared with those who continue to smoke. In one study, a ter 3 years o cessation, the risk o coronary artery disease or ormer smokers became similar to subjects who never smoked.
Hypertension Elevated blood pressure (either systolic or diastolic) augments the risk o developing atherosclerosis, coronary heart disease, and stroke (see Chapter 13). The association o elevated blood pressure with cardiovascular disease does not appear to have a specif c threshold. Rather, risk increases continuously with progressively higher pressure values. Systolic pressure predicts adverse outcomes more reliably than does diastolic pressure, particularly in older persons. Hypertension may accelerate atherosclerosis in several ways. Animal studies have shown that elevated blood pressure injures vascular endothelium and may increase the permeability o the vessel wall to lipoproteins. Cyclic circum erential strain, increased in hypertensive arteries, can enhance SMC production o proteoglycans that bind and retain LDL particles, promoting their accumulation in the intima and acilitating their oxidative modif cation. Angiotensin II, a mediator o hypertension (described in Chapter 13), acts not only as a vasoconstrictor but also as a stimulator o oxidative stress (through activation o NADPH oxidases, a source o superoxide anion, O2− ) and as a proin ammatory cytokine. Thus, hypertension may also promote atherogenesis by contributing to a prooxidant and in ammatory state.
Antihypertensive Therapy Like dyslipidemias, treatment o hypertension should start with li estyle modif cations but o ten requires pharmacologic intervention. The Dietary Approaches to Stop Hypertension (DASH) studies demonstrate that a diet high in ruits and vegetables, with dairy products low
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Chapter 5 in at and an overall reduced sodium content, signif cantly improves systolic and diastolic blood pressures. Regular exercise can also reduce resting blood pressure levels. Many medications e ectively lower blood pressure, as described in Chapters 13 and 17.
Diabetes Mellitus and the “Metabolic Syndrome” Diabetes mellitus a ects an estimated 170 million people worldwide, a prevalence projected to grow 40% worldwide by 2030. In the United States alone, 18.2 million people have diabetes, and projections suggest that one in every three children born in 2000 will eventually develop the condition. With a three- to f ve old increased risk o acute coronary events, 80% o diabetic patients succumb to atherosclerosis-related conditions, including coronary heart disease, stroke, and peripheral artery disease. The predisposition o diabetic patients to atherosclerosis may relate in part to accompanying dyslipidemia, to nonenzymatic glycation o lipoproteins (which enhances uptake o cholesterol by scavenger macrophages, as described earlier), or to the associated prothrombotic tendency and antif brinolytic state. Diabetics requently have impaired endothelial unction, gauged by the reduced bioavailability o NO, and increased leukocyte adhesion. Tight control o serum glucose levels in diabetic patients reduces the risk o microvascular complications, such as retinopathy and nephropathy. Yet demonstration o a reduction o macrovascular outcomes, such as myocardial in arction and stroke, by glycemic control remains much more elusive. Indeed, studies have suggested that intense glucose lowering may even augment the incidence o adverse cardiovascular events. In contrast to the uncertain benef ts o intense glycemic control or macrovascular events, treatment o hypertension and dyslipidemia in diabetic patients convincingly reduces the risk o cardiac and cerebrovascular complications. The metabolic syndrome (also known as the “insulin resistance syndrome”) re ers to a cluster o risk actors, including hypertension, hypertriglyceridemia, reduced HDL, hyperglycemia, and visceral obesity (excessive adipose tissue in the abdomen). This constellation associates with a high risk or atherosclerosis in both diabetic and nondiabetic patients, and using currently accepted criteria, 25% o Americans have this condition. The presence o insulin resistance in this syndrome appears to promote atherogenesis long be ore a ected persons develop overt diabetes.
Lack of Physical Activity Exercise may mitigate atherogenesis in several ways. In addition to its benef cial e ects on the lipid prof le and blood pressure, exercise enhances insulin sensitivity and endothelial production o NO. Observational studies o both men and women indicate that even modest activities, such as brisk walking, or as little as 30 minutes per day can protect against cardiovascular mortality.
Estrogen Status Cardiovascular disease dominates other causes o mortality in women, including breast and other cancers. Be ore menopause, women have a lower incidence o coronary events than men. A ter menopause, however, men and women have similar rates. This observation suggests that estrogen (the levels o which decline a ter menopause) may have atheroprotective properties. Physiologic estrogen levels in premenopausal women raise HDL and lower LDL. Experimentally, estrogen also exhibits potentially benef cial antioxidant and antiplatelet actions and improves endothelium-dependent vasodilation. Early observational studies suggested that hormone therapy reduced the risk o coronary artery disease in postmenopausal women, prompting many physicians to prescribe such medications or cardiovascular prevention purposes. However, the Heart and Estrogen/ Progestin
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Replacement Study demonstrated an association between such hormone use and an early increased risk o vascular events in women with preexisting coronary disease. Subsequent randomized primary prevention studies rom the Women’s Health Initiative were terminated prematurely because estrogen-plus-progestin treatment increased cardiovascular risk by 24% overall, with a striking 81% higher risk during the f rst year o therapy. Because currently available clinical trial data do not show that gonadal hormone therapy lowers cardiovascular events and that it may actually be harm ul, such therapy should not be commenced or the sole goal o reducing cardiovascular risk.
Biomarkers o Cardiovascular Risk Despite identif cation o the well-established risk actors just described, one out o f ve cardiovascular events occurs in patients lacking these attributes. In conjunction with growing knowledge about the pathogenesis o atherosclerosis, several novel markers o risk have emerged. These biomarkers serve three primary roles: (1) as a means to help strati y the risk o atherosclerotic disease and thus guide the choice o therapies, (2) as clinical measures to assess treatment e ects, and (3) as potential targets o new therapeutic regimens.
Lipoprotein ( a) Lipoprotein (a), re erred to as Lp(a) and pronounced “L-P-little-a,” independently predicts cardiovascular events in some studies. Lp(a) is a variant o LDL whose major apolipoprotein (apo B-100) links by a disulf de bridge to another protein, apo(a). Apo(a) structurally resembles plasminogen, a plasma protein important in the endogenous lysis o f brin clots (see Chapter 7). Thus, the detrimental e ect attributed to Lp(a) may relate to competition with normal plasminogen activity. Lp(a) is able to enter the arterial intima, and in vitro studies have shown that it encourages in ammation and thrombosis. Lp(a) levels in the population are skewed and not normally distributed, showing a trailing prevalence o the higher levels. Not all population studies support a link between Lp(a) and cardiovascular events, though people with the highest Lp(a) levels do appear to have increased risk. Recent GWAS and Mendelian randomization analyses also support a causal link between Lp(a) and cardiovascular events. Diet and exercise have little impact on Lp(a) levels. O current lipid-lowering agents, niacin has the greatest e ect on Lp(a), lowering its concentration by as much as 20% . However, thus ar, there is no evidence that reduction o Lp(a) by drug therapy improves cardiovascular outcomes.
C-Reactive Protein ( CRP) and Other Markers o Inf ammation Because the pathogenesis o atherosclerosis involves in ammation at every stage, markers o in ammation have undergone evaluation as predictors o cardiac risk. Recall that the process o lipoprotein entry and modif cation in the vessel wall triggers the release o cytokines, ollowed by leukocyte inf ltration, more cytokine release, and smooth muscle migration into— and proli eration within—the intima. Involved cytokines (e.g., IL-6) incite increased hepatic production o acute-phase reactants, including CRP, f brinogen, and serum amyloid A. O these molecules, CRP has shown the greatest promise as a marker o low-grade systemic in ammation associated with atherosclerotic disease. Large studies o apparently healthy men and women indicate that those with higher basal CRP levels have increased risk o adverse cardiovascular outcomes, independent o serum cholesterol concentrations and other traditional risk markers. Multiple prospective studies a f rm that CRP measured by a highly sensitive assay (hsCRP) independently predicts myocardial in arction, stroke, peripheral artery disease, and sudden cardiac death. Although it serves as a marker o risk not captured by traditional algorithms, CRP itsel does not mediate atherogenesis.
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Chapter 5 Recent data support the use o CRP levels to potentially guide therapy. For example, the prospective JUPITER trial studied 17,800 healthy individuals with above-median levels o CRP who did not have elevated LDL and demonstrated a reduced incidence o major cardiovascular events in patients who were treated with statin therapy, compared to those who received a placebo. Given the critical role o in ammation in atherogenesis, ongoing clinical trials are testing available and novel anti-in ammatory medications or the prevention o recurrent cardiovascular events among patients with coronary disease.
Outlook Despite accumulating knowledge o the pathogenesis o atherosclerosis and its clinical sequelae, this disease remains a major cause o death throughout the world. Although improvements in cardiovascular care have reduced age-adjusted mortality rom this condition, it will continue to grow as a menace as the population ages and as developing countries embrace the adverse dietary and activity habits o a Western li estyle. Ongoing research o the biology o atherosclerosis, as well as advances in therapeutic procedures and medications, will undoubtedly continue to urther our abilities to combat this condition. Yet we have not ully capitalized on what we already know—that much cardiovascular risk is modif able. E ective control o the risk actors described earlier remains a critical component to tame this global scourge. It is here that the relationship between the patient and health care provider, and the role o medical proessionals as community leaders advocating healthy li estyles, remain o cardinal importance.
SUMMARY • Atherosclerosis is the leading cause o mortality and morbidity in developed nations and has become a major cause o death in the developing world. • The arterial wall consists o the intima (closest to the arterial lumen), the media (the middle layer), and the adventitia (the outer layer). • The normal endothelium provides a protective, nonthrombogenic sur ace with homeostatic vasodilatory and anti-in ammatory properties. • Early in atherogenesis, injurious stimuli activate endothelial and smooth muscle cells, which recruit in ammatory cells to the vessel wall. • Atherosclerotic plaques orm over decades and can display eatures associated with clinical stability, or a propensity to provoke thrombotic events (“vulnerable” plaques). • Clinical atherosclerotic events result rom narrowing o the vessel lumen, aneurysm ormation, or plaque disruption with superimposed thrombus ormation. • Common mani estations o atherosclerosis include angina pectoris, myocardial in arction, stroke, and peripheral artery disease. • Modif able risk actors or atherosclerosis include dyslipidemia, smoking, hypertension, and diabetes. • Nonmodif able risk actors include advanced age, male sex, and a amily history o premature coronary disease. • Novel biomarkers, such as high-sensitivity C-reactive protein (hsCRP), may prove use ul in def ning risk.
Ack n ow le d gm en t s Contributors to the previous editions o this chapter were Jordan B. Strom, MD; James L. Young, MD; Mary Beth Gordon, MD; Rushika Fernandopulle, MD; Gopa Bhattacharyya, MD; and Joseph Loscalzo, MD, PhD.
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Moore KJ, Tabas I. Macrophages in the pathogenesis o atherosclerosis. Cell. 2011;145:341–355. Schunkert H, et al. Large-scale association analysis identif es 13 new susceptibility loci or coronary artery disease. Nat Genet. 2011;43:333–338. Stein EA, Mellis S, Yancopoulos GD, et al. E ect o a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–1118. Steinberg D. In celebration o the 100th anniversary o the lipid hypothesis o atherosclerosis. J Lipid Res. 2013;54:2946–2949. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment o blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. Circulation. 2013;129:S1–S45. DOI: 10.1161/ 01.cir.0000437738. 63853.7a. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk actor o cardiovascular disease: A rationale or increased e orts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60:716–721.
Ischemic Heart Disease Ja yme Wilder Ma rc S. Sa ba tine Leona rd S. Lilly
Ch a p t e r O u t l i n e Determinants of Myocardial Oxygen Supply and Demand Myocardial Oxygen Supply Myocardial Oxygen Demand Pathophysiology of Ischemia Fixed Vessel Narrowing Endothelial Cell Dys unction Other Causes o Myocardial Ischemia Consequences of Ischemia Ischemic Syndromes Clinical Features of Chronic Stable Angina History Physical Examination Diagnostic Studies Natural History Treatment Medical Treatment o an Acute Episode o Angina Medical Treatment to Prevent Recurrent Ischemic Episodes Medical Treatment to Prevent Acute Cardiac Events Revascularization Medical versus Revascularization Therapy
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I
6
n 1772, the British physician William Heberden reported a disorder in which patients developed an uncom ortable sensation in the chest when walking. Labeling it angina pectoris, Heberden noted that this discom ort would disappear soon a ter the patient stood still but would recur with similar activities. Although he did not know the cause, it is likely that he was the rst to describe the symptoms o ischemic heart disease, a condition o imbalance between myocardial oxygen supply and demand most o ten caused by atherosclerosis o the coronary arteries. Ischemic heart disease now a f icts millions o Americans and is the leading cause o death in industrialized nations. The clinical presentation o ischemic heart disease can be highly variable and orms a spectrum o syndromes (Table 6-1). For example, ischemia may be accompanied by the same exertional symptoms described by Heberden. In other cases, it may occur without any clinical mani estations at all, a condition termed silent ischemia. This chapter describes the causes and consequences o chronic ischemic heart disease syndromes and provides a ramework or the diagnosis and treatment o a ected patients. Angina pectoris remains the most common mani estation o ischemic heart disease and literally means “strangling in the chest.” Although other conditions may lead to similar discom ort, angina re ers speci cally to the uncom ortable sensation in the chest and neighboring structures that arises rom an imbalance between myocardial oxygen supply and demand.
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TABLE 6-1 Clinical Def nitions Syndrome
Description
Ischemic heart disease
Condition in which imbalance between myocardial oxygen supply and demand results in myocardial hypoxia and accumulation o waste metabolites, most o ten caused by atherosclerotic disease o the coronary arteries (o ten termed coronary artery disease) Uncom ortable sensation in the chest and neighboring anatomic structures produced by myocardial ischemia Chronic pattern o transient angina pectoris, precipitated by physical activity or emotional upset, relieved by rest within a ew minutes; episodes o ten associated with temporary depression o the ST segment, but permanent myocardial damage does not result Typical anginal discom ort, usually at rest, which develops because o coronary artery spasm rather than an increase o myocardial oxygen demand; episodes o ten associated with transient shi ts o the ST segment, usually ST elevation (also termed Prinzmetal angina) Asymptomatic episodes o myocardial ischemia; can be detected by electrocardiogram and other laboratory techniques Pattern o increased requency and duration o angina episodes produced by less exertion or at rest; high requency o progression to myocardial in arction i untreated Region o myocardial necrosis usually caused by prolonged cessation o blood supply; most o ten results rom acute thrombus at site o coronary atherosclerotic stenosis; may be a f rst clinical mani estation o ischemic heart disease, or there may be a history o angina pectoris
Angina pectoris Stable angina
Variant angina
Silent ischemia Unstable angina
Myocardial in arction
DETERMINANTS OF MYOCARDIAL OXYGEN SUPPLY AND DEMAND In the normal heart, the oxygen requirements of the myocardium are continuously matched by the coronary arterial supply. Even during vigorous exercise, when the metabolic needs of the heart increase, so does the delivery of oxygen to the myocardial cells so that the balance is maintained. The following sections describe the key determinants of myocardial oxygen supply and demand in a normal person (Fig. 6-1) and how they are altered by the presence of atherosclerotic coronary artery disease (CAD).
Myo c ardial oxyg e n s upply
Myo c ardial oxyg e n de mand
O2 c o nte nt
Wall s tre s s (P × r / 2h)
Co ro nary blo o d flow 1) corona ry pe rfus ion pre s s ure
He art rate
2) corona ry va s cula r re s is ta nce
FIGURE 6-1. Major determinants o myocardial oxygen supply and demand. P, ventricular pressure; r, ventricular radius; h, ventricular wall thickness.
a ) exte rna l compre s s ion b) intrins ic re gula tion
Co ntrac tility
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Myocardial Oxygen Supply The supply o oxygen to the myocardium depends on the oxygen content o the blood and the rate o coronary blood f ow . The oxygen content is determined by the hemoglobin concentration and the degree o systemic oxygenation. In the absence o anemia or lung disease, oxygen content remains airly constant. In contrast, coronary blood ow is much more dynamic, and regulation o that ow is responsible or matching the oxygen supply with metabolic requirements. As in all blood vessels, coronary artery ow (Q) is directly proportional to the vessel’s perusion pressure (P) and is inversely proportional to coronary vascular resistance (R). That is, P Q α R However, unlike other arterial systems in which the greatest blood ow occurs during systole, the predominance o coronary per usion takes place during diastole. The reason or this is that systolic ow is impaired by the compression o the small coronary branches as they course through the contracting myocardium. Coronary ow is unimpaired in diastole because the relaxed myocardium does not compress the coronary vasculature. Thus, in the case o the coronaries, per usion pressure can be approximated by the aortic diastolic pressure. Conditions that decrease aortic diastolic pressure (such as hypotension or aortic valve regurgitation) decrease coronary artery per usion pressure and may lessen myocardial oxygen supply. Coronary vascular resistance is the other major determinant o coronary blood ow. In the normal artery, this resistance is dynamically modulated by (1) orces that externally compress the coronary arteries and (2) actors that alter intrinsic coronary tone.
External Compression External compression is exerted on the coronary vessels during the cardiac cycle by contraction o the surrounding myocardium. The degree o compression is directly related to intramyocardial pressure and is there ore greatest during systole, as described in the previous section. Moreover, when the myocardium contracts, the subendocardium, adjacent to the high intraventricular pressure, is subjected to greater orce than are the outer muscle layers. This is one reason that the subendocardium is the region most vulnerable to ischemic damage.
Intrinsic Control of Coronary Arterial Tone Unlike most tissues, the heart cannot increase oxygen extraction on demand because in its basal state, it removes nearly as much oxygen as possible rom its blood supply. Thus, any additional oxygen requirement must be met by an increase in blood f ow, and autoregulation o coronary vascular resistance is the most important mediator o this process. Factors that participate in the regulation o coronary vascular resistance include the accumulation o local metabolites, endothelium-derived substances, and neural innervation.
Metabolic Factors The accumulation o local metabolites signif cantly a ects coronary vascular tone and acts to modulate myocardial oxygen supply to meet changing metabolic demands. During states o hypoxemia, aerobic metabolism and oxidative phosphorylation in the mitochondria are inhibited and generation o high-energy phosphates, including adenosine triphosphate (ATP), is impaired. Consequently, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) accumulate and are subsequently degraded to adenosine. Adenosine is a potent
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vasodilator and is thought to be the prime metabolic mediator o vascular tone. By binding to receptors on vascular smooth muscle, adenosine decreases calcium entry into cells, which leads to relaxation, vasodilatation, and increased coronary blood ow. Other metabolites that act locally as vasodilators include lactate, acetate, hydrogen ions, and carbon dioxide.
Endothelial Factors Endothelial cells o the arterial wall produce numerous vasoactive substances that contribute to the regulation o vascular tone. Vasodilators produced by the endothelium include nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing actor (EDHF). Endothelin 1 is an example o an endothelium-derived vasoconstrictor. The discovery and signif cance o endothelium-derived NO are highlighted in Box 6-1. In brie , NO regulates vascular tone by di using into and then relaxing neighboring arterial
BOX 6-1
Endothelium-Derived Relaxing Factor, Nitric Oxide, and the Nobel Prize
Normal arterial endothelial cells synthesize potent vasodilator substances that contribute to the modulation o vascular tone. Among the f rst o these to be identif ed were prostacyclin (an arachidonic acid metabolite) and a substance termed endothelium-derived relaxing actor (EDRF). EDRF was f rst studied in the 1970s. In experimental preparations, it was shown that acetylcholine (ACh) has two opposite actions on blood vessels. Its direct e ect on vascular smooth muscle cells is to cause vasoconstriction, but when an intact endothelial lining overlies the smooth muscle cells, vasodilatation occurs instead. Subsequent experiments showed that ACh causes the endothelial cells to release a chemical mediator (that was termed EDRF), which quickly di uses to the adjacent smooth muscle cells and results in their relaxation with subsequent vasodilatation o the vessel. Further research demonstrated that the mysterious EDRF is actually the nitric oxide (NO) radical. Binding o ACh (or another endothelial-dependent vasodilator such as serotonin or histamine) to endothelial cells catalyzes the ormation o NO rom the amino acid l -arginine (see f gure). NO then di uses to the adjacent vascular smooth muscle, where it activates guanylyl cyclase (G-cyclase). G-cyclase in turn orms cyclic guanosine monophosphate (cGMP), which results in smooth muscle cell relaxation through mechanisms that involve a reduction in cytosolic Ca+ + . AGONIST (e .g., ACh, his ta mine, s e rotonin)
Endo the lial c e ll
Nitric oxide syntha s e
L-Arginine
O2 Nitroprus s ide or nitroglyce rin S mo o th mus cle c e ll
L-Citruline
Nitric oxide
Nitric oxide
GTP
G-cycla s e
cGMP
RELAXATION (continues on page 138)
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BOX 6-1
Endothelium-Derived Relaxing Factor, Nitric Oxide, and the Nobel Prize ( continued)
In contrast to the endothelial-dependent vasodilators, some agents cause smooth muscle relaxation independent o the presence o endothelial cells. For example, the drugs sodium nitroprusside and nitroglycerin result in vasodilatation by providing an exogenous source o NO to vascular smooth muscle cells, thereby activating G-cyclase and orming cGMP without endothelial cell participation. In the cardiac catheterization laboratory, the intracoronary administration o ACh in a normal person causes vasodilatation o the vessel, presumably through the release o NO. However, in conditions o endothelial dys unction, such as atherosclerosis, intracoronary ACh administration results in paradoxical vasoconstriction instead. This likely ref ects reduced production o NO by the dys unctional endothelial cells, resulting in unopposed direct vasoconstriction o the smooth muscle by ACh. O particular interest is that the loss o vasodilatory response to in used ACh is evident in persons with certain cardiac risk actors (e.g., elevated LDL cholesterol, hypertension, cigarette smoking) even be ore the physical appearance o atheromatous plaque. Thus, the impaired release o NO may be an early and sensitive predictor or the later development o atherosclerotic lesions. The signi cance o these discoveries was highlighted in 1998, when the Nobel Prize in medicine was awarded to the scientists who discovered the critical role o NO as a cardiovascular signaling molecule.
smooth muscle by a cyclic guanosine monophosphate (cGMP)–dependent mechanism. The production o NO by normal endothelium occurs in the basal state and is additionally stimulated by many substances and conditions. For example, its release is augmented when the endothelium is exposed to acetylcholine (ACh), thrombin, products o aggregating platelets (e.g., serotonin and ADP), or even the shear stress o blood f ow. Although the direct e ect o many o these substances on vascular smooth muscle is to cause vasoconstriction, the induced release o NO rom the normal endothelium results in vasodilatation instead (Fig. 6-2). Prostacyclin, an arachidonic acid metabolite, has vasodilator properties similar to those o NO (see Fig. 6-2). It is released rom endothelial cells in response to many stimuli, including hypoxia, shear stress, ACh, and platelet products (e.g., serotonin). It causes relaxation o vascular smooth muscle by a cyclic AMP–dependent mechanism. EDHF also appears to have important vasodilatory properties. Like endothelial-derived NO, it is a di usible substance released by the endothelium that hyperpolarizes (and thereore relaxes) neighboring vascular smooth muscle cells. EDHF is released by some o the Endo the lial-de pe nde nt vas o dilato rs (ACh, s e rotonin, thrombin, s he a r s tre s s )
Endo the lial c e ll
Prosta cyclin NO
EDHF
Thrombin Angiote ns in II Epine phrine
Endothe lin 1
EDHF S mo o th mus cle c e ll
cAMP
cGMP Re laxatio n
Co ntrac tio n
FIGURE 6-2. Endothelium-derived vasoactive substances and their regulators. Endotheliumderived vasodilators are shown on the le t and include nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing actor (EDHF). Endothelin 1 is an endothelium-derived vasoconstrictor. In the normal state, the vasodilator inf uence predominates over that o vasoconstriction. ACh, acetylcholine; cGMP, cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate.
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same actors that stimulate NO, including ACh and normal pulsatile blood ow. In the coronary circulation, EDHF appears to be more important in modulating relaxation in small arterioles than in the large conduit arteries. Endothelin 1 is a potent vasoconstrictor produced by endothelial cells that partially counteracts the actions o the endothelial vasodilators. Its expression is stimulated by several actors, including thrombin, angiotensin II, epinephrine, and the shear stress o blood ow. Under normal circumstances, the healthy endothelium promotes vascular smooth muscle relaxation (vasodilatation) through elaboration o substances such as NO and prostacyclin, the in uences o which predominate over the endothelial vasoconstrictors (see Fig. 6-2). However, as described later in the chapter, dys unctional endothelium (e.g., in atherosclerotic vessels) secretes reduced amounts o vasodilators, causing the balance to shi t toward vasoconstriction instead.
Neural Factors The neural control o vascular resistance has both sympathetic and parasympathetic components. Under normal circumstances, the contribution o the parasympathetic nervous system appears minor, but sympathetic receptors play an important role. Coronary vessels contain both α-adrenergic and β2-adrenergic receptors. Stimulation o α-adrenergic receptors results in vasoconstriction, whereas β2-receptors promote vasodilatation. It is the interplay among the metabolic, endothelial, and neural regulating actors that determines the net impact on coronary vascular tone. For example, catecholamine stimulation o the heart may initially cause coronary vasoconstriction via the α-adrenergic receptor neural e ect. However, catecholamine stimulation also increases myocardial oxygen consumption through increased heart rate and contractility (β1-adrenergic e ect), and the resulting increased production o local metabolites induces net coronary dilatation instead.
Myocardial Oxygen Demand The three major determinants o myocardial oxygen demand are (1) ventricular wall stress, (2) heart rate, and (3) contractility (which is also termed the inotropic state). Additionally, very small amounts o oxygen are consumed in providing energy or basal cardiac metabolism and electrical depolarization. Ventricular wall stress (σ) is the tangential orce acting on the myocardial f bers, tending to pull them apart, and energy is expended in opposing that orce. Wall stress is related to intraventricular pressure (P), the radius o the ventricle (r), and ventricular wall thickness (h) and is approximated by Laplace’s relationship: P ×r σ= 2h Thus, wall stress is directly proportional to systolic ventricular pressure. Circumstances that increase pressure in the le t ventricle, such as aortic stenosis or hypertension, augment wall stress and myocardial oxygen consumption. Conditions that decrease ventricular pressure, such as antihypertensive therapy, reduce myocardial oxygen consumption. Because wall stress is also directly proportional to the radius o the le t ventricle, conditions that augment le t ventricular (LV) f lling (e.g., mitral or aortic regurgitation) raise wall stress and oxygen consumption. Conversely, any physiologic or pharmacologic maneuver that decreases LV f lling and size (e.g., nitrate therapy) reduces wall stress and myocardial oxygen consumption. Finally, wall stress is inversely proportional to ventricular wall thickness because the orce is spread over a greater muscle mass. A hypertrophied heart has lower wall stress and oxygen
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Chapter 6 consumption per gram o tissue than a thinned-wall heart. Thus, when hypertrophy develops in conditions o chronic pressure overload, such as aortic stenosis, it serves a compensatory role in reducing oxygen consumption. The second major determinant o myocardial oxygen demand is heart rate. I the heart rate accelerates—during physical exertion, or example—the number o contractions and the amount o ATP consumed per minute increases and oxygen requirements rise. Conversely, slowing the heart rate (e.g., with a β-blocker drug) decreases ATP utilization and oxygen consumption. The third major determinant o oxygen demand is myocardial contractility, a measure o the orce o contraction (see Chapter 9). Circulating catecholamines, or the administration o positive inotropic drugs, directly increase the orce o contraction, which augments oxygen utilization. Conversely, negative inotropic e ectors, such as β-adrenergic–blocking drugs, decrease myocardial oxygen consumption. In the normal state, autoregulatory mechanisms adjust coronary tone to match myocardial oxygen supply with oxygen requirements. In the absence o obstructive coronary disease, these mechanisms maintain a airly constant rate o coronary ow, as long as the aortic perusion pressure is approximately 60 mm Hg or greater. In the setting o advanced coronary atherosclerosis, however, the all in per usion pressure distal to the arterial stenosis, along with dys unction o the endothelium o the involved segment, sets the stage or a mismatch between the available blood supply and myocardial metabolic demands.
PATHOPHYSIOLOGY OF ISCHEMIA The traditional view has been that myocardial ischemia in CAD results rom f xed atherosclerotic plaques that narrow the vessel’s lumen and limit myocardial blood supply. However, research has demonstrated that the reduction o blood ow in this condition results rom the combination o f xed vessel narrowing and abnormal vascular tone, contributed to by atherosclerosis-induced endothelial cell dys unction.
Fixed Vessel Narrowing The hemodynamic signif cance o f xed atherosclerotic coronary artery stenoses relates to both the uid mechanics and the anatomy o the vascular supply.
Fluid Mechanics Poiseuille’s law states that or ow through a vessel, ∆P π r 4 Q= 8η L in which Q is ow, ΔP is the pressure di erence between the points being measured, r is the vessel radius, η is the uid viscosity, and L is the vessel length. By analogy to Ohm’s law, ow is also equal to the pressure di erence divided by the resistance (R) to ow: Q=
∆P R
By combining these two ormulas and rearranging, resistance to blood ow in a vessel can be expressed as R=
8η L πr 4
Ischemic Heart Disease
4x Ma xima l corona ry flow 3x
z
e
d
m
e
a
n
f
l
o
w
5x
2x
o
r
m
a
l
i
Thus, vascular resistance is governed, in part, by the geometric component L/ r 4. That is, the hemodynamic signif cance o a stenotic lesion depends on its length and, ar more importantly, on the degree o vessel narrowing (i.e., the reduction o r) that it causes.
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N
Anatomy
Re s ting corona ry flow 1x
The coronary arteries consist o large, proximal epicardial segments and smaller, 0 20 40 60 80 100 distal resistance vessels (arterioles). The Le s ion dia me te r (%) proximal vessels are subject to overt atherosclerosis that results in stenotic plaques. FIGURE 6-3. Resting and maximal coronary blood The distal vessels are usually ree o ow- f ows are a ected by the magnitude o proximal limiting plaques and can adjust their vaso- arterial stenosis ( percent lesion diameter) . The dotted line indicates resting blood f ow, and the solid motor tone in response to metabolic needs. line represents maximal blood f ow (i.e., when there These resistance vessels serve as a reserve, is ull dilatation o the distal resistance vessels). increasing their diameter with exertion to Compromise o maximal blood f ow is evident when the meet increasing oxygen demand and dilat- proximal stenosis reduces the coronary lumen diameter ing, even at rest, i a proximal stenosis is by more than approximately 70%. Resting f ow may be compromised i the stenosis exceeds approximately su f ciently severe. The hemodynamic signif cance o a coro- 90%. (Modi ed rom Gould KL, Lipscomb K. E ects o coronary stenoses on coronary f ow reserve and nary artery narrowing depends on both the resistance. Am J Cardiol. 1974;34:50.) degree o stenosis o the epicardial portion o the vessel and the amount o compensatory vasodilatation the distal resistance vessels are able to achieve (Fig. 6-3). I a stenosis narrows the lumen diameter by less than 60% , the maximal potential blood ow through the artery is not signif cantly altered and, in response to exertion, the resistance vessels can dilate to provide adequate blood ow. When a stenosis narrows the diameter by more than approximately 70% , resting blood ow is normal, but maximal blood ow is reduced even with ull dilatation o the resistance vessels. In this situation, when oxygen demand increases (e.g., rom the elevated heart rate and orce o contraction during physical exertion), coronary ow reserve is inadequate, oxygen demand exceeds supply, and myocardial ischemia results. I the stenosis compromises the vessel lumen by more than approximately 90% , then even with maximal dilatation o the resistance vessels, blood ow may be inadequate to meet basal requirements and ischemia can develop at rest. Although collateral connections (see Chapter 1) may become apparent between unobstructed coronaries and sites distal to atherosclerotic stenoses, and such ow can bu er the all in myocardial oxygen supply, it is o ten not su f cient to prevent ischemia during exertion in critically narrowed vessels.
Endothelial Cell Dys unction In addition to f xed vessel narrowing, the other major contributor to reduced myocardial oxygen supply in chronic CAD is endothelial dys unction. Abnormal endothelial cell unction can contribute to the pathophysiology o ischemia in two ways: (1) by inappropriate vasoconstriction o coronary arteries and (2) through loss o normal antithrombotic properties.
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Inappropriate Vasoconstriction In normal persons, physical activity or mental stress results in measurable coronary artery va sodila ta tion . This e ect is thought to be regulated by activation o the sympathetic nervous system, with increased blood f ow and shear stress stimulating the release o endothelial-derived vasodilators, such as NO. It is postulated that in typical people, the relaxation e ect o NO outweighs the direct α-adrenergic constrictor e ect o catecholamines on arterial smooth muscle, such that vasodilatation results. However, in patients with dys unctional endothelium (e.g., atherosclerosis), an impa ired relea se of en dothelia l va sodila tors leaves the direct catecholamine e ect unopposed, such that relative vasoconstriction occurs instead. The resultant decrease in coronary blood f ow contributes to ischemia. Even the vasodilatory e ect o local metabolites (such as adenosine) is attenuated in patients with dys unctional endothelium, urther uncoupling the regulation o vascular tone rom metabolic demands. In patients with risk actors or CAD, such as hypercholesterolemia, diabetes mellitus, hypertension, and cigarette smoking, impaired endothelial-dependent vasodilatation is noted even before visible atherosclerotic lesions have developed. This suggests that endothelial dysunction occurs very early in the atherosclerotic process. Inappropriate vasoconstriction also appears to be important in acute coronary syndromes, such as unstable angina and myocardial in arction (MI). As described in Chapter 7, the usual cause o acute coronary syndromes is disruption o atherosclerotic plaque, with superimposed platelet aggregation and thrombus ormation. Normally, the products o platelet aggregation in a developing clot (e.g., serotonin and ADP) result in vasodilatation because they stimulate the endothelial release o NO. However, with dys unctional endothelium, the direct vasoconstricting actions o platelet products predominate (Fig. 6-4), urther compromising f ow through the arterial lumen.
Loss of Normal Antithrombotic Properties In addition to their vasodilatory actions, actors released rom endothelial cells (including NO and prostacyclin) also exert antithrombotic properties by inter ering with platelet aggregation (see Fig. 6-4). However, in states o endothelial cell dys unction, release o these substances is reduced; there ore, the antithrombotic e ect is attenuated. Thus, in syndromes characterized by thrombosis (i.e., the acute coronary syndromes described in Chapter 7), the impaired release o NO and prostacyclin allows platelets to aggregate and to secrete their potentially harm ul procoagulants and vasoconstrictors.
Other Causes of Myocardial Ischemia In addition to atherosclerotic CAD, other conditions may result in an imbalance between myocardial oxygen supply and demand and result in ischemia. Other common causes o decreased myocardial oxygen supply include (1) decreased per usion pressure due to hypotension (e.g., in a patient with hypovolemia or septic shock) and (2) a severely decreased blood oxygen content (e.g., marked anemia, or impaired oxygenation o blood by the lungs). For example, a patient with massive bleeding rom the gastrointestinal tract may develop myocardial ischemia and angina pectoris, even in the absence o atherosclerotic coronary disease, because o reduced oxygen supply (i.e., the loss o hemoglobin and hypotension). On the other side o the balance, a pro ound increase in myocardial oxygen demand can cause ischemia even in the absence o coronary atherosclerosis. This can occur, or example, with rapid tachycardias, acute hypertension, or severe aortic stenosis.
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Aggre ga ting pla te le ts :
–
ADP 5-HT TXA2
+ Endothe lia l ce ll
S mooth mus cle ce ll
Pros ta cyclin NO
Co ntrac tio n
Re laxatio n
A FIGURE 6-4. The interaction between platelets and endothelial cells. A. Normal endothelium. Aggregating platelets release thromboxane (TXA2) and serotonin (5-HT), the direct vascular effects of which cause contraction of vascular smooth muscle and vasoconstriction. However, platelet products (e.g., ADP and 5-HT) also stimulate the endothelial release of the potent vasodilators nitric oxide (NO) and prostacyclin, such that the net effect is smooth muscle relaxation instead. Endothelial production of NO and prostacyclin also serves antithrombotic roles, which limit further platelet aggregation. ADP, adenosine diphosphate. B. Dysfunctional endothelium demonstrates impaired release of the vasodilator substances, such that net smooth muscle contraction and vasoconstriction supervene. The reduced endothelial release of NO and prostacyclin diminishes their antiplatelet effect, such that thrombosis proceeds unchecked.
Aggre ga ting pla te le ts :
–
ADP 5-HT TXA2
+ Dys functiona l e ndothe lium
S mooth mus cle ce ll
Pros ta cyclin
NO
Re laxatio n
Co ntrac tio n
B
CONSEQUENCES OF ISCHEMIA The consequences o ischemia ref ect the inadequate myocardial oxygenation and local accumulation o metabolic waste products. For example, during ischemia, myocytes convert rom aerobic to anaerobic metabolic pathways. The reduced generation o ATP impairs the interaction o the contractile proteins and results in a transient reduction o both ventricular systolic contraction and diastolic relaxation, as each are energy-dependent processes. The consequent elevation o LV diastolic pressure is transmitted (via the le t atrium and pulmonary veins) to the pulmonary capillaries and can precipitate pulmonary congestion and the symptom o dyspnea (shortness o breath). In addition, metabolic products such as lactate, serotonin, and adenosine accumulate locally. It is suspected that one or more o these compounds activate peripheral pain receptors in the C7 through T4 distribution and may be the mechanism by which the discom ort o angina is produced. The accumulation o local metabolites and transient abnormalities o myocyte ion transport may also precipitate arrhythmias (see Chapter 11). The ultimate ate o myocardium subjected to ischemia depends on the severity and duration o the imbalance between oxygen supply and demand. It was previously thought that ischemic cardiac injury results in either irreversible myocardial necrosis (i.e., MI) or rapid and ull recovery o myocyte unction (e.g., a ter a brie episode o typical angina). It is now known that in addition
144
Chapter 6 to those outcomes, ischemic insults can sometimes result in a period o prolonged contractile dys unction without myocyte necrosis, and recovery o normal unction may ultimately ollow. For example, stunned myocardium re ers to tissue that, a ter su ering an episode o severe acute, transient ischemia (but not necrosis), demonstrates prolonged systolic dys unction even a ter the return o normal myocardial blood f ow. In this setting, the unctional, biochemical, and structural abnormalities ollowing ischemia are reversible and contractile unction gradually recovers. The mechanism responsible or this delayed recovery o unction involves myocyte calcium overload and the accumulation o oxygen-derived ree radicals during ischemia. In general, the magnitude o stunning is proportional to the degree o the preceding ischemia, and this state is likely the pathophysiologic response to an ischemic insult that just alls short o causing irreversible necrosis. In contrast, hibernating myocardium re ers to tissue that mani ests chronic ventricular contractile dys unction due to a persistently reduced blood supply, usually because o multivessel CAD. In this situation, irreversible damage has not occurred and ventricular unction can promptly improve i appropriate blood f ow is restored by percutaneous or surgical revascularization. Special “viability” imaging studies (e.g., positron emission tomography or dobutamine echocardiography, as described in Chapter 3) o patients with CAD and contractile dys unction can di erentiate hibernating rom in arcted myocardium. That distinction can help guide the decision o whether to undertake coronary revascularization, because hibernating myocardium would be expected to regain contractile unction with restoration o blood f ow, whereas in arcted myocardium would not.
Ischemic Syndromes Depending on the underlying pathophysiologic process and the timing and severity o a myocardial ischemic insult, a spectrum o distinct clinical syndromes may result, as illustrated in Figure 6-5. e nd othe lia l c e ll
A. No rmal Iume n
• Pa te nt Iume n • Norma l e ndothe lia l function • P la te le t a ggre ga tion inhibite d
p la q ue
B. S table • Lume n na rrowe d by pla que • Ina ppropria te va s ocons triction
ang ina
C. Uns table ang ina
p la te le ts thromb us
• P la que rupture • P la te le t a ggre ga tion • Thrombus forma tion • Unoppos e d va s ocons triction
D. Variant ang ina
• No ove rt pla que s • Inte ns e va s os pa s m
FIGURE 6-5. Pathophysiologic f ndings in anginal syndromes. A. Normal coronary arteries are widely patent, and the endothelium unctions normally. B. In stable angina, atherosclerotic plaque and inappropriate vasoconstriction (caused by dys unctional endothelium) reduce the vessel lumen’s size and coronary blood f ow. C. In unstable angina, disruption o the plaque triggers platelet aggregation, thrombus ormation, and vasoconstriction, all o which contribute to reduced coronary blood supply. D. In variant angina, atherosclerotic plaques are absent; rather, ischemia is due to intense vasospasm that reduces myocardial oxygen supply.
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Stable Angina Chronic stable angina mani ests as a pattern o predictable, transient chest discom ort during exertion or emotional stress. It is generally caused by f xed, obstructive atheromatous plaque in one or more coronary arteries (see Fig. 6-5B). The pattern o symptoms is usually related to the degree o stenosis. As described in the earlier section on pathophysiology, when atherosclerotic stenoses narrow a coronary artery lumen diameter by more than approximately 70% , the reduced ow capacity may be su f cient to serve the low cardiac oxygen needs at rest but is insu f cient to compensate or any signif cant increase in oxygen demand (see Fig. 6-3). During physical exertion, or example, activation o the sympathetic nervous system results in increased heart rate, blood pressure, and contractility, all o which augment myocardial oxygen consumption. During the period that oxygen demand exceeds available supply, myocardial ischemia results, o ten accompanied by the chest discom ort o angina pectoris. The ischemia and symptoms persist until the increased demand is alleviated and oxygen balance is restored. Potentially contributing to the inadequate oxygen supply in stable angina is inappropriate coronary vasoconstriction caused, at least in part, by atherosclerosis-associated endothelial dys unction. Recall that normally, the high myocardial oxygen demand during exertion is balanced by an increased supply o blood as the accumulation o local metabolites induces vasodilatation. With endothelial cell dys unction, however, vasodilatation is impaired and the vessels may paradoxically vasoconstrict instead, in response to exercise-induced catecholamine stimulation o α-adrenergic receptors on the coronary artery smooth muscle cells. As a result, the extent o coronary artery narrowing in patients with atherosclerosis is not necessarily constant. Rather, it can vary rom moment to moment because o changes in the superimposed coronary vascular tone. For some patients with stable angina, alterations in tone play a minimal role in the decreased myocardial oxygen supply, and the level o physical activity required to precipitate angina is airly constant. These patients have f xed-threshold angina. In other cases, the degree o dynamic obstruction caused by vasoconstriction or vasospasm plays a more prominent role, and such patients may have variable-threshold angina. For example, on a given day, a patient with variable-threshold angina can exert hersel or himsel without chest discom ort, but on another day, the same degree o myocardial oxygen demand does produce symptoms. The di erence re ects alterations in vascular tone over the sites o f xed stenosis. Other clinical eatures o chronic stable angina are described in greater detail later in the chapter.
Unstable Angina A patient with chronic stable angina may experience a sudden increase in the tempo and duration o ischemic episodes, occurring with lesser degrees o exertion and even at rest. This acceleration o symptoms is known as unstable angina, which can be a precursor to an acute MI. Unstable angina and acute MI are also known as acute coronary syndromes and result rom specif c pathophysiologic mechanisms, most commonly rupture o an unstable atherosclerotic plaque with subsequent platelet aggregation and thrombosis (see Fig. 6-5C). These syndromes are described in detail in Chapter 7.
Variant Angina A small minority o patients mani est episodes o ocal coronary artery spasm in the absence o overt atherosclerotic lesions, and this syndrome is known as variant angina or Prinzmetal angina. In this case, intense vasospasm alone reduces coronary oxygen supply and results in angina (see Fig. 6-5D). The mechanism by which such pro ound spasm develops is not completely understood but may involve increased sympathetic activity in combination with
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Chapter 6 endothelial dys unction. It is thought that many patients with variant angina may actually have early atherosclerosis mani ested only by a dys unctional endothelium, because the response to endothelium-dependent vasodilators (e.g., ACh and serotonin) is o ten abnormal. Variant angina o ten occurs at rest because ischemia in this case results rom transient reduction o the coronary oxygen supply rather than an increase in myocardial oxygen demand.
Silent Ischemia Episodes o cardiac ischemia sometimes occur in the absence o perceptible discom ort or pain, and such instances are re erred to as silent ischemia. These asymptomatic episodes can occur in patients who on other occasions experience typical symptomatic angina. Conversely, in some patients, silent ischemia may be the only mani estation o CAD. It may be di f cult to diagnose silent ischemia on clinical grounds, but its presence can be detected by laboratory techniques such as continuous ambulatory electrocardiography or it can be elicited by exercise stress testing, as described later in the chapter. One study estimated that silent ischemic episodes occur in 40% o patients with stable symptomatic angina and in 2.5% to 10% o asymptomatic middleaged men. When considering the importance o anginal discom ort as a physiologic warning signal, the asymptomatic nature o silent ischemia becomes all the more concerning. The reason why some episodes o ischemia are silent whereas others are symptomatic has not been elucidated. The degree o ischemia cannot ully explain the disparity, because even MI may present without symptoms in some patients. Silent ischemia has been reported to be more common among diabetic patients (possibly due to impaired pain sensation rom peripheral neuropathy), the elderly, and in women.
Syndrome X The term syndrome X re ers to patients with typical symptoms o angina pectoris who have no evidence o signif cant atherosclerotic coronary stenoses on coronary angiograms. Some o these patients may show def nite laboratory signs o ischemia during exercise testing. The pathogenesis o ischemia in this situation may be related to inadequate vasodilator reserve o the coronary resistance vessels. It is thought that the resistance vessels (which are too small to be visualized by coronary angiography) may not dilate appropriately during periods o increased myocardial oxygen demand. Microvascular dys unction, vasospasm, and hypersensitive pain perception may each contribute to this syndrome. Patients with syndrome X have a better prognosis than those with overt atherosclerotic disease.
CLINICAL FEATURES OF CHRONIC STABLE ANGINA History The most important part o the clinical evaluation o ischemic heart disease is the history described by the patient. Because chest pain is such a common complaint, it is important to ocus on the characteristics that help distinguish myocardial ischemia rom other causes o discom ort. From a diagnostic standpoint, it would be ideal to interview and examine a patient during an actual episode o angina, but most people are asymptomatic during routine clinic examinations. There ore, a care ul history probing several eatures o the discom ort should be elicited.
Quality Angina is most o ten described as a “pressure,” “discom ort,” “tightness,” “burning,” or “heaviness” in the chest. It is rare that the sensation is actually described as a “pain,” and o ten a patient will correct the physician who re ers to the anginal symptom as such.
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Sometimes, a patient likens the sensation to “an elephant sitting on my chest.” Anginal discom ort is neither sharp nor stabbing, and it does not vary signif cantly with inspiration or movement o the chest wall. It is a steady discom ort that lasts a ew minutes, yet rarely more than 5 to 10 minutes. It always lasts more than a ew seconds, and this helps to di erentiate it rom sharper and brie er musculoskeletal pains. While describing angina, the patient may place a clenched f st over his or her sternum, re erred to as the Levine sign, as i def ning the constricting discom ort by that tight grip.
Location Anginal discom ort is usually diffuse rather than localized to a single point. It is most o ten located in the retrosternal area or in the le t precordium but may occur anywhere in the chest, back, arms, neck, lower ace, or upper abdomen. It o ten radiates to the shoulders and inner aspect o the arms, especially on the le t side.
Accompanying Symptoms During the discom ort o an acute anginal attack, generalized sympathetic and parasympathetic stimulation may result in tachycardia, diaphoresis, and nausea. Ischemia also results in transient dys unction o LV systolic contraction and diastolic relaxation. The resultant elevation o LV diastolic pressure is transmitted to the pulmonary vasculature and o ten causes dyspnea during the episode. Transient fatigue and weakness are also common, particularly in elderly patients. When such symptoms occur as a consequence o myocardial ischemia but are unaccompanied by typical chest discom ort, they are re erred to as “anginal equivalents.”
Precipitants Angina, when not caused by pure vasospasm, is precipitated by conditions that increase myocardial oxygen demand (e.g., increased heart rate, contractility, or wall stress). These include physical exertion, anger, and other emotional excitement. Additional actors that increase myocardial oxygen demand and can precipitate anginal discom ort in patients with CAD include a large meal or cold weather. The latter induces peripheral vasoconstriction, which in turn augments myocardial wall stress as the le t ventricle contracts against the increased resistance. Angina is generally relieved within minutes a ter the cessation o the activity that precipitated it and even more quickly (within 3 to 5 minutes) by sublingual nitroglycerin. This response can help di erentiate myocardial ischemia rom many o the other conditions that produce chest discom ort. Patients who experience angina primarily due to increased coronary artery tone or vasospasm o ten develop symptoms at rest, independent o activities that increase myocardial oxygen demand.
Frequency Although the level o exertion necessary to precipitate angina may remain airly constant, the requency o episodes varies considerably because patients quickly learn which activities cause their discom ort and avoid them. It is thus important to inquire about reductions in activities o daily living when taking the history.
Risk Factors In addition to the description o chest discom ort, a care ul history should uncover risk actors that predispose to atherosclerosis and CAD, including cigarette smoking, dyslipidemia, hypertension, diabetes, and a amily history o premature coronary disease (see Chapter 5).
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Chapter 6
Differential Diagnosis Several conditions can give rise to symptoms that mimic the transient chest discom ort o angina pectoris, including other cardiac causes (e.g., pericarditis), gastrointestinal disorders (e.g., gastroesophageal re ux, peptic ulcer disease, esophageal spasm, or biliary pain), and musculoskeletal conditions (including chest wall pain, spinal osteoarthritis, and cervical radiculitis). The history remains o paramount importance in distinguishing myocardial ischemia rom these disorders. In contrast to angina pectoris, gastrointestinal causes o recurrent chest pain are o ten precipitated by certain oods and are unrelated to exertion. Musculoskeletal causes o chest discom ort tend to be more superf cial or can be localized to a discrete spot (i.e., the patient can point to the pain with one f nger) and o ten vary with changes in position. Similarly, the presence o pleuritic pain (sharp pain aggravated by respiratory movements) argues against angina as the cause; this symptom is more likely a result o pericarditis, or an acute pulmonary condition such as pulmonary embolism or acute pneumothorax. Use ul di erentiating eatures o recurrent chest pain are listed in Table 6-2.
TABLE 6-2 Causes of Recurrent Chest Pain Condition Cardiac Myocardial ischemia
Pericarditis
Gastrointestinal Gastroesophageal ref ux
Peptic ulcer disease
Esophageal spasm
Biliary colic
Musculoskeletal Costochondral syndrome
Cervical radiculitis
ECG, electrocardiogram.
Differentiating Features • Retrosternal tightness or pressure; typically radiates to the neck, jaw, or le t shoulder and arm • Lasts a ew minutes (usually < 10) • Brought on by exertion, relieved by rest or nitroglycerin • ECG: transient ST depressions or elevations, or f attened or inverted T waves • Sharp, pleuritic pain that varies with position; riction rub may be present on auscultation • Can last or hours to days • ECG: di use ST elevations and PR deviation (see Chapter 14) • Retrosternal burning • Precipitated by certain oods, worsened by supine position, una ected by exertion • Relieved by antacids • Epigastric ache or burning • Occurs a ter meals, una ected by exertion • Relieved by antacids, not by nitroglycerin • Retrosternal pain accompanied by dysphagia • Precipitated by meals, una ected by exertion • May be relieved by nitroglycerin • Constant, deep pain in right upper quadrant; can last or hours • Brought on by atty oods, una ected by exertion • Not relieved by antacids or nitroglycerin • • • • •
Sternal pain worsened by chest movement Costochondral junctions tender to palpation Relieved by anti-inf ammatory drugs, not by nitroglycerin Constant ache or shooting pains, may be in a dermatomal distribution Worsened by neck motion
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Physical Examination I it is possible to examine a patient during an anginal attack, several transient physical signs may be detected (Fig. 6-6). An increased heart rate and blood pressure are common because o the augmented sympathetic response. Myocardial ischemia may lead to papillary muscle dys unction and there ore mitral regurgitation. Ischemia-induced regional ventricular contractile abnormalities can sometimes be detected as an abnormal bulging impulse on palpation o the le t chest. Ischemia decreases ventricular compliance, producing a sti ened ventricle and there ore an S4 gallop on physical examination during atrial contraction (see Chapter 2). However, i the patient is ree o chest discom ort during the examination, there may be no abnormal cardiac physical f ndings. Physical examination should also assess or signs o atherosclerotic disease in more accessible vascular beds. For example, carotid bruits may indicate the presence o cerebrovascular disease, whereas emoral artery bruits or diminished pulses in the lower extremities can be a clue to peripheral arterial disease (see Chapter 15).
Diagnostic Studies Once angina is suspected, several diagnostic procedures may be help ul in conf rming myocardial ischemia as the cause. Because many o these tests are costly, it is important to choose the appropriate studies or each patient.
Electrocardiogram One o the most use ul tools is an electrocardiogram (ECG) obtained during an anginal episode. Although this is easy to arrange when symptoms occur in hospitalized patients, it may not be possible to “catch” episodes in people seen on an outpatient basis. During myocardial ischemia, ST-segment and T-wave changes can appear (Fig. 6-7). Acute ischemia usually results in transient horizontal or downsloping ST-segment depressions and T-wave attening or inversions. Occasionally, ST-segment elevations are seen, suggesting more severe transmural myocardial ischemia, and can also be observed during the intense vasospasm o variant angina. In contrast to the ECG o a patient with an acute MI, the ST deviations seen in patients with stable angina quickly normalize with resolution o the patient’s symptoms. In act,
Myoca rdia l Is che mia
S ys tolic function
Dia s tolic complia nce
P a pilla ry mus cle dys function
S4
Mitra l re gurgita tion
S ympa the tic tone
P ulmona ry conge s tion
Dys kine tic a pica l impuls e
Ra le s
Dia phore s is He a rt ra te Blood pre s s ure
FIGURE 6-6. Pathophysiology of physical signs during acute myocardial ischemia.
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Chapter 6 Norma l
S ube ndoca rdia l is che mia
ST de pre s s ion (horizonta l)
ST de pre s s ion (downs loping)
Tra ns mura l is che mia
T wave inve rs ion
ST e leva tion
FIGURE 6-7. Common transient ECG abnormalities during ischemia. Subendocardial ischemia causes ST-segment depressions and/ or T-wave f attening or inversions. Severe transient transmural ischemia can result in ST-segment elevations, similar to the early changes in acute myocardial in arction. When transient ischemia resolves, so do the electrocardiographic changes.
ECGs obtained during periods ree o ischemia are completely normal in approximately hal o patients with stable angina. In others, chronic “nondiagnostic” ST and T-wave deviations may be present. Evidence o a previous MI (e.g., pathologic Q waves) on the ECG also points to the presence o underlying coronary disease.
Stress Testing Because ECGs obtained during or between episodes o chest discom ort may be normal, such tracings do not rule out underlying ischemic heart disease. For this reason, provocative exercise or pharmacologic stress tests are valuable diagnostic and prognostic aids.
Standard Exercise Testing For many patients suspected o having CAD, a standard exercise test is per ormed. During this test, the patient exercises on a treadmill or a stationary bicycle to progressively higher workloads and is observed or the development o chest discom ort or excessive dyspnea. The heart rate and ECG are continuously monitored, and blood pressure is checked at regular intervals. The test is continued until angina develops, signs o myocardial ischemia appear on the ECG, a target heart rate is achieved (85% o the maximal predicted heart rate [MHR]; the MHR is calculated as 220 beats/ min minus the patient’s age), or the patient becomes too atigued to continue. The test is considered abnormal i the patient’s typical chest discom ort is reproduced or i ECG abnormalities consistent with ischemia develop (i.e., greater than 1 mm horizontal or downsloping ST-segment depressions). Among patients who later undergo diagnostic coronary angiography, the ECG changes noted above have a sensitivity o approximately 65% to 70% and specif city o 75% to 80% or the detection o anatomically signif cant CAD. The stress test is considered markedly positive i one or more o the ollowing signs o severe ischemic heart disease occur: (1) ischemic ECG changes develop in the f rst 3 minutes o exercise or persist 5 minutes a ter exercise has stopped; (2) the magnitude o the ST-segment depressions is greater than 2 mm; (3) the systolic blood pressure abnormally alls during exercise (i.e., resulting rom ischemia-induced impairment o contractile unction); (4) high-grade ventricular arrhythmias develop; or (5) the patient cannot exercise or at least 2 minutes because o cardiopulmonary limitations. Patients with markedly positive tests are more likely to have severe multivessel coronary disease. The utility o a stress test may be a ected by the patient’s medications. For example, β-blockers or certain calcium channel blockers (verapamil, diltiazem) may blunt the ability to
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achieve the target heart rate. In these situations, one must consider the purpose o the stress test. I it is to determine whether ischemic heart disease is present, then those medications are typically withheld or 24 to 48 hours be ore the test. On the other hand, i the patient has known ischemic heart disease and the purpose o the test is to assess the e f cacy o the current medical regimen, testing should be per ormed while the patient takes his or her usual antianginal medications.
Nuclear Imaging Studies Since a standard exercise test relies on ischemia-related changes on the ECG, the test is less use ul in patients with baseline abnormalities o the ST segments (e.g., as seen in le t bundle branch block or LV hypertrophy). In addition, the standard exercise stress test sometimes yields equivocal results in patients or whom the clinical suspicion o ischemic heart disease is high. In these situations, radionuclide imaging can be combined with exercise testing to overcome these limitations and to increase the sensitivity and specif city o the study. As described in Chapter 3, during such myocardial per usion imaging, a radionuclide (commonly either a technetium-99m–labeled compound or thallium-201) is injected intravenously at peak exercise, a ter which imaging is per ormed. The radionuclide accumulates in proportion to the degree o per usion o viable myocardial cells. There ore, areas o poor perusion (i.e., regions o ischemia) during exercise do not accumulate radionuclide and appear as “cold spots” on the image. However, irreversibly in arcted areas also do not take up the radionuclide, and they too will appear as cold spots. To di erentiate between transient ischemia and in arcted tissue, imaging is also per ormed at rest (either be ore or several hours a ter the exercise portion o the test). I the cold spot f lls in, a region o transient ischemia has been identif ed (Fig. 3-18). I the cold spot remains unchanged, a region o irreversible infarction is likely. Standard radionuclide exercise tests are 80% to 90% sensitive and approximately 80% specif c or the detection o clinically signif cant CAD. Positron emission tomography (PET; see Chapter 3), another orm o nuclear stress imaging that is not as widely available, o ers superior spatial and temporal resolution, with sensitivity and specif city o 90% or greater. Because these nuclear imaging techniques are expensive, their use in screening or CAD should be reserved or (1) patients in whom baseline ECG abnormalities preclude interpretation o a standard exercise test or or (2) improvement in test sensitivity when standard stress test results are discordant with the clinical suspicion o coronary disease.
Exercise Echocardiography Exercise testing with echocardiographic imaging is another technique to diagnose myocardial ischemia in patients with baseline ST or T-wave abnormalities or in those with equivocal standard stress tests. In this procedure, LV contractile unction is assessed by echocardiography at baseline and immediately a ter treadmill or bicycle exercise. The test indicates inducible myocardial ischemia i regions o ventricular contractile dys unction develop with exertion and has a sensitivity o approximately 80% and a specif city o about 90% or the detection o clinically signif cant CAD.
Pharmacologic Stress Tests For patients unable to exercise (e.g., those with hip or knee arthritis), pharmacologic stress testing can be per ormed instead using various agents, including vasodilators or inotropes. The most common approach is to use a coronary vasodilator such as adenosine, regadenoson,
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Chapter 6 or dipyridamole. Adenosine and regadenoson bind to adenosine A2a receptors on vascular smooth muscle cells, resulting in coronary vasodilatation. As ischemic regions are already maximally dilated (in compensation or the epicardial coronary stenoses), the vasodilatation induced by these agents increases ow to the myocardium per used by healthy coronary arteries and thus “steals” blood away rom the diseased segments. Dipyridamole causes a similar e ect indirectly, as it blocks normal cellular uptake and destruction o adenosine, thereby increasing adenosine’s circulating concentration and subsequent stimulation o the A2a receptor. Administration o these pharmacologic agents is typically coupled with nuclear imaging, to reveal regions o impaired myocardial per usion. An alternative to vasodilating agents, pharmacologic stress testing can also be per ormed using the inotrope dobutamine, which increases myocardial oxygen demand by augmenting heart rate and the orce o contraction, thus simulating some o the e ects o exercise. Accompanying imaging (typically nuclear imaging or echocardiography) reveals regions o drug-induced ischemia. Vasodilator pharmacologic stress testing is generally pre erred over dobutamine testing or the assessment o ischemia, as the ormer produces greater incremental myocardial blood ow, and is technically easier and aster to per orm. However, the vasodilator agents can cause bronchospasm in patients with reactive airways disease (by stimulating bronchiolar adenosine A2b receptors) and should be avoided in that population, in whom dobutamine pharmacologic testing is there ore pre erred. In addition, a vasodilator study cannot be per ormed success ully in a patient who has been exposed to methylxanthines (e.g., ca eine consumption or use o the bronchodilator theophylline) on the day o the study, as such agents competitively antagonize adenosine’s interaction with its receptor and blunt its e ect.
Coronary Angiography The most direct m eans o identi ying coronary artery stenoses is by coronary angiography, in which atherosclerotic lesions are visualized radiographically ollowing the injection o radiopaque contrast material into the artery (Fig. 6-8; also see Chapter 3). Although gen erally sa e, th e procedu re is associated with a small risk o complications directly related to its invasive nature. There ore, coronary angiography is typically reserved or patients whose anginal symptoms do not respond adequately to pharm acologic th erapy, or those with an u nstable presentation , or when the resu lts o non in vasive testin g are so abn ormal that severe CAD warran ting revascu larization is likely. When the degree o stenosis o a region o intracoronary plaque, or its hemodynamic signif cance, is not clear, additional techniques can be applied in the cardiac catheterization laboratory. For example, ractional f ow reserve (FFR) measurement is a technique that can assess the unctional severity o a stenosis identif ed at angiography. A special manometer-tipped guidewire inserted through the catheter measures the pressure in the coronary artery distal to the stenosis during induced vasodilatation. The FFR FIGURE 6-8. Example of coronary angiography. value is equal to the pressure distal to the stenosis Injection of the right coronary artery demonstrates a (P d ) relative to the pressure proximal to the stenosis stenosis in the midportion of the vessel, indicated by in the aorta (Pao ). the arrow. (Courtesy of Pinak B. Shah, MD, Brigham and Women’s Hospital, Boston, MA.)
FFR = Pd / Pao
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A higher FFR value indicates a less severe stenosis. FFR values less than 0.75 to 0.80 identi y severe stenoses that typically warrant mechanical intervention. Although coronary angiography is considered the “gold standard” or the diagnosis o CAD, it should be noted that it provides only anatomic in ormation. The clinical signif cance o lesions detected by angiography depends on both the degree o narrowing and also on the pathophysiologic consequences. There ore, treatment decisions are made not only on the f nding o such stenoses but also by their unctional e ects, mani ested by the patient’s symptoms, the viability o the myocardial segments served by stenotic vessels, and the degree o ventricular contractile dys unction. Furthermore, standard arteriography does not reveal the composition o coronary atherosclerotic plaque or its vulnerability to rupture (see Chapter 5).
Noninvasive Imaging of Coronary Arteries Diagnostic alternatives to coronary angiography have been developed to noninvasively visualize the coronary arteries. Coronary CT angiography (CCTA) per ormed with administration o intravenous contrast (see Fig. 3.21) can visualize stenoses o greater than 50% o the coronary lumen with an approximate sensitivity o 90% and specif city o 65% to 90% . CCTA is considered an alternative to stress testing to help exclude signif cant CAD in low- to intermediaterisk patients who present with undef ned chest pain. The quality o images in CCTA is limited by cardiac motion, which can be reduced by slowing the heart rate with administration o a beta-blocker. Cardiac CT without contrast administration can be used as a screening test to detect coronary artery calcif cation (CAC) as described in Chapter 3. CAC correlates with the extent o atherosclerosis and thus estimates plaque burden, but does not quanti y individual coronary stenoses. The absence o CAC is a clinically use ul f nding as it strongly predicts the absence o CAD.
Natural History The patient with chronic angina may show no change in a stable pattern o ischemia or many years. In some patients, however, the course may be punctuated by the occurrence o unstable angina, MI, or sudden cardiac death. These complications are o ten related to acute thrombosis at the site o disrupted atherosclerotic plaque (see Chapter 7). Why some patients, but not others, sustain these complications remains a subject o intense clinical and basic science investigation and may relate to the vulnerability o plaque to rupture. The mortality associated with CAD has declined signif cantly in recent decades: the ageadjusted death rate has allen by more than 50% . This is likely related to (1) atherosclerotic risk reduction through improved li estyle changes (e.g., less tobacco use, less dietary at consumption, and more exercise); (2) improved therapeutic strategies and longevity ollowing acute coronary syndromes (see Chapter 7); and (3) advances in the pharmacologic and mechanical therapies or chronic CAD.
TREATMENT The goals o therapy in chronic ischemic heart disease are to decrease the requency o anginal attacks, to prevent acute coronary syndromes such as MI, and to prolong survival. A longterm crucial step is to address the risk actors that led to the development o atherosclerotic coronary disease. Data convincingly demonstrate the benef t o smoking cessation, cholesterol improvement, and blood pressure control in lowering the risk o coronary disease events (see Chapter 5). Improvements in other risk actors or CAD, including serum glucose in diabetics,
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Chapter 6 obesity and physical inactivity, may also reduce the risk o adverse outcomes although the benef ts o these interventions are less well documented. The ollowing sections describe medical and surgical strategies to (1) reduce ischemia and its symptoms by restoring the balance between myocardial oxygen supply and demand and (2) prevent acute coronary syndromes and death in patients with chronic CAD.
Medical Treatment of an Acute Episode of Angina When experiencing acute angina, the patient should cease physical activity. Sublingual nitroglycerin, an organic nitrate, is the drug o choice in this situation. Placed under the tongue, this medication produces a slight burning sensation as it is absorbed through the mucosa, and it begins to take e ect in 1 to 2 minutes. Nitrates relieve ischemia primarily through vascular smooth muscle relaxation, particularly venodilatation. Venodilatation reduces venous return to the heart, with a subsequent decline in LV volume (a determinant o wall stress). The latter decreases myocardial oxygen consumption, thus helping to restore oxygen balance in the ischemic heart. A second action o nitrates is to dilate the coronary vasculature, with subsequent augmentation o coronary blood ow. This e ect may be o little value in patients with angina in whom maximal coronary dilatation has already resulted rom the accumulation o local metabolites. However, when coronary vasospasm plays a role in the development o ischemia, nitrate-induced coronary vasodilatation may be particularly benef cial.
Medical Treatment to Prevent Recurrent Ischemic Episodes Pharmacologic agents are also the f rst line o de ense in the preven tion o anginal attacks. The goal o these agents is to decrease the cardiac workload (i.e., reduce myocardial oxygen demand) and to increase myocardial per usion. The three classes o medications most commonly used are β-adrenergic blockers, organic nitrates, and calcium channel blockers (Table 6-3). β-Blockers (see Chapter 17) exert their antianginal e ect primarily by reducing myocardial oxygen demand. They are directed against β-receptors, o which there are two classes: β1-adrenergic receptors are restricted to the myocardium, whereas β2-adrenergic receptors are located throughout the blood vessels and the bronchial tree. The stimulation o β1-receptors by endogenous catecholamines and exogenous sympathomimetic drugs increases heart rate and contractility. Consequently, β-adrenergic a n ta gon ists decrease the orce o ventricular contraction and heart rate, thereby relieving ischemia by reducing myocardial oxygen demand. In addition, slowing the heart rate may benef t myocardial oxygen supply by augmenting the time spent in diastole, the phase when coronary per usion primarily occurs. In addition to suppressing angina, several studies have shown that β-blockers decrease the rates o recurrent in arction and mortality ollowing an acute MI (see Chapter 7). Moreover, they have been shown to reduce the likelihood o an initial MI in patients with hypertension. Thus, β-blockers are f rst-line chronic therapy in the treatment o CAD. β-Blockers are generally well tolerated but have several potential side e ects. For example, they may precipitate bronchospasm in patients with underlying asthma by antagonizing β2-receptors in the bronchial tree. Although β1-selective blockers are theoretically less likely to exacerbate bronchospasm in such patients, drug selectivity or the β1-receptor is not complete, and in general, all β-blockers should be used cautiously, or avoided, in patients with signif cant obstructive airway disease. β-Blockers are also generally not used in patients with acutely decompensated LV dysunction because they could intensi y heart ailure symptoms by urther reducing inotropy. (However, as described in Chapter 9, β-blockers actually improve outcomes in patients with
Ischemic Heart Disease
TABLE 6-3
Pharmacologic Agents Used in the Prevention and Treatment of Angina
Drug Class
Mechanism of Action
Adverse Effects
Organic nitrates
↓ Myocardial O2 demand ↓ Preload (venodilatation) ↑ O2 supply ↑ Coronary per usion ↓ Coronary vasospasm ↓ Myocardial O2 demand ↓ Contractility ↓ Heart rate
• Headache • Hypotension • Ref ex tachycardia
β-Blockers
Calcium channel blockers (agent speci c; see ootnote)
Ranolazine
155
↓ Myocardial O2 demand ↓ Preload (venodilatation) ↓ Wall stress (↓BP) ↓ Contractility (V, D) ↓ Heart rate (V, D) ↑ O2 supply ↑ Coronary per usion ↓ Coronary vasospasm ↓ Late phase inward sodium current
• • • • • • • • • •
Excessive bradycardia ↓ LV contractile unction Bronchoconstriction May mask hypoglycemic symptoms Fatigue Headache, f ushing ↓ LV contractility (V, D) Marked bradycardia (V, D) Edema (especially N, D) Constipation (especially V)
• Dizziness, headache • Constipation, nausea
BP, blood pressure; D, diltiazem; LV, le t ventricular; N, ni edipine and other dihydropyridine calcium channel antagonists; V, verapamil.
stable chronic heart failure conditions.) β-Blockers are also relatively contraindicated in patients with marked bradycardia or certain types of heart block to avoid additional impairment of electrical conduction. β-Blockers sometimes cause fatigue and sexual dysfunction. They should be used with caution in insulin-treated diabetic patients because they can mask tachycardia and other catecholamine-mediated responses that can warn of hypoglycemia. One might also expect that β-blockers would decrease myocardial blood perfusion by blocking the vasodilating β2adrenergic receptors of the coronary arteries. However, this effect is usually attenuated by autoregulation and vasodilatation of the coronary vessels owing to the accumulation of local metabolites. Organic nitrates (e.g., nitroglycerin, isosorbide dinitrate, isosorbide mononitrate), as previously mentioned, relieve ischemia primarily through venodilatation (i.e., lower wall stress results from a smaller ventricular radius) and possibly through coronary vasodilatation. The organic nitrates are the oldest of the antianginal drugs and come in several preparations (also described in Chapter 17). Sublingual nitroglycerin tablets or sprays are used in the treatment of acute attacks because of their rapid onset of action. In addition, when taken immediately before a person engages in activities known to provoke angina, these rapidly acting nitrates are useful as prophylaxis against anginal attacks. Longer-acting anginal prevention can be achieved through a variety of nitrate preparations, including oral tablets of isosorbide dinitrate (or mononitrate) or a transdermal nitroglycerin patch, which is applied once a day. A limitation to chronic nitrate therapy is the development of drug tolerance (i.e., decreased effectiveness of the drug during continued
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Chapter 6 administration), which occurs to some degree in most patients. This undesired e ect can be overcome by providing a nitrate- ree interval or several hours each day, usually while the patient sleeps. There is no evidence that nitrates improve survival or prevent in arctions in patients with chronic CAD, and they are used purely or symptomatic relie . Common side e ects include headache, light-headedness, and palpitations induced by vasodilatation and re ex sinus tachycardia. The latter can be prevented by combining a β-blocker with the nitrate regimen. Calcium channel blockers (see Chapter 17) antagonize voltage-gated L-type calcium channels, but the actions o the individual drugs o this group vary. The dihydropyridines (e.g., ni edipine and amlodipine) are potent vasodilators. They relieve myocardial ischemia by (1) decreasing oxygen demand (venodila ta tion reduces ventricular f lling and size, a rteria l dila tion reduces the resistance against which the le t ventricle contracts, and both actions reduce wall stress) and (2) increasing myocardial oxygen supply via coronary dilatation. By the latter mechanism, they are also potent agents or the relie o coronary artery vasospasm. Nondihydropyridine calcium channel blockers (verapamil and diltiazem) also act as vasodilators but are not as potent in this regard as the dihydropyridines. However, these agents have additional benef cial antianginal e ects stemming rom their more potent cardiac depressant actions: they reduce the orce o ventricular contraction (contractility) and slow the heart rate. Accordingly, verapamil and diltiazem also decrease myocardial oxygen demand by these mechanisms. Questions have been raised about the sa ety o short-acting calcium channel–blocking drugs in the treatment o ischemic heart disease. In meta-analyses o randomized trials, these drugs have been associated with an increased incidence o MI and mortality. The adverse e ect may relate to the rapid hemodynamic e ects and blood pressure swings induced by the short-acting agents. There ore, only long-acting calcium channel blockers (i.e., preparations taken once a day) are recommended in the treatment o chronic angina, generally as secondline drugs i symptoms are not controlled by β-blockers and nitrates. The three standard groups o antianginal drugs described in this section can be used alone or in combination. However, care should be taken in combining a β-blocker with a nondihydropyridine calcium channel blocker (verapamil or diltiazem) because the additive negative chronotropic e ect can cause excessive bradycardia and the combined negative inotropic e ect could precipitate heart ailure in patients with LV contractile dys unction. Ranolazine, a ourth type o anti-ischemic therapy, has been shown to decrease the requency o anginal episodes and improve exercise capacity in patients with chronic CAD but di ers rom other anti-ischemic drugs in that it does not a ect the heart rate or blood pressure. Although its mechanism o action has not been ully elucidated, it is believed to inhibit the late phase o the action potential’s inward sodium current (INa + ) in ventricular myocytes. That late phase tends to be abnormally enhanced in ischemic myocardium, and the associated increased sodium in ux results in higher-than-normal intracellular Ca + + (mediated by the trans-sarcolemmal Na + –Ca + + exchanger; see Fig. 1.10). Such calcium overload is thought to result in impaired diastolic relaxation and contractile ine f ciency. Inhibition o the late INa + by ranolazine counters these pathologic e ects. Clinical studies have supported ranolazine’s e ectiveness in reducing angina, and its long-term sa ety, when used alone or in combination with other antianginal agents. Although use ul in controlling symptoms o angina, none o the antianginal drug groups has been shown to slow or reverse the atherosclerotic process responsible or the arterial lesions o chronic CAD. Moreover, although β-blockers have demonstrated mortality benef ts in patients a ter MI, none o these agents has been shown to improve longevity in patients with chronic stable angina and preserved LV unction.
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Medical Treatment to Prevent Acute Cardiac Events Platelet aggregation and thrombosis are key elements in the pathophysiology o acute MI and unstable angina (see Chapter 7). Antiplatelet therapy reduces the risk o these acute coronary syndromes in patients with chronic angina and should be a standard part o the regimen used to treat CAD. For example, aspirin has antithrombotic actions through the inhibition o synthesis o thromboxane A2, a mediator o platelet activation and aggregation, as well as anti-in ammatory properties that may be important in stabilizing atheromatous plaque. Unless contraindications are present (e.g., allergy or gastric bleeding), aspirin should be continued indef nitely in all patients with CAD. Platelet P2Y12 ADP receptor antagonists, such as clopidogrel, also prevent platelet activation and aggregation (see Chapter 17). They can be used as an antiplatelet substitute in patients who are allergic to aspirin. In addition, the combination o aspirin and a P2Y12 inhibitor is superior to aspirin alone in reducing death and ischemic complications in patients with acute coronary syndromes, in those undergoing elective percutaneous coronary stenting, and in patients with a history o MI. Lipid-regulating therapy is an additional approach to reduce cardiovascular clinical events in patients with CAD. In particular, HMG-CoA reductase inhibitors (“statins”) lower MI and death rates in patients with established coronary disease and in those at high risk o developing CAD. The benef ts o statin therapy are believed to extend beyond their lipidaltering e ects, because there is evidence that they decrease vascular in ammation and improve endothelial cell dys unction and thus may help stabilize atherosclerotic plaques. Moreover, trials o patients with established atherosclerotic disease have demonstrated a linear relationship between the magnitude o LDL lowering and the reduction in cardiovascular risk. Thus, high-in ten sity lipid lowering (resulting in reduction o LDL by more than 50% ) is superior to less intense lipid-lowering therapy in preventing uture ischemic events and cardiovascular death. An LDL less than 70 mg/ dL is a common goal or patients with CAD, and recent evidence suggests that even patients with a baseline LDL o 70 mg/ dL benef t rom high-intensity lipid lowering. As a result, current national guidelines no longer recommend treating to a specif c target LDL level. Rather, it is recommended that all patients with CAD receive a high-intensity statin regimen, with the goal o at least 50% reduction in LDL. Angiotensin-converting enzyme (ACE) inhibitors, benef cial in the treatment o hypertension (see Chapter 13), heart ailure (see Chapter 9), and ollowing MI (see Chapter 7), have also been studied as chronic therapy or patients with stable CAD not complicated by heart ailure. Some (but not all) o these trials have shown reduced rates o death, MI, and stroke. Thus, many cardiologists recommend that an ACE inhibitor be included in the medical regimen o patients with chronic CAD.
Revascularization Patients with angina that becomes asymptomatic during pharmacologic therapy are usually monitored by their physicians with continued emphasis on cardiac risk actor reduction. However, coronary revascularization is pursued i (1) the patient’s symptoms o angina do not respond adequately to antianginal drug therapy, (2) unacceptable side e ects o medications occur, or (3) the patient is ound to have high-risk coronary disease or which revascularization is known to improve survival (as described in the next section). The two techniques used to accomplish mechanical revascularization are percutaneous coronary intervention (PCI) and coronary artery bypass gra t (CABG) surgery. PCI includes percutaneous transluminal coronary angioplasty (PTCA), a procedure perormed under uoroscopy in which a balloon-tipped catheter is inserted through a peripheral artery (usually emoral, radial, or brachial) and maneuvered into the stenotic segment o a
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Chapter 6 coronary vessel. The balloon at the end o the catheter is then in ated under high pressure to dilate the stenosis, a ter which the balloon is de ated and the catheter is removed rom the body. The improvement in the size o the coronary lumen increases coronary per usion and myocardial oxygen supply. E ective dilatation o the stenosis results rom compression o the atherosclerotic plaque and o ten by creating a racture within the lesion and stretching the underlying media. The risk o MI during the procedure is less than 1.5% , and mortality is less than 1% . Un ortunately, approximately one third o patients who undergo balloon angioplasty develop recurrent symptoms within 6 months owing to restenosis o the dilated artery and require additional coronary interventions. For this reason, coronary stents were developed or implantation at the time o PCI, and have been shown to signif cantly reduce the rate o restenosis. Such stents are slender, cagelike metal support devices that in their collapsed conf guration can be threaded into the region o stenosis by a catheter. Once in position, the stent is expanded into its open position by in ating a high-pressure balloon in its interior (Fig. 6-9). The balloon and attached catheter are then removed, but the stent is le t permanently in place to serve as a sca old to maintain arterial patency. Because stents are thrombogenic, a combination o oral antiplatelet agents (commonly, aspirin plus a platelet P2Y12 receptor antagonist, such as clopidogrel) is crucial a ter stent implantation. Compared with conventional balloon angioplasty, stent implantation decreases restenosis rates and reduces the need or repeat PCIs. Although restenosis resulting rom vessel elastic recoil is greatly diminished by standard metal stent placement, neointimal proli eration (i.e., migration o smooth muscle cells and production o extracellular matrix) remains an important cause o in-stent restenosis and recurrent anginal symptoms. To address the problem o in-stent restenosis a ter PCI, drug-eluting stents were devised. These special stents are abricated with a polymer coat that incorporates an antiproli erative medication such as sirolimus (an immunosuppressive agent that inhibits T-cell activation), everolimus (an immunosuppressive similar to sirolimus), or paclitaxel (which inter eres with cellular microtubule unction). The medication is released rom the stent over a period o 2 to 4 weeks, and this approach has shown great e ect at preventing neointimal proli eration
Arte ry wa ll
Ba lloon ca the te r
A
B
C
S te nos is
S te nt in colla ps e d configura tion
Ba lloon infla tion to expa nd s te nt
FIGURE 6-9. Placement of a coronary artery stent. A. A stent, in its original collapsed state, is advanced into the coronary stenosis on a balloon catheter. B. The balloon is inf ated to expand the stent. C. The balloon is def ated, and the catheter is removed rom the body, leaving the stent permanently in place.
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and reducing the need or repeat revascularization by more than hal . However, just as neointimal proli eraInte rna l tion is slowed, so too is protective endothelialization ma mma ry Aorta o the stent. The delay in endothelial cell coverage o a rte ry gra ft the metal struts leaves patients at risk or thrombus SVC Pulmona ry ormation within the stent should antiplatelet agents a rte ry S a phe nous be discontinued prematurely. There ore, prolonged ve in gra ft courses o combination antiplatelet therapy (e.g., aspiLCx rin plus a platelet P2Y12 receptor antagonist or at least RCA 12 months) ollowed by aspirin indef nitely are necesLAD sary or patients who receive drug-eluting stents. Although percutaneous revascularization techniques are generally superior to standard medical therapy or relie o angina, it is important to note that in the setting o stable coronary disease (i.e., not an Obs tructing acute coronary syndrome), they have not been shown pla que to reduce the risk o MI or death. FIGURE 6-10. Coronary artery bypass surgery. Two CABG surgery entails gra ting portions o a types of bypasses are illustrated: (1) the left internal patient’s native blood vessels to bypass obstructed mammary artery originates from the left subclavian coronary arteries. Two types o surgical gra ts are used artery, and in this schematic, it is anastomosed to the (Fig. 6-10). The f rst employs native veins—typically, a left anterior descending (LAD) coronary artery distal section o the saphenous vein (a “super uous” vessel to obstructing plaque; (2) one end of a saphenous vein graft is sutured to the proximal aorta and the removed rom the leg) that is sutured rom the base other end to the right coronary artery (RCA) distal to o the aorta to a coronary segment downstream rom a stenotic segment. the region o stenosis. The second method uses arterial gra ts—most commonly, an internal mammary artery (IMA, a “super uous” branch o each subclavian artery)—that can be directly anastomosed distal to a stenotic coronary site. Vein gra ts have a patency rate o up to 80% at 12 months but are vulnerable to accelerated atherosclerosis; 10 years a ter surgery, more than 50% have occluded. In contrast, IMA gra ts are more resistant to atherosclerosis with a patency rate o 90% at 10 years. There ore, IMA gra ts are o ten used to per use sites o critical ow such as the le t anterior descending artery. Clinical trial evidence supports the use o aggressive lipidlowering drug therapy a ter CABG to improve the long-term patency rates o bypass gra ts. In recent years, less invasive surgical alternatives to conventional CABG have been explored. These include “minimally invasive” operations with smaller incisions, the use o transcutaneous ports with videoscopic robotic assistance, and “o -pump” procedures, which avoid the use o cardiopulmonary bypass (heart–lung) machines. While there are theoretical advantages o avoiding the latter, studies examining o -pump procedures in comparison with standard CABG have shown comparable mortality benef t, but poorer gra t patency over time and an increased need or uture revascularization. Additionally, there have been no major high-quality studies comparing benef ts o minimally invasive operations to conventional CABG. In general, patient-specif c risks and characteristics are considered by the surgeon when selecting which type o bypass procedure to undertake.
Medical versus Revascularization Therapy Many patients with chronic, stable angina can be success ully managed with pharmacologic therapy alone. However, i anginal symptoms prove re ractory despite maximal pharmacologic therapy, or i intolerable drug side e ects develop, coronary angiography is recommended or urther therapeutic planning. Moreover, or patients whose angina is controlled by medications, it is standard to per orm noninvasive testing (e.g., exercise testing, echocardiography) to identi y those with high-risk disease, because the long-term prognosis or such patients can
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TABLE 6-4 Coronary Revascularization Procedures Percutaneous Coronary Interventions ( PCI)
Coronary Artery Bypass Graft Surgery ( CABG)
Less invasive than CABG
More effective for long-term relief of angina than PCI or pharmacologic therapy Most complete revascularization
Shorter hospital stay and easier recuperation than CABG Superior to pharmacologic therapy for relief of angina
Survival advantage in patients with • > 50% left main coronary artery stenosis • Multivessel coronary disease, especially if LV contractile function is impaired
LV, left ventricle.
be improved by coronary revascularization. Those with high-risk noninvasive test f ndings then typically proceed to coronary angiography. In general, patients with stable angina ound to have a large amount o myocardium at ischemic risk, such as those with severe (≥ 70% ) stenoses in all three major coronary arteries (especially when LV contractile unction is reduced), those with multivessel disease that includes a critical narrowing o the proximal le t anterior descending artery (which thereby threatens a large portion o the le t ventricle), or those with a high-grade (≥ 50% ) stenosis o the le t main coronary artery, achieve a survival benef t rom CABG compared with medical therapy. More recent studies that have compared percutaneous coronary revascularization with CABG have demonstrated that CABG leads to a survival benef t in patients with stable angina who have severe stenoses in all three coronary arteries, a highgrade stenosis in the le t main coronary artery, or diabetes (especially with multivessel disease). In contrast, PCI is a reasonable approach in patients with less extensive disease (in whom survival benef t o CABG over PCI has not been shown) and in those at high risk o undergoing surgery (Table 6-4). Each o the described approaches or the treatment o coronary disease is benef ting rom rapidly developing research advancements. New surgical techniques (increased use o various arterial gra ts, less invasive operations), new drug-eluting stents (e.g., incorporation o bioabsorbable/ biodegradable polymers to decrease late stent thrombosis), novel adjuncts to stenting (potent antithrombotic drugs), and progress in pharmacologic management (e.g., aggressive use o statins and antithrombotic drugs) will likely urther improve outcomes and better def ne the best therapeutic approaches or specif c subsets o patients with chronic CAD.
SUMMARY • Cardiac ischemia results rom an imbalance between myocardial oxygen supply and demand. • Determinants o myocardial oxygen supply are (1) the oxygen content o the blood and (2) coronary blood ow (which is dependent on the coronary per usion pressure and coronary vascular resistance). • Key regulators o myocardial oxygen demand include (1) the heart rate, (2) contractility, and (3) myocardial wall stress. • In the presence o coronary artery disease, myocardial oxygen supply is compromised by atherosclerotic plaques that narrow the vascular lumen (reducing coronary blood ow) and by endothelial cell dys unction that causes inappropriate vasoconstriction o coronary resistance vessels.
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• Angina pectoris is the most requent symptom o intermittent myocardial ischemia. • The diagnosis o angina relies heavily on the patient’s description o the discom ort and can be aided by laboratory studies (e.g., exercise or pharmacologic stress testing). • Angina may be accompanied by signs and symptoms o adrenergic stimulation, pulmonary congestion, and transient le t ventricular systolic and diastolic dys unction. • Standard pharmacologic therapy or chronic angina includes agents to prevent ischemia and relieve symptoms (β-blockers, nitrates, calcium channel antagonists, alone or in combination) as well as agents that reduce the risk o acute coronary syndromes and death (aspirin, statins, angiotensin-converting enzyme inhibitors). • Modif able risk actors or atherosclerosis (i.e., dyslipidemia, smoking, hypertension, and diabetes) should be addressed. • Revascularization with PCI or CABG surgery provides relie rom ischemia in patients with chronic angina who are re ractory to, or unable to tolerate, medical therapy. CABG con ers improved survival rates to certain high-risk groups.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were June-Wha Rhee, MD; Haley Naik, MD; Christopher P. Chiodo, MD; Carey Farquhar, MD; Anurag Gupta, MD; Rainu Kaushal, MD; William Carlson, MD; Michael E. Mendelsohn MD; and Patrick T. O’Gara, MD.
Ad d i t i o n a l Rea d i n g Bonaca MP, Bhatt DL, Cohen M, et al. Long-term use o ticagrelor in patients with prior myocardial in arction. N Engl J Med. 2015;372:1791–1800. Douglas PS, Ho man U, Patel MR, et al. Outcomes o Anatomical versus Functional Testing or Coronary Artery Disease. N Engl J Med. 2015;372:1291–1300. Farkouh ME, Domanski M, Sleeper LA, et al. FREEDOM Trial Investigators. Strategies or multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375–2384. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/ AHA/ ACP/ AATS/ PCNA/ SCAI/ STS Guideline or the diagnosis and management o patients with stable ischemic heart disease: executive Summary. Circulation. 2012;126:3097–3137. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/ AHA/ SCAI guideline or percutaneous coronary intervention: executive summary. Circulation. 2011;124:2574–2609.
Mohr FW, Morice MC, Kappetein AP, et al. Coronary artery bypass gra t surgery versus percutaneous coronary intervention in patients with three-vessel disease and le t main coronary disease: 5-year ollowup o the randomized, clinical SYNTAX trial. La n cet. 2013;381(9867):629–638. Park S-J, Ahn J-M, Kim Y-H, et al. Trial o everolimus-eluting stents or bypass surgery or coronary disease. N Engl J Med. 2015;372:1204-1212. Tonino PA, De Bruyne B, Pijls NH, et al. FAME Study Investigators. Fractional ow reserve versus angiography or guiding percutaneous coronary intervention. N Engl J Med. 2009;360:213–224. Velazquez EJ, Lee KL, Deja MA, et al. STITCH Investigators. Coronary-artery bypass surgery in patients with le t ventricular dys unction. N Engl J Med. 2011;364:1607–1616.
Acute Coronary Syndromes
7
Ja yme Wilder Ma rc S. Sa ba tine Leona rd S. Lilly
Ch a p t e r O u t l i n e Pathogenesis o Acute Coronary Syndromes Normal Hemostasis Endogenous Antithrombotic Mechanisms Pathogenesis o Coronary Thrombosis Nonatherosclerotic Causes o Acute Myocardial In arction Pathology and Pathophysiology Pathologic Evolution o In arction Functional Alterations Clinical Features o Acute Coronary Syndromes Clinical Presentation Diagnosis o Acute Coronary Syndromes Treatment o Acute Coronary Syndromes Acute Treatment o Unstable Angina and Non–ST-Elevation Myocardial In arction Acute Treatment o ST-Elevation Myocardial In arction Adjunctive Therapies Complications Recurrent Ischemia Arrhythmias Myocardial Dys unction Right Ventricular In arction Mechanical Complications Pericarditis Thromboembolism Risk Stratif cation and Management Following Myocardial In arction 162
A
cute coronary syndromes (ACSs) are li e-threatening conditions that can punctuate the course o patients with coronary artery disease at any time. These syndromes orm a continuum that ranges rom an unstable pattern o angina pectoris to the development o a large acute myocardial in arction (MI), a condition o irreversible necrosis o heart muscle (Table 7-1). All orms o ACS share a common initiating pathophysiologic mechanism, as this chapter examines. The requency o ACS is staggering: more than 1.4 million people are admitted to hospitals in the United States each year with these conditions. Within the year a ter a f rst MI, 19% o men and 26% o women will die. Despite these daunting statistics, mortality associated with ACS has actually substantially and continuously declined in recent decades as a result o major therapeutic and preventive advances. This chapter considers the events that lead to an ACS, the pathologic and unctional changes that ollow, and therapeutic approaches that ameliorate the aberrant pathophysiology.
PATHOGENESIS OF ACUTE CORONARY SYNDROMES More than 90% o ACSs result rom disruption o an atherosclerotic plaque with subsequent platelet aggregation and ormation o an intracoronary thrombus. The thrombus trans orms a region o plaque narrowing to one o severe or complete occlusion, and the impaired blood f ow causes a marked imbalance between myocardial oxygen supply and demand. The orm o ACS that results depends on the degree o coronary obstruction and associated ischemia (see Table 7-1). A partially occlusive thrombus is the typical cause o the closely related syndromes unstable angina (UA) and non–ST-elevation myocardial infarction
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TABLE 7-1 Spectrum of Acute Coronary Syndromes Usual coronary pathology Myocyte necrosis
Unstable Angina
Non–ST-Elevation MI
ST-Elevation MI
Partially occlusive thrombus No
Partially occlusive thrombus Yes
Completely occlusive thrombus Yes
MI, myocardial infarction.
(NSTEMI), with the latter being distinguished rom the ormer by the presence o myocardial necrosis. At the other end o the spectrum, i the thrombus completely obstructs the coronary artery, the results are more severe ischemia and a larger amount o necrosis, mani esting as an ST-elevation myocardial infarction (STEMI). The responsible thrombus in ACS is generated by interactions among the atherosclerotic plaque, the coronary endothelium, circulating platelets, and the dynamic vasomotor tone o the vessel wall, which overwhelm the natural antithrombotic mechanisms described in the next section.
Normal Hemostasis When a normal blood vessel is injured, the endothelial sur ace becomes disrupted and thrombogenic connective tissue is exposed. Primary hemostasis is the f rst line o de ense against bleeding. This process begins within seconds o vessel injury and is mediated by circulating platelets, which adhere to collagen in the vascular subendothelium and aggregate to orm a “platelet plug.” While the primary hemostatic plug orms, the exposure o subendothelial tissue actor triggers the plasma coagulation cascade, initiating the process o secondary hemostasis. The plasma coagulation proteins involved in secondary hemostasis are sequentially activated at the site o injury and ultimately orm a f brin clot by the action o thrombin. The resulting clot stabilizes and strengthens the platelet plug. The normal hemostatic system minimizes blood loss rom injured vessels, but there is little di erence between this physiologic response and the pathologic process o coronary thrombosis triggered by disruption o atherosclerotic plaques.
Endogenous Antithrombotic Mechanisms Normal blood vessels, including the coronary arteries, are replete with sa eguards that prevent spontaneous thrombosis and occlusion, some examples o which are shown in Figure 7-1.
Inactivation of Clotting Factors Several natural inhibitors tightly regulate the coagulation process to oppose clot ormation and maintain blood uidity. The most important o these are antithrombin, proteins C and S, and tissue actor pathway inhibitor (TFPI). Antithrombin is a plasma protein that irreversibly binds to thrombin and other clotting actors, inactivating them and acilitating their clearance rom the circulation (see mechanism 1 in Fig. 7-1). The e ectiveness o antithrombin is increased 1,000- old by binding to heparan sul ate, a heparin-like molecule normally present on the luminal sur ace o endothelial cells. Protein C, protein S, and thrombomodulin orm a natural anticoagulant system that inactivates the “acceleration” actors o the coagulation pathway (i.e., actors Va and VIIIa). Protein C is synthesized in the liver and circulates in an inactive orm. Thrombomodulin is a thrombin-binding receptor normally present on endothelial cells. Thrombin bound to thrombomodulin cannot convert f brinogen to f brin (the f nal reaction in clot ormation). Instead,
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Chapter 7
4
Tis s ue fa c tor
tPA
P la s minoge n VII
–
Fib rin c lot
3
Xa
P la s min TFP I
Prote in S
Prote in C* TM
Fibrin s plit products
Ina ctiva te d Va ,VIIIa fa ctors
5
2
Thrombin Prote in C
Inhibits pla te le t a ctiva tion Irreve rs ible thrombin inhibition
Thrombin 1
Pros ta cyclin a nd NO
Antithrombin He p a ra n s ulfa te
FIGURE 7-1. Endogenous protective mechanisms against thrombosis and vessel occlusion. (1) Inactivation o thrombin by antithrombin (AT), the e ectiveness o which is enhanced by binding o AT to heparan sul ate. (2) Inactivation o clotting actors Va and VIIIa by activated protein C (protein C*), an action that is enhanced by protein S. Protein C is activated by the thrombomodulin (TM)–thrombin complex. (3) Inactivation o actor VII/ tissue actor complex by tissue actor pathway inhibitor (TFPI). (4) Lysis o f brin clots by tissue plasminogen activator (tPA). (5) Inhibition o platelet activation by prostacyclin and nitric oxide (NO).
the thrombin–thrombomodulin complex activates protein C. Activated protein C degrades actors Va and VIIIa (see mechanism 2 in Fig. 7-1), thereby inhibiting coagulation. The presence o protein S in the circulation enhances the inhibitory unction o protein C. TFPI is a plasma serine protease inhibitor that is activated by coagulation actor Xa. The combined actor Xa–TFPI binds to and inactivates the complex o tissue actor with actor VIIa that normally triggers the extrinsic coagulation pathway (see mechanism 3 in Fig. 7-1). Thus, TFPI serves as a negative eedback inhibitor that inter eres with coagulation.
Lysis of Fibrin Clots Tissue plasminogen activator (tPA) is a protein secreted by endothelial cells in response to many triggers o clot ormation. It cleaves the protein plasminogen to orm active plasmin, which in turn enzymatically degrades f brin clots (see mechanism 4 in Fig. 7-1). When tPA binds to f brin in a orming clot, its ability to convert plasminogen to plasmin is greatly enhanced.
Endogenous Platelet Inhibition and Vasodilatation Prostacyclin is synthesized and secreted by endothelial cells (see mechanism 5 in Fig. 7-1), as described in Chapter 6. Prostacyclin increases platelet levels o cyclic AMP and thereby strongly inhibits platelet activation and aggregation. It also indirectly inhibits coagulation via its potent vasodilating properties. Vasodilatation helps guard against thrombosis by augmenting blood ow (which minimizes contact between procoagulant actors) and by reducing shear stress (an inducer o platelet activation). Nitric oxide (NO) is similarly secreted by endothelial cells, as described in Chapter 6. It acts locally to inhibit platelet activation, and it too serves as a potent vasodilator.
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Athe ro s c le ro s is
Dys functiona l e ndothe lium
P la que rupture
Intra pla que he morrha ge
Re le a s e of tis s ue fa ctor
Ve s s e l lume n dia me te r
Activa tion of coa gula tion ca s ca de
Expos ure of s ube ndothe lia l colla ge n
Turbule nt blood flow
P la te le t a ctiva tion a nd a ggre ga tion
Va s odila tor e ffe ct
Antithrombotic e ffe ct
Va s ocons triction
Co ro nary thro mbo s is
FIGURE 7-2. Mechanisms of coronary thrombus formation. Factors that contribute to this process include plaque disruption (e.g., rupture) and inappropriate vasoconstriction and loss of normal antithrombotic defenses because of dysfunctional endothelium.
Pathogenesis of Coronary Thrombosis Normally, the mechanisms shown in Figure 7-1 serve to prevent spontaneous intravascular thrombus ormation. However, abnormalities associated with atherosclerotic lesions may overwhelm these de enses and result in coronary thrombosis and vessel occlusion (Fig. 7-2). Atherosclerosis contributes to thrombus ormation by (1) plaque rupture, which exposes the circulating blood elements to thrombogenic substances, and (2) endothelial dys unction with the loss o normal protective antithrombotic and vasodilatory properties. Atherosclerotic plaque rupture is considered the major trigger o coronary thrombosis. The underlying causes o plaque disruption are (1) chemical actors that destabilize atherosclerotic lesions and (2) physical stresses to which the lesions are subjected. As described in Chapter 5, atherosclerotic plaques consist o a lipid-laden core surrounded by a f brous external cap. Substances released rom in ammatory cells within the plaque can compromise the integrity o the f brous cap. For example, T lymphocytes release inter eron-γ (IFN-γ), which inhibits collagen synthesis by smooth muscle cells and thereby inter eres with the usual strength o the cap. Additionally, cells within atherosclerotic lesions produce enzymes (e.g., metalloproteinases) that degrade the interstitial matrix, urther compromising plaque stability. A weakened or thin-capped plaque is subject to rupture, particularly in its “shoulder” region (the border with the normal arterial wall that is subjected to high circum erential stress) either spontaneously or by physical orces, such as intraluminal blood pressure and torsion rom the beating myocardium. ACSs sometimes occur in the setting o certain triggers, such as strenuous physical activity or emotional upset. The activation o the sympathetic nervous system in these situations increases the blood pressure, heart rate, and orce o ventricular contraction—actions that may stress the atherosclerotic lesion, thereby causing the plaque to f ssure or rupture. In addition, MI is most likely to occur in the early morning hours. This observation may relate to the tendency o key physiologic stressors (such as systolic blood pressure, blood viscosity, and
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Chapter 7 plasma epinephrine levels) to be most elevated at that time o day, and these actors subject vulnerable plaques to rupture. While rupture o the f brous cap is responsible or the majority o ACSs, superf cial erosion without rupture is a less common, important mechanism o plaque disruption and thrombus ormation. Eroded plaques o ten do not have a substantial lipid burden but have been associated with smoking and are also requently ound to be the cause o ACS in premenopausal women. Following plaque disruption, thrombus ormation is provoked via mechanisms shown in Figure 7-2. For example, during plaque rupture, the exposure o tissue actor rom the atheromatous core triggers the coagulation pathway, while subendothelial collagen activates platelets. Activated platelets release the contents o their granules, which include acilitators o platelet aggregation (e.g., adenosine diphosphate [ADP] and f brinogen), activators o the coagulation cascade (e.g., actor Va), and vasoconstrictors (e.g., thromboxane and serotonin). The developing intracoronary thrombus, intraplaque hemorrhage, and vasoconstriction all contribute to narrowing the vessel lumen, creating turbulent blood ow that contributes to shear stress and urther platelet activation. Dysfunctional endothelium, which is apparent even in mild atherosclerotic coronary disease, also increases the likelihood o thrombus ormation. In the setting o endothelial dys unction, reduced amounts o vasodilators (e.g., NO and prostacyclin) are released and inhibition o platelet aggregation by these actors is impaired, resulting in the loss o a key de ense against thrombosis. Not only is dys unctional endothelium less equipped to prevent platelet aggregation but also is less able to counteract the vasoconstricting products o platelets. During thrombus ormation, vasoconstriction is promoted both by platelet products (thromboxane and serotonin) and by thrombin within the developing clot. The normal platelet-associated vascular response is vasodilatation, because platelet products stimulate endothelial NO and prostacyclin release, the in uences o which predominate over direct platelet-derived vasoconstrictors (see Fig. 6-4). However, reduced secretion o endothelial vasodilators in atherosclerosis allows vasoconstriction to proceed unchecked. Similarly, thrombin in a orming clot is a potent vascular smooth muscle constrictor in the setting o dys unctional endothelium. Vasoconstriction causes torsional stresses that can contribute to plaque rupture or can transiently occlude the stenotic vessel through heightened arterial tone. The reduction in coronary blood ow caused by vasoconstriction also reduces the washout o coagulation proteins, thereby enhancing thrombogenicity.
Signif cance o Coronary Thrombosis The ormation o an intracoronary thrombus results in one o the several potential outcomes (Fig. 7-3). For example, plaque rupture is sometimes superf cial, minor, and sel -limited, such that only a small, nonocclusive thrombus orms. In this case, the thrombus may simply become incorporated into the growing atheromatous lesion through f brotic organization, or it may be lysed by natural f brinolytic mechanisms. Recurrent asymptomatic plaque ruptures o this type may cause gradual progressive enlargement o the coronary stenosis. However, deeper plaque rupture may result in greater exposure o subendothelial collagen and tissue actor, with ormation o a larger thrombus that more substantially occludes the vessel’s lumen. Such obstruction may cause prolonged severe ischemia and the development o an ACS. I the intraluminal thrombus at the site o plaque disruption totally occludes the vessel, blood ow beyond the obstruction will cease, prolonged ischemia will occur, and an MI (usually an ST-elevation MI) will result. Conversely, i the thrombus partially occludes the vessel (or i it totally occludes the vessel but only transiently because o spontaneous recanalization or by relie o superimposed vasospasm), the severity and duration o
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Co ro nary thro mbus
S ma ll thrombus (nonflow limiting)
Pa rtia lly occlus ive thrombus
Occlus ive thrombus (With prolonge d is che mia )
No ECG cha nge s
ST-s e gme nt de pre s s ion a nd/or T-wave inve rs ion
He a ling a nd pla que e nla rge me nt
– S e rum bioma rke rs
Uns ta ble a ngina
(With tra ns ie nt is che mia )
+ S e rum bioma rke rs
Non–ST-s e gme nt e leva tion MI
ST e leva tion (Q wave s la te r)
+ S e rum bioma rke rs
ST-s e gme nt e leva tion MI
FIGURE 7-3. Consequences of coronary thrombosis. A small thrombus ormed on super cial plaque rupture may not result in symptoms or electrocardiogram (ECG) abnormalities, but healing and brous organization may incorporate the thrombus into the plaque, causing the atherosclerotic lesion to enlarge. A partially occlusive thrombus narrows the arterial lumen, restricts blood f ow, and can cause unstable angina or a non–ST-elevation MI, either o which may result in ST-segment depression and/ or T-wave inversion on the ECG. A totally occlusive thrombus with prolonged ischemia is the most common cause o ST-elevation MI, in which the ECG initially shows ST-segment elevation, ollowed by Q-wave development i early reper usion is not achieved. An occlusive thrombus that recanalizes, or one that develops in a region served by adequate collateral blood f ow, may result in less prolonged ischemia and a non–ST-elevation MI instead. Serum biomarkers o myocardial necrosis include cardiac-speci c troponins and creatine kinase MB isoenzyme.
ischemia will be less, and a smaller NSTEMI or UA is the more likely outcome. The distinction between NSTEMI and UA is based on the degree o the ischemia and whether the event is severe enough to cause necrosis, indicated by the presence o certain serum biomarkers (see Fig. 7-3). Nonetheless, NSTEMI and UA act quite alike, and the management o these entities is similar. Occasionally, a non–ST-elevation in arct may result rom total coronary occlusion. In this case, it is likely that a substantial collateral blood supply (see Chapter 1) limits the extent o necrosis, such that a larger ST-elevation MI is prevented.
Nonatherosclerotic Causes of Acute Myocardial Infarction In requently, mechanisms other than acute thrombus ormation can precipitate an acute MI (Table 7-2). These should be suspected when an ACS occurs in a young patient or a person without atherosclerotic risk actors. For example, coronary emboli rom mechanical or in ected cardiac valves may lodge in the coronary circulation, inf ammation rom acute vasculitis can initiate coronary occlusion, or patients with connective tissue disorders, or peripartum women, can rarely experience a spontaneous coronary artery dissection (a tear in
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TABLE 7-2 Causes of Myocardial Infarction • • • • • • • • •
Atherosclerotic plaque rupture with superimposed thrombus Vasculitic syndromes (see Chapter 15) Coronary embolism (e.g., rom endocarditis, artif cial heart valves) Congenital anomalies o the coronary arteries Coronary trauma or aneurysm Spontaneous coronary artery dissection Severe coronary artery spasm (primary or cocaine-induced) Increased blood viscosity (e.g., polycythemia vera, thrombocytosis) Markedly increased myocardial oxygen demand (e.g., severe aortic stenosis)
the vessel wall that may lead to occlusion, described in Chapter 15). Occasionally, intense transient coronary spasm can su f ciently reduce myocardial blood supply to result in UA or in arction. Cocaine abuse can also lead to an ACS. Cocaine increases sympathetic tone by blocking the presynaptic reuptake o norepinephrine and by enhancing the release o adrenal catecholamines, which can lead to vasospasm and there ore decreased myocardial oxygen supply. An ACS may ensue because o increased myocardial oxygen demand resulting rom cocaine-induced sympathetic myocardial stimulation (increased heart rate and blood pressure) in the ace o the decreased oxygen supply. These nonatherosclerotic causes are relatively rare causes o acute MI. However, they are important to recognize as their treatments di er rom those o typical ACSs due to plaque rupture and superimposed thrombus ormation, as discussed in this chapter.
PATHOLOGY AND PATHOPHYSIOLOGY MI (either STEMI or NSTEMI) results when myocardial ischemia is su f ciently severe to cause myocyte necrosis. Although by def nition UA does not result in necrosis, it may subsequently progress to MI i the underlying pathophysiology is not promptly corrected. In addition to their clinical classif cations, in arctions can be described pathologically by the extent o necrosis they produce within the myocardial wall. Transmural infarcts span the entire thickness o the myocardial wall and result rom total, prolonged occlusion o an epicardial coronary artery. Conversely, subendocardial infarcts exclusively involve the innermost layers o the myocardium. The subendocardium is particularly susceptible to ischemia because it is the zone subjected to the highest pressure rom the ventricular chamber, has ew collateral connections that supply it, and is per used by vessels that must pass through layers o contracting myocardium. In arction represents the culmination o a disastrous cascade o events, initiated by ischemia, that progresses rom a potentially reversible phase to irreversible cell death. Myocardium that is supplied directly by an occluded vessel may die quickly. The adjacent tissue may not necrose immediately because it may be su f ciently per used by nearby patent vessels. However, the neighboring cells may become increasingly ischemic over time, as demand or oxygen continues in the ace o reduced oxygen supply. Thus, the region o in arction may subsequently extend outward. The amount o tissue that ultimately succumbs to in arction there ore relates to (1) the mass o myocardium per used by the occluded vessel, (2) the magnitude and duration o impaired coronary blood ow, (3) the oxygen demand o the a ected region, (4) the adequacy o collateral vessels that provide blood ow rom neighboring nonoccluded coronary arteries, and (5) the degree o tissue response that modif es the ischemic process.
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Pathologic Evolution of Infarction The pathophysiologic alterations that transpire during MI occur in two stages: early changes at the time o acute in arction and late changes during myocardial healing and remodeling (Table 7-3).
Early Changes in Infarction Early changes include the histologic evolution o the in arct and the unctional impact o oxygen deprivation on myocardial contractility. These changes culminate in coagulative necrosis o the myocardium in 2 to 4 days. As oxygen levels all in the myocardium supplied by an abruptly occluded coronary vessel, there is a rapid shi t rom aerobic to anaerobic metabolism (Fig. 7-4). Because mitochondria can no longer oxidize ats or products o glycolysis, high-energy phosphate production drops dramatically and anaerobic glycolysis leads to the accumulation o lactic acid, resulting in a lowered pH. Furthermore, the paucity o high-energy phosphates such as adenosine triphosphate (ATP) inter eres with transmembrane Na + –K+ -ATPase, with resultant elevation in the concentrations o intracellular Na + and extracellular K+ . Rising intracellular Na + contributes to cellular edema. Membrane leak and rising extracellular K+ concentration contributes to alterations in the transmembrane electrical potential, predisposing the myocardium to lethal arrhythmias. Intracellular calcium accumulates in the damaged myocytes and is thought to contribute to the f nal common pathway o cell destruction through the activation o degradative lipases and proteases. Collectively, these metabolic changes decrease myocardial unction as early as 2 minutes ollowing occlusive thrombosis. Without intervention, irreversible cell injury ensues in 20 minutes and is marked by the development o membrane de ects. Proteolytic enzymes leak across the myocyte’s altered membrane, damaging adjacent myocardium, and the release o certain macromolecules into the circulation serves as a clinical marker o acute in arction. Early histological changes include myocardial edema, wavy myof bers, and the presence o contraction bands (see Table 7-3). Edema o the myocardium develops within 4 to 12 hours, as vascular permeability increases and interstitial oncotic pressure rises (because o the leak o intracellular proteins). Wavy myof bers appear as intercellular edema separates the myocardial
TABLE 7-3 Pathologic Time Line in Transmural Infarction Time Early changes 1–2 min 10 min 20–24 min 1–3 h 4–12 h 18–24 h 2–4 d Late changes 5–7 d 7+ d 7 wk
Event ATP levels all; cessation o contractility 50% depletion o ATP; cellular edema, decreased membrane potential, and susceptibility to arrhythmias Irreversible cell injury Wavy myof bers Hemorrhage, edema, PMN inf ltration begins Coagulation necrosis (pyknotic nuclei with eosinophilic cytoplasm), edema Total coagulation necrosis (no nuclei or striations, rimmed by hyperemic tissue); monocytes appear; PMN inf ltration peaks Yellow so tening rom resorption o dead tissue by macrophages Granulation tissue orms, ventricular remodeling Fibrosis and scarring complete
ATP, adenosine triphosphate; PMN, polymorphonuclear leukocyte.
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Chapter 7 Myo c ardial hypoxia ATP
Impa ire d Na , K+-ATPa s e
Ana e robic me ta bolis m
+
Extra ce llula r K+
Intra ce llula r Na +
Alte re d me mbra ne pote ntia l
Arrhythm ia s
Intra ce llula r Ca ++
Intra ce llula r H+
Chroma tin clumping Prote in de na tura tion
Intra ce llula r e de ma ATP Prote a s e s Lip a s e s
Ce ll de a th
FIGURE 7-4. Mechanisms of cell death in myocardial infarction. Acute ischemia rapidly depletes the intracellular supply of adenosine triphosphate (ATP) as aerobic metabolism fails. Subsequent intracellular acidosis and impairment of ATP-dependent processes culminate in intracellular calcium accumulation, edema, and cell death.
cells that are tugged about by the surrounding, unctional myocardium. Contraction bands can o ten be seen near the borders o the in arct: sarcomeres are contracted and consolidated and appear as bright eosinophilic belts (Fig. 7-5A). An acute in ammatory response, with inf ltration o neutrophils, begins a ter approximately 4 hours and incites urther tissue damage. Within 18 to 24 hours, coagulation necrosis is evident on light microscopy (Fig. 7-5B) with pyknotic nuclei and bland eosinophilic cytoplasm. Gross morphologic changes (dark, mottled discoloration o in arcted tissue) do not appear until 18 to 24 hours a ter coronary occlusion, although certain staining techniques (e.g., tetrazolium) permit the pathologist to identi y regions o in arction earlier.
Late Changes in Infarction Late pathologic change in the course o an MI includes (1) the clearing o necrotic myocardium and (2) the deposition o collagen to orm scar tissue. Five to seven days a ter in arction, the process o wound healing progresses. Irreversibly injured myocytes do not regenerate; rather, the cells are removed and replaced by f brous tissue. Macrophages invade the in amed myocardium shortly a ter neutrophil inf ltration and remove necrotic tissue (Fig. 7-5C). This period o tissue resorption is termed yellow softening because connective tissue elements are destroyed and removed along with dead myocardial cells. The phagocytic clearing, combined with thinning and dilatation o the in arcted zone, results in structural weakness o the ventricular wall and the possibility o myocardial wall rupture at this stage. Approximately 1 week a ter in arction, granulation tissue appears, representing the beginning o the scarring process (Fig. 7-5D). This is observed grossly as a red border at the edge o the in arct. Fibrosis subsequently ensues, and scarring is complete by 7 weeks a ter in arction (Fig. 7-5E).
Acute Coronary Syndromes
A
B
C
D
E FIGURE 7-5. Pathologic evolution in myocardial infarction. A. Acute in arct approximately 12 hours old showing contraction band necrosis, nuclear karyolysis, ocal hemorrhage, and an absence o inf ammation. B. Acute in arct approximately 24 to 48 hours old showing coagulation necrosis and dense in ltration o neutrophils. C. Healing in arct approximately 5 days old showing necrotic myocytes undergoing removal by macrophages, with the neutrophilic response having largely dissipated. D. Healing in arct approximately 10 days old showing granulation tissue with new blood vessels (neovascularization), mild chronic inf ammation (macrophages and lymphocytes), broblasts, and early collagen deposition; viable myocardium is present at the upper le t. E. Healed in arct approximately 1 to 2 months old showing dense brosis; the inf ammation and new vessels have largely regressed; viable myocardium is present at the upper le t. All images are hematoxylin and eosin–stained sections.(Courtesy o Robert Padera, MD, PhD, Brigham and Women’s Hospital, Boston, MA).
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Functional Alterations Impaired Contractility and Compliance The destruction o unctional myocardial cells in in arction quickly leads to impaired ventricular contraction (systolic dysfunction). Cardiac output is urther compromised because syn chronous contraction o myocytes is lost. Specif c terms are used to describe the types o wall motion abnormalities that can result. A localized region o reduced contraction is termed hypokin etic, a segment that does not contract at all is called akinetic, and a dyskin etic region is one that bulges outward during contraction o the remaining unctional portions o the ventricle. During an ACS, the le t ventricle is also adversely compromised by diastolic dysfunction. Ischemia and/ or in arction impair diastolic relaxation (an energy-dependent process; see Chapter 1), which reduces ventricular compliance and contributes to elevated ventricular f lling pressures.
Stunned Myocardium Sometimes transient myocardial ischemia can result in a very prolonged, but gradually reversible, period o contractile dys unction. For example, as described in Chapter 6, stunned myocardium is tissue that demonstrates prolonged systolic dys unction a ter a discrete episode o severe ischemia, despite restoration o adequate blood ow, and gradually regains contractile orce days to weeks later. For example, stunning may occur ollowing reper usion therapy or acute STEMI, in which case prolonged contractile dys unction o a ected ventricular segments may simulate in arcted tissue. However, i the tissue is simply stunned rather than necrotic, its unction will recover over time.
Ischemic Preconditioning Brie ischemic insults to a region o myocardium may render that tissue more resistant to subsequent episodes, a phenomenon termed ischemic preconditioning. The clinical relevance is that patients who sustain an MI in the context o recent angina experience less morbidity and mortality than those without preceding ischemic episodes. The mechanism o this phenomenon is not ully understood but appears to involve multiple signaling pathways that involve both local and systemic mediators. Substances released during ischemia, including adenosine and bradykinin, are believed to be key triggers o these pathways.
Ventricular Remodeling Following an MI, changes occur in the geometry o both in arcted and nonin arcted ventricular muscle. Such alterations in chamber size and wall thickness a ect long-term cardiac unction and prognosis. In the early post-MI period, in arct expansion may occur, in which the a ected ventricular segment enlarges without additional myocyte necrosis. In arct expansion represents thinning and dilatation o the necrotic zone o tissue, likely because o “slippage” between the muscle f bers, resulting in a decreased volume o myocytes in the region. In arct expansion can be detrimental because it increases ventricular size, which (1) augments wall stress, (2) impairs systolic contractile unction, and (3) increases the likelihood o aneurysm ormation. In addition to early expansion o the in arcted territory, remodeling o the ventricle may also involve dilatation o the overworked noninfarcted segments, which are subjected to increased wall stress. This dilatation begins in the early postin arct period and continues over the ensuing weeks and months. Initially, chamber dilatation serves a compensatory role because it increases
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cardiac output via the Frank–Starling mechanism (see Chapter 9), but progressive enlargement may ultimately lead to heart ailure and predisposes to ventricular arrhythmias. Adverse ventricular remodeling can be benef cially modif ed by certain interventions. At the time o in arction, or example, reper usion therapies limit in arct size and there ore decrease the likelihood o in arct expansion. In addition, drugs that inter ere with the renin– angiotensin system have been shown to attenuate progressive remodeling and to reduce short- and long-term mortality a ter in arction (as discussed later in the chapter).
CLINICAL FEATURES OF ACUTE CORONARY SYNDROMES Because ACSs represent disorders along a continuum, their clinical eatures overlap. In general, the severity o symptoms and associated laboratory f ndings progress rom UA on one side o the continuum, through NSTEMI, to STEMI on the other end o the continuum. Distinguishing among these syndromes is based on the clinical presentation, electrocardiographic f ndings, and serum biomarkers o myocardial damage. To institute appropriate immediate therapy, the most important distinction to make is between an ACS that causes ST-segment elevation on the electrocardiogram (STEMI) and those acute syndromes that do not (UA and NSTEMI).
Clinical Presentation Unstable Angina UA presents as an acceleration o ischemic symptoms in one o the ollowing three ways: (1) a crescendo pattern in which a patient with chronic stable angina experiences a sudden increase in the requency, duration, and/ or intensity o ischemic episodes; (2) episodes o angina that unexpectedly occur at rest, without provocation; or (3) the new onset o anginal episodes, described as severe, in a patient without previous symptoms o coronary artery disease. These presentations are di erent rom the pattern o chronic stable angina, in which instances o chest discom ort are predictable, brie , and nonprogressive, occurring only during physical exertion or emotional stress. Patients with UA may progress urther along the continuum o ACS and develop evidence o necrosis (i.e., acute NSTEMI or STEMI) unless the condition is recognized and promptly treated.
Acute Myocardial Infarction The symptoms and physical f ndings o acute MI (both STEMI and NSTEMI) can be predicted rom the pathophysiology described earlier in this chapter and are summarized in Table 7-4. The discom ort experienced during an MI resembles angina pectoris qualitatively but is usually more severe, lasts longer, and may radiate more widely. Like angina, the sensation may result rom the release o mediators such as adenosine and lactate rom ischemic myocardial cells onto local nerve endings. Because ischemia in acute MI persists and proceeds to necrosis, these provocative substances continue to accumulate and activate a erent nerves or longer periods. The discom ort is o ten re erred to other regions o the C7 through T4 dermatomes, including the neck, shoulders, and arms. Initial symptoms are usually rapid in onset and briskly crescendo to leave the patient with a pro ound “ eeling o doom.” Unlike a transient attack o angina, the pain does not wane with rest, and there may be little response to the administration o sublingual nitroglycerin. The chest discom ort associated with an acute MI is o ten severe but not always. In act, up to 25% o patients who sustain an MI are asymptomatic during the acute event, and the diagnosis is made only in retrospect. This is particularly common among diabetic patients who may not adequately sense pain because o associated neuropathy.
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TABLE 7-4 Signs and Symptoms o Myocardial In arction 1. Characteristic pain 2. Sympathetic e ect 3. Parasympathetic ( vagal e ect) 4. Inf ammatory response 5. Cardiac ndings
6. Other
• • • • • • • • • • •
Severe, persistent, typically substernal Diaphoresis Cool and clammy skin Nausea, vomiting Weakness Mild fever S4 (and S3 if systolic dysfunction present) gallop Dyskinetic bulge (in anterior wall MI) Systolic murmur (if mitral regurgitation or VSD) Pulmonary rales (if heart failure present) Jugular venous distention (if heart failure or right ventricular MI)
MI, myocardial infarction; S3, third heart sound; S4, fourth heart sound; VSD, ventricular septal defect.
The combination o intense discom ort and baroreceptor unloading (i hypotension is present) may trigger a dramatic sympathetic nervous system response. Systemic signs o subsequent catecholamine release include diaphoresis (sweating), tachycardia, and cool and clammy skin caused by vasoconstriction. I the ischemia a ects a su f ciently large amount o myocardium, le t ventricular (LV) contractility can be reduced (systolic dys unction), thereby decreasing the stroke volume and causing the diastolic volume and pressure within the LV to rise. The increase in LV pressure, compounded by the ischemia-induced sti ness o the chamber (diastolic dys unction), is conveyed to the le t atrium and pulmonary veins. The resultant pulmonary congestion decreases lung compliance and stimulates juxtacapillary receptors. These J receptors e ect a re ex that results in rapid, shallow breathing and evokes the subjective eeling o dyspnea. Transudation o uid into the alveoli exacerbates this symptom. Physical f ndings during an acute MI depend on the location and extent o the in arct. The S4 sound, indicative o atrial contraction into a noncompliant le t ventricle, is requently present (see Chapter 2). An S3 sound, indicative o volume overload in the presence o ailing LV systolic unction, may also be heard. A systolic murmur may appear i ischemia-induced papillary muscle dys unction causes mitral valvular insu f ciency or i the in arct ruptures through the interventricular septum to create a ventricular septal de ect (as discussed later in the chapter). Myocardial necrosis also activates systemic responses to in ammation. Cytokines such as interleukin-1 (IL-1) and tumor necrosis actor (TNF) are released rom macrophages and vascular endothelium in response to tissue injury. These mediators evoke an array o clinical responses, including low-grade ever. Not all patients with severe chest pain are in the midst o MI or UA. Table 7-5 lists other common causes o acute chest discom ort and clinical, laboratory, and radiographic eatures to di erentiate them rom an ACS.
Diagnosis o Acute Coronary Syndromes The diagnosis o , and distinctions among, the ACSs is made on the basis o (1) the patient’s presenting symptoms, (2) acute ECG abnormalities, and (3) detection o specif c serum markers o myocardial necrosis (see Table 7-6 and Fig. 7-3). Specif cally, UA is a clinical diagnosis supported by the patient’s symptoms, transient ST abnormalities on the ECG (usually ST depression and/ or T-wave inversion), and the absence o serum biomarkers o myocardial necrosis. Non–ST-segment elevation MI is distinguished rom UA by the detection o serum markers o necrosis and o ten more persistent ST or T-wave abnormalities. The hallmark o ST-elevation MI is an appropriate clinical history coupled with ST elevations on the ECG plus detection o serum markers o myocardial necrosis.
Acute Coronary Syndromes
TABLE 7-5
175
Conditions That May Be Confused with Acute Coronary Syndromes
Condition
Differentiating Features
Cardiac Acute coronary syndrome
Pericarditis
Aortic dissection
Pulmonary Pulmonary embolism
Pneumonia
Pneumothorax
Gastrointestinal Esophageal spasm Acute cholecystitis
• Retrosternal pressure, radiating to the neck, jaw, or le t shoulder and arm; more severe and lasts longer than previous anginal attacks • ECG: localized ST elevations or depressions • Sharp pleuritic pain (worsens with inspiration) • Pain varies with position (relieved by sitting orward) • Friction rub auscultated over precordium • ECG: di use ST elevations (see Chapter 14) • Tearing, ripping pain that migrates over time (chest and back; see Chapter 15) • Asymmetry o arm blood pressures • Widened mediastinum on chest radiograph • • • • • • • • • •
Localized pleuritic pain, accompanied by dyspnea Pleural riction rub may be present Predisposing conditions or venous thrombosis Pleuritic chest pain Cough and sputum production Abnormal lung auscultation and percussion (i.e., consolidation) Inf ltrate on chest radiograph Sudden sharp, pleuritic unilateral chest pain Decreased breath sounds and hyperresonance o a ected side Chest radiograph: increased lucency and absence o pulmonary markings
• • • • •
Retrosternal pain, worsened by swallowing History o dysphagia Right upper quadrant abdominal tenderness O ten accompanied by nausea History o atty ood intolerance
ECG Abnormalities ECG abnormalities, which ref ect abnormal electrical currents during an ACS, are usually maniest in characteristic ways. In UA or NSTEMI, ST-segment depression and/ or T-wave inversions may occur (Fig. 7-6). These abnormalities may be transient, occurring just during chest pain episodes in UA, or they may persist in patients with NSTEMI. In contrast, as described in Chapter 4, STEMI presents with a temporal sequence o abnormalities: initial ST-segment
TABLE 7-6
Distinguishing Features of Acute Coronary Syndromes Myocardial Infarction
Feature Typical symptoms Serum biomarkers Electrocardiogram initial f ndings
Unstable Angina Crescendo, rest, or newonset severe angina No ST depression and/ or T-wave inversion
NSTEMI
STEMI
Prolonged “crushing” chest pain, more severe and wider radiation than usual angina Yes Yes ST depression and/ or ST elevation (and T-wave inversion Q waves later)
NSTEMI, non–ST-elevation myocardial in arction; STEMI, ST-elevation myocardial in arction.
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elevation, ollowed over the course o several hours by inversion o the T wave and the appearance o pathologic Q waves (Fig. 7-7). Importantly, these Acute characteristic patterns o ECG abnormalities in ACS can be minimized or prevented by early therapeutic interventions. We e ks Norma l Historically, MIs had been classif ed as “Q-wave” la te r • T-wave inve rs ion or “non–Q-wave” in arctions be ore the advent o the terms “STEMI” and “NSTEMI,” respectively. The or older terminology, which is still occasionally encountered, re ected the act that pathologically transmu• ST & T norma l ral in arctions typically produce pathologic Q waves • no Q wave s (a ter an initial period o ST elevation), whereas subendocardial in arctions do not. However, it is now • ST de pre s s ion known that the development o Q waves does not FIGURE 7-6. ECG abnormalities in unstable angina reliably correlate with pathologic f ndings and that and non–ST-elevation myocardial infarction. much overlap exists among the types o in arction. Moreover, the f nding o new pathologic Q waves to classi y ACSs now has little therapeutic relevance because Q waves, when they occur, take hours to develop and there ore are not help ul in making acute treatment decisions. Uns table Ang ina/No n–ST-Elevatio n Myo c ardial Infarc tio n
Serum Markers of Infarction Necrosis o myocardial tissue causes disruption o the sarcolemma, so that intracellular macromolecules leak into the cardiac interstitium and ultimately into the bloodstream (Fig. 7-8). Detection o such molecules in the serum, particularly cardiac-specif c troponins, serves important diagnostic and prognostic roles. In patients with STEMI or NSTEMI, these markers rise above a threshold level in a def ned temporal sequence.
Cardiac-specif c Troponins Troponin is a regulatory protein in muscle cells that controls interactions between myosin and actin (see Chapter 1). It consists o three subunits: TnC, TnI, and TnT. Although these subunits are ound in both skeletal and cardiac muscles, the cardiac orms o troponin I (cTnI) and troponin T (cTnT) are structurally unique, and highly specif c and sensitive assays or their detection in the serum are in wide clinical use. The presence o even minor serum elevations o these biomarkers serves as evidence o cardiomyocyte injury, is diagnostic o in arction in the appropriate clinical setting, and conveys power ul prognostic in ormation. However, as new generations o these assays have become ever more sensitive, small serum ST-Elevatio n Myo c ardial Infarc tio n Norma l
Acute
Hours
• ST e leva tion
• ST e leva tion • R Wave • Q wave be gins
Days 1–2
• T-wave inve rs ion • Q wave de e pe r
FIGURE 7-7. ECG evolution during ST-elevation myocardial infarction.
Days la te r
• ST norma lize s • T wave inve rte d
We e ks la te r
• ST & T norma l • Q wave pe rs is ts
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20 Troponins
10 5
e
s
o
f
M
I
t
h
r
e
s
h
o
l
d
50
M
u
l
t
i
p
l
CK-MB 2 1
FIGURE 7-8. Evolution of serum biomarkers in acute myocardial infarction ( MI) .
MI Thre s hold
1
2
3
4
5
6
7
8
9
10
Days a fte r ons e t of infa rction
elevations can also be detected in conditions other than MI, related to acute cardiac strain or in ammation (e.g., in heart ailure, myocarditis, hypertensive crises, or pulmonary embolism [due to right ventricular strain]). In the case o MI, cardiac troponin serum levels begin to rise 3 to 4 hours a ter the onset o chest discom ort, achieve a peak level between 18 and 36 hours, and then decline slowly, allowing or detection or 10 days or more a ter a large MI. Thus, their measurement may be help ul or detection o MI or nearly 2 weeks a ter the event occurs. Given their high sensitivity and specif city, cardiac troponins are the pre erred serum biomarkers to detect myocardial necrosis.
Creatine Kinase The enzyme creatine kinase (CK) is ound in the heart, skeletal muscle, brain, and other organs. Injury to any o these tissues may lead to elevation in serum concentrations o the enzyme. There are, however, three isoenzymes o CK that improve diagnostic specif city o its origin: CK-MM ( ound mainly in skeletal muscle), CK-BB (located predominantly in the brain), and CK-MB (localized mainly in the heart). Elevation o CK-MB is highly suggestive o myocardial injury. To acilitate the diagnosis o MI using this marker, it is common to calculate the ratio o CK-MB to total CK. The ratio is usually greater than 2.5% in the setting o myocardial injury and less than that when CK-MB elevation is rom another source. The serum level o CK-MB starts to rise 3 to 8 hours ollowing in arction, peaks at 24 hours, and returns to normal within 48 to 72 hours (see Fig. 7-8). As CK-MB is not as sensitive or specif c or detection o myocardial injury as is cardiac troponin, the latter is the pre erred diagnostic biomarker in clinical use. Because troponin and CK-MB levels do not become elevated in the serum until at least a ew hours a ter the onset o MI symptoms, a single normal value drawn early in the course o evaluation (e.g., in the hospital emergency department) does not rule out an acute MI; thus, the diagnostic utility o these biomarkers is limited in that critical period. As a result, early decision making in patients with ACS o ten relies most heavily on the patient’s history and ECG f ndings.
Imaging Sometimes, the early diagnosis o MI can remain uncertain even a ter care ul evaluation o the patient’s history, ECG, and serum biomarkers. In such a situation, an additional diagnostic study that may be use ul in the acute setting is echocardiography, which o ten reveals new abnormalities o ventricular contraction in the region o ischemia or in arction.
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TREATMENT OF ACUTE CORONARY SYNDROMES Success ul management o ACS requires rapid initiation o therapy to limit myocardial damage and minimize complications. Therapy must address the intracoronary thrombus that incited the syndrome and provide anti-ischemic measures to restore the balance between myocardial oxygen supply and demand. Although certain therapeutic aspects are common to all ACS, there is a critical di erence in the approach to patients who present with ST-segment elevation (STEMI) compared with those without ST-segment elevation (UA and NSTEMI). Patients with STEMI typically have total occlusion o a coronary artery and or optimal therapy require very rapid reper usion therapy (mechanical or pharmacologic), whereas patients without ST elevation generally do not (see Fig. 7-9 and as discussed later in the chapter). General in-hospital measures or any patient with ACS include admitting the patient to an intensive care setting where continuous ECG monitoring or arrhythmias is undertaken. The patient is initially maintained at bed rest to minimize myocardial oxygen demand, while supplemental oxygen is provided (by ace mask or nasal cannula), i there is any degree o hypoxemia, to improve oxygen supply. Analgesics, such as morphine, may be administered to reduce chest pain and associated anxiety.
Acute Treatment of Unstable Angina and Non–ST-Elevation Myocardial Infarction The management o UA and NSTEMI is essentially the same and is there ore discussed as one entity, whereas the approach to STEMI is described later. The primary ocus o treatment or UA and NSTEMI consists o anti-ischemic medications to restore the balance between myocardial oxygen supply and demand, and antithrombotic therapy to prevent urther growth, and to acilitate resolution o , the underlying partially occlusive coronary thrombus.
Anti-ischemic Therapy The same pharmacologic agents used to decrease myocardial oxygen demand in chronic stable angina are appropriate in UA and NSTEMI but are o ten administered more aggressively. β-Blockers decrease sympathetic drive to the myocardium, thus reducing oxygen demand, and contribute to electrical stability. This group o drugs reduces the likelihood o progression rom UA to MI and lowers mortality rates in patients who present with in arction. In the absence o contraindications (e.g., marked bradycardia, bronchospasm, decompensated heart ailure, or hypotension), a β-blocker is usually initiated in the f rst 24 hours to achieve a target heart rate o approximately 60 beats/ min. Such therapy is usually continued indef nitely a ter hospitalization because o proven long-term mortality benef ts ollowing an MI. Nitrates help bring about anginal relie through venodilation, which lowers myocardial oxygen demand by diminishing venous return to the heart (reduced preload and there ore less ventricular wall stress). Nitrates may also improve coronary ow and prevent vasospasm through coronary vasodilation. In UA or NSTEMI, nitroglycerin is o ten initially administered by the sublingual route, ollowed by a continuous intravenous in usion. In addition to providing symptomatic relie o angina, intravenous nitroglycerin is use ul as a vasodilator in patients with ACS accompanied by heart ailure or severe hypertension. Nondihydropyridine calcium channel antagonists (i.e., verapamil and diltiazem) exert antiischemic e ects by decreasing heart rate and contractility and through their vasodilatory properties (see Chapter 6). These agents do not con er mortality benef t to patients with ACS and are reserved or those in whom ischemia persists despite β-blocker and nitrate therapies or or those with contraindications to β-blocker use. They should not be prescribed to patients with LV systolic dys unction, because clinical trials have shown adverse outcomes in that case.
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Ac ute Co ro nary S yndro me Revas c ularizatio n Pathways
ST Ele vatio n (STEMI)
No n-ST Ele vatio n (UA and NSTEMI)
Eme rge nt P CI ava ila ble within 90 min? (120 min if tra ns fe rring to a P CI-ca pa ble hos pita l)
Ris k As s e s s me nt (e.g., Troponin, ECG, TIMI S core )
Ye s
Primary PCI
No
Low
Fibrino lytic The rapy (if no contra indica tion)
Co ns e rvative s trate gy (Proce e d to ca rdia c ca th if a ngina re curs or s ubs e que nt s tre s s te s t s hows s ubs ta ntia l is che mia )
High
Invas ive s trate gy (Ea rly ca rdia c ca th with P CI or CABG a s dicta te d by corona ry a na tomy)
A Ac ute Co ro nary Syndro me Co nc urre nt Tre atme nts
Anti-is c he mic the rapie s
• -blocke r • Nitra te s • +/– CCB
Antithro mbo tic the rapie s
Adjunc tive the rapie s
Antiplate le t ag e nts
Antic o ag ulants (us e one )
• As pirin • P 2Y12 inhibitor • +/– GP IIb/IIIa inhibitor
• UFH • LMWH • Biva lirudin
• S ta tin • ACE inhibitor
B FIGURE 7-9. Initial management strategies in acute coronary syndromes ( ACS) . A. Revascularization options. Primary percutaneous coronary intervention (PCI) is the preferred approach for STEMI patients if it is available rapidly. In UA/ NSTEMI, early invasive assessment is advised in patients with high-risk features. B. Pharmacologic agents that are typically indicated in ACS. Platelet P2Y12 inhibitors include clopidogrel, ticagrelor, and prasugrel. Note that when a glycoprotein (GP) IIb/ IIIa receptor antagonist is used as an additional antiplatelet agent, it is typically initiated at the time of PCI. Bivalirudin is an anticoagulant option for patients with ACS undergoing PCI. ECG, electrocardiogram; CCB, calcium channel blocker; LMWH, low molecular weight heparin; UFH, unfractionated intravenous heparin; ACE, angiotensin-converting enzyme.
Antithrombotic Therapy The purpose of antithrombotic therapy, including antiplatelet and anticoagulant medications, is to prevent further propagation of the partially occlusive intracoronary thrombus while facilitating its dissolution by endogenous mechanisms.
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Antiplatelet Drugs The majority o patients with UA or NSTEMI should receive at least two orms o antiplatelet therapy, typically aspirin and an inhibitor o the platelet P2Y12 ADP receptor. Aspirin inhibits platelet synthesis o thromboxane A2, a potent mediator o platelet activation (see Chapter 17), and is one o the most important interventions to reduce mortality in patients with all orms o ACS. It should be administered immediately on presentation and continued indef nitely in patients without contraindications to its use (e.g., allergy or underlying bleeding disorder). Aspirin inhibits only a single pathway o platelet activation. Another important agonist is ADP, which activates platelets in part by binding to the platelet P2Y12 receptor (see Chapter 17). Antagonists o this receptor inhibit platelet activation and include clopidogrel, prasugrel, and ticagrelor. Clopidogrel is an oral thienopyridine derivative (described in Chapter 17) that urther reduces cardiovascular death, recurrent MI, and stroke rates in patients with UA or NSTEMI who are treated with aspirin. However, not all patients respond to clopidogrel with similar benef t as it is a prodrug that requires cytochrome P-450–mediated biotrans ormation to its active metabolite. Patients with reduced unction polymorphisms o the CYP2C19 gene produce lower concentrations o clopidogrel’s activate metabolite, less platelet inhibition, and attenuated clinical benef ts. Thus, newer P2Y12 ADP receptor blockers have been developed that do not have this metabolic shortcoming, have more rapid onsets o action, and achieve greater degrees o platelet inhibition than clopidogrel. For example, prasugrel is also a thienopyridine derivative. Compared to clopidogrel, it reduces coronary event rates in patients with ACS who undergo percutaneous coronary intervention (PCI), but because it is more potent, it also increases the risk o bleeding complications. Both clopidogrel and prasugrel are irreversible platelet inhibitors. Ticagrelor is a nonthienopyridine drug that is a reversible P2Y12 ADP receptor blocker. Compared to clopidogrel, it has been shown to urther decrease major cardiovascular events and mortality, without an increased risk o li e-threatening bleeding episodes; minor bleeding is, however, more common than with clopidogrel. In some circumstances, even more power ul antiplatelet agents are utilized in ACSs. The glycoprotein (GP) IIb/ IIIa receptor antagonists (which include the monoclonal antibody abciximab and the small molecules eptif batide and tirof ban) are potent antiplatelet agents that block the f nal common pathway o platelet aggregation (see Chapter 17). These agents are e ective in reducing adverse coronary events in patients undergoing PCI. In patients presenting with UA or NSTEMI, their benef t is mani est primarily in those at the highest risk o complications (e.g., the presence o elevated serum troponin levels or recurrent episodes o chest pain). When used, GP IIb/ IIIa receptor antagonists are most commonly initiated in the cardiac catheterization laboratory at the time o PCI.
Anticoagulant Drugs Intravenous unfractionated heparin (UFH) has long been standard anticoagulant therapy or UA and NSTEMI. It binds to antithrombin, which greatly increases the potency o that plasma protein in the inactivation o clot- orming thrombin. UFH additionally inhibits coagulation actor Xa, slowing thrombin ormation and thereby urther impeding clot development. In patients with UA or NSTEMI, UFH improves cardiovascular outcomes and reduces the likelihood o progression rom UA to MI. It is administered as a weight-based bolus, ollowed by continuous intravenous in usion. Because o a high degree o pharmacodynamic variability, its anticoagulant e ect must be monitored and its dose adjusted, through serial measurements o the serum activated partial thromboplastin time (aPTT). It is the least expensive o the anticoagulant drugs described in this section.
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To overcome the pharmacologic shortcomings o UFH, low molecular weight heparins (LMWHs) were developed. Like UFH, LMWHs interact with antithrombin but pre erentially inhibit coagulation actor Xa. They provide a more predictable pharmacologic response than UFH. As a result, LMWHs are easier to use, prescribed as one or two daily subcutaneous injections based on the patient’s weight. Unlike UFH, repeated monitoring o blood tests and dosage adjustments are not generally necessary. In clinical trials in patients with UA or NSTEMI, the LMWH enoxaparin (see Chapter 17) has demonstrated reduced death and ischemic event rates compared with UFH. Two other types o anticoagulants have also been shown to be benef cial in UA and NSTEMI and are sometimes used in place o UFH or LMWH. Bivalirudin is an intravenous direct thrombin inhibitor (see Chapter 17), which is equivalent to UFH plus a GP IIb/ IIIa inhibitor in preventing adverse ischemic outcomes, with less associated bleeding, in patients with UA or NSTEMI treated with an early invasive strategy. Fondaparinux is a subcutaneously administered agent that is a very specif c actor Xa inhibitor (see Chapter 17). Its e ect is similar to the LMWH enoxaparin at reducing cardiac adverse events but with ewer bleeding complications. With all o these choices, the decision o which anticoagulant to prescribe to an individual patient o ten depends on whether an initial conservative versus invasive approach is ollowed.
Conservative versus Early Invasive Management of UA and NSTEMI Many patients with UA or NSTEMI stabilize ollowing institution o the therapies described in the previous section, while others have recurrent ischemic events. There is currently no def nitive way to predict which direction a patient will take or to quickly determine which individuals have such severe underlying CAD that coronary revascularization is warranted. These uncertainties have led to two therapeutic strategies in UA/ NSTEMI: (1) an early invasive approach, in which urgent cardiac catheterization is per ormed and coronary revascularization undertaken as indicated, and (2) a conservative approach, in which the patient is managed with medications (as detailed in the previous section) and undergoes angiography only i ischemic episodes spontaneously recur or i the results o a subsequent stress test indicate substantial residual inducible ischemia. The conservative approach o ers the advantage o avoiding costly and potentially risky invasive procedures. Conversely, an early invasive strategy allows rapid identif cation and def nitive treatment (i.e., revascularization) or those with critical coronary disease. In general, an early invasive approach is recommended to patients with re ractory angina, with complications such as shock or ventricular arrhythmias, or those with the most concerning clinical eatures. Risk assessment algorithms consider such eatures and help identi y patients at high likelihood o a poor outcome. One commonly used tool is the Thrombolysis in Myocardial Infarction (TIMI) risk score that employs seven variables to predict a patient’s risk level: 1. Age greater than 65 years old 2. ≥ 3 risk actors or coronary artery disease (as described in Chapter 5) 3. Known coronary stenosis o ≥ 50% by prior angiography 4. ST-segment deviations on the ECG at presentation 5. At least two anginal episodes in prior 24 hours 6. Use o aspirin in prior 7 days (i.e., implying resistance to aspirin’s e ect) 7. Elevated serum troponin or CK-MB Clinical studies have conf rmed that a patient’s TIMI risk score predicts the likelihood o death or subsequent ischemic events, such that an early invasive strategy is recommended in patients with higher scores (≥ 3). I an early invasive approach is adopted, the patient should undergo angiography within 72 hours, or within 24 hours or patients at especially high risk.
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Acute Treatment of ST-Elevation Myocardial Infarction In contrast to UA and NSTEMI, the culprit artery in STEMI is typically completely occluded. Thus, to limit myocardial damage, the major ocus o acute treatment is to achieve very rapid reper usion o the jeopardized myocardium using either percutaneous coronary mechanical revascularization or f brinolytic drugs. These approaches reduce the extent o myocardial necrosis and greatly improve survival. To be e ective, they must be undertaken as soon as possible; the earlier the intervention occurs, the greater the amount o myocardium that can be salvaged. Decisions about therapy must be made within minutes o a patient’s assessment, based on the history and electrocardiographic f ndings, o ten be ore serum markers o necrosis would be expected to rise. In addition, as is the case in UA and NSTEMI, specif c medications should be initiated promptly to prevent urther thrombosis and to restore the balance between myocardial oxygen supply and demand. For example, antiplatelet therapy with aspirin decreases mortality rates and rates o rein arction a ter STEMI. It should be administered immediately on presentation (by chewing a tablet to acilitate absorption) and continued orally daily therea ter. An anticoagulant (e.g., intravenous UFH) is typically initiated to help maintain patency o the coronary vessel and is an important adjunct to PCI and f brinolytic regimens. β-Blockers reduce myocardial oxygen demand and lower the risk o recurrent ischemia, arrhythmias, and rein arction. In the absence o contraindications (e.g., asthma, hypotension, or signif cant bradycardia), an oral β-blocker should be administered to achieve a heart rate o 50 to 60 beats/ min. Intravenous β-blocker therapy should be reserved or patients who are hypertensive at presentation, as that route o administration has otherwise been associated with an increased risk o cardiogenic shock in STEMI. Nitrate therapy, usually intravenous nitroglycerin, is used to help control ischemic pain and also serves as a benef cial vasodilator in patients with heart ailure or severe hypertension.
Primary Percutaneous Coronary Intervention The pre erred method o reper usion therapy in patients with acute STEMI is immediate cardiac catheterization and percutaneous coronary intervention o the lesion responsible or the in arction. This approach, termed primary PCI, is a very e ective method or reestablishing coronary per usion and, in clinical trials per ormed at highly experienced medical centers, has achieved optimal ow in the in arct-related artery in more than 95% o patients. During the procedure, per ormed under uoroscopy, a catheter is inserted into a peripheral artery and directed to the site o coronary occlusion. A balloon at the end o the catheter is then in ated, compressing the thrombus and atherosclerotic plaque, and a stent is usually inserted (see Chapter 6), thereby restoring and maintaining coronary blood ow. In order to salvage as much myocardium as possible, the goal is that the time rom f rst medical contact to PCI be less than 90 minutes. At medical centers without PCI availability, the decision to trans er a patient to a PCI-capable hospital or to treat with f brinolytic therapy (discussed in next section) must be made rapidly. A delay in reper usion leads to worse outcomes or patients regardless o the mechanism chosen, and the longer the delay, the less benef t primary PCI has over f brinolytic therapy. Generally, trans er to a PCI-capable hospital is recommended i the procedure can be per ormed within 120 minutes o f rst medical contact. To reduce thrombotic complications, patients undergoing primary PCI receive a combination o medications. Aspirin and a P2Y12 receptor inhibitor (e.g., ticagrelor, prasugrel, or clopidogrel) are the antiplatelet agents typically administered prior to the procedure. A more potent GP IIb/ IIIa platelet inhibitor is also sometimes used with PCI. Anticoagulation therapy consists o either UFH or bivalirudin as the primary choices. Recent evidence shows that bivalirudin results in lower rates o bleeding in STEMI when compared to UFH plus a GP IIb/ IIIa inhibitor. However, it is also associated with a higher rate o acute stent thrombosis in this setting.
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A ter primary PCI, aspirin is continued indef nitely. For patients who receive coronary stents during PCI, a prolonged course o a P2Y12 receptor inhibitor reduces the risk o ischemic complications and stent thrombosis.
Fibrinolytic Therapy Primary PCI is the pre erred reper usion approach in acute STEMI, as it leads to greater survival with lower rates o rein arction and bleeding when compared to f brinolytic therapy. However, i PCI is not available or is likely to be delayed, f brinolytic therapy is the reper usion alternative. Fibrinolytic drugs accelerate lysis o the occlusive intracoronary thrombus in STEMI, thereby restoring blood ow and limiting myocardial damage. This section does not pertain to patients with UA or NSTEMI, as such individuals do not benef t rom f brinolytic therapy. Currently used f brinolytic agents include recombinant tissue–type plasminogen activator (alteplase, tPA), reteplase (rPA), and tenecteplase (TNK-tPA). Each drug unctions by stimulating the natural f brinolytic system, trans orming the inactive precursor plasminogen into the active protease plasmin, which lyses f brin clots. Although the intracoronary thrombus is the target, plasmin has poor substrate specif city and can degrade other proteins, including f brin’s precursor f brinogen. As a result, bleeding is the most common complication o these drugs. Administration o f brinolytic agents in the early hours o an acute STEMI restores blood ow in most (70% to 80% ) coronary occlusions and signif cantly reduces the extent o tissue damage. Improved artery patency translates into substantially increased survival rates and ewer postin arction complications. The rapid initiation o f brinolysis is crucial: patients who receive therapy within 2 hours o the onset o symptoms o STEMI have half the mortality rate o those who receive it a ter 6 hours. To prevent immediate vessel reocclusion a ter success ul thrombolysis, anticoagulants (UFH or LMWHs) and antiplatelet therapy, including aspirin and a platelet P2Y12 inhibitor, are administered. For those initially treated with f brinolytic therapy who do not demonstrate an adequate acute response, including expeditious resolution o symptoms and ST-segment elevations, trans er o the patient to a hospital capable o per orming “rescue” PCI is recommended as soon as possible. Because the major risk o thrombolysis is bleeding, contraindications to such therapy include situations in which necessary f brin clots within the circulation would be jeopardized (e.g., patients with active peptic ulcer disease or an underlying bleeding disorder, patients who have had a recent stroke, or patients who are recovering rom recent surgery). Consequently, approximately 30% o patients may not be suitable candidates or thrombolysis.
Adjunctive Therapies Angiotensin-converting enzyme (ACE) inhibitors limit adverse ventricular remodeling and reduce the incidence o heart ailure, recurrent ischemic events, and mortality ollowing an MI. Their benef t is additive to that o aspirin and β-blocker therapies, and they have shown avorable improvements especially in higher-risk patients—those with anterior wall in arctions or LV systolic dys unction. Cholesterol-lowering statins (HMG-CoA reductase inhibitors) reduce mortality rates o patients with coronary artery disease (see Chapter 5). Clinical trials o patients with ACS have demonstrated that it is sa e to begin statin therapy early during hospitalization and that a high-intensity lipid-lowering regimen, designed to reduce low-density lipoprotein (LDL) levels by greater than 50% (ideally to < 70 mg/ dL), provides greater protection against subsequent cardiovascular events and death than less intense regimens. The benef ts o statin therapy may extend beyond lipid lowering, because this group o drugs has attributes that can improve endothelial dys unction, inhibit platelet aggregation, and impair thrombus ormation. Additional LDL lowering with the cholesterol absorption inhibitor ezetimibe (see Chapter 17) a ter an ACS was recently shown to urther reduce subsequent cardiovascular event rates.
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Chapter 7 In addition to the short-term use o heparin anticoagulation described earlier, a more prolonged course, ollowed by oral anticoagulation (i.e., war arin), is appropriate or patients at high risk o thromboembolism. This includes patients with documented intraventricular thrombus (typically identif ed by echocardiography), those with atrial f brillation, and persons who have su ered a large acute anterior MI with akinesis o that territory (which is susceptible to thrombus ormation because o the stagnant blood ow). As discussed later in the chapter, impaired ventricular contractility a ter MI can lead to heart ailure. Patients with a le t ventricular ejection raction o less than 40% and symptoms o heart ailure a ter STEMI should be considered or therapy with an aldosterone antagonist (spironolactone or eplerenone) in addition to an ACE inhibitor and beta-blocker. Aldosterone augments sodium reabsorption rom the distal nephron (contributing to uid retention, an undesired e ect in heart ailure) and also promotes in ammation and myocardial f brosis. Chronic administration o an aldosterone antagonist mitigates these e ects and has been shown to decrease mortality ollowing MI in patients with le t ventricular dys unction.
COMPLICATIONS In UA, potential complications include death (5% to 10% o patients) or progression to in arction (10% to 20% o patients) over the ensuing days and weeks. Once in arction has transpired, especially STEMI, complications can result rom the in ammatory, mechanical, and electrical abnormalities induced by regions o necrosing myocardium (Fig. 7-10). Early complications result rom myocardial necrosis itsel . Those that develop several days to weeks later re ect the in ammation and healing o necrotic tissue.
Recurrent Ischemia Postin arction angina has been reported in 20% to 30% o patients ollowing an MI. This rate has not been reduced by the use o thrombolytic therapy, but it is lower in those who have undergone acute percutaneous coronary revascularization. Indicative o inadequate residual
Myo c ardial Infarc tio n
Ve ntricula r thrombus
Contra ctility
Ele ctrica l ins ta bility
Embo lis m
Cardio g e nic s ho ck
Arrhythmias
Is che mia
Tis s ue ne cros is
Pe rica rdia l infla mma tion
Pe ric arditis
Hypote ns ion Corona ry pe rfus ion pre s s ure
Pa pilla ry mus cle infa rction/ is che mia
Ve ntricula r s e pta l de fe ct
Mitra l re gurgita tion
Ve ntricula r rupture
Cardiac tampo nade
Co ng e s tive he art failure
FIGURE 7-10. Complications of MI. Infarction may result in decreased contractility, electrical instability, and tissue necrosis, which can lead to the indicated sequelae.
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TABLE 7-7 Arrhythmias in Acute Myocardial Infarction Rhythm
Cause
Sinus bradycardia
• • • • • • • • • • • •
Sinus tachycardia
APBs, atrial brillation VPBs, VT, VF AV block (1° , 2° , 3° )
↑Vagal tone ↓SA nodal artery per usion Pain and anxiety Heart ailure Volume depletion Chronotropic drugs (e.g., dopamine) Heart ailure Atrial ischemia Ventricular ischemia Heart ailure IMI: ↑vagal tone and ↓AV nodal artery f ow AMI: extensive destruction o conduction tissue
AMI, anterior myocardial in arction; APBs, atrial premature beats; AV, atrioventricular; IMI, in erior myocardial in arction; SA, sinoatrial; VPBs, ventricular premature beats; VF, ventricular brillation; VT, ventricular tachycardia.
coronary blood f ow, it is a poor omen and correlates with an increased risk or rein arction. Such patients usually require urgent cardiac catheterization, o ten ollowed by revascularization by percutaneous techniques or coronary artery bypass surgery.
Arrhythmias Arrhythmias occur requently during acute MI and are a major source o mortality prior to hospital arrival. Fortunately, modern coronary care units are highly attuned to the detection and treatment o rhythm disturbances; thus, once a patient is hospitalized, arrhythmiaassociated deaths are uncommon. Mechanisms that contribute to arrhythmogenesis a ter MI include the ollowing (Table 7-7): 1. Anatomic interruption o blood f ow to structures o the conduction pathway (e.g., sinoatrial node, atrioventricular node, and bundle branches); the normal per usion o pertinent components o the conduction system is summarized in Table 7-8. 2. Accumulation o toxic metabolic products (e.g., cellular acidosis) and abnormal transcellular ion concentrations owing to membrane leaks. 3. Autonomic stimulation (sympathetic and parasympathetic). 4. Administration o potentially arrhythmogenic drugs (e.g., dopamine).
TABLE 7-8 Blood Supply of the Conduction System Conduction Pathway
Primary Arterial Supply
SA node AV node Bundle o His Right bundle branch
• • • • •
Le t bundle branch Le t anterior ascicle Le t posterior ascicle
RCA (70% o patients) RCA (85% o patients) LAD (septal branches) Proximal portion by LAD Distal portion by RCA
• LAD • LAD and PDA
AV, atrioventricular; LAD, le t anterior descending coronary artery; PDA, posterior descending artery; RCA, right coronary artery; SA, sinoatrial.
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Ventricular Fibrillation Ventricular f brillation (rapid, disorganized electrical activity o the ventricles) is largely responsible or sudden cardiac death during the course o acute MI. Most atal episodes occur be ore hospital arrival, a trend that can be impacted by increasing availability o automatic external def brillators in public places. Episodes o ventricular f brillation that occur during the f rst 48 hours o MI are o ten related to transient electrical instability, and the long-term prognosis o survivors o such events is not adversely a ected. However, ventricular f brillation occurring later than 48 hours a ter the acute MI usually re ects severe LV dys unction and is associated with high subsequent mortality rates. Ventricular ectopic beats, ventricular tachycardia, and ventricular f brillation during an acute MI arise rom either reentrant circuits or enhanced automaticity o ventricular cells (see Chapter 11). Ventricular ectopic beats are common and usually not treated unless the beats become consecutive, multi ocal, or requent. Cardiac care unit personnel are prof cient at arrhythmia detection and institution o treatment should more malignant ventricular arrhythmias develop. Therapy or ventricular arrhythmias is described in Chapter 12.
Supraventricular Arrhythmias Supraventricular arrhythmias are also common in acute MI. Sinus bradycardia results rom either excessive vagal stimulation or sinoatrial nodal ischemia, usually in the setting o an in erior wall MI. Sinus tachycardia occurs requently and may result rom pain and anxiety, heart ailure, drug administration (e.g., dopamine), or intravascular volume depletion. Because sinus tachycardia increases myocardial oxygen demand and could exacerbate ischemia, identi ying and treating its cause are important. Atrial premature beats and atrial f brillation (see Chapter 12) may result rom atrial ischemia or atrial distention secondary to LV ailure.
Conduction Blocks Conduction blocks (atrioventricular nodal block and bundle branch blocks) develop commonly in acute MI. They may result rom ischemia or necrosis o conduction tracts, or in the case o atrioventricular blocks, they may develop transiently because o increased vagal tone. Vagal activity may be increased because o stimulation o a erent f bers by the in amed myocardium or as a result o generalized autonomic activation in association with the discom ort o an acute MI.
Myocardial Dysfunction Heart Failure Acute cardiac ischemia results in impaired ventricular contractility (systolic dys unction) and increased myocardial sti ness (diastolic dys unction), both o which may lead to symptoms o heart ailure. In addition, ventricular remodeling, arrhythmias, and acute mechanical complications o MI (described later in the chapter) may culminate in heart ailure. Signs and symptoms o such decompensation include dyspnea, pulmonary rales, and a third heart sound (S3). Treatment consists o standard heart ailure therapy, which typically includes diuretics or relie o volume overload, and ACE inhibitor and β-blocker therapies or longterm mortality benef t (see Chapter 9). As noted earlier, or patients with post-MI heart ailure and an LV ejection raction less than 40% , an aldosterone antagonist (spironolactone or eplerenone—described in Chapter 17) should be considered. However, when an aldosterone antagonist is prescribed concurrently with an ACE inhibitor, the serum potassium level should be care ully monitored to prevent hyperkalemia.
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Cardiogenic Shock Cardiogenic shock is a condition o severely decreased cardiac output and hypotension (systolic blood pressure < 90 mm Hg) with inadequate per usion o peripheral tissues that develops when more than 40% o the LV mass has in arcted. It may also ollow certain severe mechanical complications o MI described later. Cardiogenic shock is sel -perpetuating because (1) hypotension leads to decreased coronary per usion, which exacerbates ischemic damage, and (2) decreased stroke volume increases LV size and there ore augments myocardial oxygen demand (see Fig. 7-10). Cardiogenic shock occurs in up to 10% o patients a ter MI, and the mortality rate is greater than 70% . Early cardiac catheterization and revascularization can improve the prognosis. Patients in cardiogenic shock require intravenous inotropic agents (e.g., dobutamine) to increase cardiac output and, once the blood pressure has improved, arterial vasodilators to reduce the resistance to LV contraction. Patients may be stabilized by the placement o an intra-aortic balloon pump. Inserted into the aorta through a emoral artery, the pump consists o an in atable, exible chamber that expands during diastole to increase intra-aortic pressure, thus augmenting per usion o the coronary arteries. During systole, it de ates to create a “vacuum” that serves to reduce the a terload o the le t ventricle, thus aiding the ejection o blood into the aorta and improving cardiac output and peripheral tissue per usion. I more extensive and prolonged hemodynamic support is required, a percutaneous left ventricular assist device (LVAD) can be placed. Using cannulae inserted via the emoral vessels, a motor pumps oxygenated blood rom the LA or the LV (depending on the model) to the aorta and its branches, bypassing or “assisting” the LV.
Right Ventricular Infarction Approximately one third o patients with in arction o the LV in erior wall also develop necrosis o portions o the right ventricle, because the same coronary artery (usually the right coronary) per uses both regions in most individuals. The resulting abnormal contraction and decreased compliance o the right ventricle lead to signs o right-sided heart ailure (e.g., jugular venous distention) out o proportion to signs o le t-sided ailure. In addition, proound hypotension may result when the right ventricular dys unction impairs blood ow through the lungs, leading to the le t ventricle becoming underf lled. In this setting, intravenous volume in usion serves to correct hypotension, o ten guided by hemodynamic measurements via a transvenous pulmonary artery catheter (see Chapter 3).
Mechanical Complications Mechanical complications ollowing MI result rom cardiac tissue ischemia and necrosis.
Papillary Muscle Rupture Ischemic necrosis and rupture o an LV papillary muscle may be rapidly atal because o acute severe mitral regurgitation, as the valve lea ets lose their anchoring attachments. Partial rupture, with more moderate regurgitation, is not immediately lethal but may result in symptoms o heart ailure or pulmonary edema. Because it has a more precarious blood supply, the posteromedial LV papillary muscle is more susceptible to in arction than the anterolateral one.
Ventricular Free Wall Rupture An in requent but deadly complication, rupture o the LV ree wall through a tear in the necrotic myocardium may occur within the f rst 2 weeks ollowing MI. It is more common
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Chapter 7 among women and patients with a history o hypertension. Hemorrhage into the pericardial space owing to LV ree wall rupture results in rapid cardiac tamponade, in which blood f lls the pericardial space and severely restricts ventricular f lling (see Chapter 14). Survival is rare. On occasion, a pseudoaneurysm results i rupture o the ree wall is incomplete and held in check by thrombus ormation that “plugs” the hole in the myocardium. This situation is the cardiac equivalent o a time bomb, because subsequent complete rupture into the pericardium and tamponade could ollow. I detected (usually by imaging studies), surgical repair may prevent an otherwise disastrous outcome.
Ventricular Septal Rupture This complication is analogous to LV ree wall rupture, but the abnormal ow o blood is not directed across the LV wall into the pericardium. Rather, blood is shunted across the ventricular septum rom the le t ventricle to the right ventricle, usually precipitating congestive heart ailure because o subsequent volume overload o the pulmonary capillaries. A loud systolic murmur at the le t sternal border, representing transseptal ow, is common in this situation. Although each results in a systolic murmur, ventricular septal rupture can be di erentiated rom acute mitral regurgitation by the location o the murmur (see Fig. 2-11), by Doppler echocardiography, or by measuring the O2 saturation o blood in the right-sided heart chambers through a transvenous catheter. The O2 content in the right ventricle is abnormally higher than that in the right atrium i there is shunting o oxygenated blood rom the le t ventricle across the septal de ect.
True Ventricular Aneurysm A late complication o MI, a true ventricular aneurysm, may come to attention weeks to months a ter the acute in arction. It develops as the ventricular wall is weakened, but not per orated, by the phagocytic clearance o necrotic tissue, and it results in a localized outward bulge (dyskinesis) when the residual viable heart muscle contracts. Unlike the pseudoaneurysm described earlier, a true aneurysm does not involve communication between the LV cavity and the pericardium, so that rupture and tamponade do not develop. Potential complications o LV aneurysm include (1) thrombus ormation within this region o stagnant blood ow, serving as a source o emboli to peripheral organs; (2) ventricular arrhythmias associated with the stretched myof bers; and (3) heart ailure resulting rom reduced orward cardiac output, because some o the LV stroke volume is “wasted” by f lling the aneurysm cavity during systole. Clues to the presence o an LV aneurysm include persistent ST-segment elevations on the ECG weeks a ter an acute ST-elevation MI and a bulge at the LV border on chest radiography. The abnormality can be conf rmed by echocardiography or other imaging modalities.
Pericarditis Acute pericarditis may occur in the early (in-hospital) post-MI period as in ammation extends rom the myocardium to the adjacent pericardium. Sharp pain, ever, and a pericardial riction rub are typically present in this situation and help distinguish pericarditis rom the discom ort o recurrent myocardial ischemia (see Chapter 14). The symptoms usually promptly respond to aspirin therapy. Anticoagulants are relatively contraindicated in MI complicated by pericarditis to avoid hemorrhage rom the in amed pericardial lining. The requency o MI-associated pericarditis has declined since the introduction o acute reper usion strategies, because those approaches limit the extent o myocardial damage and in ammation.
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Dressler Syndrome Dressler syndrome is now a rare orm o pericarditis that can occur weeks ollowing an MI. The cause is unclear, but an immune process directed against damaged myocardial tissue is suspected to play a role. The syndrome is heralded by ever, malaise, and sharp; pleuritic chest pain typically accompanied by leukocytosis; an elevated erythrocyte sedimentation rate; and a pericardial e usion. Similar to other orms o acute pericarditis, Dressler syndrome generally responds to aspirin or other nonsteroidal anti-in ammatory therapies.
Thromboembolism Stasis o blood ow in regions o impaired LV contraction a ter an MI may result in intracavity thrombus ormation, especially when the in arction involves the LV apex or when a true aneurysm has ormed. Subsequent thromboemboli can result in in arction o peripheral organs (e.g., a cerebrovascular event [stroke] caused by embolism to the brain).
RISK STRATIFICATION AND MANAGEMENT FOLLOWING MYOCARDIAL INFARCTION The most important predictor o post-MI outcome is the extent o LV dys unction. Other eatures that portend adverse outcomes include early recurrence o ischemic symptoms, a large volume o residual myocardium still at risk because o severe underlying coronary disease, and high-grade ventricular arrhythmias. To identi y patients at high risk or complications who may benef t rom cardiac catheterization and revascularization, exercise treadmill testing is o ten per ormed (unless the patient has already undergone catheterization and corrective percutaneous revascularization or the presenting coronary syndrome). Patients with signif cantly abnormal results, or those who demonstrate an early spontaneous recurrence o angina, are customarily re erred or cardiac catheterization to def ne their coronary anatomy. Standard postdischarge therapy or the long-term includes aspirin, a β-blocker, and a high-intensity HMG-CoA reductase inhibitor (statin). A P2Y12 platelet inhibitor is continued or 12 months or longer. ACE inhibitors are prescribed to patients who have LV contractile dys unction; an aldosterone antagonist should be considered in those with heart ailure symptoms. Rigorous attention to underlying cardiac risk actors, such as smoking, hypertension, and diabetes, is mandatory, and a ormal exercise rehabilitation program o ten speeds convalescence. Patients who have an LV ejection raction o ≤ 30% a ter MI are at high risk o sudden cardiac death and are candidates or prophylactic placement o an implantable cardioverter–def brillator. Current guidelines recommend postponing such implantation or at least 40 days post-MI because clinical trials have not shown a survival benef t at earlier stages.
SUMMARY • Acute coronary syndromes (ACSs) include unstable angina (UA), non–ST-segment elevation myocardial in arction (NSTEMI), and ST-segment elevation myocardial in arction (STEMI). • Most ACS episodes are precipitated by intracoronary thrombus ormation at the site o atherosclerotic plaque disruption. • Distinctions among types o ACS are based on the severity o ischemia and whether myocardial necrosis results: STEMI is associated with an occlusive thrombus and severe ischemia
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•
• •
• • •
•
•
• •
• •
with necrosis, whereas ACSs without ST elevation (NSTEMI and UA) usually result rom partially occlusive thrombi with less intense ischemia; however, compared with UA, the insult in NSTEMI is o su f cient magnitude to cause some myocardial necrosis. ACSs result in biochemical and mechanical changes that impair systolic contraction, decrease myocardial compliance, and predispose to arrhythmias; in arction initiates an in ammatory response that clears necrotic tissue and leads to scar ormation. The diagnosis o specif c ACS relies on the patient’s history, ECG abnormalities, and the presence o specif c biomarkers in the serum (e.g., cardiac troponin T or troponin I). Acute treatment o UA and NSTEMI includes anti-ischemic therapy to restore the balance between myocardial oxygen supply and demand (e.g., β-blockers, nitrates), antithrombotic therapy to acilitate resolution o the intracoronary thrombus (e.g., aspirin, a P2Y12 ADP receptor antagonist, an anticoagulant [e.g., intravenous or low molecular weight heparin], and sometimes a glycoprotein IIb/ IIIa receptor antagonist), and high-intensity statin therapy. Early coronary angiography, with subsequent coronary revascularization, is benef cial or UA or NSTEMI patients with high-risk eatures. Acute treatment o STEMI includes rapid coronary reper usion, ideally with percutaneous catheter-based intervention i available or else f brinolytic therapy. Other important therapies or STEMI include antiplatelet therapy (aspirin, P2Y12 receptor antagonist), an anticoagulant, a β-blocker, sometimes nitrate therapy, and a statin; an ACE inhibitor is requently appropriate. Potential complications o in arction include arrhythmias (e.g., ventricular tachycardia and f brillation, and supraventricular tachycardias) and conduction blocks (atrioventricular blocks and bundle branch blocks). Heart ailure or cardiogenic shock may develop because o ventricular dys unction or mechanical complications (e.g., acute mitral regurgitation or ventricular septal de ect); wall motion abnormalities o the in arcted segment may predispose to thrombus ormation. Right ventricular in arction results in signs o right heart ailure out o proportion to le t heart ailure, o ten with intravascular volume sensitivity and hypotension. Standard pharmacologic therapy ollowing discharge rom the hospital a ter an ACS includes measures to reduce the risks o thrombosis (aspirin and a P2Y12 receptor antagonist), recurrent ischemia (a β-blocker), progressive atherosclerosis (high-intensity statin), and adverse ventricular remodeling (an ACE inhibitor, especially i le t ventricular [LV] dys unction is present). Adding an aldosterone antagonist should be considered or patients with heart ailure. Systemic anticoagulation with war arin is indicated i an intraventricular thrombus, a large akinetic segment, or atrial f brillation is present.
Ack n ow le d gm en t s The authors thank Frederick Schoen, MD, or his help ul suggestions. Contributors to previous editions o this chapter were June-Wha Rhee, MD; Haley Naik, MD; Anurag Gupta, MD; J. G. Fletcher, MD; William Carlson, MD; and Patrick T. O’Gara, MD.
Ad d i t i o n a l Rea d i n g Giugliano RP, Braunwald E. The year in non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2014;63:201–214. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ ACC Guideline or the Management o Patients With Non–ST-Elevation Acute Coronary Syndromes: A report o the American College o Cardiology/ American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130:e344-e426.
Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/ AHA Focused update o the guideline or the management o patients with unstable angina/ non-ST-elevation myocardial in arction: A report o the American College o Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circula tion . 2012;126:875–910. Mega JL, Simon T, Collet JP, et al. Reduced unction CYP2C19 genotype and risk o adverse clinical outcomes among
Acute Coronary Syndromes patients treated with clopidogrel predominately for PCI: a meta-analysis. JAMA. 2010;304:1821–1830. O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/ AHA Guideline for the management of ST-elevation myocardial infarction: Executive summary: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;127:529–555. Stone GW, Clayton T, Deliargyris EN, et al. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI trial (harmonizing outcomes with revascularization and
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stents in acute myocardial infarction). J Am Coll Ca rdiol. 2014;63:15–20. Cavender MA and Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014;384:599-606. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/ AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report on the American College of Cardiology/ American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2889–934.
Valvular Heart Disease Eliza beth Ryzna r Pa trick T. O’Ga ra Leona rd S. Lilly
Ch a p t e r O u t l i n e Mitral Valve Disease Mitral Stenosis Mitral Regurgitation Mitral Valve Prolapse Aortic Valve Disease Aortic Stenosis Aortic Regurgitation Tricuspid Valve Disease Tricuspid Stenosis Tricuspid Regurgitation Pulmonic Valve Disease Pulmonic Stenosis Pulmonic Regurgitation Prosthetic Valves Infective Endocarditis Pathogenesis Clinical Mani estations Treatment Prevention
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his chapter describes the pathophysiologic abnormalities in patients with common valvular heart diseases. Each condition is discussed separately because uni ying principles do not govern the behavior o all stenotic or regurgitant valves. E ective patient management requires accurate identif cation o the valve lesion, a determination o its severity, and a clear understanding o the pathophysiologic consequences and natural history o t he condition. The evaluation o a patient with suspected valvular disease begins at the bedside with a care ul history and physical examination rom which the trained clinician can usually identi y the type o abnormality present. Def nitive diagnosis is most o ten achieved with transthoracic echocardiography (TTE), which allows or staging o disease severity. In selected patients, additional investigation with exercise testing or cardiac catheterization may be necessary to ully def ne the signif cance o the condition and guide therapy. Management o patients with heart valve disease o ten involves serial clinical and echocardiographic assessments. Pharmacologic therapy is sometimes prescribed or symptomatic improvement, but recognition o timely indications or valve repair or replacement is essential, as will be described or each valve lesion.
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MITRAL VALVE DISEASE Mitral Stenosis Etiology By ar, the most common underlying cause o mitral stenosis (MS) is prior rheumatic ever (see Box 8-1). Approximately 50% to 70% o patients with symptomatic MS provide a history o acute rheumatic ever occurring, on average, 20 years be ore presentation. Other rare etiologies o MS include calci cation o the mitral annulus that extends onto the leaf ets, in ective
BOX 8-1
Rheumatic Fever
Acute rheumatic ever (ARF) is an inf ammatory condition that primarily a ects the heart, skin, and connective tissues. Its incidence has waned greatly in the past century in industrialized societies, where it is now rare, but it remains a major burden in developing countries. ARF arises as a complication o pharyngitis caused by group A beta-hemolytic streptococci and mainly a f icts children and young adults. During prior epidemics, approximately 3% o patients with acute streptococcal pharyngitis developed ARF 2 to 3 weeks a ter the initial throat in ection. Common presenting symptoms are chills, ever, atigue, and migratory arthritis. The cardinal clinical mani estations that establish the diagnosis are known as Jones criteria (see Table below). Involvement o the heart is thought to result rom autoimmune cross-reactivity between bacterial and cardiac antigens. Pathologically, carditis (cardiac inf ammation) a f icts all layers o the heart (pericardium, myocardium, and endocardium). Histopathologic examination may demonstrate Aschoff bodies, areas o ocal brinoid necrosis surrounded by inf ammatory cells (see Figure) that later resolve to orm brous scar tissue. During the acute episode, carditis may cause tachycardia, impaired ventricular contractility, a pericardial riction rub, and transient heart murmurs that ref ect turbulent f ow across inf amed valve leaf ets. Treatment o the acute episode includes high-dose aspirin to reduce inf ammation and penicillin to eliminate residual streptococcal in ection. The most important sequela o ARF is chronic rheumatic heart disease (RHD) characterized by permanent de ormity and impairment o one or more cardiac valves. Symptoms o valvular dys unction, however, do not mani est until 10 to 30 years a ter ARF has subsided. This latency period may be shorter with more aggressive disease sometimes observed in developing countries. RHD a ects the mitral valve in almost all cases, the aortic valve in 20% to 30%, and rarely the tricuspid valve as well. Stenosis and/ or regurgitation o each valve can result. Management o RHD includes prophylaxis against recurrent streptococcal in ection and treatment o the chronic valve lesions. Recurrences o ARF can incite urther cardiac damage, so individuals with ARF should receive preventive low-dose penicillin prophylaxis at least until early adulthood, by which time exposure and susceptibility to streptococcal in ections have diminished.
Figure. Histopathology of an Aschoff body in acute rheumatic carditis. Mononuclear inf ammatory cells surround a center o ocal necrosis. (Courtesy o Dr. Frederick J. Schoen, Brigham and Women’s Hospital, Boston.) (continues on page 194)
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BOX 8-1
Rheumatic Fever ( continued )
Criteria for Diagnosis of Rheumatic Fevera Major criteria Carditis (inf ammation o all three heart layers) Migratory arthritis (mainly large joints) Sydenham chorea (involuntary movements) Erythema marginatum (skin rash with advancing edge and clearing center) Subcutaneous nodules Minor criteria Arthralgias Fever Elevated acute-phase reactants (ESR, CRP) Prolonged PR interval on electrocardiogram Evidence of group A streptococcal infection Antistreptolysin O antibodies Positive throat culture or rapid antigen test a
Diagnosis requires evidence o streptococcal in ection and either: two major criteria or one major plus two minor criteria. ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.
endocarditis with large vegetations that obstruct the valve ori ce, and rare congenital stenosis o the valve.
Pathology Acute and recurrent inf ammation produces the typical pathologic eatures o MS due to rheumatic heart disease. These include brous thickening and calci cation o the valve leaf ets, usion o the commissures (the borders where the leaf ets meet), and thickening and shortening o the chordae tendineae.
Pathophysiology In early diastole in the normal heart, the mitral valve opens and blood f ows reely rom the le t atrium (LA) into the le t ventricle (LV), such that there is a negligible pressure di erence between the two chambers. In MS, however, there is obstruction to blood f ow across the valve such that emptying o the LA is impeded and there is an abnormal pressure gradient between the LA and LV (Figs. 8-1 and 8-2). As a result, the le t atrial pressure increases. Hemodynamic changes become apparent when the cross-sectional area o the valve, normally 4 to 6 cm 2, is reduced to less than 2 cm 2. The high le t atrial pressure in MS is transmitted retrograde to the pulmonary circulation, resulting in increased pulmonary venous and capillary pressures (see Fig. 8-1). This elevation o hydrostatic pressure in the pulmonary vasculature may cause transudation o plasma into the lung interstitium and alveoli. The patient may there ore experience dyspnea and other symptoms o heart ailure (as described in Chapter 9). In severe cases, signi cant elevation o pulmonary venous pressure leads to the opening o collateral channels between the pulmonary and bronchial veins. Subsequently, an engorged bronchial vein may rupture into a bronchus, resulting in hemoptysis (coughing up blood).
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Eleva te d pulmona ry a nd right he a rt pre s s ure s
Pre s s ure Volume
Aorta LA
FIGURE 8-1. Pathophysiology o mitral stenosis. In the normal heart, blood f ows reely rom the le t atrium (LA) into the le t ventricle (LV) during diastole (blue arrow). In mitral stenosis, there is obstruction to LA emptying (red arrow). Thus, the LA pressure increases, which in turn elevates pulmonary and right heart pressures.
LV
No rmal (dias to le )
Mitral s te no s is
The elevation o le t atrial pressure in MS can result in two distinct orms o pulmonary hypertension: passive and reactive. Most patients with MS exhibit passive pulmonary hypertension, related to the backward transmission o the elevated LA pressure into the pulmonary vasculature as described in the previous paragraph. This actually represents an “obligatory” increase in pulmonary artery pressure that preserves orward f ow in the setting o increased le t atrial and pulmonary venous pressures. Additionally, approximately 40% o patients with MS demonstrate reactive pulmonary hypertension with medial hypertrophy and intimal brosis o the pulmonary arterioles. Reactive pulmonary hypertension initially serves a “bene cial” role because the increased arteriolar resistance impedes blood f ow into the engorged pulmonary capillary bed and thus reduces capillary hydrostatic pressure (thereby “protecting” the pulmonary capillaries rom even higher pressures). However, this bene t is at the cost o decreased blood f ow through the pulmonary vasculature and elevation o the rightsided heart pressures, as the right ventricle pumps against the increased resistance. Chronic ECG
FIGURE 8-2. Hemodynamic prof le o mitral stenosis. The le t atrial (LA) pressure is elevated, and there is a pressure gradient (shaded area) between the LA and le t ventricle (LV) during diastole. Compare with schematic o normal tracing (see Fig. 2-1). Abnormal heart sounds are present: there is a diastolic opening snap (OS) that corresponds to the opening o the mitral valve, ollowed by a decrescendo murmur. There is an accentuation o the murmur just be ore S1 owing to the increased pressure gradient when the LA contracts in patients in sinus rhythm (presystolic accentuation).
LA
OS
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Chapter 8 elevation o right ventricular pressure leads to hypertrophy and dilatation o that chamber and ultimately to right-sided heart ailure. Chronic pressure overload o the LA in MS leads to le t atrial enlargement. Le t atrial dilatation stretches the atrial conduction bers and may disrupt the integrity o the cardiac conduction system, resulting in atrial f brillation (a rapid irregular heart rhythm; see Chapter 12). Atrial brillation contributes to a decline in cardiac output in MS because the increased heart rate shortens diastole. This reduces the time available or blood to f ow across the obstructed mitral valve to ll the LV, and, at the same time, urther augments the elevated le t atrial pressure. In addition, with atrial brillation, there is a loss o the late diastolic atrial contraction that normally contributes to LV lling. The relative stagnation o blood f ow in the dilated LA in MS, especially when combined with the development o atrial brillation, predisposes to intra-atrial thrombus ormation. Thromboemboli to the brain and other organs may ollow, leading to devastating complications such as cerebrovascular occlusion (stroke). Thus, MS patients who develop atrial brillation require chronic anticoagulation therapy. The consequences o MS primarily a ect the le t atrium and the pulmonary vasculature, as described above. Le t ventricular pressures are usually normal, but impaired lling o the chamber through the stenotic valve may reduce LV stroke volume and cardiac output.
Clinical Manifestations and Evaluation Presentation The natural history o MS is variable. Survival exceeds 80% in asymptomatic or minimally symptomatic patients at 10 years. However, the 10-year survival o untreated patients a ter onset o symptoms is only 50-60% . Longevity is much more limited or patients with advanced symptoms and is dismal or those who develop signi cant pulmonary hypertension, with a mean survival o less than 3 years. The clinical presentation o MS depends largely on the degree o reduction o the valve area. The more severe the stenosis, the greater the symptoms related to elevation o le t atrial and pulmonary venous pressures. The earliest mani estations are those o dyspnea and reduced exercise capacity. In mild MS, dyspnea may be absent at rest; however, it develops on exertion as LA pressure rises with the exercise-induced increase in blood f ow through the heart and aster heart rate (i.e., decreased diastolic lling time). Other conditions and activities that augment heart rate and cardiac blood f ow and precipitate or exacerbate symptoms o MS include ever, anemia, hyperthyroidism, pregnancy, rapid arrhythmias such as atrial brillation, emotional stress, and sexual intercourse. With more severe MS (i.e., a smaller valve area), dyspnea occurs even at rest. Increasing atigue and more severe signs o pulmonary congestion, such as orthopnea and paroxysmal nocturnal dyspnea (described in Chapter 9), occur. With advanced MS and pulmonary hypertension, signs o right-sided heart ailure ensue, including jugular venous distention, hepatomegaly, ascites, and peripheral edema. Compression o the recurrent laryngeal nerve by an enlarged pulmonary artery or LA may cause hoarseness (known as Ortner syndrome). Less o ten, the diagnosis o MS is heralded by one o its complications: atrial brillation, thromboembolism, in ective endocarditis, or hemoptysis, as described in the earlier section on Pathophysiology.
Examination On examination, there are several typical ndings o MS. Palpation o the chest may reveal a right ventricular “tap” in patients with increased right ventricular pressure. Auscultation discloses a loud S1 (the rst heart sound, which is associated with mitral valve closure) in the early stages o the disease. The increased S1 results rom the high pressure gradient between
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the atrium and ventricle, which keeps the mobile portions o the mitral valve leaf ets widely separated throughout diastole; at the onset o systole, ventricular contraction abruptly slams the leaf ets together rom a relatively wide position, causing the closure sound to be more prominent (see Chapter 2). In late stages o the disease, the intensity o S1 may normalize or become reduced as the valve leaf ets thicken, calci y, and become less mobile. A main eature o auscultation in MS is a high-pitched “opening snap” (OS) that ollows S2. The OS is thought to result rom the sudden tensing o the chordae tendineae and stenotic leaf ets on opening o the abnormal valve. The interval between S2 and the OS relates inversely to the severity o MS. That is, the more severe the MS, the higher the LA pressure and the earlier the valve is orced open in diastole. The OS is ollowed by a low- requency decrescendo murmur (termed diastolic rumble) caused by turbulent f ow across the stenotic valve during diastole (see Fig. 8-2). The duration, but not the intensity, o the diastolic murmur relates to the severity o MS. The more severe the stenosis, the longer it takes or the LA to empty and or the gradient between the LA and LV to dissipate. Near the end o diastole, contraction o the LA in patients in sinus rhythm causes the pressure gradient between the LA and LV to rise again (see Fig. 8-2); there ore, the murmur brief y becomes louder at that time (termed presystolic accentuation). This nal accentuation o the murmur does not occur i atrial brillation has developed because there is no e ective atrial contraction in that situation. Murmurs caused by other valve lesions are o ten ound concurrently in patients with MS. For example, mitral regurgitation (discussed later in this chapter) requently coexists with MS. Additionally, right-sided heart ailure caused by severe MS may induce tricuspid regurgitation as a result o right ventricular enlargement. A diastolic decrescendo murmur along the le t sternal border may be present owing to coexistent aortic regurgitation (because o rheumatic involvement o the aortic leaf ets) or pulmonic regurgitation (because o MS-induced pulmonary hypertension). The electrocardiogram in MS routinely shows le t atrial enlargement and, i pulmonary hypertension has developed, right ventricular hypertrophy. Atrial brillation may be present. The chest radiograph reveals le t atrial enlargement, pulmonary vascular redistribution, interstitial edema, and Kerley B lines resulting rom edema within the pulmonary septae (see Chapter 3). With the development o pulmonary hypertension, right ventricular enlargement and prominence o the pulmonary arteries appear. Echocardiography is o major diagnostic value in MS. Structural ndings include thickened mitral leaf ets with abnormal usion o their commissures and restricted separation during diastole. The degree o le t atrial enlargement can be quanti ed, and i present, intraatrial thrombus may be visualized. The mitral valve area can be measured directly on crosssectional views or calculated rom Doppler velocity measurements (a technique known as the “diastolic pressure hal -time”). Patients can be strati ed into stages o disease severity based partly on the mitral valve area. A normal mitral valve ori ce measures between 4 and 6 cm 2. Current guidelines de ne clinically important “severe” MS as a valve area ≤ 1.5 cm 2, a state that is typically accompanied by LA enlargement and elevated pulmonary artery systolic pressure. A valve area ≤ 1.0 cm 2 is termed “very severe” MS. I the ndings determined by echocardiography seem milder than the patient’s history and examination suggest, an exercise test with accompanying Doppler assessment, or cardiac catheterization may be warranted to urther de ne hemodynamic measurements.
Treatment Salt intake restriction and diuretic therapy may improve symptoms due to vascular congestion. Heart rate slowing agents, such as β-blockers or nondihydropyridine calcium channel blockers (e.g., diltiazem or verapamil, see Chapter 17), increase diastolic LV lling time and there ore ease symptoms that occur during exercise. These drugs, or digoxin, are similarly use ul to slow the ventricular rate in patients with accompanying rapid atrial brillation.
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Chapter 8 Anticoagulant therapy to prevent thromboembolism is recommended or MS patients with atrial brillation, or an identi ed atrial thrombus, or prior embolic events. Percutaneous or surgical valve interventions are the only treatments that alter the natural history o MS and are indicated in patients with severe, symptomatic MS. Percutaneous balloon mitral valvuloplasty is the treatment o choice in appropriately selected patients (those without advanced anatomic de ormity o the valve, mitral regurgitation, or le t atrial thrombus). During this procedure, a balloon catheter is advanced rom the emoral vein into the right atrium, across the atrial septum (by intentionally puncturing the interatrial septum), and through the narrowed mitral valve ori ce. The balloon is then rapidly inf ated, thereby “cracking” open the used commissures. The short- and long-term results o this procedure are typically excellent and compare avorably with those o surgical treatment in anatomically appropriate patients. In young adults with the most suitable anatomy or the procedure, the event- ree survival rate approaches 80% to 90% over 3 to 7 years o ollow-up. Approximately 5% o patients undergoing balloon mitral valvuloplasty are le t with a residual atrial septal de ect due to the transseptal puncture. Less requent complications include cerebral emboli at the time o valvuloplasty, cardiac per oration by the catheter, or the unintentional creation o substantial mitral regurgitation. Open mitral valve commissurotomy (an operation in which the stenotic commissures are separated under direct visualization) may be undertaken in patients or whom percutaneous balloon valvuloplasty is not easible or success ul. It is e ective in relieving obstruction, and restenosis occurs in ewer than 20% o patients over 10 to 20 years o ollow-up. Perioperative mortality rates are low (2% ). Mitral valve replacement is considered in patients who are not appropriate candidates or balloon valvuloplasty or open commissurotomy.
Mitral Regurgitation Etiology The mitral valve apparatus is a complex structure composed o an annulus, two leaf ets, chordae tendineae, and papillary muscles, supported by the adjacent myocardium to which the annulus and papillary muscles are attached (Fig. 8-3). Disruption to the structural integrity o any o these components or their coordinated action can result in abnormal closure o the valve during systole, with ensuing mitral regurgitation (MR). MR is categorized as Mitra l a nnulus Le ft a trium
• Annula r ca lcifica tion Le a fle ts • Myxoma tous de ge ne ra tion (“MVP ”) • Rhe uma tic dis e a s e • Endoca rditis • SAM (hype rtrophic ca rdiomyopa thy) Chorda e te ndine a e • Rupture (idiopa thic) • Endoca rditis Pa pilla ry mus cle s • Dys function or rupture Le ft ve ntricle • Cavity dila ta tion
FIGURE 8-3. The mitral valve apparatus and associated common etiologies of mitral regurgitation. MVP, mitral valve prolapse; SAM, systolic anterior motion.
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primary i it is due to a structural de ect o one or more o the valve components, or secondary i the valve is structurally normal, but regurgitation instead results rom le t ventricular enlargement. In the latter case, MR arises rom abnormal coaptation and closure o the mitral leaf ets owing to dilatation o the mitral annulus by the enlarged LV, and/ or spatial separation o the papillary muscles, which places traction o the chordae and attached leaf ets. Furthermore, depending on the nature o the valvular insult, MR can present as an “acute” or “chronic” condition, with di erent pathophysiologic consequences. Most cases o acute MR are primary in nature and result rom sudden damage to components o the valve apparatus. For example, rupture o an in arcted papillary muscle can occur within days o an acute ST-segment elevation MI, o ten resulting in severe MR (see Chapter 7). Acute MR due to sudden rupture o chordae tendineae can result rom in ective endocarditis, blunt trauma to the chest, or rom degeneration o the chordae owing to connective tissue disorders such as Mar an syndrome. Chronic MR has multiple primary causes, including myxomatous degeneration o the valve, in which “f oppy” leaf ets allow regurgitation to occur by bowing excessively into the LA during systole (termed “mitral valve prolapse” and described in the next section). Other causes o chronic primary MR include rheumatic de ormity o the valve, congenital valve de ects, and extensive calci cation o the mitral annulus, which prevents normal movement o the valve leaf ets, thus inter ering with valve closure. Secondary (also termed “ unctional”) chronic MR results rom LV enlargement and/ or dys unction as described above, as may occur with prior myocardial in arction, chronic ischemic heart disease, or dilated cardiomyopathy (see Chapter 10).
Pathophysiology In MR, a portion o the le t ventricular stroke volume is ejected backward into the lowpressure LA during systole (Fig. 8-4). As a result, the orward cardiac output (into the aorta) is less than the LV’s total output ( orward f ow plus backward leak). There ore, the Pulmona ry e de ma Aorta LA
High LA pre s s ure
Dila te d LA with le s s e leva te d pre s s ure
LV
No rmal (s ys to le )
Ac ute mitral re g urg itatio n
Chro nic mitral re g urg itatio n
FIGURE 8-4. Pathophysiology of mitral regurgitation. In the normal heart, le t ventricular (LV) contraction during systole orces blood exclusively through the aortic valve into the aorta (green arrow); the closed mitral valve prevents regurgitation into the le t atrium (LA). In mitral regurgitation (MR), a portion o LV output is orced backward into the LA (red arrows), so that orward cardiac output into the aorta is reduced. In acute MR, the LA is o normal size and is relatively noncompliant, such that the LA pressure rises signif cantly and pulmonary edema may result. In chronic MR, the LA has enlarged and is more compliant, so that the LA pressure is less elevated and pulmonary congestive symptoms are less common. The LV enlargement and the eccentric hypertrophy result rom the chronically elevated volume load.
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Chapter 8 direct consequences o MR include (1) an elevation o le t atrial volume and pressure, (2) a reduction o orward cardiac output, and (3) a volume-related stress on the LV because the regurgitant volume returns to the LV in diastole along with the normal pulmonary venous return. To meet normal circulatory needs and to eject the additional volume, LV stroke volume must rise. This increase is accomplished by the Frank–Starling mechanism (see Chapter 9), whereby the elevated LV diastolic volume augments myo ber stretch and stroke volume. The hemodynamic consequences o MR vary depending on the degree o regurgitation and how long it has been present. The severity o MR and the ratio o orward cardiac output to backward f ow are dictated by ve actors: (1) the size o the mitral ori ce during regurgitation, (2) the systolic pressure gradient between the LV and LA, (3) the systemic vascular resistance opposing orward LV blood f ow, (4) le t atrial compliance, and (5) the duration o regurgitation with each systolic contraction. The regurgitant fraction in MR is de ned as ollows: Volume o MR Total LV stroke volume
P
r
e
s
s
u
r
e
(
m
m
H
g
)
This ratio rises whenever the resistance to aortic outf ow is increased (i.e., blood ollows the path o least resistance). For example, high systemic blood pressure or the presence o aortic stenosis will increase the regurgitant raction. The extent to which le t atrial pressure rises in response to the regurgitant volume is determined by the le t atrial compliance. Compliance is a measure o the chamber’s pressure–volume relationship, ECG ref ecting the ease or di culty with which the chamber can be lled (see Table 9.1). In acute MR, le t atrial compliance undergoes little imme110 diate change. Because the LA is a relatively sti chamber, its pressure increases substantially when it is suddenly exposed 90 Ta ll v LV to a regurgitant volume load (see Fig. 8-4). This elevated preswa ve sure is transmitted backward to the pulmonary circulation and 70 can result in rapid pulmonary congestion and edema, a medical emergency. 50 In acute MR, the LA pressure, or the pulmonary capillary 30 wedge pressure (an indirect measurement o LA pressure; see Chapter 3), demonstrates a prominent v wave (o ten re erred LA 10 to as a “cv” wave when it merges with the preceding c wave), ref ecting the increased LA lling during systole (Fig. 8-5). Time Additionally, as in MS, pulmonary artery and right-heart pressures passively rise. He a rt s ounds : In acute MR, th e LV accommodates the in creased volum e load returning rom the LA according to the Frank–Starling S1 S2 relationship. The result is a compensatory increase in the FIGURE 8-5. Hemodynamic prof le o LV stroke volume and ejection raction, such that at the mitral regurgitation ( MR) . A large systolic v en d o each systolic contraction , LV volu me rem ain s normal wave is noted in the le t atrial (LA) pressure tracing. A holosystolic murmur is present in in th e n on ailin g h eart. Systolic emptying o the ven tricle chronic MR (as shown here), beginning at the is acilitated in MR by th e redu ced total impedance to LV rst heart sound (S1) and continuing through con traction (i.e., th e a terload is lower than normal), since the second heart sound (S2). In acute severe a portion o th e LV outpu t is directed in to th e relatively MR, the systolic murmur may actually have low-im pedan ce LA, rath er th an in to th e h igh er-pressu re a decrescendo quality, ref ecting rapid aorta. equilibration o LV and LA pressures owing In contrast to the acute situation, the more gradual developto the relatively low LA compliance. ECG, electrocardiogram; LV, le t ventricle. ment o chronic MR permits the LA to undergo compensatory
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changes that lessen the e ects o regurgitation on the pulmonary circulation (see Fig. 8-4). In particular, the LA dilates and its compliance increases such that the chamber is able to accommodate a larger volume without a substantial increase in pressure. Le t atrial dilatation is there ore adaptive in that it prevents signi cant increases in pulmonary vascular pressures. However, this adaptation occurs at the cost o reduced orward cardiac output, because the compliant LA becomes a pre erred low-pressure “sink” or le t ventricular ejection, compared with the aorta. Consequently, as progressively larger ractions o blood regurgitate into the LA, symptoms o chronic MR include those o low orward cardiac output (e.g., weakness and atigue). In addition, chronic le t atrial dilatation predisposes to the development o atrial brillation. Thus, major pathophysiologic di erences between acute and chronic MR relate to a great extent to le t atrial size and compliance (see Fig. 8-4): Acute MR: Normal LA size and compliance → High LA pressure → High pulmonary venous pressure → Pulmonary congestion and edema Chronic MR: Increased LA size and compliance → Relatively normal LA and pulmonary venous pressures, but decreased orward cardiac output In chronic MR, the LV also undergoes gradual compensatory dilatation in response to the volume load through eccentric hypertrophy (see Chapter 9). Compared with acute MR, the resulting increased ventricular compliance accommodates the augmented lling volume with relatively normal diastolic pressures. Forward output in chronic MR is preserved to near-normal levels or an extended period by maintaining a higher stroke volume via the Frank–Starling mechanism. Over years, however, chronic volume overload results in deterioration o systolic ventricular unction, a decline in orward output, and symptoms o heart ailure.
Clinical Manifestations and Evaluation Presentation As should be clear rom the pathophysiology discussion, patients with acute MR usually present with symptoms o pulmonary edema (see Chapter 9). The symptoms o chronic MR are predominantly due to low cardiac output, especially during exertion, and include atigue and weakness. Patients with severe MR or those who develop LV contractile dys unction o ten complain o dyspnea, orthopnea, and/ or paroxysmal nocturnal dyspnea. In chronic severe MR, symptoms o right heart ailure (e.g., increased abdominal girth, peripheral edema) may develop as well.
Examination The physical examination o a patient with chronic MR typically reveals an apical holosystolic (also termed pansystolic) murmur that o ten radiates to the axilla. The holosystolic nature o the murmur ref ects the continued pressure gradient between LV and LA throughout systole (see Fig. 8-5). This description, accurate or rheumatic MR, has several exceptions. For example, in patients with isolated posterior mitral leaf et prolapse, the regurgitant jet is directed anteriorly. In this setting, the murmur may instead radiate to the base o the heart and could be con used with the murmur o aortic stenosis (AS) in that location. Fortunately, the distinction between the systolic murmur o MR and that o AS can be made by simple bedside maneuvers. I the patient is instructed to clench his/ her sts and orearms, systemic vascular resistance will increase and the murmur o MR will intensi y, whereas the murmur o AS will not. Even more help ul in this distinction is the e ect o varying cardiac cycle length (the time between consecutive heart beats) on the intensity o the systolic murmur. In a patient with atrial brillation or with requent premature beats, the LV lls to a degree that
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Chapter 8 directly depends on the preceding cycle length (i.e., a longer cycle length permits greater le t ventricular lling). The systolic murmur o AS becomes louder in the beat a ter a long cycle length because even small pressure gradients are ampli ed as more blood is ejected across the reduced aortic ori ce. In MR, however, the intensity o the murmur does not vary signi cantly because the change in the LV-LA pressure gradient is minimally a ected by alterations in the cycle length. In addition to the systolic murmur, a common nding in chronic MR is the presence o an S3, which ref ects increased volume returning to the LV in early diastole (see Chapter 2). Additionally, in chronic MR, the cardiac apical impulse is o ten laterally displaced toward the axilla because o LV enlargement. In patients with severe acute MR, the character o the systolic murmur is o ten di erent, occurring in early to mid systole with a decrescendo quality. The length and quality o the murmur are dictated by the systolic pressure gradient between the le t ventricle and the relatively noncompliant le t atrium. That is, as the LA pressure rises in systole in acute MR, the LV and LA pressures quickly equalize, thus truncating the murmur. Patients with acute MR o ten display signs o pulmonary congestion. The chest ra diogra ph may display pulmonary edema in acute MR bu t in chronic asymptomatic MR more likely demonstrates le t ventricu lar and atrial en largement, without pulmonary con gestion. Calci cation o the mitral annu lu s may be seen i that is the cau se o the MR. In chron ic MR, the electroca rdiogra m typically demonstrates le t atrial enlargement an d signs o le t ventricu lar hypertrophy. Echoca rdiogra phy can o ten identi y the structural cause o MR and assess its severity. Ca rdia c ca theteriza tion is used to identi y accompanying coronary artery disease and le t ventriculography can con rm MR severity. The characteristic hemodynamic nding is a large v wave in the pu lmon ary capillary wedge pressure tracing (ref ective o LA pressure—see Chapter 3). The v wave becomes less conspicuous, however, with progressive LA dilatation and greater complian ce over time.
Natural History and Treatment Acute severe MR is a surgical emergency with a poor prognosis, even with appropriate treatment, with a 30-day mortality rate o 20% to 25% . The natural history o chronic MR is related to its underlying cause. For example, in RHD, the course is one o very slow progression with a 15-year survival rate o 70% . On the other hand, abrupt worsening o chronic MR o any cause can occur with superimposed complications, such as rupture o chordae tendineae or endocarditis, and can result in an immediate li e-threatening situation. The treatment o acute MR almost always requires surgical intervention. Pharmacologic therapy is use ul only to stabilize patients until surgery. For example, intravenous nitroprusside is a potent vasodilator that decreases arterial resistance, thereby augmenting orward f ow and diminishing the regurgitant volume. In this way, cardiac output and pulmonary congestion may improve at least transiently. Surgical intervention consists o either mitral valve repair (reconstruction o the native valve as described below) or replacement, depending on the underlying cause and valve anatomy. Management o chronic MR depends on the etiology. In chronic primary MR, the continuous le t ventricular volume overload can slowly impair le t ventricular contractile unction, ultimately, resulting in heart ailure. Medical treatment with vasodilators is less use ul than in acute MR and has not been shown to delay the need or valve surgery in chronic MR. Surgical intervention should be undertaken in symptomatic patients, or at the earliest sign o LV contractile dys unction on imaging studies (e.g., a all in EF to < 60% by echocardiography) even be ore symptoms develop. Surgical intervention is also sometimes recommended or patients
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with chronic asymptomatic severe primary MR with recent onset atrial brillation or ndings o pulmonary hypertension. Surgical options or chronic MR include mitral valve repair or replacement. Mitral valve repair is the pre erred operative technique when easible, and involves the reconstruction o parts o the valve responsible or the regurgitation. For example, a per orated leaf et may be patched with transplanted autologous pericardium, or ruptured chordae may be reattached to a papillary muscle. Mitral repair preserves native valve tissue, and eliminates many o the problems associated with arti cial valves described later in the chapter. In patients who undergo repair, the postoperative survival rate appears to be better than the natural history o MR and has provided impetus toward earlier surgical intervention. Operative mortality rates or unselected patients with MR in the Society or Thoracic Surgeons database are less than 2% or mitral valve repair and 5% to 7% or mitral valve replacement. These rates are higher i concurrent coronary artery bypass gra ting is per ormed. In general, mitral valve repair is more o ten appropriate or younger patients with myxomatous involvement o the mitral valve, and mitral replacement is more o ten undertaken in older patients with more extensive valve pathology. In patients with chronic, severe, symptomatic prima ry MR who are at prohibitive operative risk, a recently developed technique o transcatheter mitral valve repair can be considered. In this procedure, a catheter is advanced percutaneously rom the emoral vein into the right side o the heart, then into the le t atrium via a puncture through the interatrial septum (similar to mitral balloon valvuloplasty), and advanced into the le t ventricle. A mechanical clip is then deployed, which grasps and tethers the anterior and posterior mitral leaf ets together at one location and is le t in place, reducing the size o the regurgitant ori ce. The procedure has been shown to be sa e and e ective in prospective observational studies o high surgical risk patients, with improvement in the severity o MR and unctional status. However, in a randomized trial o percutaneous repair versus valve surgery or patients with severe primary MR, surgery proved more e ective and remains the intervention o choice is patients who are acceptable candidates or an operation. Because chronic, secondary MR is o ten a result o le t ventricular dys unction, pharmacologic rather than mechanical intervention is the mainstay o treatment, using a standard combination o heart ailure medications, including diuretics, ACE inhibitors or angiotensin receptor blockers, beta-blockers, and aldosterone antagonists (see Chapter 9). Surgical intervention is considered only when a patient with chronic, severe secondary MR has persistent symptoms despite optimal medical therapy.
Mitral Valve Prolapse Mitral valve prolapse (MVP) is characterized by abnormal billowing o a portion o one or both mitral leaf ets into the LA during ventricular systole, and is requently accompanied by MR (Fig. 8-6). Other names or this condition include f oppy mitral valve, myxomatous mitral valve, and Barlow syndrome. MVP may be inherited as a primary autosomal dominant disorder with variable penetrance, or it may accompany certain connective tissue diseases, such as Mar an syndrome or Ehlers–Danlos syndrome. Pathologically, the valve leaf ets, particularly the posterior leaf et, are enlarged, and the normal dense collagen and elastin matrix o the valvular brosa is ragmented and replaced with loose myxomatous connective tissue. Additionally, in more severe lesions, elongated or ruptured chordae, annular enlargement, or thickened leaf ets may be present. A recent rigorous echocardiographic study indicated that MVP occurs in about 2% o the population and is more common among women, especially those who are thin and lean.
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Chapter 8
MVP is o ten asymptomatic but a ected individuals may describe chest pain or palpitations because Aorta o associated arrhythmias. Most o ten it is identi ed on routine physical examination by the presence o a LA midsystolic click and late systolic murmur heard best at the cardiac apex. The midsystolic click is thought to correspond to the sudden tensing o the involved mitral leaf et or chordae tendineae as the leaf et is orced back toward the LA; the murmur corresponds to regurgitant f ow through the incompetent valve. RV The click and murmur are characteristically altered LV during dynamic auscultation at the bedside: maneuvers that increase the volume o the LV (e.g., sudden squatting, which increases venous return) place traction o the chordae tendineae, limiting and delaying FIGURE 8-6. Mitral valve prolapse. Long-axis view the occurrence o prolapse in systole and cause the o the le t ventricle (LV) demonstrates a myxomatous, click and murmur to occur later (i.e., urther rom elongated appearance o the mitral valve with prolapse S1). Conversely, i the volume o blood in the LV is o the posterior leaf et (arrow) into the le t atrium decreased (e.g., on sudden standing), prolapse occurs (LA). RV, right ventricle. (From Schoen FJ, Mitchell earlier and the click and murmur move closer to S1. RN. The heart. In: Kumar V, Abbas A, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Con rmation o the diagnosis is obtained by echoPhiladelphia, PA: Elsevier Saunders; 2015.) cardiography, which demonstrates posterior displacement o a portion o one or both mitral leaf ets into the LA during systole. The electrocardiogram and chest radiograph are usually normal unless chronic MR has resulted in le t atrial and le t ventricular enlargement. The clinical course o MVP is most o ten benign. Treatment consists o reassurance about the usually good prognosis and monitoring or the development o progressive MR. Occasionally, rupture o myxomatous chordae in this condition can cause sudden, severe regurgitation and pulmonary edema. Other potential complications include in ective endocarditis, peripheral emboli owing to microthrombus ormation on the redundant valve tissue, and atrial or ventricular arrhythmias.
AORTIC VALVE DISEASE Aortic Stenosis Etiology Among adult patients, there are three major causes o aortic stenosis (AS): (1) degenerative calci cation o a previously normal trileaf et aortic valve, (2) calci cation o a congenitally bicuspid aortic valve, and (3) rheumatic aortic valve disease. Degenerative disease o a trileaf et valve shares many pathologic eatures in common with atherosclerosis, as described below. Bicuspid aortic valves are present in 1% to 2% o the population (with men a ected more commonly than women) and such patients typically develop signs o severe valve disease about a decade earlier than patients with the trileaf et, degenerative type o AS. Rheumatic aortic valve disease is now uncommon in developed countries. It is nearly always accompanied by rheumatic involvement o the mitral valve.
Pathology The pathologic appearance in AS is dependent on its etiology. Degenerative, calci c AS results rom a dynamic process o endothelial dys unction, lipid accumulation, inf ammation,
Valvular Heart Disease and alteration o signaling pathways that appears similar to atherogenesis. Over time, valvular myo broblasts di erentiate into osteoblasts and deposit calcium hydroxyapatite crystals, resulting in leaf et thickening and sti ening. This process is likely exacerbated by abnormal shear orces, as occur with congenitally de ormed (bicuspid) valves, and could explain the earlier presentation o such patients. As with atherosclerosis, risk actors or calci c, degenerative AS include dyslipidemia, smoking, and hypertension (see Chapter 5). In rheumatic AS, endocardial inf ammation leads to organization and brosis o the valve and ultimately to usion o the commissures and ormation o calci ed masses within the aortic cusps.
Pathophysiology
205
Aorta LA
Pre s s ure
FIGURE 8-7. Pathophysiology o aortic stenosis ( AS) . The impediment to le t ventricular (LV) outf ow in AS results in elevated LV pressures and secondary concentric ventricular hypertrophy.
P
r
e
s
s
u
r
e
(
m
m
H
g
)
In AS, blood f ow across the aortic valve is impeded during systole (Fig. 8-7). Progressive reduction o the aortic valve area requires elevation o le t ventricular systolic pressure to overcome the impedance to f ow to drive blood into the aorta (Fig. 8-8). Since the obstruction in AS develops gradually, the LV is able to compensate by undergoing concentric hypertrophy in response to the increased pressure load. Initially, such hypertrophy serves an important role in reducing LV wall stress (remember rom Chapter 6 that wall stress = (P × r) ÷ 2 h, ECG in which h represents wall thickness). Over time, however, it also reduces the compliance o the ventricle. The resulting 150 elevation o diastolic LV pressure causes the LA to hypertro130 phy, which acilitates lling o the “sti ened” LV. Whereas le t atrial contraction contributes only a small portion o 110 LV the le t ventricular stroke volume in normal individuals, it may provide more than 25% o the stroke volume to the 90 sti ened LV in AS patients. Thus, le t atrial hypertrophy is Aorta 70 bene cial, and the loss o e ective atrial contraction (e.g., development o atrial brillation) can cause marked clinical 50 deterioration. Three major mani estations occur in patients with 30 advanced AS: (1) angina, (2) exertional syncope, and (3) heart ailure, all o which can be explained on the basis 10 o the underlying pathophysiology. Each mani estation, in order, heralds an increasingly ominous prognosis (Table 8-1). AS may result in an gin a because it creates a substantial imbalance between myocardial oxygen supply and demand. Myocardial oxygen dema n d is increased in two ways. First, the muscle mass o the hypertrophied LV FIGURE 8-8. Hemodynamic prof le o aortic is increased, requiring greater-than-normal per usion. stenosis. A systolic pressure gradient (shaded Second, wall stress is increased because o the elevated area) is present between the le t ventricle systolic ventricular pressure. In addition, AS reduces myo(LV) and aorta. The second heart sound (S2) is diminished in intensity, and there is a crescendo– cardial oxygen supply because the elevated le t ventricular diastolic pressure reduces the coronary per usion pressure decrescendo systolic murmur that does not extend gradient between the aorta and the myocardium. beyond S2. ECG, electrocardiogram.
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TABLE 8-1
Median Survival Time in Symptomatic Severe Aortic Stenosis
Clinical Symptoms Angina Syncope Heart failure
Median Survival 5 years 3 years 2 years
Derived from Ross J Jr, Braunwald E. Aortic stenosis. Circulation. 1968;38(suppl.v):61.
AS may cause syncope during exertion. Although le t ventricular hypertrophy allows the chamber to generate a high pressure and maintain a normal cardiac output at rest, the ventricle cannot signi cantly increase its cardiac output during exercise because o the xed stenotic aortic ori ce. In addition, exercise leads to vasodilatation o the peripheral muscle beds. Thus, the combination o peripheral vasodilatation and the inability to augment cardiac output contributes to decreased cerebral per usion pressure and, potentially, loss o consciousness on exertion. Finally, AS can result in symptoms o heart failure. Early in the course o AS, an abnormally increased le t atrial pressure occurs primarily at the end o diastole, when the LA contracts into the thickened noncompliant LV. As a result, the mean le t atrial pressure and the pulmonary venous pressure are not greatly a ected early in the disease. However, with progression o the stenosis, the LV may develop contractile dys unction because o the insurmountably high a terload, leading to increased le t ventricular diastolic volume and pressure. The accompanying marked elevation o LA and pulmonary venous pressures incites pulmonary alveolar congestion and symptoms o heart ailure. A normal aortic valve has a cross-sectional area o 3 to 4 cm 2 and a mean systolic pressure gradient between the LV and aorta o less than 5 mm Hg. As the valve area decreases in AS, the pressure gradient rises. When the valve area declines to less than 1.0 cm 2, or the mean pressure gradient increases to greater than 40 mm Hg, a patient is considered to have severe aortic stenosis and symptoms typically appear.
Clinical Manifestations and Evaluation Presentation Angina, syncope, and heart ailure may appear a ter many asymptomatic years o slowly progressive valve stenosis. Once these symptoms develop, they con er a signi cantly decreased survival i invasive correction o AS is not undertaken (see Table 8-1).
Examination Physical examination o ten permits accurate detection and estimation o the severity o AS. The key eatures o advanced AS include (1) a coarse late-peaking systolic ejection murmur and (2) a weakened (pa rvus) and delayed (ta rdus) upstroke o the carotid artery owing to the obstructed LV outf ow. Other common ndings on cardiac examination include the presence o an S4 (because o atrial contraction into the “sti ” LV—see Chapter 2) and reduced intensity, or complete absence, o the aortic component o the second heart sound (see Fig. 8-8).
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On the electroca rdiogra m, le t ventricular hypertrophy is common in advanced AS. Echoca rdiogra phy is a more sensitive technique to assess LV wall thickness and displays the abnormal anatomy and reduced excursion o the stenotic valve. The transvalvular pressure gradient and aortic valve area can be readily calculated by Doppler echocardiography (see Chapter 3). Ca rdia c ca theteriza tion is sometimes used to con rm the severity o AS and to de ne the coronary anatomy, because concurrent coronary artery bypass surgery is o ten appropriate at the time o aortic valve replacement in patients with coexisting coronary disease.
Natural History and Treatment Mild, asymptomatic AS has a slow rate o progression such that over a 20-year period, only 20% o patients will progress to severe or symptomatic disease. There is no current e ective medical therapy or slowing the rate o progression o aortic stenosis. Since the natural history o severe, symptomatic, uncorrected AS is very poor (see Table 8-1), e ective treatment requires replacement o the valve. Aortic va lve repla cemen t (AVR) is indicated when a patient with severe AS develops symptoms, or when there is evidence o progressive LV dys unction in the absence o symptoms. The le t ventricular ejection raction almost always increases a ter valve replacement, even in patients with impaired preoperative le t ventricular unction. The e ect o AVR on the natural history o AS is dramatic, as the 10-year survival rate rises to approximately 60% . Unlike its success ul role in mitral stenosis, percutaneous balloon valvuloplasty has been disappointing as a sole treatment o adults with calci c AS. Although balloon dilatation o the aortic valve ori ce can racture calci ed masses leading to a slight reduction in valve obstruction, up to 50% o patients develop restenosis within 6 months. Valvuloplasty is occasionally used as a temporizing measure in patients too ill to proceed directly to valve replacement, and can also be an e ective treatment in young patients with noncalci ed bicuspid AS. In distinction, or patients with severe AS who are at prohibitive or high risk or cardiac surgery, transcatheter aortic valve replacement (TAVR) has emerged as a success ul treatment option. This technique involves percutaneous insertion o a specially designed bioprosthetic valve into the narrowed ori ce o the stenotic native valve that is rst prepared with balloon valvuloplasty. TAVR has been validated in randomized prospective trials, and or inoperable patients, TAVR outcomes are superior to standard medical therapy. In high surgical risk patients, TAVR is nonin erior to surgical AVR, with similar 1- and 2-year survival rates, though its use is associated with higher risks o periprocedural stroke and paravalvular regurgitation. Longer-term data indicate that the di erence in stroke rates equalizes over time, and it is likely that the use o TAVR will gradually be extended to greater numbers o high and intermediate surgical risk patients.
Aortic Regurgitation Etiology Aortic regurgitation (AR), also termed aortic insu f ciency, may result either rom abnormalities o the aortic valve leaf ets or rom dilatation o the aortic root. Primary valvular causes include: (1) bicuspid aortic valve (in some patients AR predominates over aortic stenosis), (2) in ective endocarditis (due to per oration or erosion o a leaf et), and (3) rheumatic heart disease (due to thickening and shortening o the aortic valve cusps). Primary aortic root disease results in AR when the aortic annulus dilates su ciently to cause separation o the leaf ets, preventing normal coaptation in diastole. Examples include age-related degenerative dilation o the aortic root, aortic aneurysms, and aortic dissection, which are described in Chapter 15.
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Pathophysiology In AR, abnormal regurgitation o blood occurs rom the aorta into the LV during diastole. There ore, with each contraction, the LV must pump that regurgitant volume plus the normal quantity o blood entering rom the LA. Hemodynamic compensation relies on the Frank– Starling mechanism to augment stroke volume. Factors inf uencing the severity o AR are analogous to those o MR: (1) the size o the regurgitant aortic ori ce, (2) the pressure gradient across the aortic valve during diastole, and (3) the duration o diastole. As in MR, the hemodynamic abnormalities and symptoms di er in acute and chronic AR (Fig. 8-9). In acute AR, the LV is o normal size and relatively noncompliant. Thus, the volume load o regurgitation causes the LV diastolic pressure to rise substantially. The sudden high diastolic LV pressure is transmitted to the LA and pulmonary circulation, o ten producing dyspnea and pulmonary edema. Thus, acute severe AR is usually a surgical emergency, requiring immediate valve replacement. In chron ic AR, the LV undergoes compensatory adaptation in response to the longstanding regurgitation. AR subjects the LV primarily to volume overload but also to an excessive pressure load; there ore, the ventricle compensates through chronic dilatation (eccentric hypertrophy, with replication o sarcomeres in series—see Chapter 9) and, to a lesser degree, increased thickness. Over time, the dilatation increases the compliance o the LV and allows it to accommodate a larger regurgitant volume with less o an increase in diastolic pressure, reducing the pressure transmitted into the LA and pulmonary circulation. However, by accommodating the large regurgitant volume, the aortic (and there ore systemic arterial) diastolic pressure drops substantially. The combination o a high LV stroke volume (and high systolic arterial pressure) with a reduced aortic diastolic pressure produces a widened pulse pressure (the di erence between arterial systolic and diastolic pressures), a hallmark o chronic AR (Fig. 8-10). As a result o the decreased aortic diastolic pressure, the coronary artery per usion pressure alls, potentially reducing myocardial oxygen supply. This, coupled with the increase in LV size (which causes increased wall stress and myocardial oxygen demand), can produce angina, even in the absence o atherosclerotic coronary disease. Compensatory le t ventricular dilatation and hypertrophy are generally adequate to meet the demands o chronic AR or many years, during which a ected patients are asymptomatic. Gradually, however, progressive remodeling o the LV occurs, resulting in systolic
Pulmona ry conge s tion Aorta Pre s s ure
Pre s s ure
Ac ute ao rtic re g urg itatio n
Pre s s ure N-
Pre s s ure N-
Chro nic ao rtic re g urg itatio n
FIGURE 8-9. Pathophysiology of acute and chronic aortic regurgitation ( AR) . Abnormal regurgitation o blood rom the aorta into the le t ventricle (LV) is shown in each schematic drawing (red arrows). In acute AR, the LV is o normal size and relatively low compliance, such that its diastolic pressure rises signi cantly; this pressure increase is ref ected back to the le t atrium (LA) and pulmonary vasculature, resulting in pulmonary congestion or edema. In chronic AR, adaptive LV and LA enlargement have occurred, such that a greater volume o regurgitation can be accommodated with less o an increase in diastolic LV pressure, so that pulmonary congestion is less likely. N, normal.
Valvular Heart Disease dys unction. This causes decreased orward cardiac output as well as an increase in le t atrial and pulmonary vascular pressures. At that point, the patient develops symptoms o heart ailure.
Clinical Mani estations and Assessment
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ECG
Aorta
Presentation Common symptoms o chronic AR include dyspnea on exertion, atigue, decreased exercise tolerance, and the uncom ortable sensation o a orce ul heartbeat associated with the high pulse pressure.
LV
Examination FIGURE 8-10. Hemodynamic prof le o
Physical examination may show bounding pulses aortic regurgitation. During diastole, the and other stigmata o the widened pulse pressure aortic pressure alls rapidly (arrow), and (Table 8-2), in addition to a hyperdynamic LV impulse le t ventricular (LV) pressure rises as blood and a blowing murmur o AR in early diastole along regurgitates rom the aorta into the LV. A the le t sternal border (see Fig. 8-10). It is best heard diastolic decrescendo murmur, beginning at with the patient leaning orward, a ter exhaling. In the second heart sound (S2), corresponds with the abnormal regurgitant f ow. ECG, addition, a low- requency mid-diastolic rumbling electrocardiogram. sound may be auscultated at the cardiac apex in some patients with severe AR. Known as the Austin Flint murmur, it is thought to ref ect turbulence o blood f ow through the mitral valve during diastole owing to downward displacement o the mitral anterior leaf et by the regurgitant stream o AR. It can be distinguished rom the murmur o mitral stenosis by the absence o an OS or presystolic accentuation. In chronic AR, the chest radiograph shows an enlarged le t ventricular silhouette. This is usually absent in acute AR, in which pulmonary vascular congestion is the more likely nding. Doppler echocardiography can identi y and quanti y the degree o AR and o ten can identi y its cause. Cardiac catheterization with contrast angiography can be obtained or urther quanti cation o the degree o AR, and assessment o coexisting coronary artery disease.
Treatment Data rom natural history studies indicate that clinical progression o patients with asymptomatic chronic AR and normal LV contractile unction is very slow. There ore, asymptomatic patients are monitored with periodic examinations and assessment o LV unction, usually by
TABLE 8-2
Examples o Physical Findings Associated with Widened Pulse Pressure in Chronic Aortic Regurgitation
Name
Description
Bis eriens pulse Corrigan pulse Hill sign
Double systolic impulse in carotid or brachial artery “Water-hammer” pulses with marked distention and collapse Popliteal systolic pressure more than 60 mm Hg greater than brachial systolic pressure Capillary pulsations visible at the lip or proximal nail beds
Quincke sign
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Chapter 8 serial echocardiography. Patients with asymptomatic severe AR may bene t rom a terload reducing vasodilators (e.g., a calcium channel blocker or an angiotensin-converting enzyme inhibitor) or treatment o accompanying hypertension. However, such agents do not prolong the compensated stage o chronic AR. Symptomatic patients, or asymptomatic patients with severe AR and impaired LV contractile unction (i.e., an ejection raction less than 0.50), should be o ered surgical correction to prevent progressive deterioration. Studies o such patients show that without surgery, death usually occurs within 4 years a ter the development o angina or 2 years a ter the onset o heart ailure symptoms.
TRICUSPID VALVE DISEASE Tricuspid Stenosis Tricuspid stenosis (TS) is rare and is usually a long-term consequence o rheumatic ever. The OS and diastolic murmur o TS are similar to those o MS, but the murmur is heard closer to the sternum and it intensi es on inspiration because o increased right heart blood f ow. In TS, the neck veins are distended and may show a large a wave as a result o right atrial contraction against the stenotic tricuspid valve ori ce when sinus rhythm is present (see Chapter 2). Patients may develop abdominal distention and hepatomegaly owing to passive venous congestion. Percutaneous balloon dilatation or surgical correction (valvuloplasty or valve replacement) is usually required.
Tricuspid Regurgitation Tricuspid regurgitation (TR) is usually functional rather than structural in nature; that is, it most commonly results rom right ventricular enlargement (e.g., owing to pressure or volume overload) rather than rom primary valve disease. Among patients with rheumatic mitral stenosis, 20% also have signi cant TR (o whom 80% have unctional TR because o pulmonary hypertension with right ventricular enlargement, and 20% have structural TR resulting rom rheumatic involvement o the tricuspid valve). A rare cause o TR is carcinoid syndrome, in which a type o neuroendocrine tumor (usually in the small bowel or appendix, with metastases to the liver) releases serotonin metabolites into the bloodstream. These metabolites are thought to be responsible or the ormation o endocardial plaques in the right side o the heart. Involvement o the tricuspid valve immobilizes the leaf ets, o ten resulting in substantial TR and, less o ten, TS. The most common physical signs o TR are prominent v waves in the jugular veins (see Chapter 2) and a pulsatile liver because o regurgitation o right ventricular blood into the systemic veins. The systolic murmur o TR is heard at the lower le t sternal border. It is o ten so t but becomes louder on inspiration. Doppler echocardiography readily detects TR and can quanti y it. The treatment o unctional TR is directed at the conditions responsible or the elevated right ventricular size or pressure, and diuretic therapy; surgical repair o the valve is indicated in severe cases.
PULMONIC VALVE DISEASE Pulmonic Stenosis Pulmonic stenosis (PS) is rare, and its cause is almost always congenital de ormity o the valve. Carcinoid syndrome, described in the previous section, is another rare etiology, in which encasement and immobilization o the valve leaf ets can occur. The systolic
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211
crescendo–decrescendo murmur o PS is usually loudest at the second or third le t intercostal space close to the sternum. It may radiate to the neck or le t shoulder and is o ten preceded by an ejection click (see Chapter 2). PS is considered to be severe i the peak systolic pressure gradient across the valve is greater than 80 mm Hg, moderate i the gradient is 40 to 80 mm Hg, and mild i the gradient is less than 40 mm Hg. Only patients with moderate-to-severe gradients are symptomatic. In such cases, transcatheter balloon valvuloplasty is usually e ective therapy.
Pulmonic Regurgitation Pulmonic regurgitation (PR) most commonly develops in the setting o severe pulmonary hypertension and results rom dilatation o the valve ring by the enlarged pulmonary artery. Auscultation reveals a high-pitched decrescendo murmur along the le t sternal border that is o ten indistinguishable rom AR (the two conditions are easily di erentiated by Doppler echocardiography).
PROSTHETIC VALVES The patient who undergoes valve replacement surgery o ten bene ts dramatically rom hemodynamic and symptomatic improvement, but also acquires a new set o potential complications related to the valve prosthesis itsel . Because all available valve substitutes have certain limitations, valve replacement surgery is not a true “cure.” Currently available valve substitutes include mechanical and bioprosthetic (derived rom animal or human tissue) devices (Fig. 8-11). One example o a mechanical valve is the St. Jude prosthesis, a hinged bileaf et valve consisting o two pyrolytic carbon discs that open opposite one another. Mechanical valves, while durable, present oreign thrombogenic sur aces to the circulating blood and require li elong anticoagulation to prevent thromboembolism. In contrast, bioprosthetic valves display a very low rate o thromboembolism and do not require long-term anticoagulation therapy. The most commonly used bioprostheses are made rom glutaraldehyde- xed porcine (pig) valves secured in a support rame. In addition, bovine (cow) pericardium and human homogra t (aortic valves harvested and cryopreserved rom cadavers)
A
B
FIGURE 8-11. Examples of prosthetic heart valves. A. St. Jude mechanical bileaf et valve in the open position. (Courtesy o St. Jude Medical, Inc., St. Paul, MN.) B. A bioprosthetic aortic valve with leaf ets in the closed position. (Courtesy o Medtronic, Inc., Minneapolis, MN.)
212
Chapter 8 prostheses are used. For patients who undergo AVR because o endocarditis, human homogra t replacements are especially use ul because they have low rates o subsequent rein ection. Bioprosthetic valves have limited durability compared with mechanical valves, and structural ailure occurs in up to 50% by 15 years a ter implantation. The principal causes o ailure are leaf et tears and calci cation. Failure rates vary greatly depending on the position o the valve. For example, bioprosthetic valves in the mitral position deteriorate more rapidly than those in the aortic position. This is likely because the mitral valve is exposed to higher closing orces, resulting in greater leaf et stress than that experienced by aortic prostheses. Common to all types o valve replacement is the risk o in ective endocarditis (discussed in the next section), which occurs with an incidence o 1% to 2% per patient per year. I endocarditis occurs in the rst 60 days a ter valve surgery, the mortality rate is exceedingly high (50% to 80% ). I endocarditis occurs later, mortality rates range rom 20% to 50% . Reoperation is usually required when endocarditis involves a mechanical prosthesis because an adjacent abscess is requently present. Some cases o bioprosthetic valve endocarditis may respond to antibiotic therapy alone. Given their respective advantages and disadvantages, the mortality and complication rates o mechanical and bioprosthetic valves are similar or the rst 10 years a ter replacement. In 20-year ollow-up studies o randomized, controlled trials, mechanical valves have been shown to be superior to bioprosthetic valves or event- ree survival, except or bleeding complications related to anticoagulation therapy. There ore, the decision about which type o prosthesis to use in a patient o ten centers on (1) the patient’s expected li espan in comparison to the unctional longevity o the valve, (2) risk-versus-bene t considerations o chronic anticoagulation therapy, and (3) patient and surgeon pre erences. Mechanical valves are o ten recommended or younger patients and or those who will be tolerant o , and compliant with, anticoagulant therapy. Bioprosthetic valves are generally suitable choices or patients 65 years o age or older and or patients with contraindications to chronic anticoagulation.
INFECTIVE ENDOCARDITIS In ection o the endocardial sur ace o the heart, including the cardiac valves, can lead to extensive tissue damage and is o ten atal. In ective endocarditis (IE) carries an overall 6-month mortality rate o 20% to 25% , even with appropriate therapy, and a 100% mortality rate i it is not recognized and treated correctly. There are three clinically use ul ways to classi y IE: (1) by clinical course, (2) by host substrate, or (3) by the speci c in ecting microorganism. In the rst classi cation scheme, IE is termed acute bacterial endocarditis (ABE) when the syndrome presents as an acute, ulminant in ection, and a highly virulent and invasive organism such as Staphylococcus aureus is causal. Because o the aggressiveness o the responsible microorganism, ABE may occur on previously healthy heart valves. When IE presents with a more insidious clinical course, it is termed subacute bacterial endocarditis (SBE) and less virulent organisms such as viridans streptococci are typically involved. SBE most requently occurs in individuals with prior underlying valvular damage. The second means o classi cation o IE is according to the host substrate: (1) native valve endocarditis, (2) prosthetic valve endocarditis, or (3) endocarditis in the setting o intravenous drug abuse. O these, native valve endocarditis accounts or 60% to 80% o patients. Di erent microorganisms and clinical courses are associated with each o these categories. For example, the skin contaminant Staphylococcus epidermidis is a common cause o prosthetic valve endocarditis, but that is rarely the case when endocarditis occurs on a native heart valve. Intravenous drug users have a propensity or S. aureus endocarditis o the rightsided heart valves.
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The third classi cation o IE is according to the speci c in ecting microorganism (e.g. S. aureus endocarditis). As described below, the most common responsible organisms are gram-positive cocci. Certain bacterial strains that cause endocarditis are associated with particular anatomic sources. For example, viridans group streptococci usually originate rom oropharyngeal tissue. Endocarditis due to Streptococcus bovis (more recently termed S. gallolyticus) commonly arises rom the gastrointestinal tract and should prompt investigation or colonic polyps or adenocarcinoma. Although the remainder o this discussion ocuses on the endocarditis syndromes based on clinical course, it is important to recognize that all three classi cations o IE are used.
Pathogenesis The pathogenesis o endocarditis requires several conditions: (1) endocardial sur ace injury, (2) platelet– brin–thrombus ormation at the site o injury, (3) bacterial entry into the circulation, and (4) bacterial adherence to the injured endocardial sur ace. The rst two conditions provide an environment avorable to in ection, whereas the latter two permit implantation o the organism on the endocardial sur ace. The most common cause o endothelial injury is turbulent blood f ow resulting rom preexisting cardiac or intravascular abnormalities, including acquired valvular heart lesions (e.g., mitral regurgitation or aortic stenosis), congenital heart diseases, and hypertrophic cardiomyopathy (see Chapter 10). Endothelial injury may also be incited by oreign material within the circulation, such as indwelling venous catheters, prosthetic heart valves, and other implanted cardiac devices. Once an endocardial sur ace is injured, platelets adhere to the exposed subendocardial connective tissue and initiate the ormation o a sterile thrombus (termed a vegetation) through brin deposition. This process is re erred to as nonbacterial thrombotic endocarditis (NBTE). NBTE makes the endocardium more hospitable to microbes in two ways. First, the brin– platelet deposits provide a sur ace or adherence by bacteria. Second, the brin covers adherent organisms and protects them rom host de enses by inhibiting chemotaxis and migration o phagocytes. When NBTE is present, the delivery o microorganisms in the bloodstream to the injured sur ace can lead to IE. Three actors determine the ability o an organism to induce IE: (1) access to the bloodstream, (2) survival o the organism in the circulation, and (3) adherence o the bacteria to the endocardium. Bacteria can be introduced into the bloodstream whenever a mucosal or skin sur ace harboring an organism is traumatized, such as rom the mouth during dental procedures, or rom the skin during illicit intravenous drug use. However, while transient bacteremia is a relatively common event, only microorganisms suited or survival in the circulation and able to adhere to the platelet– brin mesh overlying the endocardial de ect will cause IE. For example, gram-positive organisms account or the majority o cases o endocarditis largely because o their resistance to destruction in the circulation by complement and their particular tendency to adhere to endothelial and platelet sur ace proteins. The ability o certain streptococcal species to produce dextran, a bacterial cell wall component that adheres to thrombus, correlates with their inciting endocarditis. Table 8-3 lists the in ectious agents reported to be the most common causes o endocarditis in modern tertiary centers; staphylococci (especially S. aureus) and streptococci are the most requent. O note, the proportion o patients with viridans group streptococci is higher in series o patients with community-acquired endocarditis. Once organisms adhere to the injured sur ace, they may be protected rom phagocytic activity by the overlying brin. The organisms are then ree to multiply, which enlarges the in ected vegetation. The latter provides a source or continuous bacteremia and can lead to several complications, including (1) mechanical cardiac injury, (2) thrombotic or septic
214
Chapter 8
TABLE 8-3
Microbiology of Infective Endocarditis in Tertiary Centers
Organism Staphylococci S. aureus Coagulase negative Streptococci Viridans Enterococci S. bovis Other streptococci Other organisms ( e.g., gram-negative bacteria, fungi) Culture negative or polymicrobial
Incidence ( %) 31.6 10.5 18.0 10.6 6.5 5.1 8.7 ~9.4
Derived from Fowler VG Jr, Miro JM, Hoen B, et al. Staphylococcus aureus endocarditis: a consequence of medical progress. JAMA. 2005;293:3012–3021.
emboli, and (3) immune injury mediated by antigen–antibody deposition. For example, local extension o the in ection within the heart can result in progressive valvular damage, abscess ormation, or erosion into the cardiac conduction system. Portions o a vegetation may embolize, o ten to the central nervous system, kidneys, or spleen, and incite in ection or in arction o the target organs. Each o these is a potentially atal complication. Additionally, immune complex deposition can result in glomerulonephritis, arthritis, or vasculitis. The epidemiology o IE has evolved in recent decades as bacteria resistant to antibiotics have become ubiquitous in the hospital setting and have spread into the community. Antibiotic resistant strains such as methicillin-resistant S. aureus and vancomycin-resistant enterococci have become more common and are associated with increased mortality rates rom IE.
Clinical Manifestations A patient with a cute IE is likely to report an explosive and rapidly progressive illness with high ever and shaking chills. In contrast, suba cute IE presents less dramatically with lowgrade ever o ten accompanied by nonspeci c constitutional symptoms such as atigue, anorexia, weakness, myalgia, and night sweats. These symptoms are not speci c or IE and could easily be mistaken or inf uenza or an upper respiratory tract in ection. Thus, the diagnosis o subacute IE requires a high index o suspicion. A history o a valve lesion or other condition known to predispose to endocarditis is help ul. A thorough history should also inquire about injection drug use, recent dental procedures, or other potential sources o bacteremia. Cardiac examination may reveal a murmur representing underlying valvular pathology that predisposed the patient to IE, or a new murmur o valvular insu ciency owing to IE-induced damage. The development o right-sided valve lesions (e.g., tricuspid regurgitation), although rare in normal hosts, is particularly common in endocarditis associated with intravenous drug abuse. Serial examination in ABE may be especially use ul because changes in a murmur (i.e., worsening regurgitation) over time may correspond with rapidly progressive valvular
Valvular Heart Disease
215
destruction. During the course o endocarditis, severe valvular destruction may result in signs o heart ailure, which is the leading cause o death in patients with IE. Other physical ndings that may appear in IE are those associated with septic embolism or immune complex deposition. Central nervous system emboli occur in up to 40% o patients, o ten resulting in new neurologic ndings on physical examination. Injury to the kidneys, o embolic or immunologic origin, may mani est as f ank pain, hematuria, or renal ailure. Lung in arction (septic pulmonary embolism) or in ection (pneumonia) is particularly common in endocarditis that involves right-sided valves. Embolic in arction and seeding o the vasa vasorum o arteries can cause localized aneurysm ormation (termed a mycotic aneurysm) that weakens the vessel wall and may rupture. Mycotic aneurysms may be ound in the aorta, viscera, or peripheral organs, and are particularly dangerous in cerebral vessels, because rupture there can result in atal intracranial hemorrhage. Skin ndings resulting rom septic embolism or immune complex vasculitis are o ten collectively re erred to as peripheral stigmata o endocarditis. For example, petechiae may appear as tiny, circular, red-brown discolorations on mucosal sur aces or skin. Splinter hemorrhages, the result o subungual microemboli, are small, longitudinal hemorrhages ound beneath nails. Other peripheral stigmata o IE, which are now rarely encountered, include painless, f at, irregular discolorations ound on the palms and soles called Janeway lesions; tender, peasized, erythematous nodules ound primarily in the pulp space o the ngers and toes termed Osler nodes; and emboli to the retina that produce Roth spots, microin arctions that appear as white dots surrounded by hemorrhage. The systemic inf ammatory response produced by the in ection is responsible or ever and splenomegaly, as well as or a number o laboratory ndings, including an elevated white blood cell count with a le tward shi t (increase in proportion o neutrophils and immature granulocytes), an elevated erythrocyte sedimentation rate and C-reactive protein level, and in approximately 50% o cases, an elevated serum rheumatoid actor. The electrocardiogram may help identi y extension o the in ection into the cardiac conduction system, mani est by various degrees o heart block or new arrhythmias. Echocardiography is used to visualize vegetations, valvular dys unction, and associated abscess ormation. Echocardiographic assessment can consist o transthoracic echocardiography (TTE) or transesophageal echocardiography (TEE), as described in Chapter 3. TTE is use ul in detecting large vegetations and has the advantage o being noninvasive and easy to obtain. However, while the specif city o TTE or vegetations is high, the sensitivity or nding vegetations is less than 60% . TEE, on the other hand, is much more sensitive (> 90% ) or the detection o vegetations and myocardial abscess ormation and can be particularly use ul or the evaluation o in ection involving prosthetic valves. Central to the diagnosis and appropriate treatment o endocarditis is the identi cation o the responsible microorganism by blood culture. Once positive culture results are obtained, treatment can be tailored to the causative organism according to its antibiotic sensitivities. A speci c etiologic agent is identi ed approximately 90% o the time. However, blood cultures may return negative i antibiotics have already been administered or i the organism has unusual growth requirements. Even a ter a care ul history, examination, and evaluation o laboratory data, the diagnosis o IE can be elusive. There ore, attempts have been made to standardize the diagnosis, resulting in the now widely used Duke criteria (Table 8-4). By this standard, the diagnosis o endocarditis rests on the presence o either two major criteria, one major and three minor criteria, or ve minor criteria. Positive blood cultures and endocardial involvement detected by echocardiography provide the strongest evidence or IE and are considered major criteria. Minor criteria relate to clinical risk actors and ndings on physical examination.
216
Chapter 8
TABLE 8-4
Modif ed Duke Criteria or Diagnosis o In ective Endocarditis ( IE) a
Major Criteria
Minor Criteria
I. Positive blood culture, def ned as either A or B A. Typical microorganism or IE rom two separate blood cultures 1. Streptococci viridans, S. bovis, HACEK group; or 2. Staphylococcus aureus or enterococci, in the absence o a primary ocus B. Microorganisms consistent with IE rom persistently positive blood cultures 1. Blood cultures drawn > 12 hr apart, or 2. All o three, or most o our separate cultures drawn at least 1 hr apart 3. Single positive blood culture or Coxiella burnetii or antiphase I IgG antibody titer > 1:800
Predisposing cardiac condition or intravenous drug use Fever (≥ 38.0°C) Vascular phenomena (septic arterial or pulmonary emboli, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhage, Janeway lesions) Immunologic phenomena (glomerulonephritis, Osler nodes, Roth spots, rheumatoid actor) Positive blood cultures not meeting major criteria or serologic evidence o in ection with organism consistent with IE
II. Evidence o endocardial involvement, def ned as A or B A. Echocardiogram positive or endocarditis: 1. Oscillating intracardiac mass, or 2. Myocardial abscess, or 3. New partial detachment o prosthetic valve B. New valvular regurgitation a
Clinical diagnosis o def nite endocarditis requires two major criteria, one major plus three minor criteria, or f ve minor criteria. Possible endocarditis requires one major plus one minor criteria or three minor criteria. HACEK, Haemophilus spp., Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella spp., and Kingella kingae. Derived rom Li JS, Sexton DJ, Mick N, et al. Proposed modif cations to the Duke criteria or the diagnosis o in ective endocarditis. Clin Infect Dis. 2000;30:633–638.
Treatment Treatment o endocarditis entails 4 to 6 weeks o high-dose intravenous antibiotic therapy. Although empiric broad-spectrum antibiotics may be used initially (a ter blood cultures are obtained) or patients who are severely ill or hemodynamically unstable, specif c, directed therapy is appropriate once the causative microorganism has been identif ed. Surgical intervention, usually with valve replacement, is indicated or patients with persistent bacteremia or ever despite appropriate antibiotic therapy, or those with severe valvular dys unction leading to heart ailure, and or individuals who develop myocardial abscesses or recurrent endocarditis-related thromboemboli.
Prevention An additional essential concept is prevention o endocarditis by administering antibiotics to certain susceptible individuals be ore invasive procedures that are likely to result in bacteremia. The American Heart Association recommends such antibiotic prophylaxis or the cardiac conditions that place them at the highest risk or developing an adverse outcome rom IE, as delineated in Table 8-5, when such individuals are subjected to procedures listed in the table.
Valvular Heart Disease
TABLE 8-5
217
Antibiotic Prophylaxis for Infective Endocarditis
Cardiac conditions for which antibiotic prophylaxis is reasonable a 1. Presence o a prosthetic heart valve or prior valve repair with prosthetic material 2. Prior history o endocarditis 3. Certain congenital heart diseases (CHD): • Unrepaired cyanotic CHD (described in Chapter 16) • Completely repaired congenital heart de ects with prosthetic material, during the f rst 6 months a ter the procedure (i.e., prior to protective endothelialization) • Repaired CHD with residual de ects adjacent to the site o prosthetic material (which inhibits endothelialization) 4. Cardiac transplant recipients who develop cardiac valve abnormalities Procedures that warrant antibiotic therapy for conditions listed above 1. Dental procedures that involve manipulation o gingival tissue, manipulation o periapical region o the teeth, or per oration o the oral mucosa 2. Upper respiratory tract procedures, only if involves incision or biopsy o mucosa (e.g., tonsillectomy, bronchoscopy with biopsy) 3. Genitourinary or gastrointestinal procedures, only if in ections o those systems are present 4. Procedures on infected skin or musculoskeletal tissue a
The conditions on this list have the highest risk o adverse outcomes rom endocarditis. Derived rom Wilson W, Taubert KA, Gewitz M, et al. Prevention o in ective endocarditis: guidelines rom the American Heart Association: a guideline rom the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality o Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1736–1754.
SUMMARY • Uni ying principles do not govern the behavior o all valvular heart diseases—e ective management requires identi cation o the valve abnormality, a determination o its severity, and an understanding o the pathophysiologic consequences and natural history o the condition (Table 8-6). • Diagnosis o valvular disease is assisted by transthoracic echocardiography (TTE), which allows or staging o disease severity; in selected patients, additional investigation with exercise testing or cardiac catheterization may be necessary to de ne the signi cance o the condition. • Management o patients with stenotic or regurgitant valves involves serial clinical and echocardiographic assessments; pharmacologic therapy is sometimes prescribed or symptomatic improvement, but recognition o timely indications or valve repair or replacement is essential. • Mitral stenosis usually results rom prior rheumatic ever; le t atrial (LA) enlargement and atrial brillation are common. • Mitral regurgitation (MR) results rom disruption o the structural integrity o any o the components o the mitral valve apparatus or their coordinated action; with chronic MR, LA enlargement, and le t ventricular (LV) volume overload are typical. • In mitral valve prolapse, the valve leaf ets are elongated, and the normal dense collagen and elastin matrix o the valvular brosa is ragmented and replaced with loose myxomatous connective tissue; one or both leaf ets bow into the LA during systole resulting in lack o coaptation and mitral regurgitation. • Aortic stenosis has three primary causes: (1) degenerative calci cation o a previously normal trileaf et aortic valve, (2) calci cation o a congenitally bicuspid aortic valve, and (3) rheumatic valve disease; the primary hemodynamic consequence is LV pressure overload with compensatory LV hypertrophy; cardinal symptoms are chest discom ort, exertional dyspnea, and exertional light-headedness.
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Valvular Heart Disease
219
• Aortic regurgitation may result either rom abnormalities o the aortic valve leaf ets or rom dilatation o the aortic root; the primary hemodynamic perturbation is LV volume overload. • Tricuspid stenosis is rare and is usually a long-term consequence o rheumatic ever. • Tricuspid regurgitation is usually unctional (due to RV enlargement) rather than structural in nature. • Pulmonic stenosis is rare, and its cause is almost always congenital de ormity o the valve. • Pulmonic regurgitation most commonly develops in the setting o severe pulmonary hypertension and results rom dilatation o the valve ring by an enlarged pulmonary artery. • The pathogenesis o endocarditis requires endocardial sur ace injury, platelet– brin– thrombus ormation at the site o injury, bacterial entry into the circulation, and bacterial adherence to the injured endocardial sur ace.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Christopher A. Miller, MD; Mia M. Edwards, MD; Patrick Yachimski, MD; Stephen K. Frankel, MD; Edward Chan, MD; Elia Duh, MD; Brian Stidham, MD; and John A. Bittl, MD.
Ad d i t i o n a l Rea d i n g Gerber MA, Baltimore RS, Eaton CB, et al. Prevention o rheumatic ever and diagnosis and treatment o acute streptococcal pharyngitis. Circula tion . 2009;119:1541–1551. Habib G, Hoen B, Tomos P, et al. Guidelines on the prevention, diagnosis, and treatment o in ective endocarditis (new version 2009); The Task Force on the Prevention, Diagnosis, and Treatment o In ective Endocarditis o the European Society o Cardiology. Eur Heart J. 2009;30: 2369–2413. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ ACC guideline or the management o patients with valvular heart disease: a report o the American College o Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63:e57-e185. O’Gara P, Loscalzo J. Valvular heart disease. In: Longo DL, Fauci AS, Kasper DL, et al., eds. Harrison’s Principles of
Internal Medicine. 18th ed. New York, NY: McGraw-Hill; 2012:1929–1950. Vahanian A, Al eri O, Andreotti F, et al. Guidelines on the management o valvular heart disease (version 2012); The Joint Task Force on the Management o Valvular Heart Disease o the European Society o Cardiology and the European Association or Cardio-Thoracic Surgery. Eur Heart J. 2012;33:2451–2496. Wilson W, Taubert KA, Gewitz M, et al. Prevention o in ective endocarditis: guidelines rom the American Heart Association: a guideline rom the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality o Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2007;116:1736–1754.
Heart Failure Da vid Mira nda Gregory D. Lewis Micha el A. Fifer
Ch a p t e r O u t l i n e Physiology Determinants o Contractile Function in the Intact Heart Pressure–Volume Loops Pathophysiology Heart Failure with Reduced EF Heart Failure with Preserved EF Right-Sided Heart Failure Compensatory Mechanisms Frank–Starling Mechanism Neurohormonal Alterations Ventricular Hypertrophy and Remodeling Myocyte Loss And Cellular Dysfunction Precipitating Factors Clinical Manifestations Symptoms Physical Signs Diagnostic Studies Prognosis Treatment Of Heart Failure With Reduced Ejection Fraction Diuretics Vasodilators Positive Inotropic Drugs β-Blockers Aldosterone Antagonist Therapy Additional Therapies Treatment Of Heart Failure With Preserved Ejection Fraction Acute Heart Failure Acute Pulmonary Edema
220
T
9
he heart normally accepts blood at low f lling pressures during diastole and then propels it orward at higher pressures in systole. Heart ailure is present when the heart is unable to pump blood orward at a su f cient rate to meet the metabolic demands o the body or is able to do so only i cardiac f lling pressures are abnormally high. Although conditions outside the heart may cause this def nition to be met through inadequate tissue per usion (e.g., severe hemorrhage) or increased metabolic demands (e.g., hyperthyroidism), in this chapter, only cardiac causes o heart ailure are considered. Heart ailure results in a clinical syndrome o atigue, shortness o breath, and o ten volume overload. It may be the f nal and most severe mani estation o nearly every orm o cardiac disease, including coronary atherosclerosis, myocardial in arction, valvular diseases, hypertension, congenital heart disease, and the cardiomyopathies. More than 550,000 new cases are diagnosed each year in the United States, where the current prevalence is approximately 5.8 million. The number o patients with heart ailure is increasing, not only because the population is aging but also because o interventions that prolong survival a ter damaging cardiac insults such as myocardial in arction. As a result, heart ailure now accounts or more than 12 million medical o f ce visits annually and is the most common diagnosis o hospitalized patients aged 65 years and older. Heart ailure most commonly results rom conditions o impaired le t ventricular unction. Thus, this chapter begins by reviewing the physiology o normal myocardial contraction and relaxation.
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PHYSIOLOGY Experimental studies o isolated cardiac muscle segments have revealed several important principles that can be applied to the intact heart. As a muscle segment is stretched apart, the relation between its length and the tension it passively develops is curvilinear, re ecting its intrinsic elastic properties (Fig. 9-1A, lower curve). I the muscle is f rst passively stretched and then stimulated to contract while its ends are held at f xed
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222
Chapter 9 positions (termed an isometric contraction), the total tension (the sum o active plu s passive tension) generated by the f bers is proportional to the length o the muscle at the time o stimulation (see Fig. 9-1A, upper curve). That is, stretching the muscle be ore stimu lation optimizes the overlap and in teraction o myosin and actin f lamen ts, increasing the number o cross bridges and the orce o contraction. Stretching cardiac muscle f bers also increases the sensitivity o the myof laments to calcium, which urther augments orce development. This relationship between the initial f ber length and orce development is o great importance in the intact heart: within a physiologic range, the larger the ventricular volume during diastole, the more the f bers are stretched be ore stimulation and the greater the orce o the next contraction. This is the basis o the Frank–Starling relationship, the observation that ventricular output increases in relation to the preload (the stretch on the myocardial f bers be ore contraction). A second observation rom isolated muscle experiments arises when the f bers are not tethered at a f xed length but are allowed to shorten during stimulation against a f xed load (termed the afterload). In this situation (termed an isotonic contraction), the f nal length o the muscle at the end o contraction is determined by the magnitude o the load but is independent o the length o the muscle be ore stimulation (see Fig. 9-1B). That is, (1) the tension generated by the f ber is equal to the f xed load; (2) the greater the load opposing contraction, the less the muscle f ber can shorten; (3) i the f ber is stretched to a longer length be ore stimulation but the a terload is kept constant, the muscle will shorten a greater distance to attain the same f nal length at the end o contraction; and (4) the maximum tension that can be produced during isotonic contraction (i.e., using a load su f ciently great such that the muscle is just unable to shorten) is the same as the orce produced by an isometric contraction at that initial f ber length. This concept o a terload is also relevant to the intact heart: the pressure generated by the ventricle and the size o the chamber at the end o each contraction depend on the load against which the ventricle contracts but are independent o the stretch on the myocardial f bers be ore contraction. A third key experimental observation relates to myocardial contractility, which accounts or changes in the orce o contraction independent o the initial f ber length and a terload. Contractility re ects chemical and hormonal in uences on cardiac contraction, such as exposure to catecholamines. When contractility is enhanced pharmacologically (e.g., by a norepinephrine in usion), the relation between initial f ber length and orce developed during contraction is shi ted upward (see Fig. 9-1C) such that a greater total tension develops with isometric contraction at any given preload. Similarly, when contractility is augmented and the cardiac muscle is allowed to shorten against a f xed a terload, the f ber contracts to a greater extent and achieves a shorter f nal f ber length compared with the baseline state. At the molecular level, enhanced contractility is likely related to an increased cycling rate o actin–myosin cross-bridge ormation.
Determinants of Contractile Function in the Intact Heart In a healthy person, cardiac output is matched to the body’s total metabolic need. Cardiac output (CO) is equal to the product o stroke volume (SV, the volume o blood ejected with each contraction) and the heart rate (HR): CO = SV × HR The three major determinants o stroke volume are preload, a terload, and myocardial contractility, as shown in Figure 9-2.
Heart Failure
Preload
Contra ctility
Pre loa d
223
Afte rloa d
The concept o preload (Table 9-1) in the + intact heart was described by physiologists Frank and Starling a century ago. In experS troke + – imental preparations, they showed that volume within physiologic limits, the more a nor+ mal ventricle is distended (i.e., f lled with blood) during diastole, the greater the volHe a rt Ca rdia c + rate output ume that is ejected during the next systolic contraction. This relationship is illustrated graphically by the Frank–Starling curve, FIGURE 9-2. Key mediators o cardiac output. also known as the ventricular unction Determinants o the stroke volume include contractility, curve (Fig. 9-3). The graph relates a mea- preload, and a terload. Cardiac output = heart rate × surement o cardiac per ormance (such as stroke volume. cardiac output or stroke volume) on the vertical axis as a unction o preload on the horizontal axis. As described earlier, the preload can be thought o as the amount o myocardial stretch at the end o diastole, just be ore contraction. Measurements that correlate with myocardial stretch, and that are o ten used to indicate the preload on the horizontal axis, are the ventricular end-diastolic volume (EDV) or end-diastolic pressure (EDP). Conditions that decrease intravascular volume, and thereby reduce ventricular preload (e.g., dehydration or severe hemorrhage), result in a smaller EDV and hence a reduced stroke volume during contraction. Conversely, an increased volume within the le t ventricle during diastole (e.g., a large intravenous uid in usion) results in a greater-than-normal stroke volume.
TABLE 9-1 Terms Related to Cardiac Per ormance Term
Def nition
Preload
The ventricular wall tension at the end o diastole. In clinical terms, it is the stretch on the ventricular bers just be ore contraction, o ten approximated by the end-diastolic volume or end-diastolic pressure. The ventricular wall tension during contraction; the orce that must be overcome or the ventricle to eject its contents. O ten approximated by the systolic ventricular (or arterial) pressure Property o heart muscle that accounts or changes in the strength o contraction, independent o the preload and a terload. Ref ects chemical or hormonal inf uences (e.g., catecholamines) on the orce o contraction Volume o blood ejected rom the ventricle during systole SV = End-diastolic volume – end-systolic volume The raction o end-diastolic volume ejected rom the ventricle during each systolic contraction (normal range = 55%–75%) EF = Stroke volume ÷ end-diastolic volume Volume o blood ejected rom the ventricle per minute CO = SV × Heart rate Intrinsic property o a chamber that describes its pressure–volume relationship during illing. Re lects the ease or di iculty wit h which t he chamber can be illed. Compliance = ∆ volume ÷ ∆ pressure
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224
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FIGURE 9-3. Left ventricular ( LV) performance (Frank–Starling) curves relate preload, measured as LV enddiastolic volume ( EDV) or pressure (EDP), to cardiac performance, measured as ventricular stroke volume or cardiac output. On the curve o a normal heart (middle line), cardiac per ormance continuously increases as a unction o preload. States o increased contractility (e.g., norepinephrine in usion) are characterized by an augmented stroke volume at any level o preload (upper line). Conversely, decreased LV contractility (commonly associated with heart ailure) is characterized by a curve that is shi ted downward (lower line). Point a is an example o a normal person at rest. Point b represents the same person a ter developing systolic dys unction and heart ailure (e.g., a ter a large myocardial in arction): stroke volume has allen, and the decreased LV emptying results in elevation o the EDV. Because point b is on the ascending portion o the curve, the elevated EDV serves a compensatory role because it results in an increase in subsequent stroke volume, albeit much less than i operating on the normal curve. Further augmentation o LV lling (e.g., increased circulating volume) in the heart ailure patient is represented by point c, which resides on the relatively f at part o the curve: stroke volume is only slightly augmented, but the signi cantly increased EDP results in pulmonary congestion.
Afterload A terload (see Table 9-1) in the intact heart re ects the resistance that the ventricle must overcome to empty its contents. It is more ormally def ned as the ventricular wall stress that develops during systolic ejection. Wall stress (σ), like pressure, is expressed as orce per unit area and, or the le t ventricle, may be estimated rom Laplace relationship: s =
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where P is ventricular pressure, r is ventricular chamber radius, and h is ventricular wall thickness. Thus, ventricular wall stress rises in response to a higher pressure load (e.g., hypertension) or an increased chamber size (e.g., a dilated le t ventricle). Conversely, as would be expected rom Laplace relationship, an increase in wall thickness (h) serves a compensatory role in reducing wall stress, because the orce is distributed over a greater mass per unit sur ace area o ventricular muscle.
Contractility ( Also Termed “Inotropic State”) In the intact heart, as in the isolated muscle preparation, contractility accounts or changes in myocardial orce or a given set o preload and a terload conditions, resulting rom chemical
Heart Failure
225
and hormonal in uences. By relating a measure o ventricular per ormance (stroke volume or cardiac output) to preload (le t ventricular EDP or EDV), each Frank–Starling curve is a re ection o the heart’s current inotropic state (see Fig. 9-3). The e ect on stroke volume by an alteration in preload is re ected by a change in position along a particular Frank–Starling curve. Conversely, a change in contractility shi ts the entire curve in an upward or downward direction. Thus, when contractility is enhanced pharmacologically (e.g., by an in usion o norepinephrine), the ventricular per ormance curve is displaced upward such that at any given preload, the stroke volume is increased. Conversely, when a drug that reduces contractility is administered, or the ventricle’s contractile unction is impaired (as in certain types o heart ailure), the curve shi ts in a downward direction, leading to reductions in stroke volume and cardiac output at any given preload.
Pressure–Volume Loops Another use ul graphic display to illustrate the determinants o cardiac unction is the ventricular pressure–volume loop, which relates changes in ventricular volume to corresponding changes in pressure throughout the cardiac cycle (Fig. 9-4). In the le t ventricle, f lling o the chamber begins a ter the mitral valve opens in early diastole (point a). The curve between points a and b represents diastolic f lling. As the volume increases during diastole,
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226
Chapter 9 it is associated with a small rise in pressure, in accordance with the passive length–tension properties or compliance (see Table 9-1) o the myocardium, analogous to the lower curve in Figure 9-1A or an isolated muscle preparation. Next, the onset o le t ventricular systolic contraction causes the ventricular pressure to rise. When the pressure in the le t ventricle (LV) exceeds that o the le t atrium (point b), the mitral valve is orced to close. As the pressure continues to increase, the ventricular volume does not immediately change, because the aortic valve has not yet opened; there ore, this phase is called isovolumetric contraction. When the rise in ventricular pressure reaches the aortic diastolic pressure, the aortic valve is orced to open (point c) and ejection o blood into the aorta commences. During ejection, the volume within the ventricle decreases, but its pressure continues to rise until ventricular relaxation begins. The pressure against which the ventricle ejects (a component o a terload) is represented by the curve cd. Ejection ends during the relaxation phase, when the ventricular pressure alls below that o the aorta and the aortic valve closes (point d). As the ventricle continues to relax, its pressure declines while its volume remains constant because the mitral valve has not yet opened (this phase is known as isovolumetric relaxation). When the ventricular pressure alls below that o the le t atrium, the mitral valve opens again (point a) and the cycle repeats. Note that point b represents the pressure and volume at the end o diastole, whereas point d represents the pressure and volume at the end o systole. The di erence between the EDV and end-systolic volume (ESV) represents the quantity o blood ejected during contraction (i.e., the stroke volume). Changes in any o the determinants o cardiac unction are re ected by alterations in the pressure–volume loop. By analyzing the e ects o a change in an individual parameter (preload, a terload, or contractility) on the pressure–volume relationship, the resulting modif cations in ventricular pressure and stroke volume can be predicted (Fig. 9-5).
Alterations in Preload I a terload and contractility are held constant but preload is caused to increase (e.g., by administration o intravenous uid), le t ventricular EDV rises. This increase in preload augments the stroke volume via the Frank–Starling mechanism such that the ESV achieved is the same as it was be ore increasing the preload (see Fig. 9-5A). This means that the normal le t ventricle is able to adjust its stroke volume and e ectively empty its contents to match its diastolic f lling volume, as long as contractility and a terload are kept constant. Although EDV and EDP are o ten used interchangeably as markers o preload, the relationship between f lling volume and pressure (i.e., ventricular compliance; see Table 9-1) largely governs the extent o ventricular f lling. I ventricular compliance is reduced (e.g., in severe LV hypertrophy), the slope o the diastolic f lling curve (segment ab in Fig. 9-4) becomes steeper. A “sti ” or poorly compliant ventricle reduces the ability o the chamber to f ll during diastole, resulting in a lower-than-normal ventricular EDV. In this circumstance, the stroke volume will be reduced while the ESV remains unchanged.
Alterations in Afterload I preload and contractility are held constant and a terload is augmented (e.g., in highimpedance states such as hypertension or aortic stenosis), the pressure generated by the le t ventricle during ejection increases. In this situation, more ventricular work is expended in overcoming the resistance to ejection and there ore less f ber shortening takes place. As shown in Figure 9-5B, an increase in a terload results in a higher ventricular systolic pressure and a greater-than-normal LV ESV. Thus, in the setting o increased a terload, the ventricular stroke volume (EDV-ESV) is reduced.
Heart Failure
227
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C FIGURE 9-5. The effect of varying preload, afterload, and contractility on the pressure–volume loop. A. When arterial pressure (afterload) and contractility are held constant, sequential increases (lines 1, 2, and 3) in preload (measured in this case as end-diastolic volume [EDV]) are associated with loops that have progressively higher stroke volumes but a constant end-systolic volume (ESV). B. When the preload (EDV) and contractility are held constant, sequential increases (points 1, 2, and 3) in arterial pressure (afterload) are associated with loops that have progressively lower stroke volumes and higher end-systolic volumes. There is a nearly linear relationship between the afterload and ESV, termed the end-systolic pressure–volume relation (ESPVR). C. A positive inotropic intervention shifts the end-systolic pressure–volume relation upward and leftward from ESPVR-1 to ESPVR-2, resulting in loop 2, which has a larger stroke volume and a smaller endsystolic volume than the original loop 1.
The dependence of the ESV on afterload is approximately linear: the greater the afterload, the higher the ESV. This relationship is depicted in Figure 9-5 as the end-systolic pressure– volume relation (ESPVR) and is analogous to the total tension curve in the isolated muscle experiments described earlier.
Alterations in Contractility The slope of the ESPVR line on the pressure–volume loop graph is a function of cardiac contractility. In conditions of increased contractility, the ESPVR slope becomes steeper; that is, it shifts upward and toward the left. Hence, at any given preload or afterload, the ventricle empties more completely (the stroke volume increases) and results in a smaller-than-normal ESV (see Fig. 9-5C). Conversely, in situations of reduced contractility, the ESPVR line shifts
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Chapter 9 downward, consistent with a decline in stroke volume and a higher ESV. Thus, the ESV is dependent on the a terload against which the ventricle contracts and the inotropic state, but is independent o the EDV prior to contraction. The important physiologic concepts in this section are summarized here: 1. Ventricular stroke volume is a unction o preload, a terload, and contractility. SV rises when there is an increase in preload, a decrease in a terload, or augmented contractility. 2. Ventricular EDV (or EDP) is used as a representation o preload. The EDV is in uenced by the chamber’s compliance. 3. Ventricular ESV depends on the a terload and contractility but not on the preload.
PATHOPHYSIOLOGY Chronic heart ailure may result rom a wide variety o cardiovascular insults. The etiologies can be grouped into those that (1) impair ventricular contractility, (2) increase a terload, or (3) impair ventricular relaxation and f lling (Fig. 9-6). Heart ailure that results rom an abnormality o ventricular emptying (due to impaired contractility or greatly excessive a terload) is termed systolic dysfun ction , whereas heart ailure caused by abnormalities o diastolic relaxation or ventricular f lling is termed dia stolic dysfun ction . However, there is much overlap, and many patients demonstrate both systolic and diastolic abnormalities. As a result, it is common to categorize heart ailure patients into two general categories
Afte rlo ad (Chro nic Pre s s ure Ove rlo ad a )
Impaire d Co ntrac tility
1. Adva nce d a ortic s te nos is
1. Corona ry a rte ry dis e a s e • Myoca rdia l infa rction • Tra ns ie nt myoca rdia l is che mia 2. Chronic volume ove rloa d • Mitra l re gurgita tion • Aortic re gurgita tion 3. Dila te d ca rdiomyopa thie s
2. Uncontrolle d s eve re hype rte ns ion
Re duc e d Eje c tio n Frac tio n (Sys tolic Dys func tion)
He art Failure
Pre s e rve d Eje c tio n Frac tio n (Dia s tolic Dys func tion)
Impaire d Dias to lic Filling 1. Le ft ve ntricula r hype rtrophy 2. Re s trictive ca rdiomyopa thy 3. Myoca rdia l fibros is 4. Tra ns ie nt myoca rdia l is che mia 5. Pe rica rdia l cons triction or ta mpona de
FIGURE 9-6. Conditions that cause left-sided heart failure through impairment of ventricular systolic or diastolic function. a Note that in chronic stable stages, the conditions in this box (aortic stenosis, hypertension) may instead result in heart failure with preserved EF, due to compensatory ventricular hypertrophy and increased diastolic stiffness (diastolic dysfunction).
Heart Failure based on the le t ventricular ejection (see Table 9-1): (1) heart failure w ith and (2) heart failure w ith preserved United States, approximately one hal o categories.
229
raction (EF), a measure o cardiac per ormance reduced EF (i.e., primarily systolic dys unction) EF (i.e., primarily diastolic dys unction). In the patients with heart ailure all into each o these
Heart Failure with Reduced EF
g
)
In states o systolic dys unction, the a ected ventricle has a diminished capacity to eject blood because o impaired myocardial contractility or pressure overload (i.e., excessive a terload). Loss o contractility may result rom destruction o myocytes, abnormal myocyte unction, or f brosis. Pressure overload impairs ventricular ejection by signif cantly increasing resistance to ow. Figure 9-7A depicts the e ects o systolic dys unction due to impaired contractility on the pressure–volume loop. The ESPVR is shi ted downward such that systolic emptying ceases at a higher-than-normal ESV. As a result, the stroke volume alls. When normal pulmonary venous return is added to the increased ESV that has remained in the ventricle because o incomplete emptying, the diastolic chamber volume increases, resulting in a higher-thannormal EDV and pressure. While that increase in preload induces a compensatory rise in stroke volume (via the Frank–Starling mechanism), impaired contractility and the reduced EF cause the ESV to remain elevated. During diastole, the persistently elevated LV pressure is transmitted to the le t atrium (through the open mitral valve) and to the pulmonary veins and capillaries. An elevated pulmonary capillary hydrostatic pressure, when su f ciently high (usually greater than 20 mm Hg), results in the transudation o uid into the pulmonary interstitium and symptoms o pulmonary congestion.
H
2
P
r
P
e
r
s
e
s
s
u
s
r
u
e
r
(
e
(
m
m
m
m
H
g
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2
Dia s tolic pre s s ure – volume curve Volume (mL)
A
Volume (mL)
B
FIGURE 9-7. The pressure–volume loop in systolic and diastolic dysfunction. A. The normal pressure– volume loop (solid line) is compared with one demonstrating systolic dys unction (dashed blue line). In systolic dys unction caused by decreased cardiac contractility, the end-systolic pressure–volume relation is shi ted downward and rightward ( rom line 1 to line 2). As a result, the end-systolic volume (ESV) is increased (arrow). As normal venous return is added to that greater-than-normal ESV, there is an obligatory increase in the end-diastolic volume (EDV) and pressure (preload), which serves a compensatory unction by partially elevating stroke volume toward normal via the Frank–Starling mechanism. B. The pressure–volume loop o diastolic dys unction resulting rom increased sti ness o the ventricle (dashed blue line). The passive diastolic pressure–volume curve is shi ted upward ( rom line 1 to line 2) such that at any diastolic volume, the ventricular pressure is higher than normal. The result is a decreased EDV (arrow) because o reduced f lling o the sti ened ventricle at a higher-than-normal end-diastolic pressure.
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Chapter 9
Heart Failure with Preserved EF Patients who exhibit heart ailure with preserved EF requently demonstrate abnormalities o ventricular diastolic unction: impaired early diastolic relaxation (an active, energy-dependent process), increased sti ness o the ventricular wall (a passive property), or both. Acute myocardial ischemia is an example o a condition that transiently inhibits energy delivery and diastolic relaxation. Conversely, le t ventricular hypertrophy, f brosis, or restrictive cardiomyopathy (see Chapter 10) causes the LV walls to become chronically sti ened. Certain pericardial diseases (cardiac tamponade and pericardial constriction, as described in Chapter 14) present an external orce that limits ventricular f lling and represent potentially reversible orms o diastolic dys unction. The e ect o impaired diastolic unction is re ected in the pressure–volume loop (see Fig. 9-7B): in diastole, f lling o the ventricle occurs at higher-than-normal pressures because the lower part o the loop is shi ted upward as a result o reduced chamber compliance. Patients with diastolic dys unction o ten mani est signs o vascular congestion because the elevated diastolic pressure is transmitted retrograde to the pulmonary and systemic veins.
Right-Sided Heart Failure Whereas the physiologic principles described above may be applied to both right-sided and le t-sided heart ailure, there are distinct di erences in unction between the two ventricles. Compared with the le t ventricle, the right ventricle (RV) is a thin-walled, highly compliant chamber that accepts its blood volume at low pressures and ejects against a low pulmonary vascular resistance. As a result o its high compliance, the RV has little di f culty accepting a wide range o f lling volumes without marked changes in its f lling pressure. Conversely, the RV is quite susceptible to ailure in situations that present a sudden increase in a terload, such as acute pulmonary embolism. The most common cause o right-sided heart ailure is actually the presence o le t-sided heart ailure (Table 9-2). In this situation, excessive a terload con ronts the RV because o the elevated pulmonary vascular pressures that result rom LV dys unction. Isolated right heart ailure is less common and usually re ects increased RV a terload owing to diseases o the lung parenchyma or pulmonary vasculature. Right-sided heart disease that results rom a primary pulmonary process is known as cor pulmonale, which may lead to symptoms o right heart ailure. When the RV ails, the elevated diastolic pressure is transmitted retrograde to the right atrium with subsequent congestion o the systemic veins, accompanied by signs o right-sided heart ailure as described below. Indirectly, isolated right heart ailure may also in uence le t heart unction: the decreased right ventricular output reduces blood return to the LV (i.e., diminished preload), causing le t ventricular stroke volume to decline.
TABLE 9-2 Examples of Conditions That Cause Right-Sided Heart Failure Cardiac causes Left-sided heart failure Pulmonic valve stenosis Right ventricular infarction Pulmonary parenchymal diseases Chronic obstructive pulmonary disease Interstitial lung disease (e.g., sarcoidosis) Chronic lung infection or bronchiectasis Pulmonary vascular diseases Pulmonary embolism Pulmonary arteriolar hypertension
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COMPENSATORY MECHANISMS Several natural compensatory mechanisms are called into action in patients with heart ailure that bu er the all in cardiac output and help preserve su f cient blood pressure (BP) to per use vital organs. These compensations include (1) the Frank–Starling mechanism, (2) neurohormonal alterations, and (3) the development o ventricular hypertrophy and remodeling (Fig. 9-8).
Frank–Starling Mechanism As shown in Figure 9-3, heart ailure caused by impaired le t ventricular contractile unction causes a downward shi t o the ventricular per ormance curve. Consequently, at a given preload, stroke volume is decreased compared with normal. The reduced stroke volume results in incomplete chamber emptying, so that the volume o blood that accumulates in the ventricle during diastole is higher than normal (see Fig. 9-3, point b). This increased stretch on the myof bers, acting via the Frank–Starling mechanism, induces a greater stroke volume on subsequent contraction, which helps to empty the enlarged le t ventricle and preserve orward cardiac output (see Fig. 9-8). This benef cial compensatory mechanism has its limits, however. In the case o severe heart ailure with marked depression o contractility, the curve may be nearly at at higher diastolic volumes, reducing the augmentation o cardiac output achieved by the increased chamber f lling. Concurrently in such a circumstance, marked elevation o the EDV and pressure (which is transmitted retrograde to the le t atrium, pulmonary veins, and capillaries) may result in pulmonary congestion and edema (see Fig. 9-3, point c).
Neurohormonal Alterations Several important neurohormonal compensatory mechanisms are activated in heart ailure in response to the decreased cardiac output (Fig. 9-9). Three o the most important involve (1) the adrenergic nervous system, (2) the renin–angiotensin–aldosterone system, and (3) increased production o antidiuretic hormone (ADH). In part, these mechanisms serve to increase systemic vascular resistance, which helps to maintain arterial per usion to vital
an r F
ta r S k
lin g m e c h a n is m
+
↓ S troke Volume +
tric u n e ↓V
la r
yin g t p em
↑ Wa ll n e u r s tre s s & ohor a c tiv m o n a l a tio n ↑C
o n tra
c c tile fo r
↑ Ve ntricula r e nd-dia s tolic volume ↑ Atria l pre s s ure Myoca rdia l hype rtrophy
e
FIGURE 9-8. Compensatory mechanisms in heart failure. Both the Frank–Starling mechanism (which is invoked by the rise in ventricular end-diastolic volume) and increased contractile force (due to myocardial hypertrophy from augmented wall stress and neurohormonal activation) serve to maintain forward stroke volume (dashed green arrows). However, the chronic rise in end-diastolic volume and myocardial hypertrophy passively augment atrial pressure (red arrows), which may in turn contribute to symptoms of heart failure (e.g., pulmonary congestion in the case of left-sided heart failure).
232
Chapter 9 De c re as e d Cardiac Output
Re nin–a ngiote ns in sys te m
Sympa the tic ne rvous sys te m
Contra ctility
He a rt rate
Circula ting volume
Va s ocons triction
Ve nous
Arte riola r
Ve nous re turn to he a rt ( pre loa d)
Maintain Blo o d Pre s s ure
+
Cardiac Output
Antidiure tic hormone
–
Pe riphe ra l e de ma a nd pulmona ry conge s tion
+ S troke volume
FIGURE 9-9. Compensatory neurohormonal stimulation develops in response to the reduced forward cardiac output and blood pressure of heart failure. Increased activity o the sympathetic nervous system, renin–angiotensin–aldosterone system, and antidiuretic hormone serves to support the cardiac output and blood pressure (boxes). However, adverse consequences o these activations (red lines) include an increase in a terload rom excessive vasoconstriction (which may then impede cardiac output) and excess f uid retention, which contributes to peripheral edema and pulmonary congestion.
organs, even in the setting o a reduced cardiac output. That is, because blood pressure (BP) is equal to the product o cardiac output (CO) and total peripheral resistance (TPR), BP = CO × TPR a rise in TPR induced by these compensatory mechanisms can nearly balance the all in CO and, in the early stages o heart ailure, maintain airly normal BP. In addition, neurohormonal activation results in salt and water retention, which in turn increases intravascular volume and le t ventricular preload, maximizing stroke volume via the Frank–Starling mechanism. Although the acute e ects o neurohormonal stimulation are compensatory and benef cial, chronic activation o these mechanisms o ten ultimately proves deleterious to the ailing heart and contributes to a progressive downhill course, as described later.
Adrenergic Nervous System The all in cardiac output in heart ailure is sensed by baroreceptors in the carotid sinus and aortic arch. These receptors decrease their rate o f ring in proportion to the all in BP, and the signal is transmitted by the 9th and 10th cranial nerves to the cardiovascular control
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center in the medulla. As a consequence, sympathetic out ow to the heart and peripheral circulation is enhanced, and parasympathetic tone is diminished. There are three immediate consequences (see Fig. 9-9): (1) an increase in heart rate, (2) augmentation o ventricular contractility, and (3) vasoconstriction caused by stimulation o α-receptors on the systemic veins and arteries. The increased heart rate and ventricular contractility directly augment cardiac output (see Fig. 9-2). Vasoconstriction o the venous and arterial circulations is also initially benef cial. Venous constriction augments blood return to the heart, which increases preload and raises stroke volume through the Frank–Starling mechanism, as long as the ventricle is operating on the ascending portion o its ventricular per ormance curve. Arteriolar constriction increases the peripheral vascular resistance and there ore helps to maintain blood pressure (BP = CO × TPR). The regional distribution o α-receptors is such that during sympathetic stimulation, blood ow is redistributed to vital organs (e.g., heart and brain) at the expense o the skin, splanchnic viscera, and kidneys.
Renin–Angiotensin–Aldosterone System This system is also activated early in patients with heart ailure (see Fig. 9-9), mediated by increased renin release. The main stimuli or renin secretion rom the juxtaglomerular cells o the kidney in heart ailure patients include (1) decreased renal artery per usion pressure secondary to low cardiac output, (2) decreased salt delivery to the macula densa o the kidney owing to alterations in intrarenal hemodynamics, and (3) direct stimulation o juxtaglomerular β-receptors by the activated adrenergic nervous system. Renin is an enzyme that cleaves circulating angiotensinogen to orm angiotensin I, which is then rapidly cleaved by endothelial cell–bound angiotensin-converting enzyme (ACE) to orm angiotensin II (AII), a potent vasoconstrictor (see Chapter 13). Increased AII constricts arterioles and raises total peripheral resistance, thereby serving to maintain systemic blood pressure. In addition, AII acts to increase intravascular volume by two mechanisms: (1) at the hypothalamus, it stimulates thirst and there ore water intake, and (2) at the adrenal cortex, it acts to increase aldosterone secretion. The latter hormone promotes sodium reabsorption rom the distal convoluted tubule o the kidney into the circulation (see Chapter 17), serving to augment intravascular volume. The rise in intravascular volume increases le t ventricular preload and thereby augments cardiac output via the Frank– Starling mechanism in patients on the ascending portion o the ventricular per ormance curve (see Fig. 9-3).
Antidiuretic Hormone Secretion o this hormone (also termed vasopressin) by the posterior pituitary is increased in many patients with heart ailure, presumably mediated through arterial baroreceptors, and by increased levels o AII. ADH contributes to increased intravascular volume because it promotes water retention in the distal nephron. The increased intravascular volume serves to augment le t ventricular preload and cardiac output. ADH also appears to contribute to systemic vasoconstriction. Although each o these neurohormonal alterations in heart ailure is in itia lly benef cial, continued activation ultimately proves harm ul. For example, the increased circulating volume and augmented venous return to the heart may eventually worsen engorgement o the lung vasculature, exacerbating congestive pulmonary symptoms. Furthermore, the elevated arteriolar resistance increases the a terload against which the ailing le t ventricle contracts and may there ore ultimately impa ir stroke volume and reduce cardiac output (see Fig. 9-9). In addition, the increased heart rate augments metabolic demand and can thereore urther reduce the per ormance o the ailing heart. Continuous sympathetic activation
234
Chapter 9 results in down-regulation o cardiac β-adrenergic receptors and up-regulation o inhibitory G proteins, contributing to a decrease in the myocardium’s sensitivity to circulating catecholamines and a reduced inotropic response. Chronically elevated levels o AII and aldosterone have additional detrimental e ects. They provoke the production o cytokines (small proteins that mediate cell–cell communication and immune responses), activate macrophages, and stimulate f broblasts, resulting in f brosis and adverse remodeling o the ailing heart. Because the undesired consequences o chronic neurohormonal activation eventually outweigh the benef ts, much o today’s pharmacologic therapy o heart ailure is designed to moderate these “compensatory” mechanisms, as examined later in the chapter.
Natriuretic Peptides In contrast to the ultimately adverse consequences o the neurohormonal alterations described in the previous section, the natriuretic peptides are natural “benef cial” hormones secreted in heart ailure in response to increased intracardiac pressures. The best studied o these are atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is stored in atrial cells and is released in response to atrial distention. BNP is not detected in normal hearts but is produced when ventricular myocardium is subjected to hemodynamic stress (e.g., in heart ailure or during myocardial in arction). Clinical studies have shown a close relationship between serum BNP levels and the severity o heart ailure. Actions o the natriuretic peptides are mediated by specif c natriuretic receptors and are largely opposite to those o the other hormone systems activated in heart ailure. They result in excretion o sodium and water, vasodilatation, inhibition o renin secretion, and antagonism o the e ects o AII on aldosterone and vasopressin levels. Although these e ects are benef cial to patients with heart ailure, they are usually not su f cient to ully counteract the vasoconstriction and volume-retaining e ects o the other activated hormonal systems.
Other Peptides Among other peptides that are generated in heart ailure is endothelin-1, a potent vasoconstrictor, derived rom endothelial cells lining the vasculature (see Chapter 6). In patients with heart ailure, the plasma concentration o endothelin-1 correlates with disease severity and adverse outcomes. Drugs designed to inhibit endothelin receptors (and there ore blunt adverse vasoconstriction) improve LV unction, but long-term clinical benef ts have not been demonstrated in heart ailure patients.
Ventricular Hypertrophy and Remodeling Ventricular hypertrophy and remodeling are important compensatory processes that develop over time in response to hemodynamic burdens. Wall stress (as def ned earlier) is o ten increased in developing heart ailure because o either LV dilatation (increased chamber radius) or the need to generate high systolic pressures to overcome excessive a terload (e.g., in aortic stenosis or hypertension). A sustained increase in wall stress (along with neurohormonal and cytokine alterations) stimulates the development o myocardial hypertrophy and deposition o extracellular matrix. This increased mass o muscle f bers serves as a compensatory mechanism that helps to maintain contractile orce and coun tera cts the elevated ventricular wall stress (recall that wall thickness is in the denominator o the Laplace wall stress ormula). However, because o the increased sti ness o the hypertrophied wall, these benef ts come at the expense o higher-than-normal diastolic ventricular pressures, which are transmitted to the le t atrium and pulmonary vasculature (see Fig. 9-8).
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The pattern o compensatory hypertrophy and remodeling that develops depends on whether the ventricle is subjected to chronic volume or pressure overload. Chronic chamber dilatation owing to volume overload (e.g., chronic mitral or aortic regurgitation) results in the synthesis o new sarcomeres in series with the old, causing the myocytes to elongate. The radius o the ventricular chamber there ore enlarges, doing so in proportion to the increase in wall thickness, and is termed eccentric hypertrophy. Chronic pressure overload (e.g., caused by hypertension or aortic stenosis) results in the synthesis o new sarcomeres in parallel with the old (i.e., the myocytes thicken), termed concentric hypertrophy. In this situation, the wall thickness increases without proportional chamber dilatation, and wall stress may thereore be reduced substantially. Such hypertrophy and remodeling help to reduce wall stress and maintain contractile orce, but ultimately, ventricular unction may decline urther, allowing the chamber to dilate out o proportion to wall thickness. When this occurs, the excessive hemodynamic burden on the contractile units produces a downward spiral o deterioration with progressive heart ailure symptomatology.
MYOCYTE LOSS AND CELLULAR DYSFUNCTION Impairment o ventricular unction in heart ailure may result rom the actual loss o myocytes and/ or impaired unction o living myocytes. The loss o myocytes may result rom cellular necrosis (e.g., rom myocardial in arction or exposure to cardiotoxic drugs such as doxorubicin) or apoptosis (programmed cell death). In apoptosis, genetic instructions activate intracellular pathways that cause the cell to ragment and undergo phagocytosis by other cells, without an in ammatory response. Implicated triggers o apoptosis in heart ailure include elevated catecholamines, AII, in ammatory cytokines, and mechanical strain on the myocytes owing to the augmented wall stress. Even viable myocardium in heart ailure is abnormal at the ultrastructural and molecular levels. Mechanical wall stress, neurohormonal activation, and in ammatory cytokines, such as tumor necrosis actor (TNF), are believed to alter the genetic expression o contractile proteins, ion channels, catalytic enzymes, sur ace receptors, and secondary messengers in the myocyte. Experimental evidence has demonstrated such changes at the subcellular level that a ect intracellular calcium handling by the sarcoplasmic reticulum, decrease the responsiveness o the myof laments to calcium, impair excitation–contraction coupling, and alter cellular energy production. Cellular mechanisms currently considered the most important contributors to dys unction in heart ailure include (1) a reduced cellular ability to maintain calcium homeostasis and/ or (2) changes in the production, availability, and utilization o high-energy phosphates. However, the exact subcellular alterations that result in heart ailure have not yet been unraveled, and this is an active area o cardiovascular research.
PRECIPITATING FACTORS Many patients with heart ailure remain asymptomatic or extended periods either because the impairment is mild or because cardiac dys unction is balanced by the compensatory mechanisms described earlier. O ten, clinical mani estations are precipitated by circumstances that increase the cardiac workload and tip the balanced state into one o decompensation. Common precipitating actors are listed in Table 9-3. For example, conditions o increased metabolic demand such as ever or in ection may not be matched by a su f cient increase in output by the ailing heart, so that symptoms o cardiac insu f ciency are precipitated. Tachyarrhythmias precipitate heart ailure by decreasing diastolic ventricular f lling time and by increasing myocardial oxygen demand. Excessively low heart rates directly cause a drop in cardiac output (remember, cardiac output = stroke volume × heart rate). An increase in salt
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Chapter 9
TABLE 9-3
Factors That May Precipitate Symptoms in Patients with Chronic Compensated Heart Failure
Increased metabolic demands Fever In ection Anemia Tachycardia Hyperthyroidism Pregnancy Increased circulating volume ( increased preload) Excessive sodium content in diet Excessive f uid administration Renal ailure Conditions that increase afterload Uncontrolled hypertension Pulmonary embolism (increased right ventricular a terload) Conditions that impair contractility Negative inotropic medications Myocardial ischemia or in arction Excessive ethanol ingestion Failure to take prescribed heart failure medications Excessively slow heart rate
ingestion, renal dys unction, or ailure to take prescribed diuretic medications may increase the circulating volume, thus promoting systemic and pulmonary congestion. Uncontrolled hypertension depresses systolic unction because o excessive a terload. A large pulmonary embolism results in both hypoxemia (and there ore decreased myocardial oxygen supply) and augmented right ventricular a terload. Ischemic insults (i.e., myocardial ischemia or in arction), ethanol ingestion, or negative inotropic medications (e.g., large doses o β-blockers) can all depress myocardial contractility and precipitate symptoms in the otherwise compensated congestive heart ailure patient.
CLINICAL MANIFESTATIONS The clinical mani estations o heart ailure result rom impaired orward cardiac output and/ or elevated venous pressures and relate to the ventricle that has ailed (Table 9-4). A patient may present with the chronic progressive symptoms o heart ailure described here or, in certain cases, with sudden decompensation o le t-sided heart unction (e.g., acute pulmonary edema, as described later in the chapter).
Symptoms The most prominent mani estation o chronic le t ventricular ailure is dyspnea (breathlessness) on exertion. Controversy regarding the cause o this symptom has centered on whether it results primarily rom pulmonary venous congestion or rom decreased orward cardiac output. A pulmonary venous pressure that exceeds approximately 20 mm Hg leads to transudation o f uid into the pulmonary interstitium and congestion o the lung parenchyma. The resulting reduced pulmonary compliance increases the work o breathing to move the same volume o air. Moreover, the excess f uid in the interstitium compresses the walls o the bronchioles and alveoli, increasing the resistance to airf ow and requiring greater e ort
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TABLE 9-4 Common Symptoms and Physical Findings in Heart Failure Symptoms Left sided Dyspnea Orthopnea Paroxysmal nocturnal dyspnea Fatigue
Right sided Peripheral edema Right upper quadrant discomfort (because of hepatic enlargement)
Physical Findings Diaphoresis (sweating) Tachycardia, tachypnea Pulmonary rales Loud P2 S3 gallop (in systolic dysfunction) S4 gallop (in diastolic dysfunction) Jugular venous distention Hepatomegaly Peripheral edema
o respiration. In addition, juxtacapillary receptors (J receptors) are stimulated and mediate rapid shallow breathing. The heart ailure patient can also su er rom dyspnea even in the absence o pulmonary congestion, because reduced blood ow to overworked respiratory muscles and accumulation o lactic acid may also contribute to that sensation. Heart ailure may initially cause dyspnea only on exertion, but more severe dys unction results in symptoms at rest as well. Other mani estations o low orward output in heart ailure may include dulled mental status because o reduced cerebral per usion and impaired urine output during the day because o decreased renal per usion. The latter o ten gives way to increased urinary requency at night (nocturia) when, while supine, blood ow is redistributed to the kidney, promoting renal per usion and diuresis. Reduced skeletal muscle per usion may result in fatigue and weakness. Other congestive mani estations o heart ailure include orthopnea, paroxysmal nocturnal dyspnea (PND), and nocturnal cough. Orthopnea is the sensation o labored breathing while lying at and is relieved by sitting upright. It results rom the redistribution o intravascular blood rom the gravity-dependent portions o the body (abdomen and lower extremities) toward the lungs a ter lying down. The degree o orthopnea is generally assessed by the number o pillows on which the patient sleeps to avoid breathlessness. Sometimes, orthopnea is so signif cant that the patient may try to sleep upright in a chair. PND is severe breathlessness that awakens the patient rom sleep 2 to 3 hours a ter retiring to bed. This rightening symptom results rom the gradual reabsorption into the circulation o lower extremity interstitial edema a ter lying down, with subsequent expansion o intravascular volume and increased venous return to the heart and lungs. A nocturnal cough is another symptom o pulmonary congestion and is produced by a mechanism similar to orthopnea. Hemoptysis (coughing up blood) may result rom rupture o engorged bronchial veins. In right-sided heart ailure, the elevated systemic venous pressures can result in abdominal discomfort because the liver becomes engorged and its capsule stretched. Similarly, anorexia (decreased appetite) and nausea may result rom edema within the gastrointestinal tract. Peripheral edema, especially in the ankles and eet, also re ects increased hydrostatic venous pressures. Because o the e ects o gravity, it tends to worsen while the patient is upright during the day and is o ten improved by morning a ter lying supine at night. Even be ore peripheral edema develops, the patient may note an unexpected weight gain resulting rom the accumulation o interstitial uid.
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TABLE 9-5
New York Heart Association Classif cation o Chronic Heart Failure
Class
Def nition
I II
No limitation of physical activity Slight limitation of activity. Dyspnea and fatigue with moderate exertion (e.g., walking up stairs quickly) Marked limitation of activity. Dyspnea with minimal exertion (e.g., slowly walking up stairs) Severe limitation of activity. Symptoms are present even at rest.
III IV
The symptoms o heart ailure are commonly graded according to the New York Heart Association (NYHA) classif cation (Table 9-5), and patients may shi t rom one class to another, in either direction, over time. A newer system classif es patients according to their stage in the temporal course o heart ailure (Table 9-6). In this system, progression is in only one direction, rom Stage A to Stage D, re ecting the typical sequence o heart ailure maniestations in clinical practice.
Physical Signs The physical signs o heart ailure depend on the severity and chronicity o the condition and can be divided into those associated with le t or right heart dys unction (see Table 9-4). Patients with only mild impairment may appear well. However, a patient with severe chronic heart ailure may demonstrate cachexia (a rail, wasted appearance) owing in part to poor appetite and to the metabolic demands o the increased e ort in breathing. In decompensated le t-sided heart ailure, the patient may appear dusky (decreased cardiac output) and diaphoretic (sweating because o increased sympathetic nervous activity), and the extremities are cool because o peripheral arterial vasoconstriction. Tachypnea (rapid breathing) is common. The pattern o Cheyne–Stokes respiration may also be present in advanced heart ailure, characterized by periods o hyperventilation separated by intervals o apnea (absent breathing). This pattern is related to the prolonged circulation time between the lungs and respiratory center o the brain in heart ailure that inter eres with the normal eedback mechanism
TABLE 9-6
Stages o Chronic Heart Failure
Stage
Description
A
The patient is at risk of developing heart failure but has not yet developed structural cardiac dysfunction (e.g., patient with coronary artery disease, hypertension, or family history of cardiomyopathy). The patient with structural heart disease associated with heart failure but has not yet developed symptoms The patient with current or prior symptoms of heart failure associated with structural heart disease The patient with structural heart disease and refractory heart failure symptoms despite maximal medical therapy who requires advanced interventions (e.g., cardiac transplantation)
B C D
Derived from Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA Guideline for the Management of Heart Failure: Executive Summary A Report of the American College of Cardiology Foundation/ American heart Association Task Force on Practice Guidelines. Circulation. 2013;128:1810–1852.
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o systemic oxygenation. Sinus tachycardia (resulting rom increased sympathetic nervous system activity) is also common. Pulsus alternans (alternating strong and weak contractions detected in the peripheral pulse) may be present as a sign o advanced ventricular dys unction. In le t-sided heart ailure, the auscultatory f nding o pulmonary rales (“crackles”) is created by the “popping open” o small airways during inspiration that had been closed o by edema uid. This f nding is initially apparent at the lung bases, where hydrostatic orces are greatest; however, more severe pulmonary congestion is associated with additional rales higher in the lung f elds. Compression o conduction airways by pulmonary congestion may produce coarse rhonchi and wheezing; the latter f nding in heart ailure is termed cardiac asthma. Depending on the cause o heart ailure, palpation o the heart may show that the le t ventricular impulse is not ocal but di use (in dilated cardiomyopathy), sustained (in pressure overload states such as aortic stenosis or hypertension), or li ting in quality (in volume overload states such as mitral regurgitation). Because elevated le t heart f lling pressures result in increased pulmonary vascular pressures, the pulmonic component o the second heart sound is o ten louder than normal. An early diastolic sound (S3) is requently heard in adults with systolic heart ailure and is caused by abnormal f lling o the dilated chamber (see Chapter 2). A late diastolic sound (S4) results rom orce ul atrial contraction into a sti ened ventricle and is common in states o decreased LV compliance (diastolic dys unction). The murmur o mitral regurgitation is sometimes auscultated in le t-sided heart ailure i LV dilatation has stretched the valve annulus and spread the papillary muscles apart rom one another, thus preventing proper closure o the mitral lea ets in systole. In right-sided heart ailure, di erent physical f ndings may be present. Cardiac examination may reveal a palpable parasternal right ventricular heave, representing RV enlargement, or a right-sided S3 or S4 gallop. The murmur o tricuspid regurgitation may be auscultated and is due to right ventricular enlargement, analogous to mitral regurgitation that develops in patients with LV dilatation. The elevated systemic venous pressure produced by right heart ailure is mani ested by distention of the jugular veins as well as hepatic enlargement with abdominal right upper quadrant tenderness. Edema accumulates in the dependent portions o the body, beginning in the ankles and eet o ambulatory patients and in the presacral regions o those who are bedridden. Pleural e usions may develop in either le t- or right-sided heart ailure, because the pleural veins drain into both the systemic and pulmonary venous beds. The presence o pleural e usions is suggested on physical examination by dullness to percussion over the posterior lung bases.
Diagnostic Studies A normal mean le t atrial (LA) pressure is ≤ 10 mm Hg (see Fig. 3-13). I the LA pressure exceeds approximately 15 mm Hg, the chest radiograph shows upper-zone vascular redistribution, such that the vessels supplying the upper lobes o the lung are larger than those supplying the lower lobes (see Fig. 3-5). This is explained as ollows: when a patient is in the upright position, blood ow is normally greater to the lung bases than to the apices because o the e ect o gravity. Redistribution o ow occurs with the development o interstitial and perivascular edema, because such edema is most prominent at the lung bases (where the hydrostatic pressure is the highest), such that the blood vessels in the bases are compressed, whereas ow into the upper lung zones is less a ected. When the LA pressure surpasses 20 mm Hg, interstitial edema is usually mani ested on the chest radiograph as indistinctness o the vessels and the presence o Kerley B lines (short linear markings at the periphery o the lower lung f elds indicating interlobular edema— see Fig. 3-5C). I the LA pressure exceeds 25 to 30 mm Hg, alveolar pulmonary edema may develop, with opacif cation o the air spaces. The relationship between LA pressure and chest
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Chapter 9 radiograph f ndings is modif ed in patients with chronic heart ailure because o enhanced lymphatic drainage, such that higher pressures can be accommodated with ewer radiologic signs. Depending on the cause o heart ailure, the chest radiograph may show cardiomegaly, def ned as a cardiothoracic ratio greater than 0.5 on the posteroanterior image. A high right atrial pressure also causes enlargement o the azygous vein silhouette. Pleural e usions may be present. Assays or BNP, described earlier in the chapter, correlate well with the degree o LV dysunction and prognosis. Furthermore, an elevated serum level o BNP can help distinguish heart ailure rom other causes o dyspnea, such as pulmonary parenchymal diseases. The cause o heart ailure is o ten evident rom the history, such as a patient who has sustained a large myocardial in arction, or by physical examination, as in a patient with a murmur o valvular heart disease. When the cause is not clear rom clinical evaluation, the f rst step is to determine whether systolic ventricular unction is normal or depressed (see Fig. 9-6). O the several noninvasive tests that can help make this determination, echocardiography is especially use ul and readily available.
PROGNOSIS The prognosis o heart ailure is dismal in the absence o a correctable underlying cause. The 5-year mortality rate ollowing the diagnosis ranges between 45% and 60% , with men having worse outcomes than women. Patients with severe symptoms (i.e., NYHA class III or IV) are the least well, having a 1-year survival rate o only 40% . The greatest mortality is due to re ractory heart ailure, but many patients die suddenly, presumably because o associated ventricular arrhythmias. Heart ailure patients with preserved EF have similar rates o hospitalization, in-hospital complications, and mortality as those with reduced EF. Ventricular dys unction usually begins with an inciting insult, but is a progressive process, contributed to by the maladaptive activation o neurohormones, cytokines, and continuous ventricular remodeling. Thus, it should not be surprising that measures o neurohormonal and cytokine stimulation predict survival in heart ailure patients. For example, adverse prognosis correlates with the serum norepinephrine level (marker o sympathetic nervous system activity), serum sodium (reduced level re ects activation o renin–angiotensin–aldosterone system and alterations in intrarenal hemodynamics), endothelin-1, BNP, and TNF levels. Despite the generally bleak prognosis, a heart ailure patient’s outlook can be substantially improved by specif c interventions, as discussed in the ollowing sections.
TREATMENT OF HEART FAILURE WITH REDUCED EJECTION FRACTION There are f ve main goals o therapy in patients with chronic heart ailure and a reduced EF: 1. Identif cation and correction o the underlying condition causing heart ailure. In some patients, this may require surgical repair or replacement o dys unctional cardiac valves, coronary artery revascularization, aggressive treatment o hypertension, or cessation o alcohol consumption. 2. Elimination o the acute precipitating cause o symptoms in a patient with heart ailure who was previously in a compensated state. This may include, or example, treating acute in ections or arrhythmias, removing sources o excessive salt intake, or eliminating drugs that can aggravate symptomatology (e.g., certain calcium channel blockers, which have a negative inotropic e ect, or nonsteroidal anti-in ammatory drugs, which can contribute to volume retention). 3. Management o heart ailure symptoms: a. Treatment o pulmonary and systemic vascular congestion. This is most readily accomplished by dietary sodium restriction and diuretic medications. b. Measures to increase orward cardiac output and per usion o vital organs through the use o vasodilators and positive inotropic drugs.
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4. Modulation of the neurohormonal response to prevent adverse ventricular remodeling in order to slow the progression o LV dys unction. 5. Prolongation of long-term survival. There is strong evidence rom clinical trials that longevity is enhanced by specif c therapies, as described below.
Diuretics
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The mechanisms o action o diuretic drugs are summarized in Chapter 17. By promoting the elimination o sodium and water through the kidney, diuretics reduce intravascular volume and thus venous return to the heart. As a result, the preload o the le t ventricle is decreased, and its diastolic pressure alls out o the range that promotes pulmonary congestion (Fig. 9-10, point b). The intent is to reduce the EDP (and there ore hydrostatic orces contributing to pulmonary congestion) without a signif cant all in stroke volume. The judicious use o diuretics does not signif cantly reduce stroke volume and cardiac output in this setting, because the ailing ventricle is operating on the “ at” portion o a depressed Frank–Starling curve. However, overly vigorous diuresis can lower LV f lling pressures into the steep portion o the ventricular per ormance curve, resulting in an undesired all in cardiac output (see Fig. 9-10, point b′). Thus, diuretics should be used only i there is evidence o pulmonary congestion (rales) or peripheral interstitial uid accumulation (edema). Agents that act primarily at the renal loop o Henle (e.g., urosemide, torsemide, and bumetanide) are the most potent diuretics in heart ailure. Thiazide diuretics (e.g.,
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FIGURE 9-10. The effect of treatment on the left ventricular ( LV) Frank–Starling curve in patients who have heart failure with reduced EF. Point a represents the ailing heart on a curve that is shi ted downward compared with normal. The stroke volume is reduced (with blood pressure bordering on hypotension), and the LV end-diastolic pressure (LVEDP) is increased, resulting in symptoms o pulmonary congestion. Therapy with a diuretic or pure venous vasodilator (point b on the same Frank–Starling curve) reduces LV pressure without much change in stroke volume (SV). However, excessive diuresis or venous vasodilatation may result in an undesired all in SV with hypotension (point b′). Inotropic drug therapy (point c) and arteriolar (or “balanced”) vasodilator therapy (point d) augment SV, and because o improved LV emptying during contraction, the LVEDP lessens. Point e represents the potential added benef t o combining an inotrope and vasodilator together. The middle curve shows one example o how the Frank–Starling relationship shi ts upward during inotropic/ vasodilator therapy but does not achieve the level o a normal ventricle.
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Chapter 9 hydrochlorothiazide and metolazone) are also use ul but are less e ective in the setting o decreased renal per usion, which is o ten present in this condition. The potential adverse e ects o diuretics are described in Chapter 17. The most important in heart ailure patients include overly vigorous diuresis resulting in a all in cardiac output and electrolyte disturbances (particularly hypokalemia and hypomagnesemia), which may contribute to arrhythmias. In patients with acute heart ailure exacerbations, diuretics should be administered intravenously (either by bolus injections or continuous in usion) because venous congestion can limit the absorption o oral diuretics rom the gut.
Vasodilators One o the most important cardiac advances in the late twentieth century was the introduction o vasodilator therapy or the treatment o heart ailure, particularly ACE inhibitors. As indicated earlier, neurohormonal compensatory mechanisms in heart ailure o ten lead to excessive vasoconstriction, volume retention, and ventricular remodeling, with progressive deterioration o cardiac unction. Vasodilator drugs help to reverse these adverse consequences. Moreover, multiple studies have shown that certain vasodilator regimens signif cantly extend survival in patients with heart ailure. The pharmacology o these drugs is described in Chapter 17. Ven ous va sodilators (e.g., nitrates) increase venous capacitance and thereby decrease venous return to the heart and le t ventricular preload. Consequently, LV diastolic pressures all and the pulmonary capillary hydrostatic pressure declines, similar to the hemodynamic e ects o diuretic therapy. As a result, pulmonary congestion improves, and as long as the heart ailure patient is on the relatively “ at” part o the depressed Frank–Starling curve (see Fig. 9-10), the cardiac output does not all despite the reduction in ventricular f lling pressure. However, venous vasodilatation in a patient who is operating on the steeper part o the curve may result in an undesired all in stroke volume, cardiac output, and blood pressure. Pure arteriolar vasodilators (e.g., hydralazine) reduce systemic vascular resistance and there ore LV a terload, which in turn permits increased ventricular muscle f ber shortening during systole (see Fig. 9-5B). This results in an augmented stroke volume and is represented on the Frank–Starling diagram as a shi t in an upward direction (see Fig. 9-10, point d). Although an arterial vasodilator might be expected to reduce blood pressure—an undesired e ect in patients with heart ailure who may already be hypotensive—this generally does not happen. As resistance is reduced by arteriolar vasodilatation, a concurrent rise in cardiac output usually occurs, such that blood pressure remains constant or decreases only mildly. Some groups o drugs result in vasodilatation o both the venous and arteriolar circuits (“balanced” vasodilators). O these, the most important are agents that inhibit the renin– angiotensin–aldosterone system. ACE inhibitors (described in Chapters 13 and 17) interrupt the production o AII, thereby modulating the vasoconstriction incited by that hormone in heart ailure patients. In addition, because aldosterone levels all in response to ACE inhibitor therapy, sodium elimination is acilitated, resulting in reduced intravascular volume and improvement o systemic and pulmonary vascular congestion. ACE inhibitors also augment circulating levels o bradykinin (see Chapter 17), which is thought to contribute to benef cial vasodilatation in heart ailure. As a result o these e ects, ACE inhibitors limit maladaptive ventricular remodeling in patients with chronic heart ailure and ollowing acute myocardial in arction (see Chapter 7). Supporting the benef cial hemodynamic and neurohormonal blocking e ects o ACE inhibitors, many large clinical trials have shown that these drugs reduce heart ailure symptoms, reduce the need or hospitalization, and most importantly, extend survival in patients with heart ailure with reduced EF. Thus, ACE inhibitors are standard f rst-line chronic therapy or patients with LV systolic dys unction. The renin–angiotensin–aldosterone system can also be therapeutically inhibited by angiotensin II receptor blockers (ARBs), as described in Chapters 13 and 17. Since AII can be
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ormed by pathways other than ACE, ARBs provide a more complete inhibition o the system than ACE inhibitors, through blockade o the actual AII receptor (see Fig. 17.6). Conversely, ARBs do not cause the potentially benef cial rise in serum bradykinin. The net result is that the hemodynamic e ects and mortality benef t o ARBs in heart ailure are similar to those o ACE inhibitors. Thus, they are prescribed to heart ailure patients mainly when ACE inhibitors are not tolerated (e.g., because o bradykinin-mediated side e ects such as cough or angioedema). Chronic therapy using the combination o the venous dilator isosorbide dinitrate plus the arteriolar dilator hydralazine has also been shown to improve survival in patients with moderate symptoms o heart ailure. However, when the ACE inhibitor enalapril was compared with the hydralazine–isosorbide dinitrate (H-ISDN) combination, the ACE inhibitor was shown to produce the greater improvement in survival. Thus, H-ISDN is generally substituted when a patient cannot tolerate ACE inhibitor or ARB therapy (e.g., because o renal insu f ciency or hyperkalemia). O note, the A rican American Heart Failure trial demonstrated that the addition o H-ISDN to standard heart ailure therapy (including a diuretic, β-blocker, and ACE inhibitor or ARB) in black patients with heart ailure urther improved unctional status and survival. Nesiritide (human recombinant BNP) is an intravenous vasodilator drug available or hospitalized patients with decompensated heart ailure. It causes rapid and potent vasodilatation, reduces elevated intracardiac pressures, and augments orward cardiac output. However, it is an expensive drug that does not improve outcomes and may worsen renal unction, so its use should be restricted to patients who have not responded to, or cannot tolerate, other intravenous vasodilators, such as intravenous nitroglycerin or nitroprusside (see Chapter 17).
Positive Inotropic Drugs Inotropic drugs include β-adrenergic agonists, digitalis glycosides, and phosphodiesterase type 3 inhibitors (see Chapter 17). By increasing the availability o intracellular calcium, each o these drug groups enhances the orce o ventricular contraction and there ore shi ts the Frank–Starling curve in an upward direction (see Fig. 9-10). As a result, stroke volume and cardiac output are augmented at any given ventricular EDV. There ore, these agents may be use ul in treating patients with systolic dys unction, but typically not those with heart ailure with preserved EF. β-Adrenergic agonists (e.g., dobutamine and dopamine) are administered intravenously or temporary hemodynamic support in acutely ill, hospitalized patients. Their long-term use is limited by the lack o an oral orm o administration and by the development o drug tolerance. The latter re ers to the progressive decline in e ectiveness during continued administration o the drug, possibly owing to down-regulation o myocardial adrenergic receptors. Likewise, the role o phosphodiesterase 3 inhibitors (e.g., milrinone) is limited to the intravenous treatment o congestive heart ailure in acutely ill patients. Despite the initial promise o e ective oral phosphodiesterase 3 inhibitors, studies thus ar actually demonstrate reduced survival among patients receiving this orm o treatment. One o the oldest orms o inotropic therapy is digitalis (see Chapter 17), which can be administered intravenously or orally. Digitalis preparations enhance contractility, reduce cardiac enlargement, improve symptoms, and augment cardiac output in patients with systolic heart ailure. Digitalis also increases the sensitivity o the baroreceptors, so that the compensatory sympathetic drive in heart ailure is blunted, a desired e ect that reduces le t ventricular a terload. By slowing AV nodal conduction and thereby reducing the rate o ventricular contractions, digitalis has an added benef t in patients with congestive heart ailure who have concurrent atrial f brillation. Although digitalis can improve symptomatology and reduce the rate o hospitalizations in heart ailure patients, it has not been shown to improve long-term survival. Thus, its use is limited to patients who remain symptomatic despite other standard therapies or to help slow the ventricular rate i atrial f brillation is also present. Digitalis is not use ul in the treatment o heart ailure with preserved EF because it does not improve ventricular relaxation properties.
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β-Blockers Historically, β-blockers were thought to be contraindicated in patients with systolic dys unction because their negative inotropic e ect would be expected to worsen symptomatology. However, clinical trials have actually shown that long-term β-blocker therapy has important benef ts in patients with stable chronic heart ailure with reduced EF, including augmented cardiac output, reduced hemodynamic deterioration, the need or ewer hospitalizations, and improved survival. The explanation or these desired e ects remains conjectural but may relate to the drugs’ e ects on reducing heart rate and blunting chronic sympathetic activation or to their anti-ischemic properties. The three β-blockers that have been shown to be benef cial in randomized clinical trials o heart ailure include carvedilol (a nonselective β-blocker with weak α-blocking properties— see Chapter 17) and the β1-selective agents metoprolol succinate and bisoprolol. These drugs are well tolerated in stable patients (i.e., those without recent deterioration o heart ailure symptoms or active volume overload). Nonetheless, β-blockers should always be used cautiously in heart ailure to prevent acute deterioration related to their negative inotropic e ect. Regimens should be started at low dosage and augmented gradually.
Aldosterone Antagonist Therapy There is evidence that chronic excess o aldosterone in heart ailure contributes to cardiac f brosis and adverse ventricular remodeling. Antagonists o this hormone (which have been used historically as mild diuretics—see Chapter 17) have shown clinical benef t in heart ailure patients. For example, in a clinical trial o patients with advanced heart ailure (i.e., NYHA Class III to IV) who were already taking an ACE inhibitor and diuretics, the aldosterone receptor antagonist spironolactone substantially reduced mortality rates and improved heart ailure symptoms. Eplerenone, a more specif c aldosterone receptor inhibitor, has been shown to improve survival o patients with congestive heart ailure a ter acute myocardial in arction (see Chapter 7) as well as patients with more mild orms o chronic heart ailure (i.e., NYHA Class II to III). Although aldosterone antagonists have been well tolerated in careully controlled studies, the serum potassium level must be monitored to prevent hyperkalemia, especially i there is renal impairment or concomitant ACE inhibitor therapy. In summary, standard therapy o chronic heart ailure with reduced EF should include several drugs, the cornerstones o which are an ACE inhibitor and a β-blocker. An accepted sequence o therapy is to start with an ACE inhibitor as well as a diuretic i pulmonary or systemic congestive symptoms are present. I the patient is unable to tolerate the ACE inhibitor, then an ARB (or hydralazine plus isosorbide dinitrate) may be substituted. For patients without recent clinical deterioration or volume overload, a β-blocker should be added. Those with persistent symptomatic heart ailure may benef t rom the addition o an aldosterone antagonist. For re ractory symptoms, digoxin can be prescribed or its hemodynamic benef t.
Additional Therapies Arrhythmia Management Atrial and ventricular arrhythmias requently accompany chronic heart ailure. For example, atrial f brillation is very common in this setting and conversion back to sinus rhythm (see Chapter 11) can substantially improve cardiac output. Ventricular arrhythmias are also requent in heart ailure and may lead to sudden death. The antiarrhythmic drug that is most e ective at suppressing arrhythmias and least likely to provoke other dangerous rhythm disorders in heart ailure patients is amiodarone. However, studies o amiodarone
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or the treatment o asymptomatic ventricular arrhythmias in heart ailure have not shown a consistent survival benef t. In addition, heart ailure patients with symptomatic or sustained ventricular arrhythmias, or those with inducible ventricular tachycardia during electrophysiologic testing, benef t more rom the insertion o an impla n ta ble ca rdioverter– def brilla tor (ICD; see Chapter 11). Based on the results o large-scale randomized trials, ICD implantation is indicated or many patients with heart ailure and at least moderately reduced systolic unction (e.g., LVEF ≤ 35% ), regardless o the presence o ventricular arrhythmias, because this approach reduces the likelihood o sudden cardiac death in this population.
Cardiac Resynchronization Therapy Intraventricular conduction abnormalities with widened QRS complexes (especially le t bundle branch block) are common in patients with advanced heart ailure. Such abnormalities can actually contribute to cardiac symptoms because o the resultant uncoordinated pattern o right and le t ventricular contraction. Advanced pacemakers have been developed that stimulate both ventricles simultaneously, thus resynchronizing the contractile e ort. This technique o biventricular pacing, also termed cardiac resynchronization therapy (CRT), has been shown to augment le t ventricular systolic unction, improve exercise capacity, and reduce the requency o heart ailure exacerbations and mortality. Thus, CRT is appropriate or selected patients with advanced systolic dys unction (LV EF ≤ 35% ), a prolonged QRS duration (> 120 ms) and continued symptoms o heart ailure despite appropriate pharmacologic therapies. Since patients who receive CRT are typically also candidates or an ICD, modern devices combine both unctions in a single, small implantable unit.
Cardiac Mechanical Circulatory Support and Replacement Therapy A patient with severe LV dys unction whose condition remains re ractory to maximal medical management may be a candidate or cardiac transplantation. However, only approximately 4,000 transplants are per ormed worldwide each year because o a shortage o donor hearts, many ewer than the number o patients with re ractory heart ailure symptoms. For certain patients who are too ill to wait or a heart donor, or who are not eligible or a transplant, alternative mechanical therapies are in selected use. Ventricular assist devices (VADs) and implantable total artif cial hearts can be used to support cardiac pump unction in such patients. Recent technological advances in continuous- ow le t-sided VADs have resulted in 1-year survival rates greater than 70% , compared to less than 25% survival rates in similar groups o advanced heart ailure patients treated with medical therapy alone.
TREATMENT OF HEART FAILURE WITH PRESERVED EJECTION FRACTION The goals o therapy in heart ailure with preserved EF include (1) the relie o pulmonary and systemic congestion and (2) addressing correctable causes o the impaired diastolic unction (e.g., hypertension, coronary artery disease). Diuretics reduce pulmonary congestion and peripheral edema but must be used cautiously to avoid under f lling o the le t ventricle. A sti ened le t ventricle relies on higher-than-normal pressures to achieve adequate diastolic f lling (see Fig. 9-7B), and excessive diuresis could reduce f lling and there ore impair stroke volume and cardiac output (see Fig. 9-10, point b′). Unlike patients with impaired systolic unction, β-blockers, ACE inhibitors, and ARBs have no demonstrated mortality benef t in patients with heart ailure with preserved EF. The aldosterone antagonist spironolactone was recently shown to reduce the requency o hospitalizations or heart ailure in this population, but did not improve the survival rate. Since contractile unction is preserved, inotropic drugs have no therapeutic role in this syndrome.
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ACUTE HEART FAILURE
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In contrast to the f ndings o chronic heart ailure described to this point, patients with acute heart ailure are those who present with urgent and o ten li e-threatening symptomatology. Acute heart ailure may develop in a previously asymptomatic patient (e.g., resulting rom an acute coronary syndrome [Chapter 7], severe hypertension [Chapter 13], or acute valvular regurgitation [Chapter 8]), or it may complicate chronic compensated heart ailure ollowing a precipitating trigger (see Table 9-3). Management o acute heart ailure typically requires hospitalization and prompt interventions. The classif cation o patients with acute heart ailure, and the approach to therapy, can be tailored based on the presence or absence o two major f ndings at the bedside: (1) volume overload (i.e., “wet” vs. “dry”) as a re ection o elevated LV f lling pressures and (2) signs o decreased cardiac output with reduced tissue per usion (“cold” vs. “warm” extremities). Examples o a “wet” prof le, indicative o volume overload, include pulmonary rales, jugular venous distension, and edema o the lower extremities. Figure 9-11 shows how patients with acute heart ailure can be divided into our prof les based on observations o these parameters. Prof le A indicates normal hemodynamics. Cardiopulmonary symptoms in such patients would be due to actors other than heart ailure, such as parenchymal lung disease or transient myocardial ischemia. Prof les B and C are typical o patients with acute pulmonary edema (described below). Those with Prof le B have “wet” lungs but preserved (“warm”) tissue per usion. Prof le C is more serious; in addition to congestive f ndings, impaired orward cardiac output results in marked systemic vasoconstriction (e.g., activation o the sympathetic nervous system) and there ore “cold” extremities. Patients with Prof le C have a prognosis worse than those with Prof le B, who in turn have poorer outcomes than those with Prof le A. Patients with Prof le L do not represent an extension o this continuum. Rather, they display “cold” extremities due to low output (hence the label “L”) but no signs o vascular congestion. This prof le may arise in patients who are actually volume deplete, or those with very limited cardiac reserve in the absence o volume overload (e.g., a patient with a dilated le t ventricle and mitral regurgitation who becomes short o breath with activity because o the inability to generate adequate orward cardiac output). These prof les o acute heart ailure should not be con used with the classif cation o chronic heart ailure (Stages A through D) presented in Table 9-6. The goals o therapy in acute heart ailure are to (1) normalize ventricular f lling pressures and (2) restore adequate tissue per usion. Identif cation o the patient’s prof le type guides therapeutic interventions. For example, a patient with Prof le B would require diuretic LV filling Pre s s ure s (Pulmona ry a nd/or Sys te mic Conge s tion) and/ or vasodilator therapy or pulmonary edema (described in the next section), No Ye s and those with Prof le C may additionally require intravenous inotropic medications Profile A Profile B to strengthen cardiac output. Patients with No “Wa rm a nd Dry” “Wa rm a nd We t” Prof le L may require volume expansion. The presence o prof le A would prompt a search or contributions to the patient’s Profile L Profile C symptoms other than heart ailure. Ye s “Cold a nd Dry”
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Acute Pulmonary Edema A common mani estation o acute le tsided heart ailure (e.g., typical o Prof les B and C) is cardiogenic pulmonary edema, in which elevated capillary hydrostatic
FIGURE 9-11. Hemodynamic prof les in acute heart ailure. (Derived rom Nohria A, Tsang SW, Fang JC, et al. Clinical assessment identif es hemodynamic prof les that predict outcomes in patients admitted with heart ailure. J Am Coll Cardiol. 2003;41:1797–1804.)
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pressure causes rapid accumulation o uid within the interstitium and alveolar spaces o the lung. In the presence o normal plasma oncotic pressure, pulmonary edema develops when the pulmonary capillary wedge pressure, which re ects LV diastolic pressure, exceeds approximately 25 mm Hg. This condition is requently accompanied by hypoxemia because o shunting o pulmonary blood ow through regions o hypoventilated alveoli. Like other mani estations o acute heart ailure, pulmonary edema may appear suddenly in a previously asymptomatic person (e.g., in the setting o an acute myocardial in arction) or in a patient with chronic compensated congestive heart ailure ollowing a precipitating event (see Table 9-3). Pulmonary edema is a horri ying experience or the patient, resulting in severe dyspnea and anxiety while struggling to breathe. On examination, the patient is tachycardic and may demonstrate cold, clammy skin owing to peripheral vasoconstriction in response to increased sympathetic out ow (i.e., Prof le C). Tachypnea and coughing o “ rothy” sputum represent transudation o uid into the alveoli. Rales are present initially at the bases and later throughout the lung f elds, sometimes accompanied by wheezing because o edema within the conductance airways. Pulmonary edema is a li e-threatening emergency that requires immediate improvement o systemic oxygenation and elimination o the underlying cause. The patient should be seated upright to permit pooling o blood within the systemic veins o the lower body, thereby reducing venous return to the heart. Supplemental oxygen is provided by a ace mask. Morphine sul ate is administered intravenously to reduce anxiety and also acts as a venous dilator to acilitate pooling o blood peripherally. A rapidly acting diuretic, such as intravenous urosemide, is administered to urther reduce LV preload and pulmonary capillary hydrostatic pressure. Other means o reducing preload include administration o nitrates (o ten intravenously). Intravenous inotropic drugs (e.g., dopamine) may increase orward CO and are used primarily in patients with Prof le C. During resolution o the pulmonary congestion and hypoxemia, attention should be directed at identi ying and treating the underlying precipitating cause. An easy-to-remember mnemonic or the principal components o management o pulmonary edema is the alphabetic sequence LMNOP: Lasix (trade name or urosemide) Morphine Nitrates Oxygen Position (sit upright)
SUMMARY • Ventricular stroke volume (SV) is a unction o preload, a terload, and contractility; SV rises when there is an increase in preload, a decrease in a terload, or augmented contractility. • Cardiac output = heart rate × stroke volume. • Ventricular EDV (or EDP) represents preload and is in uenced by the chamber’s compliance. • Ventricular ESV depends on the a terload and contractility but not on the preload. • Heart ailure is a clinical syndrome in which cardiac output (CO) ails to meet the metabolic demands o the body or meets those demands only i cardiac f lling pressures are abnormally high. • Chronic heart ailure may be classif ed into two categories: (1) heart ailure with reduced EF owing to impaired le t ventricular systolic unction and (2) heart ailure with preserved EF (e.g., diastolic dys unction). • Compensatory mechanisms in heart ailure that initially maintain circulatory unction include (1) preload augmentation with increased stroke volume via the Frank–Starling
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mechanism, (2) activation o neurohormonal systems, and (3) ventricular hypertrophy; however, these compensations eventually become maladaptive, contributing to adverse ventricular remodeling and progressive deterioration o ventricular unction. Symptoms o heart ailure may be exacerbated by precipitating actors that increase metabolic demand (e.g., tachycardia), increase circulating volume, augment a terload, or decrease contractility. Treatment o heart ailure includes addressing the underlying cause o the condition, eliminating precipitating actors, and modulating detrimental neurohormonal activations. Standard therapy o symptomatic heart ailure with reduced EF includes an ACE inhibitor, β-blocker, and sometimes an aldosterone antagonist; or patients who do not tolerate an ACE inhibitor, an AII receptor blocker or the combination o hydralazine plus nitrates can be substituted. Diuretics should be used to treat volume overload, and inotropic drugs are typically reserved or acute “rescue” management o low CO states. For patients with heart ailure with reduced EF who meet specif c criteria, an implantable cardioverter–def brillator and/ or cardiac resynchronization therapy (biventricular pacing) may be indicated. For re ractory end-stage heart ailure, cardiac transplantation and/ or mechanical circulatory support should be considered in care ully selected patients. Therapy or heart ailure with preserved EF relies primarily on diuretics to relieve pulmonary congestion, but such therapy must be administered cautiously to avoid excess reduction o preload and hypotension. Acute heart ailure can be prof led by, and treatment decisions based on, the presence or absence o (1) elevated le t heart f lling pressures (wet vs. dry) and (2) reduced systemic tissue per usion with elevated systemic vascular resistance (i.e., cold vs. warm).
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Neal Anjan Chatterjee; Ravi V. Shah, MD; George S. M. Dyer, MD; Stephen K. Frankel, MD; Arthur Coday Jr., MD; and Vikram Janakiraman, MD.
Ad d i t i o n a l Rea d i n g Braunwald E. Heart ailure. JACC: Hea rt Fa ilure. 2013;1: 1–20. Hsich EM, Pina IL. Heart ailure in women. J Am Coll Cardiol. 2009;54:491–498. Maeder MT, Kaye DM. Heart ailure with normal le t ventricular ejection raction. J Am Coll Ca rdiol. 2009;53: 905–918. Maron BA, Leopold JA. Aldosterone receptor antagonists: e ective but o ten orgotten. Circula tion . 2010;121: 934–939. McMurray JJV. Systolic heart ailure. N Engl J Med. 2010;362: 228–238.
Stewart G, Givertz M. Mechanical circulatory support or advanced heart ailure: patients and technology in evolution. Circulation. 2012;125:1304–1315. Triposkiadis F, Karayannis G, Giamouzis G, et al. The sympathetic nervous system in heart ailure: physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54:1747–1762. Yancy C, Jessup M, Bozkurt B, et al. 2013 ACCF/ AHA guideline or the management o heart ailure: executive summary a report o the American College o Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:1810–1852.
The Cardiomyopathies P. Connor Johnson G. Willia m Dec Leona rd S. Lilly
Ch a p t e r O u t l i n e Dilated Cardiomyopathy Etiology Pathology Pathophysiology Clinical Findings Physical Examination Diagnostic Studies Treatment Hypertrophic Cardiomyopathy Etiology Pathology Pathophysiology Clinical Findings Physical Examination Diagnostic Studies Treatment Prognosis Restrictive Cardiomyopathy Pathophysiology Clinical Findings Physical Examination Diagnostic Studies Treatment Other Forms of Cardiomyopathy Le t Ventricular Noncompaction Arrhythmogenic Right Ventricular Cardiomyopathy
10
C
ardiomyopathies are a diverse set o heart muscle disorders that cause mechanical and/ or electrical dys unction o the myocardium. Excluded rom the def nition o this group o diseases is heart muscle impairment resulting rom other specif c cardiovascular disorders such as hypertension, valvular abnormalities, or congenital heart disease. Cardiomyopathies o ten result in inappropriate ventricular hypertrophy or dilatation, and progressive heart ailure and cardiovascular death are common end mani estations. These conditions can involve the heart alone or may be a component o a systemic syndrome. Cardiomyopathies can be classif ed into three main types based on the anatomic appearance and abnormal physiology o the le t ventricle (LV) (Fig. 10-1). Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement with impaired systolic contractile unction; hypertrophic cardiomyopathy (HCM), by an abnormally thickened ventricular wall with abnormal diastolic relaxation but usually intact systolic unction; and restrictive cardiomyopathy, by an abnormally sti ened myocardium (because o f brosis or an inf ltrative process) leading to impaired diastolic relaxation, but systolic contractile unction is typically normal or near normal.
DILATED CARDIOMYOPATHY Etiology Myocyte damage and cardiac enlargement in DCM result rom a wide spectrum o genetic, in ammatory, toxic, and metabolic causes (Table 10-1). Although many cases are currently classif ed as idiopathic (i.e., the cause is undetermined), examples o def ned conditions associated with DCM include viral myocarditis, chronic excessive alcohol
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Aorta LA
Dila te d LV with minima l hype rtrophy
LV
No rmal
A
B
Dilate d c ardio myo pathy
Infiltra te d or fibrotic LV
Ma rke d LV hype rtrophy
C
Hype rtro phic c ardio myo pathy
D
Re s tric tive c ardio myo pathy
FIGURE 10-1. Anatomic appearance o the cardiomyopathies ( CMPs) . A. Normal heart demonstrating le t ventricle (LV) and le t atrium (LA). B. Dilated CMP is characterized by ventricular enlargement with only mildly increased thickness. C. Hypertrophic CMP demonstrates marked ventricular hypertrophy, either asymmetrically, or symmetrically (as drawn here). D. Restrictive CMP is caused by inf ltration or f brosis o the ventricles, usually without chamber enlargement. LA enlargement is common to all three types o CMP.
TABLE 10-1
Examples o Dilated Cardiomyopathies
Idiopathic Familial ( genetic) Inf ammatory In ectious (especially viral) Nonin ectious Connective tissue diseases Peripartum cardiomyopathy Sarcoidosis Toxic Chronic alcohol ingestion Chemotherapeutic agents (e.g., doxorubicin, trastuzumab) Metabolic Hypothyroidism Chronic hypocalcemia or hypophosphatemia Neuromuscular Muscular or myotonic dystrophy
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ingestion, the peripartum state, specif c gene mutations, and exposure to potentially cardiotoxic antineoplastic agents, such as doxorubicin. Acute viral myocarditis generally a icts young, previously healthy people. Common responsible in ecting organisms include coxsackievirus group B, parvovirus B19, and adenovirus, among many others. Viral myocarditis is usually a sel -limited illness with ull recovery, but or unknown reasons, some patients progress to DCM. It is hypothesized that myocardial destruction and f brosis result rom immune-mediated injury triggered by viral constituents. Nonetheless, immunosuppressive drugs have not been shown to improve the prognosis o this condition. Transvenous ventricular biopsy during acute myocarditis may demonstrate active in ammation, but specif c viral genomic sequences have been demonstrated in only a minority o patients. DCM develops in a small number o people who consume alcoholic beverages excessively and chronically. Although the pathogenesis o the condition is unknown, ethanol is thought to impair cellular unction by impacting mitochondrial oxidative unction, myof lament protein synthesis, cytosolic calcium levels, and myocyte apoptosis. While its clinical presentation and histologic eatures are similar to those o other dilated cardiomyopathies, alcoholic cardiomyopathy is important to identi y because it is potentially reversible; cessation o ethanol consumption can lead to dramatic recovery o ventricular unction. Peripartum cardiomyopathy is a orm o DCM that presents with heart ailure symptoms between the last month o pregnancy and up to 6 months postpartum. Risk actors include older maternal age, being A rican American, and having multiple pregnancies. A uni ying etiology o this condition has not yet been identif ed. Ventricular unction returns to normal in approximately 50% o a ected women in the months ollowing pregnancy, but recurrences o DCM with subsequent pregnancies have been reported. Other potentially reversible causes o DCM include toxic drug exposures, metabolic abnormalities (such as hypothyroidism), and certain in ammatory etiologies, including sarcoidosis and connective tissue diseases. Several amilial orms o DCM have been identif ed and are believed to be responsible or 20% to 30% o what were once classif ed as idiopathic DCM. Autosomal dominant, autosomal recessive, X-linked, and mitochondrial patterns o inheritance have been described, leading to de ects in contractile orce generation, orce transmission, energy production, and myocyte viability. Identif ed mutations occur in genes that code or cardiac cytoskeletal, myof brillar, and nuclear membrane proteins (Table 10-2).
TABLE 10-2
Familial Forms o Dilated and Hypertrophic Cardiomyopathies
Protein Cytoskeletal proteins Desmin Dystrophin Myosin-binding protein C Sarcoglycans Titin Myof brillar proteins β-Myosin heavy chain Cardiac troponin T Cardiac troponin I Cardiac troponin C α-Tropomyosin Essential myosin light chain Cardiac actin Nuclear membrane protein Lamin A/ C
Mutations Identif ed in DCM √ √ √ √ √ √ √ √ √ √ √ √
Mutations Identif ed in HCM
√ √ √ √ √ √ √ √ √
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Pathology Marked enlargement o all our cardiac chambers is typical o DCM (Fig. 10-2), although sometimes the disease is limited to the le t or right side o the heart. The thickness o the ventricular walls may be increased, but chamber dilatation is out o proportion to any concentric hypertrophy. Microscopically, there is evidence o myocyte degeneration with irregular hypertrophy and atrophy o myof bers. Interstitial and perivascular f brosis is o ten extensive.
Pathophysiology
FIGURE 10-2. Transverse sections of a normal heart ( right) and a heart from a patient with dilated cardiomyopathy ( DCM) . In the DCM specimen, there is biventricular dilatation without a proportional increase in wall thickness. LV, le t ventricle; RV, right ventricle. (Modif ed rom Emmanouilides GC, ed. Moss and Adams’ Heart Disease in Infants, Children, and Adolescents. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 1995:86.)
The hallmark o DCM is ventricular dilatation with decreased contractile unction (Fig. 10-3). Most o ten in DCM, both ventricles are impaired, but sometimes dys unction is limited to the LV and even less commonly to the right ventricle (RV). As ventricular stroke volume and cardiac output decline because o impaired myocyte contractility, two compensatory e ects are activated: (1) the Frank–Starling mechanism, in which the elevated ventricular diastolic volume increases the stretch o the myof bers, thereby increasing the subsequent stroke volume; and (2) neurohormonal activation, initially mediated by the sympathetic nervous system (see Chapter 9). The latter contributes to an increased heart rate and contractility, which help to bu er the all in cardiac output. These compensations may render the patient asymptomatic during the early stages o ventricular dys unction; however, as progressive myocyte degeneration and volume overload ensue, clinical symptoms o heart ailure develop.
Myo c yte injury ↓ Co ntrac tility ↓ S tro ke vo lume
↑ Ve ntric ular filling pre s s ure s
LV dilatatio n
↓ Fo rward c ardiac o utput • Fa tigue • We a kne s s
Pulmo nary c o ng e s tio n
Sys te mic c o ng e s tio n
• Dys pne a • Orthopne a • Ra le s
• J VD • He pa tome ga ly • Ede ma
Mitral re g urg itatio n
FIGURE 10-3. Pathophysiology of dilated cardiomyopathy. The reduced ventricular stroke volume results in decreased orward cardiac output and increased ventricular f lling pressures. The listed clinical mani estations ollow. JVD, jugular venous distention.
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With a persistent reduction o cardiac output, the decline in renal blood ow prompts the kidneys to increase secretion o renin. This activation o the renin–angiotensin–aldosterone axis increases peripheral vascular resistance (mediated through angiotensin II) and intravascular volume (because o increased aldosterone). As described in Chapter 9, these e ects are also initially help ul in bu ering the all in cardiac output. Ultimately, however, the “compensatory” e ects o neurohormonal activation prove detrimental. Arteriolar vasoconstriction and increased systemic resistance render it more di f cult or the LV to eject blood in the orward direction, and the rise in intravascular volume urther burdens the ventricles, resulting in pulmonary and systemic congestion. In addition, chronically elevated levels o angiotensin II and aldosterone directly contribute to pathologic myocardial remodeling and f brosis. As the cardiomyopathic process causes the ventricles to enlarge over time, the mitral and tricuspid valves may ail to coapt properly in systole, and valvular regurgitation ensues. This regurgitation has three detrimental consequences: (1) excessive volume and pressure loads are placed on the atria, causing them to dilate, o ten leading to atrial f brillation; (2) regurgitation o blood into the le t atrium urther decreases orward stroke volume into the aorta and systemic circulation; and (3) when the regurgitant volume returns to the LV during each diastole, an even greater volume load is presented to the dilated LV.
Clinical Findings The clinical mani estations o DCM are those o congestive heart ailure. The most common symptoms o low orward cardiac output include atigue, light-headedness, and exertional dyspnea associated with decreased tissue per usion. Pulmonary congestion results in dyspnea, orthopnea, and paroxysmal nocturnal dyspnea, whereas chronic systemic venous congestion causes ascites and peripheral edema. Because these symptoms may develop insidiously, the patient may complain only o recent weight gain (because o interstitial edema) and shortness o breath on exertion.
Physical Examination Signs o decreased cardiac output are o ten present and include cool extremities (owing to peripheral vasoconstriction) and low arterial pressure. Pulmonary venous congestion results in auscultatory rales (crackles), and basilar chest dullness to percussion may be present because o pleural e usions. Cardiac examination shows an enlarged heart with le tward displacement o the apical impulse. On auscultation, a third heart sound (S3) is common as a sign o poor systolic unction. The murmur o mitral valve regurgitation is o ten present as a result o the signif cant le t ventricular dilatation (see Chapter 8). I right ventricular heart ailure has developed, signs o systemic venous congestion may include jugular vein distention, hepatomegaly, ascites, and peripheral edema. Right ventricular enlargement and contractile dys unction are o ten accompanied by the murmur o tricuspid valve regurgitation.
Diagnostic Studies The chest radiograph shows an enlarged cardiac silhouette. I heart ailure has developed, then pulmonary vascular redistribution, interstitial and alveolar edema, and pleural e usions are evident (see Fig. 3-5). The electrocardiogram (ECG) usually demonstrates atrial and ventricular enlargement. Patchy f brosis o the myof bers results in a variety o arrhythmias, most importantly atrial f brillation and ventricular tachycardia. Conduction de ects (le t or right bundle branch block) are common. In addition, regions o dense myocardial f brosis may produce localized Q waves, resembling the pattern o previous transmural myocardial in arction.
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Chapter 10 Echocardiography in DCM typically demonstrates enlargement o the a ected ventricle(s) with little concentric hypertrophy, and global reduction o systolic ventricular unction. Mitral and/ or tricuspid regurgitation is requently detected due to ventricular dilatation. Cardiac catheterization or CT angiography is o ten per ormed to determine whether coexistent coronary artery disease is contributing to the impaired ventricular unction. This is most use ul diagnostically in patients who have symptoms o angina or evidence o prior myocardial in arction on the ECG. Typically, hemodynamic measurements show elevated right- and le t-sided diastolic pressures and diminished cardiac output. A transvenous biopsy o the RV is sometimes per ormed in the catheterization laboratory, in an attempt to clari y the etiology o the cardiomyopathy. Cardiac magnetic resonance imaging (MRI) (described in Chapter 3) is o ten help ul in the evaluation o DCM, particularly to assess or contributory myocardial in ammation (myocarditis).
Treatment The goal o therapy in DCM is to promote reverse remodeling o dilated ventricles, enhance myocardial unction, relieve symptoms, prevent complications, and improve long-term survival. Thus, in addition to treating any identif ed underlying cause o DCM, therapeutic considerations include those described in the ollowing sections.
Medical Treatment of Heart Failure Symptoms Approaches or the relie o vascular congestion and improvement in orward cardiac output are the same as standard therapies or heart ailure (see Chapter 9). Initial therapy typically includes salt restriction and diuretics i volume overload is present, vasodilator therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), and a β-blocker in hemodynamically stable patients. For patients with persistent symptoms, the addition o an aldosterone antagonist should be considered. These measures have been shown to improve symptoms and reduce mortality in patients with DCM.
Prevention and Treatment of Arrhythmias Atrial and ventricular arrhythmias are common in advanced DCM, and approximately 40% o deaths in this condition result rom ventricular tachycardia or f brillation. It is important to maintain serum electrolytes (notably, potassium and magnesium) within their normal ranges, especially during diuretic therapy, to avoid provoking serious arrhythmias. Studies have shown that available antiarrhythmic drugs do not prevent death rom ventricular arrhythmias in DCM. In act, when used in patients with poor LV unction, many antiarrhythmic drugs may worsen the rhythm disturbance. Amiodarone is the antiarrhythmic drug studied most extensively in patients with DCM. Whereas there is no convincing evidence that it reduces mortality rom ventricular arrhythmias in DCM, it is the sa est antiarrhythmic or treating atrial f brillation and other supraventricular arrhythmias in this population. In contrast to antiarrhythmic drugs, the placement o an implantable cardioverter–def brillator (ICD) does reduce arrhythmic deaths in patients with DCM. There ore, based on large-scale randomized trials, an ICD is recommended or patients with chronic symptomatic DCM and at least moderately reduced systolic unction (e.g., LV ejection raction ≤ 35% ), regardless o whether ventricular arrhythmias have been detected. Many patients with DCM have electrical conduction abnormalities that contribute to dyssynchronous ventricular contraction and there ore reduced cardiac output. Electronic pacemakers capable o stimulating both ventricles simultaneously have been devised to better coordinate systolic contraction as an adjunct to medical therapy (termed cardiac resynchronization
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therapy, as described in Chapter 9). Demonstrated benef ts o this approach include improved quality o li e and exercise tolerance, ewer hospitalizations or heart ailure, and reduced mortality, particularly in those with pretreatment le t bundle branch block or other conduction abnormalities with a markedly prolonged QRS duration.
Prevention of Thromboembolic Events Patients with DCM are at increased risk o thromboembolic complications or reasons that include (1) blood stasis in the ventricles resulting rom poor systolic unction, (2) stasis in the atria due to chamber enlargement or atrial f brillation, and (3) systemic venous stasis because o poor circulatory ow. Peripheral venous or right ventricular thrombi may lead to pulmonary emboli, whereas thromboemboli o le t ventricular origin may lodge in a systemic artery, resulting in, or example, cerebral, myocardial, or renal in arctions. In DCM with heart ailure, systemic anticoagulation should be considered or patients with a history o venous or systemic thromboembolism, atrial f brillation, or those with le t ventricular thrombi identif ed by cardiac imaging, especially those that are mobile or protrude into the LV cavity (and are there ore more likely to embolize).
Cardiac Transplantation In suitable highly symptomatic patients, cardiac transplantation o ers a substantially better 5-year prognosis than do standard therapies or DCM described above. The 5- and 10-year survival rates a ter transplantation are 74% and 55% , respectively. However, the scarcity o donor hearts greatly limits the availability o this technique. As a result, other mechanical options have been explored and continue to undergo experimental ref nements, including ventricular assist devices and completely implanted artif cial hearts.
HYPERTROPHIC CARDIOMYOPATHY With an incidence o about 1 o 500 in the general population, HCM is characterized by le t ventricular hypertrophy that is not caused by chronic pressure overload (i.e., not the result o hypertension or aortic stenosis [AS]). Other terms used to describe this disease are “hypertrophic obstructive cardiomyopathy” and “idiopathic hypertrophic subaortic stenosis.” In this condition, systolic LV contractile unction is vigorous but the thickened muscle is sti , resulting in impaired ventricular relaxation and high diastolic pressures. HCM has received notoriety in the lay press because it is the most common cardiac abnormality ound in young athletes in the United States who die suddenly during vigorous physical exertion.
Etiology HCM is a amilial disease in which inheritance ollows an autosomal dominant pattern with variable penetrance, and hundreds o mutations in several di erent genes have been implicated. The proteins encoded by the responsible genes are all part o the sarcomere complex and include β-myosin heavy chain (β-MHC), cardiac troponins, and myosin-binding protein C (see Table 10-2). The incorporation o these mutated peptides into the sarcomere is thought to cause impaired contractile unction. The resultant increase in myocyte stress is then hypothesized to lead to compensatory hypertrophy and proli eration o f broblasts. The pathophysiology and natural history o amilial HCM are variable and appear related to particular mutations within the disease-causing gene, rather than the actual gene involved. In act, it has been shown that the precise genetic mutation determines the age o onset o hypertrophy, the extent and pattern o cardiac remodeling, and the person’s risk o developing symptomatic heart ailure or sudden death. For example, mutations in the β-MHC gene that alter electrical charge in the encoded protein are associated with worse prognoses than other mutations.
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Pathology Although hypertrophy in HCM may involve any portion o the ventricles, a symmetric hypertrophy o the ventricular septum (Fig. 10-4) is most commonly ound (approximately 90% o cases). Less o ten, the hypertrophy involves the ventricular walls symmetrically or is localized to the apex or mid-region o the LV. Unlike ventricular hypertrophy resulting rom hypertension in which the myocytes enlarge uni ormly and remain orderly, the histology o HCM is unusual. The myocardial f bers are in a pattern o extensive disarray (Fig. 10-5). Short, wide, hypertrophied f bers are oriented in chaotic directions and are surrounded by numerous cardiac f broblasts and extracellular matrix. This myocyte disarray and f brosis are characteristic o HCM and play a role in the abnormal diastolic sti ness and the arrhythmias common to this disorder.
IVS
Pathophysiology FIGURE 10-4. Postmortem heart specimen from a patient with hypertrophic cardiomyopathy. Marked le t ventricular hypertrophy is present, especially o the interventricular septum (IVS).
The predominant eature o HCM is marked ventricular hypertrophy that reduces the compliance and diastolic relaxation properties o the chamber, such that f lling becomes impaired (Fig. 10-6). Patients who have asymmetric hypertrophy o the proximal interventricular septum may display additional f ndings related to transient obstruction o le t ventricular out ow during systole. It is use ul to consider the pathophysiology o HCM based on whether such systolic out ow tract obstruction is present.
A
B
C
FIGURE 10-5. Light microscopy of hypertrophic myocardium. A. Normal myocardium. B. Hypertrophied myocytes in a patient with valvular heart disease. C. Myocyte disarray with f brosis in a patient with hypertrophic cardiomyopathy.
The Cardiomyopathies Myo c yte hype rtro phy
Myofibe rs in dis a rray
Ve ntricula r a rrhythmia s
Dynamic LV o utflow o bs truc tio n
LVH
Impa ire d re la xa tion (dia s tolic dys function)
257
↑ Sys tolic pre s s ure
Mitra l re gurgita tion
Fa ilure to ↑ CO with exe rtion
↑ MVO 2
↑ LVEDP
S udde n de ath
Sync o pe
Dys pne a
Ang ina
FIGURE 10-6. Pathophysiology o hypertrophic cardiomyopathy. The disarrayed and hypertrophied myocytes may lead to ventricular arrhythmias (which can cause syncope or sudden death) and impaired diastolic le t ventricular (LV) relaxation (which causes elevated LV lling pressures and dyspnea). I dynamic LV outf ow obstruction is present, mitral regurgitation o ten accompanies it (which contributes to dyspnea), and the impaired ability to raise cardiac output with exertion can lead to exertional syncope. The thickened LV wall, and increased systolic pressure associated with outf ow tract obstruction, each contribute to increased myocardial oxygen consumption (MVO2) and can precipitate angina. CO, cardiac output; LVEDP, LV end-diastolic pressure; LVH, LV hypertrophy.
HCM without Outf ow Tract Obstruction Although systolic contraction o the LV is usually vigorous in HCM, hypertrophy o the walls results in increased sti ness and impaired relaxation o the chamber. The reduced ventricular compliance alters the normal pressure–volume relationship, causing the passive diastolic f lling curve to shi t upward (see Fig. 9-7B). The associated rise in diastolic LV pressure is transmitted backward, leading to elevated le t atrial, pulmonary venous, and pulmonary capillary pressures. Dyspnea, especially during exertion, is thus a common symptom in this disorder.
HCM with Outf ow Obstruction Approximately one third o patients with HCM mani est systolic out ow tract obstruction. The mechanism o systolic obstruction involves abnormal motion o the anterior mitral valve lea et toward the LV out ow tract where the thickened septum protrudes (Fig. 10-7). The process is explained as ollows: (1) during ventricular contraction, ejection o blood toward the aortic valve is more rapid than usual, because it must ow through an out ow tract that is narrowed by the thickened septum; (2) this rapid ow creates Venturi orces that abnormally draw the anterior mitral lea et toward the septum during contraction; and (3) the anterior mitral lea et approaches and abuts the hypertrophied septum, causing transient obstruction o blood ow into the aorta. In patients with out ow obstruction, elevated le t atrial and pulmonary capillary wedge pressures result rom both the decreased ventricular compliance and the out ow obstruction during contraction. During systolic obstruction, a pressure gradient develops between the main body o the LV and the out ow tract distal to the obstruction (see Fig. 10-7).
258
Chapter 10
Aorta
LA
MR
AML
S e ptum
LV
Early s ys to le
Mid-to -late s ys to le
FIGURE 10-7. Pathophysiology o le t ventricular ( LV) outf ow obstruction and mitral regurgitation ( MR) in hypertrophic cardiomyopathy. Le t panel. The LV outf ow tract is abnormally narrowed between the hypertrophied interventricular septum and the anterior leaf et o the mitral valve (AML). It is thought that the rapid ejection velocity through the narrowed tract in early systole draws the AML toward the septum (short red arrow). Right panel. As the mitral valve anterior leaf et abnormally moves toward, and contacts, the septum, outf ow into the aorta is transiently obstructed. Because the mitral leaf ets do not coapt normally in systole, MR also results (long red arrow).
The elevated ventricular systolic pressure increases wall stress and myocardial oxygen consumption, which can result in angina (see Fig. 10-6). In addition, because obstruction is caused by abnormal motion o the anterior mitral lea et toward the septum (and there ore away rom the posterior mitral lea et), the mitral valve does not close properly during systole, and mitral regurgitation may result. Such regurgitation urther elevates le t atrial and pulmonary venous pressures and may worsen symptoms o dyspnea, as well as contribute to the development o atrial f brillation. The systolic pressure gradient observed in obstructive HCM is dynamic in that its magnitude varies during contraction and depends, at any given time, on the distance between the anterior lea et o the mitral valve and the hypertrophied septum. Situations that decrease LV cavity size (e.g., reduced venous return owing to intravascular volume depletion) bring the mitral lea et and septum into closer proximity and promote obstruction. Conversely, conditions that enlarge the LV (e.g., augmented intravascular volume) increase the distance between the anterior mitral lea et and septum and reduce the obstruction. Positive inotropic drugs (which augment the orce o contraction; see Chapter 17) also orce the mitral lea et and septum into closer proximity and contribute to obstruction, whereas negative inotropic drugs (e.g., β-blockers, verapamil) have the opposite e ect. Although dynamic systolic out ow tract obstruction creates an impressive murmur and receives great attention, the symptoms o obstructive HCM appear to primarily stem rom the increased LV sti ness and diastolic dys unction that are also present in the nonobstructive orm.
Clinical Findings The symptoms o HCM vary widely in a ected individuals, rom none to marked physical limitations (see Fig. 10-6). The average age o presentation is the mid-20s. The most requent symptom is dyspnea owing to elevated diastolic LV (and there ore pulmonary capillary) pressure. This symptom is urther exacerbated by the high systolic LV pressure and mitral regurgitation ound in patients with out ow tract obstruction.
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Angina is o ten described by patients with HCM, even in the absence o obstructive coronary artery disease. Myocardial ischemia may be contributed to by (1) the high oxygen demand o the increased muscle mass and (2) the narrowed small branches o the coronary arteries within the hypertrophied ventricular wall. I out ow tract obstruction is present, the high systolic ventricular pressure increases myocardial oxygen demand because o the increased wall stress and contributes to ischemia. Syncope in HCM may result rom cardiac arrhythmias that arise because o the structurally abnormal myof bers. In patients with out ow tract obstruction, syncope may also be induced by exertion, when the pressure gradient is made worse by the increased orce o contraction, thereby causing a transient all in cardiac output. Orthostatic light-headedness is also common in patients with out ow tract obstruction. This occurs because venous return to the heart is reduced on standing by the gravitational pooling o blood in the lower extremities. The LV thus decreases in size and out ow tract obstruction intensif es, transiently reducing cardiac output and cerebral per usion. When arrhythmias occur, symptoms o HCM may be exacerbated. For example, atrial f brillation is not well tolerated because the loss o the normal atrial “kick” urther impairs diastolic f lling and can there ore worsen symptoms o pulmonary congestion. O greatest concern, the f rst clinical mani estation o HCM may be ventricular f brillation, resulting in sudden cardiac death, particularly in young adults with HCM during strenuous physical exertion. Risk actors or sudden death among patients with HCM include a history o syncope, a amily history o sudden death, certain high-risk HCM mutations, and extreme hypertrophy o the LV wall (> 30 mm in thickness).
Physical Examination A patient with a mild orm o HCM may have a normal cardiac examination. Otherwise, a common f nding is a ourth heart sound (S4), generated by le t atrial contraction into the sti ened LV (see Chapter 2). The orce ul atrial contraction may also result in a palpable presystolic impulse over the cardiac apex (a “double apical impulse”). Other f ndings are typical in patients with systolic out ow obstruction. The carotid pulse rises briskly in early systole but then quickly declines as obstruction to cardiac outow appears. The characteristic systolic murmur o LV out ow obstruction is rough and crescendo–decrescendo in shape, heard best at the le t lower sternal border (in proximity to the turbulent ow through the narrowed out ow tract), and unlike AS, does not typically radiate to the carotid arteries. In addition, as the stethoscope is moved toward the apex, the holosystolic blowing murmur o accompanying mitral regurgitation may be auscultated. Although the LV out ow obstruction murmur may be so t at rest, bedside maneuvers that alter preload and a terload can dramatically increase its intensity and help di erentiate this murmur rom other conditions, such as AS (Table 10-3). A commonly used technique in this regard is the Valsalva maneuver, produced by asking the patient to “bear down” (technically def ned as orce ul exhalation with the nose, mouth, and glottis closed). The Valsalva maneuver increases intrathoracic pressure, which decreases venous return to the heart and transiently reduces LV size. This action brings the
TABLE 10-3 HCM murmur AS murmur
Effect of Maneuvers on Murmurs of AS and HCM Valsalva
Squatting
Standing
↑ ↓
↓ ↑
↑ ↓
HCM, hypertrophic cardiomyopathy; AS, aortic stenosis.
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Chapter 10 hypertrophied septum and anterior lea et o the mitral valve into closer proximity, creating greater obstruction to orward ow. Thus, during Valsalva, the murmur o HCM increases in intensity. In contrast, the murmur o AS decreases in intensity during Valsalva because o the reduced ow across the stenotic valve. Conversely, a change rom standing to a squatting position suddenly augments venous return to the heart (which increases preload) while simultaneously increasing the systemic vascular resistance. The increased preload raises the stroke volume and there ore causes the murmur o AS to become louder. In contrast, the transient increase in LV size during squatting reduces the LV out ow tract obstruction in HCM and so tens the intensity o that murmur. Sudden standing rom a squatting position has the opposite e ect on each o these murmurs (see Table 10-3).
Diagnostic Studies The ECG typically shows le t ventricular hypertrophy and le t atrial enlargement. Prominent Q waves are common in the in erior and lateral leads, representing amplif ed orces o initial depolarization o the hypertrophied septum directed away rom those leads. In some patients, di use T wave inversions are present, which can predate clinical, echocardiographic, or other electrocardiographic mani estations o HCM. Atrial and ventricular arrhythmias are requent, especially atrial f brillation. Ventricular arrhythmias are particularly ominous because they may herald ventricular f brillation and sudden death, even in previously asymptomatic patients. Echocardiography is very help ul in the evaluation o HCM. The degree o LV hypertrophy can be measured and regions o asymmetrical wall thickness readily identif ed. Signs o le t ventricular out ow obstruction may also be demonstrated and include abnormal anterior motion o the mitral valve as it is drawn toward the hypertrophied septum during systole, and partial closure o the aortic valve in midsystole as ow across it is transiently obstructed. Doppler recordings during echocardiography accurately measure the out ow pressure gradient and quanti y any associated mitral regurgitation. Children and adolescents with apparently mild HCM should undergo serial echocardiographic assessment over time, because the degree o hypertrophy may increase during puberty and early adulthood. Ca rdia c ca theteriza tion is reserved or patients or whom the diagnosis is uncertain or i percutaneous septal ablation (described in the “Treatment” section) is planned. The major eature in patients with obstruction is the f nding o a pressure gradient within the out ow portion o the LV, either at rest or during maneuvers that transiently reduce LV size and promote out ow tract obstruction. Myocardial biopsy at the time o catheterization is not necessary because histologic f ndings do not predict disease severity or long-term prognosis. Finally, genetic testing can be help ul in establishing, or excluding, the diagnosis o HCM in amily members o an a ected patient when a specif c mutation in that amily has been identif ed.
Treatment β-Blockers are standard therapy or HCM because they (1) reduce myocardial oxygen demand by slowing the heart rate and the orce o contraction (and there ore diminish angina and dyspnea); (2) lessen any LV out ow gradient during exercise by reducing the orce o contraction (allowing the chamber size to increase, thus separating the anterior lea et o the mitral valve rom the ventricular septum); (3) increase passive diastolic ventricular f lling time owing to the decreased heart rate; and (4) decrease the requency o ventricular ectopic beats. Despite their antiarrhythmic e ect, β-blockers do not prevent sudden arrhythmic death in this condition, nor have they been shown to slow disease progression.
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Certain calcium cha n n el a n ta gon ists (e.g., verapamil) may have benef cial e ects on ventricular relaxation and f lling and are sometimes use ul in improving exercise capacity in patients who ail to respond to β-blockers. Patients who develop pulmonary congestion may benef t rom mild diuretic therapy, but these drugs must be administered cautiously to avoid volume depletion; reduced intravascular volume decreases LV size and could exacerbate outow tract obstruction. Vasodilators (including nitrates) similarly reduce LV size and should be avoided. Atrial f brillation is poorly tolerated in HCM and should be controlled aggressively, most commonly with antiarrhythmic drugs. E ective and use ul antiarrhythmic drugs or atrial f brillation in HCM include amiodarone and disopyramide (a class IA antiarrhythmic drug that also possesses negative inotropic properties that may help reduce LV out ow tract obstruction; see Chapter 17). Digitalis should be avoided in HCM because its positive inotropic e ect increases the orce o contraction and can worsen LV out ow tract obstruction. Sudden cardiac death has a propensity to occur in patients with HCM in association with physical exertion; there ore, strenuous exercise and competitive sports should be avoided. Sudden death in this syndrome is almost always caused by ventricular tachycardia or f brillation. Although amiodarone may reduce the requency o ventricular arrhythmias, HCM patients who are at high risk (i.e., a amily history o sudden death, extreme hypertrophy with ventricular wall thickness > 30 mm, unexplained prior syncopal episodes, history o high-grade ventricular tachyarrythmias) should receive an ICD. ICD therapy is li e saving or both primary prevention in such patients, and or HCM patients who have already survived a cardiac arrest. Some studies have shown clinical improvement when patients with the obstructive orm o HCM are treated with a dual-chamber permanent pacemaker, the two electrodes o which are placed in the right atrium and RV. The LV out ow gradient may become reduced by this procedure, possibly by altering the normal sequence o ventricular contraction, such that septal–mitral valve apposition becomes less prominent. However, this technique seems to be use ul or only a small percentage o markedly symptomatic patients. Surgical therapy (myomectomy) is considered or patients whose symptoms do not respond adequately to pharmacologic therapy. This procedure involves excision o portions o the hypertrophied septal muscle mass and usually improves out ow tract obstruction, symptoms, and exercise capacity. Myomectomy is the “gold standard” approach to treatment o re ractory symptoms in this condition. A less invasive alternative in select patients is percutaneous septal ablation, per ormed in the cardiac catheterization laboratory, in which ethanol is injected directly into the f rst major septal coronary artery (a branch o the le t anterior descending artery), causing a small, controlled myocardial in arction. The desired and o ten achieved result is reduction o septal thickness and improvement in out ow tract obstruction. Theoretically, in ective endocarditis could develop in patients with the obstructive orm o HCM because o turbulent blood ow through the LV out ow tract and the associated mitral regurgitation. However, that is rare and routine antibiotic prophylaxis or prevention o endocarditis prior to invasive dental work is not recommended in this condition by current U.S. guidelines (see Chapter 8). Finally, genetic counseling should be provided to all patients with HCM. Because it is an autosomal dominant disease, children o a ected persons have a 50% chance o inheriting the abnormal gene. First-degree relatives o patients with HCM should be screened by physical examination, electrocardiography, echocardiography, and sometimes genetic testing. Even asymptomatic HCM patients are at risk o complications, including sudden death.
Prognosis The incidence o sudden death in HCM is 2% to 4% per year in adults and 4% to 6% in children and adolescents. It has become clear that di erent mutations produce vastly
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Chapter 10 di erent phenotypes. Some cause extreme hypertrophy in childhood without any clinical symptoms until the occurrence o sudden death; others present later in li e with heart ailure symptoms. Most mutations produce only mild hypertrophy and are associated with a normal li e expectancy.
RESTRICTIVE CARDIOMYOPATHY The restrictive cardiomyopathies are less common than DCM and HCM. They are characterized by abnormally rigid (but not necessarily thickened) ventricles with impaired diastolic f lling but usually normal, or near normal, systolic unction. This condition results rom either (1) f brosis or scarring o the endomyocardium or (2) inf ltration o the myocardium by an abnormal substance (Table 10-4). The most common recognized cause o restrictive cardiomyopathy in nontropical countries is amyloidosis. In this systemic disease, insoluble mis olded amyloid f brils deposit within tissues, including the heart, causing organ dys unction. Amyloid deposition is diagnosed histologically by the Congo red stain, which displays amyloid f brils with a characteristic green bire ringence under polarized light. Amyloid f brils can develop rom several di erent proteins that distinguish the categories o disease. Primary amyloidosis is caused by deposition o immunoglobulin light chain AL ragments secreted by a plasma cell tumor (usually, multiple myeloma). In contrast, secondary amyloidosis is characterized by the presence o AA amyloid (derived rom the in ammatory marker serum amyloid A) in a variety o chronic in ammatory conditions, such as rheumatoid arthritis. Less common is hereditary amyloidosis, an autosomal dominant condition in which amyloid f brils orm rom point mutations in the protein transthyretin. Senile amyloidosis re ers to a condition in the elderly, in which amyloid deposits, derived rom transthyretin or other proteins, are ound scattered throughout the vascular system, muscles, kidney, and lung. In each orm o amyloidosis, cardiac involvement is marked by deposition o extracellular amyloid between myocardial f bers in the atria and ventricles, in the coronary arteries and veins, and in the heart valves. Clinical mani estations o cardiac involvement are most common in the primary (AL) orm o amyloidosis and typically relate to the development o restrictive cardiomyopathy because o the inf ltrating amyloid protein. Diastolic dys unction is the prominent cardiac abnormality; systolic dys unction may also develop later in the disease. Orthostatic hypotension is
TABLE 10-4
Examples o Restrictive Cardiomyopathy
Noninf ltrative Idiopathic Scleroderma Inf ltrative Amyloidosis Sarcoidosis Storage diseases Hemochromatosis Glycogen storage diseases Endomyocardial disease Endomyocardial f brosis Hypereosinophilic syndrome Metastatic tumors Radiation therapy
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present in about 10% o patients, likely contributed to by amyloid deposition in the autonomic nervous system and peripheral blood vessels. Inf ltration o amyloid into the cardiac conduction system can cause arrhythmias and conduction impairments, which can result in syncope or sudden death.
Pathophysiology Reduced compliance o the ventricles in restrictive cardiomyopathy, whether due to inf ltration or f brosis, results in an upward shi t o the passive ventricular f lling curve (see Fig. 9-7B), leading to abnormally high diastolic pressures. This has two major consequences: (1) elevated systemic and pulmonary venous pressures, with signs o right- and le t-sided vascular congestion, and (2) reduced ventricular cavity size with decreased f lling, stroke volume, and cardiac output.
Clinical Findings It ollows rom the underlying pathophysiology that signs o le t- and right-sided heart ailure are expected (Fig. 10-8). Decreased cardiac output is mani ested by atigue and decreased exercise tolerance. Systemic congestion (o ten more prominent than pulmonary congestion in this syndrome) leads to jugular venous distention, peripheral edema, and ascites with a large, tender liver. Arrhythmias, including atrial f brillation, are common. Inf ltrative etiologies that involve the cardiac conduction system can cause conduction blocks (described in Chapter 12).
Physical Examination Signs o congestive heart ailure are o ten present, including pulmonary rales, distended neck veins, ascites, and peripheral edema. Similar to constrictive pericarditis (see Chapter 14), jugular venous distention may paradoxically worsen with inspiration (the Kussmaul sign) because the sti ened RV cannot accommodate the increased venous return.
Diagnostic Studies The chest radiograph usually shows a normal-sized heart with signs o pulmonary congestion. The ECG o ten displays nonspecif c ST and T wave abnormalities; conduction disturbances such as atrioventricular block or a bundle branch block may be present.
↑ Dia s tolic ve ntricula r pre s s ure
Ve nous conge s tion
↓ Ve ntricula r filling
↓ CO
• Jugula r ve in dis te ntion • He pa tome ga ly a nd a s cite s • Pe riphe ra l e de ma
Rig id myo c ardium • We a kne s s • Fa tigue
FIGURE 10-8. Pathophysiology of restrictive cardiomyopathy. The rigid myocardium results in elevated ventricular diastolic pressures and decreased ventricular f lling. The resultant symptoms can be predicted rom these abnormalities. CO, cardiac output.
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Chapter 10 The restrictive cardiomyopathies share nearly identical symptoms, physical signs, and hemodynamic prof les with constrictive pericarditis, as described in Chapter 14. However, it is important to distinguish these two entities because constrictive pericarditis is o ten correctable, whereas interventions or the restrictive cardiomyopathies are more limited. The most use ul diagnostic tools to di erentiate restrictive cardiomyopathy rom constrictive pericarditis are transvenous endomyocardial biopsy, computed tomography (CT), and MRI. For example, in restrictive cardiomyopathies, transvenous endomyocardial biopsy may demonstrate the cause o the condition (e.g., the presence o amyloid f brils in amyloidosis, or iron deposits in patients with hemochromatosis [a condition o iron overload]). CT or MRI scans accurately identi y the thickened pericardium present in most patients with constrictive pericarditis, a f nding that is not present in states causing restrictive cardiomyopathy.
Treatment Restrictive cardiomyopathy typically has a very poor prognosis, except when treatment can target an underlying cause. For example, phlebotomy and iron chelation therapy may be helpul in the early stages o hemochromatosis. Symptomatic therapy or all etiologies includes salt restriction and cautious use o diuretics to improve symptoms o systemic and pulmonary congestion. Unlike the dilated cardiomyopathies, vasodilators are not help ul because systolic unction is usually preserved. Maintenance o sinus rhythm (e.g., converting atrial f brillation i it occurs) is important to maximize diastolic f lling and orward cardiac output. Some restrictive cardiomyopathies are prone to intraventricular thrombus ormation, thus warranting chronic oral anticoagulant therapy. In the case o primary (AL) amyloidosis, chemotherapy ollowed by autologous bone marrow stem cell transplantation has proved e ective in selected patients with early cardiac involvement.
OTHER FORMS OF CARDIOMYOPATHY Not all orms o cardiac muscle disease f t into the traditional categories o cardiomyopathy described in this chapter. Examples o exceptions include (1) le t ventricular noncompaction (LVNC), and (2) arrhythmogenic right ventricular cardiomyopathy (ARVC).
Left Ventricular Noncompaction LVNC is a rare condition with eatures that overlap with hypertrophic, restrictive and dilated cardiomyopathies. It is mani est by a thickened myocardium with very prominent trabeculae and deep recesses that extend rom the LV cavity into the intertrabecular spaces. The abnormal regions o myocardium typically contract poorly, o ten demonstrate characteristics o impaired diastolic relaxation, and predispose to rhythm disturbances and thrombus ormation. Patients with this condition may present in childhood or adulthood with symptoms o heart ailure (due to systolic and/ or diastolic dys unction), ventricular arrhythmias, or thromboembolism. LVNC appears to result rom arrested development o the myocardium during etal development, though the exact mechanism has not been ully elucidated. Up to 50% o patients with this condition have a ected amily members, and autosomal dominant, autosomal recessive and X-linked patterns o inheritance have been ound. Mutations in at least nine genes encoding sarcomere proteins have been identif ed in patients with LVNC (including mutations that have also been associated with hypertrophic and dilated cardiomyopathies), resulting in either the isolated disorder or a syndrome with other orms o congenital heart disease.
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The diagnosis is usu ally established by typical eatures on 2-dim ensional and color Doppler ech ocardiography or by cardiac MRI. Th e progn osis is variable, bu t is worse amon g sym ptom atic patien ts com pared to th ose ou n d to h ave th e disorder in ciden tally by im agin g stu dies. On e series in dicated th at 60% o patien ts h ad died or requ ired cardiac transplantation w ithin 6 years o diagn osis, but oth er studies have reported less dire ou tcom es. Management is aimed at treating the symptoms and complications o LVNC as there is no corrective therapy or the underlying condition itsel . Depending on the clinical maniestations, approaches may include standard treatment o heart ailure (Chapter 9), ICD implantation or management o li e-threatening ventricular arrhythmias, chronic anticoagulation or those with accompanying atrial f brillation or signif cant contractile dys unction to prevent thromboembolism, and cardiac transplantation or those with advanced, re ractory heart ailure.
Arrhythmogenic Right Ventricular Cardiomyopathy ARVC, also termed arrhythmogenic right ventricular dysplasia, is another genetic orm o cardiomyopathy. It is characterized by replacement o right ventricular (and occasionally le t ventricular) myocardium with adipose and f brous tissue, resulting in rhythm disturbances and contractile dys unction. Ventricular arrhythmias originating rom the abnormal ventricle are common and may result in palpitations, syncope, and even sudden cardiac death. Symptoms o ten begin in the teen years, and ARVC is another cause o sudden death among young athletes. Both autosomal dominant and recessive inheritance orms o ARVC have been identif ed. The majority o mutations occur in genes that encode components o desmosomes, cell membrane structures responsible or cell-to-cell adhesion, leading to f brosis and aberrant signaling with proli eration o adipose tissue in the myocardium. Transvenous endomyocardial biopsy o the RV may demonstrate atty or f bro atty replacement o the myocardium, but has a high alse negative rate or identi ying the disorder. Thus, diagnostic criteria also rely on amily history, ECG abnormalities (see Chapter 12, Box 12-1), the presence o arrhythmias emanating rom the RV, morphologic abnormalities detected by imaging studies (especially cardiac MRI), and genetic testing or specif c mutations. Management o ARVC typically includes ICD implantation because the disease is progressive and li e-threatening ventricular tachycardia is common.
SUMMARY • Cardiomyopathies are a group o heart muscle disorders that cause mechanical and/ or electrical dys unction o the myocardium, and o ten result in inappropriate ventricular hypertrophy or dilatation (Table 10-5); heart ailure and cardiovascular death are common end mani estations. • DCM is characterized by progressive ventricular chamber enlargement with impaired systolic contractile unction, o ten leading to symptomatic heart ailure, ventricular arrhythmias, and/ or embolic complications. • HCM is characterized by an abnormally thickened ventricular wall with abnormal diastolic relaxation but usually intact systolic unction; dynamic LV out ow tract obstruction during systole may be present, and the most common symptoms are dyspnea and exertional angina. • Ventricular arrhythmias in HCM may lead to sudden cardiac death. • Restrictive cardiomyopathies are uncommon and are characterized by an abnormally sti ened myocardium (because o f brosis or an inf ltrative process) leading to impaired diastolic relaxation, but systolic contractile unction is typically normal or near normal; symptoms o heart ailure are typical.
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Chapter 10
TABLE 10-5
Summary of the Cardiomyopathies
Ventricular morphology
Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy
Restrictive Cardiomyopathy
Dilated LV with little concentric hypertrophy
Marked hypertrophy, o ten asymmetric
Fibrotic or in ltrated myocardium
Amyloidosis, hemochromatosis, scleroderma, radiation therapy Dyspnea, atigue
LA
LV
Etiologies
Genetic, in ectious, alcoholic, peripartum
Genetic
Symptoms
Fatigue, weakness, dyspnea, orthopnea, PND Pulmonary rales, S3; i RV ailure present: JVD, hepatomegaly, peripheral edema
Dyspnea, angina, syncope
Physical exam
Pathophysiology
Impaired systolic contraction
Cardiac size on chest radiograph Echocardiogram
Enlarged Dilated, poorly contractile LV
S4; i outf ow obstruction present: systolic murmur loudest at le t sternal border, accompanied by mitral regurgitation Impaired diastolic relaxation; LV systolic unction vigorous, o ten with dynamic obstruction Normal or enlarged
Predominantly signs o RV ailure: JVD, hepatomegaly, peripheral edema
LV hypertrophy, o ten more pronounced at septum; systolic anterior movement o MV with mitral regurgitation
Usually normal systolic contraction; “speckled” appearance in in ltrative disorders
“Sti ” LV with impaired diastolic relaxation but usually normal systolic unction Usually normal
LV, le t ventricle; PND, paroxysmal nocturnal dyspnea; RV, right ventricle; JVD, jugular venous distension; MV, mitral valve.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Christopher T. Lee, MD; Marc N. Wein, MD; Yi-Bin Chen, MD; David Grayzel, MD; and Kay Fang, MD.
Ad d i t i o n a l Rea d i n g Arbustini E, Narula J, Tavazzi J, et al. The MOGE(S) classif cation o cardiomyopathy or clinicians. J Am Coll Cardiol. 2014;64:304–318. Bhatia NL, Tajik AJ, Wilansky S, et al. Isolated noncompaction o the le t ventricular myocardium in adults: A systematic overview. J Card Fail. 2011;17:771–778. Elkayam U. Clinical characteristics o peripartum cardiomyopathy in the United States: Diagnosis, prognosis, and management. J Am Coll Cardiol. 2011;58:659–670.
Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/ AHA guideline or the diagnosis and treatment o hypertrophic cardiomyopathy: Executive summary. J Am Coll Cardiol. 2011;58:2703–2738. Guan J, Mishra S, Falk RH, et al. Current perspectives on cardiac amyloidosis. Am J Physiol Heart Circ Physiol. 2012;302:H544–H552. Maron BJ, Ommen SR, Semsarian C, et al. Hypertrophic cardiomyopathy: Present and uture, with translation into contemporary cardiovascular medicine. J Am Coll Cardiol. 2014;64:83–99.
The Cardiomyopathies Maron BJ, Towbin JA, Thiene G, et al. Contemporary def nitions and classif cation o the cardiomyopathies: An American Heart Association scientif c statement rom the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality o Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups;
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and Council on Epidemiology and Prevention. Circulation. 2006;113:1807–1816. Murray B. Arrhythmogenic right ventricular dysplasia/ cardiomyopathy (ARVD/ C): A review o molecular and clinical literature. J Genet Couns. 2012;21:494–504. Sturm AC. Genetic testing in the contemporary diagnosis o cardiomyopathy. Curr Heart Fail Rep. 2013;10:63–72.
Mechanisms of Cardiac Arrhythmias
11
Morga n J. Prust Willia m G. Stevenson Ga ry R. Stricha rtz Leona rd S. Lilly
Ch a p t e r O u t l i n e Normal Impulse Formation Ionic Basis o Automaticity Native and Latent Pacemakers Overdrive Suppression Electrotonic Interactions Altered Impulse Formation Alterations in Sinus Node Automaticity Escape Rhythms Enhanced Automaticity o Latent Pacemakers Abnormal Automaticity Triggered Activity Altered impulse conduction Conduction Block Unidirectional Block and Reentry Physiologic Basis of Antiarrhythmic Therapy Bradyarrhythmias Tachyarrhythmias
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N
ormal cardiac unction relies on the ow o electric impulses through the heart in an exquisitely coordinated ashion. Abnormalities o the electric rhythm are known as arrhythmias (also termed dysrhythmias) and are among the most common clinical problems encountered. The presentations o arrhythmias range rom common benign palpitations to severe symptoms o low cardiac output and death. There ore, a thorough understanding o these disorders is important to the daily practice o medicine. Abnormally slow heart rhythms are termed bradycardias (or bradyarrhythmias). Fast rhythms are known as tachycardias (or tachyarrhythmias). Tachycardias are urther characterized as supraventricular when they involve the atrium or atrioventricular (AV) node and designated ventricular when they originate rom the His–Purkinje system or ventricles. This chapter extends the description o basic cardiac electrophysiology presented in Chapter 1 and explains the mechanisms by which arrhythmias develop, ollowed by a general approach to their management. Chapter 12 describes specif c rhythm disorders, including how to recognize and treat them. Disorders o heart rhythm result rom alterations o impulse formation, impulse conduction, or both. The chapter f rst addresses how abnormalities o impulse ormation and conduction occur and under what circumstances they cause arrhythmias. Figure 11-1 provides an organizational schema or this presentation. While studying the concepts in this chapter, it is important to recall that cardiac tissue is composed o cells that are electrically coupled and operate as a syncytium. As myocytes depolarize and ionic currents result in individual action potentials,
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the electrical activity rapidly propagates from one cell to the next with minimal resistance, spreading through a large mass of tissue. As a result, the leading edge of a depolarization may be located several centimeters ahead of its trailing edge, and this property plays an important role in the genesis of certain arrhythmias, as will be described.
NORMAL IMPULSE FORMATION As described in Chapter 1, electric impulse ormation in the heart arises rom the intrinsic automaticity o specialized cardiac cells. Automaticity re ers to a cell’s ability to spontaneously depolarize to a threshold voltage to generate an action potential. Although atrial and ventricular myocytes do not have this property under normal conditions, the cells o the specialized conducting system do possess natural automaticity and are there ore termed pacemaker cells. The specialized conducting system includes the sinoatrial (SA) node, the AV nodal region, and the ventricular conducting system. The latter is composed o the bundle o His, the bundle branches, and the Purkinje bers. In pathologic situations, myocardial cells outside the conducting system may also acquire automaticity.
Ionic Basis of Automaticity Cells with natural automaticity do not have a static resting voltage. Rather, they inherently display gradual depolarization during phase 4 o the action potential (Fig. 11-2). I this spontaneous diastolic depolarization reaches the threshold condition, an action potential upstroke is generated. An important ionic current largely responsible or phase 4 spontaneous depolarization is known as the pacemaker current (If). The channels that carry this current are activated by hyperpolarization (increasingly negative voltages) and mainly conduct sodium ions. I channels begin to open when the membrane voltage becomes more negative than approximately − 50 mV and are different entities than the ast sodium channels responsible or rapid phase 0 depolarization in ventricular and atrial myocytes. The inward f ow o Na + through these slow channels, driven by its concentration gradient and the negative intracellular potential, depolarizes the membrane toward threshold.
Tac hyarrhythmias (incre a s e d firing ra te ) Automa ticity of SA node
Automa ticity of la te nt pa ce ma ke rs
Abnorma l a utoma ticity
Trigge re d a ctivity
Unidire ctiona l block a nd re e ntry
Enha nce d a utoma ticity
Alte re d impuls e fo rmatio n
Alte re d impuls e c o nduc tio n
Automa ticity of SA node
Conduction block
Bradyarrhythmias (de cre a s e d firing ra te )
FIGURE 11-1. Arrhythmias result from alterations in impulse formation and/ or impulse conduction. Tachyarrhythmias result from enhanced automaticity, unidirectional block with reentry, or triggered activity. Bradyarrhythmias result from decreased automaticity or conduction block. SA, sinoatrial.
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Chapter 11
If influx
FIGURE 11-2. The action potential ( AP) of a pacemaker cell ( e.g., the sinus node) . The slow phase 4 depolarization is largely caused by the I (pacemaker) inward current, which drives the cell to threshold (approximately − 40 mV). The upstroke o the AP is caused by the slow inward current o Ca+ + ions. Reduction o the Ca+ + current (due to inactivation o calcium channels) and progressive K+ e f ux through voltage-gated potassium channels are responsible or repolarization. MDP, maximum negative diastolic potential; TP, threshold potential.
In the pacemaker cells o the SA node, three other ionic currents also contribute to phase 4 gradual depolarization: (1) a slowly increasing inward calcium current, carried mostly by L-type Ca + + channels that become activated at voltages reached near the end o phase 4; (2) a progressively declining outward potassium current; and (3) an additional inward sodium current mediated by activation o the electrogenic sodium–calcium exchanger by calcium release rom the sarcoplasmic reticulum. When the membrane potential o a pacemaker cell reaches the threshold condition, the upstroke o the action potential is generated. In contrast to the phase 0 upstroke o cells in the Purkinje system, that o cells in the sinus and AV nodes is much slower (see Fig. 11-2). The reason or the di erence is that the membrane potential determines the proportion o ast sodium channels that are in a resting state capable o depolarization, compared with an inactivated state. The number o available (or resting-state) ast sodium channels decreases as the resting (diastolic) membrane potential becomes less negative. Because sinus and AV nodal cells have less negative maximum diastolic membrane voltages (− 50 to − 60 mV) than do Purkinje cells (− 90 mV), the large majority o ast sodium channels is inactivated in these pacemaker cells. Thus, the action potential upstroke relies to a great extent on a smaller calcium current (through the relatively slower opening o L-type Ca + + channels) and has a less rapid rate o rise than do cells o the Purkinje system or ventricular myocardium. The repolarization phase o pacemaker cells results rom both the inactivation o the open calcium channels and the opening o voltage-gated potassium channels that permit e f ux o potassium rom the cells (see Fig. 11-2).
Native and Latent Pacemakers The distinct populations o automatic cells in the specialized conduction pathway have di erent intrinsic rates o ring. These rates are determined by three variables that inf uence how ast the membrane potential reaches the threshold condition: (1) the rate (i.e., the slope) o phase 4 spontaneous depolarization, (2) the maximum negative diastolic potential, and (3) the threshold potential. A more negative maximum diastolic potential, or a less negative threshold potential, slows the rate o impulse initiation because it takes longer to reach the threshold value (Fig. 11-3). Conversely, the greater the I , the steeper the slope o phase 4 and the aster the cell depolarizes. The size o I depends on the number and opening kinetics o the individual pacemaker channels through which this current f ows. Since all healthy myocardial cells are electrically connected by gap junctions, an action potential generated in one part o the myocardium will ultimately spread to all other regions. When an impulse arrives at a cell that is not yet close to threshold, current rom the depolarized cell will bring the adjacent cell’s membrane potential to the threshold level so that it will re (regardless o how close its intrinsic I has brought it to threshold). Thus, the pacemaker cells with the astest rate o depolarization set the heart rate. In the normal heart, the dominant
Mechanisms o Cardiac Arrhythmias a
FIGURE 11-3. Determinants o cell f ring rates. A. Alterations in the pacemaker current (I ) and in the magnitude o the maximum diastolic potential (MDP) alter the cell f ring rate. (a) The normal action potential (AP) o a pacemaker cell. (b) Reduced I renders the slope o phase 4 less steep; thus, the time required to reach threshold potential (TP) is increased. (c) The MDP is more negative; there ore, the time required to reach TP is increased. B. Alterations in TP change the f ring rate o the cell. Compared with the normal TP (a), the TP in b is less negative; thus, the duration o time to achieve threshold is increased, and the f ring rate decreases.
271
b c
A a
b
B
pacemaker is the sinoatrial node, which at rest initiates impulses at a rate o 60 to 100 bpm. Because the sinus node rate is aster than that o the other tissues that possess automaticity, its repeated discharges prevent spontaneous ring o other potential pacemaker sites. The SA node is known as the native pacemaker because it normally sets the heart rate. Other cells within the specialized conduction system harbor the potential to act as pacemakers i necessary and are there ore called latent pacemakers (or ectopic pacemakers). In contrast to the SA node, the AV node and the bundle o His have intrinsic ring rates o 50 to 60 bpm, and cells o the Purkinje system have rates o approximately 30 to 40 bpm. These latent sites may initiate impulses and take over the pacemaker unction i the SA node slows or ails to re or i conduction abnormalities block the normal wave o depolarization rom reaching them.
Overdrive Suppression Not only does the cell population with the astest intrinsic rhythm preempt all other automatic cells rom spontaneously ring but it also directly suppresses their automaticity. This phenomenon is called overdrive suppression. Cells maintain their transsarcolemmal ion distributions because o the continuously active Na + K+ -ATPase that extrudes three Na+ ions rom the cell in exchange or two K+ ions transported in (Fig. 11-4). Because its net transport e ect is one positive charge in the outward direction, Na + K+ -ATPase creates a hyperpolarizing current (i.e., it tends to make the inside o the cell more negative). As the cell potential becomes increasingly negative, additional time is required or spontaneous phase 4 depolarization to reach the threshold voltage (see Fig. 11-3A), and there ore, the rate o spontaneous ring is decreased. Although the hyperpolarizing current moves the membrane voltage away rom threshold, pacemaker cells ring at their own intrinsic rate have an I current su ciently large to overcome this hyperpolarizing inf uence (see Fig. 11-4). The hyperpolarizing current increases when a cell is caused to re more requently than its intrinsic pacemaker rate. The more o ten the cell is depolarized, the greater the quantity o Na+ ions that enter the cell per unit time. As a result o the increased intracellular Na + content, Na+ K+ -ATPase becomes more active, thereby tending to restore the normal transmembrane Na+ gradient. This
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Chapter 11 increased pump activity provides a larger hyperpolarizing current, opposing the depolarizing current I , and urther decreases the rate o spontaneous depolarization. Thus, overdrive suppression decreases a cell’s automaticity when that cell is driven to depolarize aster than its intrinsic discharge rate.
Electrotonic Interactions
FIGURE 11-4. Competition between the depolarizing pacemaker current (If) and Na+ K+ ATPase, which produces a hyperpolarizing current. Na+ K+ -ATPase transports three Na+ ions outside the cell in exchange or two K+ ions transported inward. The hyperpolarizing current acts to suppress automaticity by antagonizing I and contributes to overdrive suppression in cells that are stimulated more rapidly than their intrinsic f ring rate.
In addition to overdrive suppression, anatomic connections between pacemaker and nonpacemaker cells are important in determining how adjacent cells suppress latent pacemaker oci. Myocardial cells in the ventricle and Purkinje system repolarize to a resting potential o approximately − 90 mV, whereas pacemaker cells in the sinus and AV nodes repolarize to a maximum diastolic potential o about − 60 mV. When these two cell types are adjacent to one another, they are electrically coupled through low-resistance gap junctions concentrated in their intercalated discs. This coupling results in a compromise o electric potentials owing to electrotonic current f ow between the cells, causing relative hyperpolarization o the pacemaker cell and relative depolarization o the nonpacemaker cell (Fig. 11-5). Hyperpolarization Myo c ardial c e ll
Pac e make r c e ll
RP = –90 mV
MDP = –60 mV
Pac e make r ac tio n po te ntial
TP MDP If Time
A
Te nds to de pola rize (le s s ne ga tive volta ge )
Te nds to hype rpola rize (more ne ga tive volta ge )
TP ↓ MDP
Inte rce llula r curre nt If
B
Time
FIGURE 11-5. Electrotonic interaction between pacemaker ( e.g., AV nodal) and nonpacemaker ( myocardial) cells. A. Pacemaker cells that are not coupled to myocardial cells have a maximum diastolic potential (MDP) o approximately − 60 mV, whereas myocardial cells have a resting potential (RP) o approximately − 90 mV. B. When pacemaker cells and myocytes are neighbors, they may be connected electrically by gap junctions at their intercalated discs (e.g., at the AV node). In this situation, electric current ows between the pacemaker cell and the myocardial cell, tending to hyperpolarize the ormer and depolarize the latter, driving their membrane potentials closer to one another. The hyperpolarizing current renders the MDP more negative, causing it to take longer or spontaneous depolarization to reach the threshold value, thereby suppressing automaticity. I a disease state impairs coupling between cells, the in uence o surrounding myocytes on the pacemaker cell is reduced, allowing I to depolarize to threshold more readily and enhancing automaticity. TP, threshold potential.
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moves the diastolic potential urther rom threshold and thus slows the heart rate (as shown in Fig. 11-3A). Electrotonic e ects may be particularly important in suppressing automaticity in the AV node (via connections between atrial myocytes and AV nodal cells) and in the distal Purkinje bers (which are coupled to ventricular myocardial cells). In contrast, cells in the center o the SA node are less tightly coupled to atrial myocytes; thus, their automaticity is less subject to electrotonic interactions. Decoupling o normally suppressed cells, such as those in the AV node (e.g., by ischemic damage), may reduce the inhibitory electrotonic inf uence and enhance automaticity, producing ectopic rhythms by the latent pacemaker tissue.
ALTERED IMPULSE FORMATION Arrhythmias may arise rom altered impulse ormation at the SA node or rom other sites, including the specialized conduction pathways or regions o cardiac muscle. The main abnormalities o impulse initiation that lead to arrhythmias are (1) altered automaticity (o the sinus node or latent pacemakers within the specialized conduction pathway), (2) abnormal automaticity in atrial or ventricular myocytes, and (3) triggered activity.
Alterations in Sinus Node Automaticity The rate o impulse initiation by the sinus node, as well as by the latent pacemakers o the specialized conducting system, is regulated primarily by neurohumoral actors. C
A
B
Increased Sinus Node Automaticity The most important modulator o normal sinus node automaticity is the autonomic nervous system. Sympathetic stimulation, acting through β1-adrenergic receptors, increases the open probability o the pacemaker channels (Fig. 11-6), through which I can f ow. The increase in I leads to a steeper slope o phase 4 depolarization, causing the SA node to reach threshold and re earlier than normal and the heart rate to increase. In addition, sympathetic stimulation shi ts the action potential threshold to more negative voltages by increasing the probability that voltage-sensitive Ca + + channels are capable o opening (recall that calcium carries the current o phase 0 depolarization in pacemaker cells). There ore, phase 4 depolarization reaches the threshold potential earlier. Sympathetic activity thus increases sinus node automaticity both by increasing the rate o pacemaker depolarization via I and by causing the action potential threshold to become more negative. Examples o this normal physiologic e ect occur during physical exercise or emotional stress, when sympathetic stimulation appropriately increases the heart rate.
FIGURE 11-6. Effect of sympathetic and parasympathetic ( cholinergic) stimulation on pacemaker current channels. The channels through which the pacemaker current (I ) ows are voltage gated, opening at more negative membrane potentials. At any given voltage, there exists a probability between 0 and 1 that a specif c channel will be open. Compared with normal baseline behavior (curve A), sympathetic stimulation (curve B) or treatment with anticholinergic drugs shi ts this probability to a higher value or any given level o membrane voltage, thus increasing the number o open channels and the rate at which the cell will f re. Curve C shows that parasympathetic cholinergic stimulation (or treatment with a β-blocker, which antagonizes sympathetic stimulation) has the opposite e ect, decreasing the probability o a channel being open and there ore inhibiting depolarization.
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Decreased Sinus Node Automaticity Normal decreases in SA node automaticity are mediated by reduced sympathetic stimulation and by increased activity o the parasympathetic nervous system. Whereas activation o the sympathetic nervous system has a major role in increasing the heart rate during times o stress, the parasympathetic nervous system is the major controller o the heart rate at rest. Cholinergic (i.e., parasympathetic) stimulation via the vagus nerve acts at the SA node to reduce the probability o pacemaker channels being open (see Fig. 11-6). Thus, I and the slope o phase 4 depolarization are reduced, and the intrinsic ring rate o the cell is slowed. In addition, the probability o the Ca + + channels being open is decreased, such that the action potential threshold increases to a less negative potential. Furthermore, cholinergic stimulation increases the probability o acetylcholine-sensitive K+ channels being open at rest. Positively charged K+ ions exit through these “inward recti er” channels, which di er rom the K+ channels that are active in phase 3 repolarization (see Chapter 1), producing an outward current that drives the diastolic potential more negative. The overall e ect o reduced I , a more negative maximum diastolic potential, and a less negative threshold level is a slowing o the intrinsic ring rate and there ore a reduced heart rate. It ollows that the use o pharmacologic agents that modi y these e ects o the autonomic nervous system will also a ect the ring rate o the SA node. For example, β-receptor blocking drugs (“β-blockers”) antagonize the β-adrenergic sympathetic e ect; there ore, they decrease the rate o phase 4 depolarization o the SA node and slow the heart rate. Conversely, atropine, an anticholinergic (antimuscarinic) drug, has the opposite e ect: by blocking parasympathetic activity, the rate o phase 4 depolarization increases and the heart rate accelerates.
Escape Rhythms I the sinus node becomes suppressed and res much less requently than normal, the site o impulse ormation may shi t to a latent pacemaker within the specialized conduction pathway. An impulse initiated by a latent pacemaker because the SA node rate has slowed is called an escape beat. Persistent impairment o the SA node will allow a continued series o escape beats, termed an escape rhythm. Escape rhythms are protective in that they prevent the heart rate rom becoming pathologically slow when SA node ring is impaired. As discussed in the previous section, suppression o sinus node activity may occur because o increased parasympathetic tone. Di erent regions o the heart have varied sensitivities to parasympathetic (vagal) stimulation. The SA node and the AV node are most sensitive to such an inf uence, ollowed by atrial tissue. The ventricular conducting system is the least sensitive. There ore, moderate parasympathetic stimulation slows the sinus rate and allows the pacemaker to shi t to the AV node. However, very strong parasympathetic stimulation suppresses excitability at both the SA node and AV node and may there ore result in the emergence o a ventricular escape pacemaker.
Enhanced Automaticity of Latent Pacemakers Another means by which a latent pacemaker can assume control o impulse ormation is i it develops an intrinsic rate o depolarization faster than that o the sinus node. Termed an ectopic beat, such an impulse is premature relative to the normal rhythm, whereas an escape beat is late and terminates a pause caused by a slowed sinus rhythm. A sequence o similar ectopic beats is called an ectopic rhythm. Ectopic beats may arise in several circumstances. For example, high catecholamine concentrations can enhance the automaticity o latent pacemakers, and i the resulting rate o depolarization exceeds that o the sinus node, then an ectopic rhythm will develop. Ectopic
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beats are also commonly induced by hypoxemia, ischemia, electrolyte disturbances, and certain drug toxicities (such as digitalis, as described in Chapter 17).
Abnormal Automaticity Cardiac tissue injury may lead to pathologic changes in impulse ormation whereby myocardial cells outside the specialized conduction system acquire automaticity and spontaneously depolarize. Although such activity may appear similar to impulses originating rom latent pacemakers within the specialized conduction pathways, these ectopic beats arise rom cells that do not usually possess automaticity. I the rate o depolarization o such cells exceeds that o the sinus node, they transiently take over the pacemaker unction and become the source o an abnormal ectopic rhythm. Because these myocardial cells have ew or no activated pacemaker channels, they do not normally carry I . How injury allows such cells to spontaneously depolarize has not been ully elucidated. However, when cardiac tissue becomes injured, its cellular membranes become “leaky.” As such, they are unable to maintain the concentration gradients o ions, and the resting potential becomes less negative (i.e., the cell partially depolarizes). When a cell’s membrane potential is reduced to a value less negative than − 60 mV, gradual phase 4 depolarization can be demonstrated even among nonpacemaker cells. This spontaneous depolarization probably results rom a very slowly inactivating calcium current, a decrease in the outward potassium current that normally acts to repolarize the cell, and less e ect o the inward rectif er K+ current that normally holds cells at a more negative potential range.
Triggered Activity Under certain conditions, an action potential can “trigger” abnormal depolarizations that result in extra heart beats or tachyarrhythmias. This process may occur when the f rst action potential leads to oscillations o the membrane voltage known as afterdepolarizations. Unlike the spontaneous activity seen when enhanced automaticity occurs, this type o automaticity is stimulated by a preceding action potential. As illustrated in Figures 11-7 and 11-8, there are two types o a terdepolarizations depending on their timing a ter the inciting action potential: early a terdepolarizations occur during the repolarization phase o the inciting beat, whereas delayed a terdepolarizations occur shortly a ter repolarization has been completed. In either case, abnormal action potentials are triggered i the a terdepolarization reaches a threshold voltage. Early afterdepolarizations are changes o the membrane potential in the positive direction that interrupt normal repolarization (see Fig. 11-7). They can occur either during the plateau o the action potential (phase 2) or during rapid repolarization (phase 3). Early a terdepolarizations are more likely to develop in conditions that prolong the action potential duration (and there ore the electrocardiographic QT interval), as may occur during therapy with certain drugs (see Chapter 17) and in the inherited long QT syndromes (see Chapter 12).
FIGURE 11-7. Triggered activity. An early afterdepolarization (arrow) occurs before the action potential (AP) has fully repolarized. Repetitive afterdepolarizations (dashed curve) may produce a rapid sequence of triggered action potentials and hence a tachyarrhythmia.
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FIGURE 11-8. Triggered activity. A delayed afterdepolarization (arrow) arises after the cell has fully repolarized. If the delayed afterdepolarization reaches the threshold voltage, a propagated action potential (AP) is triggered (dashed curve).
The ionic current responsible or an early a terdepolarization depends on the membrane voltage at which the triggered event occurs. I the early a terdepolarization occurs during phase 2 o the action potential, when most o the Na + channels are still in an inactivated state, the upstroke o the triggered beat relies mostly on an inward Ca + + current. I , however, the a terdepolarization occurs during phase 3 (when the membrane voltage is more negative), there is partial recovery o the inactivated Na + channels, which then contribute more to the current underlying the triggered beat. An early a terdepolarization-triggered action potential can be sel -perpetuating and lead to a series o depolarizations and there ore a tachyarrhythmia (see Fig. 11-7). Early a terdepolarizations appear to be the initiating mechanism o the polymorphic ventricular tachycardia known as torsades de pointes, which is described in Chapter 12. Delayed afterdepolarizations may appear shortly a ter repolarization is complete (see Fig. 11-8). They most commonly develop in states o high intracellular calcium, as may be present with digitalis intoxication (see Chapter 17), or during marked catecholamine stimulation. It is thought that intracellular Ca + + accumulation causes the activation o chloride currents, or o the Na + –Ca + + exchanger, that results in brie inward currents that generate the delayed a terdepolarization. As with early a terdepolarizations, i the amplitude o the delayed a terdepolarization reaches a threshold voltage, an action potential will be generated. Such action potentials can be sel -perpetuating and lead to tachyarrhythmias. Some idiopathic ventricular tachycardias that occur in otherwise structurally normal hearts are likely due to this mechanism, as are atrial and ventricular tachycardias associated with digitalis toxicity (see Chapter 17).
ALTERED IMPULSE CONDUCTION Alterations in impulse conduction also lead to arrhythmias. Conduction blocks generally slow the heart rate (bradyarrhythmias); however, under certain circumstances, the process o reentry (described later) can ensue and produce abnormal ast rhythms (tachyarrhythmias).
Conduction Block A propagating impulse is blocked when it encounters a region o the heart that is electrically unexcitable. Conduction block can be either transient or permanent and may be unidirectional (i.e., conduction proceeds when the involved region is stimulated rom one direction but not when stimulated rom the opposite direction) or bidirectional (conduction is blocked in both directions). Various conditions may cause conduction block, including ischemia, brosis, inf ammation, and certain drugs. When conduction block occurs because a propagating impulse encounters cardiac cells that are still re ractory rom a previous depolarization, the block is said to be functional. A propagating impulse that arrives a short time later, when the tissue is no longer re ractory, may be conducted appropriately. For example, antiarrhythmic
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drugs that prolong the action potential duration (described in Chapter 17) tend to produce unctional conduction blocks. Conversely, when conduction block is caused by a barrier imposed by brosis or scarring that replaces myocytes, the block is said to be f xed. Conduction block within the specialized conducting system o the AV node or the His– Purkinje system prevents normal propagation o the cardiac impulse rom the sinus node to more distal sites. This atrioventricular block (AV block) removes the normal overdrive suppression that keeps latent pacemakers in the His–Purkinje system in check. Thus, conduction block usually results in emergence o escape beats or escape rhythms, as the more distal sites assume the pacemaker unction. AV block is common and a major reason or implantation o a permanent pacemaker, as discussed in Chapter 12.
Unidirectional Block and Reentry A common mechanism by which altered impulse conduction leads to tachyarrhythmias is termed reentry. During such a rhythm, an electric impulse circulates repeatedly around a reentry path, recurrently depolarizing a region o cardiac tissue. During normal cardiac conduction, each electric impulse that originates in the SA node travels in an orderly, sequential ashion through the rest o the heart, ultimately depolarizing all the myocardial bers. The re ractory period o each cell prevents immediate reexcitation rom adjacent depolarized cells, so that the impulse stops when all o the heart muscle has been excited. However, conduction blocks that prevent rapid depolarization o parts o the myocardium can create an environment conducive to continued impulse propagation and reentry, as illustrated in Figure 11-9. The gure depicts electric activity as it f ows through a branch point anywhere within the conduction pathways. Panel A shows propagation o a normal action potential. At point x, the impulse branches into two pathways (α and β) and travels down each into the more distal conduction tissue. In the normal heart, the α and β pathways have similar conduction velocities and re ractory periods such that portions o the wave ronts that pass through them may collide in the distal conduction tissue and extinguish each other, as shown by the red line. Panel B shows what happens i conduction is blocked in one limb o the pathways. In this example, the action potential is obstructed when it encounters the β pathway rom above and there ore propagates only down the α tract into the distal tissue. As the impulse continues to spread, it encounters the distal end o the β pathway (at point y). I the tissue in the distal β tract is also unable to conduct, the impulse simply continues to propagate into the deeper tissues and reentry does not occur. However, i the impulse at point y is able to propagate retrogradely (backward) into pathway β, one o the necessary conditions or reentry is met. When an action potential can conduct in a retrograde direction in a conduction pathway, whereas it had been prevented rom doing so in the orward direction, unidirectional block is said to be present. Unidirectional block tends to occur in regions where the re ractory periods o adjacent cells are heterogeneous, such that some cells recover be ore others. In addition, unidirectional block may occur in states o cellular dys unction and in regions where brosis has altered the myocardial structure. As shown in panel C o Figure 11-9, i the impulse is able to propagate retrogradely up the β pathway, it will again arrive at point x. At that time, i the α pathway has not yet repolarized rom the previous action potential that had occurred moments earlier, that limb is re ractory to repeat stimulation and the returning impulse simply stops there. However, panel D illustrates what happens i the velocity o retrograde conduction in the diseased β path is not normal but slower than normal. In that case, su cient time may elapse or the α pathway to repolarize be ore the returning impulse reaches point x rom the β limb.
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No rmal
x
Dis ta l conduction tis s ue
A
Unidire c tio nal blo ck x
y
B Norma l re trogra de conduction ve locity
S lowe d re trogra de conduction ve locity
x
x
y
y
C
D
FIGURE 11-9. Mechanism of reentry. A. Normal conduction. When an action potential (AP) reaches a branch in the conduction pathway (point x), the impulse travels down both f bers (α and β) to excite distal conduction tissue. B. Unidirectional block. Forward passage o the impulse is blocked in the β pathway but proceeds normally down the α pathway. When the impulse reaches point y, i retrograde conduction o the β pathway is intact, the AP can enter β rom below and conduct in a retrograde ashion. C. When point x is reached again, i the α pathway has not had su f cient time to repolarize, then the impulse stops. D. However, i conduction through the retrograde pathway is su f ciently slow (jagged line), it reaches point x a ter the α pathway has recovered. In that circumstance, the impulse is able to excite the α pathway again and a reentrant loop is ormed.
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Then, the invading impulse is able to stimulate the α pathway once again, and the cycle repeats itsel . This circular stimulation can continue inde nitely, and each pass o the impulse through the loop excites cells o the distal conduction tissue, which propagates to the rest o the myocardium, at an abnormally high rate, resulting in a tachyarrhythmia. For the mechanism o reentry to occur, the propagating impulse must continuously encounter excitable tissue. Thus, the time it takes or the impulse to travel around the reentrant loop must be greater than the time required or recovery (the re ractory period) o the tissue, and this must be true or each point in the circuit. I the conduction time is shorter than the recovery time, the impulse will encounter re ractory tissue and stop. Because normal conduction velocity in ventricular muscle is approximately 50 cm/ s and the average e ective re ractory period is about 0.2 seconds, a reentry path circuit would need to be at least 10 cm long or reentry to occur in a normal ventricle. However, with slower conduction velocities, a shorter reentry circuit is possible. Most clinical cases o reentry occur within small regions o tissue because the conduction velocity within the reentrant loop is, in act, abnormally slow. In summary, the two critical conditions or reentry are (1) unidirectional block and (2) slowed conduction through the reentry path. These conditions commonly occur in regions where brosis has developed, such as in arction scars. In some cases, reentry occurs over an anatomically xed circuit or path, such as AV reentry using an accessory pathway (as discussed in the ollowing section). Reentry around distinct anatomic pathways usually appears as a monomorphic tachycardia on the electrocardiogram (ECG); that is, in the case o ventricular tachycardia, each QRS has the same appearance as the preceding and subsequent QRS complexes. This is because the reentry path is the same rom beat to beat, producing a stable, regular tachycardia. This is the most common mechanism o ventricular tachycardia associated with areas o ventricular scar, as may result rom a prior myocardial in arction. Other types o reentry do not require a stable, xed path. For example, one orm can occur in electrically heterogeneous myocardium, in which waves o reentrant excitation spiral through the tissue, continually changing direction. These so-called “spiral waves” can be initiated when a wave ront o depolarization encounters a broad region o unctional block, which could be re ractory rom a preceding wave ront, be poorly excitable tissue due to myocardial ischemia, or be under the inf uence o certain antiarrhythmic medications. Forward propagation o the wave ront is asymmetrically blocked by this region, as the remainder o the ront proceeds around the block. As the region repolarizes and becomes excitable again, parts o the wave ront then spread retrogradely through it and continue in a spiral path ollowing in the wake o the depolarization that had just passed. Unlike an anatomically xed reentrant tract, the center o the spiral wave can move through the myocardium and even split into two or more reentry waves. In the ventricles, the resulting tachycardia has a continually changing QRS appearance, producing polymorphic ventricular tachycardia. I such activation is rapid and very disorganized, no distinct QRS complexes will be discernable and the rhythm is ventricular f brillation (as described in Chapter 12).
Accessory Pathways and the Wolff–Parkinson–White Syndrome The mechanism o reentry is dramatically illustrated by the Wolff–Parkinson–White (WPW) syndrome. In the normal heart, an impulse generated by the SA node propagates through atrial tissue to the AV node, where expected slower conduction causes a short delay be ore continuing on to the ventricles. However, approximately 1 in 1,500 people has the WPW syndrome and is born with an additional connection between an atrium and ventricle. Termed an accessory pathway (or bypass tract), this connection allows conduction between the atria and ventricles to bypass the AV node. The most common type o accessory pathway consists
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No rm a l ECG QRS
SA node P
Bypa s s tra ct
T
ECG with byp a s s tra c t Wide ne d QRS Right bundle bra nch
De lta wave Le ft bundle bra nch
S horte ne d P R
FIGURE 11-10. Accessory pathway ( also termed a bypass tract) . Example of an atrioventricular bypass tract (bundle of Kent), shown schematically, which can conduct impulses from the atrium directly to the ventricles, bypassing the AV node. The ECG demonstrates a shortened PR interval and a “delta wave” caused by early excitation of the ventricles via the accessory pathway. ECG, electrocardiogram; SA, sinoatrial.
o microscopic f bers (known as a bundle of Kent) that span the AV groove somewhere along the mitral or tricuspid annuli, as shown in Figure 11-10. Because accessory pathway tissue conducts impulses aster than the AV node, stimulation o the ventricles during sinus rhythm begins earlier than normal and the PR interval o the ECG is there ore shortened (usually < 0.12 seconds, or < 3 small boxes). In this situation, the ventricles are said to be “preexcited.” However, the accessory pathway connects to ventricular myocardium rather than to the Purkinje system, such that the subsequent spread o the impulse through the ventricles rom that site is slower than usual. In addition, because normal conduction over the AV node proceeds concurrently, ventricular depolarization represents a combination o the electric impulse traveling via the accessory tract and that conducted through the normal Purkinje system. As a result, the QRS complex in patients with WPW is wider than normal and demonstrates an abnormally slurred initial upstroke, known as a delta wave (Fig. 11-10). During sinus rhythm, simultaneous conduction through the accessory pathway and AV node results in this interesting ECG appearance but causes no symptoms. The presence o the abnormal pathway, however, creates an ideal condition or reentry because the re ractory period o the pathway is usually di erent rom that o the AV node. An appropriately timed abnormal impulse (e.g., a premature beat) may encounter block in the accessory pathway but conduct through the AV node or vice versa. I the propagating impulse then f nds that the initially blocked pathway has recovered (unidirectional block), it can conduct in a retrograde direction up to the atrium and then down the other pathway back to the ventricles. Thus, a large anatomic loop is established, with the accessory pathway serving as one limb and the normal conduction pathway through the AV node as the other. The clinical characteristics o the WPW syndrome, including the types o reentrant tachycardia associated with it, are described in Chapter 12. The mechanisms o altered impulse ormation and conduction orm the basis o all common arrhythmias, both abnormally slow rhythms (bradyarrhythmias) and abnormally ast ones (tachyarrhythmias). Table 11-1 lists the underlying mechanisms and examples o their commonly associated rhythm disturbances.
Mechanisms o Cardiac Arrhythmias
TABLE 11-1
Mechanisms of Arrhythmia Development
Abnormality Bradyarrhythmias Altered impulse formation • Decreased automaticity
Altered impulse conduction • Conduction blocks Tachyarrhythmias Altered impulse formation • Enhanced automaticity Sinus node AV node Ectopic ocus • Triggered activity Early a terdepolarization Delayed a terdepolarization Altered impulse conduction • Reentry Anatomical
Functional
281
Mechanism
Examples
Decreased phase 4 depolarization (e.g., parasympathetic stimulation)
Sinus bradycardia
Ischemic, anatomic, or drug-induced impaired conduction
First-, second-, and third-degree AV blocks
Increased phase 4 depolarization (e.g., sympathetic stimulation)
Sinus tachycardia
Acquires phase 4 depolarization
AV junctional tachycardia Ectopic atrial tachycardia and some orms o VT
Prolonged action potential duration Intracellular calcium overload (e.g., digitalis toxicity)
Torsades de pointes APBs, VPBs, digitalis-induced arrhythmias, “idiopathic” VT
Unidirectional block plus slowed conduction Atrial utter, AV nodal reentrant tachycardia, VT related to ventricular scar tissue Atrial f brillation, polymorphic VT, ventricular f brillation
AV, atrioventricular; APB, atrial premature beat; VPB, ventricular premature beat; VT, ventricular tachycardia.
PHYSIOLOGIC BASIS OF ANTIARRHYTHMIC THERAPY Appropriate treatment o a rhythm disorder depends on its severity and its likely mechanism. When an arrhythmia produces severe hypotension or cardiac arrest, it must be immediately terminated to restore e ective cardiac unction. Therapy or termination may include electrical cardioversion (an electric “shock”) or tachycardias, cardiac pacing or bradycardias, or administration o medications. Additional therapy to prevent recurrences is guided by the etiology o the rhythm disturbance. Correctable actors that contribute to abnormal impulse ormation and conduction (such as ischemia or electrolyte abnormalities) should be corrected. I there is a risk o recurrent arrhythmia, medications that alter automaticity, conduction, and/ or re ractoriness may be administered, or catheter or surgical ablation o conduction pathways is undertaken to physically disrupt the region responsible or the arrhythmia. Other advanced options include implantation o a permanent pacemaker or serious bradyarrhythmias or an internal cardioverter–def brillator (ICD) to automatically terminate malignant tachyarrhythmias should they recur. The ollowing sections summarize the common therapeutic modalities, and Chapter 12 describes how they are used to address specif c rhythm disorders.
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Bradyarrhythmias Not all slow heart rhythms require specif c treatment. For those that do, pharmacologic therapy can increase the heart rate acutely, but the e ect is transient. Electronic pacemakers are used when more sustained therapy is needed.
Pharmacologic Therapy Pharmacologic therapy o bradyarrhythmias modif es the autonomic input to the heart in one o two ways: 1. Anticholinergic drugs (i.e., antimuscarinic agents such as atropine). Vagal stimulation reduces the rate o sinus node depolarization (which slows the heart rate) and decreases conduction through the AV node, through the release o acetylcholine onto muscarinic receptors. Anticholinergic drugs competitively bind to muscarinic receptors and thereby reduce the vagal e ect. This results in an increased heart rate and enhanced AV nodal conduction. 2. β1-Receptor agonists (e.g., isoproterenol). Mimicking the e ect o endogenous catecholamines, these drugs increase heart rate and speed AV nodal conduction. Atropine and isoproterenol are administered intravenously. Although these drugs are useul in managing certain slow heart rhythms emergently, it is not practical to continue them over the long term to treat persistent bradyarrhythmias.
Electronic Pacemakers Electronic pacemakers apply repeated electric stimulation to the heart to initiate depolarizations at a desired rate, thereby assuming control o the rhythm. Pacemakers may be installed on a temporary or a permanent basis. Temporary units are used to stabilize patients who are awaiting implantation o a permanent pacemaker or to treat transient bradyarrhythmias, such as those caused by reversible drug toxicities. There are two types o temporary pacemakers. External transthoracic pacemakers deliver electric pulses to the patient’s chest through large adhesive electrodes placed on the skin. The advantage o this technique is that it can be applied rapidly. Un ortunately, because the current used must be su f cient to initiate a cardiac depolarization, it stimulates thoracic nerves and skeletal muscle, which can be quite uncom ortable. There ore, this orm o pacing is usually used only on an emergency basis until another means o treating the arrhythmia can be implemented. The other option or temporary pacing is a transvenous unit. In this case, an electrodetipped catheter is inserted percutaneously into the venous system, passed into the heart, and connected to an external power source (termed a pulse generator). Electric pulses are applied directly to the heart through the electrode catheter, which is typically placed in the right ventricle or right atrium. This type o pacing is not pain ul and can be e ective or days. There is, however, a risk o in ection and/ or thrombosis associated with the catheter. Permanent pacemakers are more sophisticated than the temporary variety. Various conf gurations can sense and capture the electric activity o the atria and/ or ventricles. One or more wires (known as leads) with pacing electrodes are passed through an axillary or subclavian vein into the right ventricle or right atrium, or through the coronary sinus into a cardiac vein (to stimulate the le t ventricle). The pulse generator, similar in size to two silver dollars stacked on top o one another, is connected to the leads and then implanted under the skin, typically in the in raclavicular region. The pacemaker battery typically lasts about 10 years. Modern permanent pacemakers sense cardiac activity and pace only when needed. They incorporate complex unctions to track the patient’s normal heart rate and can stimulate beats
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automatically in response to activity. They can also record use ul data, such as whether ast rates have been sensed (that might indicate a tachyarrhythmia), the amount o pacing that has been required, and other parameters o pacemaker unction. An external radio requency programming device is used to “interrogate” the pacemaker to obtain the recorded in ormation and to adjust the pacing unctions. Although the most common indications or permanent pacemakers are bradyarrhythmias, pacemakers that incorporate a le t ventricular pacing lead are also used to improve cardiac perormance in some patients with heart ailure (cardiac resynchronization therapy—see Chapter 9).
Tachyarrhythmias The treatment o tachyarrhythmias is directed at (1) protection o the patient rom the consequences o the arrhythmia and (2) the specif c mechanism responsible or the abnormal rhythm. Pharmacologic agents and cardioversion/ def brillation are commonly used approaches, but innovative electronic devices and transvenous catheter–based techniques to intentionally damage (ablate) arrhythmia-causing tissue have revolutionized treatment o these disorders.
Pharmacologic Therapy Pharmacologic management o tachyarrhythmias is directed against the underlying mechanism (abnormal automaticity, reentrant circuits, or triggered activity). Many antiarrhythmic drugs are available, and the choice o which to use relies on the cause o the specif c arrhythmia. From consideration o the arrhythmia mechanisms presented in this chapter, the ollowing strategies emerge: Desired Drug Effects to Eliminate Rhythms Caused by Increased Automaticity: 1. Reduce the slope o phase 4 spontaneous depolarization o the automatic cells 2. Make the diastolic potential more negative (hyperpolarize) 3. Make the threshold potential less negative Desired Antiarrhythmic Effects to Interrupt Reentrant Circuits: 1. Inhibit conduction in the reentry circuit to the point that conduction ails, thus stopping the reentry impulse 2. Increase the re ractory period within the reentrant circuit so that a propagating impulse f nds tissue within the loop unexcitable and the impulse stops 3. Suppress premature beats that can initiate reentry Desired Drug Effects to Eliminate Triggered Activity: 1. Shorten the action potential duration (to prevent early a terdepolarizations) 2. Correct conditions o calcium overload (to prevent delayed a terdepolarizations) Drugs used to achieve these goals modulate the action potential through interactions with ion channels, sur ace receptors, and transport pumps. Many drugs have multiple e ects and may attack arrhythmias through more than one mechanism. The commonly used antiarrhythmic drugs and their actions are described in Chapter 17. It is important to recognize that although these drugs suppress arrhythmias, they also have the potential to aggravate or provoke certain rhythm disturbances. This undesired consequence is re erred to as proarrhythmia and is a major limitation o contemporary antiarrhythmic drug therapy. For example, antiarrhythmic agents that act therapeutically to prolong the action potential duration can, as an undesired e ect, cause early a terdepolarizations, the mechanism underlying the polymorphic ventricular tachycardia torsades de pointes (see
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Chapter 11 Chapter 12). In addition, most agents used to treat tachyarrhythmias have the potential to aggravate bradyarrhythmias, and all antiarrhythmics have potentially toxic noncardiac side e ects. These shortcomings have led to an increased reliance on nonpharmacologic treatment options, as described in the ollowing sections.
Vagotonic Maneuvers Many tachycardias involve transmission o impulses through the AV node, a structure that is sensitive to vagal modulation. Vagal tone can be transiently increased by a number o bedside maneuvers, and per orming these may slow conduction, which terminates some reentrant tachyarrhythmias. For example, carotid sinus massage is per ormed by rubbing rmly or a ew seconds over the carotid sinus, located at the bi urcation o the internal and external carotid arteries on either side o the neck. This maneuver stimulates the baroreceptor ref ex (see Chapter 13), which elicits the desired increase in vagal tone and withdrawal o sympathetic tone. This maneuver should be per ormed on only one carotid sinus at a time (to prevent inter erence with brain per usion) and is best avoided in patients with known advanced atherosclerosis involving the carotid arteries.
Electric Cardioversion and Def brillation Cardioversion and de brillation involve the application o an electric shock to terminate a tachycardia. A shock with su cient energy depolarizes the bulk o excitable myocardial tissue, interrupts reentrant circuits, establishes electric homogeneity, and allows the sinus node (the site o astest spontaneous discharge) to regain pacemaker control. Tachyarrhythmias that are caused by reentry can usually be terminated by this procedure, whereas arrhythmias due to abnormal automaticity may simply persist. External cardioversion is used to terminate supraventricular tachycardias or organized ventricular tachycardias. It is per ormed by brief y sedating the patient and then placing two large electrode paddles (or adhesive electrodes) against the chest on either side o the heart. The electric discharge is electronically synchronized to occur at the time o a QRS complex (i.e., when ventricular depolarization occurs). This prevents the possibility o discharge during the T wave, when a shock could induce reentry (leading to ventricular brillation) because regions o myocardium are in di erent phases o depolarization and recovery. External def brillation is per ormed to terminate ventricular brillation, employing the same equipment as that used or cardioversion. However, during brillation, there is no organized QRS complex on which to synchronize the electric discharge, so it is delivered using the “asynchronous” mode o the device.
Implantable Cardioverter–Def brillators ICDs automatically terminate dangerous ventricular arrhythmias using internal cardioversion/ de brillation or by way o a special type o arti cial pacing. These devices are implanted, in a manner similar to that o permanent pacemakers, in patients at high risk o sudden cardiac death rom ventricular arrhythmias. The device continuously monitors cardiac activity, and i the heart rate exceeds a certain programmable threshold or a speci ed time, the ICD delivers an appropriate intervention, such as an electric shock. Internal cardioversion or de brillation requires substantially less energy than does external de brillation but is still pain ul i the patient is conscious. The majority o monomorphic ventricular tachycardias can be terminated by an ICD with a rapid burst o electric impulses, termed antitachycardia pacing (ATP), rather than a shock. The goal is to arti cially pace the heart at a rate aster than the tachycardia to prematurely depolarize a portion o a reentrant circuit, thereby rendering it re ractory to urther immediate
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stimulation. Consequently, when a reentrant impulse returns to the zone that has already been depolarized by the device, it encounters unexcitable tissue, it cannot propagate urther, and the circuit is broken. An advantage o the ATP technique is that, unlike internal cardioversion, it is painless. However, ATP is not e ective or terminating ventricular f brillation, a situation in which the device is programmed to deliver an electric shock instead.
Catheter Ablation I an arrhythmia originates rom a distinct anatomical reentry circuit or an automatic ocus, electrophysiologic mapping techniques can be used to localize the region o myocardium or conduction tissue responsible or the disturbance. It is then o ten possible to ablate the site via a catheter that applies radio requency current to heat and destroy the tissue. Such procedures have revolutionized the management o patients with many types o tachycardias, because they o ten o er a permanent therapeutic solution that spares patients rom prolonged antiarrhythmic drug therapy. Additionally, or patients with ICDs and recurrent ventricular tachycardias causing def brillator shocks, ablation is o ten e ective in reducing the requency o episodes.
SUMMARY • Arrhythmias result rom disorders o impulse ormation, impulse conduction, or both. • Bradyarrhythmias (abnormally slow heart rhythms) develop because o decreased impulse ormation (e.g., sinus bradycardia) or decreased impulse conduction (e.g., AV nodal conduction blocks). • Tachyarrhythmias (abnormally ast rhythms) result rom increased automaticity (o the SA node, latent pacemakers, or abnormal myocardial sites), triggered activity, or reentry. • The two critical conditions or reentry are (1) unidirectional block and (2) slowed conduction through the reentry path; these conditions commonly occur in regions where f brosis has developed, such as in arction scars. • Bradyarrhythmias are usually treated acutely with drugs that accelerate the rate o sinus node discharge and enhance AV nodal conduction (atropine, isoproterenol) or with temporary electronic pacemakers. • Permanent electronic pacemakers are implanted when more sustained therapy or bradyarrhythmias is needed. • Pharmacologic therapy or tachyarrhythmias is directed at the mechanism responsible or the rhythm disturbance. • For re ractory tachyarrhythmias, or in emergency situations, electrical cardioversion or def brillation is utilized. • Catheter-based ablative techniques are use ul or long-term control o certain tachyarrhythmias. • ICDs are li esaving devices implanted in patients at high risk o sudden cardiac death. • For patients with ICDs and recurrent ventricular tachycardias causing def brillator shocks, ablation techniques are o ten e ective in reducing the requency o episodes. Chapter 12 describes the diagnosis and management o the most common arrhythmias. Chapter 17 describes commonly used antiarrhythmic drugs.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Ranliang Hu, MD; Hillary K. Rolls, MD; Jenni er E. Ho, MD; Mark S. Sabatine, MD; Wendy Armstrong, MD; Nicholas Boulis, MD; Elliott M. Antman, MD; and Leonard I. Ganz, MD.
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Ad d i t i o n a l Rea d i n g Chen PS, Joung B, Shinohara T, et al. The initiation of the heart beat. Circ J. 2010;74:221–225. DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010;106:434–446. Grant AO. Cardiac ion channels. Circ Arrhythm Electrophysiol. 2009;2:185–194.
Katritsis DG, Camm AJ. Atrioventricular nodal reentrant tachycardia. Circulation. 2010;122:831–840. Spector P. Principles of cardiac electric propagation and their implications for re-entrant arrhythmias. Circ Arrhythm Electrophysiol. 2013;6:655–661.
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Morga n J. Prust Willia m G. Stevenson Leona rd S. Lilly
Ch a p t e r O u t l i n e Bradyarrhythmias Sinoatrial Node Escape Rhythms Atrioventricular Conduction System Tachyarrhythmias Supraventricular Arrhythmias Ventricular Arrhythmias
C
hapter 11 presented the mechanisms by which abnormal heart rhythms develop. This chapter describes how to recognize and treat specif c arrhythmias. Table 12-1 categorizes the common rhythm disorders considered in this chapter. There are f ve basic questions to consider when con ronted with a patient with an abnormal heart rhythm, as detailed in the sections that ollow: 1. Identif cation: What is arrhythmia? 2. Pathogenesis: What is the underlying mechanism? 3. Precipitating actors: What conditions provoke it? 4. Clinical presentation: What symptoms and signs accompany the arrhythmia? 5. Treatment: What to do about it?
BRADYARRHYTHMIAS The normal resting heart rate, resulting rom repetitive depolarization o the sinus node, ranges rom 60 to 100 bpm. Bradyarrhythmias are rhythms in which the heart rate is less than 60 bpm. They arise rom disorders o impulse ormation or impaired impulse conduction, as described in Chapter 11.
Sinoatrial Node Sinus Bradycardia Sinus bradycardia (Fig. 12-1) is a slowing o the normal heart rhythm, as a result o decreased f ring o the sinoatrial (SA) node, to a rate less than 60 bpm. Sinus bradycardia at rest or during sleep is normal and a benign f nding in many people. Conversely, pathologic sinus bradycardia can result rom either intrinsic SA node disease or extrinsic actors that a ect the node. Depressed intrinsic automaticity can be caused by aging or any disease process that a ects the
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TABLE 12-1
Common Arrhythmias
Location
Bradyarrhythmias
Tachyarrhythmias
SA node
Sinus bradycardia Sick sinus syndrome
Sinus tachycardia
Atria
AV node Ventricles
Conduction blocks Junctional escape rhythm Ventricular escape rhythm
Atrial premature beats Atrial f utter Atrial brillation Paroxysmal supraventricular tachycardias Focal atrial tachycardia Multi ocal atrial tachycardia Paroxysmal reentrant tachycardias (AV or AV nodal) Ventricular premature beats Ventricular tachycardia Torsades de pointes Ventricular brillation
AV, atrioventricular; SA, sinoatrial.
atrium, including ischemic heart disease or cardiomyopathy. Extrinsic actors that suppress SA nodal activity include medications (e.g., β-blockers and certain calcium channel blockers) and metabolic causes (e.g., hypothyroidism). Trained athletes o ten have elevated vagal tone, which results in physiologic and asymptomatic resting sinus bradycardia. Transient periods o high vagal tone can also occur in individuals as a ref ex response to pain or ear, resulting in inappropriate sinus bradycardia. Mild sinus bradycardia is usually asymptomatic and does not require treatment. However, a pronounced reduction o the heart rate can produce a all in cardiac output with atigue, light-headedness, con usion, or syncope. In such cases, any extrinsic provocative actors should be corrected, and speci c therapy, as described in the next section, may be needed.
Sick Sinus Syndrome Intrinsic SA node dys unction that causes periods o inappropriate bradycardia is known as sick sinus syndrome (SSS). This condition o ten produces symptoms o dizziness, con usion, or syncope. Patients with this syndrome (or any cause o symptomatic sinus bradycardia) can be treated acutely with intravenous anticholinergic drugs (e.g., atropine) or β-adrenergic agents (e.g., isoproterenol), which transiently accelerate the heart rate. I the problem is chronic and not corrected by removal o aggravating actors, placement o a permanent pacemaker is required.
FIGURE 12-1. Sinus bradycardia. The P wave and QRS complexes are normal, but the rate is less than 60 bpm.
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FIGURE 12-2. Bradycardia–tachycardia syndrome. A brief irregular tachycardia is followed by slow sinus node discharge.
SSS is common in elderly patients, who are also susceptible to supraventricular tachycardias (SVTs), most commonly atrial brillation (AF). This combination o slow and ast dysrhythmias is known as the bradycardia–tachycardia syndrome (Fig. 12-2) and is thought to result rom atrial brosis that impairs unction o the SA node and predisposes to AF and atrial f utter. During the tachyarrhythmia, overdrive suppression o the SA node occurs (as described in Chapter 11), and when the tachycardia terminates, a period o pro ound sinus bradycardia may ensue. Treatment generally requires the combination o antiarrhythmic drug therapy to suppress the tachyarrhythmias plus a permanent pacemaker to prevent bradycardia.
Escape Rhythms Cells in the atrioventricular (AV) node and His–Purkinje system are capable o automaticity but typically have slower ring rates than do those in the sinus node and are there ore suppressed during normal sinus rhythm. However, i SA node activity becomes impaired or i there is conduction block o the impulse rom the SA node, escape rhythms can emerge rom the more distal latent pacemakers (Fig. 12-3). Junctional escape beats arise rom the AV node or proximal bundle o His. They are characterized by a normal, narrow QRS complex, and when they occur in sequence (termed a junctional escape rhythm), appear at a rate o 40 to 60 bpm. The QRS complexes are not preceded by normal P waves because the impulse originates below the
A
B FIGURE 12-3 Escape rhythms. No P waves are evident. A. Junctional escape rhythm with normal-width QRS complexes. B. Wide QRS complexes typical of a ventricular escape rhythm.
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Chapter 12 atria. However, retrogra de P waves may be observed as an impulse propagates rom the more distal pacemaker backward to the atrium. Retrograde P waves typically follow the QRS complex and are abnormally in verted (negative def ection on the electrocardiogram [ECG]) in limb leads II, III, and aVF, indicating activation o the atria rom the in erior direction. Ventricular escape rhythms are characterized by even slower rates (30 to 40 bpm) and abnormally widened QRS complexes. The complexes are wide because the ventricles are not depolarized by the normal rapid simultaneous conduction over the right and le t bundle branches but rather rom a more distal point in the conduction system. The morphology that the QRS shows depends on the site o origin o the escape rhythm. For example, an escape rhythm originating rom the le t bundle branch will cause a right bundle branch block QRS pattern, because the impulse depolarizes the le t ventricle rst and then spreads more slowly through the right ventricle (RV). Conversely, an escape rhythm originating in the right bundle branch causes the QRS to appear with a le t bundle branch block con guration. Escape rhythms that originate more distally, in the ventricular myocardium itsel , are characterized by even wider QRS complexes because such impulses are conducted outside the rapidly propagating Purkinje bers. Junctional and ventricular escape rhythms are protective backup mechanisms that maintain a heartbeat and cardiac output when the sinus node or normal AV conduction ails. The clinical ndings and treatment o bradycardia associated with escape rhythms are identical to those o SSS described earlier.
Atrioventricular Conduction System The AV conduction system includes the AV node, bundle o His, and the le t and right bundle branches. Impaired conduction between the atria and ventricles can result in three degrees (types) o AV conduction block.
First-Degree AV Block First-degree AV block, shown in Figure 12-4, indicates prolongation o the normal delay between atrial and ventricular depolarization, such that the PR interval is lengthened (> 0.2 seconds, which is > 5 small boxes on the ECG). In this situation, the 1:1 relationship between P waves and QRS complexes is preserved. The impairment o conduction is usually within the AV node itsel and can be caused by a transient reversible inf uence or a structural de ect. Reversible causes include heightened vagal tone, transient AV nodal ischemia, and drugs that depress conduction through the AV node, including β-blockers, certain calcium channel antagonists, digitalis, and other antiarrhythmic medications. Structural causes o rst-degree AV block include myocardial in arction and chronic degenerative diseases o the conduction system, which commonly occur with aging.
P
P
P
FIGURE 12-4. First-degree AV block. The PR interval is prolonged.
P
P
Clinical Aspects of Cardiac Arrhythmias
P
P
P
P
P
291
P
FIGURE 12-5. Second-degree AV block: type I ( Wenckebach) . The P-wave rate is constant, but the PR interval progressively lengthens until a QRS is completely blocked (after the fourth P wave).
Generally, f rst-degree AV block is a benign, asymptomatic condition that does not require treatment. However, it can indicate disease in the AV node associated with susceptibility to higher degrees o AV block i drugs are administered that urther impair AV conduction or i the conduction disease progresses.
Second-Degree AV Block Second-degree AV block is characterized by in termitten t fa ilure o AV conduction, resulting in some P waves that are not ollowed by a QRS complex. There are two orms o seconddegree AV block. In type I block (also termed Wenckebach block), shown in Figure 12-5, the degree o AV delay gradually increases with each beat until an impulse is completely blocked, such that there is no QRS a ter the P wave or a single beat. There ore, the ECG shows a progressive increase in the PR interval rom one beat to the next until a single QRS complex is absent, a ter which the PR interval shortens to its initial length, and the cycle starts anew. Type I block almost always results rom impaired conduction in the AV node (rather than more distally in the conduction system). It is usually benign and may be seen in children, trained athletes, and people with high vagal tone, particularly during sleep. It may also occur during an acute myocardial in arction because o increased vagal tone or ischemia o the AV node, but the block is usually temporary. Treatment o type I block is typically not necessary, but in symptomatic cases, administration o intravenous atropine or isoproterenol usually improves AV conduction transiently. Occasionally, placement o a permanent pacemaker is required or symptomatic block that does not resolve spontaneously or persists despite the correction o aggravating actors. In contrast, type II second-degree AV block is a more dangerous condition. It is characterized by the sudden intermittent loss o AV conduction, without preceding gradual lengthening o the PR interval (Fig. 12-6). The block may persist or two or more beats (i.e., two sequential P waves not ollowed by QRS complexes), in which case it is known as high-grade AV
P
P
P
P
P
FIGURE 12-6. Second-degree AV block: type II. A QRS complex is blocked (after the fourth P wave) without gradual lengthening of the preceding PR intervals. While the QRS width in this example is normal, it is often widened in patients with type II block.
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P
P
P
P
P
P
FIGURE 12-7. High-grade AV block. Sequential QRS complexes are blocked (after the second and third P waves).
block (Fig. 12-7). Type II block is usually caused by conduction block distal to the AV node (in the bundle of His or more distally in the Purkinje system), and the QRS pattern often is widened in a pattern of right or left bundle branch block. This type of block may arise from extensive myocardial infarction involving the septum or from chronic degeneration of the His–Purkinje system. It usually indicates severe disease and may progress to complete heart block without warning; therefore, a pacemaker is usually warranted, even in asymptomatic patients.
Third-Degree AV Block Third-degree AV block, also termed complete heart block (Fig. 12-8), is present when there is complete failure of conduction between the atria and ventricles. In adults, the most common causes are acute myocardial infarction and chronic degeneration of the conduction pathways with advanced age. Third-degree AV block electrically disconnects the atria and ventricles; there is no relationship between the P waves and QRS complexes because the atria depolarize in response to SA node activity, while a more distal escape rhythm drives the ventricles independently. Thus, the P waves “march out” at a rate that is not related to the intervals at which QRS complexes appear. Depending on the site of the escape rhythm, the QRS complexes may be of normal width and occur at 40 to 60 bpm (originating from the AV node) or may be widened and occur at slower rates (originating from the His–Purkinje system). As a result of the slow rate, patients frequently experience light-headedness or syncope. Permanent pacemaker implantation is almost always necessary. The term AV dissociation is a general description that refers to any situation in which the atria and ventricles beat independently, without any direct relationship between P waves and QRS complexes. Third-degree AV block is one example of AV dissociation.
P
P
P
P
P
P
P
P
FIGURE 12-8. Third-degree AV block. The P wave and QRS rhythms are independent of one another. The QRS complexes are widened as they originate within the distal ventricular conduction system, not at the bundle of His. The second and fourth P waves are superimposed on normal T waves.
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TACHYARRHYTHMIAS When the heart rate is greater than 100 bpm for three beats or more, a tachyarrhythmia is present. Tachyarrhythmias result from one of the three mechanisms described in Chapter 11: enhanced automaticity, reentry, or triggered activity. Tachyarrhythmias are categorized into those that arise above the ventricles (supraventricular) and those that arise within the ventricles.
Supraventricular Arrhythmias Figure 12-9 presents a schema to help organize the common supraventricular tachyarrhythmias presented in this section.
Sinus Tachycardia Sinus tachycardia is characterized by an SA node discharge rate greater than 100 bpm (typically 100 to 180 bpm) with normal P waves and QRS complexes (Fig. 12-10). This rhythm most often results from increased sympathetic and/ or decreased vagal tone. Sinus tachycardia is an appropriate physiologic response to exercise. However, it may also result from sympathetic stimulation in pathologic conditions, including fever, hypoxemia, hyperthyroidism, hypovolemia, and anemia. In disease states, sinus tachycardia is usually a sign of the severity of the primary pathophysiologic process, and treatment should be directed at the underlying cause.
S uprave ntricula r Ta chya rrhythmia s
Re gula r rhythm (cons ta nt P –P inte rva l)
Irre gula r rhythm ≥ 3 P wave s ha p e s
No d is tinc t P wave s
Multifo c al atrial tachyc ardia
Atrial fibrillatio n
Atria l ra te (b p m)
P-wave morp hology
Re s p ons e to ca rotid s inus ma s s a g e
S inus tachyc ardia
100–180
Norma l
Atria l ra te may s low
Re e ntrant SVTs (e .g ., AVNRT, ARVT)
140–250
Hidde n or re trogra de
May a bruptly te rmina te
Fo c al atrial tac hyc ardia
130–250
Diffe rs from norma l P
AV block may incre a s e ; doe s n’t us ua lly reve rt
Atrial flutte r
180–350
“Saw-toothe d”
AV block may incre a s e
FIGURE 12-9. Differentiation of common supraventricular tachyarrhythmias.
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FIGURE 12-10. Sinus tachycardia. The P wave and QRS complexes are normal, but the rate is greater than 100 bpm.
Atrial Premature Beats Atrial premature beats (APBs) are common in healthy as well as diseased hearts (Fig. 12-11). They originate rom automaticity or reentry in an atrial ocus outside the SA node and are o ten exacerbated by sympathetic stimulation. APBs are usually asymptomatic but may cause palpitations. On the ECG, an APB appears as an earlier-than-expected P wave with an abnormal shape (the impulse does not arise rom the SA node, resulting in an abnormal sequence o conduction through the atria). The QRS complex that ollows the P wave is usually normal, resembling the QRS during sinus rhythm, because ventricular conduction is not impaired. However, i the abnormal atrial ocus res very soon a ter the previous beat, the impulse may encounter an AV node that is still re ractory to excitation, resulting in a blocked impulse that does not conduct to the ventricles. In that case, the premature P wave is not ollowed by a QRS complex and is termed a blocked APB. Similarly, i the ectopic ocus res just a bit later in diastole, it may conduct through the AV node but encounter portions o the His–Purkinje system (typically the right or le t bundle branch) that are still re ractory. As a result o ailure o conduction in one o the bundle branches, the impulse is conducted through a portion o the ventricles more slowly than normal, producing QRS complexes that are abnormally wide (termed an APB with aberrant conduction). APBs require treatment only i they are symptomatic. Because ca eine, alcohol, and adrenergic stimulation (e.g., emotional stress) can all predispose to APBs, it is important to address these actors. β-Blockers are the initial pre erred pharmacologic treatment i needed.
Atrial Flutter Atrial f utter is characterized by rapid, regular atrial activity at a rate o 180 to 350 bpm (Fig. 12-12). Many o these ast impulses reach the AV node during its re ractory period and do not conduct to the ventricles, resulting in a slower ventricular rate, o ten an even raction o the atrial rate. Thus, i the atrial rate is 300 bpm and 2:1 block occurs at the AV node (i.e., every other atrial impulse nds the AV node re ractory), the ventricular rate is 150 bpm. Because vagal maneuvers (e.g., carotid sinus massage) decrease AV nodal conduction, they increase the degree o block, temporarily slowing the ventricular rate, which allows better visualization o the underlying atrial activity. In general, atrial f utter is caused by reentry over a large anatomically xed circuit. In the common orm o atrial f utter, this circuit is the
APB
FIGURE 12-11. Atrial premature beat (APB). The P wave occurs earlier than expected, and its shape is abnormal.
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FIGURE 12-12. Atrial utter is typif ed by rapid “saw-toothed” atrial activity ( arrows) .
atrial tissue along the tricuspid valve annulus: the circulating depolarization wave propagates up the interatrial septum, across the roo and down the ree wall o the right atrium, and nally along the f oor o the right atrium between the tricuspid valve annulus and in erior vena cava. Because large parts o the atrium are depolarized throughout the cycle, P waves o ten have a sinusoidal or “sawtooth” appearance. Large f utter circuits can occur in other parts o the right or le t atrium as well, usually associated with areas o atrial scarring rom disease, prior heart surgery, or ablation procedures. Atrial f utter generally occurs in patients with preexisting heart disease. It may be paroxysmal and transient, persistent (lasting or days or weeks), or permanent. Symptoms o atrial f utter depend on the accompanying ventricular rate. I the rate is less than 100 bpm, the patient may be asymptomatic. Conversely, aster rates o ten cause palpitations, dyspnea, or weakness. Paradoxically, antiarrhythmic medications that reduce the rate o atrial f utter by slowing conduction in the atrium may make the rhythm more dangerous by allowing the AV node more time to recover between impulses. In this situation, the AV node may begin to conduct in a 1:1 ashion, producing very rapid ventricular rates. For example, a patient with atrial f utter at a rate o 280 bpm and 2:1 conduction block at the AV node would have a ventricular rate o 140 bpm. I the atrial rate then slows to 220 bpm, the AV node may be able to recover su ciently between depolarizations to conduct every atrial impulse, causing the ventricular rate to accelerate to 220 bpm. In patients with limited cardiac reserve, this acceleration may result in a pro ound reduction o cardiac output and hypotension. Atrial f utter also predisposes to atrial thrombus ormation, and anticoagulation therapy is o ten appropriate, as described below or atrial brillation. Several approaches or the conversion o atrial f utter to sinus rhythm are available: 1. For symptomatic patients with recent-onset atrial f utter, the most expeditious therapy is electrical cardioversion to restore sinus rhythm. This technique is also used to revert chronic atrial f utter that has not responded to other approaches. 2. Flutter can be terminated by rapid atrial stimulation (burst pacing) using a temporary or permanent pacemaker (see Chapter 11). This procedure can be used when temporary atrial pacing wires are already present, as in the days ollowing cardiac surgery. In addition, certain types o permanent pacemakers and implanted de brillators can be programmed to per orm burst pacing automatically when atrial f utter occurs. 3. Patients without an immediate need or cardioversion can begin pharmacologic therapy. First, the ventricular rate is slowed by drugs that increase AV block: β-blockers, certain calcium channel blockers (e.g., verapamil, diltiazem), or digoxin. Once the rate is e ectively slowed, attempts can be made to restore sinus rhythm using antiarrhythmic drugs that slow conduction or prolong the re ractory period o the atrial myocardium (usually class IC or class III agents; see Chapter 17). Should these drugs ail to convert the rhythm, electrical cardioversion can be undertaken. Once sinus rhythm has been restored, antiarrhythmic drugs may be administered chronically to prevent recurrences.
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Chapter 12 4. When chronic therapy is required to prevent recurrences, catheter ablation is o ten a better alternative than pharmacologic approaches. In this method, an electrode catheter is inserted into the emoral vein, passed via the in erior vena cava to the right atrium, and used to localize and cauterize (ablate) part o the reentrant loop to permanently interrupt the f utter circuit.
Atrial Fibrillation AF is a chaotic rhythm with an atrial rate so ast (350 to 600 discharges/ min) that distinct P waves are not discernible on the ECG (Fig. 12-13). As with atrial f utter, many o the atrial impulses encounter re ractory tissue at the AV node, allowing only some o the depolarizations to be conducted to the ventricles in a very irregular ashion (indicated by a characteristic “irregularly irregular” rhythm). The average ventricular rate in untreated AF is approximately 140 to 160 bpm. Because discrete P waves are not visible on the ECG, the baseline shows low-amplitude undulations punctuated by QRS complexes and T waves. The mechanism o AF likely involves multiple wandering reentrant circuits within the atria, and in some patients, the rhythm repetitively shi ts between brillation and atrial f utter. When brillation is paroxysmal (i.e., sudden, unpredictable episodes), it is o ten initiated by rapid ring o oci in sleeves o atrial muscle that extend into the pulmonary veins. To sustain AF, a minimum number o reentrant circuits is needed, and an enlarged atrium increases the potential or this to occur. Thus, AF is o ten associated with right or le t atrial enlargement. Accordingly, diseases that increase atrial pressure and size promote AF, including heart ailure, hypertension, coronary artery disease, and pulmonary disease. Thyrotoxicosis and alcohol consumption can also precipitate AF in some individuals. In addition, AF is a common rhythm disturbance in the elderly. As with atrial f utter, when the ventricular rate is less than 100 beats/ min, AF may be asymptomatic. When the rate is aster, as may occur be ore treatment is instituted and when AV nodal conduction is acilitated by elevated sympathetic tone during illness, the rapid ventricular rate may compromise cardiac output, resulting in hypotension and pulmonary congestion (especially in patients with a hypertrophied or “sti ” le t ventricle in whom the loss o normal atrial contraction can signi cantly reduce le t ventricular lling and stroke volume). AF is also an important cause o stroke. The absence o organized atrial contraction promotes blood stasis in the atria, increasing the risk o thrombus ormation in the le t atrial appendage (LAA), which can embolize to the cerebral circulation and other systemic sites. Thus, treatment o AF is directed at three aspects o the arrhythmia: (1) ventricular rate control, (2) assessment o the need or anticoagulation to prevent thromboembolism, and (3) consideration o methods to restore sinus rhythm. Antiarrhythmic drug treatment o AF is similar to that o atrial f utter. β-Blockers or certain Ca + + channel antagonists (diltiazem, verapamil) are administered to promote block at the AV node so as to reduce the ventricular rate. Digitalis is less e ective or this purpose, although it may be use ul in patients with accompanying impairment o ventricular contractile unction. For those who remain symptomatic despite adequate rate control, conversion to sinus rhythm is usually attempted, as described in the next paragraph. AF that has been present
FIGURE 12-13. Atrial f brillation is characterized by chaotic atrial activity without organized P waves and by irregularity o the ventricular ( QRS) rate.
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or more than 48 hours may predispose to atrial thrombus ormation, and systemic anticoagulation ( or at least 3 weeks) is usually warranted prior to cardioversion to reduce the risk o thromboembolism. Alternatively, a transesophageal echocardiogram can be per ormed to evaluate or the presence o thrombus; i none is ound, cardioversion may proceed directly, with minimum thromboembolic risk, provided that anticoagulation is instituted or several weeks therea ter (since recovery o normal atrial contraction may be delayed or a period o time ollowing cardioversion). Anticoagulant drugs are described in Chapter 17. Cardioversion to sinus rhythm can be attempted chemically by administration o class IC, IA, or III antiarrhythmic drugs (see Chapter 17 or descriptions o these classes). Alternatively, electrical cardioversion can be undertaken. Following success ul conversion to sinus rhythm, antiarrhythmic drugs are o ten continued in an attempt to prevent recurrences. Note that these drugs have the capacity to cause serious, sometimes lethal, side e ects (see Chapter 17). Thus, in patients with asymptomatic AF, it is o ten appropriate to simply control the ventricular rate and continue anticoagulation therapy chronically, rather than to pursue cardioversion. Such an approach is supported by clinical trials o AF that have assessed long-term clinical outcomes. Because the e f cacies and toxicities o antiarrhythmic drugs have been disappointing, nonpharmacologic options or the management o AF have been devised. For example, the surgical maze procedure places multiple incisions in the le t and right atria to prevent the ormation o reentry circuits and is sometimes per ormed in patients undergoing cardiac surgery or coronary artery or valve disease who also have AF. A less invasive approach is percutaneous catheter ablation. In this approach, areas o the le t atrium around the pulmonary veins are cauterized to interrupt potential reentry circuits and oci that initiate AF. Doing so requires extensive catheter manipulation and ablation in the le t atrium, and risks o the procedure includes stroke rom systemic thromboembolism and cardiac per oration that can cause pericardial tamponade. Thus, catheter ablation or AF is usually reserved or patients who remain symptomatic despite pharmacologic approaches. When sinus rhythm cannot be maintained and the heart rate cannot be controlled adequately with medications, catheter ablation of the AV node is another available procedure. This method intentionally creates complete heart block as a means to permanently slow the ventricular rate. Permanent ventricular pacemaker placement is then also required to generate an adequate ventricular rate. Left atrial appendage (LAA) ligation or occlusion, which can be per ormed through open surgical or percutaneous techniques, excludes the LAA rom the circulation, removing it as a source o thrombi that can embolize to cause strokes. The advantages and risks o such approaches to prevent stroke in AF are still being def ned.
Paroxysmal Supraventricular Tachycardias Paroxysmal supraventricular tachycardias (PSVTs) are mani ested by (1) sudden onset and termination, (2) atrial rates between 140 and 250 bpm, and (3) narrow (normal) QRS complexes (Fig. 12-14), unless aberrant conduction is present, as summarized later. The mechanism o
FIGURE 12-14. Paroxysmal supraventricular tachycardia caused by AV nodal reentry. Retrograde P waves in this example occur simultaneously with, and are “hidden” in, the QRS complexes.
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Chapter 12 PSVTs is most o ten reentry involving the AV node, atrium, or an accessory pathway between an atrium and a ventricle. Enhanced automaticity and triggered activity in the atrium or AV node are less common causes.
AV Nodal Reentrant Tachycardia Atrioventricular nodal reentrant tachycardia (AVNRT) is the most common orm o PSVT in adults. In the normal heart, the AV node is a lobulated structure that consists o a compact portion and several atrial extensions. The latter constitute two (or more) potential pathways or conduction through the AV node (Fig. 12-15). In some people, these extensions have di erent conduction times, providing both slow- and ast-conducting pathways. The ast pathway is characterized by a rapid conduction velocity, whereas the slow pathway demonstrates slower conduction but typically has a shorter re ractory period than does the ast pathway. Thus, although the ast pathway conducts rapidly, it takes longer to recover between impulses compared with the slow pathway. Normally, a stimulus arriving at the AV node travels down both pathways, but the impulse traveling down the ast pathway reaches the bundle o His rst. By the time the impulse traversing the slow pathway reaches the bundle o His, it encounters re ractory tissue and is extinguished. Thus, under normal conditions, only the ast pathway impulse makes its way orward to the ventricles (see Fig. 12-15A). In contrast, consider what happens when an APB spontaneously occurs (Fig. 12-15B). Because the re ractory period o the ast pathway is relatively long, an APB would nd that pathway unexcitable and unable to conduct the impulse. However, the impulse is able to conduct over the slow pathway (which is excitable because it has a shorter re ractory period than does the ast pathway and has already repolarized when the APB arrives). By the time this impulse travels down the slowly conducting pathway and reaches the compact portion o the AV node, the distal end o the ast pathway may have had time to repolarize, and the impulse is able to propagate both distally (to the bundle o His and ventricles) and backward to the atria, up the ast pathway in a retrograde direction. On reaching the atria, the impulse can then circulate back down the slow pathway, completing the reentrant loop and initiating tachycardia as this sequence repeats. Thus, the undamental conditions or reentry in AVNRT in this example are transient unidirectional block in the ast pathway (an APB encountering re ractory tissue) and relatively slow conduction through the other pathway. The ECG in AVNRT shows a regular tachycardia with normal-width QRS complexes. P waves may not be apparent, because retrograde atrial depolarization typically occurs simultaneously with ventricular depolarization (see Fig. 12-14). Thus, the retrograde P wave and QRS are inscribed at the same time, and the P is typically “hidden” in the QRS complex. When P waves are visible, they are superimposed on the terminal portion o the QRS complex and inverted (negative def ection) in limb leads II, III, and aVF, because o the caudocranial direction o atrial activation. Rarely, the reentrant loop revolves in the reverse direction, with anterograde conduction down the ast pathway and retrograde conduction up the slow pathway. This is known as uncommon AVNRT and, unlike the more common rhythm, typically results in clearly visible retrograde P waves ollowing the QRS complex on the ECG. AVNRT o ten presents in teenagers or young adults. It is usually well tolerated but causes palpitations that many patients nd rightening, and rapid tachycardias can cause lightheadedness or shortness o breath. In elderly patients or those with underlying heart disease, more severe symptoms may result, such as syncope, angina, or pulmonary edema. Acute treatment o AVNRT is aimed at terminating reentry by impairing conduction in the AV node. Transient increases in vagal tone produced by the Valsalva maneuver or carotid sinus massage (see Chapter 11) may block AV conduction, stopping the tachycardia. The most rapidly e ective pharmacologic treatment is intravenous adenosine, which impairs AV
Clinical Aspects o Cardiac Arrhythmias
299
Compa ct AV node
Fa s t pa thway
Bundle of His
Right a trium
IVS Impuls e from SA node
S low pa thway
Tricus pid va lve
A
Re tro g ra d e c o n d u c tio n Un id ire c tio n a l b lo ck
Bundle of His
Atria l pre ma ture be a t
B FIGURE 12-15. Common mechanism of AV nodal reentry. In most patients, the AV node is a lobulated structure consisting proximally o several atrial extensions and distally o a compact node portion. A. In patients with AV nodal reentry, two unctionally distinct tracts exist within the AV node (termed the slow and ast pathways). The slow pathway conducts slowly and has a short re ractory period, whereas the ast pathway conducts more rapidly but has a long re ractory period. Impulses rom above conduct down both pathways; because the ast pathway impulse reaches the distal common pathway f rst, it continues to the bundle o His. Conversely, the slow pathway impulse arrives later and encounters re ractory tissue. B. An atrial premature beat arrives at the entrance o the two pathways. The ast pathway is still re ractory rom the preceding beat and the impulse is blocked, but the slow pathway has repolarized and is able to conduct. When the impulse reaches the distal portion o the ast pathway a ter traveling down the slower pathway, the ast pathway has repolarized and is able to conduct the impulse in a retrograde direction (exempli ying unidirectional block) as shown by the green pathway. The impulse can then travel back to the slow pathway, and a reentrant loop is initiated.
nodal conduction and o ten aborts the reentrant rhythm (see Chapter 17). Other drug options include intravenous calcium channel antagonists (verapamil and diltiazem) or β-blockers. Most patients with AVNRT have in requent episodes that terminate with vagal maneuvers and do not require other specif c interventions. Frequent symptomatic episodes, particularly when requiring visits to the emergency department or treatment, warrant preventive therapy: oral
300
Chapter 12 β-blockers, calcium channel blockers, or digoxin is o ten success ul or this purpose. Catheter ablation o the slow AV nodal pathway is usually curative and recommended when pharmacologic therapy ails or is not desired by the patient, but has a small risk (< 2% ) o heart block owing to unintended damage to the ast AV nodal pathway, a complication that requires permanent pacemaker implantation. Chronic class IC or IA antiarrhythmic drugs are also e ective but are o ten less desirable than catheter ablation, because o associated potential drug toxicities.
Atrioventricular Reentrant Tachycardias Atrioventricular reentrant tachycardias (AVRTs) are similar to AVNRTs except that in the ormer, one limb o the reentrant loop is constituted by an accessory pathway (bypass tract), rather than by separate ast and slow pathways within the AV node itsel . As described in Chapter 11, an accessory pathway is an abnormal band o myocytes that spans the AV groove and connects atrial to ventricular tissue separately rom the normal conduction system (see Fig. 11-10). Approximately 1 in 1,500 people has such a pathway. Accessory pathways allow an impulse to conduct rom atrium to ventricle (anterograde conduction), rom ventricle to atrium (retrograde conduction), or in both directions. Depending on the characteristics o the pathway, one o two characteristic entities can result: (1) the ventricular preexcitation syndrome or (2) PSVT resulting rom a concealed accessory pathway. Some pathways do not conduct impulses at rates su f cient to cause tachycardias and cause no symptoms at all.
Ventricular Preexcitation Syndrome In patients with ventricular preexcitation (also termed Wol –Parkinson–White [WPW] syndrome; see Chapter 11), atrial impulses can pass in an anterograde direction to the ventricles through both the AV node and the accessory pathway. Because conduction through the accessory pathway is usually aster than that via the AV node, the ventricles are stimulated earlier than by normal conduction over the AV node. During sinus rhythm, activation o the ventricle rom the accessory pathway causes a characteristic ECG appearance: (1) the PR interval is shortened (less than 0.12 seconds) because ventricular stimulation begins earlier than normal through the accessory pathway, (2) the QRS has a slurred rather than a sharp upstroke (re erred to as a delta wave) because the initial ventricular activation by the accessory pathway is slower than activation over the Purkinje system, and (3) the QRS complex is widened because it represents usion o two excitation wave ronts through the ventricles, one rom the accessory pathway and one rom the normal His–Purkinje system (Figs. 12-16 and 12-17). Patients with WPW syndrome are predisposed to PSVTs because the accessory pathway provides a potential limb o a reentrant loop. The most common PSVT in these patients is orthodromic AVRT. During this tachycardia, an impulse travels anterogradely down the AV node to the ventricles and then retrogradely up the accessory tract back to the atria (see Fig. 12-17B).
FIGURE 12-16. Wolff–Parkinson–White syndrome. The delta wave (arrow) indicates preexcitation of the ventricles. Note the shortened PR interval.
Clinical Aspects of Cardiac Arrhythmias A
B S inus Rhythm
Orthodromic Atrio ventric ular Reentrant Tac hycardia
C
301
Antidro mic Atrio ve ntricular Re entrant Tachycardia
AP
FIGURE 12-17. Wolff–Parkinson–White syndrome. A. During normal sinus rhythm, the shortened PR interval, delta wave, and widened QRS complex indicate fusion of ventricular activation via the AV node and accessory pathway (AP). B. An atrial premature beat can trigger an orthodromic atrioventricular reentrant tachycardia, in which impulses are conducted anterogradely down the AV node and retrogradely up the accessory pathway. Retrograde P waves are visible immediately after the QRS complex. There is no delta wave because anterograde ventricular stimulation passes exclusively through the AV node. C. Antidromic atrioventricular reentrant tachycardia in which impulses are conducted anterogradely down the accessory tract and retrogradely up the AV node. The QRS complex is greatly widened because the ventricles are stimulated by abnormal conduction through the accessory pathway rather than via the His-Purkinje system. SA, sinoatrial.
Because the ventricles in this situation are depolarized exclusively via the normal conduction system (through the AV node and the bundle o His), there is no delta wave during the tachycardia and the width o the QRS is usually normal. Retrograde P waves are o ten visible soon a ter each QRS complex because the atria are stimulated rom below via retrograde conduction through the accessory pathway. In ewer than 10% o patients with AVRT involving an accessory pathway, the reentrant arrhythmia travels in the opposite direction. Impulses travel anterogradely down the accessory pathway and retrogradely up the AV node (see Fig. 12-17C). Termed antidromic AVRT, its ECG pattern is characterized by a wide QRS complex because the ventricles are activated entirely rom anterograde conduction over the accessory pathway. From the ECG alone, such antidromic tachycardia is di cult to distinguish rom ventricular tachycardia (described later in the chapter). A third type o arrhythmia encountered in patients with WPW syndrome is anterograde conduction over the accessory pathway when AF or atrial f utter is present. Some accessory pathways have short re ractory periods that allow aster rates o ventricular stimulation than does the AV node. Thus, during AF or atrial f utter, ventricular rates as ast as 300 bpm may result. Such rates are poorly tolerated and can lead to ventricular brillation and cardiac arrest, even in a young, otherwise healthy patient. Pharmacologic management o arrhythmias in patients with the WPW syndrome requires greater caution than that o those with AVNRTs. Although digitalis, β-blockers, and certain
302
Chapter 12 calcium channel blockers are e ective at blocking conduction through the AV node, they do not slow conduction over most accessory pathways. Sometimes these drugs actually shorten the re ractory period o the accessory pathway, thus speeding conduction. There ore, the drugs could precipitate even aster ventricular rates (and hemodynamic collapse) when administered to patients with WPW syndrome who develop AF or f utter. In contrast, sodium channel blockers (speci cally, class IA and IC antiarrhythmics) and some class III antiarrhythmic drugs slow conduction and prolong the re ractory period o accessory pathways as well as the AV node; there ore, these are the pre erred pharmacologic agents or this condition. When a patient with WPW presents with a wide QRS tachycardia, acute therapy depends on the patient’s tolerance o the arrhythmia. I accompanied by hemodynamic collapse, immediate cardioversion is required. Conversely, i the patient is hemodynamically stable, intravenous administration o procainamide (a class IA agent that slows conduction in the accessory pathway) or ibutilide (a class III agent that prolongs re ractoriness in the accessory pathway) will o ten terminate the arrhythmia. Patients who have WPW with symptomatic arrhythmias should generally undergo an invasive electrophysiologic study with radio requency ablation o the accessory pathway. Ablation abolishes conduction over the pathway, curing the condition. I this procedure is not an option, chronic oral therapy should include a drug that slows accessory pathway conduction (i.e., a class IA, IC, or III agent). The Low n–Ganong–Levine syndrome is also characterized by a short PR interval but a normal, narrow QRS complex (i.e., no delta wave during sinus rhythm). It used to be considered a orm o preexcitation, but most patients just have enhanced conduction through the normal AV node, thus shortening the PR interval. When PSVT occurs in these patients, it is usually simply due to AV nodal reentry.
Concealed Accessory Pathways Accessory pathways do not always result in ECG ndings o ventricular preexcitation (i.e., short PR, delta wave). Many are capable o only retrograde conduction. In this case, during sinus rhythm, the ventricles are depolarized normally through the AV node alone and the ECG is normal (i.e., the accessory pathway is concealed). However, because the accessory pathway is capable o retrograde conduction, it can orm a limb o a reentrant circuit under appropriate circumstances and result in orthodromic AVRT. Management o patients with tachycardia involving a concealed accessory pathway is the same as or patients with AVNRT. Because the reentrant circuit travels anterogradely down the AV node, vagal maneuvers and drugs that interrupt conduction over the AV node (e.g., adenosine, verapamil, diltiazem, and β-blockers) can terminate the tachycardia. Another option or recurrent episodes is catheter ablation o the accessory pathway, which is curative in most patients.
Focal Atrial Tachycardia Focal atrial tachycardia (AT) results rom either automaticity o an atrial ectopic site or reentry. The ECG has the appearance o sinus tachycardia, with a P wave be ore each QRS complex, but the P-wave morphology is di erent rom that o sinus rhythm, indicating depolarization o the atrium rom an abnormal location. The arrhythmia can be paroxysmal and o limited duration, or it can persist. Short, asymptomatic bursts o AT are commonly observed on 24-hour ECG recordings, even in otherwise healthy people. AT can be caused by digitalis toxicity and is also aggravated by elevated sympathetic tone (e.g., during exertion or periods o illness). Initial treatment includes correction o any contributing actors. Unlike AVNRT or AVRT, vagal maneuvers (such as carotid sinus massage) may have no e ect on atrial discharges rom an ectopic pacemaker ocus. However,
Clinical Aspects of Cardiac Arrhythmias
P
P
P
P
P
P
P
P
P
303
P
FIGURE 12-18. Multifocal atrial tachycardia. The rhythm is irregular, and each QRS is preceded by a P wave of varying morphology.
β-blockers, calcium channel blockers, and class IC, IA, and III antiarrhythmic drugs can be e ective. Catheter ablation is also a use ul option or symptomatic patients.
Multifocal Atrial Tachycardia In multi ocal atrial tachycardia (MAT), the ECG shows an irregular rhythm with multiple (at least three di erent) P-wave morphologies, and the average atrial rate is greater than 100 bpm (Fig. 12-18). An isoelectric (i.e., “f at”) baseline between P waves distinguishes MAT rom the chaotic baseline o AF. This rhythm is likely caused by either abnormal automaticity in several oci within the atria or triggered activity and occurs most o ten in the setting o severe pulmonary disease and hypoxemia. Because patients with this rhythm are o ten critically ill rom the underlying disease, the mortality rate is high, and treatment is aimed at the causative disorder. The calcium channel blocker verapamil is o ten e ective at slowing the ventricular rate as a temporizing measure.
Ventricular Arrhythmias Ventricular arrhythmias include (1) ventricular premature beats (VPBs), (2) ventricular tachycardia (VT), and (3) ventricular brillation (VF). Ventricular arrhythmias are usually more dangerous than supraventricular rhythm disorders and are responsible or many o the approximately 300,000 sudden cardiac deaths that occur every year in the United States.
Ventricular Premature Beats A VPB arises when an ectopic ventricular ocus res an action potential. On the ECG, a VPB appears as a widened QRS complex, because the impulse travels rom its ectopic site through the ventricles via slow cell-to-cell connections rather than through the normal rapidly conducting His– Purkinje system (Fig. 12-19). Furthermore, the ectopic beat is not related to a preceding P wave. VPBs can also occur in repeating patterns. When every alternate beat is a VPB, the rhythm is termed bigeminy. When two normal beats precede every VPB, trigeminy is present. Consecutive VPBs are re erred to as couplets (two in a row) or triplets (three in a row). Similar to APBs, VPBs are common even among healthy people and are o ten asymptomatic and benign. Speci c precipitants o VPBs include medications (e.g., β-adrenergic receptor
FIGURE 12-19. Ventricular premature beats ( arrows) .
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Chapter 12
FIGURE 12-20. Monomorphic ventricular tachycardia.
agonists), ca eine, electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), and hypoxia. VPBs are not dangerous by themselves, and in patients without heart disease, they con er no added risk o a li e-threatening arrhythmia. They can, however, be an indication o an underlying cardiac disorder and take on added signif cance in that case. For example, in patients with structural heart disease, VPBs generally increase in requency in relation to the severity o depressed ventricular contractility. They have been associated with an increased risk o sudden death in patients with heart ailure or prior myocardial in arction. In otherwise healthy persons, treatment o VPBs mainly involves reassurance and, i needed, symptomatic control using β-blockers. In patients with advanced structural heart disease with eatures that place them at risk o li e-threatening ventricular arrhythmias, placement o an implantable cardioverter–def brillator (ICD) is typically recommended.
Ventricular Tachycardia VT is a series o three or more consecutive VPBs (Fig. 12-20). VT is divided arbitrarily into two categories. I it persists or more than 30 seconds, produces severe symptoms, such as syncope, or requires termination by cardioversion or administration o an antiarrhythmic drug, it is designated as sustained VT; shorter, sel -terminating episodes are termed nonsustained VT. Both orms o VT are ound most commonly in patients with structural heart disease, including myocardial ischemia and in arction, heart ailure, ventricular hypertrophy, primary electrical diseases (e.g., long-QT syndromes [LQTS]; see Box 12-1), valvular heart diseases, and congenital cardiac abnormalities.
BOX 12-1
Genetic Mutations and Ventricular Arrhythmias
Genetic causes o arrhythmias occur either in association with various types o structural heart disease or as isolated conditions. Examples o inherited structural disease that can be complicated by li e-threatening ventricular arrhythmias include hypertrophic cardiomyopathy, the familial dilated cardiomyopathies, and arrhythmogenic right ventricular cardiomyopathy (ARVC), which are all described in Chapter 10. ARVC may be suspected on routine ECG by the presence o inverted T waves in leads V1 through V1 Eps ilon wave V3 and occasionally an epsilon wave, a terminal notch o the QRS complex in lead V1 (see arrow in the adjacent gure), which ref ects abnormal RV activation. Several other inherited arrhythmic disorders occur in the absence o structural cardiac disease. These occur in requently but are important because they can cause li e-threatening polymorphic VT or VF in young, otherwise healthy people without prior warning. The most common o these conditions are (1) the Brugada syndrome, (2) the congenital LQTS, and (3) amilial catecholaminergic polymorphic VT. The Brugada syndrome is inherited in an autosomal dominant ashion and has been linked in some (but not all) amilies to mutations in a sodium channel subunit gene (SCN5A). A clue to the
Clinical Aspects o Cardiac Arrhythmias
BOX 12-1
Genetic Mutations and Ventricular Arrhythmias
305
( continued)
presence o this syndrome is a speci c ECG nding o prominent ST elevation in leads V1 through V3 (see adjacent gure). This pattern may be present chronically or intermittently; in the latter case, the syndrome may be unmasked by administering sodium channel blocking antiarrhythmic drugs (e.g., f ecainide, procainamide, which are described in Chapter 17). Brugada syndrome is a potentially lethal condition, and ICD implantation is the most e ective way to prevent an arrhythmic death. The congenital long QT syndromes are associated with V1 prolonged ventricular repolarization (hence the long QT interval), which can lead to li e-threatening polymorphic VT (i.e., torsades de pointes). Mutations in a number o di erent genes result in LQTS (the three most common are listed in the table below) by prolonging the action potential duration. Most identi ed mutations alter ion channel unction to either enhance the depolarizing Na+ current or impair the repolarizing K+ current. Autosomal dominant and recessive patterns o inheritance occur. Gene penetrance and symptomatology o patients with LQTS is highly variable, even or individuals with the same mutation. The degree o QT prolongation and, in some cases, the patient’s gender are predictors o arrhythmic risk when a mutation is present. An a ected patient may be asymptomatic and come to medical attention only as a result o the abnormal ECG or because o a amily member who died suddenly. Others present with syncope or sudden death caused by torsades de pointes. The most common orms (LQT1 and LQT2) are associated with ventricular arrhythmias during physical exercise (particularly swimming) or emotional stress. Conversely, those with LQT3 are much more likely to experience cardiac events at rest or during sleep. Other acquired conditions that urther prolong the QT interval can trigger li e-threatening arrhythmias in patients with LQTS, including hypokalemia, hypomagnesemia, hypocalcemia, and several medications (including many antiarrhythmic drugs). Conversely, β-blockers reduce the risk o arrhythmias in many orms o congenital LQTS, even though they do not shorten the QT interval. For patients at high risk o li e-threatening arrhythmias, ICD implantation is warranted. Familial catecholaminergic polymorphic VT, inherited in autosomal dominant and recessive patterns, is marked by VT and/ or VF during exercise or emotional arousal. The mechanism is thought to be triggered activity resulting rom delayed a terdepolarizations (described in Chapter 11). Mutations in a ected amilies have been demonstrated in at least two genes involved in intracellular calcium handling, including a missense mutation in the locus that codes or the cardiac ryanodine receptor (see Chapter 1). Treatment with a β-blocker, calcium channel blocker, and/ or drug that inhibits ryanodine receptor–mediated calcium release (e.g., the class IC antiarrhythmic f ecainide has this additional attribute) may be e ective; an ICD is also o ten recommended.
Genetic Basis of the Three Most Common Congenital Long QT Syndromes Type
Gene ( Location)
Protein
Mechanism of Prolonged Repolarization
Inheritance
LQT1
KCNQ1 (11p15)
↓ Outward K+ current
AD and AR
LQT2
KCNH2 (7q35)
KvLQT1 (α subunit o I Ks K+ channel) HERG (α subunit o IKr K+ channel)
↓ Outward K+ current
AD
LQT3
SCN5A (3p21)
Nav 1.5 (Na+ channel)
↑ Inward Na+ current
AD
AD, autosomal dominant; AR, autosomal recessive.
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Chapter 12 The QRS complexes o VT are typically wide (greater than 0.12 seconds) and occur at a rate o 100 to 200 bpm or sometimes aster. VT is urther categorized according to its QRS morphology. When every QRS complex appears the same and the rate is regular, it is re erred to as monomorphic VT (see Fig. 12-20). Sustained monomorphic VT usually indicates a structural abnormality that supports a reentry circuit, most commonly a region o myocardial scar rom an old in arction or cardiomyopathy. Occasionally, sustained monomorphic VT occurs as a result o an ectopic ventricular ocus in an otherwise healthy person (re erred to as idiopathic VT). When the QRS complexes continually change in shape and the rate varies rom beat to beat, the VT is re erred to as polymorphic. Multiple ectopic oci or a continually changing reentry circuit is the cause. Torsades de pointes (discussed later in the chapter) and acute myocardial ischemia or in arction are the most common causes o polymorphic VT. Rare, inherited predispositions to polymorphic VT and sudden death arise rom abnormalities o cardiac ion channels or calcium handling (e.g., the long QT syndromes, the Brugada syndrome, amilial catecholaminergic polymorphic VT), as described in Box 12-1. Sustained polymorphic VT usually degenerates to VF. The symptoms o VT vary depending on the rate o the tachycardia, its duration, and the underlying condition o the heart. Sustained VT can cause low cardiac output resulting in loss o consciousness (syncope), pulmonary edema, or progress to cardiac arrest. These severe consequences o VT are most likely in patients who have underlying depressed contractile unction. Conversely, i sustained VT is at a relatively slow rate (e.g., less than 130 bpm), it may be well tolerated and cause only palpitations.
Distinguishing Monomorphic VT from Supraventricular Tachycardia VT can usually be distinguished rom SVT by the width o the QRS complex: it is routinely wide in the ormer and narrow (i.e., normal) in the latter. However, under certain circumstances, arrhythmias that originate rom sites above the ventricles ca n result in wide QRS complexes and may appear similar to monomorphic VT. This situation is termed SVT with aberra n t ven tricula r con duction , or simply SVT with a berra n cy, and may arise in three scenarios: (1) a patient has an underlying conduction abnormality (e.g., a bundle branch block), such that the QRS is abnormally wide even when in normal sinus rhythm; (2) repetitive rapid ventricular stimulation during SVT nds one o the bundle branches re ractory (because o insu cient time to recover rom the previous depolarization), such that the impulse propagates abnormally through the ventricles, causing the QRS to be distorted and wide; or (3) a patient develops antidromic tachycardia through an accessory pathway (described earlier). Certain clinical and electrocardiographic eatures can help to distinguish wide QRS complexes o monomorphic VT rom those o supraventricular rhythms with aberrant conduction. In patients with a history o prior myocardial in arction, congestive heart ailure, or le t ventricular dys unction, a wide complex tachycardia is more likely to be VT rather than SVT with aberrancy. At the bedside, SVT is more probable i vagal maneuvers (such as carotid sinus massage) a ect the rhythm (see Fig. 12-9). Electrocardiographically, a supraventricular tachyarrhythmia is more likely i the morphology o the QRS at the rapid rate is similar to that on the patient’s ECG tracing obtained while in sinus rhythm (i.e., the complex is widened because o an underlying bundle branch block). Conversely, VT is more likely i (1) there is no relationship between the QRS complexes and any observed P waves (AV dissociation) or (2) the QRS complexes in each o the chest leads (V1 through V6) have a similar appearance, with a dominant positive or negative def ection (i.e., there is “concordance” o the precordial QRS complexes). These eatures are summarized in Table 12-2. Other morphologic ECG eatures have been used to distinguish VT rom SVT with aberrancy, but the distinction is o ten very di cult. Most patients with wide QRS tachycardia should be managed as though they have VT until proven otherwise.
Clinical Aspects of Cardiac Arrhythmias
TABLE 12-2
307
Differentiation of Wide Complex Tachycardias
Supports SVT with Aberrant Conduction
Supports Ventricular Tachycardia
QRS morphology same as when in sinus rhythm
History of prior MI or heart failure No relationship between P waves and QRS complexes Concordance of QRS complexes in the chest leads (V1–V6)
Rhythm responds to vagal maneuvers (see Fig. 12-9)
MI, myocardial infarction; SVT, supraventricular tachycardia.
Management of Patients with VT Sustained episodes o VT are dangerous because they can produce syncope or deteriorate into VF, which is atal i not quickly corrected. Acute treatment usually consists o electrical cardioversion. Intravenous administration o certain antiarrhythmic drugs, such as amiodarone, procainamide, or lidocaine, can be considered i the patient is hemodynamically stable. A ter sinus rhythm is restored, a patient who has had sustained VT requires care ul evaluation to de ne whether underlying structural heart disease is present and to correct any aggravating actors, such as myocardial ischemia, electrolyte disturbances, or drug toxicities. Patients who have su ered VT in the setting o structural heart disease have a high risk o recurrence and sudden cardiac death; implantation o an ICD is usually warranted to automatically and promptly terminate uture episodes. Patients who experience VT in the absence o underlying structural heart disease are usually ound to have idiopathic VT. This type o arrhythmia tends to originate rom oci in the right ventricular outf ow tract or in the septal portion o the le t ventricle. It is rarely li e threatening. β-Blockers, calcium channel blockers, or catheter ablation is commonly e ective to control symptomatic episodes o idiopathic VT.
Torsades de Pointes Torsades de pointes (“twisting o the points”) is a orm o polymorphic VT that presents as varying amplitudes o the QRS, as i the complexes were “twisting” about the baseline (Fig. 12-21). It can result rom early a terdepolarizations (triggered activity), particularly in patients who have a prolon ged QT in terva l. QT prolongation (which indicates a lengthened action potential duration) can result rom electrolyte disturbances (hypokalemia or hypomagnesemia), persistent bradycardia, and drugs that block cardiac potassium currents, including many antiarrhythmic agents (particularly the class III drugs sotalol, ibutilide, and do etilide and some class I drugs, including quinidine, procainamide, and disopyramide). Many medications administered or noncardiac illnesses can also prolong
FIGURE 12-21. Torsade de pointes. The widened polymorphic QRS complexes demonstrate a waxing and waning pattern.
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Chapter 12
FIGURE 12-22. Ventricular f brillation.
the QT interval and predispose to torsades de pointes, including erythromycin, phenothiazines, haloperidol, and methadone. A rare group o hereditary ion channel abnormalities produces con gen ita l QT prolongation, which can also lead to torsades de pointes (see Box 12-1). Torsades de pointes is usually symptomatic, causing light-headedness or syncope, but is requently sel -limited. Its main danger results rom degeneration into VF. When it is drug or electrolyte induced, correcting the underlying trigger abolishes recurrences, but measures to suppress episodes are required to allow time to address the cause. Administration o intravenous magnesium o ten suppresses repeated episodes. Additional preventive strategies are aimed at shortening the QT interval by increasing the underlying heart rate with intravenous β-adrenergic stimulating agents (e.g., isoproterenol) or an artif cial pacemaker. When torsades de pointes results rom congenital prolongation o the QT interval (i.e., in the long QT syndromes), β-blocking drugs are the treatment o choice, because sympathetic stimulation actually aggravates the arrhythmia.
Ventricular Fibrillation VF is an immediately li e-threatening arrhythmia (Fig. 12-22). It results in disordered, rapid stimulation o the ventricles with no coordinated contractions. The result is essentially cessation o cardiac output and death i not quickly reversed. This rhythm most o ten occurs in patients with severe underlying heart disease and is the major cause o mortality in acute myocardial in arction. VF is o ten initiated by an episode o VT, which degenerates, it is believed, by the breakup o excitation waves into multiple smaller wavelets o reentry that wander through the myocardium. On the ECG, VF is characterized by a chaotic irregular appearance without discrete QRS wave orms. Untreated, VF rapidly leads to death. The only e ective therapy is prompt electrical def brillation. As soon as the heart has been converted to a sa e rhythm, the underlying precipitant o the arrhythmia (e.g., myocardial ischemia, electrolyte imbalances, hypoxemia, or acidosis) should be sought and corrected to prevent urther episodes. Intravenous antiarrhythmic drug therapy may be administered to prevent immediate recurrences. I no reversible inciting precipitant is ound, survivors o VF usually receive an ICD.
SUMMARY • Disorders o impulse ormation and conduction result in bradyarrhythmias (heart rate <60 bpm) and tachyarrhythmias (heart rate > 100 bpm or three beats or more). • The f ve basic considerations when con ronted with a patient with an abnormal heart rhythm are (1) identif cation, (2) pathogenesis, (3) precipitating actors, (4) clinical presentation, and (5) treatment. • When evaluating a patient with a slow heart rhythm, two key questions should be addressed: (1) are P waves present? and (2) what is the relationship between the P waves and the QRS complexes?
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• Di erentiation o tachyarrhythmias requires assessment o (1) the width o the QRS complex (normal or wide), (2) the morphology and rate o the P waves, (3) the relationship between the P waves and the QRS complexes, and (4) the response to vagal maneuvers. • The ECG texts listed at the end o Chapter 4 provide multiple examples o arrhythmias and are suited or practicing the principles described in this chapter.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Ranliang Hu, MD; Hillary K. Rolls, MD; Wendy Armstrong, MD; Nicholas Boulis, MD; Jenni er E. Ho, MD; Marc S. Sabatine, MD; Elliott M. Antman, MD; and Leonard I. Ganz, MD.
Ad d i t i o n a l Rea d i n g January CT, Wann LS, Alpert JS, et al. 2014 AHA/ ACC/ HRS guideline or the management o patients with atrial f brillation: A report o the American College o Cardiology/ American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014;130(23):2071–2104. Link MS. Clinical practice. Evaluation and initial treatment o supraventricular tachycardia. N Engl J Med. 2012;367:1438–1448. Pediatric Congenital Electrophysiology Society, Heart Rhythm Society, American College o Cardiology Foundation, et al. PACES/ HRS expert consensus statement on the management o the asymptomatic young patient with
a Wol -Parkinson-White (WPW, ventricular preexcitation) electrocardiographic pattern. Heart Rhythm. 2012;9:1006–1024. Roden DM. Clinical practice. Long-QT syndrome. N Engl J Med. 2008;358:169–176. Stevenson WG. Current treatment o ventricular arrhythmias: State o the art. Heart Rhythm. 2013;10:1919–1926. Tracy CM, Epstein AE, Darbar D, et al. 2012 ACCF/ AHA/ HRS ocused update o the 2008 guidelines or device-based therapy o cardiac rhythm abnormalities: A report o the American College o Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60:1297–1313.
Hypertension Joshua Dra go Gordon H. Willia ms Leona rd S. Lilly
Ch a p t e r O u t l i n e What Is Hypertension? How Is Blood Pressure Regulated? Hemodynamic Factors Blood Pressure Re exes Essential Hypertension Genetics and Epidemiology Experimental Findings Natural History Secondary Hypertension Patient Evaluation Exogenous Causes Renal Causes Mechanical Causes Endocrine Causes Consequences of Hypertension Clinical Signs and Symptoms Organ Damage Caused by Hypertension Hypertensive Crisis Treatment of Hypertension Nonpharmacologic Treatment Pharmacologic Treatment
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13
ver 70 million Americans, and 1 billion people throughout the world, have hypertension—a blood pressure (BP) high enough to be a danger to their well-being. This number will undoubtedly rise; data rom the Framingham Heart Study indicate that 90% o people over age 55 will develop hypertension during their li etimes. Thus, this condition represents a great public health concern because it is a major risk actor or coronary artery disease, stroke, heart ailure, renal disease, and peripheral vascular disease. Surprisingly, two thirds o hypertensive persons are either unaware o their elevated BP or are not treated adequately to minimize the cardiovascular risk. Moreover, because elevated BP is usually asymptomatic until an acute cardiovascular event strikes, screening or hypertension is a critical aspect o preventive medicine. Hypertension is also a scientif c problem o unexpected complexity. In approximately 90% o a ected patients, the cause o the BP elevation is unknown, a condition termed primary or essential hypertension ( EH) . Evidence suggests that the causes o EH are multiple and diverse, but considerable insight into those causes can be achieved by studying the normal physiology o BP control, as examined in this chapter. High BP attributed to a def nable cause is termed secondary hypertension. Although ar less common than EH, conditions that cause secondary hypertension are important because many are amenable to permanent cure. Notably, many o the conditions now understood to cause secondary hypertension were once unknown, and a ected patients were there ore considered to have EH. As more is learned about the pathophysiology o high BP, ewer cases o hypertension will likely be considered to be o the essential type. Following the descriptions o EH and secondary hypertension, this chapter considers the clinical consequences o elevated BP and approaches to treatment.
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WHAT IS HYPERTENSION? BP values vary widely in the population and tend to increase with age, as illustrated in Figure 13-1. The risk o a vascular complication increases progressively and linearly with higher BP values, so the exact cuto points to def ne stages o hypertension are somewhat arbitrary. The currently accepted criteria are listed in Table 13-1. By this classif cation, a diastolic pressure consistently ≥ 90 mm Hg or a systolic pressure ≥ 140 mm Hg establishes the diagnosis o hypertension. Those with prehyperten sion (systolic 120 to 139 mm Hg or diastolic 80 to 99 mm Hg) have an increased risk o developing def nite hypertension over time. Although the emphasis has historically been on the level o dia stolic pressure, more recent evidence suggests that systolic pressure more accurately predicts cardiovascular complications.
HOW IS BLOOD PRESSURE REGULATED?
Sys tolic
Dia s tolic
FIGURE 13-1. Relationship between blood pressure and age (n = 1,029). Systolic (upper curves) and diastolic (lower curves) values are shown. Notice that by age 60, the average systolic pressure o women exceeds that o men. (Modif ed rom Kotchen JM, McKean HE, Kotchen TA. Blood pressure trends with aging. Hypertension. 1982;4(suppl. 3):111–129.)
Hemodynamic Factors BP is the product o cardiac output (CO) and total peripheral resistance (TPR): BP = CO × TPR And CO is the product o cardiac stroke volume (SV) and heart rate (HR): CO = SV × HR As described in Chapter 9, SV is determined by (1) cardiac contractility; (2) the venous return to the heart (preload); and (3) the resistance the le t ventricle must overcome to eject blood into the aorta (a terload). It ollows that at least our systems are directly responsible or BP regulation: the heart, which supplies the pumping pressure; the blood vessel tone, which largely determines systemic resistance; the kidney, which regulates intravascular volume; and hormones, which modulate the unctions o the other three systems. Figure 13-2 shows how actors related to these systems contribute to CO and TPR.
TABLE 13-1
Classif cation o Blood Pressure in Adults
Category Normal Prehypertension Stage 1 hypertension Stage 2 hypertension
Systolic Pressure ( mm Hg) < 120 120–139 140–159 ≥ 160
Diastolic Pressure ( mm Hg) And Or Or Or
< 80 80–89 90–99 ≥ 100
Modif ed rom Chobanian AV, Bakris GL, Black HR, et al. The seventh report o the Joint National Committee on Prevention, Detection, Evaluation, and Treatment o High Blood Pressure. JAMA. 2003;289:2560–2572.
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Chapter 13 Blood Pre s s ure
Ca rdia c Output
HR
Pe riphe ra l Re s is ta nce
SV
Circula ting re gula tors
Dire ct inne rva tion
• Angiote ns in II (↑ ) • α 1 -Re ce ptors (↑ ) • Ca te chola mine s (↑ ) • β 2 -Re ce ptors (↓ )
• P S NS (↓ ) • S NS (↑ ) • Ca te chola mine s (↑ )
Loca l re gula tors
Blood vis cos ity
• He ma tocrit (↑ ) • Nitric oxide (↓ ) • [H+] (↓ ) • Ade nos ine (↓ ) • Pros ta gla ndins (↓ ) • Endothe lin (↑ ) • Oxyge n (↑ )
Ve nous re turn
Contra ctility • Ca te chola mine s (↑ ) • S NS (↑ ) Blood volume
Ve nous tone • S NS (↑ ) • Ca te chola mine s (↑ )
Re na l re te ntion (Na +, H2 O)
• Thirs t (↑ )
• Aldos te rone (↑ ) • ADH (↑ ) • S NS (↑ ) • NP (↓ )
FIGURE 13-2. Regulation of systemic blood pressure. The small arrows indicate whether there is a stimulatory (↑) or inhibitory (↓) effect on the boxed parameters. ADH, antidiuretic hormone; HR, heart rate; NP, natriuretic peptides; PSNS, parasympathetic nervous system; SNS, sympathetic nervous system; SV, stroke volume.
The renal component o BP regulation deserves special mention, in light o the temptation to view hypertension simply as a cardiovascular problem. No matter how high the CO or TPR, renal excretion has the capacity to completely return BP to normal by reducing intravascular volume. There ore, the maintenance o chronic hypertension requires renal participation. Transplantation studies have conf rmed this point: the implantation o a kidney rom a normotensive person into a hypertensive one typically improves the BP. Similarly, surgical placement o a kidney rom a genetically hypertensive rat into a previously normotensive one usually leads to hypertension. In the presence o normally unctioning kidneys, an increase in BP leads to augmented urine volume and sodium excretion, which then returns the BP to normal. This process, known as pressure natriuresis, is blunted in the kidneys o hypertensive patients; thus, higher pressures are required to excrete a given sodium and water load. Current evidence suggests at least two possible reasons or this blunted response. First, microvascular and tubulointerstitial injury within the kidneys o hypertensive patients impairs sodium excretion. Second, the de ect may lie with hormonal actors critical to appropriate renal reactions to the sodium and intravascular volume environment (e.g., the renin–angiotensin system, as described later in the chapter). In contrast to the f rst possibility, abnormalities o hormonal regulation are amenable to correction with appropriate therapy.
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Blood Pressure Ref exes The cardiovascular system is endowed with eedback mechanisms that continuously monitor arterial pressure: they sense when the pressure becomes excessively high or low and then respond rapidly to those changes. One such mechanism is the baroreceptor ref ex, which is mediated by receptors in the walls o the aortic arch and the carotid sinuses. The baroreceptors monitor changes in pressure by sensing the stretch and de ormation o the arteries. I the arterial pressure rises, the baroreceptors are stimulated, increasing their transmission o impulses to the central nervous system (i.e., the medulla). Negative eedback signals are then sent back to the circulation via the autonomic nervous system, causing the BP to all back to its baseline level. The higher the BP rises, the more the baroreceptors are stretched and the greater the impulse transmission rate to the medulla. Signals rom the carotid sinus receptors are carried by the glossopharyngeal nerve (cranial nerve IX), whereas those rom the aortic arch receptors are carried by the vagus nerve (cranial nerve X). These nerve bers converge at the tractus solitarius in the medulla, where the baroreceptor impulses inhibit sympathetic nervous system outf ow and excite parasympathetic e ects. The net result is (1) a decline in peripheral vascular resistance (i.e., vasodilation) and (2) a reduction in CO (because o a lower HR and reduced contractility). Each o these e ects tends to lower arterial pressure back toward its baseline. Conversely, when a fall in systemic pressure is sensed by the baroreceptors, ewer impulses are transmitted to the medulla, leading to a ref exive increase in BP. The main e ect o the baroreceptor mechanism is to modulate moment-by-moment variations in systemic BP. However, the baroreceptor ref ex is not involved in the long-term regulation o BP and does not prevent the development o chronic hypertension. The reason or this is that the baroreceptors constantly reset themselves. A ter a day or two o exposure to higher-than-baseline pressures, the baroreceptor- ring rate slows back to its control value, and a new set point is established.
ESSENTIAL HYPERTENSION Approximately 90% o hypertensive patients have BPs that are elevated or no readily de nable reason, and are considered to have EH. The diagnosis o EH is one o exclusion; it is the option le t to the clinician a ter considering the causes o secondary hypertension described later in this chapter. EH is more a description than a diagnosis, indicating only that a patient mani ests a speci c physical nding (high BP) or which no cause has been ound. In all likelihood, di erent underlying de ects are responsible or the elevated pressure in di erent subpopulations o patients. Because the exact nature o these de ects is unknown, to understand EH is to understand the possibilities: what could go wrong with normal physiology to produce chronically elevated BP? This description o EH there ore ref ects what is currently known about its genetics and epidemiology, experimental ndings, and natural history. The picture that emerges is that EH likely results rom multiple de ects o BP regulation that interact with environmental stressors. The regulatory de ects may be acquired or genetically determined and may be independent o one another. As a result, EH patients exhibit varied combinations o abnormalities and, there ore, have various physiologic bases or their elevated BPs.
Genetics and Epidemiology Strong support or the role o heredity in EH is evident in the higher rate o elevated BP among rst-degree relatives o hypertensive patients than in the general population. Further, concordance between identical twins is high and signi cantly greater than it is that between dizygotic twins. However, no singular, consistent genetic marker or hypertension has been identi ed. Instead, it seems likely that EH is a complex polygenic disorder, involving several loci.
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Chapter 13 While autosomal dominant contributors to elevated BP have been discovered, such abnormalities are rare and are thought to represent only a small raction o hypertensive patients. With respect to loci that a ect hypertension in a polygenic way, genes regulating the renin–angiotensin–aldosterone axis have been most thoroughly studied because o the central role o this system in determining intravascular volume and vascular tone. Within this group, certain polymorphisms in the genes or angiotensinogen, angiotensin-converting enzyme (ACE), the angiotensin type-1 receptor, and aldosterone synthase con er a small increase in the risk o developing hypertension. Additionally, polymorphisms in the gene or alpha-adducin, a cytoskeletal protein, may be involved in a subgroup o EH patients, possibly by increasing renal tubular sodium absorption. Finally, as described later in the chapter, signif cant associations exist among hypertension and obesity, insulin resistance, and diabetes. These conditions are all characterized by similar complex inheritance patterns, some o which may overlap with the genetic underpinnings o hypertension. As genetics cannot explain the complete basis o hypertension, it stands to reason that the environment also plays a role. Indeed, hypertension has been epidemiologically linked to low socioeconomic status, certain dietary and exercise patterns, poor access to health care, and comorbid medical conditions such as obesity, diabetes, and kidney disease. Thus, the heritable traits described above most likely predispose individuals to develop hypertension a ter exposure to certain environmental triggers.
Experimental Findings Systemic Abnormalities Multiple de ects in BP regulation have been ound in EH patients and their relatives. By themselves, or in conjunction with one another, these abnormalities may contribute to chronic BP elevation. The heart can contribute to a high CO-based hypertension owing to sympathetic overactivity. For example, when tested under psychologically stress ul conditions, hypertensive patients (and their f rst-degree relatives) o ten develop excessive HR acceleration compared with control subjects, suggesting an excessive sympathetic response. The blood vessels may contribute to peripheral vascular resistance–based hypertension by constricting in response to (1) increased sympathetic activity; (2) abnormal regulation o vascular tone by local actors, including nitric oxide, endothelin, and natriuretic actors; or (3) ion channel de ects in contractile vascular smooth muscle. The kidn ey can induce volu me-based hyperten sion by retain in g excessive sodium an d water as a resu lt o (1) ailu re to regu late renal blood low appropriately; (2) ion ch an nel de ects (e.g., reduced basolateral Na + K+ -ATPase), wh ich directly cause sodiu m retention ; or (3) in appropriate h ormon al regu lation . For example, th e ren in –an giotensin–aldosterone axis is an important hormonal regulator o peripheral vascular resistance. Renin levels in EH patien ts (compared with those in norm oten sive person s) are subnorm al in 25% , n ormal in approxim ately 60% , and h igh in 10% to 15% . Because ren in secretion should be suppressed by h igh BP, even “n ormal” levels are in appropriate in hyperten sives. Thus, abnormalities o this system’s regulation may play a role in some individuals with EH. Figure 13-3 highlights these and other potential mechanisms o EH. Note that although the heart, blood vessels, and kidneys are the organs ultimately responsible or producing the pressure, primary de ects may be located elsewhere as well (e.g., the central nervous system, arterial baroreceptors, and adrenal hormone secretion). Yet, although abnormal regulation at these sites can contribute to elevated BP, it is important to remember that without renal complicity, mal unction o other systems would not produce sustained hypertension, since the normal kidney is capable o eliminating su f cient volume to return the BP to normal.
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CNS Blo o d ve s s e l Func tiona l: • ↓ Nitric oxide s e cre tion • ↑ Endothe lin production • Ca ++ or Na +/K+ cha nne l de fe cts • Hype rre s pons ive ne s s to ca te chola mine s
• ↑ Ba s a l s ympa the tic tone • Abnorma l s tre s s re s pons e • Abnorma l re s pons e to s igna ls from ba rore ce ptors a nd volume re ce ptors Pre s s ure /vo lume re c e pto rs • De s e ns itiza tion
S truc tura l: • Exa gge ra te d me dia l hype rtrophy
Adre nal • Ca te chola mine le a k or ma lre gula tion
Kidne y • RAA dys function • Ion cha nne l de fe cts (e .g., Na +/K+/2 Cl – cotra ns porte r, ba s ola te ra l Na +/ K+ ATP a s e , Ca ++ ATP a s e )
FIGURE 13-3. Potential primary abnormalities in essential hypertension ( EH) . These de ects are supported by experimental evidence, but their specif c contributions to EH remain unknown. CNS, central nervous system; RAA, renin–angiotensin–aldosterone system.
Insulin Resistance, Obesity, and the Metabolic Syndrome Recent research has suggested that the hormone insulin may play a role in the development o EH. In many people with hypertension, especially those who are obese or have type 2 diabetes, there is impaired insulin-dependent transport o glucose into many tissues (termed insulin resistance). As a result, serum glucose levels rise, stimulating the pancreas to release additional insulin. Elevated insulin levels may contribute to hypertension via increased sympathetic activation or by stimulation o vascular smooth muscle cell hypertrophy, which increases vascular resistance. Smooth muscle cell hypertrophy may be caused by a direct mitogenic e ect o insulin or through enhanced sensitivity to platelet-derived growth actor. Obesity itsel has been directly associated with hypertension. Possible explanations or this relationship include (1) the release o angiotensinogen rom adipocytes as substrate or the renin–angiotensin system; (2) augmented blood volume related to increased body mass; and (3) increased blood viscosity caused by adipocyte release o prof brinogen and plasminogen activator inhibitor 1. The current epidemic o obesity has led to a dramatic increase in the number o people with metabolic syndrome. As described in Chapter 5, this condition represents a clustering o atherogenic risk actors, including hypertension, hypertriglyceridemia, low serum high-density lipoprotein (HDL), a tendency toward glucose intolerance, and truncal obesity. Current evidence suggests that insulin resistance is central to the pathogenesis o this clustering.
Natural History EH characteristically arises a ter young adulthood. Its prevalence increases with age, and more than 60% o Americans older than 60 years are hypertensive. In addition, the hemodynamic characteristics o BP elevation in EH tend to change over time. The systolic pressure increases throughout adult li e, while the diastolic pressure rises until about the age o
Chapter 13 100% 90% 80% Is ola te d sys tolic hype rte ns ion
60% Sys tolic a nd dia s tolic hype rte ns ion
50%
r
e
q
u
e
n
c
y
70%
F
316
40%
Is ola te d dia s tolic hype rte ns ion
30% 20% 10% 0%
<40
40–49
50–59 60–69 Age (ye a rs )
70–79
>80
FIGURE 13-4. Categories of blood pressure elevation in untreated hypertensive patients. Isolated systolic hypertension predominates in patients older than 50 years, primarily as a result o decreased vascular compliance. (Modif ed rom Franklin SS, Jacobs MJ, Wong ND, et al. Predominance o isolated systolic hypertension among middle aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES III). Hypertension. 2001;37:869–874.)
50 and then declines slightly therea ter (see Fig. 13-1). Accordingly, diastolic hypertension is more common in young people, while a substantial number o hypertensive patients over age 50 have isolated systolic hypertension with normal diastolic values (see Fig. 13-4). In younger persons with hypertension, elevated BP tends to be driven by high CO in the setting o relatively normal peripheral vascular resistance, termed the hyperkinetic phase o EH (Fig. 13-5). With advancing age, however, the e ect o CO declines, perhaps because o the development o le t ventricular hypertrophy (LVH) and its consequent reduced diastolic f lling (which in turn reduces SV and CO). Conversely, vascular resistance increases with age due to medial hypertrophy as the vessels adapt to the prolonged pressure stress. Thus, younger hypertensive patients o ten display augmented CO as the principal abnormality, and older patients tend to have elevated TPR as the major hemodynamic f nding. In summary, EH is a syndrome that may arise rom many potential abnormalities, but it exhibits a characteristic hemodynamic prof le and natural history. It is likely that multiple de ects, separately inherited or acquired, act together to chronically raise BP. Although we may not understand the precise underlying mechanisms in individual hypertensive patients, we can at least describe the kinds o pathophysiology that might be at ault.
CO
Ca rdia c output (CO) contribution to blood pre s s ure
TP
R
Pe riphe ra l re s is ta nce (TP R) contribution to blood pre s s ure
Incre a s ing a ge
FIGURE 13-5. Hemodynamic progression of essential hypertension ( EH) . Schematic representation o the changing contribution o cardiac output (CO) and total peripheral resistance (TPR) as age increases in many patients with EH.
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SECONDARY HYPERTENSION Although EH dominates the clinical picture, a de ned structural or hormonal cause or hypertension may be ound in a small percentage o patients. Identi cation o such cases o secondary hypertension is important because the underlying conditions may require therapy di erent rom that administered or EH, and they are o ten curable. Moreover, i secondary hypertension is le t uncontrolled, adaptive cardiovascular changes may develop analogous to those o long-standing EH that could cause the elevated pressures to persist even a ter the underlying cause is corrected. Although secondary orms should be considered in the workup o all patients with hypertension, there are clues that a given patient may have one o the correctable conditions (Table 13-2): 1. Age. I a patient develops hypertension be ore age 20 or a ter age 50 (outside the usual range o EH), secondary hypertension is more likely. 2. Severity. Secondary hypertension o ten causes BP to rise dramatically, whereas most EH patients usually have mild-to-moderate hypertension. 3. Onset. Secondary orms o hypertension o ten present abruptly in a patient who was previously normotensive, rather than gradually progressing over years as is the usual case in EH. 4. Associated signs and symptoms. The process that induces hypertension may give rise to other characteristic abnormalities, identi ed by the history and physical examination. For example, a renal artery bruit (swishing sound caused by turbulent blood f ow through a stenotic artery) may be heard on abdominal examination in a patient with renal artery stenosis. 5. Family history. EH patients o ten have hypertensive rst-degree relatives, whereas secondary hypertension more commonly occurs sporadically.
Patient Evaluation The usual clinical evaluation o a patient with recently diagnosed hypertension begins with a care ul history and physical examination, including a search or clues to the secondary orms. For example, repeated urinary tract in ections may suggest the presence o chronic pyelonephritis
TABLE 13-2
Causes of Hypertension
Type Essential
Chronic renal disease Primary aldosteronism
Renovascular
Percent of Hypertensive Patients ~90%
2%–4% < 2%–15% (varies by sensitivity of screening) 1%
Pheochromocytoma
0.2%
Coarctation of the aorta
0.1%
Cushing syndrome
0.1%
Clinical Clues • • • • •
• • • • • • • • •
Age of onset: 20–50 years Family history of hypertension Normal serum K+ , urinalysis ↑ Creatinine, abnormal urinalysis ↓ Serum K+
Abdominal bruit Sudden onset (especially if age > 50 or < 20) ↓ Serum K+ Paroxysms of palpitations, diaphoresis, and headache Weight loss Episodic hypertension in one third of patients Blood pressure in arms > legs, or right arm > left arm Midsystolic murmur between scapulae Chest x-ray: aortic indentation, rib notching due to arterial collaterals • “Cushingoid” appearance (e.g., central obesity, hirsutism)
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Chapter 13 with renal damage as the cause o hypertension. Excessive weight loss may be an indicator o pheochromocytoma, whereas weight gain may point to the presence o Cushing syndrome (these conditions are described below). The history also should include an assessment o li estyle behaviors that may contribute to hypertension, such as excessive alcohol consumption, and the patient’s medications should be reviewed because certain drugs (see next section) may elevate BP. Obstructive sleep apnea is commonly associated with hypertension and should be considered particularly in patients who snore and have a history o hypertension re ractory to medications. Laboratory tests commonly per ormed in the initial evaluation o the hypertensive patient, including general screening or secondary causes, are (1) urinalysis and measurement o the serum concentration o creatinine and blood urea nitrogen to evaluate or renal abnormalities; (2) serum potassium level (abnormally low in renovascular hypertension [RH] or aldosteronism); (3) blood glucose level (elevated in diabetes, which is strongly associated with hypertension and renal disease); (4) serum cholesterol, HDL cholesterol, and triglyceride levels, as part o the global vascular risk screen; and (5) an electrocardiogram ( or evidence o LVH caused by chronic hypertension). I no abnormalities are ound that suggest a secondary orm o hypertension, the patient is presumed to have EH and treated accordingly. I , however, the patient’s BP continues to be elevated despite standard treatments, then more detailed diagnostic testing may be undertaken to search or specif c secondary causes.
Exogenous Causes Several medications can elevate BP. For example, oral contraceptives may cause secondary hypertension in some women. The mechanism is likely related to increased activity o the renin–angiotensin system. Estrogens increase the hepatic synthesis o angiotensinogen, leading to greater production o angiotensin II (Fig. 13-6). Angiotensin II raises BP by several
ANGIOTENS INOGEN (s e cre te d by live r) RENIN (s e c re te d by kid ney) ANGIOTENS IN I ANGIOTENS INCONVERTING ENZYME
ANGIOTENS IN II
ANGIOTENS IN II RECEP TORS (AT1 s ubtype ) Arte ria l s mooth mus c le : Ad re na l g la nd : Symp a the tic ne rvous sys te m: Kid ney: Bra in: He a rt:
Va s ocons triction ↑ Aldos te rone (↑ re na l Na + re a bs orption) Fa cilita te s re le a s e of nore pine phrine ↑ Re na l tubula r Na + re a bs orption S timula te s thirs t a nd va s opre s s in s e cre tion Enha nce s contra ctility a nd ve ntricula r hype rtrophy
FIGURE 13-6. The renin– angiotensin–aldosterone system. Liver-derived angiotensinogen is cleaved in the circulation by renin (of kidney origin) to form angiotensin I (AI). AI is rapidly converted to the potent vasoconstrictor angiotensin II (AII) by angiotensin-converting enzyme. AII also modulates the release of aldosterone from the adrenal cortex. Aldosterone in turn acts to reabsorb Na+ from the distal nephron, resulting in increased intravascular volume. The other listed effects of AII receptor stimulation may also contribute to the development and maintenance of hypertension.
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mechanisms, most notably by direct vasoconstriction and by stimulating the adrenal release o aldosterone. The latter hormone causes renal sodium retention and, there ore, increased intravascular volume. Other medications that can raise BP include glucocorticoids, cyclosporine (an antirejection drug used in patients with organ transplants), erythropoietin (a hormone that increases bone marrow red blood cell ormation and elevates BP by increasing blood viscosity and reversing local hypoxic vasodilatation), and sympathomimetic drugs (which are common in over-thecounter cold remedies). Nonsteroidal anti-inf ammatory drugs can contribute to hypertension through dose-related augmentation o renal sodium and water retention. Two other substances that may contribute to hypertension are ethanol (i.e., chronic excessive consumption) and cocaine. Both o these are associated with increased sympathetic nervous system activity.
Renal Causes Given the crucial role o the kidney in the control o BP, it is not surprising that renal dys unction can lead to hypertension. In act, renal disease contributes to two important endogenous causes o secondary hypertension: renal parenchymal disease, accounting or 2% to 4% o hypertensive patients, and RH (renal arterial stenosis), which accounts or approximately 1% .
Renal Parenchymal Disease Parenchymal damage to the kidney can result rom diverse pathologic processes. The major mechanism by which injury leads to elevated BP is through increased intravascular volume. Damaged nephrons are unable to excrete normal amounts o sodium and water, leading to a rise in intravascular volume, elevated CO, and hence increased BP. I renal unction is only mildly impaired, BP may stabilize at a level at which the higher systemic pressure (and there ore renal per usion pressure) enables sodium excretion to balance sodium intake. Conversely, i a patient has end-stage renal ailure, the glomerular ltration rate may be so greatly decreased that the kidneys simply cannot excrete su cient volume, and malignant-range BP may ollow. Renal parenchymal disease may urther contribute to hypertension even i the glomerular ltration rate is not greatly reduced, through the excessive elaboration o renin.
Renovascular Hypertension Stenosis o one or both renal arteries leads to hypertension. Although emboli, vasculitis, and external compression o the renal arteries can be responsible, the two most common causes o RH are atherosclerosis and bromuscular dysplasia. Atherosclerotic lesions arise rom extensive plaque ormation either within the renal artery or in the aorta at the origin o the renal artery. This orm accounts or about two thirds o cases o RH and occurs most commonly in elderly men. In contrast, f bromuscular lesions consist o discrete regions o brous or muscular proli eration, generally within the arterial media. Fibromuscular dysplasia accounts or one third o cases o RH and characteristically occurs in young women. The elevated BP in RH arises rom reduced renal blood f ow to the a ected kidney, which responds to the lower per usion pressure by secreting renin. The latter raises the BP through the subsequent actions o angiotensin II (vasoconstriction) and aldosterone (sodium retention), as shown in Figure 13-6. The diagnosis o RH is suggested by an abdominal bruit, which can be ound in 40% to 60% o patients, or by the presence o unexplained hypokalemia (owing to excessive renal
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Chapter 13 excretion o potassium as a result o an elevated aldosterone level). The diagnosis can be conrmed, when invasive interventions are being considered, by duplex Doppler ultrasonography, computed tomographic angiography (CTA), or magnetic resonance angiography o the renal arteries. Therapy o RH with antihypertensive drugs is o ten e ective, particularly when an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker is included. These inhibitors o the renin–angiotensin system negate the hypertensive e ects o elevated circulating renin in RH by impeding the ormation or action o angiotensin II (see Chapter 17). However, these classes o drugs should be avoided, or used cautiously, in patients with bilateral renal artery stenotic lesions. The inhibition o angiotensin II may excessively reduce intraglomerular pressure and ltration, and worsen renal unction, in patients with bilateral disease who already have compromised per usion to both kidneys. In select patients with RH (e.g., those with recent onset hypertension due to RH, those whose BP remains elevated despite medical therapy, or those with progressive renal insu ciency due to renal artery stenosis) percutaneous catheter interventions or surgical reconstruction o the stenosed vessel may be more e ective than continued medical antihypertensive therapy alone.
Mechanical Causes Coarctation of the Aorta Coarctation is an in requent congenital narrowing o the aorta typically located just distal to the origin o the le t subclavian artery (see Chapter 16). As a result o the relative obstruction to f ow, the BP in the aortic arch, head, and arms is higher than that in the descending aorta and its branches and in the lower extremities. Sometimes the coarctation involves the origin o the le t subclavian artery, causing lower pressure in the le t arm compared with the right arm. Hypertension in this condition arises by two mechanisms. First, reduced blood f ow to the kidneys stimulates the renin–angiotensin system, resulting in vasoconstriction (via angiotensin II). Second, high pressures proximal to the coarctation sti en the aortic arch through medial hyperplasia and accelerated atherosclerosis, blunting the normal baroreceptor response to elevated intravascular pressure. Clinical clues to the presence o coarctation include symptoms o inadequate blood f ow to the legs or le t arm, such as claudication or atigue, or the nding o weakened or absent emoral pulses. A midsystolic murmur associated with the stenotic segment o the aorta may be auscultated, especially over the back, between the scapulae. The chest radiograph may show indentation o the aorta at the level o the coarctation. It may also demonstrate a notched appearance o the ribs secondary to the enlargement o collateral intercostal arteries, which shunt blood around the aortic narrowing. Treatment options include angioplasty or surgery to correct the stenosis. However, hypertension may not abate completely a ter mechanical correction, in part because o persistent desensitization o the arterial baroreceptors.
Endocrine Causes Circulating hormones play an important role in the control o normal BP, so it should not be surprising that endocrine diseases may cause hypertension. When suspected, the presence o such conditions is evaluated in our ways: 1. History o characteristic signs and symptoms 2. Measurement o hormone levels 3. Assessment o hormone secretion in response to stimulation or inhibition 4. Imaging studies to identi y tumors secreting the excessive hormone
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Pheochromocytoma Pheochromocytomas are catecholamine-secreting tumors o neuroendocrine cells (usually in the adrenal medulla) that account or approximately 0.2% o cases o hypertension. The release o epinephrine and norepinephrine by the tumor results in intermittent or chronic vasoconstriction, tachycardia, and other sympathetic-mediated e ects. A characteristic presentation consists o paroxysmal rises in BP accompanied by “autonomic attacks” caused by the increased catecholamine levels: severe throbbing headaches, pro use sweating, palpitations, and tachycardia. Although some patients are actually normotensive between attacks, most have sustained hypertension. Ten percent o pheochromocytomas are malignant. Determination o plasma catecholamine levels, or urine catecholamines and their metabolites (e.g., vanillylmandelic acid and metanephrine), obtained under controlled circumstances, are used to identi y this condition. Because some pheochromocytomas secrete only episodically, diagnosis may require measurement o catecholamines immediately ollowing an attack. Pharmacologic therapy o pheochromocytomas includes the combination o an α-receptor blocker (e.g., phenoxybenzamine) combined with a β-blocker. However, once the tumor is localized by computed tomography, magnetic resonance imaging, or angiography, the def nitive therapy is surgical resection. For patients with inoperable disease, treatment consists o α- and β-blockade as well as drugs that inhibit catecholamine biosynthesis (e.g., α-methyltyrosine).
Adrenocortical Hormone Excess Among the hormones produced by the adrenal cortex are mineralocorticoids and glucocorticoids. Excess o either o these can result in hypertension. Mineralocorticoids, primarily aldosterone, increase blood volume by stimulating reabsorption o sodium into the circulation by the distal portions o the nephron. This occurs in exchange or potassium excretion into the urine, and the resulting hypokalemia is an important marker o mineralocorticoid excess. Primary aldosteronism results either rom an adrenal adenoma (termed Conn syndrome) or rom bilateral hyperplasia o the adrenal glands. While once considered rare, recent data suggest that the requency o primary aldosteronism may be as high as 10% to 15% among hypertensives, depending on the sensitivity o screening, with a substantial majority having the bilateral hyperplasia orm. The diagnosis may be suspected by the presence o hypokalemia and is conf rmed by the f nding o excessive plasma aldosterone and a suppressed renin level. Therapy includes either surgical removal o the responsible adenoma (i present) or medical management with aldosterone receptor antagonists. Glucocorticoid-remediable aldosteronism (GRA), an uncommon hereditary (autosomal dominant) orm o primary aldosteronism, results rom a genetic rearrangement in which aldosterone synthesis abnormally comes under the regulatory control o adrenocorticotropic hormone (ACTH). This condition typically presents as severe hypertension in childhood or young adulthood, as opposed to the more common orms o primary aldosteronism, which are generally diagnosed in the third through sixth decades. Unlike other orms o hypertension, GRA-related BP elevation responds to glucocorticoid therapy, which suppresses ACTH release rom the pituitary gland. Secondary aldosteronism can result rom increased angiotensin II production stimulated by rare renin-secreting tumors. More commonly, secondary elevation o aldosterone is a result o augmented circulating angiotensin II in women taking oral contraceptives (which stimulate hepatic production o angiotensinogen, as described earlier) or because o impaired angiotensin II degradation in chronic liver diseases. Glucocorticoids, such as cortisol, elevate BP when present in excess amounts, likely via blood volume expansion and stimulated synthesis o components o the renin–angiotensin system. In addition, though mineralocorticoids are more potent activators o mineralocorticoid receptors in the renal tubules, excess glucocorticoids may also activate them.
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Chapter 13 Nearly 80% o patients with Cushing syn drome, a disorder o glucocorticoid excess, have some degree o hypertension. These patients o ten present with classic “cushingoid” eatures: a characteristic rounded acial appearance, central obesity, proximal muscle weakness, and hirsutism. The cause o the excess glucocorticoids may be either a pituitary ACTH-secreting adenoma, a peripheral ACTH-secreting tumor (either o which causes adrenal cortical hyperplasia), or an adrenal cortisol-secreting adenoma. The diagnosis o Cushing syndrome is con rmed by a 24-hour urine collection or the measurement o cortisol, or by a dexamethasone test, which evaluates whether exogenous glucocorticoids can suppress cortisol secretion.
Thyroid Hormone Abnormalities Approximately one third o hyperthyroid and one ourth o hypothyroid patients have signi cant hypertension. Thyroid hormones exert their cardiovascular e ects by (1) inducing sodium–potassium ATPases in the heart and vessels; (2) increasing blood volume; and (3) stimulating tissue metabolism and oxygen demand, with secondary accumulation o metabolites that modulate local vascular tone. Hyperthyroid patients develop hypertension through cardiac hyperactivity with an increase in blood volume. Hypothyroid patients demonstrate predominantly diastolic hypertension and an increase in peripheral vascular resistance. Though the precise mechanism is unclear, the latter e ect appears to be mediated by sympathetic and adrenal activation in hypothyroidism.
CONSEQUENCES OF HYPERTENSION Whatever the cause o BP elevation, the ultimate consequences are similar. High BP itsel is generally asymptomatic but can result in devastating e ects on many organs.
Clinical Signs and Symptoms In the past, “classic” symptoms o hypertension were considered to include headache, epistaxis (nose bleeds), and dizziness. However, the use ulness o these symptoms has been called into question by studies that indicate that they are ound no more requently among hypertensive patients than in the general population. Other symptoms, such as f ushing, sweating, and blurred vision, do seem more common in the hypertensive population. In general, however, most hypertensive patients are asymptomatic and are diagnosed simply by BP measurement during routine physical examinations. Several physical signs o hypertension discussed in the ollowing sections result directly rom elevated pressure, including LVH and retinopathy. In addition, hypertension complicated by atherosclerosis can mani est by arterial bruits, particularly in the carotid and emoral arteries.
Organ Damage Caused by Hypertension Target organ complications o hypertension ref ect the degree o chronic BP elevation. Such organ damage can be attributed to (1) the increased workload o the heart and (2) arterial damage resulting rom the combined e ects o the elevated pressure itsel (weakened vessel walls) and accelerated atherosclerosis (Fig. 13-7). Abnormalities o the vasculature that result rom elevated pressure include smooth muscle hypertrophy, endothelial cell dys unction, and atigue o elastic bers. Chronic hypertensive trauma to the endothelium promotes atherosclerosis possibly by disrupting normal protective mechanisms, such as the secretion o nitric oxide. Arteries lined by atherosclerotic plaque may thrombose or may serve as a source o cholesterol emboli that occlude distal vessels, causing organ in arction (such as cerebrovascular occlusion, resulting in stroke). In addition, atherosclerosis o large arteries hinders
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Hype rte ns ion
↑ Afte rloa d
Sys tolic dys function
LVH
Arte ria l da ma ge
↑ Myoca rdia l oxyge n de ma nd
Dia s tolic dys function
Acce le ra te d a the ros cle ros is
We a ke ne d ve s s e l wa ll
(Corona ry) (Ce re bra l/ca rotid)
↓ Myoca rdia l oxyge n s upply
(Aorta)
(Ce re bra l he morrha ge )
(Eye )
Thrombos is & a the roe mboli
Ao rtic ane urys m & dis s e c tio n
He art failure
(Kidney)
Myo c ardial is c he mia & infarc tio n
Ne phro s cle ro s is & re nal failure
S tro ke
Re tino pathy
FIGURE 13-7. Pathogenesis of the major consequences of arterial hypertension. LVH, left ventricular hypertrophy.
their elasticity, resulting in systolic pressure spikes that can further traumatize endothelium or provoke events such as aneurysm rupture. The major target organs for the destructive complications of chronic hypertension are the heart, the cerebrovascular system, the aorta and peripheral vascular system, the kidney, and the retina (Table 13-3). Left untreated, approximately 50% of hypertensive patients die of coronary artery disease or congestive heart failure, about 33% succumb to stroke, and 10% to 15% die from complications of renal failure.
Heart The major cardiac effects of hypertension relate to the increased afterload against which the heart must contract and accelerated atherosclerosis within the coronary arteries.
TABLE 13-3
Target Organ Damage in Hypertension
Organ System
Manifestations
Heart
• • • • • • • • • •
Cerebrovascular Aorta and peripheral vascular Kidney Retina
Left ventricular hypertrophy Heart failure Myocardial ischemia and infarction Stroke Aortic aneurysm and/ or dissection Arteriosclerosis Nephrosclerosis Renal failure Arterial narrowing Hemorrhages, exudates, papilledema
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Left Ventricular Hypertrophy and Diastolic Dysfunction The high arterial pressure (heightened a terload) increases the wall tension o the le t ventricle, which compensates through hypertrophy. Concentric hypertrophy (without dilatation) is the normal pattern o compensation, although conditions that elevate BP by virtue o increased circulating volume (e.g., primary aldosteronism) may instead cause eccentric hypertrophy with chamber dilatation (see Chapter 9). LVH results in increased sti ness o the le t ventricle with diastolic dys unction, mani ested by elevation o LV lling pressures that can result in pulmonary congestion (i.e., heart ailure with preserved ejection raction—see Chapter 9). Physical ndings o LVH may include a heaving LV impulse on chest palpation, indicative o the increased muscle mass. It is requently accompanied by a ourth heart sound (S4), as the le t atrium contracts into the sti ened le t ventricle (see Chapter 2). LVH is one o the strongest predictors o cardiac morbidity in hypertensive patients. The degree o hypertrophy correlates with the development o congestive heart ailure, angina, arrhythmias, myocardial in arction, and sudden cardiac death.
Systolic Dysfunction Although LVH initially serves a compensatory role, later in the course o systemic hypertension, the increased LV mass may be insu cient to balance the high wall tension caused by the elevated pressure. As LV contractile capacity deteriorates, ndings o systolic dys unction become evident (i.e., reduced CO and pulmonary congestion). Systolic dys unction is also provoked by the accelerated development o coronary artery disease with resultant periods o myocardial ischemia.
Coronary Artery Disease Chronic hypertension is a major contributor to the development o myocardial ischemia and in arction. These complications ref ect the combination o accelerated coronary atherosclerosis (decreased myocardial oxygen supply) and the high systolic workload (increased oxygen demand). In addition, hypertensives have a higher incidence o postmyocardial in arction complications such as rupture o the ventricular wall, LV aneurysm ormation, and congestive heart ailure.
Cerebrovascular System Hypertension is the major modi able risk actor or strokes, also termed cerebrovascular accidents (CVAs). Although diastolic pressure is important, it is the magnitude o the systolic pressure that has been most closely linked to CVAs. The presence o isolated systolic hypertension more than doubles a person’s risk or this complication. Hypertension-induced strokes can be hemorrhagic or, more commonly, atherothrombotic. Hemorrhagic CVAs result rom rupture o microaneurysms induced in cerebral parenchymal vessels by longstanding hypertension. Atherothrombotic (also called thromboembolic) CVAs arise when portions o atherosclerotic plaque within the carotids or major cerebral arteries, or thrombi that orm on those plaques, break o , and embolize to smaller distal vessels. Additionally, intracerebral vessels may be directly occluded by local atherosclerotic plaque rupture and thrombosis. Occlusion o small penetrating brain arteries can result in multiple tiny in arcts. As these lesions so ten and are absorbed by phagocytic cells, small (≤ 3 mm diameter) cavities orm, termed lacunae. These lacunar in arctions are seen almost exclusively in patients with longstanding hypertension and are usually localized to the penetrating branches o the middle and posterior circulation o the brain.
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In addition, the generalized arterial narrowing ound in hypertensive patients reduces collateral f ow to ischemic tissues and imposes structural requirements or higher per usion pressure to maintain adequate tissue f ow. This leaves the hypertensive patient vulnerable to cerebral in arcts in areas supplied by the distal ends o arterial branches (“watershed” in arcts) i BP should all suddenly. E ective treatment o hypertension diminishes the risk o stroke and has contributed to a 50% reduction in deaths attributed to cerebrovascular events in recent decades.
Aorta and Peripheral Vasculature The accelerated atherosclerosis associated with hypertension may result in plaque ormation and narrowing throughout the arterial vasculature. In addition to the coronary arteries, lesions most commonly appear within the aorta and the major arteries that serve the lower extremities, neck, and brain. Chronic hypertension may lead to the development o aneurysms, particularly o the abdominal aorta. An abdominal aortic aneurysm represents prominent dilatation o the vessel, usually located below the level o the renal arteries, contributed to by the mechanical stress o the high pressure on an arterial wall already weakened by medial damage and atherosclerosis (see Chapter 15). Aneurysms greater than 6 cm in diameter have a very high likelihood o rupture within 2 years i not surgically corrected. Another li e-threatening vascular consequence o high BP is aortic dissection (see Chapter 15). Elevated BP, especially in the highest ranges, accelerates degenerative changes in the media o the aorta. When the weakened wall is urther exposed to high pressure, the intima may tear, allowing blood to dissect into the aortic media and propagate in either direction within the vessel wall, “clipping o ” and obstructing major branch vessels along the way (including coronary or carotid arteries). The treatment o aortic dissection requires rigorous BP control, and urgent surgical repair i the proximal aorta is involved.
Kidney Hypertension-induced kidney disease (nephrosclerosis) is a leading cause o renal ailure that results rom damage to the organ’s vasculature. Histologically, the vessel walls become thickened with a hyaline in ltrate, known as hyaline arteriolosclerosis (Fig. 13-8). Greater levels o hypertension can induce smooth muscle hypertrophy and necrosis o capillary walls, termed f brinoid necrosis. These changes result in reduced vascular supply and subsequent ischemic atrophy o tubules and, to a lesser extent, glomeruli. Because intact nephrons can usually compensate or those damaged by patchy ischemia, mild hypertension rarely leads to renal insu ciency in the absence o other insults to the kidney. However, malignant levels o hypertension can inf ict permanent damage leading to chronic renal ailure. One o the consequences o hypertensive renal ailure is perpetuation o elevated BP. For example, progressive renal dys unction compromises the ability o the kidney to regulate blood volume, which contributes urther to chronic hypertension.
Retina The retina is the only location where systemic arteries can be directly visualized by physical examination. High BP induces abnormalities that are collectively termed hypertensive retinopathy. Although vision may be compromised when the damage is extensive, more commonly the changes serve as an asymptomatic clinical marker or the severity o hypertension and its duration. Severe hypertension that is acute in onset (e.g., uncontrolled and/ or malignant hypertension) may burst small retinal vessels, causing hemorrhages, exudation o plasma lipids, and areas o local in arction. I ischemia o the optic nerve develops, patients may describe
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FIGURE 13-8. Hypertension-associated kidney injury. The arteriolar walls are thickened by hyaline inf ltrate (short arrows). The glomeruli (long arrow) appear sclerosed because o reduced vascular supply. (Courtesy o Dr. Helmut G. Rennke, Brigham and Women’s Hospital, Boston, MA.)
generalized blurred vision. Retinal ischemia caused by hemorrhage leads to more patchy loss o vision. Papilledema, or swelling o the optic disk with blurring o its margins, may arise rom high intracranial pressure when the BP reaches malignant levels and cerebrovascular autoregulation begins to ail. Chronically elevated BP results in a di erent set o retinal ndings. Papilledema is absent, but vasoconstriction results in arterial narrowing, and medial hypertrophy thickens the vessel wall, which “nicks” (indents) crossing veins. With more severe chronic hypertension, arterial sclerosis is evident as an increased ref ection o light through the ophthalmoscope (termed “copper” or “silver” wiring). Although these changes are not in themselves o major unctional importance, they indicate that the patient has had long-standing, poorly controlled hypertension.
HYPERTENSIVE CRISIS A hypertensive crisis is a medical emergency characterized by a severe elevation o BP. In the past, this type o elevation was usually a consequence o inadequate BP treatment. Now a hypertensive crisis is more o ten caused by an acute hemodynamic insult (e.g., acute renal disease) superimposed on a chronic hypertensive state. As a result o rapid pathologic changes ( brinoid necrosis) within the blood vessels and kidneys, a spiraling increase in BP evolves. Further volume expansion and vasoconstriction occur as renal per usion drops and serum renin and angiotensin levels rise. Severe BP elevation results in increased intracranial pressure, and patients may present with hypertensive encephalopathy mani ested by headache, blurred vision, con usion,
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somnolence, and sometimes coma. When hypertension results in acute damage to retinal vessels, accelerated-malignant hypertension is said to be present. Funduscopic examination shows the e ects o the rapid pressure rise as hemorrhages, exudates, and sometimes papilledema, as described earlier. The increased load on the le t ventricle during a hypertensive crisis may precipitate angina (because o increased myocardial oxygen demand) or pulmonary edema. A hypertensive crisis requires rapid therapy to prevent permanent vascular complications. Correction o BP is generally ollowed by reversal o the acute pathologic changes, including papilledema and retinal exudation, although renal damage o ten persists.
TREATMENT OF HYPERTENSION The therapeutic approach to the hypertensive patient should be inf uenced by two considerations. First, a single elevated BP measurement does not establish the diagnosis o hypertension because BP varies considerably rom day to day. Moreover, BP measurement in the hospital or doctor’s o ce may be a ected by the “white coat” e ect resulting rom patient anxiety. The average o multiple readings taken at two or three o ce visits and/ or in the home provides a more reliable basis or labeling a patient as hypertensive. There is also evidence that automatic ambulatory BP measurements, taken over the course o 24 hours while the patient ollows a daily routine, are more predictive o cardiovascular mortality than traditional in-clinic measurements. Second, although even mild hypertension is a major public health problem because o its high prevalence, or the person with stage 1 hypertension, the risks are small. For example, the additional risk o a stroke is approximately 1 in 850 per year. Hence, observation over time to determine whether the low-level hypertension persists, or whether li estyle changes can reduce the pressure, is o ten a recommended alternative to immediate drug therapy. This is especially true in the absence o other cardiovascular risk actors such as smoking, diabetes, or high serum cholesterol. However, or patients with established cardiovascular disease or or those who have other major atherosclerotic risk actors, a more aggressive approach to pharmacologic therapy is usually warranted to reduce the risk burden. For most hypertensive patients, drug therapy is ultimately the most e ective way to prevent uture complications, but that should not deter consideration o other bene cial li estyle changes.
Nonpharmacologic Treatment Certain li estyle modi cations have been shown to be e ective in lowering BP and should be considered in the treatment plan or any patient with hypertension.
Weight Reduction Studies have consistently ound obesity and hypertension to be highly correlated, especially when the obesity is o a central (abdominal) distribution. BP reduction ollows weight loss in a large portion o hypertensive patients who are more than 10% above their ideal weights. Each 10 kg o weight loss is associated with a 5 to 20 mm Hg all in systolic BP.
Exercise Sedentary normotensive people have a 20% to 50% higher risk o developing hypertension than do their more active peers. Regular aerobic exercise, such as walking, jogging, or bicycling, has been shown to contribute to BP reduction over and above any resulting weight loss. A hypertensive patient who becomes physically conditioned mani ests a lower resting HR and reduced levels o circulating catecholamines than be ore training, suggesting a all in sympathetic tone.
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Diet In addition to caloric restriction or weight loss, changes in the composition o a patient’s diet may be important or BP reduction. For example, a diet high in ruits, vegetables, and low- at dairy products has been shown to signif cantly reduce BP.
Sodium Salt restriction or people with high BP is a controversial issue, but there are several epidemiologic and clinical trials that support the benef t o moderating sodium intake. In normotensive persons, excess salt ingestion is simply excreted by the kidneys, but approximately 50% o patients with EH are ound to have BPs that vary with sodium intake, suggesting a de ect in natriuresis. Sensitivity to sodium levels is more common in A rican American and elderly hypertensive patients. Because low-salt diets tend to increase the e ectiveness o antihypertensive medications in general, the current recommendation is to limit salt intake to less than 6 g o sodium chloride (less than 2.3 g sodium) per day, which is one third less than the average United States consumption.
Potassium Total body potassium content tends to decrease when a person eats a diet low in ruits and vegetables or takes potassium-wasting diuretics. Potassium def ciency has several theoretical e ects that may raise BP and contribute to adverse cardiovascular outcomes, such that dietary supplements are routinely recommended to help replete low serum K+ levels. There is no convincing evidence that prescribing potassium supplements to a normokalemic hypertensive patient will lower BP.
Alcohol The chronic excessive intake o alcoholic beverages correlates with high BP and resistance to antihypertensive medications. Moreover, experimental evidence shows that BP (especially systolic) may rise acutely ollowing alcohol consumption. The reason or this link remains incompletely understood, but decreasing chronic alcohol intake has been shown to lower BP.
Other Low calcium intake and magnesium depletion have been associated with elevated BP, but the responsible mechanisms and the implications or therapy are unclear. Ca eine ingestion transiently increases BP (as much as 5 to 15 mm Hg a ter two cups o co ee), but routine use does not seem to produce chronic pressure elevation.
Smoking Cessation Cigarette smoking transiently increases BP, likely because o the e ect o nicotine on autonomic ganglia, and is a risk actor or the development o sustained hypertension. In addition, the atherogenic e ect o smoking may contribute to the development o RH. Cigarette usage is associated with many other health hazards, and all patients should be discouraged rom smoking.
Relaxation Therapy BP requently rises under conditions o stress. In addition, essential hypertensive patients and their relatives o ten show higher-than-normal basal sympathetic tone and exaggerated autonomic responses to mental stress. Hence, relaxation techniques have been advocated as
Hypertension
TABLE 13-4
329
Classes of Antihypertensive Medications
Drug Class
Examples ( See Chapter 17)
Physiologic Action
Diuretics
Thiazides Potassium-sparing diuretics Loop diuretics β-Blockers
↓ Circulating volume
Sympatholytics
Combined α- and β-blockers
Vasodilators Renin–angiotensin– aldosterone system antagonists
Central α2-agonists Peripheral α1-antagonists Calcium channel blockers Direct vasodilators (e.g., hydralazine, minoxidil) Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Direct renin inhibitors
↓ Heart rate, cardiac contractility, and renin secretion Same as β-blocker plus vascular smooth muscle relaxation ↓ Sympathetic tone Vascular smooth muscle relaxation ↓ Peripheral vascular resistance ↓ Peripheral vascular resistance and ↓ Sodium retention
a method to control hypertension. Available methods include bio eedback and meditation. The e ectiveness o such therapy has not been consistently demonstrated in clinical trials and seems to depend on the patient’s attitude and long-term compliance. In summary, nonpharmacologic therapy o ers a wide range o options that do not have the expense and potential side e ects o prescribed drug use. The e ectiveness o these therapies should come as no surprise, given the extent to which environmental actors play a role in hypertension. There ore, behavior-based interventions are recommended as f rst-line therapy in any patient whose hypertension is not an immediate danger.
Pharmacologic Treatment Antihypertensive medications are the standard means to lower chronically elevated BP and are indicated i nonpharmacologic treatment proves inadequate. More than 100 drug preparations are available to treat hypertension, but ortunately the most commonly used medications all into our classes: diuretics, sympatholytics, vasodilators, and drugs that inter ere with the renin–angiotensin system (Table 13-4). The individual actions o these groups on the physiologic abnormalities in hypertension are shown in Figure 13-9. The pharmacology and use o antihypertensive drugs are described in greater detail in Chapter 17. Diuretics have been in use or many decades to treat hypertension. They reduce circulatory volume, CO, and mean arterial pressure, and are most e ective in patients with mildto-moderate hypertension who have normal renal unction. They are especially e ective in A rican American or elderly persons, who tend to be salt sensitive. In clinical trials, diuretics have reduced the risk o strokes and cardiovascular events in hypertensive patients and are inexpensive compared with other agents. Thiazide diuretics (e.g., hydrochlorothiazide) and pota ssium-sparin g diuretics (e.g., spironolactone) promote Na + excretion in the distal nephron (see Chapter 17). Loop diuretics (e.g., urosemide) are generally too potent and their actions too short-lived or use as antihypertensive agents; however, they are use ul in lowering BP in patients with renal insu f ciency, who o ten do not respond to other diuretics. Thiazides, the most commonly used diuretics in hypertension, may result in adverse metabolic side e ects, including elevation o serum glucose, cholesterol, and triglyceride levels. In addition, hypokalemia, hyperuricemia, and decreased sexual unction are potential side e ects.
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Chapter 13 Blood Pre s s ure
Ca rdia c Output
HR
Pe riphe ra l Re s is ta nce
Circula ting re gula tors
SV
• β-Blocke rs • S ome CCB Contra ctility
Ve nous re turn
Dire ct inne rva tion
• CCB a nd dire ct va s odila tors
• RAS blocke rs • α 1 -Blocke rs • α 1 -Blocke rs • Ce ntra l α 2 -a gonis ts • Ce ntra l α 2 -a gonis ts
• β-Blocke rs • CCB Blood volume
Ve nous tone
• Diure tics • RAS blocke rs
• RAS blocke rs • CCB • α 1 -Blocke rs
FIGURE 13-9. Physiologic effects of antihypertensive medications. Notice that some antihypertensive medications work at multiple sites. CCB, calcium channel blockers; HR, heart rate; RAS blockers, renin– angiotensin system blockers (i.e., angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers); SV, stroke volume.
However, when diuretics are prescribed in low dosages, it is o ten possible to accrue the desired antihypertensive e ect while minimizing adverse complications. Sympatholytic agents include (1) β-blockers, (2) central α-adrenergic agonists, and (3) systemic α-adrenergic-blocking drugs. β-Blockers are believed to lower BP through several mechanisms, including (1) reducing CO through a decrease in HR and a mild decline in contractility and (2) decreasing the secretion o renin (and there ore levels o angiotensin II), which leads to a reduction in TPR. β-Blockers are less e ective than diuretics in elderly and A rican American hypertensive patients. Adverse e ects o β-blockers include bronchospasm (because o bronchiolar β2-receptor blockade), atigue, impotence, and hyperglycemia. They may also adversely alter lipid metabolism. Most β-blockers cause an increase in serum triglyceride levels and a decrease in “good” HDL cholesterol levels. However, β-blockers with intrinsic sympathomimetic activity (see Chapter 17) or those with combined α- and β-blocking properties (such as labetalol) do not adversely a ect HDL levels. Centrally acting α 2-adrenergic agonists, such as methyldopa and clonidine, reduce sympathetic outf ow to the heart, blood vessels, and kidneys. These are now rarely used owing to their high requency o side e ects (e.g., dry mouth, sedation). Systemic α 1-antagonists, such as prazosin, terazosin, and doxazosin, cause a decrease in TPR through relaxation o vascular smooth muscle. They may be use ul or hypertension in some older men because the drugs also improve symptoms o prostatic enlargement. However, they are otherwise not o ten recommended or treatment o hypertension because a major clinical trial showed that diuretic therapy is superior to an α1-antagonist in the prevention o adverse cardiovascular events. Peripheral vasodilators include calcium channel blockers, hydralazine, and minoxidil. Calcium channel blockers reduce the inf ux o Ca + + responsible or cardiac and vascular smooth muscle contraction, thus reducing cardiac contractility and TPR (see Chapter 17). Clinical trials in patients with hypertension have shown that calcium channel blockers reduce the risk o myocardial in arction and stroke. Thus, long-acting (i.e., sustained-release drugs taken once a day) members o this group are requently used to treat hypertension. Shorteracting calcium channel blocker preparations are not used or this purpose; they are less convenient and have actually been associated with adverse cardiovascular outcomes (see Chapter 6).
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Hydralazine and minoxidil lower BP by directly relaxing vascular smooth muscle o precapillary resistance vessels. However, the resultant vasodilatation can result in a ref ex increase in HR, so that combined β-blocker therapy is requently necessary. The use o these direct vasodilators in treating hypertension has waned with the advent o newer agents with ewer side e ects. Drugs that inter ere with the renin–angiotensin–aldosterone system include ACE inhibitors, angiotensin II receptor blockers, and direct renin inhibitors. ACE inhibitors decrease BP by blocking the conversion o angiotensin I to angiotensin II (see Fig. 17-6), thereby reducing the vasopressor e ect o angiotensin II and the secretion o aldosterone. As a result, peripheral vascular resistance alls and sodium retention by the kidney declines. An additional antihypertensive e ect o ACE inhibitors occurs via an increase in the concentration o the circulating vasodilator bradykinin (see Fig. 17-6). ACE inhibitors are important drugs that have been shown to reduce mortality rates in patients ollowing an acute myocardial in arction, in patients with chronic heart ailure with reduced ejection raction (see Chapter 9), and even in people at high risk or developing cardiovascular disease. The drugs also slow the deterioration o renal unction in patients with diabetic nephropathy. The most common side e ect o ACE inhibitors is the development o a reversible dry cough (likely related to the increased bradykinin e ect); hyperkalemia and azotemia may also occur, as described in Chapter 17. Angiotensin II receptor blockers (ARBs) block the binding o angiotensin II to its receptors (i.e., subtype AT1 receptors) in blood vessels and other targets (see Fig. 17-6). By inhibiting the e ects o angiotensin II (and thereby causing vasodilatation and reduced secretion o aldosterone), BP alls. In clinical trials, the antihypertensive e cacy o this group is similar to that o ACE inhibitors. They are very well-tolerated drugs, and unlike ACE inhibitors, cough is not a common side e ect. Like ACE inhibitors, ARBs have been shown to reduce cardiovascular event rates (including myocardial in arction and stroke) in high-risk patients. The oral direct renin inhibitor aliskiren reduces levels o angiotensin I and angiotensin II by binding to the proteolytic site o renin, thus inhibiting cleavage o angiotensinogen. Antihypertensive e ectiveness is no greater than that o other drugs that inhibit the renin– angiotensin–aldosterone axis and long-term e ects on cardiovascular event rates are not yet known. Given the large number o e ective antihypertensive medications that are available, the choice o which drug to use as initial therapy in an individual patient can seem daunting. Besides the exceptions noted above, clinical trial data reveal little di erence between antihypertensive agents on cardiovascular outcomes in the average hypertensive subject as long as equivalent decreases in BP are achieved. As o this writing, national guidelines recommend the use o either a thiazide diuretic, calcium channel blocker, ACE inhibitor, or an ARB as equally e ective rst-line treatment options or EH. Thiazide diuretics remain among the most popular choices by health care providers because o long-proven bene ts and low cost. In certain circumstances, or i initial therapy with a single agent is not su cient, another type o antihypertensive should be substituted or added (Table 13-5). For example, an ACE inhibitor would be given prime consideration in patients with hypertension who also have chronic heart ailure, diabetes, or LV dys unction ollowing myocardial in arction. A β-blocker would be an appropriate choice in a patient with concurrent ischemic heart disease. There are some other guiding principles. First, the chosen drug regimen should con orm to the patient’s speci c needs. For example, an anxious young patient in the throes o the hyperkinetic phase o EH might be treated with a β-blocker, whereas a more e ective choice or the same patient many years later, a ter the pressure becomes more dependent on peripheral vascular resistance, could be a vasodilator (e.g., long-acting calcium channel blocker). Because therapy is likely to continue or many years, consideration o adverse e ects and impact o drug therapy on the patient’s quality o li e are very important.
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TABLE 13-5
Indications or Specif c Antihypertensive Medications
Concurrent Condition
Initial Therapy Drug Classes
Heart failure
Diuretics β-Blockers ACE inhibitors Angiotensin II receptor blockers Aldosterone antagonists (e.g., spironolactone—see Chapter 9) β-Blockers ACE inhibitors Angiotensin II receptor blockers Aldosterone antagonists ACE inhibitors Angiotensin II receptor blockers Calcium channel blockers ACE inhibitors Angiotensin II receptor blockers
Postmyocardial infarction
Diabetes
Chronic kidney disease
ACE, angiotensin-converting enzyme.
Another principle o antihypertensive drug therapy concerns the use o multiple agents. The e ects o one drug, acting at one physiologic control point, can be de eated by natural compensatory mechanisms. For example, the drop in renal per usion by a direct vasodilator can activate the renin–angiotensin system, prompting the kidney to retain volume, thereby blunting the antihypertensive benef t. Combination drug therapy is aimed at preventing such an action by using agents acting at di erent complementary sites. In this example, a direct vasodilator is o ten paired with a low-dose diuretic to avoid the undesired volume expansion e ect. In conclusion, hypertension emerges as a tremendously important clinical problem because o its prevalence and potentially devastating consequences. The evaluation and treatment o a patient with hypertension require methodical consideration o the ways in which normal cardiovascular physiology may have gone awry. Because most patients still all into the idiopathic category o EH, there is still much room or creative thought and research in this area.
SUMMARY • Hypertension is def ned as a chronic diastolic BP ≥ 90 mm Hg and/ or systolic BP ≥ 140 mm Hg. • Those with prehypertension (systolic 120 to 139 mm Hg or diastolic 80 to 99 mm Hg) have an increased risk o developing def nite hypertension over time. • Hypertension is o unknown etiology in the vast majority o patients (termed EH), and is a diagnosis o exclusion. • Secondary hypertension may arise rom: (1) renal abnormalities (e.g., renal parenchymal disease and renal artery stenosis); (2) coarctation o the aorta; and (3) endocrine abnormalities (e.g., pheochromocytoma, primary or secondary aldosteronism, Cushing syndrome, and thyroid abnormalities). • Most hypertensive patients remain asymptomatic until complications arise. • Potential complications include stroke, myocardial in arction, heart ailure, aortic aneurysm and dissection, renal damage, and retinopathy. • Treatment o hypertension includes li estyle and dietary improvements and pharmacologic therapy. • The most commonly recommended antihypertensive drugs include diuretics, ACE, angiotensin receptor blockers, long-acting calcium channel blockers, and sometimes β-blockers.
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Ack n ow le d gm en t s Contributors to previous editions o this chapter were Christopher T. Lee, MD; Payman Zamani, MD; Rajeev Malhotra, MD; Rahul Deshmukh, MD; Allison McDonough, MD; Rajesh S. Magrulkar, MD; Peter A. Nigrovic, MD; and Thomas J. Moore, MD.
Ad d i t i o n a l Rea d i n g Cooper CJ, Murphy TP, Cutlip DE, et al. Stenting and medical therapy or atherosclerotic renal-artery stenosis. N Engl J Med. 2014;370:13–22. Franceschini N, Reiner AP, Heiss G. Recent f ndings in the genetics o blood pressure and hypertension traits. Am J Hypertens. 2011;24:392–400. Go AS, Bauman MA, Coleman King SM, et al. An e ective approach to high blood pressure control: a science advisory rom the American Heart Association, the American College o Cardiology, and the Centers or Disease Control and Prevention. Hypertension. 2014;63:878–885.
James PA, Oparil S, Carter BL, et al. Evidence-based guideline or the management o high blood pressure in adults: report rom the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–520. Raman SV. The hypertensive heart: an integrated understanding in ormed by imaging. J Am Coll Cardiol. 2010;55:91–96. Weber MA, Schi rin EL, White WB, et al. Clinical practice guidelines or the management o hypertension in the community: a statement by the American Society o Hypertension and the International Society o Hypertension. J Clin Hypertension. 2014;16:14–26.
Diseases of the Pericardium
14
Leona rd S. Lilly
Ch a p t e r O u t l i n e Anatomy and Function Acute Pericarditis Etiology Pathology Clinical Features Diagnostic Studies Treatment Pericardial Effusion Etiology Pathophysiology Clinical Features Diagnostic Studies Treatment Cardiac Tamponade Etiology Pathophysiology Clinical Features Diagnostic Studies Treatment Constrictive Pericarditis Etiology and Pathogenesis Pathology Pathophysiology Clinical Features Diagnostic Studies Treatment
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D
iseases of the pericardium form a spectrum that ranges from benign, self-limited pericarditis to life-threatening cardiac tamponade. The clinical manifestations of these disorders and approaches to their management can be predicted from an understanding of pericardial anatomy and pathophysiology, as presented in this chapter.
ANATOMY AND FUNCTION The pericardium is a two-layered sac that encircles the heart. The inner serosal layer (visceral pericardium) adheres to the outer wall o the heart and is re ected back on itsel , at the level o the great vessels, to line the tough f brous outer layer (parietal pericardium). A thin f lm o pericardial uid slightly separates the two layers and decreases the riction between them. The pericardium appears to serve three unctions: (1) it f xes the heart within the mediastinum and limits its motion, (2) it prevents extreme dilatation o the heart during sudden rises o intracardiac volume, and (3) it may unction as a barrier to limit the spread o in ection rom the adjacent lungs. However, patients with complete absence o the pericardium (either congenitally or a ter surgical removal) are generally asymptomatic, casting doubt on its actual importance in normal physiology. Yet like the unnecessary appendix, the pericardium can become diseased and cause great harm. In the healthy heart, intrapericardial pressure varies during the respiratory cycle rom − 5 mm Hg (during inspiration) to + 5 mm Hg (during expiration) and nearly equals the pressure within the pleural space. However, pathologic changes in pericardial sti ness, or the accumulation o uid within the pericardial sac, may pro oundly increase this pressure.
Diseases of the Pericardium 335
ACUTE PERICARDITIS The most common a iction o the pericardium is acute pericarditis, which re ers to in ammation o its layers. Many disease states and etiologic agents can produce this syndrome (Table 14-1), the most requent o which are described here.
Etiology Infectious Idiopathic and Viral Pericarditis Acute pericarditis is most o ten o idiopathic origin, meaning that the actual cause is unknown. However, serologic studies have demonstrated that many such episodes are actually caused by viral in ection, especially by echovirus or coxsackievirus group B. Although a viral origin could be conf rmed in in ected patients by comparing antiviral titers o acute and convalescent serum, this is rarely done in the clinical setting because the patient has usually recovered by the time those results would be available. Thus, idiopathic and viral pericarditis are considered similar clinical entities, and the terms are used interchangeably. Other viruses known to cause pericarditis include those responsible or in uenza, varicella, mumps, hepatitis B, and in ectious mononucleosis. Pericarditis is the most common mani estation o cardiovascular disease in patients with AIDS, arising rom HIV in ection itsel or rom superimposed tuberculous or other bacterial in ections in this immunocompromised population.
Tuberculous Pericarditis Although tuberculosis remains a worldwide problem, its incidence in the United States is low. It is, however, an important cause o pericarditis in immunosuppressed patients. Tuberculous pericarditis arises rom reactivation o the organism in mediastinal lymph nodes, with spread into the pericardium. It can also extend directly rom a site o tuberculosis within the lungs, or the organism can arrive at the pericardium by hematogenous dissemination.
Nontuberculous Bacterial Pericarditis (Purulent Pericarditis) Bacterial pericarditis is a ulminant illness but is rare in otherwise healthy persons; it is most likely to occur in immunocompromised patients, including those with severe burns and malignancies. Pneumococci and staphylococci are responsible most requently, whereas
TABLE 14-1
Causes of Acute Pericarditis
Infectious Viral Tuberculosis Pyogenic bacteria Noninfectious Postmyocardial infarction or after cardiac surgery Uremia Neoplastic disease Radiation induced Connective tissue diseases Drug induced
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Chapter 14 gram-negative in ection occurs less o ten. Mechanisms by which bacterial invasion o the pericardium develops include (1) per orating trauma to the chest (e.g., stab wound); (2) contamination during chest surgery; (3) extension o an intracardiac in ection (i.e., in ective endocarditis); (4) extension o pneumonia or a subdiaphragmatic in ection; and (5) hematogenous spread rom a remote in ection.
Noninfectious Pericarditis following Myocardial Infarction There are two orms o pericarditis associated with acute myocardial in arction (MI). The early type occurs within the f rst ew days a ter an MI. It likely results rom in ammation extending rom the epicardial sur ace o the injured myocardium to the adjacent pericardium; there ore, it is more common in patients with transmural (as opposed to subendocardial) in arctions. The prognosis ollowing acute MI is not a ected by the presence o pericarditis; its major importance is in distinguishing it rom the pain o recurrent myocardial ischemia. This orm o pericarditis occurs in ewer than 5% o patients with acute MI who are treated with acute reper usion strategies (see Chapter 7), but it is more common in those who are not (and who, there ore, sustain larger in arctions). The second orm o post-MI pericarditis is known as Dressler syndrome, which can develop 2 weeks to several months ollowing an acute in arction. Its cause is unknown, but it is thought to be o autoimmune origin, possibly directed against antigens released rom necrotic myocardial cells. Dressler syndrome has become very rare since the advent o reper usion therapies or acute MI. A clinically similar orm o pericarditis may occur weeks to months ollowing heart surgery, termed postpericardiotomy pericarditis.
Uremic Pericarditis Pericarditis is a potentially serious complication o untreated chronic renal ailure. While its pathogenesis in this setting is unknown, it has become uncommon with the widespread availability o dialysis. Pericarditis may also appear or the f rst time in patients already treated with chronic dialysis therapy, and o ten responds to intensif cation o dialysis.
Neoplastic Pericarditis Tumor involvement o the pericardium most commonly results rom metastatic spread or local invasion by cancer o the lung, breast, or lymphoma. Primary tumors o the pericardium are rare. Neoplastic e usions are usually large and hemorrhagic and requently lead to cardiac tamponade, a li e-threatening complication described later in the chapter.
Radiation-Induced Pericarditis Pericarditis may complicate radiation therapy to the thorax (e.g., administered or the treatment o certain tumors), especially i the cumulative dose has exceeded 4,000 cGy. Radiationinduced damage causes a local in ammatory response that can result in pericardial e usions and ultimately f brosis. Cytologic examination o the pericardial uid helps to distinguish radiation-induced pericardial damage rom that o tumor invasion.
Pericarditis Associated with Connective Tissue Diseases Pericardial involvement is common in many connective tissue diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, and progressive systemic sclerosis. For example, 20% to 40% o patients with SLE experience clinically detectable pericarditis during
Diseases of the Pericardium 337 the course o the disease. Customary treatment o the underlying connective tissue disease usually ameliorates the pericarditis as well.
Drug-Induced Pericarditis Several pharmaceutical agents can cause pericarditis as a side e ect, o ten by inducing a systemic lupus-like syndrome (Table 14-2). These drugs include the antiarrhythmic procainamide and the vasodilator hydralazine. Drug-induced pericarditis usually abates when the causative agent is discontinued.
Pathogenesis Similar to other in ammatory processes, pericarditis is characterized by three stages: (1) local va sodila tion with transudation o protein-poor, cell- ree uid into the pericardial space; (2) in crea sed va scula r permea bility, with leak o protein into the pericardial space; and (3) leukocyte exudation, initially by neutrophils, ollowed later by mononuclear cells. The leukocytes are o critical importance because they help contain or eliminate the o ending in ectious or autoimmune agent. However, metabolic products released by these cells may prolong in ammation, cause pain and local cellular damage, and mediate somatic symptoms such as ever. There ore, the immune response to pericardial injury may signif cantly contribute to tissue damage and symptomatology.
Pathology The pathologic appearance o the pericardium depends on the underlying cause and severity o in ammation. Serous pericarditis is characterized by scant polymorphonuclear leukocytes, lymphocytes, and histiocytes. The exudate is a thin uid secreted by the mesothelial cells lining the serosal sur ace o the pericardium. This likely represents the early in ammatory response common to all types o acute pericarditis. Serof brinous pericarditis is the most commonly observed morphologic pattern in patients with pericarditis. The pericardial exudate contains plasma proteins, including f brinogen, yielding a grossly rough and shaggy appearance (termed “bread and butter” pericarditis). Portions o the visceral and parietal pericardium may become thickened and used. Occasionally, this process leads to a dense scar that restricts movement and diastolic f lling o the cardiac chambers, as described later in the chapter. Suppurative (or purulent) pericarditis is an intense in ammatory response associated most commonly with bacterial in ection. The serosal sur aces are erythematous and coated with purulent exudate. Hemorrhagic pericarditis re ers to a grossly bloody orm o pericardial in ammation and is most o ten caused by tuberculosis or malignancy.
TABLE 14-2
Examples of Drug-Induced Pericarditis
Related to drug-induced SLE-like syndrome Procainamide Hydralazine Methyldopa Isoniazid Phenytoin Not related to drug-induced SLE-like syndrome Anthracycline antineoplastic agents (doxorubicin, daunorubicin) Minoxidil SLE, systemic lupus erythematosus.
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Chapter 14
TABLE 14-3
Clinical Features of Acute Pericarditis
Pleuritic chest pain Fever Pericardial friction rub ECG abnormalities ECG, electrocardiogram.
Clinical Features History The most requent symptoms o acute pericarditis are chest pain and fever (Table 14-3). The pain may be severe and usually localizes to the retrosternal area and le t precordium; it may also radiate to the back and to the ridge o the le t trapezius muscle. What di erentiates it rom myocardial ischemia or in arction is that the pain o pericarditis is typically sharp, pleuritic (it is aggravated by inspiration and coughing), and positional (e.g., sitting and leaning orward o ten lessen the discom ort). Dyspnea is common during acute pericarditis but is not exertional and probably results rom a reluctance o the patient to breathe deeply because o pleuritic pain. Patients with idiopathic or viral pericarditis are typically young and previously healthy. Pericarditis o other causes should be suspected in patients with the underlying conditions listed in Table 14-1 who develop the typical sharp, pleuritic chest pains and ever.
Physical Examination A scratchy pericardial friction rub is common in acute pericarditis and is believed to be produced by the movement o the in amed pericardial layers against one another. Auscultation o the rub is best heard using the diaphragm o the stethoscope with the patient leaning orward while exhaling (which brings the pericardium closer to the chest wall and stethoscope). In its ull orm, the rub consists o three components, corresponding to the phases o greatest cardiac movement: ventricular contraction, ventricular relaxation, and atrial contraction. Characteristically, the pericardial rub is evanescent, coming and going rom one examination to the next.
Diagnostic Studies The presence o pleuritic, positional chest pain and the characteristic pericardial riction rub implicate the presence o acute pericarditis. However, certain laboratory studies are help ul to conf rm the diagnosis and to assess or impending complications. The electrocardiogram (ECG) is abnormal in 90% o patients with acute pericarditis and helps to distinguish it rom other orms o cardiac disease, such as an acute coronary syndrome. The most important ECG pattern, which re ects in ammation o the adjacent myocardium, consists o diffuse ST-segment elevation in most o the ECG leads, usually with the exception o aVR and V1 (Fig. 14-1). In addition, PR-segment depression in several leads is o ten evident, re ecting abnormal atrial repolarization related to atrial epicardial in ammation. These abnormalities are in contrast to the ECG o acute ST-segment elevation MI, in which the ST segments are elevated only in the leads overlying the region o in arction, and PR depression is not expected. Blood studies typically reveal signs o acute in ammation, including an increased white blood cell count (usually a mild lymphocytosis in acute viral/ idiopathic pericarditis) and
Diseases of the Pericardium 339
FIGURE 14-1. Electrocardiogram in acute pericarditis. Diffuse ST-segment elevation is present. Also notice depression of the PR segment (arrow).
elevation o serum in ammatory markers (e.g., erythrocyte sedimentation rate and C-reactive protein). Some patients with acute pericarditis also demonstrate elevated serum cardiac biomarkers (e.g., cardiac troponins), suggesting in ammation o the neighboring myocardium. Further testing in acute pericarditis o ten includes echocardiography to evaluate or the presence and hemodynamic signif cance o a pericardial e usion. Additional studies that may be use ul in individual cases to def ne the cause o pericarditis include (1) purif ed protein derivative skin test or tuberculosis, (2) serologic tests (antinuclear antibodies and rheumatoid actor) to screen or connective tissue diseases, and (3) a care ul search or malignancy, especially o the lung and breast (physical examination supplemented by chest radiography and mammography). The yield o diagnostic pericardiocentesis (removal o pericardial uid through a needle) in uncomplicated acute pericarditis is low and should be reserved or patients with very large e usions or evidence o cardiac chamber compression, as described below.
Treatment Idiopathic or viral pericarditis is a sel -limited disease that usually runs its course in 1 to 3 weeks. Management consists o rest, to reduce the interaction o the in amed pericardial layers, and pain relief by analgesic and anti-in ammatory drugs (aspirin, ibupro en, and other nonsteroidal anti-in ammatory agents). Colchicine, a drug with anti-in ammatory properties usually used to treat gout, may be use ul as an additional agent in acute pericarditis. It has been shown to decrease the recurrence rate a ter an initial episode. Oral corticosteroids are e ective or severe or recurrent pericardial pain but should not be used in uncomplicated cases because o potentially signif cant side e ects and because steroid use is associated with an increased rate o recurrent episodes o pericarditis. The orms o pericarditis related to MI are treated in a similar ashion, with rest and aspirin. Other nonsteroidal anti-in ammatory agents are o ten avoided immediately ollowing an MI because o experimental evidence linking them to delayed healing o the in arct. Purulent pericarditis requires more aggressive treatment, including catheter drainage o the pericardium and intensive antibiotic therapy. Nevertheless, even with such therapy, the mortality rate is very high. Tuberculous pericarditis requires prolonged multidrug antituberculous therapy. Pericarditis in the setting o uremia o ten resolves ollowing intensive dialysis. Neoplastic pericardial disease usually indicates widely metastatic cancer, and therapy is un ortunately only palliative.
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Chapter 14
PERICARDIAL EFFUSION Etiology The normal pericardial space contains 15 to 50 mL o pericardial uid, a plasma ultraf ltrate secreted by the mesothelial cells that line the serosal layer. A larger volume o uid may accumulate in association with any o the orms o acute pericarditis previously described. In addition, nonin ammatory serous e usions may result rom conditions o (1) increased capillary permeability (e.g., severe hypothyroidism), (2) increased capillary hydrostatic pressure (e.g., congestive heart ailure), or (3) decreased plasma oncotic pressure (e.g., cirrhosis or the nephrotic syndrome). Chylous e usions may occur in the presence o lymphatic obstruction o pericardial drainage, most commonly caused by neoplasms and tuberculosis.
Pathophysiology
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Because the pericardium is a relatively sti structure, the relationship between its internal volume and pressure is not linear, as shown in curve A in Figure 14-2. Notice that the initial portion o the curve is nearly at, indicating that at the low volumes normally present within the pericardium, a small increase in volume leads to only a small rise in pressure. However, when the intrapericardial volume expands beyond a critical level (see Fig. 14-2, arrow), a dramatic increase in pressure is incited by the nondistensible sac. At that point, even a minor increase in volume can translate into an enormous compressive orce on the heart. Three actors determine whether a pericardial e usion remains clinically silent or whether symptoms o cardiac compression ensue: (1) the volume o uid, (2) the rate at which the uid accumulates, and (3) the compliance characteristics o the pericardium. A sudden increase o pericardial volume, as may occur in chest trauma with intrapericardial hemorrhage, results in marked elevation o pericardial pressure (see Fig. 14-2, steep portion o curve A) and the potential or severe cardiac chamber compression. Even lesser amounts o uid may cause signif cant elevation o pressure i the pericardium is pathologically
Tota l pe rica rdia l volume (mL)
FIGURE 14-2. Schematic representation of the volume–pressure relationship of normal pericardium. A. At the very lowest levels, a small rise in volume results in a small rise in pressure. However, when the limits o pericardial stretch are reached (arrow), the curve becomes very steep, and a urther small rise in intrapericardial volume results in signif cantly increased pressure. B. Chronic slow accumulation o volume allows the pericardium to gradually stretch over time; thus, the curve shi ts to the right and much larger volumes are accommodated at lower pressures. (Modif ed rom Freeman GL, LeWinter MM. Pericardial adaptations during chronic dilation in dogs. Circ Res. 1984;54:294.)
Diseases of the Pericardium 341
TABLE 14-4
Clinical Features of Large Pericardial Effusion
Soft heart sounds Reduced intensity of friction rub Ewart sign (dullness over posterior left lung)
noncompliant and sti , as may occur in the presence o tumor or f brosis o the sac. In contrast, i the pericardial e usion accumulates slowly, over weeks to months, the pericardium gradually stretches, such that the volume–pressure relationship curve shi ts toward the right (see Fig. 14-2, curve B). With this adaptation, the pericardium can accommodate larger volumes without marked elevation o intrapericardial pressure.
Clinical Features A spectrum o possible symptoms is associated with pericardial e usions. For example, the patient with a large e usion may be asymptomatic, may complain o a dull constant ache in the le t side o the chest, or may present with f ndings o cardiac tamponade, as described later in the chapter. In addition, the e usion may cause symptoms resulting rom compression o adjacent structures, such as dysphagia (di f culty swallowing because o esophageal compression), dyspnea (shortness o breath resulting rom lung compression), hoarseness (due to recurrent laryngeal nerve compression), or hiccups (resulting rom phrenic nerve stimulation). On examination (Table 14-4), a large pericardial uid “insulates” the heart rom the chest wall, and the heart sounds may be mu ed. In act, a riction rub that had been present during the acute phase o pericarditis may disappear i a large e usion develops and separates the in amed layers rom one another. Dullness to percussion o the le t lung over the angle o the scapula may be present (known as the Ewart sign) owing to compressive atelectasis by the enlarged pericardial sac.
Diagnostic Studies The chest ra diogra ph may be normal i only a small pericardial e usion is present. However, i more than approximately 250 mL has accumulated, the cardiac silhouette enlarges in a globular, symmetric ashion. In large e usions, the ECG may demonstrate reduced voltage o the complexes. In the presence o very large e usions, the height o the QRS complex may vary rom beat to beat (electrica l a ltern a n s), a result o a constantly changing electrical axis as the heart swings rom side to side within the large pericardial volume (Fig. 14-3).
FIGURE 14-3. Electrical alternans. Rhythm strip of lead V1 showing alternating height of the QRS complex from beat to beat, due to shifting of the cardiac axis as the heart swings within a large pericardial effusion.
342
Chapter 14 One o the most use ul laboratory tests in the evaluation o an e usion is echocardiography (Fig. 14-4), which can identi y pericardial collections as small as 20 mL. This noninvasive technique can quanti y the volume o pericardial uid, determine whether ventricular f lling is compromised, and when necessary, help direct the placement o a pericardiocentesis needle.
PE
LV
Treatment I the cause o the e usion is known, therapy is directed toward the underlying disorder (e.g., intensive dialysis or ureFIGURE 14-4. Two-dimensional echocardiogram mic e usion). I the cause is not evident, ( parasternal short-axis view) of a pericardial the clinical state o the patient determines effusion ( PE) surrounding the heart. LV, left wh eth er pericardiocen tesis (rem oval o ventricle. pericardial uid) should be undertaken. An asymptomatic e usion, even o large volume, can be observed or long periods without specif c intervention. However, i serial examination demonstrates a precipitous rise in pericardial volume or i hemodynamic compression o the cardiac chambers becomes evident, then pericardiocentesis should be per ormed or therapeutic drainage and or analysis o the uid.
CARDIAC TAMPONADE At the opposite end o the spectrum rom the asymptomatic pericardial e usion is cardiac tamponade. In this condition, pericardial uid accumulates under high pressure, compresses the cardiac chambers, and severely limits f lling o the heart. As a result, ventricular stroke volume and cardiac output decline, potentially leading to hypotensive shock and death.
Etiology Any etiology o acute pericarditis (see Table 14-1) can progress to cardiac tamponade, but the most common causes are neoplastic, postviral, and uremic pericarditis. Acute hemorrhage into the pericardium is also an important cause o tamponade, which can result (1) rom blunt or penetrating chest trauma, (2) rom rupture o the le t ventricular (LV) ree wall ollowing MI (see Chapter 7), or (3) as a complication o a dissecting aortic aneurysm (see Chapter 15).
Pathophysiology As a result o the surrounding tense pericardial uid, the heart is compressed, and the diastolic pressure within each chamber becomes elevated and equal to the pericardial pressure. The pathophysiologic consequences o this are illustrated in Figure 14-5. Because the compromised cardiac chambers cannot accommodate normal venous return, the systemic and pulmonary venous pressures rise. The increase o systemic venous pressure results in signs o right-sided heart ailure (e.g., jugular venous distention), whereas elevated pulmonary venous pressure leads to pulmonary congestion. In addition, reduced f lling o the ventricles during diastole decreases the systolic stroke volume, and the cardiac output declines.
Diseases o the Pericardium 343 Ca rdia c ta mpona de
Cons trictive pe rica rditis
Pe rica rdia l fluid unde r pre s s ure
S ca rre d, rigid pe rica rdium
Impa ire d dia s tolic filling of ve ntricle s
Eleva te d ve nous pre s s ure s
Sys te mic ve nous conge s tion
Impa ire d s troke volume
Pulmona ry ve nous conge s tion
De cre a s e d ca rdia c output
Hypote ns ion Jugula r ve nous dis te ntion He pa tome ga ly & a s cite s Pe riphe ra l e de ma
Pulmona ry ra le s
Re flex ta chyca rdia
FIGURE 14-5. Pathophysiology of cardiac tamponade and constrictive pericarditis. The symptoms and signs (orange boxes) arise rom impaired diastolic f lling o the ventricles in both conditions.
These derangements trigger compensatory mechanisms aimed at maintaining tissue per usion, initially through activation o the sympathetic nervous system (e.g., increased heart rate and contractility). Nonetheless, ailure to evacuate the e usion leads to inadequate per usion o vital organs, shock, and ultimately death.
Clinical Features Cardiac tamponade should be suspected in any patient with known pericarditis, pericardial e usion, or chest trauma who develops signs and symptoms o systemic vascular congestion and decreased cardiac output (Table 14-5). The key physical f ndings include (1) jugular venous distention, (2) systemic hypotension, and (3) a “small, quiet heart” on physical examination, a result o the insulating e ects o the e usion. Other signs include sinus tachycardia and pulsus paradoxus (described later). Dyspnea and tachypnea re ect pulmonary congestion and decreased oxygen delivery to peripheral tissues. I tamponade develops suddenly, symptoms o pro ound hypotension are evident, including con usion and agitation. However, i the e usion develops more slowly, over a period o weeks, then atigue (caused by low cardiac output) and peripheral edema (owing to rightsided heart ailure) may be the presenting complaints.
TABLE 14-5
Clinical Features of Cardiac Tamponade
Jugular venous distention Hypotension with pulsus paradoxus Quiet precordium on palpation Sinus tachycardia
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BOX 14-1
Measurement of Pulsus Paradoxus at the Bedside
Pulsus paradoxus is an exaggeration o the normal decline in systolic blood pressure that occurs with inspiration. It can be measured at the bedside using a manual sphygmomanometer. First, inf ate the sphygmomanometer to a level greater than the patient’s systolic pressure. As the cu is slowly def ated, care ully listen or the appearance o the rst Korotko sounds. This level marks the maximum systolic pressure and occurs during expiration. I the pressure is held at that level (i.e., i you stop def ating the cu ) in a patient with pulsus paradoxus, the Korotko sounds will dri t in and out, audible with expiration, and absent with inspiration. That is, the systolic pressure will all during inspiration to a level below the cu ’s pressure and no sound will be heard during that time. Next, slowly def ate the cu and continue listening. When the cu pressure alls to the level just below the patient’s systolic pressure during inspiration, the Korotko sounds stop dri ting in and out (i.e., they are audible during both inspiration and expiration). Pulsus paradoxus is calculated as the di erence between the initial systolic pressure (when the intermittent Korotko sounds are rst heard) and this pressure (when the sounds are rst audible throughout the respiratory cycle). In the presence o cardiac tamponade, this pressure di erence is greater than 10 mm Hg.
Pulsus paradoxus is an important physical sign in cardiac tamponade that can be recognized at the bedside using a standard blood pressure cu . It re ers to a decrease of systolic blood pressure (more than 10 mm Hg) during normal inspiration (see Box 14-1). Pulsus paradoxus is not really “paradoxical”; it is just an exaggeration o appropriate cardiac physiology. Normally, expansion o the thorax during inspiration causes the intrathoracic pressure to become more negative compared with the expiratory phase. This acilitates systemic venous return to the chest and augments f lling o the right ventricle (RV). The transient increase in RV size shi ts the interventricular septum toward the le t, which diminishes LV f lling. As a result, in normal persons, LV stroke volume and systolic blood pressure decline slightly ollowing inspiration. In cardiac tamponade, this situation is exaggerated because both ventricles share a reduced, f xed volume as a result o external compression by the tense pericardial uid. In this case, the inspiratory increase o RV volume and bulging o the interventricular septum toward the le t have a proportionally greater e ect on the limitation o LV f lling. Thus, in tamponade, there is a more substantial reduction o LV stroke volume (and there ore systolic blood pressure) ollowing inspiration. Pulsus paradoxus may also be mani ested by other conditions in which inspiration is exaggerated, including severe asthma and chronic obstructive airway disease.
Diagnostic Studies Echocardiography is the most use ul noninvasive technique to evaluate whether pericardial e usion has led to cardiac tamponade physiology. An important indicator o high-pressure pericardial uid is compression o the RV and right atrium during diastole (see Fig. 3-12). In addition, echocardiography can di erentiate between cardiac tamponade and other causes o low cardiac output, such as ventricular contractile dys unction. The def nitive diagnostic procedure or cardiac tamponade is cardiac catheterization with measurement o intracardiac and intrapericardial pressures, usually combined with therapeutic pericardiocentesis, as described in the next section.
Treatment Removal o the high-pressure pericardial uid is the only intervention that reverses the li ethreatening physiology o this condition. Pericardiocentesis is best per ormed in the cardiac catheterization laboratory, where the hemodynamic e ect o uid removal can be assessed. The patient is positioned head up at a 45-degree angle to promote pooling o the e usion, and
Diseases o the Pericardium 345 a needle is inserted into the pericardial space through the skin, usually just below the xiphoid process (which is the sa est location to avoid piercing a coronary a A artery). A catheter is then threaded into the pericarv dial space and connected to a transducer or pressure Norma l x y measurement. Another catheter is threaded through a systemic vein into the right side o the heart, and simultaneous recordings o intracardiac and intrapericardial pressures are compared. In tamponade, the pericardial a B pressure is elevated and is equal to the diastolic presv y sures within all o the cardiac chambers, re ecting the x Ta mpona de compressive orce o the surrounding e usion. In addition, the right atrial pressure tracing, which is equivalent to the jugular venous pulsation a observed on physical examination, displays a characC v teristic abnormality (Fig. 14-6). During early diastole Cons trictive x y in a normal person, as the RV pressure alls and the pe rica rditis tricuspid valve opens, blood quickly ows rom the right atrium into the RV, leading to a rapid decline in the right atrial pressure (the y descent). In tamponTricus pid ade, however, the pericardial uid compresses the va lve RV and prevents its rapid expansion. Thus, the right ope ns atrium cannot empty quickly, and the y descent is FIGURE 14-6. Schematic diagrams of right atrial ( or blunted. jugular venous) pressure recordings. A. Normal. The Following success ul pericardiocentesis, the pericarinitial a wave represents atrial contraction. The v wave dial pressure alls to normal and is no longer equal to ref ects passive lling o the atrium during systole, the diastolic pressures within the heart chambers, which when the tricuspid valve is closed. A ter the tricuspid also decline to their appropriate levels. A ter initial aspivalve opens, the right atrial pressure alls (y descent) ration o uid, the pericardial catheter may be le t in as blood empties into the right ventricle. B. Cardiac tamponade. High-pressure pericardial f uid compresses place or 1 to 2 days to allow more complete drainage. the heart, impairing right ventricular lling, so that When pericardial uid is obtained or diagnostic the y descent is blunted. C. Constrictive pericarditis. purposes, it should be stained and cultured or bacThe earliest phase o diastolic lling is not impaired teria, ungi, and acid- ast bacilli (tuberculosis), and so that the y descent is not blunted. The y descent cytologic examination should be per ormed to evaluappears accentuated because it descends rom a ate or malignancy. Other common measurements o higher-than-normal right atrial pressure. The right pericardial uid include cell counts (e.g., white cell atrial c wave (described in Chapter 2) is not shown. count is elevated in bacterial in ections and other in ammatory conditions) and protein and lactate dehydrogenase levels. I the concentration ratio o pericardial protein to serum protein is greater than 0.5, or that o pericardial LDH to serum LDH is greater than 0.6, then the uid is consistent with an exudate; otherwise, it is more likely a transudate. When tuberculosis is suspected, it is also use ul to measure the level o adenosine deaminase in the pericardial uid. Studies have indicated that an elevated level is highly sensitive and specif c or tuberculosis. I cardiac tamponade recurs ollowing pericardiocentesis, the procedure can be repeated. In some cases, a more def nitive surgical undertaking (removal o part or all o the pericardium) is required to prevent reaccumulation o the e usion. ECG
CONSTRICTIVE PERICARDITIS The other major potential complication o pericardial diseases is constrictive pericarditis. This is a condition not requently encountered but is important to understand, because it can masquerade as other more common disorders. In addition, it is an a iction that may cause pro ound symptoms yet is o ten ully correctable i recognized.
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Etiology and Pathogenesis In the early part o the 20th century, tuberculosis was the major cause o constrictive pericarditis but that is much less common today in industrialized societies. The most requent cause now is “idiopathic” (i.e., months to years ollowing presumed idiopathic or viral acute pericarditis). However, any etiology o pericarditis can lead to this complication, including prior radiation therapy to the le t side o the chest.
Pathology Following an episode o acute pericarditis, any pericardial e usion that has accumulated usually undergoes gradual resorption. However, in patients who later develop constrictive pericarditis, the uid undergoes organization, with subsequent usion o the pericardial layers, ollowed by f brous scar ormation. In some patients, calcif cation o the adherent layers ensues, urther sti ening the pericardium.
Pathophysiology The pathophysiologic abnormalities in constrictive pericarditis occur during diastole; systolic contraction o the ventricles is usually normal. In this condition, a rigid, scarred pericardium encircles the heart and inhibits normal f lling o the cardiac chambers. For example, as blood passes rom the right atrium into the RV during diastole, the RV size expands and quickly reaches the limit imposed by the constricting pericardium. At that point, urther f lling is suddenly arrested, and venous return to the right heart ceases. Thus, systemic venous pressure rises, and signs o right-sided heart ailure ensue. In addition, the impaired f lling o the le t ventricle causes a reduction in stroke volume and cardiac output, which leads to lower blood pressure.
Clinical Features The symptoms and signs o constrictive pericarditis usually develop over months to years. They result rom (1) reduced cardiac output ( atigue, hypotension, and re ex tachycardia) and (2) elevated systemic venous pressures (jugular venous distention, hepatomegaly with ascites, and peripheral edema). Because the most impressive physical f ndings are o ten the insidious development o hepatomegaly and ascites, patients may be mistakenly suspected o having hepatic cirrhosis or an intra-abdominal tumor. However, care ul inspection o the elevated jugular veins can point to the correct diagnosis o constrictive pericarditis. On cardiac examination, an early diastolic “knock” may ollow the second heart in patients with severe calcif c constriction. It represents the sudden cessation o ventricular diastolic f lling imposed by the rigid pericardial sac. In contrast to cardiac tamponade, pericardial constriction results in pulsus paradoxus less requently. Recall that in tamponade, this f nding re ects inspiratory augmentation o RV f lling, at the expense o LV f lling. However, in constrictive pericarditis, the negative intrathoracic pressure generated by inspiration is not easily transmitted through the rigid pericardial shell to the right-sided heart chambers; there ore, inspiratory augmentation o RV f lling is more limited. Rather, when a patient with severe pericardial constriction inhales, the negative intrathoracic pressure draws blood toward the thorax, where it cannot be accommodated by the constricted right-sided cardiac chambers. As a result, the increased venous return accumulates in the intrathoracic systemic veins, causing the jugular veins to become more distended during inspiration (Kussmaul sign). This is the opposite o normal physiology, in which inspiration results in a declin e in jugular venous pressure,
Diseases o the Pericardium 347 as venous return is drawn into the heart. Thus, typical f ndings in pericardial disease can be summarized as ollows:
Pulsus paradoxus Kussmaul sign
Constrictive Pericarditis
Cardiac Tamponade
+
+++
+++
–
Diagnostic Studies The chest radiograph in constrictive pericarditis shows a normal or mildly enlarged cardiac silhouette. Calcif cation o the pericardium can be detected in some patients with severe chronic constriction. The ECG generally shows nonspecif c ST and T-wave abnormalities; atrial arrhythmias are common. Echocardiographic evidence o constriction is subtle. The pericardium, i well imaged, is thickened. The ventricular cavities are small and contract vigorously, but ventricular f lling terminates abruptly in early diastole, as the chambers reach the limit imposed by the surrounding rigid shell. Aberrant diastolic motion o the interventricular septum, and alterations o LV in ow velocities during respiration assessed by Doppler, also re ect the abnormal pattern o diastolic f lling. Computed tomography or magnetic resonance imaging is superior to echocardiography in the assessment o pericardial anatomy and thickness. The presence o normal pericardial thickness (less than 2 mm) by these modalities makes constrictive pericarditis a much less likely diagnosis. The diagnosis o constrictive pericarditis can be conf rmed by cardiac catheterization, which reveals our key eatures: 1. Elevation and equalization o the diastolic pressures in each o the cardiac chambers. 2. An early diastolic “dip and plateau” conf guration in the RV and LV tracings (Fig. 14-7). This pattern re ects blood ow into the ventricles at the very onset o diastole, just a ter the tricuspid and mitral valves open, ollowed by sudden cessation o f lling as urther expansion o the ventricles is arrested by the surrounding rigid pericardium. ECG
ECG
100
100 LV LV g H m e r
e
RV
s
40
P
r
e
RV
P
r
s
u
r u s
40
e
s
60
(
m
60
(
m
m
H
g
)
80
)
80
20
P la te a u 20 Ea rly dia s tolic filling wave
Time
A
Time
B
FIGURE 14-7. Schematic tracings of left ventricular ( LV) and right ventricular ( RV) pressures in a normal heart ( A) and in constrictive pericarditis ( B) . In the latter situation, early diastolic ventricular f lling abruptly halts as the volume in each ventricle quickly reaches the limit imposed by the constricting pericardium. Throughout most o diastole, the LV and RV pressures are abnormally elevated and equal.
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Chapter 14 3. A prominent y descent in the right atrial pressure tracing (see Fig. 14-6). A ter the tricuspid valve opens, the right atrium quickly empties into the RV (and its pressure rapidly alls) during the very brie period be ore f lling is arrested. This is in contrast to cardiac tamponade, in which the external compressive orce throughout the cardiac cycle prevents rapid ventricular f lling, even in early diastole, such that the y descent is blunted. 4. During the respiratory cycle, there is discordance in the RV and LV systolic pressures (the RV systolic pressure rises with inspiration, while that o the LV declines). This is explained as ollows: in normal persons, the negative intrathoracic pressure induced by inspiration causes the systolic pressure o both ventricles to decline slightly. In contrast, in constrictive pericarditis, the heart is isolated rom the rest o the thorax by the surrounding rigid shell. In this circumstance, negative intrathoracic pressure induced by inspiration decreases the pressure in the pulmonary veins but not in the le t-sided cardiac chambers. This causes a decline in the pressure gradient driving blood back to the le t side o the heart rom the pulmonary veins, such that le t ventricle f lling is diminished. Less ventricular f lling reduces the stroke volume and results in a lower LV systolic pressure (and is the likely mechanism o pulsus paradoxus in some patients with constrictive pericarditis). Simultaneously, because the two ventricles share a f xed space limited by the rigid pericardium, the reduced LV volume allows the interventricular septum to shi t toward the le t, which enlarges the RV (this reciprocal behavior is termed ventricular interdependence). The subsequent increase in RV f lling augments systolic pressure during inspiration. During expiration, the situation is reversed, with the RV systolic pressure declining and that o the LV increasing. The clinical and hemodynamic f ndings o constrictive pericarditis are o ten similar to those o restrictive cardiomyopathy (see Chapter 10), another uncommon condition. Distinguishing between these two syndromes is important because pericardial constriction is o ten correctable, whereas most cases o restrictive cardiomyopathy have very limited e ective treatments (Table 14-6). An endomyocardial biopsy is sometimes necessary to distinguish between these (the biopsy results are normal in constriction but usually abnormal in restrictive cardiomyopathy; see Chapter 10).
TABLE 14-6
Differences between Constrictive Pericarditis and Restrictive Cardiomyopathy
Feature Chest radiography • Pericardial calcif cations CT or MRI • Thickened pericardium Echocardiography • Thickened pericardium • Respiratory cycle e ect on transvalvular Doppler velocities Cardiac catheterization • Equalized LV and RV diastolic pressures • Elevated PA systolic pressure • E ect o inspiration on systolic pressures Endomyocardial biopsy
Constrictive Pericarditis
Restrictive Cardiomyopathy
Yes (25%–30% o patients)
Absent
Yes
No
Yes (but di f cult to visualize) Exaggerated variations
No Normal
Yes
O ten, LV > RV
Uncommon Discordant : LV↓, RV↑
Common Concordant: LV↓, RV↓
Normal
Abnormal (e.g., amyloid)
CT, computed tomography; LV, le t ventricle; MRI, magnetic resonance imaging; PA, pulmonary artery; RV, right ventricle.
Diseases of the Pericardium 349
Treatment The only e ective treatment o severe constrictive pericarditis is surgical removal o the pericardium. Symptoms and signs o constriction may not resolve immediately a ter surgery because o the associated sti ness o the neighboring outer walls o the heart, but subsequent clinical improvement is the rule in patients with otherwise intact cardiac unction. The degree o improvement depends on the underlying etiology, with the most avorable outcomes in patients with an idiopathic/ post–viral pericarditis origin, and the least avorable benef t when prior radiation therapy is the cause.
SUMMARY • Acute pericarditis is characterized by three stages: (1) local vasodilation with transudation o protein-poor, cell- ree uid into the pericardial space; (2) increased vascular permeability, with leak o protein into the pericardial space; and (3) leukocyte exudation, initially by neutrophils, ollowed later by mononuclear cells. • Acute pericarditis is most o ten o idiopathic or viral cause and is usually a sel -limited illness. • Common clinical f ndings in acute pericarditis include pleuritic chest pain, ever, pericardial riction rub, and di use ST-segment elevation on the ECG, o ten accompanied by PR-segment depression. • Treatment o common acute pericarditis (i.e., viral or idiopathic pericarditis) consists o a nonsteroidal anti-in ammatory drug; the addition o colchicine may reduce the requency o recurrences and shorten the duration o the acute illness. • Glucocorticoid drugs should not be used as initial therapy or acute pericarditis as they increase the likelihood o recurrences. • Complications o pericarditis include cardiac tamponade (accumulation o pericardial uid under high pressure, which compresses the cardiac chambers) and constrictive pericarditis (restricted f lling o the heart because o the surrounding rigid pericardium). • Distinguishing between constrictive pericarditis and restrictive cardiomyopathy is important because pericardial constriction is o ten correctable with surgical removal o the pericardium, whereas most cases o restrictive cardiomyopathy have very limited e ective treatments.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Yin Ren, MD; Yanerys Ramos, MD; Thomas G. Roberts, MD; Angela Fowler, MD; Kathy Glatter, MD; and Alan Braverman, MD.
Ad d i t i o n a l Rea d i n g ESC Committee or Practice Guidelines. Guidelines on the diagnosis and management o pericardial diseases, executive summary. Eur Heart J. 2004;25:587–610. Herzog E, ed. Management of Pericardial Disease. London, UK: Springer-Verlag; 2014. Imazio M, Brucato A, Cemin R, et al. A randomized trial o colchicine or acute pericarditis. N Engl J Med. 2013;369:1522–1528. Khandaker MH, Espinosa RE, Nishimura RA, et al. Pericardial disease: diagnosis and management. Mayo Clin Proc. 2010;85:572–593.
Klein AL, Abbara S, Agler DA, et al. American Society o Echocardiography clinical recommendations or multimodality cardiovascular imaging o patients with pericardial disease. J Am Soc Echocardiogr. 2013;26:965–1012. Lilly LS. Treatment o acute and recurrent idiopathic pericarditis. Circulation. 2013;127:1723–1726. Shabetai R. The Pericardium. Boston, MA: Kluwer Academic; 2003.
Diseases of the Peripheral Vasculature
15
Sruthi Rena ti Ma rk A. Crea ger
Ch a p t e r O u t l i n e Diseases of the Aorta Aortic Aneurysms Aortic Dissection Peripheral Artery Diseases Peripheral Atherosclerotic Vascular Disease Acute Arterial Occlusion Vasculitic Syndromes Vasospasm: Raynaud Phenomenon Venous Disease Varicose Veins Chronic Venous Insu ciency Venous Thromboembolism
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P
eripheral vascular disease is an umbrella term that includes a number o diverse pathologic entities that a ect arteries, veins, and lymphatics. Although this terminology makes a distinction between the “central” coronary and “peripheral” systemic vessels, the vasculature as a whole comprises a dynamic, integrated, and multi unctional organ system that does not naturally comply with this semantic division. Blood vessels serve many critical unctions. First, they regulate the di erential distribution o blood and delivery o nutrients and oxygen to tissues. Second, blood vessels actively synthesize and secrete vasoactive substances that regulate vascular tone, and antithrombotic substances that maintain the f uidity o blood and vessel patency (see Chapters 6 and 7). Third, the vessels play an integral role in the transport and distribution o immune cells to traumatized or in ected tissues. Disease states o the peripheral vasculature inter ere with these essential unctions. Peripheral vascular diseases result rom processes that can be grouped into three categories: (1) structural changes in the vessel wall secondary to degenerative conditions, in ection, or inf ammation that lead to dilatation, aneurysm, dissection, or rupture; (2) narrowing of the vascular lumen caused by atherosclerosis, thrombosis, or inf ammation; and (3) spasm o vascular smooth muscle. These processes can occur in isolation or in combination.
Diseases of the Peripheral Vasculature
351
DISEASES OF THE AORTA The aorta is the largest conductance vessel o the vascular system. In adults, its diameter is approximately 3 cm at its origin at the base o the heart. The ascending aorta, 5 to 6 cm in length, leads to the aortic arch, rom which arise three major branches: the brachiocephalic (which bi urcates into the right common carotid and subclavian arteries), the le t common carotid, and the le t subclavian arteries. As the descending aorta continues beyond the arch, its diameter narrows to approximately 2 to 2.5 cm in healthy adults. As the aorta pierces the diaphragm, it becomes the abdominal aorta, providing arteries to the abdominal viscera be ore bi urcating into the le t and right common iliac arteries, which supply the pelvic organs and lower extremities. The aorta, like other arteries, is composed o three layers (see Fig. 5-1). At the luminal sur ace, the intima is composed o endothelial cells overlying the internal elastic lamina. The endothelial layer is a unctional inter ace between the vasculature and circulating blood cells and plasma. The media is composed o smooth muscle cells and a matrix that includes collagen and elastic bers. Collagen provides tensile strength that enables the vessels to withstand high-pressure loads. Elastin is capable o stretching to 250% o its original length and con ers a distensible quality on vessels that allows them to recoil under pressure. The adventitia is composed primarily o collagen bers, perivascular nerves, and vasa vasorum, a rich vascular network that supplies oxygenated blood to the aorta. The aorta is subject to injury rom mechanical trauma because it is continuously exposed to high pulsatile pressure and shear stress. The predominance o elastin in the media (2:1 over collagen) allows the aorta to expand during systole and recoil during diastole. The recoil o the aorta against the closed aortic valve contributes to the distal propagation o blood f ow during the phase o le t ventricular relaxation. With advancing age, the elastic component o the aorta and its branches degenerates, and as collagen becomes more prominent, the arteries sti en. Systolic blood pressure (SBP), there ore, tends to rise with age because less energy is dissipated into the aorta during le t ventricular contraction. Diseases o the aorta most commonly appear as one o three clinical conditions: aneurysm, dissection, or obstruction.
Aortic Aneurysms An aneurysm is an abnormal localized dilatation o an artery. In the aorta, aneurysms are distinguished rom diffuse ectasia, which is a generalized yet lesser increase o the aortic diameter. Ectasia develops in older patients as elastic ber ragments, smooth muscle cells decrease in number, and acid mucopolysaccharide ground substance accumulates within the vessel wall. The term aneurysm is applied when the diameter o a portion o the aorta has increased by at least 50% compared with normal. A true aneurysm represents a dilatation o all three layers o the aorta, creating a large bulge o the vessel wall. True aneurysms are characterized as either usi orm or saccular, depending on the extent o the vessel’s circum erence within the aneurysm. A fusiform aneurysm, the more common type, is characterized by symmetrical dilation o the entire circum erence o a segment o the aorta. A saccular aneurysm is a localized outpouching involving only a portion o the circum erence. In contrast, a pseudoaneurysm (also termed false aneurysm) is a contained rupture o the vessel wall that develops when blood leaks out o the vessel lumen through a hole in the intimal and medial layers and is contained by a layer o adventitia or perivascular organized thrombus. Pseudoaneurysms develop at sites o vessel injury caused by in ection or trauma, such as puncture o the vessel during surgery or percutaneous catheterization. They are very unstable and are prone to rupture completely. Aneurysms may be con ned to the abdominal aorta (most common), the thoracic aorta, or involve both locations. They may also appear in peripheral and cerebral arteries.
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Etiology and Pathogenesis of True Aortic Aneurysms The etiology o aortic aneurysm ormation varies depending on the location o the lesion (Table 15-1). Ascending thoracic aortic aneurysms typically are characterized by cystic medial degeneration (also termed cystic medial necrosis), a condition o degeneration and ragmentation o elastic bers, with subsequent accumulation o collagenous and mucoid material within the medial layer. Cystic medial degeneration occurs normally with aging but is also associated with hypertension. Additionally, it develops in certain inherited disorders o connective tissue that a ect the structural integrity o the aortic wall, including Mar an syndrome, Loeys–Dietz syndrome, the vascular orm o Ehlers–Danlos syndrome (type IV), and amilial thoracic aortic aneurysms. Marfan syndrome is caused by missense mutations o the brillin-1 gene (FBN1), which impair ormation o unctional micro brils in elastin. Abnormal brillin-1 also limits the binding and inactivation o trans orming growth actor β (TGF-β), a signaling molecule that regulates cellular proli eration and di erentiation. Loeys–Dietz syndrome is an autosomal dominant disorder caused by genetic mutations o TGF-β receptors. While thoracic aortic aneurysms have been associated with both increased activity o TGF-β and mutations o its receptors, the mechanism by which aberrant TGF-β signaling alters vascular integrity is not yet known. Ehlers–Danlos type IV syndrome results rom mutations encoding type III procollagen. Familial thoracic aortic aneurysms are caused by mutations o the TGF-β receptor as well as o genes encoding the smooth muscle–speci c alpha-actin (ACTA2) and beta-myosin heavy chain (MYH11), which are essential components o the contractile complex in vascular smooth muscle cells. Cystic medial degeneration also characterizes the orm o thoracic aortic aneurysm o ten associated with bicuspid aortic valves. Aneurysms o the descending thoracic and abdominal aorta are usually associated with atherosclerosis and its risk actors, including smoking, hypertension, dyslipidemia, male gender, and advanced age. However, it is unlikely that atherosclerosis alone is responsible or such aneurysm development. Rather, other important pathophysiologic mechanisms include a genetic predisposition, local vessel inf ammation, and an imbalance between synthesis and degradation o extracellular matrix proteins. For example, speci c proteases (e.g., elastase, collagenase) and matrix metalloproteinases derived rom inf ammatory cells and vascular endothelial and smooth muscle cells may contribute to the breakdown o elastin and collagen. Aneurysm ormation is also associated with markers o inf ammation, including C-reactive protein (CRP) and cytokines such as interleukin-6 (IL-6). Levels o both CRP and IL-6 have been shown to correlate with the size o aneurysms, and inf ammatory cells such as B and T lymphocytes and macrophages are requently ound on histologic examination. Angiotensin II, via its e ect on inf ammation and oxidative stress, has also been implicated in experimental models o abdominal aortic aneurysms.
TABLE 15-1
Conditions Associated with True Aortic Aneurysms
1. Cystic medial degeneration (usually affects ascending thoracic aorta) • Marfan syndrome • Loeys–Dietz syndrome • Ehlers–Danlos syndrome (type IV) • Bicuspid aortic valve • Familial 2. Atherosclerosis/ degenerative (usually affects descending thoracic and abdominal aorta) 3. Infections of arterial wall 4. Vasculitis • Takayasu arteritis • Giant cell arteritis
Diseases of the Peripheral Vasculature
353
In requent causes o aortic aneurysms (Table 15-1) include weakness o the media rom in ections o the vessel wall by Salmonella species, staphylococci, streptococci, tuberculosis, syphilis, or ungi. Inf ammatory diseases such as Takayasu arteritis or giant cell arteritis (both described later in the chapter) may similarly weaken the vessel and result in aneurysm ormation.
Clinical Presentation and Diagnosis Most aneurysms are asymptomatic, though some patients, especially those with abdominal aortic aneurysms, may be aware o a pulsatile mass. Others present with symptoms related to compression o neighboring structures by an expanding aneurysm. Thoracic aortic aneurysms may compress the trachea or mainstem bronchus, resulting in cough, dyspnea, or pneumonia. Compression o the esophagus can result in dysphagia, and involvement o the recurrent laryngeal nerve may lead to hoarseness. Aneurysms o the ascending aorta may dilate the aortic ring, resulting in aortic regurgitation and symptoms o congestive heart ailure. Abdominal aortic aneurysms may cause abdominal or back pain or nonspeci c gastrointestinal symptoms. Aortic aneurysms are o ten rst suspected when dilatation o the vessel is observed on chest or abdominal radiographs, particularly i the wall is calci ed. Aneurysms o the abdominal aorta or o the large peripheral arteries may also be discovered by care ul palpation during physical examination. The diagnosis is con rmed by ultrasonography, contrast-enhanced computed tomography (CT), or magnetic resonance (MR) imaging (Fig. 15-1). The most devastating consequence o an aortic aneurysm is rupture, which can be atal. An aneurysm may leak slowly or burst suddenly, resulting in pro ound blood loss
FIGURE 15-1. Abdominal aortic aneurysm. Computed tomographic angiogram (CTA) of an abdominal aortic aneurysm, indicated by the green arrow. (Courtesy of Frank Rybicki MD, Brigham and Women’s Hospital, Boston, MA.)
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Chapter 15 and hypotension. Thoracic aortic aneurysms may rupture into the pleural space, mediastinum, or bronchi. Abdominal aortic aneurysms may rupture into the retroperitoneal space or abdominal cavity or erode into the intestines, resulting in massive gastrointestinal bleeding. Natural history studies have shown that the risk o rupture is related to the size o the aneurysm, as predicted by the Laplace relationship (i.e., wall tension is proportional to the product o pressure and radius). The mean rates o thoracic and abdominal aortic aneurysms expansion are 0.1 and 0.4 cm/ year, respectively. Thoracic aneurysms rupture at an annual rate o 2% or aneurysms less than 5 cm in diameter, 3% or aneurysms 5 to 5.9 cm, and 7% or aneurysms greater than 6 cm. Abdominal aneurysms less than 4 cm, 4 to 4.9 cm, and 5 to 5.9 cm have annual rates o rupture o 0.3% , 1.5% , and 6.5% , respectively. Abdominal aneurysms greater than 6 cm have a markedly higher risk o rupture.
Treatment Treatment o an aortic aneurysm is based on its size and the patient’s overall medical condition. Once an aneurysm is identif ed, its dimensions should be closely monitored through repeated imaging, typically every 6 to 12 months depending on size. In general, surgical treatment is considered or ascending aortic aneurysms greater than 5.5 to 6.0 cm. Ascending aortic aneurysms in patients with Mar an syndrome (in whom the risk o complications is greater) should be considered or surgical repair i the diameter is greater than 5 cm. Surgical repair is generally recommended or descending thoracic aortic aneurysms measuring 6.5 to 7.0 cm, or abdominal aortic aneurysms measuring 5.5 cm or more, and or smaller aneurysms that enlarge at a rate greater than 1.0 cm/ year. The mortality associated with elective surgical repair o thoracic aortic aneurysms is 3% to 5% . Patients are maintained on cardiopulmonary bypass as the aneurysm is resected and replaced with a prosthetic Dacron gra t. Patients with aneurysms involving multiple aortic segments have staged repairs, in which one segment is corrected at a time. Some patients with thoracic aortic aneurysms may be candidates or minimally invasive repair, in which a transluminally placed endovascular stent gra t is positioned across the aneurysm. Surgical repair o abdominal aortic aneurysms involves placement o a prosthetic gra t. The operative mortality or such procedures at high-volume institutions is 1% to 2% . Percutaneous endovascular repair o in rarenal abdominal aortic aneurysms with stent gra ts can be per ormed in selected patients with less acute morbidity, and long-term results are similar to that o surgical repair. Medical management, including risk- actor reduction (e.g., smoking cessation), is currently recommended or patients with small aneurysms. β-Blockers may reduce the expansion rate o thoracic aortic aneurysms in patients with Mar an syndrome; it is not clear whether they are e ective or other causes or types o aneurysms. Angiotensin II receptor antagonists, which also inhibit TGF-β, are undergoing clinical trials in Mar an syndrome.
Aortic Dissection Aortic dissection is a li e-threatening condition in which blood rom the vessel lumen passes through a tear in the intima into the medial layer and spreads along the artery. Other related acute syndromes include aortic intramural hematoma, penetrating aortic ulcer, and aortic rupture. Acute intramural hematoma is a variant o aortic dissection characterized by a hemorrhage in the wall o the aorta without evidence o an intimal tear. A penetrating atherosclerotic ulcer results rom erosion o a plaque into the aortic wall. Aortic rupture may be a complication o aortic dissection, intramural hematoma, penetrating atherosclerotic ulcer, or result rom trauma.
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Etiology, Pathogenesis, and Classif cation Aortic dissection arises rom a circum erential or transverse tear in the intimal layer o the vessel wall that allows blood rom the lumen, under the driving orce o the systemic pressure, to enter into the media and propagate along the plane o the muscle layer. Another potential origin o aortic dissection is rupture o vasa vasorum with hemorrhage into the media, orming a hematoma in the arterial wall that subsequently tears through the intima and into the vessel’s lumen. Any condition that inter eres with the normal integrity o the elastic or muscular components o the medial layer can predispose to aortic dissection. Such degeneration may arise rom chronic hypertension, aging, and/ or cystic medial degeneration (which, as described earlier, is a eature o certain hereditary connective tissue disorders, such as Mar an syndrome and Ehlers–Danlos syndrome). In addition, traumatic insult to the aorta (e.g., blunt chest trauma or accidental vessel damage during intra-arterial catheterization or cardiac surgery) can also initiate dissection. Aortic dissection is most common in the sixth and seventh decades and occurs more requently in men. More than two thirds o patients have a history o hypertension. Dissection most commonly involves the ascending thoracic aorta (65% ) and descending thoracic aorta (20% ), while the aortic arch (10% ) and abdominal aortic (5% ) segments are less commonly a ected. Dissections are commonly classif ed into two categories (Stan ord types A and B), depending on their location and extent (Fig. 15-2). In a type A dissection (proximal), the ascending aorta and/ or aortic arch is involved, regardless o the site o the primary tear. A type B dissection (distal) does not involve the ascending aorta or arch and is, there ore, conf ned to the descending thoracic and abdominal aorta. This distinction is important because treatment strategies and prognoses are determined by location. Proximal aortic involvement tends to be more devastating because o the potential or extension into the coronary and arch vessels, the support structures o the aortic valve, or the pericardial space. Approximately two thirds o dissections are type A and one third are type B. Dissections may also be classif ed as acute or chronic, with acute dissections presenting with symptoms o less than 2 weeks’ duration.
Clinical Presentation and Diagnosis The most common symptom o aortic dissection is sudden, severe pain with a “tearing” or “ripping” quality in the anterior chest (typical o type A dissections) or between the scapulae (type B dissections). The pain travels as the dissection propagates along the aorta and can radiate anywhere in the thorax or abdomen. Painless dissection is possible but uncommon (6.4% o cases).
TYPE A
FIGURE 15-2. Aortic dissection. Type A involves the ascending aorta, whereas type B does not. (Reprinted from Braverman AC, Thompson R, Sanchez L. Diseases of the aorta. In: Bonow RO, Mann DL, Zipes DP, et al., eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Elsevier; 2012.)
TYPE B
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TABLE 15-2
Complications of Aortic Dissection
Rupture Pericardial tamponade Hemomediastinum Hemothorax (usually left sided) Occlusion of aortic branch vessels Carotid (stroke) Coronary (myocardial infarction) Splanchnic (visceral infarction) Renal (acute renal failure) Iliac, brachiocephalic, subclavian (limb ischemia) Distortion of aortic annulus Aortic regurgitation
Other symptoms relate to the catastrophic complications that can occur at the time o presentation or therea ter (Table 15-2) and include (1) rupture through the adventitia anywhere along the aorta (o ten into the le t pleural space or pericardium); (2) occlusion o major branches o the aorta by the propagating hematoma within the vessel wall, which compresses the lumen and can result in myocardial in arction (coronary artery involvement), stroke (carotid artery involvement), visceral ischemia, renal ailure, or loss o pulse in an extremity; and (3) extension into the aortic root, with disruption o the aortic valve support apparatus causing aortic regurgitation. Several important physical ndings may be present. Hypertension is requently detected, either as an underlying cause o dissection, a result o the sympathetic nervous system response to the severe pain, or because o diminished renal vascular f ow, with activation o the renin–angiotensin system. I the dissection has occluded one o the subclavian arteries, a di erence in SBP between the arms is noted. Neurologic de cits may accompany dissection into the carotid vessels. I a type A dissection results in aortic regurgitation, an early diastolic murmur can be detected on auscultation. Leakage rom a type A dissection into the pericardial sac may produce signs o cardiac tamponade (see Chapter 14). The diagnosis o aortic dissection must not be delayed, because catastrophic complications or death may rapidly ensue. The con rmatory imaging techniques most use ul in detecting dissection include contrast-enhanced CT, transesophageal echocardiography (TEE), MR angiography, and contrast angiography. Each o these techniques has speci c advantages and disadvantages, and the decision o which to employ is o ten guided by a hospital’s local expertise. In emergency situations, CT scanning or TEE can generally be obtained rapidly and o er excellent sensitivity and speci city or the diagnosis.
Treatment The goal o acute treatment is to arrest progression o the dissecting channel. Suspicion o acute aortic dissection warrants immediate medical therapy to reduce SBP (aiming or a systolic pressure o 100 to 120 mm Hg) and to decrease the orce o le t ventricular contraction and thus minimize aortic wall shear stress. Use ul pharmacologic agents in this regard include β-blockers (to reduce the orce o contraction and heart rate as well as to lower blood pressure) and vasodilators such as sodium nitroprusside (to rapidly reduce blood pressure). In proximal (type A) dissections, early surgical correction has been shown to improve outcomes compared with medical therapy alone. Surgical therapy involves repairing the intimal tear, suturing the edges o the alse channel, and i necessary, inserting a synthetic aortic gra t.
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In contrast, patients with uncomplicated type B dissections are initially managed with aggressive medical therapy alone; early surgical intervention does not urther improve the outcome in these patients. Surgery is indicated, however, i there is clinical evidence o propagation o the dissection, compromise o major branches o the aorta, impending rupture, or continued pain. Percutaneous catheter-based repair with endovascular stent gra ts has been used success ully in selected stable patients with type B dissections. The gra t seals the entry site o the dissection, resulting in thrombosis o the alse lumen.
PERIPHERAL ARTERY DISEASES Peripheral artery disease (PAD) is de ned by the presence o a f ow-limiting lesion in an artery that provides blood supply to the limbs. The major causes o such arterial stenosis or occlusion are atherosclerosis, thromboembolism, and vasculitis. The clinical presentation o these disorders results rom decreased per usion to the a ected extremity.
Peripheral Atherosclerotic Vascular Disease Etiology and Pathogenesis The most common cause o PAD is atherosclerosis. It is a prevalent vascular disorder, a ecting approximately 4% o persons over the age o 40 and 15% to 20% o those over the age o 70. The pathology o atherosclerotic PAD is identical to that o coronary artery disease (CAD), and the major coronary risk actors (e.g., cigarette smoking, diabetes mellitus, dyslipidemia, and hypertension) are also associated with PAD. Approximately 40% o patients with PAD actually have clinically signi cant CAD. As a consequence o the systemic nature o atherosclerosis, patients with PAD have a two old to ve old increased risk o cardiovascular death compared with patients who do not have this condition. Thus, detection o PAD is use ul in identi ying patients at increased risk o adverse cardiovascular events. The pathophysiology o atherosclerotic PAD is also similar to that o CAD. Ischemia o the a ected region occurs when the balance between oxygen supply and demand is upset; exercise raises the demand or blood f ow in the limbs’ skeletal muscle, and a stenosed or obstructed artery cannot provide an adequate supply. Rest improves symptoms as the balance between oxygen supply and demand is restored. Recall rom Chapter 6 that the degree o blood f ow reduction relates closely to the extent o vessel narrowing, the length o the stenosis, and blood viscosity. The Poiseuille equation describes this relationship: DP p r 4 Q= 8h L in which Q = f ow, ∆ P = pressure drop across the stenosis, r = vessel radius, η = blood viscosity, and L = length o stenosis. Thus, the degree o vessel narrowing by the stenosis (i.e., the change in r) has the greatest impact on f ow. For example, i the radius is reduced by one hal , the f ow will be reduced to 1/ 16th o its baseline. The equation also indicates that or stenoses o the same length and radius, higher f ow rates correspond to greater pressure drops across the stenoses. That is, as the f ow velocity increases across a stenotic vessel, the blood turbulence results in a loss o kinetic energy. The result is a decline in per usion pressure distal to the stenosis. During exercise, products o skeletal muscle metabolism (e.g., adenosine) act locally to dilate arterioles. The resulting decrease in vascular resistance serves to increase blood f ow to the active muscle (recall that f ow = pressure/ resistance). In turn, the increased f ow stimulates healthy arterial endothelium to release vasodilating actors such as nitric oxide, thereby increasing the radii o upstream conduit vessels. However, in PAD, obstructed arteries cannot respond to the vasodilating stimuli, thereby limiting f ow increases. In addition,
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Chapter 15 dys unctional atherosclerotic endothelium does not release normal amounts o vasodilating substances (see Chapter 6). Thus, the physical properties o a stenosis and the reduced vasodilator activity imposed by diseased endothelium prevent adequate blood f ow rom reaching distal tissues and contribute to ischemia. Hemodynamic changes alone cannot account or the dramatic reductions in exercise capacity experienced by PAD patients; changes in muscle structure and unction are also seen. One such change is the denervation and dropout o muscle bers, which is thought to occur as an adaptation to intermittent ischemia. The loss o such bers can explain the reduced muscle strength and atrophy that occur in PAD patients. Even viable muscle bers in a ected limbs may show abnormalities o mitochondrial oxidative metabolism. In summary, atherosclerotic lesions produce stenoses in peripheral conduit vessels and limit blood f ow to the a ected extremity. Mechanisms normally in place to compensate or increased demand, such as endogenous release o vasodilators during exercise and recruitment o microvessels, ail in the ace o endothelial dys unction and diminished f ow velocity. Thus, states o increased oxygen demand are not met with adequate supply, producing limb ischemia. Adaptations to ischemia include changes in muscle ber metabolism and muscle ber dropout. Together, these physical and biochemical changes result in weak lower limbs that su er ischemic discom ort during exercise. Severe peripheral atherosclerosis may reduce limb blood f ow to such an extent that it cannot satis y resting metabolic requirements. This results in critical limb ischemia, which may progress to tissue necrosis and gangrene that may threaten viability o the extremity.
Clinical Presentation and Diagnosis PAD may a ect the aorta or the iliac, emoral, popliteal, and tibioperoneal arteries (Fig. 15-3). Patients with PAD may there ore develop buttock, thigh, or cal discom ort precipitated by walking and relieved by rest. FIGURE 15-3. An angiogram This classic symptom o exertional limb atigue and demonstrating peripheral artery pain is known as claudication. In severe PAD, patients disease. There is occlusion of the left may experience pain at rest, usually a ecting the eet femoral artery (blue arrow) and stenosis of the right popliteal artery (green or toes. The chronically reduced blood f ow in this case arrow). Collateral vessels that circumvent predisposes the extremity to ulceration, in ection, and areas of stenosis and occlusion are skin necrosis (Fig. 15-4). Patients who smoke or have present (red arrows). (Courtesy of Michael diabetes mellitus are at high risk o these complications. L. Steigner MD, Brigham and Women’s The location o claudication corresponds to the dis- Hospital, Boston, MA.) eased artery, with the emoral and popliteal arteries being the most common sites (Table 15-3). The arteries o the upper extremities are less requently a ected, but brachiocephalic or subclavian artery disease can cause arm claudication.
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FIGURE 15-4. Leg ulcers. A. Ulceration a ecting the oot in a patient with diabetes and peripheral artery disease. (Courtesy o Christian E. Sampson MD, Brigham and Women’s Hospital, Boston, MA.) B. Venous insu f ciency ulcer near the medial malleolus o the right leg. Notice the venous stasis pigmentation o the surrounding skin. (Courtesy o Lauren R. Bayer PA, Brigham and Women’s Hospital, Boston, MA.)
Physical examination generally reveals loss o pulses distal to the stenotic segment. Bruits (swishing sounds auscultated over a region o turbulent blood f ow) may be audible in the abdomen (because o stenoses within the mesenteric or renal arteries) or over iliac, emoral, or subclavian arterial stenoses. In patients with chronic severe ischemia, the lack o blood per usion results in muscle atrophy, pallor, cyanotic discoloration, hair loss, and occasionally gangrene and necrosis o the oot and digits. Ischemic ulcers resulting rom PAD o ten begin as small traumatic wounds in areas o increased pressure or in regions prone to injury, such as the tips o the toes and the volar sur ace o the oot (see Fig. 15-4A). These o ten pain ul ulcers ail to heal owing to the inadequate blood supply. Diabetic patients with peripheral sensory neuropathies are particularly susceptible to ulcers at sites o trauma or pressure rom ill- tting ootwear. Ischemic ulcers can be distinguished rom venous insu ciency ulcers, which develop more proximally and on the medial portion o the leg. Venous ulcers are also associated with reddish-brown pigmentation and varicose veins (see Fig. 15-4B). In the evaluation o PAD, it is help ul to measure the ratio o blood pressure in the ankles to that in the arms (termed the ankle–brachial index [ABI]) using a blood pressure cu and a Doppler instrument to detect blood f ow (Box 15-1). Other testing to assess peripheral
TABLE 15-3
Relation of Stenotic Site to Claudication Symptoms
Site
Location of Claudication Symptoms
Distal aorta or iliac arteries Femoral or popliteal arteries Subclavian or axillary arteries
Buttocks, hips, thighs, or calves Calves Arms
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BOX 15-1
Measurement and Interpretation of the Ankle–Brachial Index
The ABI is the ratio o the SBP measured at the ankle to that measured at the brachial artery. To determine the ABI, the patient should lie supine or 10 minutes with the head and heels ully supported. A Doppler ultrasound probe is used to detect f ow in the brachial, posterior tibial (PT), and dorsalis pedis (DP) arteries. A blood pressure cu is placed on each arm to measure the SBP at the brachial arteries and on each o the lower calves, just above the malleoli, to measure the SBP at the PT and DP arteries. Use the higher o the PT and DP values on each side as the ankle pressure measurement. Finally, divide the ankle pressure measurement by the higher o the two brachial artery pressure measurements to determine the ABI. A normal ABI is ≥ 1.0. An index < 0.9 is diagnostic o PAD. Patients with PAD may be asymptomatic or have symptoms o intermittent claudication or rest pain. An index < 0.5 is ound in patients with severe PAD and critical limb ischemia.
Ankle Pressure Measurement using a Doppler Probe at the Right Dorsalis Pedis Artery
per usion includes limb segmental systolic pressure measurements (using pneumatic cu s placed along the extremity) and pulse volume recordings (i.e., graphical measurement o volume changes in segments o the extremity with each pulse). Duplex ultrasonography is a commonly used noninvasive method to visualize and assess the extent o arterial stenoses and the corresponding reductions in blood f ow. Other more advanced imaging studies (e.g., MR angiography, CT angiography, or intra-arterial contrast angiography) are obtained when revascularization procedures are planned.
Treatment For patients with PAD, antiplatelet therapy and risk actor modi cation (including smoking cessation, lipid lowering, and control o diabetes and hypertension) are important in reducing the likelihood o coron a ry events. Platelet inhibitors, such as aspirin and clopidogrel, reduce cardiovascular morbidity and mortality in patients with PAD. It has not been established i antiplatelet agents reduce symptoms or prevent thrombotic complications o PAD itsel . Speci c treatment o PAD includes supportive care o the eet to prevent trauma or restriction o blood f ow. Exercise, particularly walking, improves endurance in part by increasing metabolic e ciency in the skeletal muscle o the legs. A ormal exercise program is considered rst-line therapy in the management o PAD. Certain medical therapies are sometimes use ul in the treatment o claudication. Cilosta zol is a selective phosphodiesterase inhibitor that increases cyclic adenosine monophosphate
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and has vasodilator and platelet-inhibiting properties; it has been shown to improve exercise capacity in patients with PAD. Pen toxifyllin e is a drug purported to improve the de ormability o red and white blood cells and may improve claudication symptoms in some patients. Conversely, most vasodilator drugs (see Chapter 17) are not help ul in relieving claudication. More e ective medical therapies or PAD are on the horizon. Advances in angiogenesis research and clinical trials provide hope that revascularization through delivery o angiogenic growth actors (e.g., vascular endothelial growth actor and basic broblast growth actor), and regenerative cell-based therapies, including use o endothelial progenitor cells, may be possible. Mechanical revascularization is indicated when medical therapy has ailed or patients with disabling claudication and as rst-line therapy in cases o critical limb ischemia. In advanced cases, therapy is directed at healing ischemic ulcerations and preventing limb loss. Catheterbased interventions, such as percutaneous transluminal angioplasty and stent implantation, can be per ormed on selected patients with low morbidity. Surgical procedures include bypass operations to circumvent the occluded arteries using saphenous vein or prosthetic gra ts. However, amputation may be necessary i blood f ow cannot be satis actorily reestablished to maintain limb viability.
Acute Arterial Occlusion Acute arterial occlusion is caused either by embolization rom a cardiac or proximal vascular site or by thrombus ormation in situ. The origin o arterial emboli is most o ten the heart, usually resulting rom disorders involving intracardiac stasis o f ow (Table 15-4). Emboli may also originate rom thrombus or atheromatous material overlying a segment o the aorta. Rarely, arterial emboli originate rom the venous circulation. I a venous clot travels to the right-heart chambers and is able to pass through an abnormal intracardiac communication (e.g., an atrial septal de ect), it then enters the systemic arterial circulation (a condition known as a paradoxical embolism). Primary arterial thrombus ormation may appear at sites o endothelial damage or atherosclerotic stenoses, or within bypass gra ts. The extent o tissue damage rom thromboembolism depends on the site o the occluded artery, the duration o occlusion, and the degree o collateral circulation serving the tissue beyond the obstruction. Common symptoms and signs that may develop rom abrupt reduction in blood supply include pain, pallor, paralysis, paresthesia, and pulselessness (termed the “ ve Ps”). A sixth P, poikilothermia (coolness), is also o ten mani est. Patients with a proven acute arterial occlusion should be treated with a parenteral anticoagulant such as heparin ( ollowed by oral war arin) to prevent propagation o the clot
TABLE 15-4
Origins of Arterial Emboli
Cardiac origin Stagnant le t atrial f ow (e.g., atrial brillation, mitral stenosis) Le t ventricular mural thrombus (e.g., dilated cardiomyopathy, myocardial in arction, ventricular aneurysm) Valvular lesions (endocarditis, thrombus on prosthetic valve) Le t atrial myxoma (mobile tumor in le t atrium) Aortic origin Thrombus material overlying atherosclerotic segment Venous origin Paradoxical embolism travels through intracardiac shunt
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Chapter 15 and to reduce the likelihood o additional embolic events. A revascularization procedure ( catheter-based thrombolysis or thrombectomy, surgical embolectomy, or bypass surgery) is indicated i limb viability is at risk. Atheroembolism is the condition o peripheral arterial occlusion by atheromatous material (i.e., cholesterol, platelets, and brin) derived rom more proximal vascular sites, such as atherosclerotic lesions or aneurysms. The emboli lodge distally, resulting in occlusion o small arteries in the muscle and skin. Patients typically present with acute pain and tenderness at the involved site. Occlusion o digital vessels may result in the “blue toe” syndrome, culminating in gangrene and necrosis. Other ndings may include livedo reticularis (purplish mottling o involved skin), kidney ailure (caused by renal atheroembolism), and intestinal ischemia. Although an estimated 50% to 60% o cases are spontaneous, atheroembolism may occur a ter intra-arterial procedures (e.g., cardiac catheterization) when atherosclerotic material is unintentionally dislodged rom the proximal vasculature. Ischemia resulting rom atheroemboli is di cult to manage because the heterogeneous composition and distribution o emboli o ten precludes surgical removal or thrombolytic therapy. Surgical intervention to remove or bypass the source o emboli may be necessary to prevent recurrences.
Vasculitic Syndromes Vasculitis (vessel wall inf ammation) results rom immune complex deposition or cell-mediated immune reactions directed against the vessel wall. Immune complexes activate the complement cascade with subsequent release o chemoattractants and anaphylatoxins that direct neutrophil migration to the vessel wall and increase vascular permeability. Neutrophils injure the vessel by releasing lysosomal contents and producing toxic oxygen-derived ree radicals. In cell-mediated immune reactions, T lymphocytes bind to vascular antigens and release lymphokines that attract additional lymphocytes and macrophages to the vessel wall. These inf ammatory processes can cause end-organ ischemia through vascular necrosis or local thrombosis. The cause o most o the vasculitic syndromes is unknown, but they o ten can be distinguished rom one another by the pattern o involved vessels and by histologic characteristics. Three important examples o vasculitic syndromes are Takayasu arteritis, giant cell arteritis, and thromboangiitis obliterans. Takayasu arteritis is a chronic vasculitis o unknown etiology that targets the aorta and its major branches. The estimated annual incidence is 1.2 to 2.6 cases per million. Between 80% and 90% o a ected persons are women, with onset typically between the ages o 10 and 40. Most reported cases have been rom Asia and A rica, but it is a worldwide disease. Patients typically present with systemic complaints such as malaise and ever; ocal symptoms are related to inf ammation o the a ected vessel and include cerebrovascular ischemia (brachiocephalic or carotid artery involvement), myocardial ischemia (coronary artery), arm claudication (brachiocephalic or subclavian artery), or hypertension (renal artery). The carotid and limb pulses are diminished or absent in nearly 85% o patients at the time o diagnosis; hence, this condition is o ten termed “pulseless” disease. Takayasu arteritis is also an uncommon cause o aortic aneurysm or aortic dissection. Histologic examination o a ected vessels reveals continuous or patchy granulomatous inf ammation with lymphocytes, histiocytes, and multinucleated giant cells, resulting in intimal proli eration, disruption o the elastic lamina, and brosis. Antiendothelial antibodies may also play a role in the disease. Steroid and cytotoxic drugs may reduce vascular inf ammation and alleviate symptoms o Takayasu arteritis. Surgical bypass o obstructed vessels may be help ul in severe cases. The 5-year survival rate is 80% to 90% . Giant cell arteritis (also termed temporal arteritis) is a chronic vasculitis o mediumsized to large arteries that most commonly involves the cranial vessels or the aortic arch and its branches. It is an uncommon disease, with an incidence o 24 per 100,000, and the typical onset is a ter age 50; 65% o patients are emale. Giant cell arteritis may be associated with the inf ammatory condition known as polymyalgia rheumatica. Histologic ndings in a ected
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vessels include lymphocyte and macrophage in ltration, intimal brosis, and ocal necrosis, with granulomas containing multinucleated giant cells. Symptoms and signs o giant cell arteritis depend on the distribution o a ected arteries and may include diminished temporal pulses, prominent headache (temporal artery involvement), or acial pain and claudication o the jaw while chewing ( acial artery involvement). Ophthalmic artery arteritis leads to impaired vision, with permanent partial or complete loss in 15% to 20% o patients. Serum markers o inf ammation (e.g., erythrocyte sedimentation rate and CRP) are invariably elevated in patients with giant cell arteritis. Ultrasound examination can support the diagnosis by demonstrating a hypoechoic halo around the involved arterial lumen with vessel stenosis and/ or occlusion. The diagnosis can be con rmed by biopsy o an involved vessel, usually a temporal artery, but treatment should not wait or biopsy results. High-dose systemic steroids are e ective in treating vasculitis and preventing visual complications. Giant cell arteritis usually has a sel -limited course o 1 to 5 years. Thromboangiitis obliterans (Buerger disease) is a segmental inf ammatory disease o small and medium-sized arteries, veins, and nerves involving the distal vessels o the upper and lower extremities. It is most prevalent in the Far and Middle East and has a very strong association with cigarette smoking. It is most common in men younger than age 45; only 10% to 25% o patients are emale. There is an increased incidence o human leukocyte antigen A9 (HLA-A9) and HLA-B5 in a ected persons. Thromboangiitis obliterans presents with a triad o symptoms and signs: distal arterial occlusion, Raynaud phenomenon (described in the next section), and migrating super cial vein thrombophlebitis. Arterial occlusion results in arm and oot claudication as well as ischemia o the digits. Traditional laboratory markers o inf ammation and autoimmune disease are usually not detected. Arteriographic eatures o involved arteries include areas o stenosis interspersed with normal-appearing vessels with more severe disease distally, collateral vessels with a “corkscrew” appearance around the stenotic regions, and lack o atherosclerosis in proximal arteries. The diagnosis can be established by tissue biopsy, although this is rarely needed. Biopsy specimens o a ected vessels reveal an occlusive, highly cellular, inf ammatory thrombus, with limited involvement o the vessel wall and preservation o the internal elastic lamina (Fig. 15-5). The most important treatment or thromboangiitis obliterans is smoking cessation, which usually prevents progression o the disease and its complications. Debridement o necrotic tissue may be necessary in advanced cases. Revascularization is not usually an option because o the distal location o the arterial lesions.
Acute pha s e : Thrombus including ne utrophils a nd gia nt ce lls occlude s the ve s s e l lume n but s pa re s the wa ll.
S uba cute pha s e : Progre s s ive orga niza tion of the thrombus ta ke s pla ce .
P la te le ts
Chronic pha s e : Infla mma tion is no longe r pre s e nt a nd orga nize d thrombus a nd va s cula r fibros is re ma in.
Erythrocyte
FIGURE 15-5. Pathophysiologic phases of thromboangiitis oblit erans. (Reprinted from Piazza G, Creager MA. Thromboangiitis obliterans. Circulation. 2010;121(16):1858–1861.)
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VASOSPASM: RAYNAUD PHENOMENON Raynaud phenomenon is a vasospastic disease o the digital arteries that occurs in susceptible people when exposed to cool temperatures or sometimes during emotional stress. Vasospasm is an extreme vasoconstrictor response that temporarily obliterates the vascular lumen, inhibiting blood f ow. Typically, such episodes are characterized by a triphasic color response. First, the ngers and/ or toes blanch to a distinct white as blood f ow is interrupted (Fig. 15-6). The second phase is characterized by cyanosis, related to local accumulation o desaturated hemoglobin, ollowed by a third phase o ruddy color as blood f ow resumes. The color response may be accompanied by numbness, paresthesias, or pain o the a ected digits. This condition may occur as an isolated disorder, termed primary Raynaud phenomenon or Raynaud disease. Patients are predominantly FIGURE 15-6. Raynaud phenomenon. Blanching women between the ages o 20 and 40. Primary of the fourth digit (red arrow) is evident (phase 1 Raynaud phenomenon most o ten mani ests of the tricolor response). in the ngers, but 40% o patients also have involvement o the toes. The prognosis o primary Raynaud phenomenon is relatively benign, with only a minority reporting a worsening o symptoms over time. Secondary Raynaud phenomenon may appear as a component o other conditions. Common causes include connective tissue diseases (e.g., scleroderma and systemic lupus erythematosus) and arterial occlusive disorders. Other causes o secondary Raynaud phenomenon include carpal tunnel syndrome, thoracic outlet syndrome, blood dyscrasias, certain drugs, and thermal or vibration injury. Even in healthy vessels, cold exposure normally produces a vasoconstrictor response. Cooling stimulates the sympathetic nervous system, resulting in local discharge o norepinephrine, which binds to vascular adrenergic receptors. In the ngers and toes, only vasoconstricting α receptors are present; other regional circulations have both constrictor and dilator adrenergic responses. Thus, a modest vasoconstriction o the digits results when healthy people are exposed to cooling. In contrast, in Raynaud phenomenon, cold exposure induces severe vasoconstriction. A variety o mechanisms have been proposed to explain the vasospastic response to cold and stress in patients with primary Raynaud phenomenon, including an exaggerated sympathetic discharge in response to cold, heightened vascular sensitivity to adrenergic stimuli, or excessive release o vasoconstrictor stimuli, such as serotonin, thromboxane, and endothelin. In patients with secondary Raynaud phenomenon caused by connective tissue diseases or arterial occlusive disease, the digital vascular lumen is largely obliterated by sclerosis or inf ammation, resulting in lower intraluminal pressure and greater susceptibility to sympathetically mediated vasoconstriction. Treatm ent o Raynaud ph enomenon involves avoiding cold environmen ts, dressing in warm clothes, and wearing in su lated gloves or ootwear. There has also been som e su ccess in preven ting vasospasm with ph armacologic agen ts th at relax vascu lar ton e, in clu din g calciu m chan nel blockers, α-adrenergic blockers, and phosphodiesterase type 5 inh ibitors su ch as sildena il (see Ch apter 17), bu t such therapies are reserved or severe cases.
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VENOUS DISEASE Veins are high-capacitance vessels that contain more than 70% o the total blood volume. In contrast to the muscular structure o arteries, the subendothelial layer o veins is thin, and the tunica media comprises ewer, smaller bundles o smooth muscle cells intermixed with reticular and elastic f bers. While veins o the extremities possess intrinsic vasomotor activity, transport o blood back to the heart relies greatly on external compression by the surrounding skeletal muscles and on a series o one-way endothelial valves. Veins o the extremities are classif ed as either deep or superf cial. In the lower extremities, where most peripheral venous disorders occur, the deep veins generally course along the arteries, whereas the superf cial veins are located subcutaneously. The superf cial vessels drain into deeper veins through a series o per orating connectors, ultimately returning blood to the heart.
Varicose Veins Varicose veins (Fig. 15-7) are dilated, tortuous superf cial vessels that o ten develop in the lower extremities. Clinically apparent varicose veins occur in 10% to 20% o the general population. They a ect women two to three times more requently than men, and roughly hal o patients have a amily history o this condition. Varicosities can occur in any vein in the body but are most common in the saphenous veins o the leg and their tributaries. They may also develop in the anorectal area (hemorrhoids), in the lower esophageal veins (esophageal varices), and in the spermatic cord (varicocele). Varicosity is thought to result rom intrinsic weakness o the vessel wall, rom increased intraluminal pressure, or rom congenital de ects in the structure and unction o venous valves. Varicose veins in the lower extremities are classif ed as either primary or secondary. Primary varicose veins originate in the superf cial system, and actors that lead to their development include pregnancy, prolonged standing, and obesity. During pregnancy or prolonged standing, the high venous pressure within the legs contributes to varicosities when there is underlying weakness o the vessel walls. In obese patients, the adipose tissue surrounding vessel walls o ers less structural support to veins than does lean mass. Secondary varicose veins occur when an abnormality in the deep venous system is the cause o superf cial varicosities. These may develop in the setting o deep venous insu f ciency or occlusion or when the per orating veins are incompetent. In such cases, deep venous blood is shunted retrogradely through per orating channels into superf cial veins, increasing intraluminal pressure and volume and causing dilatation and varicosity ormation. Many people with varicose veins are FIGURE 15-7. A patient with varicose veins of the asymptomatic but seek treatment or cos- left leg ( arrow) . (Courtesy of Marie Gerhard-Herman metic reasons. When symptoms do develop, MD, Brigham and Women’s Hospital, Boston, MA.)
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Chapter 15 they include a dull ache, “heaviness,” or a pressure sensation in the legs a ter prolonged standing. Super cial venous insu ciency may result when venous valves are unable to unction normally in the dilated veins. This can cause swelling and skin ulceration that is particularly severe near the ankle. Stasis o blood within varicose veins can promote super cial vein thrombosis, and varicosities can also rupture, causing a localized hematoma. Varicose veins are usually treated conservatively. Patients should elevate their legs while supine, avoid prolonged standing, and wear external compression stockings that counterbalance the increased venous hydrostatic pressure. Varicose veins that are symptomatic, or associated with signs o venous insu ciency, may be treated with more advanced techniques, including sclerotherapy, thermal ablation, or surgery. Sclerotherapy involves the localized intravenous administration o an irritating chemical agent to brose varicose veins. Endovenous thermal ablation procedures use laser or radio requency catheters to deliver heat energy, which induces thromboses and is used to obliterate varicose great saphenous veins. Surgical therapy involves direct vein ligation and removal.
Chronic Venous Insu f ciency Chronic venous insu ciency (CVI) is characterized by elevated venous pressure with extravasation o edema into the tissues o the lower extremities. CVI develops when venous blood return to the heart is impaired by mechanisms that include valvular incompetence o deep or super cial veins, venous obstruction, and cal muscle pump dys unction. A secondary orm o CVI is postphlebitic syndrome, resulting rom venous valvular damage or persistent venous occlusion a ter deep vein thrombosis (described below). Patients with CVI may experience pain or achiness in the legs, particularly when standing or prolonged periods. Physical ndings include varicose veins, edema, skin inf ammation and hyperpigmentation, and ulcerations. Noninvasive testing with duplex ultrasound is useul to detect the cause o CVI, such as venous obstruction. Compression stockings are the mainstay o treatment. Associated venous ulcerations are treated with compression bandages and absorbent dressings. Venous ablation techniques as described in the previous section are used to treat varicose veins that contribute to CVI.
Venous Thromboembolism The term venous thrombosis or thrombophlebitis is used to describe thrombus ormation within a super cial or deep vein and the inf ammatory response in the vessel wall that it incites. Thrombi in the lower extremities are classi ed by location as either deep venous thrombi or super cial venous thrombi. Initially, the venous thrombus is composed principally o platelets and brin. Later, red blood cells become interspersed within the brin, and the thrombus tends to propagate in the direction o blood f ow. The changes in the vessel wall can be minimal or can include granulocyte in ltration, loss o endothelium, and edema. Thrombi may diminish or obstruct vascular f ow, or they may dislodge and orm thromboemboli.
Deep Venous Thrombosis Epidemiology, Etiology, and Pathophysiology Deep venous thrombosis (DVT) occurs most commonly in the veins o the calves but may also develop initially in more proximal veins such as the popliteal, emoral, and iliac vessels. I le t untreated, 20% to 30% o DVTs that arise in the calves propagate to these proximal veins. The two major consequences o DVT are pulmonary embolism (PE) (also termed venous thromboembolism) and postphlebitic syndrome.
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Conditions that Predispose to DVT and Pulmonary Embolism
Stasis o blood f ow Prolonged inactivity ( ollowing surgery, prolonged travel) Immobilized extremity ( ollowing bone racture) Heart ailure (with systemic venous congestion) Hyperviscosity syndromes (e.g., polycythemia vera) Hypercoagulable states Inherited disorders o coagulation Resistance to activated protein C ( actor V Leiden) Prothrombin gene mutation (PT G20210A) Antithrombin def ciency Def ciency o protein C or protein S Antiphospholipid antibodies/ lupus anticoagulant Neoplastic disease (e.g., pancreatic, lung, stomach, or breast cancers) Pregnancy and oral contraceptive use Myeloproli erative diseases Smoking Vascular damage Instrumentation (e.g., intravenous catheters) Trauma
In 1856, Virchow described a triad o actors that predispose to venous thrombosis: (1) stasis o blood f ow, (2) hypercoagulability, and (3) vascular damage. Stasis disrupts laminar f ow and brings platelets into contact with the endothelium. This allows coagulation actors to accumulate and retards the inf ux o clotting inhibitors. Factors that slow venous f ow and induce stasis include immobilization (e.g., prolonged bed rest a ter surgery or sitting in a car or an airplane or a long trip), cardiac ailure, and hyperviscosity syndromes (Table 15-5). Various clinical disorders cause systemic hypercoagulability, including resistance o coagulation actor V to activated protein C, a prothrombin gene mutation, and inherited de ciencies o antithrombin, protein C, and protein S. Pancreatic, lung, stomach, breast, and genitourinary tract adenocarcinomas are associated with a high prevalence o venous thrombosis. This is thought to occur in part because necrotic tumor cells release thrombogenic actors. Other conditions that contribute to hypercoagulability are listed in Table 15-5. Vascular damage, either by external injury or by intravenous catheters, can denude the endothelium and expose subendothelial collagen. Exposed collagen acts as a substrate or the binding o von Willebrand actor and platelets and initiates the clotting cascade, leading to clot ormation. Less severe damage can cause endothelial dysfunction that contributes to thrombosis by disrupting the production o vasodilating and antiplatelet substances (e.g., nitric oxide and prostacyclin, as explained in Chapter 6) and antithrombotic molecules such as thrombomodulin and heparan sul ate (described in Chapter 7). Recent evidence indicates that atherosclerotic risk actors, such as hyperlipidemia and diabetes, are also associated with DVT ormation. The risk o venous thrombosis is particularly high a ter ractures o the spine, pelvis, and bones o the lower extremities. The risk ollowing bone racture may be related to stasis o blood f ow, increased coagulability, and possibly traumatic endothelial damage. In addition, venous thrombosis may arise in patients ollowing surgical procedures, particularly major orthopedic operations.
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Chapter 15 Women have a several- old increase in the incidence o venous thrombus ormation during late pregnancy and the early postpartum period. In the third trimester, the etus compresses the in erior vena cava and can cause stasis o blood f ow, and high levels o circulating estrogen may induce a hypercoagulable state. Oral contraceptives and other pharmacologic estrogen products also predispose to thrombus ormation.
Clinical Presentation Patients with DVT may be asymptomatic, may describe cal or thigh discom ort when standing or walking, or may report unilateral leg swelling. The physical signs o proximal DVT include edema o the involved leg and occasionally localized warmth and erythema. Tenderness may be present over the course o the phlebitic vein, and a deep venous cord (induration along the thrombosed vessel) is occasionally palpable. Cal pain produced by dorsif exion o the oot (the Homan sign) is a nonspeci c and unreliable marker o DVT.
Diagnosis The primary laboratory tests or the diagnosis o DVT include measurement o the serum d -dimer level and venous compression ultrasonography. d -dimer, a by-product o brin degradation that can be measured in a peripheral blood sample, is highly sensitive or the diagnosis o DVT and/ or acute PE. Because d -dimer may also be elevated in many other conditions (such as cancer, inf ammation, in ection, and necrosis), a positive test result is not specif c or DVT. Thus, a normal d -dimer value helps exclude the presence o DVT, but an elevated level does not de nitively con rm the diagnosis. Venous compression duplex ultrasonography is a readily available noninvasive technique that is 95% sensitive or the diagnosis o symptomatic DVT in a proximal vein but only 75% sensitive or diagnosing symptomatic cal vein thrombi. This technique uses real-time ultrasound scanning to image the vein and pulsed Doppler ultrasound to assess blood f ow within it (Fig. 15-8). Criteria used or diagnosis o DVT with duplex ultrasonography include the inability to compress the vein with direct pressure (suggesting the presence o an intraluminal thrombus), direct visualization o the thrombus, and absence o blood f ow within the vessel. Other diagnostic techniques are sometimes used. For example, MR venography can aid in the diagnosis o proximal DVT, particularly pelvic vein thrombi, which are di cult to detect by ultrasound. Contrast venography is now a rarely used invasive imaging technique that can provide a de nitive diagnosis. Radiocontrast material is injected into a oot vein, and images are obtained as the contrast ascends through the venous system o the leg. DVT is diagnosed by the presence o a lling de ect (see Fig. 15-8).
Treatment In patients with proximal DVT, elevation o the a ected extremity above the level o the heart helps reduce edema and tenderness, and anticoagulation prevents extension o the thrombus and PE. Initial anticoagulation typically consists o subcutaneous low molecular weight heparin (LMWH). Intravenous un ractionated heparin is a cost-e ective alternative that has been used success ully or this purpose or many years, but LMWH is more convenient to administer. War arin, an oral anticoagulant, is then prescribed or long-term management and is continued or several months, depending on the underlying cause o DVT. Newer oral anticoagulants, such as the actor Xa inhibitors rivaroxaban and apixaban (see Chapter 17), allow a broader range o options or acute and long-term treatment o DVT. Catheter-based thrombolysis may be use ul or selected patients with ilio emoral deep vein thrombosis. Treatment o patients with cal DVT (i.e., thrombus con ned to below the knee) is more controversial because pulmonary emboli rom that site are uncommon. Some experts advocate
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C
A
B
FIGURE 15-8. Diagnostic imaging of deep venous thrombosis. A. Normal venogram. Contrast material was injected into a oot vein and f lls the leg veins in this radiograph. B. Venogram demonstrating extensive thrombosis o the deep cal veins, popliteal vein, and emoral vein. Arrow indicates a f lling de ect in the emoral vein due to the presence o thrombus. The deep cal veins are f lled with thrombus and cannot be visualized. C. Ultrasound indicating deep venous thrombosis. The thrombus appears as an echogenic area (arrow) within the emoral vein (V). A healthy vein would be easily compressible by the ultrasound transducer. This vein, however, has the same diameter at baseline ( top panel) and a ter compression ( bottom panel) , conf rming the presence o thrombus within it. Art, artery.
serial noninvasive monitoring to determine i the thrombus propagates into proximal veins, whereas others treat such thrombosis with heparin (un ractionated or low molecular weight) ollowed by war arin or 3 to 6 months. Prophylaxis against DVT is appropriate in clinical situations in which the risk o developing the condition is high, such as during bed rest ollowing surgery. Prophylactic measures may include subcutaneous un ractionated heparin, LMWH, low-dose oral war arin, or one o the newer oral anticoagulants, as well as compression stockings, and/ or intermittent external pneumatic compression o the legs to prevent venous stasis.
Pulmonary Embolism Epidemiology, Etiology, and Pathophysiology PE supervenes when a clot, most o ten derived rom DVT in a proximal vein o the lower extremities, dislodges and travels through the in erior vena cava and right heart chambers, f nally reaching and obstructing a portion o the pulmonary vasculature. PE is common (incidence o approximately 600,000 per year in the United States) and is o ten atal, with an untreated mortality rate o 30% to 40% . In patients with PE, gas exchange is o ten impaired because o the associated anatomic dead space and ventilation–per usion mismatches that ensue in the lungs. As
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Chapter 15 a result, the alveolar–arterial oxygen gradient increases and hypoxemia may occur. Pulmonary vascular resistance may rise as a consequence o the mechanical obstruction and because vasoactive and bronchoconstrictive mediators released by platelets within emboli induce constriction o the pulmonary vasculature and bronchospasm, respectively. The increased pulmonary vascular resistance may lead to elevation o right ventricular (RV) wall stress, dilatation, and contractile ailure, compromising cardiac output. Recurrent and chronic PE can cause remodeling o the pulmonary vasculature with pulmonary hypertension leading to right-sided heart ailure.
Clinical Presentation Patients with PE may experience dyspnea, pleuritic chest pain (due to pleural irritation), hemoptysis, cough, or syncope (due to reduced cardiac output). Signs may include tachypnea, bronchospasm, and evidence o elevated pulmonary artery pressure, including an accentuated pulmonic component o the second heart sound and jugular venous distention.
Diagnosis Many o the diagnostic tests used or DVT are also use ul or PE. Additional tests are use ul in the evaluation o suspected PE. The most common electrocardiographic abnormality is sinus tachycardia; there may be evidence o RV strain (e.g., inverted T waves in leads V1–V4 or an “S1–Q3–T3” pattern: a prominent S wave in lead I, Q wave in lead III, inverted T wave in lead III). RV strain may also produce elevated serum levels o cardiac-specif c troponins or B-type natriuretic peptide (described in Chapters 7 and 9, respectively). Arterial blood gas analysis may show decreased arterial oxygenation but is insensitive to the diagnosis o PE. The pre erred test to conf rm the diagnosis is computed tomographic angiography (CTA; Fig. 15-9). For patients who cannot tolerate CTA, such as those with renal insu f ciency or hypersensitivity to radioiodinated contrast agents, radionuclide ventilation–perfusion (V/ Q) lung scanning may be obtained instead but is less precise or the diagnosis. Catheter-based pulmonary angiography is rarely necessary or conf rmation.
Treatment In patients with established PE, urgent anticoagulation is instituted to prevent recurrent embolism. Anticoagulation measures are similar to those used or DVT. In patients with proximal DVT or established PE who cannot be treated with anticoagulants (e.g., because o a bleeding
FIGURE 15-9. CT angiogram displaying a massive pulmonary embolism. There is a large f lling de ect in the main pulmonary artery that extends into branches o both le t and right pulmonary arteries (blue arrow). (Courtesy o Andetta Hunsaker MD, Brigham and Women’s Hospital, Boston, MA.)
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disorder), an intravascular lter can be percutaneously inserted into the in erior vena cava to prevent emboli rom reaching the lungs. Occasionally, systemic thrombolytic therapy or surgical pulmonary embolectomy is undertaken or patients with massive PE.
Superf cial Thrombophlebitis Super cial thrombophlebitis is a benign disorder associated with inf ammation and thrombosis o a super cial vein, just below the skin. It may occur, or example, as a complication o an in-dwelling intravenous catheter. It is characterized by erythema, tenderness, and edema over the involved vein. Treatment consists o local heat and rest o the involved extremity. Aspirin or other anti-inf ammatory medications may relieve the associated discom ort. Unlike DVT, super cial thrombophlebitis does not lead to PE.
SUMMARY • True aneurysms are caused by degenerative changes in the aortic wall; cystic medial degeneration is associated with ascending thoracic aortic aneurysms, and atherosclerosis is commonly ound in descending thoracic and abdominal aortic aneurysms. • A alse aneurysm (pseudoaneurysm) represents a hole in the arterial intima and media contained by a layer o adventitia or perivascular clot. • Symptoms o aortic aneurysms relate to compression o adjacent structures (back pain, dysphagia, respiratory symptoms) or blood leakage, with the most severe consequence being aneurysm rupture. • Aortic dissection results rom a tear in the intima that allows blood to enter into the medial layer, o ten in the setting o advanced age, hypertension, or cystic medial degeneration. • Type A (proximal) aortic dissections involve the ascending aorta, are li e threatening, and require surgical repair. • Type B dissections are con ned to the descending aorta and are o ten managed by pharmacologic therapy alone. • PAD is a common atherosclerotic disease o large and medium-sized arteries, o ten resulting in claudication o the limbs. • PAD is treated by risk actor modi cation, exercise, antiplatelet agents, and sometimes cilostazol, a selective phosphodiesterase inhibitor. • Arterial embolism arises rom thrombus within the heart, rom proximal arterial sites, or paradoxically rom the systemic veins in the presence o an intracardiac shunt (e.g., atrial septal de ect). • Therapeutic options or acute arterial occlusion include anticoagulation, thrombolysis, and surgical or endovascular interventions. • Vasculitic syndromes are inf ammatory diseases o blood vessels that impair arterial f ow and result in localized and systemic symptoms; such syndromes are distinguished rom one another by the pattern o vessel involvement and morphologic ndings. • Raynaud phenomenon is an episodic vasospasm o arteries that supply the digits o the upper and lower extremities; it may be a primary condition (Raynaud disease) or may appear in association with other disorders such as connective tissue diseases or blood dyscrasias. • Varicose veins are dilated tortuous vessels that may present cosmetic problems; they may cause discom ort, become thrombosed, or lead to venous insu ciency. • Initial management o varicose veins is conservative, with periodic leg elevation and compression stockings; severe symptomatic varicose veins can be treated with sclerotherapy, radio requency or laser ablation, or surgical ligation and removal. • CVI develops when venous pressure is increased and return o blood f ow is impaired by venous valvular ref ux, resulting in chronic lower extremity edema, varicosities, and skin ulceration.
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Chapter 15 • Venous thrombosis results rom stasis o blood f ow, hypercoagulability, and vascular damage; the major complication is PE. • d -dimer assay and venous compression ultrasonography are the primary tools used to diagnose DVT. • Anticoagulation therapy with LMWH or un ractionated intravenous heparin (UFH), ollowed by oral war arin, is the usual treatment or DVT; newer targeted oral anticoagulant therapies are also available. • PE can be con rmed by CT angiography or ventilation–per usion scintigraphy. • Anticoagulant agents (LMWH or UFH ollowed by war arin or a newer oral anticoagulant) constitute usual PE therapy; however, i anticoagulants are contraindicated, an in erior vena cava lter is inserted to prevent recurrent PE.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Fan Liang, MD; Arash Mostaghimi, MD; Mary Beth Gordon, MD; Geo rey McDonough, MD; Michael Diminick, MD; Stuart Kaplan, MD; and Jesse Salmeron, MD.
Ad d i t i o n a l Rea d i n g Braverman AC. Acute aortic dissection: clinician update. Circulation. 2010;122:184–188. Creager MA, Beckman JA, Loscalzo J, eds. Vascular Medicine: A Companion to Braunwald’s Heart Disease. Philadelphia, PA: Elsevier Saunders; 2013. Creager MA, Loscalzo J. Diseases o the aorta. In: Kasper D, Fauci A, Hauser S, et al., eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015, pp.1637–1643. Creager MA, Loscalzo J. Arterial diseases o the extremities. In: Kasper D, Fauci A, Hauser S, et al., eds. Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015, pp.1643–1650. Gloviczki P, Comerota AJ, Dalsing MC, et al. The care o patients with varicose veins and associated chronic venous
diseases: clinical practice guidelines o the Society or Vascular Surgery and the American Venous Forum. J Vasc Surg. 2011;53:2S–48S. Goldhaber SZ, Bounzameaux H. Pulmonary embolism and deep vein thrombosis. Lancet. 2012;379:1835–1846. Gornik HL, Creager MA. Aortitis. Circulation. 2008;117:3039–3051. Hiratzka LF, et al. ACCF/ AHA 2010 guidelines or the diagnosis and management o patients with thoracic aortic disease. J Am Coll Cardiol. 2010;55:e27–e129. Patel MR, Conte MS, Cutlip DE, et al. State-o -the-art review: Evaluation and treatment o patients with lower extremity peripheral artery disease. J Am Coll Cardiol. 2015;65:931–941. Verma S, Siu SC. Aortic dilatation in patients with bicuspid aortic valve. N Engl J Med 2014;370:1920–1929.
Congenital Heart Disease Zena L. Knight Da vid W. Brown
Ch a p t e r O u t l i n e Normal Development of the Cardiovascular System Development o the Heart Tube Formation o the Heart Loop Septation Development o the Cardiac Valves Fetal and Transitional Circulations Fetal Circulation Transitional Circulation Common Congenital Heart Lesions Acyanotic Lesions Cyanotic Lesions Eisenmenger Syndrome
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C
ongenital heart diseases are the most common orm o birth de ects and are the leading cause o death rom birth abnormalities in the rst year o li e. These conditions a ect approximately 8 o 1,000 live births, and an estimated 1 million people in the United States have congenital heart lesions. Some abnormalities are severe and require immediate medical attention, whereas many are less pronounced and have minimal clinical consequences. Although congenital heart de ects are present at birth, milder de ects may remain inapparent or weeks, months, or years and may even escape detection until adulthood. The past hal -century has witnessed tremendous advances in the understanding o the pathophysiology o congenital heart diseases and substantial improvements in the ability to evaluate and treat those a f icted. Research has shown that genetic mutations, environmental actors, maternal illness, or ingestion o toxins during pregnancy can contribute to cardiac mal ormations. However, speci c etiologies remain unknown in most cases. The survival o children with congenital heart disease has also improved dramatically in recent decades, largely because o better diagnostic and interventional techniques. However, the li elong needs o a ected patients include guidance regarding physical activity, pregnancy, and employment. Formation o the cardiovascular system begins during the 3rd week o embryonic development. Soon a ter, a unique circulation develops that allows the etus to mature in the uterus, using the placenta as the primary organ o gas, nutrient, and waste exchange. At birth, the etal lungs inf ate and become unctional, making the placenta unnecessary and dramatically altering circulation patterns to allow the 373
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neonate to adjust to life outside the womb. Given the remarkable complexity of these processes, it is easy to envision ways that cardiovascular malfunctions could develop. This chapter begins with an overview of fetal cardiovascular development and then describes the most common forms of congenital heart disease.
NORMAL DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM By the 3rd week o gestation, the nutrient and gas exchange needs o the rapidly growing embryo can no longer be met by di usion alone, and the tissues begin to rely on the developing cardiovascular system to deliver these substances over long distances.
Dors a l a orta
Development of the Heart Tube In the middle o the 3rd week o embryogenesis, mesodermal cells proli erate at the cranial end o the early embryonic disc. They eventually orm two longitudinal cell clusters known as angioblastic cords. These cords canalize and become paired endothelial heart tubes (Fig. 16-1). Lateral embryonic olding gradually causes these two tubes to oppose one another and allows them to use in the ventral midline, orming a single endocardial tube by day 22. From inside to outside, the layers o this primitive heart tube are an endothelial lining that becomes the endocardium, a layer o gelatinous connective tissue (cardiac jelly), and a thick muscular layer that is derived rom the splanchnic mesoderm and develops into the myocardium. The endocardial tube is continuous with the aortic arch system rostrally and with the venous system caudally. The primitive heart begins to beat around day 22 or 23, causing blood to circulate by the beginning o the 4th week. The space overlying the developing cardiac area eventually becomes the pericardial cavity, housing the uture heart.
A
Endoca rdia l he a rt tube
Fore gut
B
Fus ing e ndoca rdia l he a rt tube s
Fore gut
P e rica rdia l ca vity
Formation of the Heart Loop As the tubular heart grows and elongates, it develops a series o alternate constrictions and dilations, creating the f rst sign o the primitive heart chambers—the truncus arteriosus, the bulbus cordis, the primitive ventricle, the primitive atrium,
C
Endoca rdia l he a rt tube
FIGURE 16-1. Embryonic transverse sections illustrating fusion of the two heart tubes into a single endocardial heart tube. A. 18 days. B. 21 days. C. 22 days.
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To a ortic a rche s
Truncus a rte rios us
[Aorta , pulmona ry a rte ry]
Bulbus cordis
[Outle t of ve ntricle s ]
Primitive ve ntricle
[Inle t of ve ntricle s ]
Primitive a trium
[Right a nd le ft a tria ]
S inus ve nos us
[Pa rt of right a trium]
Atriove ntricula r ca na l
FIGURE 16-2. The straight heart tube at approximately 22 days. The structures that will ultimately orm rom each segment are listed in brackets.
and the sinus venosus (Fig. 16-2). Continued growth and elongation within the con ned pericardial cavity orce the heart tube to bend on itsel on day 23, eventually orming a U-shaped loop with the round end pointing ventrally and to the right by day 28. The result o this looping is placement o the atrium and sinus venosus above and behind the truncus arteriosus, bulbus cordis, and ventricle (Fig. 16-3). At this point, neither de nitive septa between the developing chambers nor de nitive valvular tissue have ormed. The connection between the primitive atrium and ventricle is termed the atrioventricular (AV) canal. In time, the AV canal becomes two separate canals, one housing the tricuspid valve and the other the mitral valve. The sinus venosus is eventually incorporated into the right atrium, orming both the coronary sinus and a portion o the right atrial wall. The bulbus cordis and truncus arteriosus contribute to the uture ventricular outf ow tracts, orming parts o the proximal aorta and pulmonary artery.
Septation Septation o the developing atrium, AV canal, and ventricle occurs between the 4th and 6th weeks. Although these events are described separately here, they actually occur simultaneously.
Truncus a rte rios us
Truncus a rte rios us
Primitive a trium
A
Bulbus cordis
Primitive right a trium
Bulbove ntricula r s ulcus
Primitive right ve ntricle
B
Primitive le ft a trium Conus cordis Primitive le ft ve ntricle
C
FIGURE 16-3. Formation of the heart loop. A,B. By day 23, continued growth and elongation within the conf ned pericardial space necessitate bending o the heart tube on itsel , orming a U-shaped loop that points ventrally and to the right. C. Looping eventually places the atria above and behind the primitive ventricles.
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Septation of the Atria The primary atrial septum, also known as the septum primum, begins as a ridge o tissue on the roo o the common atrium that grows downward into the atrial cavity (Fig. 16-4). As the septum primum advances, it leaves a large opening known as the ostium primum between the crescent-shaped leading edge o the septum and the endocardial cushions surrounding the AV canal. The ostium primum allows passage o blood between the orming atria. Eventually, the septum primum uses with the superior aspect o the endocardial cushions (described in more detail in the next section), obliterating the ostium primum. However, be ore closure o the ostium primum is complete, small per orations appear in the center o the septum primum that ultimately coalesce to orm the ostium secundum, preserving a pathway or blood f ow between the atria (see Fig. 16-4). Following closure o the ostium primum, a second, more muscular membrane, the septum secundum, begins to develop immediately to the right o the superior aspect o the septum primum. This septum grows downward and overlaps the ostium secundum. The septum secundum eventually uses with the endocardial cushions, although only in a partial ashion, leaving an ovalshaped opening known as the foramen ovale. The superior edge o the septum primum then gradually regresses, leaving the lower edge to act as a “f ap-like” valve that allows only right-to-le t f ow through the oramen ovale (Fig. 16-5). During gestation, blood passes rom the right atrium to the le t atrium because the pressure in the etal right atrium is greater than that in the le t atrium. This pressure gradient changes direction postnatally, causing the valve to close, as described later.
Septation of the Atrioventricular Canal Growth o the endocardial cushions contributes to atrial septation and, as described later, to the membranous portion o the interventricular septum. Endocardial cushions initially S e ptum s e cundum Os tium primum
Os tium s e cundum
S e ptum primum
Inte rve ntricula r fora me n
Endoca rdia l cus hion
A
B Os tium s e cundum
S e ptum s e cundum S e ptum s e cundum Inte rve ntricula r fora me n
Fora me n ova le
S e ptum primum
S e ptum primum Mus cula r inte rve ntricula r s e ptum
C
Me mbra nous inte rve ntricula r s e ptum
D
FIGURE 16-4. Atrial septal formation at 30 days (A), 33 days (B), and 37 days (C) of development as well as in the newborn (D). As the septum primum grows toward the ventricles, the opening between it and the AV canal is the ostium primum. Be ore the ostium primum completely closes, per orations within the upper portion o the septum primum orm the ostium secundum. A second ridge o tissue, the septum secundum, grows downward to the right o the septum primum, partially covering the ostium secundum. The oramen ovale is an opening o the septum secundum that is covered by the “f ap valve” o the lower septum primum. (Modi ed rom Moss AJ, Adams FH. Heart Disease in Infants, Children, and Adolescents. Baltimore, MD: Williams & Wilkins; 1968:16.)
Congenital Heart Disease begin as swellings o the gelatinous connective tissue layer within the AV canal. They are then populated by migrating cells rom the primitive endocardium and subsequently trans orm into mesenchymal tissue. Tissue growth occurs primarily in the horizontal plane, resulting in septation o the AV canal through the continued growth o the lateral, superior, and in erior endocardial cushions (Fig. 16-6). Septation creates the right and le t canals that later give rise to the tricuspid and mitral orif ces, respectively.
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S hunt
A
Septation o the Ventricles and Ventricular Outf ow Tracts At the end o the 4th week, the primitive ventricle begins to grow, leaving a median muscular ridge, the primitive interventricular septum. Most o the early increase in height o the septum results rom dilation o the two new ventricles orming on either side o it. Only later does new cell growth in the septum itsel contribute to its size. The ree edge o the muscular interventricular septum does not use with the endocardial cushions; the opening that remains and allows communication between the right ventricle (RV) and le t ventricle (LV) is the interventricular foramen (Fig. 16-7). This remains open until the end o the 7th week o gestation, when the usion o tissue rom the right and le t bulbar ridges and the endocardial cushions orms the membranous portion o the interventricular septum.
S upe rior e ndoca rdia l cus hion La te ra l e ndoca rdia l cus hion Common a triove ntricula r ca na l
B FIGURE 16-5. Diagrammatic depiction o the f ap-type valve o the oramen ovale. A. Be ore birth, the valve permits only right-to-le t f ow o blood rom the higher-pressured right atrium (RA) to the lower-pressured le t atrium (LA). B. Following birth, the pressure in the LA becomes greater than that in the RA, causing the septum primum to close rmly against the septum secundum. (Derived rom Moore KL, Persaud TVN. The Developing Human. Philadelphia, PA: WB Saunders; 1993:318.)
Le ft a triove ntricula r ca na l La te ra l e ndoca rdia l cus hion
Infe rior e ndoca rdia l cus hion
Right a triove ntricula r ca na l
FIGURE 16-6. The progression o septal ormation in the atrioventricular canal through successive stages. The septum orms through growth o the superior, in erior, and lateral endocardial cushions. The endocardial cushions are masses o mesenchymal tissue that surround the atrioventricular canal and aid in the ormation o the ori ces o the mitral and tricuspid valves, as well as the upper interventricular septum and lower interatrial septum.
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Chapter 16 During the 5th week, neural crest–derived mesenchymal proli eration occurring in the bulbus cordis and truncus arteriosus creates a pair o protrusions known as the bulbar ridges (Fig. 16-8). These ridges use in the midline and undergo a 180-degree spiraling process, orming the aorticopulmonary septum. This septum divides the bulbus cordis and the truncus arteriosus into two arterial channels, the pulmonary artery and the aorta, the ormer continuous with the RV and the latter with the LV.
Inte rve ntricula r fora me n Mus cula r inte rve ntricula r s e ptum
Development of the Cardiac Valves FIGURE 16-7. The interventricular septum and the interventricular foramen. (Derived rom Moore KL, Persaud TVN. The Developing Human. Philadelphia, PA: WB Saunders; 1993:325.)
Semilunar Valve Development ( Aortic and Pulmonary Valves)
The semilunar valves start to develop just be ore the completion o the aorticopulmonary septum. The process begins when three outgrowths o subendocardial mesenchymal tissue orm around both the aortic and pulmonary ori ces. These growths are ultimately shaped and excavated by the joint action o programmed cell death and blood f ow to create the three thin-walled cusps o both the aortic and pulmonary valves.
Aorta
Pulmona ry a rte ry Le ft bulba r ridge
Right bulba r ridge
A
Inte rve ntricula r fora me n Mus cula r pa rt of inte rve ntricula r s e ptum Fus e d e ndoca rdia l cus hions
Pulmona ry a rte ry Aorticopulmona ry s e ptum Right ve ntricle Me mbra nous pa rt of inte rve ntricula r s e ptum
C
Mus cula r pa rt of inte rve ntricula r s e ptum
Right a triove ntricula r ca na l
B
Inte rve ntricula r fora me n Le ft a triove ntricula r ca na l Endoca rdia l cus hions
FIGURE 16-8. Formation of the aorticopulmonary septum occurs via fusion of the bulbar ridges, resulting in division of the bulbus cordis and truncus arteriosus into the aorta and pulmonary artery ( A, 5 weeks; B, 6 weeks; C, 7 weeks) . The bulbus cordis becomes the right ventricular outf ow tract. Fusion o tissue rom the endocardial cushions, the aorticopulmonary septum, and the muscular interventricular septum creates the membranous interventricular septum. (Derived rom Moore KL, Persaud TVN. The Developing Human. Philadelphia, PA: WB Saunders; 1993:322.)
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Atrioventricular Valve Development ( Mitral and Tricuspid Valves) A ter the endocardial cushions use to orm the septa between the right and le t AV canals, the surrounding subendocardial mesenchymal tissue proli erates and develops outgrowths similar to those o the semilunar valves. These are also sculpted by programmed cell death that occurs within the in erior sur ace o the nascent leaf ets and in the ventricular wall. This process leaves behind only a ew ne muscular strands to connect the valves to the ventricular wall (Fig. 16-9). The superior portions o these strands eventually degenerate and are replaced by strings o dense connective tissue, becoming the chordae tendineae.
Inte rve ntricula r fora me n Lume n of le ft ve ntricle
A
De ve loping mitra l va lve
FETAL AND TRANSITIONAL CIRCULATIONS The etal circulation elegantly serves the needs o in utero development. At birth, the circulation automatically undergoes modi cations that establish the normal blood f ow pattern o a newborn in ant.
Fetal Circulation
Me mbra nous pa rt of inte rve ntricula r s e ptum
B
Tra be cula e ca rne a e
Atriove ntricula r node
In etal li e, oxygenated blood leaves the plaMitra l va lve centa through the umbilical vein (Fig. 16-10). Approximately hal o this blood is shunted Chorda e te ndine a e through the etal ductus venosus, bypassing the hepatic vasculature and proceeding directly into the in erior vena cava (IVC). P a pilla ry mus cle The remaining blood passes through the Ve ntricula r conduction portal vein to the liver and then into the IVC s ys te m through the hepatic veins. IVC blood is there- C ore a mixture o well-oxygenated umbilical FIGURE 16-9. Proliferation of mesenchymal tissue venous blood and the blood o low oxygen surrounding the atrioventricular canals forms the atrioventricular valves. A–C. Progression of the tension returning rom the systemic veins o process, including degeneration of myocardium and the etus. Because o this mixture, the oxygen replacement by connective tissue that forms the tension o in erior vena caval blood is higher chordae tendineae; their muscular attachments to the than that o blood returning to the etal ventricular wall are the papillary muscles. (Derived right atrium rom the superior vena cava. from Moore KL, Persaud TVN. The Developing Human. This distinction is important because these Philadelphia, PA: WB Saunders; 1993:325.) two streams o blood are partially separated within the right atrium to ollow di erent circulatory paths. The consequence o this separation is that the etal brain and myocardium receive blood o relatively higher oxygen content, whereas the more poorly oxygenated blood is diverted to the placenta (via the descending aorta and umbilical arteries) or subsequent oxygenation.
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Chapter 16
S upe rior ve na ca va
Arch of a orta Duc tus arte rio s us P ulmona ry trunk
Lung
P ulmona ry ve ins Fo rame n o vale
Le ft a trium
Right a trium
Infe rior ve na ca va Le ft he pa tic ve in
Right he pa tic ve in
Duc tus ve no s us De s ce nding a orta s in l a t Po r
us
P orta l ve in Umbilica l ve in Umbilicus
Oxyge n s a tura tion of blood:
Urina ry bla dde r
High Umbilica l a rte rie s
Me dium Low
P la ce nta
Le gs
Inte rna l ilia c a rte ry
FIGURE 16-10. The fetal circulation. Arrows indicate the direction o blood f ow. Three shunts (ductus venosus, oramen ovale, and ductus arteriosus) allow most o the blood to bypass the liver and lungs during etal li e but cease to unction shortly a ter birth. (Modi ed rom Moore KL, Persaud TVN. The Developing Human. Philadelphia, PA: WB Saunders; 1993:344.)
Most IVC blood entering the right atrium is directed to the le t atrium through the oramen ovale. This intracardiac shunt o relatively well-oxygenated blood is acilitated by the in erior border o the septum secundum, termed the crista dividens, which is positioned such that it overrides the opening o the IVC into the right atrium. This shunted blood then mixes with the small amount o poorly oxygenated blood returning to the le t atrium through the etal pulmonary veins (remember that the lungs are not ventilated in utero; the developing pulmonary tissues actually remove oxygen rom the blood). From the le t atrium, blood f ows into the LV and is then pumped into the ascending aorta. This welloxygenated blood is distributed primarily to three territories: (1) approximately 9% enters
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the coronary arteries and per uses the myocardium, (2) 62% travels in the carotid and subclavian vessels to the upper body and brain, and (3) 29% passes into the descending aorta to the rest o the etal body. The remaining well-oxygenated in erior vena caval blood entering the right atrium mixes with poorly oxygenated blood rom the superior vena cava and passes to the RV. In the etus, the RV is the actual “workhorse” o the heart, providing two thirds o the total cardiac output. This output f ows into the pulmonary artery and rom there either into the lungs (12% o RV output), or through the ductus arteriosus into the descending aorta (88% o RV output), where it mixes with the better oxygenated blood rom the LV described in the previous paragraph. This unequal distribution o right ventricular outf ow is actually quite e cient. Bypassing the lungs is desired because the etal lungs are lled with amniotic f uid and are incapable o gas exchange. The low oxygen tension o this f uid causes constriction o the pulmonary vessels, which increases pulmonary vascular resistance and acilitates shunting o blood through the ductus arteriosus to the systemic circulation. From the descending aorta, blood is distributed to the lower body and to the umbilical arteries, leading back to the placenta or gas exchange.
Transitional Circulation Immediately ollowing birth, the neonate rapidly adjusts to li e outside the womb. The newly unctioning lungs replace the placenta as the organ o gas exchange, and the three shunts (ductus venosus, oramen ovale, and ductus arteriosus) that operated during gestation ultimately close. This shi t in the site o gas exchange and the resulting changes in cardiovascular architecture allow the newborn to survive independently. As the umbilical cord is clamped or constricts naturally, the low-resistance placental f ow is removed rom the arterial system, resulting in an increase in systemic vascular resistance. Simultaneously, pulmonary vascular resistance alls or two reasons: (1) the mechanical inf ation o the lungs a ter birth stretches the lung tissues, causing pulmonary artery expansion and wall thinning, and (2) vasodilatation o the pulmonary vasculature occurs in response to the rise in blood oxygen tension accompanying aeration o the lungs. This reduction in pulmonary resistance results in a dramatic rise in pulmonary blood f ow. It is most marked within the rst day a ter birth but continues or the next several weeks until adult levels o pulmonary resistance are achieved. As pulmonary resistance alls and more blood travels to the lungs through the pulmonary artery, venous return rom the pulmonary veins to the le t atrium also increases, causing le t atrial pressure to rise. At the same time, cessation o umbilical venous f ow and constriction o the ductus venosus cause a all in IVC and right atrial pressures. As a result, the le t atrial pressure becomes greater than that in the right atrium, and the valve o the oramen ovale is orced against the septum secundum, eliminating the previous f ow between the atria (see Fig. 16-5). Failure o the valve to permanently use to the septum secundum results in a patent foramen ovale (PFO), as described later in this chapter. With oxygenation now occurring in the newborn lungs, the ductus arteriosus becomes superf uous and closes. During etal li e, a high circulating level o prostaglandin E1 (PGE1) is generated in response to relative hypoxia, which causes the smooth muscle o the ductus arteriosus to relax, keeping it patent. A ter birth, PGE1 levels decline as the oxygen tension rises and the ductus there ore constricts. In a healthy ull-term in ant, this occurs during the rst hours to days a ter delivery. The responsiveness o the ductus to vasoactive substances depends on the gestational age o the etus, and it o ten ails to constrict in premature in ants. This results in the congenital anomaly known as patent ductus arteriosus (PDA) (described below). With the anatomic separation o the circulatory paths o the right and le t sides o the heart now complete, the stroke volume o the LV increases and that o the RV decreases, equalizing
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Chapter 16 the cardiac output rom both ventricles. The augmented pressure and volume load placed on the LV induces the myocardial cells o that chamber to hypertrophy, while the decreased pressure and volume loads on the RV result in gradual regression o RV wall thickness.
COMMON CONGENITAL HEART LESIONS Congenital heart de ects are generally well tolerated be ore birth. The etus bene ts rom shunting o blood through the ductus arteriosus and the oramen ovale, allowing the bypass o most de ects. It is only a ter birth, when the neonate has been separated rom the maternal circulation and the oxygenation it provides, and the etal shunts have closed, that congenital heart de ects usually become mani est. Congenital heart lesions can be categorized as cya notic or a cyan otic. Cyanosis re ers to a blue-purple discoloration o the skin and mucous membranes caused by an elevated blood concentration o deoxygenated hemoglobin (usually > 4 g/ dL, which corresponds to an arterial O2 saturation o approximately 80% to 85% in a neonate with a normal total hemoglobin level). In congenital heart disease, cyanosis results rom de ects that allow poorly oxygenated blood rom the right side o the heart to be shunted to the le t side, bypassing the lungs. Acyanotic lesions include intracardiac or vascular stenoses, valvular regurgitation, and de ects that result in left-to-right shunting o blood. Large le t-to-right shunts at the atrial, ventricular, or great vessel level (all described in the ollowing sections) cause the pulmonary artery volume and pressure to increase and can be associated with the later development o pulmonary arteriolar hypertrophy and subsequently increased resistance to f ow. Over time, the elevated pulmonary resistance may orce the direction o the original shunt to reverse, causing right-to-left f ow to supervene, accompanied by the physical ndings o hypoxemia and cyanosis. The development o pulmonary vascular disease as a result o a chronic large le t-to-right shunt is known as Eisen men ger syn drome and is described later in the chapter. Patients with congenital heart disease are susceptible to in ective endocarditis. Chapter 8 describes the pathophysiology o endocarditis and summarizes the appropriate selection o patients or antibiotic prophylaxis prior to procedures that can result in bacteremia.
Acyanotic Lesions Atrial Septal Defect An atrial septal de ect (ASD) is a persistent opening in the interatrial septum a ter birth that allows direct communication between the le t and right atria. ASDs are relatively common, occurring with an incidence o 1 in 1,500 live births. They can occur anywhere along the atrial septum, but the most common site is at the region o the oramen ovale, termed an ostium secundum ASD (Fig. 16-11). This de ect arises rom inadequate ormation o the septum secundum, excessive resorption o the septum primum, or a combination. Less commonly, an ASD appears in the in erior portion o the interatrial septum, adjacent to the AV valves. Named as ostium primum de ect, this abnormality results rom the ailure o the septum primum to use with the endocardial cushions. A third type o atrial septal abnormality is termed a sinus venosus defect and is closely related to ASDs but is morphologically distinct. This condition represents an “unroo ng” de ect with absence o normal tissue between the right pulmonary vein(s) and the right atrium but is technically not a de ciency o the anatomic atrial septum (i.e., requently the atrial septum itsel is ully intact). As sinus venosus de ects are o ten large and result in f ow rom the right pulmonary veins and le t atrium into the right atrium, the pathophysiology is similar to that o a true ASD.
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Ao RA SVC
LA AS D
PA LA RV
LV
RA LV PA
Ao
RV IVC
A
B
FIGURE 16-11. Atrial septal defect ( ASD) , ostium secundum type. A. The arrow indicates shunted f ow rom the le t atrium (LA) into the right atrium (RA). B. Schematic representation o blood f ow through an uncomplicated ASD, resulting in enlargement o the RA, right ventricle (RV), and pulmonary artery (PA). Ao, aorta; IVC, in erior vena cava; LV, le t ventricle; SVC, superior vena cava.
Another distinct condition related to ASDs is patent foramen ovale, which is present in approximately 20% o the general population. It too is not a true ASD (i.e., no atrial septal tissue is “missing”) but represents persistence o normal etal anatomy. As described earlier, the oramen ovale typically unctionally closes in the days a ter birth, and it is permanently sealed by the age o 6 months through usion o the atrial septa. A PFO remains when this usion ails to occur. A PFO is usually clinically silent because the one-way valve, though not sealed, remains unctionally closed since the le t atrial pressure is higher than that in the right atrium. However, a PFO takes on signif cance i the right atrial pressure becomes elevated (e.g., in states o pulmonary hypertension or right-heart ailure), resulting in pathologic right-to-left intracardiac shunting. In that case, deoxygenated blood passes directly into the arterial circulation. Occasionally, a PFO can be implicated in a patient who has su ered a systemic embolism (e.g., a stroke). This situation, termed paradoxical embolism, occurs when thrombus in a systemic vein breaks loose, travels to the right atrium, then passes across the PFO to the le t atrium if right-heart pressures are elevated, at least transiently (e.g., during a cough, sneeze, or Valsalva type maneuver), and then into the systemic arterial circulation.
Pathophysiology In the case o an uncomplicated ASD, oxygenated blood rom the le t atrium is shunted into the right atrium, but not vice versa. Flow through the de ect is a unction o its size and the f lling properties (compliance) o the ventricles into which the atria pass their contents. Normally a ter birth, the RV becomes more compliant than does the LV, owing to the regression o right ventricular wall thickness and an increase in LV thickness, acilitating the le t-to-right directed shunt at the atrial level. The result is volume overload and enlargement o the right atrium and RV (see Fig. 16-11B). I right ventricular compliance diminishes over time (because o the excessive load), the le t-to-right shunt may lessen. Occasionally, i
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Chapter 16 severe pulmonary vascular disease develops (e.g., Eisenmenger syndrome), the direction o the shunt may actually reverse (causing right-to-le t f ow), such that desaturated blood enters the systemic circulation, resulting in hypoxemia and cyanosis.
Symptoms Most in ants with ASDs are asymptomatic. The condition may be detected by the presence o a murmur on routine physical examination during childhood or adolescence, but the exam ndings are subtle and 25% o ASDs are not diagnosed until adulthood. I symptoms do occur, they include dyspnea on exertion, atigue, and recurrent lower respiratory tract in ections. The most common symptoms in adults are decreased stamina and palpitations due to atrial tachyarrhythmias resulting rom right atrial enlargement.
Physical Examination A prominent systolic impulse may be palpated along the lower-le t sternal border, representing contraction o the dilated RV (termed an RV hea ve). The second heart sound (S2) demonstrates a widened, xed splitting pattern (see Chapter 2). This occurs because the normal respiratory variation in systemic venous return is countered by reciprocal changes in the volume o blood shunted across the ASD. In addition, the increased volume o blood f owing across the pulmonary valve o ten creates a systolic murmur at the upper-le t sternal border. A mid-diastolic murmur may also be present at the lower-le t sternal border owing to the increased f ow across the tricuspid valve. Blood traversing the ASD itsel does not produce a murmur because o the absence o a signi cant pressure gradient between the atria.
Diagnostic Studies On chest radiograph, the heart is usually enlarged because o right atrial and right ventricular dilatation, and the pulmonary artery is prominent with increased pulmonary vascular markings. The electrocardiogram (ECG) shows right ventricular hypertrophy, o ten with right atrial enlargement and incomplete or complete right bundle branch block. In patients with the ostium primum type o ASD, le t axis deviation is common and is thought to be a result o displacement and hypoplasia o the le t bundle branch’s anterior ascicle. Echocardiography demonstrates right atrial and right ventricular enlargement; the ASD may be visualized directly, or its presence may be implied by the demonstration o a transatrial shunt by Doppler f ow assessment. The magnitude and direction o shunt f ow and an estimation o right ventricular systolic pressure can also be determined by echo Doppler measurements. Given the high sensitivity o echocardiography, it is rarely necessary to per orm cardiac catheterization to con rm the presence o an ASD. However, catheterization may be use ul to assess pulmonary vascular resistance and to diagnose concurrent coronary artery disease in older adults. In a normal person undergoing cardiac catheterization, the oxygen saturation measured in the right atrium is similar to that in the superior vena cava. However, an ASD with le t-to-right shunting o well-oxygenated blood causes the saturation in the right atrium to be much greater than that o the superior vena cava.
Treatment Most patients with ASDs remain asymptomatic. However, i the volume o shunted blood is hemodynamically signi cant (even in the absence o symptoms), elective surgical repair is recommended to prevent the development o heart ailure or chronic pulmonary vascular disease. The de ect is repaired by direct suture closure or with a pericardial or synthetic patch.
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In children and young adults, morphologic changes in the right heart o ten return to normal a ter repair. Percutaneous ASD repair, using a closure device deployed via an intravenous catheter, is a less invasive alternative to surgery in selected patients with secundum ASDs.
Ventricular Septal Defect A ventricular septal de ect (VSD) is an abnormal opening in the interventricular septum (Fig. 16-12). VSDs are relatively common, having an incidence o 1.5 to 3.5 per 1,000 live births. They are most o ten located in the membranous (70% ) and muscular (20% ) portions o the septum. Rare VSDs occur just below the aortic valve or adjacent to the AV valves.
Pathophysiology The hemodynamic changes and magnitude o the shunt that accompany VSDs depend on the size o the de ect and the relative resistances o the pulmonary and systemic vasculatures. In small VSDs, the de ect itsel o ers more resistance to f ow than the pulmonary or systemic vasculature, thereby preventing a signi cant quantity o le t-to-right shunting. Conversely, with larger “nonrestrictive” de ects, the volume o the shunt is determined by the relative pulmonary and systemic vascular resistances. In the perinatal period, the pulmonary vascular resistance approximates the systemic vascular resistance, and minimal shunting occurs between the two ventricles. A ter birth, however, as the pulmonary vascular resistance alls, an increasing le t-to-right shunt through the de ect develops. When this shunt is large, the RV, pulmonary circulation, le t atrium, and LV experience a relative volume overload. Initially, the increased blood return to the LV augments stroke volume (via the Frank–Starling mechanism); but over time, the increased volume load can result in progressive chamber dilatation, systolic dys unction, and symptoms o heart ailure. In addition, the augmented circulation
Ao RA
LA
SVC PA LA RV
LV VS D
RA LV
PA
Ao
RV IVC
A
B
FIGURE 16-12. Ventricular septal defect ( VSD) . A. The arrow indicates shunted f ow rom the le t ventricle (LV) toward the right ventricular (RV) outf ow tract. B. Schematic representation o blood f ow through an uncomplicated VSD. The dashed lines represent increased blood return to the le t side o the heart as a result o the shunt, which causes enlargement primarily o the le t atrium (LA) and LV. Ao, aorta; IVC, in erior vena cava; PA, pulmonary artery; RA, right atrium; SVC, superior vena cava.
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Chapter 16 through the pulmonary vasculature can cause pulmonary vascular disease as early as 2 years o age. As pulmonary vascular resistance eventually approaches or exceeds systemic resistance, the intracardiac shunt may reverse its direction (i.e., Eisenmenger syndrome), leading to systemic hypoxemia and cyanosis.
Symptoms Patients with small VSDs typically remain symptom ree. Conversely, 10% o in ants with VSDs have large de ects and develop early symptoms o heart ailure, including tachypnea, poor eeding, ailure to thrive, and requent lower respiratory tract in ections. Patients with VSDs complicated by pulmonary vascular disease and reversed shunts may present with dyspnea and cyanosis. Bacterial endocarditis (see Chapter 8) can develop, regardless o the size o the VSD.
Physical Examination The most common physical nding is a harsh holosystolic murmur that is best heard at the le t sternal border. Smaller de ects tend to have the loudest murmurs because o the great turbulence o f ow that they cause. A systolic thrill can commonly be palpated over the region o the murmur. In addition, a mid-diastolic rumbling murmur can o ten be heard at the apex owing to the increased f ow across the mitral valve. I pulmonary vascular disease develops, the holosystolic murmur diminishes as the pressure gradient across the de ect decreases. In such patients, an RV heave, a loud pulmonic closure sound (P2), and cyanosis may be evident.
Diagnostic Studies On chest radiographs, the cardiac silhouette may be normal in patients with small de ects, but in those with large shunts, cardiomegaly and prominent pulmonary vascular markings are present. I pulmonary vascular disease has developed, enlarged pulmonary arteries with peripheral tapering may be evident. The ECG shows le t atrial enlargement and le t ventricular hypertrophy in those with a large shunt, and right ventricular hypertrophy is usually evident i pulmonary vascular disease has developed. Echocardiography with Doppler studies can accurately determine the location o the VSD, identi y the direction and magnitude o the shunt, and provide an estimate o right ventricular systolic pressure. Cardiac catheterization demonstrates increased oxygen saturation in the RV compared with the right atrium, the result o shunting o highly oxygenated blood rom the LV into the RV.
Treatment By age 2, at least 50% o small and moderate-sized VSDs undergo su cient partial or complete spontaneous closure to make intervention unnecessary. Surgical correction o the de ect is recommended in the rst ew months o li e or children with accompanying heart ailure or pulmonary vascular hypertension. Moderate-sized de ects without pulmonary vascular disease but with signi cant le t-to-right shunting can be corrected later in childhood. Lessinvasive catheter-based treatments are also used in selected patients.
Patent Ductus Arteriosus The ductus arteriosus is the vessel that connects the pulmonary artery to the descending aorta during etal li e. PDA results when the ductus ails to close a ter birth, resulting in a persistent connection between the great vessels (Fig. 16-13). It has an overall incidence o about 1 in 2,500 to 5,000 live term births. Risk actors or its presence include rst trimester maternal rubella in ection, prematurity, and birth at a high altitude.
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RA
LA
RV
LV
387
Ao SVC PA LA
RA LV
PA
RV
P DA
IVC
A
Ao
B
FIGURE 16-13. Patent ductus arteriosus ( PDA) . A. The arrow indicates shunted f ow rom the descending aorta (Ao) toward the pulmonary artery (PA). B. Schematic representation o blood f ow through an uncomplicated PDA. The dashed lines represent increased blood return to the le t side o the heart as a result o the shunt, which causes enlargement o the le t atrium (LA), le t ventricle (LV), and Ao. IVC, in erior vena cava; RA, right atrium; RV, right ventricle; SVC, superior vena cava.
Pathophysiology As described earlier, the smooth muscle o the ductus arteriosus usually constricts a ter birth owing to the sudden rise in blood oxygen tension and a reduction in the level o circulating prostaglandins. Over the next several weeks, intimal proli eration and brosis result in permanent closure. Failure o the ductus to close results in a persistent shunt between the descending aorta and the le t pulmonary artery. The magnitude o f ow through the shunt depends on the cross-sectional area and length o the ductus itsel as well as the relative resistances o the systemic and pulmonary vasculatures. Prenatally, when the pulmonary vascular resistance is high, blood is diverted away rom the immature lungs to the aorta. As the pulmonary resistance drops postnatally, the shunt reverses direction, and blood f ows rom the aorta into the pulmonary circulation instead. Because o this le t-toright shunt, the pulmonary circulation, le t atrium, and LV become volume overloaded. This can lead to le t ventricular dilatation and le t-sided heart ailure, whereas the right heart remains normal unless pulmonary vascular disease ensues. I the latter does develop, Eisenmenger syndrome results, with reversal o the shunt causing blood to f ow rom the pulmonary artery, through the ductus, to the descending aorta. In this case, the resulting f ow o desaturated blood to the lower extremities causes cyanosis o the eet; the upper extremities are not cyanotic, because they receive normally saturated blood rom the aorta proximal to the ductus.
Symptoms Children with small PDAs are generally asymptomatic. Those with large le t-to-right shunts develop early congestive heart ailure with tachycardia, poor eeding, slow growth, and recurrent lower respiratory tract in ections. Moderate-sized lesions can present with atigue, dyspnea, and palpitations in adolescence and adult li e. Atrial brillation may occur owing to
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Chapter 16 le t atrial dilatation. Turbulent blood f ow across the de ect can set the stage or endovascular in ection, similar to endocarditis but more accurately termed endarteritis.
Physical Examination The most common nding in a patient with a le t-to-right shunt through a PDA is a con tin uous, ma chin e-like murmur (see Fig. 2-10), heard best at the le t subclavicular region. The murmur is present throughout the cardiac cycle because a pressure gradient exists between the aorta and pulmonary artery in both systole and diastole. However, i pulmonary vascular disease develops, the gradient between the aorta and the pulmonary artery decreases, leading to diminished f ow through the PDA, and the murmur becomes shorter (the diastolic component may disappear). I Eisenmenger syndrome develops, lower extremity cyanosis and clubbing may be present as poorly oxygenated blood is shunted to the descending aorta.
Diagnostic Studies With a large PDA, the chest radiograph shows an enlarged cardiac silhouette (le t atrial and le t ventricular enlargement) with prominent pulmonary vascular markings. In adults, calci cation o the ductus may be visualized. The ECG shows le t atrial enlargement and le t ventricular hypertrophy when a large shunt is present. Echocardiography with Doppler imaging can visualize the de ect, demonstrate f ow through it, and estimate right-sided systolic pressures. Cardiac catheterization is usually unnecessary or diagnostic purposes. When perormed in patients with a le t-to-right shunt, it demonstrates a step up in oxygen saturation in the pulmonary artery compared with the RV, and angiography shows the abnormal f ow o blood through the PDA.
Treatment In the absence o other congenital cardiac abnormalities or severe pulmonary vascular disease, a PDA should generally be therapeutically occluded. Although many spontaneously close during the rst months a ter birth, this rarely occurs later. Given the constant risk o endarteritis and the minimal complications o corrective procedures, even a small asymptomatic PDA is commonly re erred or closure. For neonates and premature in ants with congestive heart ailure, a trial o prostaglandin synthesis inhibitors (e.g., indomethacin) can be administered in an attempt to constrict the ductus. De nitive closure can be accomplished by surgical division or ligation o the ductus or by transcatheter techniques in which an occluding device is placed.
Congenital Aortic Stenosis Congenital aortic stenosis (AS) is most o ten caused by abnormal structural development o the valve leaf ets. It occurs in 5 o 10,000 live births and is our times as common in males as in emales. Twenty percent o patients have an additional abnormality, most commonly coarctation o the aorta (discussed later). The aortic valve in congenital AS usually has a bicuspid leaf et structure instead o the normal three-leaf et con guration, causing an eccentric stenotic opening through which blood is ejected. Most bicuspid aortic valves are actually nonobstructive at birth and there ore only rarely result in congenital AS. More o ten, bicuspid valves become progressively stenotic over a great many years, as the lea lets progressively brose and calci y, and represent a common cause o AS in adults (see Chapter 8).
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Pathophysiology Because the valvular orif ce is signif cantly narrowed, le t ventricular systolic pressure must increase to pump blood across the valve into the aorta. In response to this increased pressure load, the LV hypertrophies (Fig. 16-14). The high-velocity jet o blood that passes through the stenotic valve may impact the proximal aortic wall and contribute to dilatation o that vessel.
Symptoms The clinical picture o AS depends on the severity o the lesion. Fewer than 10% o in ants experience symptoms o heart ailure be ore age 1, but i they do, they mani est tachycardia, tachypnea, ailure to thrive, and poor eeding. Most older children with congenital AS are asymptomatic and develop normally. When symptoms do occur, they are similar to those o adult AS and include atigue, exertional dyspnea, angina pectoris, and syncope (see Chapter 8).
Physical Examination Auscultation reveals a harsh crescendo–decrescendo systolic murmur, loudest at the base o the heart with radiation toward the neck. It is o ten preceded by a systolic ejection click (see Chapter 2), especially when a bicuspid valve is present. Unlike the murmurs o ASD, VSD, or PDA, the murmur o congenital AS is characteristically present rom birth because it does not depend on the postnatal decline in pulmonary vascular resistance. With advanced disease, the ejection time becomes longer, causing the peak o the murmur to occur later in systole. In severe disease, the signif cantly prolonged ejection time causes a delay in closure o the aortic valve such that A2 occurs after P2—a phenomenon known as reversed splitting (also termed “paradoxical splitting”) o S2 (see Chapter 2).
Ao SVC
RA
LA
RV
LV
PA
Ao
PA LA
RA LV RV IVC
A
B
FIGURE 16-14. Congenital aortic valve stenosis. A. The jagged arrow traverses the narrowed aortic valve. B. Schematic representation o obstructed f ow through the narrowed aortic valve (jagged arrow). Le t ventricular (LV) hypertrophy results rom the chronically increased pressure load. Poststenotic dilatation o the aorta (Ao) is common. IVC, in erior vena cava; LA, le t atrium; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SVC, superior vena cava.
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Diagnostic Studies The chest radiograph o an in ant with AS may show an enlarged LV and a dilated ascending aorta. The ECG o ten shows le t ventricular hypertrophy. Echocardiography identi es the abnormal structure o the aortic valve and the degree o le t ventricular hypertrophy. Doppler assessment can accurately measure the pressure gradient across the stenotic valve and allow calculation o the valve area. Cardiac catheterization con rms the pressure gradient across the valve.
Treatment In its milder orms, congenital AS does not need to be corrected but should be ollowed closely as the degree o stenosis may worsen over time. Severe obstruction o the aortic valve during in ancy may mandate immediate repair. Transcatheter balloon valvuloplasty is the rst line o intervention, but surgical repair may be necessary i valvuloplasty ails to relieve the obstruction or i signi cant aortic regurgitation results rom balloon dilation. O ten, valvuloplasty in in ancy is only palliative, and repeat catheter balloon dilation or surgical revision is needed later.
Pulmonic Stenosis Obstruction to right ventricular outf ow may occur at the level o the pulmonic valve (e.g., rom congenitally used valve commissures), within the body o the RV (i.e., in the RV outf ow tract), or in the pulmonary artery. Valvular pulmonic stenosis is the most requent orm (Fig. 16-15).
Ao
RA
SVC
LA
PA LA RV
LV
RA LV
PA
Ao
RV IVC
A
B
FIGURE 16-15. Congenital pulmonary valve stenosis. A. The jagged arrow traverses the narrowed pulmonary valve. B. Schematic representation o obstructed f ow through the narrowed pulmonary valve (jagged arrow). Right ventricular hypertrophy results rom the chronically increased pressure load. Ao, aorta; IVC, in erior vena cava; LA, le t atrium; LV, le t ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SVC, superior vena cava.
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Pathophysiology The consequence o pulmonic stenosis is impairment o right ventricular outf ow, which leads to increased RV pressures and chamber hypertrophy. The clinical course is determined by the severity o the obstruction. Although mild pulmonic stenosis rarely progresses and is unlikely to a ect RV unction, untreated severe pulmonic stenosis typically results in rightsided heart ailure.
Symptoms Children with mild or moderate pulmonary stenosis are asymptomatic. The diagnosis is o ten rst made on discovery o a murmur during a routine physical examination. Severe stenosis may cause mani estations such as dyspnea with exertion, exercise intolerance, and with decompensation, symptoms o right-sided heart ailure such as abdominal ullness and pedal edema.
Physical Examination The physical ndings in pulmonic stenosis depend on the severity o the obstruction. I the stenosis is severe with accompanying right ventricular hypertrophy, a prominent jugular venous a wave can be observed (see Chapter 2) and an RV heave is palpated over the sternum. A loud, late-peaking, crescendo–decrescendo systolic ejection murmur is heard at the upper le t sternal border, o ten associated with a palpable thrill. Widened splitting o the S2 with a so t P 2 component is caused by the delayed closure o the stenotic pulmonary valve. In more moderate stenosis, a pulmonic ejection sound (a high-pitched “click”) ollows S1 and precedes the systolic murmur. It occurs during the early phase o right ventricular contraction as the stenotic valve leaf ets suddenly reach their maximum level o ascent into the pulmonary artery, just be ore blood ejection. Unlike other sounds and murmurs produced by the right side o the heart, the pulmonic ejection sound diminishes in intensity during inspiration. This occurs because with inspiration, the augmented right-sided lling elevates the leaf ets into the pulmonary artery prior to RV contraction, preempting the rapid tensing in early systole that is thought to produce the sound.
Diagnostic Studies The chest radiograph may demonstrate an enlarged right atrium and ventricle with poststenotic pulmonary artery dilation (thought to be caused by the impact o the high-velocity jet o blood against the wall o the pulmonary artery). The ECG shows right ventricular hypertrophy with right axis deviation. Echocardiography with Doppler imaging assesses the pulmonary valve morphology, determines the presence o right ventricular hypertrophy, and accurately measures the pressure gradient across the obstruction.
Treatment Mild pulmonic stenosis usually does not progress or require treatment. Moderate or severe valvular obstruction at the valvular level can be relieved by dilating the stenotic valve by means o transcatheter balloon valvuloplasty. Long-term results o this procedure have been uni ormly excellent, and right ventricular hypertrophy usually regresses subsequently.
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Coarctation of the Aorta Le ft s ubclavia n Coarctation o the aorta typically consists a rte ry o a discrete narrowing o the aortic lumen (Fig. 16-16). This anomaly has an incidence o Aortic a rch Coa rcta tion 1 in 6,000 live births, and the most common associated cardiac abnormality is a bicuspid aortic valve. Aortic coarctation o ten occurs in Cons tricte d ductus patients with Turner syndrome (45, XO). In the past, coarctations were described as either “preductal” (in antile) or “postductal” (adult-type) based on the location o the aortic narrowing in relation to the Pulmona ry ductus arteriosus. These terms have been a rte ry largely abandoned because the vast majority o coarctations are actually juxtaductal FIGURE 16-16. Coarctation of the aorta. A pressure (i.e., “next to” the ductus) and etiologic gradient is present across the narrowed lumen of the di erences between the preductal and post- aorta. ductal categories have not been substantiated. While the actual pathogenesis o aortic coarctation has not been de ned, one theory contends that reduced antegrade blood f ow through the le t side o the heart and ascending aorta during etal li e leads to hypoplastic development o the aorta (“no f ow, no grow”). Another theory is that ectopic muscular ductus arteriosus tissue extends into the aorta during etal li e and constricts ollowing birth at the same time the ductus is caused to close. More recent evidence suggests that aortic coarctation may be just one mani estation o a more di use aortic disease.
Pathophysiology Because o the impedance o aortic narrowing in coarctation, the LV aces an increased a terload. Blood f ow to the head and upper extremities is preserved because the vessels supplying these areas usually branch o the aorta proximal to the obstruction, but f ow to the descending aorta and lower extremities may be diminished. I coarctation is not corrected, compensatory alterations include (1) development o le t ventricular hypertrophy and (2) dilatation o collateral blood vessels rom the intercostal arteries that bypass the coarctation and provide blood to the more distal descending aorta. Eventually, these collateral vessels enlarge and can erode the undersur ace o the ribs.
Symptoms Patients with severe coarctation usually present very shortly a ter birth with symptoms o heart ailure. In ants may also exhibit differential cyanosis i the ductus arteriosus ails to constrict and remains patent. The upper hal o the body, supplied by the LV and the ascending aorta, is per used with well-oxygenated blood; however, the lower hal appears cyanotic because it is largely supplied by right-to-le t f ow o poorly oxygenated blood rom the pulmonary artery, across the PDA, and into the descending aorta, beyond the coarctation. When the coarctation is less severe, a patient may be asymptomatic or experience only mild weakness or pain in the lower extremities ollowing exercise (i.e., claudication). In asymptomatic cases, coarctation may be suspected by the nding o upper extremity hypertension later in li e (see Chapter 13).
Physical Examination On examination, the emoral pulses are weak and delayed. An elevated blood pressure in the upper body is the most common nding. I the coarctation occurs distal to the takeo o the le t
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subclavian artery, the systolic pressure in the arms is greater than that in the legs. I the coarctation occurs proximal to the takeo o the le t subclavian artery, the systolic pressure in the right arm may exceed that in the le t arm. A systolic pressure in the right arm that is 15 to 20 mm Hg greater than that in a leg is su cient to suspect coarctation, because normally the systolic pressure in the legs is higher than that in the arms. A midsystolic ejection murmur (caused by turbulent f ow through the coarctation) may be audible over the chest and/ or back. A prominent tortuous collateral arterial circulation may create continuous murmurs over the chest in adults.
Diagnostic Studies In adults with uncorrected coarctation o the aorta, chest radiography generally reveals notching o the in erior sur ace o the posterior ribs owing to enlarged intercostal vessels supplying collateral circulation to the descending aorta. An indented aorta at the site o coarctation may also be visualized. The ECG shows le t ventricular hypertrophy resulting rom the pressure load placed on that chamber. Doppler echocardiography con rms the diagnosis o coarctation and assesses the pressure gradient across the lesion. Magnetic resonance (or CT) imaging demonstrates in detail the length and severity o coarctation (see Fig. 16-17). Diagnostic catheterization and angiography are rarely necessary.
Treatment In neonates with severe obstruction, prostaglandin in usion is administered to keep the ductus arteriosus patent, thus maintaining blood f ow to the descending aorta be ore surgery is undertaken. In children, elective repair is usually per ormed to prevent systemic hypertension. Several e ective surgical procedures are available, including excision o the narrowed aortic segment with end-to-end reanastomosis and direct repair o the coarctation, sometimes using synthetic patch material. For older children, adults, and patients with recurrent coarctation a ter previous repair, transcatheter interventions (balloon dilatation with or without stent placement) are usually success ul.
Cyanotic Lesions Tetralogy of Fallot Tetralogy o Fallot results rom a single developmental de ect: an abnormal anterior and cephalad displacement o the in undibular (outf ow tract) portion o the interventricular septum. As a consequence, our anomalies arise that characterize this condition, as shown in Figure 16-18: (1) a VSD caused by anterior malalignment o the interventricular septum, (2) subvalvular pulmonic stenosis because o obstruction rom the displaced in undibular septum (o ten with valvular pulmonic stenosis), (3) an overriding aorta that receives blood rom both ventricles, and (4) right ventricular hypertrophy owing to the high-pressure load placed on the RV by the pulmonic stenosis. Tetralogy o Fallot is the most common orm o cyanotic congenital heart disease a ter
FIGURE 16-17. Magnetic resonance imaging of coarctation of the aorta. This lateral view demonstrates coarctation, manifest as a focal aortic narrowing (white arrow). AA, ascending aorta; DA, descending aorta; LA, left atrium; RA, right atrium; TAA, transverse aortic arch.
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Ao SVC PA LA Ove rriding a orta RA LV RV IVC Ve ntricula r s e pta l de fe ct
Right ve ntricula r hype rtrophy
FIGURE 16-18. Tetralogy of Fallot is characterized by four associated anomalies. (1) A ventricular septal de ect, (2) obstruction to right ventricular outf ow (jagged arrow), (3) an overriding aorta that receives blood rom both ventricles, and (4) right ventricular hypertrophy. Ao, aorta; IVC, in erior vena cava; LA, le t atrium; LV, le t ventricle; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SVC, superior vena cava.
in ancy, occurring in 5 o 10,000 live births and is o ten associated with other cardiac de ects, including a right-sided aortic arch (25% o patients), ASD (10% o patients), and less o ten, an anomalous origin o the le t coronary artery. A microdeletion in chromosome 22 (22q11) has been identif ed in patients with a syndrome that includes tetralogy o Fallot as one o the cardiovascular mani estations (see Box 16-1).
BOX 16-1
Genetic Abnormalities in Congenital Heart Disease
Progress in understanding o genetic inf uences on cardiac development and congenital heart disease is proceeding at a brisk pace. Although nearly all cardiac congenital anomalies can occur as isolated ndings, the clustering o certain orms with heritable syndromes and known genetic abnormalities provides clues to the underlying basis o certain de ects. Among in ants with Down syndrome (trisomy 21), the incidence o congenital heart de ects is nearly 40%. Many o these are common abnormalities such as ASDs, VSDs, and PDAs. There is also a high incidence o a rarer condition known as common AV canal, which consists o a large primum ASD and VSD and a common (undivided) AV valve. These central heart structures are usually ormed by the endocardial cushions and cells o neural crest origin, which are known to have abnormal migration patterns in patients with trisomy 21. Turner syndrome (45, XO) is another heritable condition associated with congenital heart disease. Le t-sided obstructive congenital heart lesions are common in patients with this syndrome, including bicuspid aortic valve, coarctation o the aorta, and occasionally hypoplastic le t heart syndrome (underdevelopment o the LV and aorta). The speci c genes responsible or these abnormalities have not yet been elucidated. In contrast, discrete gene abnormalities have been identi ed in other syndrome-associated orms o congenital heart disease. Many patients with Williams syndrome (characterized by mental retardation, hypercalcemia, renovascular hypertension, acial abnormalities, and short stature) have supravalvular AS, and some have a more di use arteriopathy o the aorta as well as pulmonary artery obstruction. The genetic abnormality in Williams syndrome is a deletion on chromosome 7
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Genetic Abnormalities in Congenital Heart Disease ( continued)
(7q11.23), a region that includes the elastin gene. Abnormalities in the production o elastin, a critical component o the arterial wall, may be responsible or the observed arteriopathy. DiGeorge syndrome (characterized by pharyngeal de ects, hypocalcemia due to absent parathyroid glands, and T-cell dys unction secondary to hypoplasia o the thymus) is associated with congenital abnormalities o the cardiac outf ow tracts, including tetralogy o Fallot, truncus arteriosus (a large VSD over which a single large outf ow vessel arises), and interrupted aortic arch. Most patients with DiGeorge syndrome have a microdeletion within chromosome 22 (22q11), a region that contains the TBX1 gene. This gene encodes a transcription actor that appears to play a critical role in developmental patterning o the cardiac outf ow tracts. CHARGE syndrome (the acronym or coloboma [congenital absence o portions o eye structures], heart de ects, choanal atresia [nasal passage obstruction], retardation o growth and development, genitourinary mal ormation, ear abnormalities) is an autosomal dominant disorder that includes some or all o the listed components. Associated cardiac abnormalities include interrupted aortic arch, tetralogy o Fallot, double outlet right ventricle, and AV septal de ects. The incidence o the syndrome is approximately 1:10,000 children, and most are ound to have a mutation or microdeletion in the CHD7 gene, the protein product o which is a transcription regulator associated with several tissue-speci c target genes. Several other transcription actors involved in heart development likely contribute to congenital heart disease. Some amilies with heritable orms o ASDs have mutations in the transcription actor gene Nkx2.5. An associated transcription actor gene GATA4 appears to collaborate with Nkx2.5 and has also been implicated in amilial septal de ect syndromes. Mutations in TBX5, yet another transcription actor gene, are responsible or Holt–Oram syndrome (also known as the heart–hand syndrome), an autosomal dominant disorder whose characteristic cardiac de ects include secundum ASDs and VSDs. Further deciphering o the genome will undoubtedly improve understanding o cardiac development and the molecular de ects that lead to congenital heart abnormalities.
Pathophysiology Increased resistance by the subvalvular pulmonic stenosis causes deoxygenated blood returning rom the systemic veins to be diverted rom the RV, through the VSD to the LV, and into the systemic circulation, resulting in systemic hypoxemia and cyanosis. The magnitude o shunt f ow across the VSD is primarily a unction o the severity o the pulmonary stenosis, but acute changes in systemic and pulmonary vascular resistances can a ect it as well.
Symptoms Children with tetralogy o Fallot o ten experience dyspnea on exertion. “Spells” may occur ollowing exertion, eeding, or crying when systemic vasodilatation results in an increased rightto-le t shunt. Mani estations o such spells include irritability, cyanosis, hyperventilation, and occasionally syncope or convulsions. Children learn to alleviate their symptoms by squatting down, which is thought to increase systemic vascular resistance by “kinking” the emoral arteries, thereby decreasing the right-to-le t shunt and directing more blood rom the RV to the lungs.
Physical Examination Children with tetralogy o Fallot and moderate pulmonary stenosis o ten have mild cyanosis, most notably o the lips, mucous membranes, and digits. In ants with severe pulmonary stenosis may present with pro ound cyanosis in the rst ew days o li e. Chronic hypoxemia
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Chapter 16 caused by the right-to-le t shunt commonly results in clubbing o the ngers and toes. Right ventricular hypertrophy may be appreciated on physical examination as a palpable heave along the le t sternal border. The S2 is single, composed o a normal aortic component; the pulmonary component is so t and usually inaudible. A systolic ejection murmur heard best at the upper le t sternal border is created by turbulent blood f ow through the stenotic right ventricular outf ow tract. There is usually no distinct murmur related to the VSD, because it is typically large and thus generates little turbulence.
Diagnostic Studies Chest radiography demonstrates prominence o the RV and decreased size o the main pulmonary artery segment, giving the appearance o a “boot-shaped” heart. Pulmonary vascular markings are typically diminished because o decreased f ow through the pulmonary circulation. The ECG shows right ventricular hypertrophy with right axis deviation. Echocardiography details the right ventricular outf ow tract anatomy, the malaligned VSD, right ventricular hypertrophy, and other associated de ects, as does cardiac catheterization.
Treatment Be ore de nitive surgical correction o tetralogy o Fallot was developed, several orms o palliative therapy were undertaken. These involved creating anatomic communications between the aorta (or one o its major branches) to the pulmonary artery, establishing a le t-to-right shunt to increase pulmonary blood f ow. Such procedures are occasionally used today in in ants or whom de nitive repair is planned at an older age. Complete surgical correction o tetralogy o Fallot involves closure o the VSD and enlargement o the subpulmonary in undibulum with the use o a pericardial patch. Elective repair is usually recommended at 6 to 12 months o age to decrease the likelihood o uture complications. Most patients who have undergone success ul repair grow to become asymptomatic adults. However, antibiotic prophylaxis to prevent endocarditis is required in some patients (see Chapter 8).
Transposition of the Great Arteries In transposition o the great arteries (TGAs), each great vessel inappropriately arises rom the opposite ventricle; that is, the aorta originates rom the RV and the pulmonary artery originates rom the LV (Fig. 16-19). This anomaly accounts or approximately 7% o congenital heart de ects, a ecting 40 o 100,000 live births. Whereas tetralogy o Fallot is the most common etiology o cyanosis a ter in ancy, TGA is the most common cause o cyanosis in the neonatal period. The precise cause o transposition remains unknown. One theory contends that ailure o the aorticopulmonary septum to spiral in a normal ashion during etal development is the underlying problem. It
SVC
Ao PA
LA
RA LV RV IVC
FIGURE 16-19. Transposition of the great arteries. The aorta (Ao) and pulmonary artery (PA) arise abnormally from the right ventricle (RV) and left ventricle (LV), respectively. IVC, inferior vena cava; LA, left atrium; RA, right atrium; SVC, superior vena cava.
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has also been suggested that the de ect may be the result o abnormal growth and absorption o the subpulmonary and subaortic in undibuli during the division o the truncus arteriosus. Normally, reabsorption o the subaortic in undibulum places the orming aortic valve posterior and in erior to the pulmonary valve and in continuity with the LV. In TGA, the process o in undibular reabsorption may be reversed, placing the pulmonary valve over the LV instead.
Pathophysiology TGA separates the pulmonary and systemic circulations by placing the two circuits in parallel rather than in series. This arrangement orces desaturated blood rom the systemic venous system to pass through the RV and then return to the systemic circulation through the aorta without undergoing normal oxygenation in the lungs. Similarly, oxygenated pulmonary venous return passes through the LV and then back through the pulmonary artery to the lungs without imparting oxygen to the systemic circulation. The result is an extremely hypoxic, cyanotic neonate. Without intervention to create mixing between the two circulations, TGA is a lethal condition. TGA is compatible with li e in utero because f ow through the ductus arteriosus and oramen ovale allows communication between the two circulations. Oxygenated etal blood f ows rom the placenta through the umbilical vein to the right atrium, and then most o it travels into the le t atrium through the oramen ovale. The oxygenated blood in the le t atrium passes into the LV and is pumped out the pulmonary artery. Most o the pulmonary artery f ow travels through the ductus arteriosus into the aorta, instead o the high-resistance pulmonary vessels, such that oxygen is provided to the developing tissues. A ter birth, normal physiologic closure o the ductus and the oramen ovale eliminates the shunt between the parallel circulations and, without intervention, would result in death because oxygenated blood does not reach the systemic tissues. However, i the ductus arteriosus and oramen ovale remain patent (either naturally or with exogenous prostaglandins or surgical intervention), communication between the parallel circuits is maintained, and su ciently oxygenated blood may be provided to the brain and other vital organs.
Symptoms and Physical Examination In ants with transposition appear blue, with the intensity o the cyanosis dependent on the degree o intermixing between the parallel circuits. In most cases, generalized cyanosis is apparent on the rst day o li e and progresses rapidly as the ductus arteriosus closes. Palpation o the chest reveals a right ventricular impulse at the lower sternal border as the RV aces systemic pressures. Auscultation may reveal an accentuated S2, which ref ects closure o the anteriorly placed aortic valve just under the chest wall. Prominent murmurs are uncommon and may signal an additional de ect.
Diagnostic Studies Chest radiography is usually normal, although the base o the heart may be narrow owing to the more anterior–posterior orientation o the aorta and pulmonary artery. The ECG demonstrates right ventricular hypertrophy, ref ecting the act that the RV is the systemic “high-pressure” pumping chamber. The de nitive diagnosis o transposition can be made by echocardiography, which demonstrates the abnormal orientation o the great vessels.
Treatment TGA is a medical emergency. Initial treatment includes maintenance o the ductus arteriosus by prostaglandin in usion and creation o an interatrial communication using a balloon catheter (termed the Rashkind procedure). Such intervention allows adequate mixing o the two
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Chapter 16 circulations until de nitive corrective surgery can be per ormed. The current corrective procedure o choice is the “arterial switch” operation (Jatene procedure), which involves transection o the great vessels above the semilunar valves and origin o the coronary arteries. The great vessels are then reversed to the natural con guration, so the aorta arises rom the LV and the pulmonary artery arises rom the RV. The coronary arteries are then relocated to the new aorta.
EISENMENGER SYNDROME Eisenmenger syndrome is the condition o severe pulmonary vascular obstruction that results rom chronic le t-to-right shunting through a congenital cardiac de ect. The elevated pulmonary vascular resistance causes reversal o the original shunt (to the right-to-le t direction) and systemic cyanosis. The mechanism by which increased pulmonary f ow causes this condition is unknown. Histologically, the pulmonary arteriolar media hypertrophies and the intima proli erates, reducing the cross-sectional area o the pulmonary vascular bed. Over time, the vessels become thrombosed, and the resistance o the pulmonary vasculature rises, causing the original le t-to-right shunt to decrease. Eventually, i the resistance o the pulmonary circulation exceeds that o the systemic vasculature, the direction o shunt f ow reverses. With reversal o the shunt to the right-to-le t direction, symptoms arise rom hypoxemia, including exertional dyspnea and atigue. Reduced hemoglobin saturation stimulates the bone marrow to produce more red blood cells (erythrocytosis), which can lead to hyperviscosity, symptoms o which include atigue, headaches, and stroke (caused by cerebrovascular occlusion). In arction or rupture o the pulmonary vessels can result in hemoptysis. On examination, a patient with Eisenmenger syndrome appears cyanotic with digital clubbing. A prominent a wave in the jugular venous pulsation ref ects elevated right-sided pressure during atrial contraction. A loud P2 is common. The murmur o the inciting le t-to-right shunt is usually absent, because the original pressure gradient across the lesion is negated by the elevated right-heart pressures. Chest radiography in Eisenmenger syndrome is notable or proximal pulmonary artery dilatation with peripheral tapering. Calci cation o the pulmonary vasculature may be seen. The ECG demonstrates right ventricular hypertrophy and right atrial enlargement. Echocardiography with Doppler studies can usually identi y the underlying cardiac de ect and quantitate the pulmonary artery systolic pressure. Treatment includes the avoidance o activities that can exacerbate the right-to-le t shunt. These include strenuous physical activity, high altitude, and the use o peripheral vasodilator drugs. Pregnancy is especially dangerous; the rate o spontaneous abortion is 20% to 40% , and the incidence o maternal mortality is approximately 45% . Supportive measures or Eisenmenger syndrome include prompt treatment o in ections, management o rhythm disturbances, and phlebotomy or patients with symptomatic erythrocytosis. Although there are no remedies that reverse the disease process in Eisenmenger syndrome, pulmonary vasodilator therapy can provide symptomatic relie and improve the patient’s quality o li e. E ective agents include endothelin receptor antagonists, prostacyclin analogs, and phosphodiesterase inhibitors (see Chapter 17). The only e ective long-term strategy or severely a ected patients is lung or heart–lung transplantation. Fortunately, with the dramatic advances that have been made in the detection and early correction o severe congenital heart de ects, Eisenmenger syndrome has become less common.
SUMMARY • Formation o the cardiovascular system begins during the 3rd week o embryonic development; soon a ter, a unique circulation develops that allows the etus to mature in the uterus, using the placenta as the primary organ o gas, nutrient, and waste exchange.
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• At birth, the etal lungs inf ate and become unctional, making the placenta unnecessary and altering circulation patterns to allow the neonate to adjust to li e outside the womb. • Cardiac mal ormations occur in 0.8% o live births, representing the most common orm o birth de ects and the leading cause o death rom birth abnormalities in the rst year o li e. • Congenital heart lesions can be grouped into cyanotic or acyanotic de ects, depending on whether the abnormality results in right-to-le t shunting o blood. • Acyanotic de ects o ten result in either volume overload (ASD, VSD, PDA) or pressure overload (AS, pulmonic stenosis, coarctation o the aorta). • Chronic volume overload resulting rom a large le t-to-right shunt can ultimately result in increased pulmonary vascular resistance, reversal o the direction o shunt f ow, and subsequent cyanosis (Eisenmenger syndrome). • Among the most common cyanotic de ects are tetralogy o Fallot and transposition o the great arteries.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were David D. Berg, MD; Vijay G. Sankaran, MD; Yi-Bin Chen, MD; Douglas W. Green, MD; Raymond Tabibiazar, MD; Lakshmi Halasyamani, MD; Andrew Karson, MD; Michael D. Freed, MD; and Richard Liberthson, MD.
Ad d i t i o n a l Rea d i n g Allen HD, Driscoll DJ, Shaddy RE, et al., eds. Moss and Adams’ Heart Disease in Infants, Children, and Adolescents: Including the Fetus and Young Adult. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013. Bruneau BG. The developmental genetics o congenital heart disease. Nature. 2008;451:943–948. Kemper AR, Mahle WT, Martin GR, et al. Strategies or implementing screening or critical congenital heart disease. Pediatrics. 2011;128:e1259–e1267. Moore KL, Persaud TVN. The Developing Human: Clinically Oriented Embryology. 9th ed. Philadelphia, PA: Saunders; 2013. Park MK. Pediatric Cardiology for Practitioners. 6th ed. Philadelphia, PA: Saunders; 2014.
Perlo JK. The Clinical Recognition of Congenital Heart Disease. 6th ed. Philadelphia, PA: Saunders; 2012. Pierpont ME, Basson CT, Benson DW Jr, et al. Genetic basis or congenital heart de ects: current knowledge: a scienti c statement rom the American Heart Association Congenital Cardiac De ects Committee, Council on Cardiovascular Disease in the Young: endorsed by the American Academy o Pediatrics. Circulation. 2007;115:3015–3038. Sadler TW. Langman’s Medical Embryology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012. Warnes CA, Williams RG, Bashore TM, et al. ACC/ AHA 2008 Guidelines or the management o adults with congenital heart disease: executive summary. J Am Coll Cardiol. 2008;52:1890–1947.
Cardiovascular Drugs Andrey V. Dolinko Micha el T. Kuntz Elliott M. Antma n Ga ry R. Stricha rtz Leona rd S. Lilly
17
Ch a p t e r O u t l i n e Inotropic Drugs and Vasopressors Cardiac Glycosides (Digitalis) Sympathomimetic Amines Phosphodiesterase-3 Inhibitors Vasopressin Vasodilator Drugs Angiotensin-Converting Enzyme Inhibitors Angiotensin II Type 1 Receptor Antagonists Direct-Acting Vasodilators Calcium Channel Blockers Organic Nitrates Natriuretic Peptides Phosphodiesterase-5 Inhibitors Endothelin Receptor Antagonists Antiadrenergic Drugs Central Adrenergic Inhibitors (CNS α2-Agonists) Sympathetic Nerve-Ending Antagonists Peripheral α-Adrenergic Receptor Antagonists β-Adrenergic Receptor Antagonists Antiarrhythmic Drugs Class IA Antiarrhythmics Class IB Antiarrhythmics Class IC Antiarrhythmics Class II Antiarrhythmics Class III Antiarrhythmics Class IV Antiarrhythmics Adenosine 400
Diuretics Loop Diuretics Thiazide Diuretics Potassium-Sparing Diuretics Antithrombotic Drugs Platelet Inhibitors Anticoagulant Drugs: Parenteral Agents Anticoagulant Drugs: Oral Agents Lipid-Regulating Drugs HMG-CoA Reductase Inhibitors Bile Acid–Binding Agents Cholesterol Absorption Inhibitors Niacin Fibrates
T
his chapter reviews the physiologic basis and clinical use of cardiovascular drugs. Although a multitude of drugs are available to treat cardiac disorders, these agents can be grouped by their pharmacologic actions into a small number of categories. Additionally, many drugs are useful in more than one form of heart disease.
INOTROPIC DRUGS AND VASOPRESSORS Inotropic drugs are used to increase the force of ventricular contraction when myocardial systolic function is impaired. The pharmacologic agents in this category include the cardiac glycosides, sympathomimetic amines, and phosphodiesterase-3 inhibitors (Table 17-1). Although they work through different mechanisms, they are all thought to enhance cardiac contraction by increasing the
Cardiovascular Drugs
TABLE 17-1
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Inotropic Drugs
Class
Examples
Cardiac glycosides Sympathomimetic amines
Digoxin Dopamine Dobutamine Norepinephrine Epinephrine Isoproterenol Milrinone
Phosphodiesterase-3 inhibitors
intracellular calcium concentration, thus augmenting actin and myosin interaction. The hemodynamic e ect is to shi t a depressed ventricular per ormance curve (Frank–Starling curve) in an upward direction (Fig. 17-1), so that or a given ventricular f lling pressure, stroke volume and cardiac output (CO) are increased.
Cardiac Glycosides ( Digitalis) The cardiac glycosides are called “digitalis” because the drugs o this class are based on extracts o the oxglove plant, Digitalis purpurea. The most commonly used member o this group is digoxin.
Mechanism of Action The two desired e ects o digoxin are (1) to improve contractility o the ailing heart (mechanical e ect) and (2) to prolong the re ractory period o the atrioventricular (AV) node in patients with supraventricular arrhythmias (electrical e ect).
Mechanical Effect The action by which digoxin improves contractility appears to be inhibition o sarcolemmal Na + K+ -ATPase, which is normally responsible or maintaining transmembrane Na + and K+
i C
a
r
d
Inotrop ic the ra py
Diure tic the ra py
yp
o
t
e
n
s
i
o
n
He a rt fa ilure
H
FIGURE 17-1. Ventricular performance ( Frank–Starling) curve. In systolic heart failure, the curve is displaced downward, so that at a given left ventricular end-diastolic pressure (LVEDP), the cardiac output is lower than in a normal heart. Diuretics reduce LVEDP but do not change the position of the curve; thus, pulmonary congestion improves but cardiac output may fall. Inotropic drugs shift the curve upward, toward normal, so that at any LVEDP, the cardiac output is greater.
a
c
o
u
t
p
u
t
Norma l
Pulmona ry conge s tion Le ft ve ntricula r e nd-dia s tolic pre s s ure
402
Chapter 17 gradients. By binding to and inhibiting this transporter, digitalis causes the intracellular [Na + ] to rise. As shown in Figure 17-2, an increase in intracellular sodium content reduces Ca + + extrusion rom the cell via the Na + / Ca + + exchanger. Consequently, more Ca + + is pumped into the sarcoplasmic reticulum, and when subsequent action potentials excite the cell, a greater-than-normal amount o Ca + + is released to the myo laments, thereby enhancing the orce o contraction.
Electrical Effect The major therapeutic electrical e ect o digoxin occurs at the AV node, where it slows conduction and increases re ractoriness (Table 17-2). While digoxin has modest direct e ects on the electrical properties o cardiac tissue, more importantly, it modies autonomic nervous system output by enhancing vagal tone and reducing sympathetic activity. As a result, digitalis decreases the requency o transmission o atrial impulses through the AV node.
A – DIGITALIS
B
C
FIGURE 17-2. Mechanism of action of digitalis ( inotropic effect) . A. Digitalis inhibits the sarcolemmal Na+ K+ -ATPase, causing intracellular [Na+ ] to rise. B. Increased cytosolic [Na+ ] reduces the transmembrane Na+ gradient; thus, the Na+ / Ca+ exchanger drives less Ca+ + out of the cell. C. The increased intracellular [Ca+ + ] is stored in the sarcoplasmic reticulum, such that with subsequent action potentials, greater-than-normal Ca+ + is released to the contractile elements in the cytoplasm, intensifying the force of contraction.
Clinical Uses The most common use o digoxin historically has been as an inotropic agent to treat heart ailure caused by decreased ventricular contractility (see Chapter 9). By increasing the orce o contraction and augmenting CO, digoxin improves le t ventricular emptying, reduces le t ventricular size, and lowers the elevated ventricular lling pressures typical o patients with systolic dys unction. It is not bene cial in orms o heart ailure associated with normal ventricular contractility (i.e., heart ailure with preserved ejection raction). Although no longer a mainstay o therapy in heart ailure, digitalis is sometimes use ul in treating patients with heart ailure complicated by atrial brillation (it has the added bene t o slowing the ventricular heart rate) or when symptoms do not respond adequately to angiotensin-converting enzyme (ACE) inhibitors and β-blockers. Unlike ACE inhibitors and β-blockers, digoxin does not prolong the li e expectancy o patients with chronic heart ailure. Digoxin is also occasionally prescribed as an antiarrhythmic agent, although other agents are more e ective, sa er, and used more requently. By impairing AV nodal conduction, digitalis reduces the rate o ventricular stimulation in patients with rapid supraventricular tachycardias (SVTs) such as atrial brillation or atrial f utter. Digitalis may also terminate supraventricular reentrant tachycardias (e.g., AVNRT—see Chapter 12), likely through enhancement o vagal tone, which slows impulse conduction and prolongs the e ective re ractory period o the AV node.
Pharmacokinetics and Toxicity Digoxin is typically administered orally or intravenously and is excreted unchanged by the kidney. A series o loading doses is necessary to raise the drug’s concentration into the therapeutic range. The subsequent maintenance dosage depends on the patient’s renal unction.
Cardiovascular Drugs
TABLE 17-2
403
Electrophysiologic Effects of Digitalis
Region Therapeutic effects AV node
Toxic effects Sinoatrial node
Atrium
AV node AV junction (between AV node and His bundle) Purkinje f bers and ventricular muscle
Mechanism of Action
Clinical Effect
Vagal e ect ↓ Conduction velocity ↑ E ective re ractory period
• ↓ Rate o transmission o atrial impulses to the ventricles in supraventricular tachyarrhythmias • May interrupt reentrant circuits passing through the AV node
↑ Vagal e ect and direct suppression
• Sinus bradycardia • Sinoatrial block (impulse not transmitted rom SA node to atrium) • Atrial premature beats • Nonreentrant SVT (ectopic rhythm) • Reentrant PSVT
Delayed a terdepolarizations (triggered activity), ↑ slope o phase 4 depolarization (↑ automaticity) Variable e ects on conduction velocity and ↑ re ractory period (can ragment conduction and lead to reentry) Direct and vagal-mediated conduction block Delayed a terdepolarizations (triggered activity), ↑ slope o phase 4 depolarization (↑ automaticity) Delayed a terdepolarizations (triggered activity), ↓ conduction velocity and ↑ re ractory period (can lead to reentry) ↑ Slope o phase 4 depolarization (↑ automaticity)
• AV block (f rst, second, or third degree) • Accelerated junctional rhythm
• Ventricular premature beats
• Ventricular tachycardia
AV, atrioventricular; PSVT, paroxysmal supraventricular tachycardia; SA, sinoatrial; SVT, supraventricular tachycardia.
The potential or digitalis toxicity is signif cant because o a narrow therapeutic window. Many actors contribute to digitalis intoxication, the most common o which is hypokalemia, o ten caused by concurrent administration o diuretics. Hypokalemia exacerbates digitalis toxicity because it urther inhibits Na + K+ -ATPase. Other conditions that promote digitalis toxicity include hypomagnesemia and hypercalcemia. In addition, the administration o other drugs (e.g., amiodarone) may raise the serum digoxin concentration by altering its clearance or volume o distribution. Extracardiac signs o acute digitalis toxicity are o ten gastrointestinal (e.g., nausea, vomiting, anorexia), thought to be mediated by e ects on the area postrema o the brain stem. Cardiac toxicity, which may precede extracardiac warning signs, includes several types o arrhythmias, some o which may be li e threatening (Table 17-2). In atrial tissue and ventricular Purkinje f bers, a high digoxin concentration has three important actions that may lead to dangerous arrhythmias (Fig. 17-3): 1. Less negative resting potential. Inhibition o Na + K+ -ATPase causes the resting potential to become less negative. Consequently, there is a voltage-dependent partial inactivation o the ast Na + channels, which leads to a slower rise o phase 0 depolarization and a reduction in conduction velocity (Fig. 1-16). The slowed conduction, i present heterogeneously among neighboring cells, enhances the possibility o reentrant arrhythmias.
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Chapter 17
B
A
C
FIGURE 17-3. Direct effects of digitalis on the Purkinje cell action potential. The solid tracing represents depolarization and repolarization of a normal cell; the dashed tracing demonstrates the effects of digitalis. A. The maximum diastolic potential is less negative, and there is an increase in the slope of phase 4 depolarization, endowing the cell with intrinsic automaticity, and the potential for ectopic rhythms. B. Because depolarization of the cell occurs at a more positive voltage, there is partial inactivation of fast sodium channels, the rate of rise of phase 0 is decreased, and conduction velocity is slowed, which, if present heterogeneously among neighboring cells, produces conditions for reentry. C. Delayed afterdepolarizations may develop at high concentrations of digitalis in association with the increased intracellular calcium concentration and can result in triggered tachyarrhythmias.
2. Decreased action potential duration. Digitalis-induced elevated intracellular [Ca + + ] increases the activity o a Ca + + -dependent K+ channel. The opening o this channel promotes K+ e f ux and more rapid repolarization. In addition, high intracellular [Ca + + ] inactivates Ca + + channels, decreasing the inward depolarizing Ca + + current. These e ects decrease the action potential duration and shorten the re ractory period, increasing the time during which cardiac bers are responsive to external stimulation and allowing greater opportunity or propagation o arrhythmic impulses. 3. Enhanced automaticity. Digoxin enhances automaticity and may generate ectopic rhythms by two mechanisms: a. The less negative membrane resting potential may induce phase 4 gradual depolarization, even in nonpacemaker cells (see Chapter 11), and an action potential is triggered each time that threshold voltage is reached. b. The digoxin-induced increase in intracellular [Ca + + ] may trigger delayed a terdepolarizations (Fig. 17-3 and Chapter 11). I an a terdepolarization reaches the threshold voltage, an action potential (ectopic beat) is generated. Ectopic beats may lead to additional a terdepolarizations and sel -sustaining arrhythmias such as ventricular tachycardia. In addition, the augmented direct and indirect vagal e ects o toxic doses o digitalis slow conduction through the AV node, such that various degrees o AV block, including complete heart block, can occur. The treatment o digitalis-induced tachyarrhythmias may include administration o potassium (i hypokalemia is present), intravenous atropine or bradyarrhythmias, or lidocaine (discussed later in the chapter) or ventricular ectopy. High-grade AV block may require temporary pacemaker therapy. In patients with severe intoxication, administration o digoxinspeci c antibodies may be li esaving.
Sympathomimetic Amines Sympathomimetic amines are inotropic drugs that bind to cardiac β1-receptors. Stimulation o these receptors increases the activity o adenylate cyclase, causing increased ormation o cyclic adenosine monophosphate (cAMP; Fig. 17-4). Increased cAMP activates speci c
Cardiovascular Drugs
FIGURE 17-4. Mechanism by which β-adrenergic stimulation increases contractility. β1-Receptor stimulation acts through G proteins (guanine nucleotide regulatory proteins), the alpha subunit (α) o which activates adenylate cyclase. The latter increases cyclic adenosine monophosphate (cAMP) production, which mediates protein kinase phosphorylation o cellular proteins, including ion channels. Phosphorylation o the slow Ca+ + channel increases calcium inf ux, which augments the orce o contraction. cAMP is degraded by phosphodiesterase (PD).
+
405
Ade nyla te cycla s e
G S prote in ATP
+
cAMP PD AMP
Ina ctive prote in kina s e s
Active prote in kina s e s
Myo c yte
protein kinases, which promote intracellular calcium inf ux by phosphorylating L-type calcium channels. The increased calcium entry triggers a corresponding rise in Ca + + release rom the sarcoplasmic reticulum, which enhances the orce o contraction. Intravenous dopamine and dobutamine are commonly used sympathomimetic amines in the treatment o acute heart ailure. Norepinephrine, epinephrine, and isoproterenol are prescribed in special circumstances, as described in the ollowing paragraphs. Table 17-3 summarizes the receptor actions and major hemodynamic e ects o these agents. Dopamine is an endogenous catecholamine and the precursor o norepinephrine. It possesses an unusual combination o actions that makes it attractive in the treatment o heart ailure associated with hypotension and poor renal per usion. There are various types o receptors with di erent a nities or dopamine. At low dosages, less than 2 µg/ kg/ min, dopamine interacts primarily with dopaminergic receptors distributed in the renal and mesenteric vascular beds. Stimulation o these receptors causes local vasodilation and increases renal blood f ow and glomerular ltration, acilitating diuresis. Medium dosages o dopamine, 2 to 10 µg/ kg/ min, increase inotropy directly by stimulating cardiac β1-receptors and indirectly by promoting norepinephrine release rom sympathetic nerve terminals. These actions increase heart rate, cardiac contractility, and stroke volume, all o which augment CO.
TABLE 17-3
Sympathomimetic Drug Effects Receptor Stimulation
Drug Dopamine Dobutamine Norepinephrine Epinephrine Isoproterenol a
Low dosage. b High dosage.
D1 ( ↑ Renal Perfusion)
α ( Vasoconstriction)
β1 ( ↑ Contractility)
β 2 ( Vasodilation)
+a 0 0 0 0
++++b + ++++ ++++b 0
++++ ++++ ++++ ++++ ++++
++ + 0 ++ ++++
406
Chapter 17 At high dosages, greater than 10 µg/ kg/ min, dopamine also stimulates systemic α-receptors, thereby causing vasoconstriction and elevating systemic resistance. High-dose dopamine is indicated in hypotensive states such as shock. However, these doses are inappropriate in most patients with cardiac ailure because the peripheral vasoconstriction increases the resistance against which the heart contracts (i.e., higher a terload), which could impair le t ventricular output. The major toxicity o dopamine arises in patients who are treated with high-dose therapy. The most important side e ects are acceleration o the heart rate and tachyarrhythmias. Dobutamine is a synthetic analog o dopamine that stimulates β1-, β2-, and α-receptors. It increases cardiac contractility by virtue o the β1 e ect but does not increase peripheral resistance because o the balance between α-mediated vasoconstriction and β2-mediated vasodilation. Thus, it is use ul in the treatment o heart ailure not accompanied by hypotension. Unlike dopamine, dobutamine does not stimulate dopaminergic receptors (i.e., no renal vasodilating e ect), nor does it acilitate the release o norepinephrine rom peripheral nerve endings. Like dopamine, it is use ul or short-term therapy (less than 1 week), a ter which time it loses its e f cacy, presumably because o down-regulation o adrenergic receptors. The major adverse e ect is the provocation o tachyarrhythmias. Norepinephrine is an endogenous catecholamine synthesized rom dopamine in adrenergic postganglionic nerves and in adrenal medullary cells (where it is both secreted and serves as a precursor o epinephrine). Through its β1 activity, norepinephrine has positive inotropic and chronotropic e ects. Acting at peripheral α-receptors, it is also a potent vasoconstrictor. The increase in total peripheral resistance causes the mean arterial blood pressure to rise. With these e ects, norepinephrine is use ul in patients su ering rom “warm shock,” in which the combination o cardiac contractile dys unction and peripheral vasodilation lowers blood pressure. However, the intense vasoconstriction elicited by this drug makes it less attractive than others in treating most other types o shock. Norepinephrine’s side e ects include precipitation o myocardial ischemia (because o the augmented orce o contraction and increased a terload) and tachyarrhythmias. Epinephrine, ormed by the addition o a methyl group to norepinephrine, is the predominant endogenous catecholamine produced in the adrenal medulla. Administered as an intravenous in usion at low dosages, its stimulation o β1-receptors enhances ventricular contractility and speeds impulse generation, thus increasing stroke volume, heart rate, and CO. However, at this dosage range, β2-mediated vasodilation may reduce total peripheral resistance and blood pressure. At higher dosages, epinephrine is a potent vasopressor because α-mediated constriction dominates over β2-mediated vasodilation. In this case, the e ects o positive inotropy, positive chronotropy, and vasoconstriction act together to raise systemic blood pressure. Epinephrine is there ore used most o ten when the combination o inotropic and chronotropic stimulation is desired, such as in the setting o cardiac arrest. The α-associated vasoconstriction may also help support blood pressure in that setting. The most common toxic e ect is the precipitation o tachyarrhythmias. Epinephrine should be avoided in patients receiving β-blocker therapy, because unopposed α-mediated vasoconstriction could produce signif cant hypertension. Isoproterenol is a synthetic epinephrine analog. Unlike norepinephrine and epinephrine, it is a “pure” β-agonist, having activity almost exclusively at β1- and β2-receptors, with almost no α-receptor e ect. In the heart, isoproterenol has positive inotropic and chronotropic e ects, thereby increasing CO. In peripheral vessels, stimulation o β2-receptors results in vasodilation and reduced peripheral resistance, which may cause blood pressure to all. Isoproterenol is sometimes used in emergency circumstances to increase the heart rate in patients with bradycardia or heart block (e.g., as a temporizing measure be ore pacemaker implantation). It may also be use ul in patients with systolic dys unction and slow heart rates with high systemic vascular resistance (a situation sometimes encountered a ter cardiac surgery in patients who had previously been receiving β-blocker therapy). Isoproterenol should be avoided in patients with myocardial ischemia, in whom the increased heart rate and inotropic stimulation would urther increase myocardial oxygen consumption.
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Phosphodiesterase-3 Inhibitors Milrinone, a nondigitalis, noncatecholamine agent, exerts its positive inotropic actions by inhibiting phosphodiesterase type 3 in cardiac myocytes (Fig. 17-4). This inhibition slows the breakdown o intracellular cAMP, the ultimate result o which is enhanced Ca + + entry into the cell and increased orce o contraction. Additionally, in vascular smooth muscle, milrinoneinduced augmentation o cAMP results in bene cial vasodilation (in vascular tissue, cAMP inhibits myosin light chain kinase and cross-bridge ormation between myosin heads and actin laments). Milrinone is sometimes used in the treatment o acute heart ailure when there has been insu cient improvement with conventional vasodilators, inotropic agents, and diuretics. It has the potential or serious adverse e ects, including provocation o ventricular arrhythmias, and chronic milrinone therapy is associated with increased mortality. Its use is there ore limited to hospitalized patients or short-term therapy. Table 17-4 summarizes the actions and toxicities o commonly used inotropic drugs.
Vasopressin Vasopressin, the endogenous antidiuretic hormone secreted by the posterior pituitary, primarily unctions to maintain water balance (see Chapter 9). It also acts as a potent nonadrenergic vasoconstrictor when administered intravenously at supraphysiologic doses, by directly stimulating vascular smooth muscle V1 receptors. It has proved use ul or maintaining blood pressure in patients with vasodilatory shock, as may occur in sepsis. It may also be bene cial during advanced li e support or cardiac arrest because it increases coronary per usion pressure, augments blood f ow to vital organs, and improves the likelihood o success ul resuscitation in patients with ventricular brillation.
TABLE 17-4
Summary of Actions and Adverse Effects of Selected Inotropic Drugs
Drug
Mechanism of Action
Cardiac glycosides Digoxin Inhibition of sarcolemmal Na+ K+ -ATPase Enhanced vagal tone
Sympathomimetic amines Dopamine Low dosage (< 2 µg/ kg/ min): D1 receptor stimulation results in mesenteric and renal arterial dilatation (facilitates diuresis). Medium dosage (2–10 µg/ kg/ min): β1-receptor stimulation and release of norepinephrine from sympathetic nerve terminals (inotropic effect) High dosage (> 10 µg/ kg/ min): α-receptor stimulation (peripheral vasoconstriction) Dobutamine β1-, β2-, and α-receptor stimulation Phosphodiesterase-3 inhibitors Milrinone Increased intracellular cAMP due to inhibition of its breakdown by phosphodiesterase AV, atrioventricular; cAMP, cyclic adenosine monophosphate; D1, dopamine 1.
Major Adverse Effects Gastrointestinal: nausea, vomiting Cardiac: atrial, nodal, and ventricular tachyarrhythmias; high-degree AV block Tachycardia, arrhythmias, hypertension
Tachyarrhythmias Gastrointestinal: nausea, vomiting Cardiac: arrhythmias
408
Chapter 17
VASODILATOR DRUGS Vasodilator drugs play a central role in the treatment o heart ailure and hypertension. As described in Chapter 9, the all in CO in heart ailure triggers important compensatory pathways, including the adrenergic nervous system and the renin–angiotensin–aldosterone system (see Fig. 9-9). As a result o activating these pathways, two potent natural vasoconstrictors are released into the circulation: norepinephrine and angiotensin II (AII). These hormones bind to receptors in arterioles and veins, where they cause vascular smooth muscle contraction. Initially, such vasoconstriction is benef cial in heart ailure because it maximizes le t ventricular preload (the increased venous tone enhances venous return) and helps to maintain systemic blood pressure (because o arteriolar constriction). However, venous constriction may ultimately cause excessive venous return to the heart, with a rise in the pulmonary capillary hydrostatic pressure and development o pulmonary congestion. In addition, excessive arteriolar constriction increases the resistance against which the le t ventricle must contract (i.e., increased a terload) and there ore ultimately impedes orward CO. Vasodilator therapy is directed at modulating such excessive constriction o veins and arterioles, thus reducing pulmonary congestion and augmenting orward CO (see Fig. 9-10). Vasodilators are also use ul antihypertensive drugs. Recall rom Chapter 13 that blood pressure is the product o CO and total peripheral resistance (BP = CO × TPR). Vasodilator drugs decrease arteriolar resistance and there ore lower blood pressure. Individual vasodilator drug classes act at specif c vascular sites (Fig. 17-5). Nitrates, or example, are primarily venodilators, whereas hydralazine is a pure arteriolar dilator. Some drugs, such as ACE inhibitors, α-blockers, sodium nitroprusside, and nesiritide, are balanced vasodilators that act on both sides o the systemic circulation. Agents that act as pulmonary arteriolar vasodilators are described later in this section.
Angiotensin-Converting Enzyme Inhibitors The renin–angiotensin system plays a critical role in cardiovascular homeostasis. The major e ector o this pathway (Fig. 17-6) is AII, which is ormed by the cleavage o angiotensin I by ACE. All the actions o AII known to a ect blood pressure are mediated by its binding to the angiotensin II type 1 (AT1) receptor (see Fig. 13-6). Interaction with this receptor generates a series o intracellular reactions that causes, among other e ects, vasoconstriction and the adrenal release o aldosterone, which promotes Na + reabsorption rom the distal nephron. As a result o these actions on vascular tone and sodium homeostasis, AII plays a major role in blood pressure and blood volume regulation. By blocking the ormation o AII, ACE inhibitors decrease systemic arterial pressure, acilitate natriuresis (by decreasing aldosterone production, thus reducing Na + reabsorption), and limit adverse ventricular remodeling (see Chapter 9). Va s odila tor Drugs
Ve nodila tors (↓ Pulmona ry conge s tion) Nitra te s
Mixe d Va s odila tors
Arte riola r Dila tors (↑ Ca rdia c output)
Nitroprus s ide
Hydra la zine
ACE inhibitors a nd ARBs
Minoxidil
α -Adre ne rgic blocke rs
Ca ++ cha nne l blocke rs
α 2 -Ce ntra l a gonis ts Ne s iritide
FIGURE 17-5. Examples of systemic vasodilator drugs and their sites of action: the venous bed, the arteriolar bed, or both. ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.
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Angiote ns inoge n R ENIN Bra dykinin Angiote ns in I
Va s odila tion Ac tio n e nhanc e d by ACE inhibito r
ANGIOTENS INCONVERTING ENZYME –
Angiote ns in II AT1 re c e p tor a nta g onis t
ACE inhib itor
–
Ina ctive me ta bolite s
AT1 Re ce ptor
Va s ocons triction
↑Aldos te rone
↑ Sympa the tic a ctivity
↑ Na + re te ntion Ac tio ns impaire d by ACE inhibito r o r AT1 re c e pto r antag o nis t
FIGURE 17-6. The renin–angiotensin system. Angiotensin-converting enzyme (ACE) generates angiotensin II, which results in actions that include vasoconstriction, sodium retention, and increased sympathetic activity. ACE inhibitors and angiotensin II type 1 (AT1) receptor antagonists impair these effects. ACE also promotes the degradation of the natural vasodilator bradykinin; thus, ACE inhibition—but not AT1 receptor inhibition— results in accumulation of bradykinin and enhanced vasodilation.
Another action o ACE inhibitors, which likely contributes to their hemodynamic e ects, is related to bradykinin (BK) metabolism (Fig. 17-6). The natural vasodilator BK is normally degraded to inactive metabolites by ACE. Because ACE inhibitors impede that degradation, BK accumulates and contributes to the antihypertensive e ect, likely by stimulating the endothelial release o nitric oxide and biosynthesis o vasodilating prostaglandins.
Clinical Uses Hypertension In hypertensive patients, ACE inhibitors lower blood pressure with little change in CO or heart rate. One might assume that because they inter ere with the renin–angiotensin system, ACE inhibitors would be e ective only in patients with “high-renin” hypertension, but that is not the case. Rather, they reduce blood pressure in most hypertensive patients, regardless o serum renin levels. The reason or this is not clear but may relate to the additional antihypertensive e ects o BK previously described. ACE inhibitors increase renal blood f ow, usually without altering the glomerular ltration rate (GFR), because o dilation o both the a erent and e erent glomerular arterioles. Used alone, ACE inhibitors show similar antihypertensive e cacy as diuretics and β-blockers, but unlike the latter drugs, they do not adversely a ect serum glucose or lipid concentrations. ACE inhibitors are o ten recommended therapy in diabetic hypertensive patients, because the drugs slow the development o diabetic nephropathy (a syndrome o progressive renal deterioration, proteinuria, and hypertension) through avorable e ects on intraglomerular pressure.
410
Chapter 17
Heart Failure In heart ailure, ACE inhibitors reduce peripheral vascular resistance (↓a terload), reduce cardiac f lling pressures (↓preload), and increase CO. The rise in CO usually matches the all in peripheral resistance such that blood pressure tends not to all signif cantly when used in heart ailure (remember, BP = CO × TPR), except in patients with intravascular volume depletion as might result rom overly vigorous diuretic therapy. The augmented CO reduces the drive or compensatory neurohormonal stimulation in heart ailure (see Chapter 9), such that elevated levels o norepinephrine all. In addition, clinical trials have shown that ACE inhibitors signif cantly improve survival in patients with chronic heart ailure and ollowing myocardial in arction. Some studies have shown that ACE inhibition also reduces the risk o myocardial in arction and death in patients with chronic vascular disease, including coronary artery disease (CAD), even i le t ventricular unction is not impaired. The primary excretory pathway o most ACE inhibitors is via the kidney (Table 17-5), so their dosages should generally be reduced in patients with renal dys unction.
Adverse Effects Cough Irritation o the upper airways resulting in a dry cough is reported in up to 20% o patients receiving ACE inhibitor therapy. Its mechanism may relate to the increased BK concentration provoked by ACE inhibitors. This side e ect may last weeks a ter the drug is discontinued.
Hypotension This is a rare side e ect when ACE inhibitors are used to treat hypertension. It is more likely to occur in heart ailure patients in whom intravascular volume depletion has resulted rom vigorous diuretic use. As such, patients have signif cant activation o the renin–angiotensin
TABLE 17-5
Drugs that Interfere with the Renin–Angiotensin System
Drug ACE inhibitors Benazepril Captopril Enalapril Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril Angiotensin II receptor antagonists Candesartan Eprosartan Irbesartan Losartan Olmesartan Telmisartan Valsartan
Major Elimination Pathway Renal Renal Renal Hepatic/ renal Renal Hepatic/ renal Renal Renal Renal Hepatic/ renal Hepatic/ renal Hepatic/ renal Hepatic/ renal Hepatic/ renal Hepatic/ renal Hepatic Hepatic/ renal
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system and blood pressure is largely maintained by the vasoconstricting action o AII; the administration o an ACE inhibitor can result in hypotension because o the sudden reduction o circulating AII. This side e ect is avoided by temporarily reducing the diuretic regimen and starting ACE inhibitor therapy at low dosage.
Renal Insu f ciency Administration o an ACE inhibitor to patients with intravascular volume depletion may result in hypotension, decreased renal per usion, and azotemia. Correction o volume depletion, or reduction o the ACE inhibitor dosage, usually improves this complication. ACE inhibitor therapy can also precipitate renal ailure in patients with bilateral renal artery stenosis because such patients rely on high e erent glomerular arteriolar resistance (which is highly dependent on AII) to maintain glomerular pressure and f ltration. Administering an ACE inhibitor decreases e erent arteriolar tone and glomerular hydrostatic pressure and may there ore worsen GFR in this setting.
Hyperkalemia ACE inhibitors indirectly reduce the serum aldosterone concentration, such that the serum potassium concentration may rise. Conditions that may urther increase serum potassium levels and can result in dangerous hyperkalemia during ACE inhibitor use include renal insu f ciency, diabetes (owing to hyporeninemic hypoaldosteronism, a condition o ten present in elderly diabetics), and concomitant use o potassium-sparing diuretics.
Other E ects Very rare adverse reactions to ACE inhibitors include angioedema and agranulocytosis. ACE inhibitors should not be used in pregnancy because they have been shown to cause etal injury.
Angiotensin II Type 1 Receptor Antagonists AT1 receptor antagonists, also termed angiotensin receptor blockers (ARBs), are a second group o drugs that inter ere with the renin–angiotensin system. There are at least two distinct subtypes o AII receptors: AT1 and AT2. All the actions o AII known to a ect blood pressure (e.g., vasoconstriction, aldosterone release, renal Na + reabsorption, and sympathetic nervous system stimulation) are mediated by its binding to receptors o the AT1 subtype. The AT2 receptor subtype is abundant during etal development and has been located in some adult tissues, but its precise role in normal physiology is unknown. ARBs compete with AII or AT1 receptors and there ore inhibit AII-mediated e ects (Fig. 17-6), thus lowering the blood pressure o hypertensive patients. ARBs provide a more substantial blockade o the renin–angiotensin system than ACE inhibitors, because the latter do not completely block ormation o AII (some AI is converted to AII by circulating enzymes other than ACE). Unlike ACE inhibitors, ARBs do not raise serum BK levels. Each o the available ARBs (listed in Table 17-5) is excreted primarily in the bile, but most are also partly excreted in the urine. Trials have demonstrated that ARBs are as e ective as ACE inhibitors in treating hypertension, and they are among the best tolerated antihypertensive drugs. As with ACE inhibitors, the blood pressure–lowering e ect o ARBs is enhanced by concurrent use o a thiazide diuretic. Also, like ACE inhibitors, ARBs have the potential side e ects o hypotension and hyperkalemia (owing to reduced aldosterone levels). Unlike ACE inhibitors, ARBs typically do not commonly cause cough. In the setting o moderate-to-severe heart ailure, ARBs display hemodynamic benef ts similar to those o ACE inhibitors (see Chapter 9). Thus, ARBs are generally recommended
412
Chapter 17 in heart ailure or patients who are intolerant o ACE inhibitors (e.g., because o ACE inhibitor–induced cough). Studies in patients with type 2 diabetes have demonstrated that ARBs (like ACE inhibitors) slow the progression o renal disease. In addition to ACE inhibitors and ARBs, other antagonists o the renin–angiotensin system in the treatment o hypertension include the direct renin inhibitor aliskiren (see Chapter 13) and aldosterone receptor antagonists (described later in this chapter).
Direct-Acting Vasodilators Hydralazine, minoxidil, sodium nitroprusside, and enoldopam are examples o direct-acting vasodilators (Table 17-6). Hydralazine and minoxidil are used primarily as long-term oral vasodilators, whereas nitroprusside and enoldopam are administered intravenously in acute settings. Hydralazine is a potent and direct arteriolar dilator that acts at the level o precapillary arterioles and has no e ect on systemic veins. The cellular mechanism o its e ect has not been clearly established. The all in blood pressure ollowing arteriolar dilation results in a baroreceptor-mediated increase in sympathetic outf ow and cardiac stimulation (e.g., ref ex tachycardia), which could precipitate myocardial ischemia in patients with underlying CAD. There ore, hydralazine is o ten combined with a β-blocker to blunt this undesired response. As newer drugs have emerged, hydralazine is now used only occasionally as an antihypertensive. It is sometimes prescribed concurrently with the venodilator isosorbide dinitrate to treat heart ailure in patients with systolic dys unction. This combination improves symptoms in patients with mild-to-moderate heart ailure and has been shown to reduce morbidity and mortality rates (see Chapter 9). Hydralazine possesses low bioavailability because o extensive rst-pass hepatic metabolism. However, such metabolism depends on whether the patient displays ast or slow hepatic acetylation; approximately hal o the American population acetylates rapidly and hal slowly. Slow acetylators show less hepatic degradation, higher bioavailability, and increased antihypertensive e ects, whereas ast acetylators demonstrate the opposite responses. Hydralazine has a short hal -li e (2 to 4 hours) in the circulation, but its e ect persists as long as 12 hours because the drug binds avidly to vascular tissues. The most common side e ects o hydralazine include headache (owing to cerebral vasodilation), palpitations (ref ex tachycardia), f ushing (increased systemic vasodilation), nausea,
TABLE 17-6
Direct Vasodilators
Drug
Clinical Use
Route of Administration
Major Adverse Effects
Hydralazine
• Hypertension (chronic and acute therapy) • CHF
Oral, intravenous bolus, intramuscular
Minoxidil
• Chronic therapy o hypertension
Oral
Nitroprusside
• Hypertensive emergencies • Acute CHF • Hypertensive emergencies
Intravenous in usion
• • • • • • • • •
Fenoldopam
CHF, congestive heart ailure.
Intravenous in usion
Hypotension, tachycardia Headache, f ushing Angina Drug-induced lupus Ref ex tachycardia Na+ retention Hypertrichosis Hypotension Thiocyanate and cyanide toxicity • Hypotension • Increased intraocular pressure
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and anorexia. In addition, a syndrome similar to systemic lupus (characterized by arthralgias, myalgia, skin rashes, and ever) may develop, especially in patients who are slow acetylators. Minoxidil also results in arteriolar vasodilation without signi cant venodilation. Its mechanism o action involves an increase in potassium channel permeability, which results in smooth muscle cell hyperpolarization and relaxation. Like other agents that selectively cause arteriolar dilation, ref ex adrenergic stimulation leads to increased heart rate and contractility, an undesired e ect that can be blunted by coadministration o a β-blocker. In addition, decreased renal per usion o ten results in f uid retention, so that a diuretic must usually be administered concurrently. Minoxidil is now used rarely, and its primary clinical use is in the treatment o intractable hypertension. For example, it may occasionally be prescribed to patients with renal ailure who are re ractory to other antihypertensive regimens. It is well absorbed rom the gastrointestinal tract and is metabolized primarily by hepatic glucuronidation, but approximately one th is excreted unchanged by the kidney. Although it has a short hal -li e, its pharmacologic e ects persist even a ter serum drug concentration alls, probably because, like hydralazine, the drug binds avidly to vascular tissues. Side e ects o minoxidil, in addition to ref ex sympathetic stimulation and f uid retention, include hypertrichosis (excessive hair growth) and occasional pericardial e usions (unknown mechanism). Sodium nitroprusside, a potent dilator o both arterioles and veins, is administered intravenously to treat hypertensive emergencies and, in intensive care settings, or blood pressure control. It is also prescribed or preload and a terload modulation in severe heart ailure. Sodium nitroprusside is a complex o iron, cyanide groups, and a nitroso moiety, and its metabolism by red blood cells results in the liberation o nitric oxide (Fig. 17-7). Nitric oxide causes vasodilation through activation o guanylate cyclase in vascular smooth muscle (as described later in this chapter; see also Chapter 6). Sodium nitroprusside’s hemodynamic e ects result rom its ability to decrease arterial resistance and to increase venous capacitance. In patients with normal le t ventricular unction, it can actually decrease CO because o the reduction in venous return (see Fig. 9-10). However, in a patient with impaired le t ventricular contractile unction, the decreased systemic resistance induced by sodium nitroprusside (i.e., decreased a terload) augments orward CO, while venous dilation reduces return o blood to the heart. The latter decreases pulmonary capillary hydrostatic pressure and improves symptoms o pulmonary congestion. Sodium nitroprusside is o ten the treatment o choice or hypertensive emergencies because o its great potency and rapid action. A β-blocker is o ten administered concurrently to counteract the ref ex increase in sympathetic outf ow that may occur with this drug. Sodium nitroprusside is administered by continuous intravenous in usion. Its onset o action begins within 30 seconds, and its peak e ect is achieved in 2 minutes. Its e ectiveness
Nitroprus s ide
Nitric oxide
Va s odila tion
Cya nide
Live r
S ulfhydryl donor
Thiocya na te
Re na l excre tion
FIGURE 17-7. Sodium nitroprusside is a complex of iron, cyanide, and a nitroso group. Erythrocyte metabolism liberates cyanide and the active vasodilator nitric oxide. The cyanide is metabolized in the liver to thiocyanate, which is eliminated by the kidneys.
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Chapter 17 dissipates within minutes o its discontinuation. A ter sodium nitroprusside is metabolized into nitric oxide and cyanide, the liver, in the presence o a sul hydryl donor, trans orms cyanide into thiocyanate; the thiocyanate, in turn, is excreted by the kidney. Thiocyanate accumulation and toxicity, mani ested by blurred vision, tinnitus, disorientation, and/ or nausea, may occur with continued use, especially in the setting o renal impairment. Thus, it is important to monitor serum levels o thiocyanate i sodium nitroprusside is administered or more than 24 hours. In addition, excessive in usion rates o sodium nitroprusside, or a de ciency in hepatic thiosul ate stores, can result in lethal cyanide toxicity, the early signs o which include metabolic acidosis, headache, and nausea, ollowed by loss o consciousness. Fenoldopam is a rapidly acting potent arteriolar vasodilator administered intravenously to treat severe hypertension. It is a selective agonist o peripheral dopamine 1 (D1) receptors, the activation o which results in arteriolar vasodilation through a cAMP-dependent mechanism. Unlike other intravenous antihypertensive agents, it bene cially maintains or enhances renal per usion, and its activation o renal tubular D1 receptors acilitates natriuresis. Unlike dopamine, enoldopam does not stimulate α- or β-adrenergic receptors. Fenoldopam is administered by continuous intravenous in usion. Its onset o action is rapid, achieving 50% o its maximal e ect within 15 minutes and a steady state in 30 to 60 minutes. It is metabolized by the liver to inactive substances that are excreted through the kidney. It has a rapid o set o action a ter discontinuation (an elimination hal -li e o less than 10 minutes), which is a desirable e ect that minimizes the risk o excessive blood pressure reduction during the treatment o hypertensive emergencies. These pharmacologic properties also make enoldopam use ul or controlling hypertension in the postoperative setting. However, nitroprusside works even aster and remains more popular or this purpose. Unlike nitroprusside, enoldopam does not cause thiocyanate toxicity. The most common side e ects are headache, dizziness, and tachycardia. Fenoldopam also increases intraocular pressure (probably by slowing aqueous humor drainage) and should there ore be avoided in patients with glaucoma.
Calcium Channel Blockers The calcium channel blockers (CCBs) are described here as a group, but di erences exist among the drugs o this class. The common property o CCBs is their ability to impede the inf ux o Ca + + through membrane channels in cardiac and smooth muscle cells. Two principal types o voltage-gated Ca + + channels have been identi ed in cardiac tissue, termed L and T. The L-type channel is responsible or the Ca + + entry that maintains phase 2 o the action potential (the “plateau” in Fig. 1-13). The T-type Ca + + channel likely plays a role in the initial depolarization o nodal tissues. It is the L-type channel that is antagonized by available CCBs.
Mechanism of Action Intracellular calcium modulates contractile orce in the myocardium and in vascular smooth muscle. At both sites, the e ect o Ca + + channel blockade is to decrease the amount o Ca + + available to the contractile proteins within these cells, which results in vasodilation o vascular smooth muscle and a negative inotropic e ect in cardiac muscle.
Vascular Smooth Muscle Contraction o vascular smooth muscle depends on the cytoplasmic Ca + + concentration, which is regulated by the transmembrane f ow o Ca + + through voltage-gated channels during depolarization. Intracellular Ca + + interacts with calmodulin to orm a Ca + + –calmodulin complex. This complex stimulates myosin light chain kinase, which phosphorylates myosin light chains and leads to cross-bridge ormation between myosin heads and actin, causing smooth
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muscle contraction. CCBs promote relaxation o vascular smooth muscle by inhibiting Ca + + entry through the voltage-gated channels. Other organs possessing smooth muscle (including gastrointestinal, uterine, and bronchiolar tissues) are also susceptible to this relaxing e ect.
Cardiac Cells As described in Chapter 1, cardiac muscle also depends on Ca + + inf ux during depolarization or contractile protein interactions, but by a di erent mechanism than that in vascular smooth muscle. Ca + + entry into the cardiac cell during depolarization triggers additional intracellular Ca + + release rom the sarcoplasmic reticulum, leading to contraction. By blocking Ca + + entry, CCBs inter ere with excitation–contraction coupling and decrease the orce o contraction. Because the pacemaker tissues o the heart (e.g., sinoatrial [SA] and AV node) are the most dependent on the inward Ca + + current or phase 0 depolarization, one would expect that CCBs would reduce the rate o sinus ring and AV nodal conduction. Some, but not all, CCBs have this property (Table 17-7). The e ect on cardiac conduction appears to depend not only on whether the speci c CCB reduces the inward Ca + + current but also on whether it delays recovery o the Ca + + channel to its preactivated state. Verapamil and diltiazem have this property, whereas nifedipine and the other dihydropyridine CCBs do not.
Clinical Uses As a result o their actions on vascular smooth muscle and cardiac cells, CCBs are use ul in several cardiovascular disorders through the mechanisms summarized in Table 17-8. In angina pectoris, they exert bene cial e ects by reducing myocardial oxygen consumption as well as by potentially increasing oxygen supply through coronary dilatation. The latter e ect is also use ul in the management o coronary artery vasospasm. CCBs are o ten used to treat hypertension. More so than β-blockers or ACE inhibitors, CCBs are particularly e ective in elderly patients. Ni edipine and the other dihydropyridines are the most potent vasodilators o this class. CCBs are usually administered orally, and long-acting once-a-day ormulations are available or these agents. Routes o excretion vary. For example, ni edipine and verapamil are
TABLE 17-7
Calcium Channel Blockers Vasodilation
Negative Inotropic Effect
Suppress AV Node Conduction
Verapamil
+
+++
+++
Diltiazem
++
++
++
+++
0 to +
0
Drug
Dihydropyridines Amlodipine Felodipine Isradipine Nicardipine Ni edipine Nisoldipine AV, atrioventricular.
Major Adverse Effects • • • • • • • • • •
Hypotension Bradycardia, AV block Constipation Peripheral edema Hypotension Bradycardia, AV block Peripheral edema Hypotension Headache, f ushing Peripheral edema
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Chapter 17
TABLE 17-8
Clinical Effects of Calcium Channel Blockers
Condition
Mechanism
Angina pectoris
↓ Myocardial oxygen consumption ↓ Blood pressure (↓ afterload) ↓ Contractility ↓ Heart rate (verapamil and diltiazem) ↑ Myocardial oxygen supply ↑ Coronary dilatation Coronary artery vasodilation Arteriolar smooth muscle relaxation (Verapamil and diltiazem): decrease conduction velocity and increase refractoriness of atrioventricular node
Coronary artery spasm Hypertension Supraventricular arrhythmias
eliminated primarily in the urine, whereas diltiazem is excreted through the liver. Common side effects (Table 17-7) include hypotension (owing to excessive vasodilation) and ankle edema (caused by local vasodilation of peripheral vascular beds). Since verapamil and diltiazem may result in bradyarrhythmias, they should be used with caution in patients already receiving β-blocker therapy. The safety of short-acting forms of CCBs has been called into question. In observational studies, a higher incidence of myocardial infarction or death has been reported in patients with hypertension or coronary disease taking such agents. In contrast, these adverse outcomes have not been demonstrated with long-acting CCBs (i.e., formulations meant for oncea-day ingestion). Thus, the long-acting versions should generally be prescribed for extended use. Also, recall from Chapter 6 that β-blockers and/ or nitrates are generally preferred over CCBs for initial therapy in patients with CAD.
Organic Nitrates Nitrates constitute one of the oldest treatments of angina pectoris. They are also used in acute ischemic syndromes and in heart failure. The main physiologic action of nitrates is vasodilation, particularly of systemic veins.
Mechanism of Action Nitrates produce vascular smooth muscle relaxation. The proposed mechanism involves the conversion of the administered drug to nitric oxide at or near the plasma membrane of vascular smooth muscle cells (Fig. 17-8). Nitric oxide, in turn, activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), and the intracellular accumulation of cGMP leads to smooth muscle relaxation (see Chapter 6). This mechanism of vascular smooth muscle relaxation is similar to that associated with nitroprusside and endogenous endothelialderived nitric oxide.
Hemodynamic Effects and Clinical Uses At low doses, n itroglycerin , th e prototypical organ ic n itrate, produ ces greater dilation of vein s th an of arterioles. Th e ven odilation resu lts in ven ou s poolin g, dimin ish ed ven ou s return, and hence decreased right and left ventricular filling. Systemic arterial resistance is generally unaffected, but CO m ay fall because of the dim inished preload, especially in patien ts with in travascu lar volu me depletion (see Fig. 9-10). Arteria l dilation
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Endothe lia l-de pe nde nt Va s odila tors (e.g., ACh, s e rotonin)
End othe lia l c e ll
FIGURE 17-8. Organic nitrates incite vascular smooth muscle ( SM) relaxation by conversion to nitric oxide ( NO) at or near the cell membrane. Nitroprusside and endothelial-dependent vasodilators also promote NO delivery to vascular smooth muscle and cause relaxation. In the SM, NO stimulates formation of cyclic guanosine monophosphate (cGMP), which mediates relaxation.
417
Nitra te s or Nitroprus s ide
Nitric oxide
Nitric oxide S mooth mus c le c e ll
G-cycla s e GTP
cGMP
Re la xa tion
occurs to som e extent in the coronary arteries and m ay also occur in the acial vessels an d th e men in geal arterioles, givin g rise to th e side e ects o lu sh in g an d h eadach e, respectively. At high doses, nitrates can result in widespread arteriolar dilation, which may result in systemic hypotension and ref ex tachycardia. However, the increase in heart rate is not typically mani est in patients with heart ailure, because decreasing a terload in that situation may actually improve CO and reduce the sympathetic drive. The major use o nitrates is in the treatment o angina pectoris through venodilation, leading to reduced le t ventricular preload. The smaller le t ventricular size lowers ventricular wall stress and myocardial oxygen consumption, which alleviates the oxygen imbalance in ischemic states. Nitrates are also use ul in patients with coronary artery spasm (Prinzmetal variant angina) by dilating the coronary arterioles.
Agents and Pharmacokinetics Many ormulations o nitrates are available. When the relie o acute angina is the objective, rapid onset o action is essential. However, in the long-term prevention o anginal attacks in a patient with chronic CAD, duration o action and predictability o e ect are more crucial than the speed o drug e ect. Sublingual nitroglycerin tablets or sprays are used in the treatment o acute angina attacks. The peak action o these agents occurs within 3 minutes, because they are rapidly absorbed into the bloodstream via the oral mucosa. Their e ect, however, diminishes rapidly, alling o within 15 to 30 minutes, as the drug is deactivated in the liver. These orms o nitroglycerin are also e ective when taken prophylactically, immediately be ore situations known by the patient to produce angina (e.g., be ore walking up a hill). Long-acting nitrates are used to prevent chest discom ort in the chronic management o CAD and must be given in su cient dosage to saturate the liver’s deactivating capacity. For this purpose, oral doses o sustained-release nitroglycerin, isosorbide dinitrate, or isosorbide mononitrate are used. These agents have a duration o action o 2 to 14 hours. Transdermal nitroglycerin patches or nitroglycerin paste applied to the skin also delivers a sustained release o nitroglycerin. O note, the e cacy o long-acting nitrate therapy is attenuated by the rapid development o drug tolerance with continuous use. For this reason,
418
Chapter 17 it is important that the dosing regimens allow a drug- ree interval o several hours each day to maintain e cacy. Intravenous nitroglycerin is administered by continuous in usion. This orm is most useul in the treatment o hospitalized patients with unstable angina or acute heart ailure.
Adverse Effects The most common adverse e ects o nitrates include hypotension, ref ex tachycardia, headache, and f ushing.
Natriuretic Peptides As described in Chapter 9, natriuretic peptides are secreted rom atrial and ventricular myocardium in patients with heart ailure. Among their bene cial physiologic e ects, these peptides promote vasodilation and result in sodium and water excretion. The pharmacologic agent nesiritide (human recombinant B-type natriuretic peptide) replicates these e ects and is available or intravenous administration to hospitalized patients with decompensated heart ailure. It results in vasodilation, augmented CO, and reduction o the undesired activation o the renin–angiotensin and sympathetic nervous systems that are typical in heart ailure. In some patients, it promotes diuresis. Nesiritide binds to G protein–coupled receptors in multiple tissues, including blood vessels (resulting in vasodilation), the kidneys, and the adrenal glands. In the kidney, natriuresis is a consequence o several e ects o the drug. An augmented GFR results rom dilation o a erent renal arterioles and constriction o e erent renal arterioles, thereby increasing the ltered load o sodium. In the proximal tubule, AII-mediated sodium uptake is inhibited and results in sodium excretion. In the distal tubule, natriuretic peptides appear to urther reduce sodium reabsorption through epithelial sodium channels. In the adrenal zona glomerulosa, the drug inhibits aldosterone synthesis, which leads to enhanced sodium excretion in the distal nephron. Despite these bene ts, the clinical role o nesiritide is still being de ned, because its use has not been shown to improve survival in heart ailure patients and in one study was actually associated with increased mortality.
Phosphodiesterase-5 Inhibitors Sildena l and tadala l, phosphodiesterase type 5 (PDE5) inhibitors used to treat erectile dysunction, have been shown to improve exercise capacity in patients with pulmonary arterial hypertension (PAH), a condition associated with increased pulmonary vascular resistance. These drugs inhibit the breakdown o cGMP in the pulmonary vasculature, which enhances vasodilation and oxygenation. However, i administered concurrently with a nitrate, PDE5 inhibitors can cause severe hypotension and that combination o drugs is contraindicated.
Endothelin Receptor Antagonists Endothelin-1 (ET-1) is a vasoactive peptide that is synthesized and released primarily by endothelial cells. ET-1 binds to two types o receptors: ETA and ETB. Both receptor types are present on vascular smooth muscle cells, where their activation results in vasoconstriction (Fig. 17-9). This e ect is mediated by G protein–coupled activation o phospholipase C, which promotes ormation o inositol triphosphate (IP3). IP3 stimulates Ca + + release rom intracellular stores, resulting in smooth muscle contraction and there ore vasoconstriction. ETB receptors are also located on endothelial cells, where their stimulation promotes vasodilation instead, via increased production o nitric oxide (Fig. 17-9). In the intact blood vessel,
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ETB End othe lia l c e ll
419
Endothelin-1
Nitric oxide ET
B
S mooth mus c le c e ll
Gq
P IP 2
Nitric oxide
ET
A
PLC GTP
G-cycla s e
cGMP –
+
IP 3
Contra c tion
Va s oc ons tric tion
FIGURE 17-9. Endothelin-1 receptors and modulation of vascular tone. Endothelin-1 (ET-1) binds to ETB and ETA receptors on vascular smooth muscle, which are coupled to Gq protein, activating phospholipase C (PLC) and catalyzing the hydrolysis of phosphatidylinositol bisphosphate (PIP2) to inositol triphosphate (IP3). IP3 stimulates the release of calcium from intracellular stores, resulting in smooth muscle cell contraction and vasoconstriction. Conversely, ET-1 activation of the ETB receptor on endothelial cells promotes vasodilation via increased production of nitric oxide. The vasoconstrictive effect predominates in the intact blood vessel. Therefore, ET-1 receptor blockade with currently available pharmaceuticals (either nonselective blockade of both receptors or selective ETA receptor blockade) results in vasodilation.
smooth muscle vasoconstriction by ET-1 dominates over the vasodilator e ect in both systemic and pulmonary arteries. Drugs that antagonize ET-1 receptors act as vasodilators, and the main therapeutic use o this class is in the treatment o PAH, which is associated with activation o the ET-1 system. Among agents in this group, bosentan and macitentan antagonize both ETA and ETB receptors. Ambrisentan selectively inhibits the ETA receptor. Each o these orally administered drugs reduces pulmonary vascular resistance and pulmonary artery pressure and improves exertional capacity and dyspnea in patients with PAH. Endothelin receptor antagonists are generally well tolerated. The main adverse e ects are a reversible elevation o hepatic transaminases, and peripheral edema. These agents are also teratogenic and should not be prescribed to pregnant women.
ANTIADRENERGIC DRUGS Drugs that inter ere with the sympathetic nervous system act at various sites, including the central nervous system (CNS), postganglionic sympathetic nerve endings, and peripheral αand β-receptors (Fig. 17-10). Normally, when a sympathetic nerve is stimulated, norepinephrine is released, traverses the synapse, and stimulates postsynaptic α- and β-receptors. Norepinephrine within the synapse can also bind to presynaptic β- and α2-receptors, providing a eedback mechanism that modulates urther release o the hormone. The presynaptic β-receptors increase, and the α2receptors inhibit, urther norepinephrine release. The consequences o receptor stimulation depend on the organ involved (Table 17-9). The e ect o α1-receptor stimulation on vascular smooth muscle is vasoconstriction, whereas β2-stimulation causes vasodilation. In the CNS, α2-stimulation inhibits sympathetic outf ow to the periphery, thereby contributing to vasodilation.
Alpha -me thyldopa
–
+
FIGURE 17-10. Sites of action of the antiadrenergic drugs. Note that receptors at the sympathetic nerveending bind norepinephrine (NE) and provide feedback: the β-receptor stimulates, and the α2-receptor inhibits, further NE release. CNS, central nervous system.
TABLE 17-9
Responses to Adrenergic Receptor Stimulation
Receptor Type
Distribution
Response
α1 α2
Vascular smooth muscle (arterioles and veins) Presynaptic adrenergic nerve terminals Vascular smooth muscle (coronary and renal arterioles) Heart
Vasoconstriction Inhibition of NE release Vasoconstriction
β1
β2
Kidney (JG cells) Presynaptic adrenergic nerve terminals Adipose tissue Vascular smooth muscle (arterioles, except skin and cerebral) Bronchial smooth muscle Liver
AV, atrioventricular; JG, juxtaglomerular; NE, norepinephrine.
Increases heart rate Increases contractility Speeds AV node conduction Increases renin release Increases NE release Stimulates lipolysis Vasodilation Bronchodilation Stimulates glycogenolysis
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Central Adrenergic Inhibitors ( CNS α 2 -Agonists) α2-Receptors are located in the presynaptic neurons o the CNS. When stimulated by an α2-agonist, diminished sympathetic outf ow rom the medulla results. This action reduces peripheral vascular resistance and decreases cardiac stimulation, resulting in a all in blood pressure and heart rate. CNS α2-agonists were once among the most commonly used antihypertensive drugs but have largely given way to better tolerated agents. They are not su ciently potent to serve as vasodilators in the treatment o heart ailure. The drugs in this group are listed in Figure 17-10. They are all available as oral preparations, and clonidine can also be prescribed as a skin patch that is applied and le t in place or 1 week at a time, acilitating drug compliance. Side e ects o CNS α2-agonists include sedation, dry mouth, bradycardia, and, i the drug is stopped suddenly, the possibility o a sudden, paradoxical rise in blood pressure.
Sympathetic Nerve-Ending Antagonists Reserpine was the rst drug ound to inter ere with the sympathetic nervous system. It inhibits the uptake o norepinephrine into storage vesicles in postganglionic and central neurons, leading to norepinephrine degradation. The antihypertensive e ect results rom the depletion o catecholamines, which causes the orce o myocardial contraction and total peripheral resistance to decrease. Reserpine’s CNS toxicity represents its chie drawback. It o ten produces sedation and can impair concentration. The most serious potential toxicity is psychotic depression. Newer, better tolerated antihypertensive agents have largely supplanted the use o reserpine and other sympathetic nerve-ending antagonists.
Peripheral α-Adrenergic Receptor Antagonists Peripheral α-antagonists (Table 17-10) are divided into those that act on both α1- and α2receptors and those that inhibit α1 alone. α1-Selective receptor antagonists (prazosin, terazosin, doxazosin) are occasionally prescribed in the treatment o hypertension. Their selectivity or the α1-receptor explains their ability to produce less ref ex tachycardia than nonselective agents. Normally, drug-induced vasodilation results in baroreceptor-mediated stimulation o the sympathetic nervous system and an undesired increase in heart rate. This e ect is ampli ed by drugs that block the presynaptic α2-receptor, because eedback inhibition o norepinephrine release is prevented. However, α1-selective agents do not block the negative eedback on the α2-receptor. Thus, urther norepinephrine release and ref ex sympathetic side e ects are blunted.
TABLE 17-10
α-Receptor Antagonists
Mechanism/ Drug Selective peripheral α 1 -blockade Prazosin Terazosin Doxazosin Nonselective α-blockade Phentolamine Phenoxybenzamine
Indications
Major Adverse Effects
• Hypertension • Benign prostatic hyperplasia
• Postural hypotension • Headache, dizziness
• Pheochromocytoma
• Postural hypotension • Ref ex tachycardia • Arrhythmias
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Chapter 17 Historically, the principal indication or α1-antagonists has been in the treatment o hypertension. However, in a large prospective, randomized trial, patients treated with the α1-antagonist doxazosin experienced more adverse cardiac outcomes than those treated with a thiazide diuretic. Thus, α1-antagonists have allen out o avor in the management o hypertension. Terazosin and doxazosin are mainly used today to treat the symptoms o benign prostatic hyperplasia, because the drugs also benef cially relax prostatic smooth muscle. Phentolamine and phenoxybenzamine are nonselective α-blockers. They are used in the treatment o pheochromocytoma, a tumor that abnormally secretes catecholamines into the circulation (see Chapter 13). Otherwise, these drugs are rarely used because the α2-blockade impairs the normal eedback inhibition o norepinephrine release, an undesired e ect, as indicated earlier.
β-Adrenergic Receptor Antagonists The β-adrenergic antagonists are used or a number o cardiovascular conditions, including ischemic heart disease, hypertension, heart ailure, and tachyarrhythmias. Because catecholamines increase inotropy, chronotropy, and conduction velocity in the heart, it ollows that β-receptor antagonists decrease inotropy, slow the heart rate, and decrease conduction velocity. When stimulation o β-receptors is at a low level, as in a normal resting person, the e ect o blocking agents is likewise mild. However, when the sympathetic nervous system is activated (e.g., during exercise), these antagonists can substantially diminish catecholamine-mediated e ects. β-Blockers can be distinguished rom one another by specif c properties (Table 17-11): (1) the relative a f nity o the drug or β1- and β2-receptors, (2) whether partial β-agonist activity is present, (3) whether the drug also has vasodilator properties (e.g., via α1-receptor blockade), and (4) di erences in pharmacokinetic properties. The goal o β1-selective agents is to achieve myocardial receptor blockade, with less e ect on bronchial and vascular smooth muscle (tissues that exhibit β2-receptors), thus producing less bronchospasm and vasoconstriction in susceptible patients. Agents with partial β-agonist e ects (termed intrinsic sympathomimetic activity) slow the heart rate less than other β-blockers and may be better tolerated by patients with resting bradycardia. During short-term use, nonselective β-antagonists tend to reduce CO because they decrease heart rate and contractility as well as slightly increase peripheral resistance (via β2-receptor blockade). β-Antagonists that have partial agonist activity (such as pindolol) or those that possess some α-blocking activity (such as labetalol) can actually lower peripheral resistance by interacting with their respective β2- and α-receptors.
TABLE 17-11
β-Adrenergic Blockers
Activity
Nonselective β-Blockers
β1 -Selective β-Blockers
No β-agonist activity
Carvedilola Labetalola Propranolol Nadolol Timolol
β-Agonist activity
Carteolol Penbutolol Pindolol
Atenolol Betaxolol Bisoprolol Esmololb Metoprolol Nebivololc Acebutolol
Also has α1-adrenergic–blocking properties. b Administered intravenously only. c Also has vasodilating properties, likely mediated by nitric oxide. a
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Clinical Uses Ischemic Heart Disease The bene cial e ects o β-blockers in ischemic heart disease are related to their ability to decrease myocardial oxygen demand. They reduce the heart rate, blood pressure (a terload), and contractility. The negative inotropic e ect is directly related to blockade o the cardiac β-receptor, which results in decreased calcium inf ux into the myocyte (see Fig. 17-4). β-Blockers also improve survival ollowing acute myocardial in arction. Agents with intrinsic sympathomimetic activity are less bene cial in this regard than β-blockers without it.
Hypertension β-Blockers are sometimes used as antihypertensive agents, though the mechanisms responsible or blood pressure lowering are not completely understood. With initial use, the antihypertensive action is thought to result rom a decrease in CO, in association with slowing o the heart rate and mild decrease in contractility. However, with chronic administration, other mechanisms are likely at work, including reduced renal secretion o renin and possibly CNS e ects.
Heart Failure The negative inotropic e ect o β-blockade would be expected to worsen heart ailure symptoms in patients with underlying le t ventricular systolic dys unction. However, trials in patients with all classes o clinically stable chronic heart ailure have actually shown a survival benef t with long-term β-blocker administration using carvedilol, metoprolol succinate, or bisoprolol (see Chapter 9). The mechanism may relate to blunting o the cardiotoxic e ects o excessive circulating catecholamines. Because o the potential risk o transiently worsening heart ailure in tenuous patients, β-blocker therapy should be started at low dosage, augmented slowly, and care ully monitored. Other conditions that bene t rom β-blocker therapy include tachyarrhythmias (as discussed later in the chapter) and hypertrophic cardiomyopathy (see Chapter 10).
Adverse Effects Fatigue may occur during β-blocker therapy and is most likely a CNS side e ect. β-Blockers with less lipid solubility (e.g., nadolol) penetrate the blood–brain barrier poorly and may have ewer CNS adverse e ects than more lipid-soluble drugs, such as propranolol. Other potential adverse e ects relate to the predictable consequences o β-blockade: 1. β2-Blockade associated with use o nonselective agents (or large doses o β1-selective blockers) can exacerbate bron chospa sm, worsening preexisting asthma or chronic obstructive lung disease. 2. The impairment o AV nodal conduction by β1-blockade can cause conduction blocks. 3. β2-Blockade can precipitate arterial vasospasm, which could result in Raynaud phenomenon (see Chapter 15) or worsen symptoms o peripheral vascular disease. 4. Abrupt withdrawal o a β-antagonist a ter chronic use could precipitate myocardial ischemia in patients with CAD. 5. Undesirable reduction o serum high-density lipoprotein (HDL) cholesterol and elevation o triglycerides can occur through an unknown mechanism. This e ect appears to be less pronounced with β-blockers that have partial β-agonist activity or combined β- and α-blocking properties.
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Chapter 17 6. β2-Blockade may impair recovery rom hypoglycemia in diabetics su ering an insulin reaction. In addition, β-blockers may mask the sympathetic warning signs o hypoglycemia, such as tachycardia. I β-blockers are used in diabetics, β1-selective agents are generally pre erred. Other potential side e ects include insomnia, depression, and impotence. Finally, β-antagonists should be used with caution in combination with nondihydropyridine CCBs (verapamil or diltiazem), because both types o drugs can impair myocardial contractility and AV nodal conduction, possibly precipitating heart ailure or AV conduction blocks.
ANTIARRHYTHMIC DRUGS Drug therapy is a common approach to treat cardiac tachyarrhythmias. However, antiarrhythmic drugs are among the most dangerous pharmacologic agents because o potential serious adverse e ects. There ore, a thorough understanding o their mechanisms o action, indications, and toxicities is o particular importance. Although a number o classif cation systems exist, antiarrhythmic drugs are commonly separated into our groups based on their primary electrophysiologic mechanisms o action (known as the Vaughan–Williams classif cation; Table 17-12): 1. Class I drugs primarily block the ast sodium channel responsible or phase 0 depolarization o the action potential in cardiac muscle cells and Purkinje f bers (see Chapter 1). These drugs are urther divided into three subtypes based on the degree o sodium channel blockade and the e ect on the cell’s action potential duration. 2. Class II drugs are β-adrenergic receptor antagonists (β-blockers). 3. Cla ss III drugs predominantly block potassium channels responsible or repolarization, thereby prolonging the action potential with little e ect on the rise o phase 0 depolarization. 4. Class IV drugs block the L-type calcium channel.
TABLE 17-12
Classif cation o Antiarrhythmic Drugs
Class
General Mechanism
I IA
Na+ channel blockade Moderate block (↓↓ phase 0 upstroke rate; prolonged AP duration)
IB
Mild block (↓phase 0 upstroke rate; shortened AP duration)
IC
Marked block (↓↓↓ phase 0 upstroke rate; no change in AP duration) β-Adrenergic receptor blockade
II
III
K+ channel blockade (prolongation of AP duration)
IV
Ca+ + channel antagonists
AP, action potential.
Examples Quinidine Procainamide Disopyramide Lidocaine Mexiletine Flecainide Propafenone Propranolol Esmolol Metoprolol Amiodarone Dronedarone Sotalol Ibutilide Dofetilide Verapamil Diltiazem
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Drugs that do not conveniently f t into these classes Prolong (and are discussed separately) include adenosine and Impa ir conduction re fra ctory digitalis glycosides. eve n more pe riod Regardless o the class, the goal o antiarrhythmic drugs is to abolish the mechanisms by which tachyarrhythmias occur. As described in Chapter 11, these mechanisms are (1) increased automaticity o pacemaker or nonpacemaker cells, (2) reentrant circuits, and (3) triggered activity. FIGURE 17-11. Two strategies to interrupt reentry. In the case o arrhythmias caused by increased A. Prolonging the tissue re ractory period causes automaticity, treatment is aimed at lowering the maxireturning impulses to f nd the tissue unexcitable. mum requency at which cardiac action potentials can B. Further impairing conduction causes the impulse occur by (1) reducing the slope o spontaneous phase to “die out” in the slow retrograde limb o the circuit. 4 diastolic depolarization and/ or (2) prolonging the e ective re ractory period. Antiarrhythmic drugs inhibit reentrant rhythms by a di erent mechanism. The initiation o a reentrant circuit relies on a region o unidirectional block and slowed conduction (Fig. 17-11). For a reentrant rhythm to sustain itsel , the length o time it takes or an impulse to propagate around the circuit must exceed the e ective re ractory period o the tissue. I an impulse returns to an area o myocardium that was depolarized moments earlier but has not yet recovered excitability, it cannot restimulate that tissue. Thus, one strategy to stop reentry is to lengthen the tissue’s re ractory period. When the re ractory period is pharmacologically prolonged, a propagating impulse con ronts inactive sodium channels, cannot conduct urther, and is extinguished. A second means to interrupt reentrant circuits is to additionally impair impulse propagation within the already slowed retrograde limb. This is accomplished via pharmacologic blockade o the Na + channels responsible or phase 0 depolarization. Such blockade ully abolishes the compromised impulse conduction within the retrograde limb and breaks the sel -sustaining loop. The elimination o the third type o tachyarrhythmia, triggered activity, requires suppression o early and delayed a terdepolarizations. An ideal pharmacologic agent would suppress ectopic oci and interrupt reentrant loops without a ecting normal conduction pathways. Un ortunately, when the concentrations o antiarrhythmic drugs exceed their narrow therapeutic ranges, even normal electrical activity may become suppressed. In addition, most antiarrhythmic drugs have the potential to aggravate rhythm disturbances (termed proarrhythmic effect). For example, this may occur when an antiarrhythmic drug prolongs the action potential and induces early a terdepolarizations, resulting in a triggered type o arrhythmia, such as li e-threatening torsades de pointes (see Chapter 12). Drug-induced proarrhythmia occurs most o ten in patients with le t ventricular dys unction or in those with an increased QT interval (a sign that the action potential is already prolonged). A.
B.
Class IA Antiarrhythmics Mechanism of Action E ect on Reentrant Arrhythmias Class IA agents produce moderate blockade o the ast sodium channels, thus slowing the rate o phase 0 depolarization and reducing tissue conduction velocities (Fig. 17-12). I impaired su f ciently within a reentrant circuit, the impulse will die out within the already slowed retrograde limb, aborting the rhythm. In addition, class IA agents prolong the cell’s action potential and the re ractory period (largely via blockade o potassium channels responsible or repolarization). Thus, an impulse traveling in the reentrant loop encounters unexcitable tissue and is extinguished.
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Chapter 17 Clas s IA
Clas s IB
Prolonge d re pola riza tion Mode ra te Na + cha nne l block
Clas s IC
S horte ne d re pola riza tion Mild cha nne l block
Ma rke d Na + cha nne l block
Na +
Na + cha nne l blocka de
↓ P ha s e 0 ups troke ve locity
↓ conduction ve locity ↓ Re e ntry
[cla s s IA]: Prolonge d re pola riza tion
↑ e ffe ctive re fra ctory pe riod
FIGURE 17-12. Electrophysiologic effects of the class I antiarrhythmic drugs on the Purkinje cell action potential.
Effect on Arrhythmias Caused by Increased Automaticity In atrial and ventricular ectopic pacemaker cells, class IA agents depress the slope o phase 4 depolarization (through inhibition o pacemaker channels) and raise the threshold to a less negative voltage (by blocking excitable sodium channels). As a result, it takes longer to reach threshold and f re the action potential, thus suppressing automatic activity.
Effect on the Electrocardiogram Because the conduction velocity is decreased and the action potential duration and repolarization are prolonged, the e ect o class IA agents is to mildly prolong the QRS duration in some patients and the QT interval in most patients (Table 17-13). At higher dosages, the drugs may substantially lengthen these intervals, potentially setting the stage or a terdepolarizations (described in Chapter 11) and drug-induced arrhythmias.
TABLE 17-13
Effect of Antiarrhythmic Drugs on Electrocardiographic Intervals a ECG Appearance
Class
a
PR
QRS
QT
IA
0
↑
↑
IB
0
0
0 or ↓
IC
↑
↑
0 or ↑
II
0 or ↑
0
0
III
0 or ↑
0 or ↑
↑
IV
↑
0
0
The predominant effects on the electrocardiographic segments are shown in red.
Normal ECG
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Clinical Uses Class IA drugs are effective in treating reentrant and ectopic supraventricular and ventricular tachycardias (Table 17-14). However, their use has declined because of the development of more effective and less proarrhythmic strategies, as discussed later in the chapter.
Specif c Class IA Drugs Quinidine displays the electrophysiologic effects inherent to class IA agents but also has anticholinergic properties that may augment conduction at the AV node, thus antagonizing its direct suppressant effect. Because quinidine is metabolized primarily by the liver, its dosage must be reduced in patients with hepatic dysfunction. Noncardiac and cardiac side effects occur frequently during quinidine therapy. The most common are related to the gastrointestinal tract, including nausea, vomiting, and diarrhea. Cinchonism refers to CNS toxicity by quinidine manifested by tinnitus, confusion, hearing loss, and visual disturbances. Quinidine can cause excessive prolongation of the QT interval, which may lead to torsades de pointes. Procainamide has similar electrophysiologic effects as quinidine, though it does not prolong the action potential (and therefore QT interval) as much. Procainamide has mild ganglionic blocking effects that may cause peripheral vasodilation and a negative cardiac inotropic effect. Procainamide is available for oral or parenteral administration and is primarily used when intravenous delivery of a class IA drug is desired. More than 50% of the drug is excreted unchanged in the urine; the remainder undergoes acetylation by the liver to form N-acetyl procainamide (NAPA), which is subsequently excreted by the kidneys. In renal failure, or in patients who are rapid acetylators, high serum levels of NAPA may accumulate. NAPA shares procainamide’s ability to prolong the action potential and refractory period, but it does not alter the rate of phase 4 depolarization or the slope of phase 0 upstroke of the action potential. Noncardiac side effects of procainamide are common and include fever, myalgias, and gastrointestinal upset (less frequently than with quinidine). Approximately one third of patients develop a systemic lupus–like syndrome after 6 months of therapy, manifested by arthralgias,
TABLE 17-14
Common Clinical Uses o Antiarrhythmic Drugs
Class
Use
IA
• • • • • • • • • • • • • • • •
IB IC II
III
IV
Atrial brillation and f utter PSVT Ventricular tachycardia Ventricular tachycardia Digitalis-induced arrhythmias Atrial brillation and PSVT Atrial or ventricular premature beats PSVT Atrial brillation and f utter Ventricular tachycardia Ventricular tachycardia (amiodarone and sotalol) Atrial brillation and f utter Bypass tract–mediated PSVT PSVT Atrial brillation and f utter (↓ VR) Multi ocal atrial tachycardia (↓ VR)
PSVT, paroxysmal supraventricular tachycardia (e.g., AV nodal reentrant tachycardia); VR, ventricular rate.
428
Chapter 17 rash, and connective tissue inf ammation. It most o ten occurs among patients who are slow acetylators and is reversible on cessation o drug therapy. As a result o these side e ects, procainamide is generally reserved or short-term use. Disopyramide’s electrophysiologic and antiarrhythmic e ects are similar to those o quinidine, but it has a greater anticholinergic e ect. More so than quinidine or procainamide, disopyramide also has a pronounced negative inotropic e ect and must be used with caution in patients with le t ventricular systolic dys unction. However, its negative inotropic property renders it a use ul antiarrhythmic agent or patients who also have hypertrophic cardiomyopathy with dynamic outf ow tract obstruction, or whom a reduced orce o contraction is desired (see Chapter 10). Disopyramide is administered orally. The primary excretory pathway is via the kidneys, and toxic levels may accumulate in patients with renal insu ciency. QT prolongation and precipitation o ventricular arrhythmias (including torsades de pointes) can occur, and anticholinergic side e ects, such as constipation, urinary retention, and glaucoma exacerbation, are common.
Class IB Antiarrhythmics Mechanism of Action Class IB drugs inhibit the ast sodium channel, but unlike IA agents, they typically shorten the action potential duration and the re ractory period. Such shortening is attributed to blockade o small noninactivating sodium currents that normally continue through phase 2 o the action potential. Class IB drugs at therapeutic concentrations do not substantially alter the electrical activity o normal tissue; rather, they pre erentially act on diseased or ischemic cells (Box 17-1). Conditions present during ischemia—acidosis, aster rates o cell stimulation, and increased extracellular potassium concentration (and consequently a less negative diastolic membrane
BOX 17-1
Use Dependence of Class I Antiarrhythmic Drugs
An important characteristic o class I antiarrhythmic drugs is their “state-dependent” (also termed “use-dependent”) binding to the Na+ channel. Con ormational di erences in the channel’s states result in a relatively low a f nity o these drugs or resting closed channels, and a higher a f nity, and there ore greater blocking potency, or channels in their open or inactivated states (re er to Chapter 1 or a description o channel states). There ore, class I drugs exhibit their greatest e ect in cardiac cells that are depolarized. There are two therapeutic consequences:
1. In injured or ischemic tissue, there is constant partial depolarization o cells, which shi ts some o the Na+ channels persistently into the inactivated state. The associated slowed conduction in such tissue may set the stage or reentrant types o arrhythmias (see Chapter 11). By pre erentially binding and blocking Na+ channels in the persistently depolarized, injured membrane, class I drugs prevent their participation in such slow conduction and thus have the capacity to suppress reentrant rhythms. 2. During normal rhythmic depolarizations, a class I agent binds avidly to the inactivated Na+ channels that develop during phase 2 o the action potential. Subsequently, the drug dissociates rom the channel in diastole, as inactivated channels revert to the resting closed state upon repolarization. However, during ast heart rates (i.e., tachyarrhythmias), the interval between depolarizations becomes shorter, and drug dissociation is there ore less complete. This results in an accumulating raction o drug-blocked channels, and the potential or too ew available unblocked channels to support a subsequent action potential, thus accentuating the antiarrhythmic e ect o the drug at aster heart rates.
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potential)—increase the ability o class IB drugs to block the sodium channel. This blockade reduces the slope o phase 0 depolarization and slows the conduction velocity, thus impairing conduction in ischemic cells and inhibiting reentrant arrhythmias (see Fig. 17-12). The automaticity o ectopic pacemakers is also suppressed by decreasing phase 4 spontaneous depolarization and (in the case o some drugs o this class) by raising the threshold potential. In addition, intravenous lidocaine, a member o this class, suppresses delayed a terdepolarizations. Because the QT interval is not prolonged by class IB drugs, and may actually be shortened (Table 17-13), early a terdepolarizations do not occur, and torsades de pointes is not an expected complication.
Clinical Uses The most common use o class IB drugs is in the suppression o ventricular arrhythmias, especially those that appear in association with ischemia or digitalis toxicity. Conversely, they have little e ect on atrial tissue at therapeutic concentrations because o the shorter action potential duration o atrial cells, which allows less time or the drug to bind and block the Na + channel. Thus, these agents are ine ective in atrial brillation, atrial f utter, and SVTs.
Specif c Class IB Drugs Lidocaine, administered intravenously, is used to suppress some ventricular arrhythmias in hospitalized patients. As a result o rapid distribution and hepatic metabolism, lidocaine must be administered as a continuous in usion ollowing a loading bolus. Because the hal -li e o the drug depends greatly on hepatic unction, the in usion rate should be lowered in patients with reduced hepatic blood f ow (as in heart ailure or in older individuals) or intrinsic liver disease. The most common side e ects o lidocaine are related to the CNS and include con usion, paresthesias, dizziness, and seizures. These e ects are dosage related and can be prevented by monitoring serum levels o the drug. Mexiletine, administered orally, is structurally similar to lidocaine and shares its electrophysiologic properties. Ninety percent o mexiletine is metabolized in the liver to inactive products, and the dosage o the drug should be reduced in patients with hepatic dys unction. Dose-related side e ects o mexiletine are common, especially o the CNS (dizziness, tremor, slurred speech) and the gastrointestinal tract (nausea, vomiting).
Class IC Antiarrhythmics Mechanism o Action Class IC drugs are the most potent sodium channel blockers. They markedly decrease the upstroke o the action potential, and conduction velocity in atrial, ventricular, and Purkinje bers (see Fig. 17-12). Although they have little e ect on the duration o the action potential or re ractory period o Purkinje bers, they signi cantly prolong the re ractory period within the AV node and in accessory bypass tracts. The e ect o class IC drugs on decreasing the action potential upstroke tends to prolong the QRS duration on the ECG, while the QT interval is typically not prolonged since the total action potential duration is not lengthened (see Table 17-13).
Clinical Uses Class IC agents were originally developed to treat ventricular arrhythmias. However, that use has diminished because studies have shown an increased mortality rate in patients taking class IC drugs or ventricular ectopy ollowing myocardial in arction and in those who have
430
Chapter 17 survived cardiac arrest. In patients with underlying le t ventricular dys unction, class IC drugs can precipitate heart ailure. Thus, drugs o this subclass should be avoided in patients who have other underlying heart abnormalities, such as CAD or LV dys unction. Class IC drugs have been shown to be bene cial (and generally sa e) in the treatment o supraventricular arrhythmias, including atrial brillation and AV nodal reentrant tachycardia, in patients who have otherwise structurally normal hearts (see Table 17-14).
Specif c Class IC Drugs Flecainide is well absorbed a ter oral administration. Approximately 40% o the drug is excreted unchanged in the urine, and the remainder is converted to inactive metabolites by the liver. Dose-dependent noncardiac side e ects are re erable to the CNS and include con usion, dizziness, and blurred vision. The electrophysiologic properties o propafenone are similar to those o f ecainide, but additionally, it exhibits weak β-adrenergic blocking activity. Propa enone is metabolized by the liver, but because the level o genetic variation is high, a patient’s dosage must be titrated by observing the drug’s e ect. Extracardiac side e ects are not common and include dizziness and disturbances o taste.
Class II Antiarrhythmics Mechanism o Action Class II drugs are β-adrenergic receptor antagonists, which are used in the management o both supraventricular and ventricular arrhythmias. Most o the antiarrhythmic properties o class II agents can be attributed to inhibition o cardiac sympathetic activity. Additional actions o some β-blockers, such as β1-cardioselectivity or a membrane-stabilizing e ect, seem to make no contribution to antiarrhythmic activity. Chapter 11 describes how β-adrenergic stimulation results in a more rapid upslope o phase 4 depolarization and an increased ring rate o the SA node. β-Adrenergic antagonists inhibit these e ects, thus reducing automaticity (Fig. 17-13). This action extends to the cardiac Purkinje bers, where arrhythmias due to enhanced automaticity are inhibited. β-Blockers also decrease conduction velocity and lengthen the re ractory period o the AV node, thus bene cially slowing the ventricular rate in patients with rapid atrial rhythms. In addition, because delayed a terdepolarizations may be caused by excessive catecholamines, β-blockers may prevent triggered arrhythmias induced by that mechanism. Prolonge d re pola riza tion (a t AV node )
Pac e make r c e ll ac tio n po te ntial
Thre s hold pote ntia l
De cre a s e d s lope of pha s e 4 de pola riza tion
↓ P ha s e 4 s lope Prolonge d re pola riza tion of AV node
↓ Rate of firing ↑ Effe ctive re fra ctory pe riod
↓ Auto matic ity ↓ Re e ntry
FIGURE 17-13. Electrophysiologic e ects o the class II antiarrhythmic drugs on the pacemaker cell action potential.
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β-Blockers may also have a bene cial antiarrhythmic e ect by decreasing myocardial oxygen demand, thus reducing myocardial ischemia. Several drugs rom this group have been shown to reduce mortality ollowing myocardial in arction (see Chapter 7), which may in part relate to their antiarrhythmic e ect. Since the AV nodal conduction time is prolonged by β-blockers, the PR interval on the ECG may become prolonged (see Table 17-13). The QRS and QT intervals are usually una ected.
Clinical Uses β-Blockers are most use ul in suppressing tachyarrhythmias induced by excessive catecholamines (e.g., during exercise or emotional stimulation). They are also requently used to slow the ventricular rate in atrial f utter and brillation by impairing conduction and increasing the re ractoriness o the AV node. In addition, β-blockers may terminate reentrant supraventricular arrhythmias in which the AV node constitutes one limb o the reentrant pathway. β-Blockers are e ective in suppressing ventricular premature beats and other ventricular arrhythmias, especially when induced by exercise. They are also e ective in treating ventricular arrhythmias related to prolongation o the QT interval because, unlike group IA agents, they do not lengthen that interval.
Class III Antiarrhythmics Mechanism o Action Class III drugs are structurally dissimilar rom one another but share the property o signi cantly prolonging the action potential o Purkinje and ventricular muscle bers (Fig. 17-14), predominantly by blocking the outward K+ current o phase 3 repolarization. Unlike class I agents, class III antiarrhythmics generally have little e ect on phase 0 depolarization or conduction velocity.
Specif c Class III Drugs Amiodarone Amiodarone is a power ul antiarrhythmic with many potential adverse reactions. Its major therapeutic e ect is to prolong the action potential duration and re ractoriness o all cardiac regions. However, it also shares actions with each o the other antiarrhythmic classes. The slope o phase 0 depolarization may be depressed through sodium channel blockade (class I e ect), it exerts a β-blocking e ect (class II), and it also demonstrates weak calcium channel blockade (class IV). As a result, the electrophysiologic e ects o amiodarone are to decrease the SA node ring rate, suppress automaticity, interrupt reentrant circuits, and prolong the PR, QRS, and Ma rke dly QT intervals on the ECG (see Table 17-13). prolonge d Purkinje In addition, amiodarone is a vasodilator (because o re pola riza tion c e ll α-receptor and calcium channel blocking e ects) and ac tio n a negative inotrope (β-blocker and CCB e ects). The po te ntial resulting vasodilation is more prominent than the negative inotropic e ect, so that CO does not usually su er. Amiodarone is more e ective than most other antiarrhythmic drugs or a wide spectrum o ventricular ↑ Effe ctive re fra ctory ↓ Re e ntry pe riod and supraventricular tachyarrhythmias. It is a rstline agent or the emergency treatment o ventricular FIGURE 17-14. Electrophysiologic e ects o the arrhythmias during cardiac resuscitation (including class III antiarrhythmic drugs on the Purkinje cell action potential. ventricular brillation and ventricular tachycardia
432
Chapter 17 re ractory to electrical shocks) and is more e ective than lidocaine or this purpose. It is commonly used to treat arrhythmias in patients with ventricular systolic dys unction because it causes ewer proarrhythmic complications in that population than other agents. In addition, low-dose amiodarone is e ective or long-term suppression o atrial brillation and f utter. Amiodarone is absorbed slowly rom the gastrointestinal tract, requiring 5 to 6 hours to reach peak plasma concentrations. It is highly lipophilic and extensively sequestered in tissues, and it undergoes very slow hepatic metabolism. Its elimination hal -li e is long and variable, averaging 25 to 60 days. The drug is excreted by the biliary tract, lacrimal glands, and skin but not by the kidney. Because the drug’s action has a delayed onset and very long duration, its e ects cannot be altered quickly i side e ects ensue. There are numerous potential adverse reactions o amiodarone. The most serious is pulmonary toxicity, mani est by pneumonitis leading to pulmonary brosis. Its origin is unclear but may represent a hypersensitivity reaction and, i recognized early, is reversible. Other li e-threatening side e ects o amiodarone relate to cardiac toxicity: symptomatic bradycardia and aggravation o ventricular arrhythmias, each occurring in approximately 2% o patients. Because amiodarone signi cantly prolongs the QT interval, early a terdepolarizations and torsades de pointes can occur, but this happens only rarely. Intravenously administered amiodarone occasionally causes hypotension. Abnormalities o thyroid unction are common during amiodarone treatment, because the drug contains a signi cant iodine load and because it inhibits the peripheral conversion o T4 to T3. During the rst ew weeks o therapy, it is common to observe transient abnormalities o thyroid biochemical tests without clinical ndings o thyroid disease: serum TSH and T4 rise, and serum T3 alls. Over time, some patients develop overt hypothyroidism (owing mostly to the antithyroid e ects o excessive iodine) or hyperthyroidism (because o either an iodine e ect in iodine-de cient communities or a direct thyroid inf ammatory process incited by amiodarone in susceptible patients). Gastrointestinal side e ects o amiodarone include anorexia, nausea, and elevation o liver unction blood tests, all o which improve with lower doses o the drug. Neurologic side e ects include proximal muscle weakness, peripheral neuropathy, ataxia, tremors, and sleep disturbances. Corneal microdeposits can be detected in patients receiving chronic amiodarone therapy, but these rarely a ect vision. As a result o these potential adverse e ects, ECGs, thyroid and liver unction blood tests, chest radiographs, and sometimes pulmonary unction studies are per ormed on a regular basis in patients receiving chronic therapy. Amiodarone interacts with, and increases the activity o , certain drugs including war arin and digoxin, such that the dosages o those agents must be adjusted.
Other Class III Drugs Dronedarone, a noniodinated analog o amiodarone, is used to maintain sinus rhythm in patients with a history o atrial brillation. Similar to amiodarone, it blocks potassium, sodium, and L-type calcium channels and inhibits β- and α-adrenergic receptors. It is administered orally and reaches a steady state in 4 to 8 days, much aster than oral amiodarone. It is not as potent an antiarrhythmic drug as amiodarone, but it lacks the latter’s pulmonary, thyroid, and liver toxicities. The major side e ects are gastrointestinal, including nausea, vomiting, and diarrhea. Dronedarone can increase the QT interval but only rarely results in torsades de pointes. Dronedarone is contraindicated in patients with advanced heart ailure (New York Heart Association class IV) and those with recent decompensation o heart ailure o any stage requiring hospitalization, as increased mortality has been demonstrated with the drug’s use in such patients. Furthermore, the drug increases mortality in patients with permanent atrial brillation; it should only be used over the long term to prevent recurrences o atrial brillation in patients who have converted back to sinus rhythm.
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Sotalol is a nonselective β-blocker, but it is used in practice as an oral antiarrhythmic drug because o its additional class III properties. It prolongs the duration o the action potential, increases the re ractory period o atrial and ventricular tissue, and inhibits conduction in accessory bypass tracts. The phase 0 upstroke velocity is not altered in the usual dosage range. It is e ective in the treatment o both supraventricular and ventricular arrhythmias. Because sotalol is excreted exclusively by the kidneys, its dosage should be adjusted in the presence o renal disease. Potential side e ects include those o the β-blockers described earlier. Because the drug prolongs the QT interval, the most serious potential adverse e ect is torsades de pointes. This complication occurs in approximately 2% o patients and is more common in patients with a history o heart ailure and in women ( or unknown reasons). Dofetilide is another oral class III agent that blocks the outward potassium current, causing prolongation o the action potential duration and an increase in the e ective re ractory period. It is used in the management o atrial brillation and atrial f utter. Do etilide is excreted by the kidney, and its dose must be adjusted in patients with renal ailure. QT prolongation complicated by torsades de pointes is the major potential adverse e ect. Ibutilide is a class III drug used intravenously or the acute conversion o atrial brillation or atrial f utter o recent onset. This agent prolongs the action potential duration and increases atrial and ventricular re ractoriness. Unlike other class III drugs, its major mechanism relates to activation o a slow inward sodium current that prolongs the plateau (phase 2) o the action potential. Because ibutilide prolongs the QT interval, torsades de pointes can be precipitated, especially in patients with underlying ventricular dys unction.
Class IV Antiarrhythmics Mechanism of Action Class IV drugs exert their electrophysiologic e ects by selective blockade o L-type cardiac calcium channels and include verapamil and diltiazem, but not ni edipine or the other dihydropyridine CCBs. They are most potent in tissues such as the SA and AV nodes in which the action potential upstroke depends on calcium currents. Within nodal tissue, calcium channel blockade decreases the rate o rise o phase 0 depolarization and conduction velocity and lengthens the re ractory period o the AV node (Fig. 17-15). These agents also raise the threshold potential at the SA node. The resulting clinical e ects are as ollows: (1) the heart rate slows; (2) transmission o rapid atrial impulses through the AV node to the ventricles decreases, thus slowing the ventricular rate in atrial brillation and atrial f utter; and (3) reentrant rhythms traveling through the AV node may terminate. In normal sinus rhythm, the PR interval on the ECG may be prolonged in a patient taking a class IV agent since AV nodal conduction time is prolonged (see Table 17-13). S lowe d ris e of a ction pote ntia l Pac e make r c e ll ac tio n po te ntial
Prolonge d re pola riza tion (a t AV node )
Thre s hold
↑ Thre s hold pote ntia l of SA node
FIGURE 17-15. Electrophysiologic effects of the class IV antiarrhythmic drugs on the pacemaker cell action potential.
↓ He art rate
↓ Conduction ve locity of AV node ↓ Re e ntry ↑ Effe ctive re fra ctory pe riod of AV node
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Chapter 17
Clinical Uses A primary use o class IV drugs is or the treatment o reentrant SVTs (e.g., AV nodal reentrant tachycardia). At one time, intravenous verapamil was the treatment o choice or acute episodes o such rhythms, but intravenous adenosine (described in the next section) has assumed that role. The pharmacology and toxicities o CCBs were presented earlier in this chapter. The most important side e ect o verapamil and diltiazem, when administered intravenously, is hypotension. In addition, these agents should be avoided, or used cautiously, in patients receiving β-blocker therapy, because the combined negative inotropic and chronotropic e ects may precipitate heart ailure and/ or signif cant bradycardia.
Adenosine Adenosine is an endogenous nucleoside with a very short hal -li e. Administered intravenously, it is the most e ective drug or the rapid termination o reentrant SVT, such as AV nodal reentrant tachycardia. Adenosine has substantial electrophysiologic e ects on specialized conduction tissues, especially the SA and AV nodes. By binding to adenosine receptors on cardiac cells, it activates potassium channels that are open during diastole (Fig. 17-16). The resultant increase in the outward potassium current hyperpolarizes the membrane, which suppresses spontaneous depolarization o the SA node and slows conduction through the AV node. In addition, adenosine decreases the intracellular cAMP concentration by inhibiting adenylate cyclase. The result is a decrease in the inward pacemaker current (I ) and the inward calcium current (Fig. 17-16). Thus, the net e ect o adenosine is to slow the SA node f ring rate and to decrease AV nodal conduction. By inducing transient AV nodal
+ DIPYRIDAMOLE
ADENOS INE
XANTHINES If
– Ade nos ine re ce ptor
αi
–
Ade nyla te cycla s e
G prote ins + K+
βγ
–
ATP cAMP (↓ )
– Ina ctive prote in kina s e s
Active prote in kina s e s (↓ )
Myo c yte
FIGURE 17-16. Mechanism of antiarrhythmic action of adenosine. Stimulation o the myocyte adenosine A1 receptor activates inward rectif er potassium channels via direct binding o the G protein βγ subunit, and the resultant outward K+ current urther hyperpolarizes the membrane during diastole, resulting in decreased automaticity. Adenosine also inhibits membrane adenylate cyclase activity, via the G protein αi-subunit. The subsequent decline in cAMP has two pertinent e ects: the inward pacemaker current (I ) is diminished and the production o active protein kinases is lessened, leading to a reduction o the inward Ca+ + current. These e ects contribute to decreased automaticity and slowed conduction through the AV node. Xanthines compete or the receptor, blocking adenosine’s e ects. Conversely, dipyridamole inter eres with cellular uptake and degradation o adenosine and there ore amplif es its e ect.
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block, adenosine terminates reentrant pathways that include the AV node as part o the circuit. Ventricular myocytes are relatively immune to these e ects, in part because the speci c potassium channels responsive to adenosine are not so important or conduction in those cells. With a hal -li e o only 10 seconds, adenosine has very transient side e ects (headache, chest pain, f ushing, bronchoconstriction). Because methylxanthines (ca eine, theophylline) competitively antagonize the adenosine receptor, higher doses o adenosine may be necessary in patients using those substances. Conversely, dipyridamole inhibits the breakdown o adenosine and ampli es its e ect.
DIURETICS Diuretics are most o ten used to treat heart ailure and hypertension. In heart ailure, enhanced renal reabsorption o sodium and water, with subsequent expansion o the extracellular volume, contributes to peripheral edema and pulmonary congestion. Diuretics eliminate excess sodium and water through renal excretion and are there ore a cornerstone o therapy (see Fig. 17-1 and Chapter 9). In the treatment o hypertension, diuretics similarly reduce intravascular volume and in some cases promote vascular dilatation. To better understand these intended unctions o diuretics, the section begins with a brie review o normal renal transport o sodium and water. In the kidney, the rate o glomerular ltration typically averages 135 to 180 L/ day in normal adults. Most o the ltered Na + is reabsorbed by the renal tubules, leaving only a small quantity in the nal urine (Fig. 17-17). Approximately 65% to 70% o the ltered Na + is reabsorbed isosmotically in the proximal tubule by active transport. In the thick ascending limb o the loop o Henle, an additional 25% o the ltered sodium is reabsorbed, through
GLOMERULUS Na HCO 3
DISTAL CONVOLUTED TUBULE
Carbo nic anhydras e inhibito rs P ROXIMAL CONVOLUTED TUBULE
C ORTEX
Na Cl THICK AS CENDING LIMB
K+, H+ Na + 2CI–
MEDULLA
Lo o p diure tic s
ADH
Thiazide s Na +, K+
H2 O
H2 O
K+s paring diure tic s
LOOP OF HENLE
U R I N E
COLLECTING DUCT
FIGURE 17-17. Schematic diagram of the renal tubules. Approximately 70% o f ltered sodium is reabsorbed in the proximal convoluted tubule, 25% in the thick ascending limb o the loop o Henle, 5% in the distal convoluted tubule, and 1% to 2% in the cortical collecting tubule (mediated by the action o aldosterone). Antidiuretic hormone (ADH) increases the permeability o the distal nephron or water. Diuretic drugs are secreted into the proximal convoluted tubule and act at the sites shown.
436
Chapter 17 a Na + –K+ cotransport system coupled to the uptake o two Cl− ions. Because this region is impermeable to the reabsorption o water, it is the site o hypotonic tubular f uid ormation, and the surrounding interstitium becomes hypertonic. In the distal convoluted tubule, an additional small raction o NaCl is reabsorbed (approximately 5% ). In the cortical collecting duct, Na + permeability is modulated by an aldosterone-sensitive mechanism, such that Na + is reabsorbed into the tubular cells in the presence o aldosterone, creating a lumen-negative potential di erence that enhances K+ and H+ excretion. Approximately 1% to 2% o sodium reabsorption takes place at this location. Most o the distal tubule is impermeable to water. In the collecting tubule, however, water permeability and reabsorption are promoted by antidiuretic hormone and driven by the osmotic gradient between the tubule and the hypertonic interstitium. There ore, substances that inter ere with antidiuretic hormone, such as ethanol, have diuretic actions. The three most commonly used groups o diuretics are loop diuretics, thiazide diuretics, and potassium-sparing diuretics (Table 17-15 and Fig. 17-17). These classes are distinguished by the site o the kidney tubule where they act and by their potency. Loop diuretics impair absorption in the thick ascending limb o the loop o Henle, thiazide diuretics act on the distal tubule and collecting segment, and potassium-sparing diuretics act on the aldosteronesensitive region o the cortical collecting tubule. Members o a ourth group, the carbonic anhydrase inhibitors, are weak diuretics rarely used in the treatment o hypertension or heart ailure. They act at the proximal convoluted tubule, resulting in a loss o bicarbonate (and sodium) in the urine.
TABLE 17-15
Commonly Used Diuretics
Diuretic
Method of Administration
Onset of Action ( Hours)
Duration of Action ( Hours)
Potential Adverse Effects
Thiazides and related compounds Chlorothiazide Hydrochlorothiazide Chlorthalidone Metolazone Indapamide
Loop diuretics Furosemide Bumetanide Torsemide Ethacrynic acid K+ -sparing diuretics Spironolactone Eplerenone Triamterene Amiloride
PO IV PO PO PO PO
1 0.25 2 2 1 1–2
6–12 2 12 24 12–24 16–36
Hypokalemia, hypomagnesemia, hyponatremia, hypercalcemia, hyperglycemia, hyperuricemia, hypercholesterolemia, hypertriglyceridemia, metabolic alkalosis
PO IV PO IV PO IV IV
1 5 min 0.5–1 0.25 <1 10 min 0.25
6 2 4–6 0.5–1 6–8 6–8 3
Hypotension, hypokalemia, hypomagnesemia, hyperglycemia, hyperuricemia, metabolic alkalosis
PO PO PO PO
> 24 > 24 2 2
2–3 d 24 12–16 24
Hyperkalemia, GI disturbances; gynecomastia (spironolactone only)
GI, gastrointestinal; IV, intravenous; PO, by mouth.
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Loop Diuretics These agents are so named because they act principally on the thick ascending limb o the loop o Henle. They are power ul diuretics that result in the excretion o 20% to 25% o the f ltered Na + load through inhibition o the Na + –2Cl− –K+ cotransport system. Because inhibition at this site impairs the generation o a hypertonic interstitium, the gradient or passive water movement out o the collecting duct is diminished and water diuresis results. Loop diuretics are o great importance in the acute management o pulmonary edema (administered intravenously) and in the treatment o chronic heart ailure or peripheral edema (taken orally). Unlike other diuretics, they tend to be e ective in the setting o impaired renal unction. In addition to the diuretic e ect, and even preceding it, drugs o this class may induce venous vasodilation, which is also benef cial in reducing venous return to the heart and pulmonary congestion (see Chapter 9). The mechanism o venous vasodilation appears to involve drug-induced prostaglandin and nitric oxide generation rom endothelial cells, which act to relax vascular smooth muscle (see Chapter 6). The most common side e ects o the loop diuretics are intravascular volume depletion, hypokalemia, and metabolic alkalosis. Hypokalemia arises because (1) these agents impair the reabsorption o sodium in the loop o Henle, such that an increased amount o Na + is delivered to the distal tubule, where it prompts greater-than-normal exchange or potassium (and there ore more K+ excretion into the urine) and (2) diuretic-induced intravascular volume depletion activates the renin–angiotensin system. The subsequent rise in aldosterone promotes additional Na + –K+ exchange. Metabolic alkalosis during loop diuretic therapy results rom two mechanisms: (1) increased H+ secretion into the distal tubule (and there ore into the urine) due to the secondary hyperaldosteronism described earlier and (2) contraction alkalosis, in which reduced intravascular volume promotes increased sodium bicarbonate reabsorption by the proximal tubule (see Fig. 17-17). Additional side e ects may also occur during continued loop diuretic therapy. Hypomagnesemia may result, because magnesium reabsorption depends on NaCl transport in the thick ascending limb o the loop o Henle, the action blocked by these drugs. Ototoxicity (cranial nerve VIII toxicity) occasionally develops, impairing hearing and vestibular unction. It is thought to arise rom electrolyte disturbances o the endolymphatic system, most likely because o Na + –2Cl− –K+ cotransport inhibition by the diuretic at that site. The most commonly used loop diuretic is furosemide, the oral orm o which demonstrates reliable gastrointestinal absorption but a short duration o action (4 to 6 hours) that limits its use ulness in the chronic treatment o hypertension. Bumetanide is similar to urosemide and shares its actions and adverse e ects but has greater potency and bioavailability. It also appears to have a lower incidence o ototoxicity than the other drugs o this class. Bumetanide is sometimes use ul in heart ailure patients when edema is re ractory to other agents and in some patients who are allergic to urosemide. Torsemide is also similar to urosemide, with more complete bioavailability. Ethacrynic acid is the only nonsul onamide loop diuretic, so it can be prescribed to patients with sul onamide intolerance. It is otherwise not widely used because o its high incidence o ototoxicity.
Thiazide Diuretics Thiazides and related compounds (chlorthalidone, indapamide, and metolazone) are commonly used diuretics because they demonstrate excellent gastrointestinal absorption when administered orally and are usually well tolerated. Though less potent than the loop diuretics, their sustained action makes them use ul in chronic conditions such as hypertension and mild congestive heart ailure (CHF). Thiazides act at the distal tubule, where they block the reabsorption o approximately 3% to 5% o the f ltered sodium (see Fig. 17-17). Na + reabsorption at this site is mediated
438
Chapter 17 through a Na + –Cl− cotransporter on the luminal membrane. The thiazides inhibit this carrier by a mechanism that has not been elucidated but may involve competition or the Cl− site. The antihypertensive e ect is initially associated with a decrease in CO due to reduced intravascular volume with unchanged peripheral resistance. With long-term thiazide use, however, CO o ten returns to normal as vasodilation leads to a reduction in vascular resistance. Indapamide is unique among this class in that it displays a particularly prominent vasodilating e ect. Thiazides are typically administered orally. Diuresis occurs a ter 1 to 2 hours, but the ull antihypertensive e ect o continued therapy may not emerge or up to 12 weeks (possibly related to the vasodilator mechanism alluded to in the previous paragraph). Chlorothiazide, the parent compound, has low lipid solubility and hence low bioavailability; higher doses are there ore required to achieve therapeutic levels compared with the more commonly used hydrochlorothiazide. Chlorthalidone is slowly absorbed and hence has a long duration o action. Metolazone, unlike other drugs o this class, is sometimes e ective in patients with reduced renal unction. Clinically, the thiazides di er rom the loop diuretics in that they are less potent, have a longer duration o action, and (with the exception o metolazone) demonstrate poor diuretic e f cacy in the setting o impaired renal unction: generally, they are not e ective when the GFR is less than 25 mL/ min. Thiazides serve as a cornerstone o antihypertensive therapy because o their low cost, e ectiveness, and proven benef ts in reducing the risk o stroke and cardiac events. They are sometimes used in heart ailure, generally or patients with mild chronic congestive symptoms. In addition, they can be added to loop diuretic therapy or patients who have become re ractory to the diuretic e ect o the latter. Since they act on sequential segments o the renal tubule, the combination produces a more pro ound natriuretic e ect than either agent used alone. Among the most important potential adverse e ects o thiazides are (1) hypokalemia and metabolic alkalosis, which result rom increased Na + delivery to the distal tubule, where exchange or K+ and H+ takes place, and rom volume contraction and secondary hyperaldosteronism, as previously described or the loop diuretics; (2) hyponatremia, during prolonged treatment because o continued Na + excretion in the setting o chronic ree water consumption; (3) hyperuricemia (and possible precipitation o gout) owing to decreased clearance o uric acid; (4) hyperglycemia, because o either impaired pancreatic insulin release or decreased peripheral glucose utilization; (5) alterations in serum lipids (at least transiently), characterized by increased low-density lipoprotein (LDL) cholesterol and triglycerides; and (6) weakness, fatigability, and paresthesias, which can occur with long-term use because o volume depletion and hypokalemia. In addition, serum calcium levels o ten rise slightly during thiazide therapy, but this is rarely clinically signif cant.
Potassium-Sparing Diuretics These are relatively weak diuretics that antagonize physiologic Na + reabsorption at the distal convoluted tubule and cortical collecting tubule. Potassium-sparing agents reduce K+ excretion; thus, unlike other diuretics, hypokalemia is not a side e ect. They are used when maintenance o serum potassium levels is crucial and in states characterized by aldosterone excess (e.g., primary or secondary hyperaldosteronism). Two types o drugs make up this group: (1) aldosterone antagonists (e.g., spironolactone and eplerenone) and (2) direct inhibitors o Na + permeability in the collecting duct, which act independently o aldosterone (e.g., triamterene and amiloride). Na + and K+ exchange in the collecting tubules accounts or only a small percentage o sodium reuptake, so diuretic e ectiveness is modest when these agents are used alone. They are o ten used in combination with the loop or thiazide classes or additive diuretic e ect and to prevent hypokalemia.
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Spironolactone is a synthetic steroid that competes or the cytoplasmic aldosterone receptor, thereby inhibiting the aldosterone-sensitive Na + channel in the kidney. Because Na + reabsorption through the sodium channel is inhibited, no lumen-negative potential exists to drive K+ and H+ ion excretion at the distal nephron sites; thus, K+ and H+ ions are retained in the circulation. Spironolactone also displays benef cial cardiac antiremodeling e ects in patients with heart ailure (see Chapter 9). In a trial o patients with severe heart ailure, spironolactone (added to an ACE inhibitor and a loop diuretic) improved heart ailure symptoms and reduced mortality rates. The most serious potential complication o spironolactone is hyperkalemia, resulting rom the impaired excretion o that ion. Thus, caution should be observed when administering K+ supplements, ACE inhibitors, or ARBs concurrently with potassium-sparing diuretics because they could contribute to this complication. Spironolactone also displays antiandrogenic activity that may produce gynecomastia in men and menstrual irregularities in women. Eplerenone is a more specif c inhibitor o the aldosterone receptor that does not have the systemic antiandrogenic e ects o spironolactone. Like spironolactone, it is used in the treatment o hypertension and chronic systolic heart ailure. In patients with clinical evidence o heart ailure ollowing a myocardial in arction, eplerenone has also been shown to improve survival when added to usual care. Triamterene and amiloride are structurally related potassium-sparing diuretics that act independently o aldosterone. At the distal tubules, they inhibit the reabsorption o Na + , which subsequently diminishes the excretion o K+ and H+ . Triamterene is metabolized by the liver, and its active product is secreted into the proximal tubule by the organic cation transport system. Amiloride is secreted directly into the proximal tubule and appears unchanged in the urine. As with spironolactone, the most important potential adverse e ect o these drugs is hyperkalemia.
ANTITHROMBOTIC DRUGS Platelets and the coagulation proteins play a key role in the pathogenesis o many cardiovascular disorders, including acute coronary syndromes, deep venous thrombosis (DVT), and thrombi that may complicate atrial f brillation, dilated cardiomyopathy, or mechanical prosthetic heart valves. There ore, the modulation o platelet unction and o the coagulation pathway is o ten critically important in cardiovascular therapeutics. The ormation o a thrombus, whether in normal hemostasis or in pathologic clot ormation, requires three events: (1) exposure o circulating blood elements to thrombogenic material (e.g., unmasking o subendothelial collagen a ter atherosclerotic plaque rupture); (2) activation and aggregation o platelets; and (3) triggering o the coagulation cascade, ultimately resulting in a f brin clot. Hemostasis e ected by platelets and the coagulation system is closely interlinked: activated platelets accelerate the coagulation pathway, and certain coagulation proteins (e.g., thrombin) contribute to platelet aggregation. This section ocuses f rst on drugs that inter ere with platelet unction and then on those that inhibit the coagulation cascade. Fibrinolytic agents, which dissolve clots that have already ormed, are described in Chapter 7.
Platelet Inhibitors Platelets are responsible or primary hemostasis by a three-part process: (1) adhesion to the site o injury, (2) release reaction (secretion o platelet products and activation o key sur ace receptors), and (3) aggregation. For example, ollowing blood vessel injury, platelets quickly adhere to exposed subendothelial collagen by means o membrane glycoprotein (GP) receptors, a process that depends on von Willebrand actor. Following adhesion to the vessel wall, platelets release the pre ormed contents o their granules in response to agonists (including
440
Chapter 17 collagen and thrombin) that bind to platelet receptors. Among these prepackaged substances are adenosine diphosphate (ADP), serotonin, f brinogen, growth actors, and procoagulants. Concurrently within the activated platelet, there is de novo synthesis and secretion o thromboxane A2 (TXA2), a power ul vasoconstrictor (Fig. 17-18). Certain agonists, including ADP, thrombin, and TXA2, stimulate platelets to aggregate and orm the primary hemostatic plug as additional platelets are recruited rom the circulation. During this process, platelet membrane GP IIb/ IIIa receptors undergo a critical con ormational change. This alteration allows the previously inactive GP IIb/ IIIa receptor to bind f brinogen molecules, an action that tightly links platelets to one another and constitutes the f nal common pathway o platelet aggregation. The developing clump o platelets is stabilized and tethered to the site o injury by a mesh o f brin, which is produced by the simultaneous activation o the coagulation protein cascade.
P 2Y12 RECEP TOR ANTAGONISTS Pros ta cyclin
TXA2
VORAPAXAR ADP
S e rotonin
–
– P 2Y12
P LA2
Gs
AC
+
–
Gi
PAR-1
P 2Y1
Gi
P LC
P IP 2
IP 3
ATP Ara chidonic a cid
Thrombin
cAMP AMP
PD
–
+
– COX – TXA2
DIPYRIDAMOLE Ca ++
Ca ++ DENS E TUBULES
AS P IRIN P LATELET ACTIVATION
GP IIb /IIIa RECEP TOR ANTAGONISTS Gra nule s e cre tion
Cytos ke le ta l re orga niza tion
Activa tion of glycoprote in IIb/IIIa re ce ptor
–
FIGURE 17-18. Platelet activation is mediated by cytosolic Ca+ + . Factors that promote and inhibit calcium release rom the platelet-dense tubules are shown. Thrombin and serotonin, acting at their specif c receptors, stimulate the ormation o inositol triphosphate (IP3) rom phosphatidylinositol bisphosphate (PIP2) by phospholipase C (PLC). IP3 subsequently enhances the intracellular release o calcium. Thromboxane A2 (TXA2) also acilitates calcium release. It inhibits adenyl cyclase (AC) and reduces cyclic adenosine monophosphate (cAMP) ormation. Because cAMP normally prevents Ca+ + release rom the dense tubules, the reduction o this e ect by TXA2 increases Ca+ + release into the cytosol. Conversely, endothelial-derived prostacyclin has the opposite e ect. It reduces intraplatelet calcium release because it stimulates AC activity and cAMP ormation. ADP also stimulates calcium release via its two receptors (see text or details). Calcium promotes the action o phospholipase A2 (PLA2), which generates the precursors o TXA2 rom the cell membrane. Platelet activation modulated by Ca+ + ultimately results in granule secretion, cytoskeletal reorganization, and the critical con ormational change in GP IIb/ IIIa receptors that is necessary or platelet aggregation. The sites o action o commonly used antiplatelet drugs are shown. COX, cyclooxygenase; PAR-1, protease-activated receptor-1.
Cardiovascular Drugs
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Platelet activation is regulated to a great extent by release o stored Ca + + rom the platelet dense tubular system. This action results in an increase in cytosolic calcium concentration, with activation o protein kinases and phosphorylation o intraplatelet regulatory proteins. The augmented cytosolic Ca + + also stimulates phospholipase A2 (PLA2), causing the release o arachidonic acid, the precursor o TXA2 (see Fig. 17-18). The critical release o calcium is modulated by several actors. Acting at their respective platelet membrane receptors, thrombin and other agonists generate intermediaries that stimulate the release o calcium rom the dense tubules. TXA2 increases the intracellular Ca + + by binding to its platelet receptor, which inhibits the activity o adenylate cyclase and thereby reduces cAMP ormation, an action that augments the release o Ca + + rom the dense tubules (see Fig. 17-18). Conversely, endothelial cell-derived prostacyclin (PGI2) stimulates adenylate cyclase activity and increases platelet cAMP concentration, which inhibits Ca + + release rom the dense tubular system. Antiplatelet drugs inter ere with platelet unction at various points along the sequence o activation and aggregation (see Fig. 17-18). The most commonly used antiplatelet drug is aspirin, but the roles o newer antiplatelet drugs, especially P2Y12 receptor antagonists and GP IIb/ IIIa receptor antagonists, have rapidly expanded.
Aspirin As described in the previous section, TXA2 is an important mediator o platelet activation and clot ormation. Aspirin (acetylsalicylic acid) acts by irreversibly acetylating (and thus blocking the action o ) cyclooxygenase, an enzyme essential to TXA2 production rom arachidonic acid (see Fig. 17-18). The orm o the enzyme ound in platelets is cyclooxygenase-1 (COX-1), which is e ectively inhibited by the nonselective action o aspirin (but it is not inhibited by selective COX-2 antagonists, such as celecoxib). Because platelets lack nuclei and there ore cannot synthesize new proteins (including cyclooxygenase), aspirin permanently disables TXA2 production in exposed cells. The prostaglandin PGI2, a major antagonist o TXA2 that is produced by endothelial cells, shares a dependency on cyclooxygenase activity or its ormation, and aspirin, at high doses, impairs its synthesis as well. Unlike platelets, however, endothelial cells are able to generate new cyclooxygenase to replace what has been deactivated by acetylation. Thus, when used at low doses, aspirin e ectively inhibits platelet TXA2 synthesis without signif cantly inter ering with the presence and benef cial actions o PGI2. Because the antiplatelet e ect o aspirin is limited to inhibition o TXA2 ormation, platelet aggregation induced by other actors (e.g., ADP) is not signif cantly impeded. Thus, aspirin is not a “complete” antithrombotic agent.
Clinical Uses Aspirin has many proven clinical benef ts in patients with cardiovascular disease (Table 17-16). In individuals with unstable angina, acute myocardial in arction, or a history o myocardial in arction, aspirin reduces the incidence o uture atal and non atal coronary events. Similarly, in patients with chronic stable angina without a history o myocardial in arction, aspirin lessens the occurrence o subsequent myocardial in arction and mortality. In patients who have su ered a minor stroke or transient cerebral ischemic attack, aspirin reduces the rate o uture stroke and cardiovascular events. Additionally, aspirin lowers the likelihood o gra t occlusion in patients who have undergone coronary artery bypass surgery. Less clear is the benef t o aspirin or primary prevention (i.e., in individuals without a history o cardiovascular events or symptoms). When tested in a large cohort o healthy American middle-aged men, aspirin was associated with a reduced incidence o non atal myocardial in arction but an increased rate o non atal hemorrhagic stroke and gastrointestinal
442
Chapter 17
TABLE 17-16
Cardiovascular Uses of Antithrombotic Drugs Chronic Angina
Drug Platelet inhibitors Aspirin P2Y12 antagonists GP IIb/ IIIa antagonists Dipyridamole Anticoagulants—parenteral UFH LMWH Direct thrombin inhibitors Fondaparinux Anticoagulants—oral Warfarin Newer oral anticoagulants (e.g., dabigatran, rivaroxaban, apixaban, edoxaban)
+
Unstable Angina/ NSTEMI
STEMI
+ + +
+ + (4)
Mechanical DVT Heart Valve (1)
Atrial Fibrillation
PCI
(2)
+ (3) +
(6)
+
HIT
(5) + + (7) (8)
+ +
+ +
(6)
+
+
+ (9)
+ +
+
+ +
(1) Sometimes used in combination with warfarin. (2) If patient has a low risk of stroke, or if anticoagulation is contraindicated. (3) When intracoronary stent is implanted. (4) If PCI undertaken. (5) Sometimes used in combination with warfarin for recurrent thromboembolism. (6) For hospitalized patients unable to take warfarin. (7) If undergoing PCI. (8) Occasional use. (9) For 3–6 months after MI if large akinetic segment is present. DVT, deep venous thrombosis; HIT, heparin-induced thrombocytopenia; LMWH, low molecular weight heparin; NSTEMI, non–ST elevation myocardial infarction (MI); PCI, percutaneous coronary intervention; STEMI, ST-elevation MI; UFH, unfractionated heparin.
bleeding; there was no e ect on total vascular mortality. Subsequent meta-analyses o clinical trials have similarly concluded that aspirin is e ective or primary prevention o myocardial in arction in patients with coronary risk actors, but it also increases the risk o hemorrhagic stroke. In the prospective, primary prevention trial known as the Women’s Health Initiative, aspirin lowered the risk o ischemic stroke in women but did not reduce the incidence o MI or death rom cardiovascular disease. Thus, whereas aspirin plays an extremely important role in patients with known cardiovascular disease, it is not evident that otherwise healthy people should routinely take aspirin or “cardiovascular protection.” Current recommendations are that aspirin (at a dosage o 75 to 325 mg/ day) be administered to patients with clinical mani estations o coronary disease in the absence o contraindications (i.e., aspirin allergy or complications described in the next section). It should not be prescribed routinely or primary prevention purposes in completely healthy individuals who are at low risk o cardiovascular disease. However, or individuals without an elevated bleeding tendency, many experts do recommend aspirin or men greater than age 45 whose risk actors place them at high probability or a uture f rst myocardial in arction and or women greater than age 55 who are at increased risk or stroke (see Chapter 5). In addition, the American Diabetes Association recommends that diabetics with at least one other coronary
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risk actor take aspirin or cardiovascular protection. Finally, aspirin is not as benef cial as war arin (described later in the chapter) or the prevention o stroke in high-risk patients with atrial f brillation.
Adverse Effects The most common adverse e ects o aspirin are related to the gastrointestinal system, including dyspepsia and nausea, which o ten can be ameliorated by lowering the dosage and/ or using enteric-coated or bu ered tablets. More serious potential side e ects include gastrointestinal bleeding, hemorrhagic strokes, allergic reactions, and asthma exacerbation in aspirinsensitive patients. Because aspirin is excreted by the kidneys and competes with uric acid or the renal proximal tubule organic anion transporter, it may also occasionally exacerbate gout.
Platelet P2Y12 Receptor Antagonists During platelet activation, ADP is released and extracellular ADP then contributes to urther platelet activation and promotes aggregation by binding to two types o sur ace purinoceptors. The f rst (P2Y1 receptor) acts through phospholipase C to increase intraplatelet [Ca + + ]. The second purinoceptor (P2Y12) is linked to an inhibitory G protein and reduces cAMP production, thus also raising intraplatelet [Ca + + ] and promoting continued platelet activation (see Fig. 17-18). ADP-induced platelet aggregation requires that ADP simultaneously activate both P2Y1 and P2Y12 receptors. Current antagonists o such ADP activation inter ere with the P2Y12 receptor, either irreversibly (e.g., the thienopyridines) or reversibly (e.g., ticagrelor).
Thienopyridines Clopidogrel, ticlopidine, and prasugrel are oral thienopyridines approved or clinical use. These drugs irreversibly block P2Y12 by covalently binding the receptor. All are well absorbed and have good bioavailability. Meta-analyses o the use o ticlopidine or clopidogrel in patients at risk or coronary syndromes have shown that these drugs are modestly superior to aspirin in reducing the risk o myocardial in arction, stroke, or vascular deaths, but at an increased risk o side e ects. Studies evaluating the combination o aspirin plus clopidogrel in patients with unstable angina, non–ST elevation myocardial in arction (NSTEMI), and ST-elevation myocardial in arction (STEMI) have demonstrated a signif cant benef t in cardiovascular outcomes compared with aspirin alone, though at an increased bleeding risk. Thienopyridines are currently used as antiplatelet substitutes in patients allergic to aspirin and to prevent thrombotic complications ollowing percutaneous coronary stenting (see Chapter 6). The combination o clopidogrel plus aspirin is also approved or patients with unstable angina, NSTEMI, or STEMI to reduce the rate o recurrent cardiac events (see Chapter 7). Side e ects o the thienopyridines include bleeding, dyspepsia, and diarrhea. In addition, ticlopidine is now rarely used because o potentially li e-threatening adverse reactions: severe neutropenia (occurring in 0.8% to 2.5% o patients) and thrombotic thrombocytopenic purpura (in approximately 0.02% o patients). These hematologic complications are much rarer with the other agents o this class. Clopidogrel is a prodrug that requires cytochrome P450–mediated biotrans ormation to the active metabolite, which contributes to the drug’s delayed onset o action and to variability in its antiplatelet e ect. For example, patients with common reduced- unction polymorphisms o the cytochrome P450 2C19 (CYP2C19) gene demonstrate weakened platelet inhibition and less clinical benef t. In addition, studies have implicated proton pump inhibitors (e.g., omeprazole) as drugs that can inter ere with hepatic CYP2C19 activation o clopidogrel and its cardiovascular benef t.
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Chapter 17 Newer drugs address these shortcomings. For example, prasugrel, another thienopyridine, is metabolized to an active orm more readily than clopidogrel and has a more potent antiplatelet e ect. Compared to clopidogrel, it has been shown to urther reduce the risk o uture myocardial in arction in patients with ACS who undergo percutaneous coronary intervention. This benef t comes with an increased risk o bleeding, a complication that is more likely to occur in patients who are elderly, those with prior cerebrovascular disease, and individuals with a low body weight. A limitation o the thienopyridines, including clopidogrel, ticlopidine, and prasugrel, is that they are irreversible platelet inhibitors. I a thienopyridine-treated patient with an ACS requires coronary artery bypass surgery, a waiting period o several days is necessary to allow adequate return o platelet unction to prevent perioperative bleeding complications.
Ticagrelor Unlike the thienopyridines, ticagrelor is an oral reversible P2Y12 receptor blocker that provides aster onset o action and greater inhibition o platelet aggregation than clopidogrel. Rather than covalently binding the P2Y12 receptor, ticagrelor causes a con ormational change o the receptor, resulting in reversible and concentration-dependent inhibition. In addition, the antiplatelet e ect resolves more quickly when the drug is discontinued compared to the irreversible thienopyridines. In a large clinical trial, ticagrelor reduced the rate o MI and cardiovascular death compared with clopidogrel in patients with acute coronary syndromes, without a di erence in major bleeding episodes.
Thrombin Receptor Antagonist ( PAR-1 Antagonist) In 2014, the FDA approved the use o vorapaxar, an antagonist o the platelet proteaseactivated receptor-1 (PAR-1), which inhibits thrombin-induced platelet aggregation (see Fig. 17-18). When administered to patients with prior MI or peripheral vascular disease already on standard antiplatelet therapy, vorapaxar reduced the risk o subsequent MI, stroke, cardiovascular death, or need or urgent coronary revascularization in a large placebo-controlled clinical trial. However, the drug was associated with increased bleeding complications, and it should not be prescribed to patients at high risk o intracranial hemorrhage (e.g., patients with history o stroke, TIA, or prior intracranial bleed).
Glycoprotein IIb/ IIIa Receptor Antagonists The GP IIb/ IIIa receptor antagonists constitute one o the most potent classes o antiplatelet agents. This group reversibly inhibits the critical and f nal common pathway o platelet aggregation—the binding o activated platelet GP IIb/ IIIa receptors to f brinogen and von Willebrand actor. As a result, platelets are inhibited rom “sticking” to one another, impairing the ormation o a hemostatic plug. Three types o GP IIb/ IIIa receptor antagonists have been developed: (1) monoclonal antibodies (e.g., abciximab, which is the Fab ragment o a chimeric human–mouse monoclonal antibody); (2) synthetic peptide antagonists (e.g., eptif batide); and (3) synthetic nonpeptide antagonists (e.g., tirof ban). As described in Chapters 6 and 7, the GP IIb/ IIIa antagonists signif cantly improve outcomes o patients undergoing percutaneous coronary interventions and in high-risk acute coronary syndromes. All the GP IIb/ IIIa receptor inhibitors in current use must be administered intravenously. Oral GP IIb/ IIIa receptor inhibitors have been developed but have not demonstrated benef cial outcomes in clinical trials. The major side e ects o the GP IIb/ IIIa receptor inhibitors are bleeding (in 1% to 10% o patients) and thrombocytopenia (in approximately 2% o patients treated with abciximab and less commonly with the other agents). Abciximab has a short plasma hal -li e
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(30 minutes); thus, its e ects can be reversed by discontinuing the drug or by administering a platelet trans usion. Because the other GP IIb/ IIIa receptor antagonists have longer hal -lives, they may continue to inactivate trans used platelets. Nonetheless, bleeding complications are in requent using current protocols and care ul dosing.
Dipyridamole The antiplatelet drug dipyridamole is uncommonly prescribed by itsel . Rather, a capsule ormulation that combines dipyridamole with low-dose aspirin is e ective and approved or the prevention o stroke in patients with prior cerebrovascular symptomatology. Dipyridamole is also occasionally prescribed in combination with war arin or augmented antithrombotic e ect in patients with recurrent thromboembolism rom prosthetic heart valves, but the pairing o aspirin plus war arin is more e ective. Dipyridamole’s mechanism o antiplatelet action involves an increase in platelet cAMP levels by (1) inhibiting the destruction o cAMP by phosphodiesterase (see Fig. 17-18) and (2) impeding cellular uptake and destruction o adenosine, thereby augmenting adenosine’s availability to stimulate the platelet A2 receptor, which enhances the production o cAMP via adenylate cyclase. cAMP in turn reduces the intracellular Ca + + concentration, thus inhibiting platelet activation (see Fig. 17-18).
Anticoagulant Drugs: Parenteral Agents Anticoagulant drugs (see Table 17-16) inter ere with the coagulation cascade and impair secondary hemostasis. Because the f nal step in both the intrinsic and extrinsic coagulation pathways is the ormation o a f brin clot by the action o thrombin, major goals o anticoagulant therapy are to inhibit the activation o thrombin by actor Xa (e.g., using un ractionated heparin [UFH], low molecular weight heparin [LMWH], or actor Xa inhibitors), to inhibit thrombin itsel (e.g., UFH or direct thrombin inhibitors), or to decrease the production o unctional prothrombin (e.g., war arin). This section describes anticoagulants that are administered by intravenous or subcutaneous administration, while the next section considers oral anticoagulants.
Unfractionated Heparin UFH is a heterogeneous mixture o glycosaminoglycans. Although it has little anticoagulant action by itsel , it associates with antithrombin (AT) in the circulation, greatly increasing its e ect. AT is a natural protein that inhibits the action o thrombin and other clotting actors. When UFH complexes with AT, the a f nity o AT or thrombin increases 1,000- old, markedly reducing thrombin’s ability to generate f brin rom f brinogen. The UFH–AT complex also inhibits activated actor X, additionally contributing to the anticoagulant action. Furthermore, UFH has antiplatelet properties by binding to, and blocking the action o , von Willebrand actor. UFH is administered parenterally because it is not absorbed rom the gastrointestinal tract. For most acute indications, an intravenous bolus is ollowed by a continuous in usion o the drug. The bioavailability o UFH varies rom patient to patient because it is a heterogeneous collection o molecules that bind to plasma proteins, macrophages, and endothelial cells. The dosage–e ect relationship is o ten not predictable; thus, requent blood samples are required to monitor the degree o anticoagulation (most commonly, measurement o the activated partial thromboplastin time), so that the in usion rate can be adjusted accordingly. The usual cardiovascular settings in which intravenous UFH is indicated include (1) unstable angina and NSTEMI (see Chapter 6), (2) acute myocardial infarction a ter f brinolytic therapy or i an extensive wall motion abnormality is present (see Chapter 7), and (3) pulmonary embolism or deep venous thrombosis (see Chapter 15). Among hospitalized or bedridden patients not receiving intravenous heparin, f xed low dosages o subcutaneous UFH are o ten administered to prevent DVT.
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Chapter 17 The most important side e ect o heparin is bleeding. An overdose o UFH can be treated with intravenous protamine sulfate, which orms a stable complex with UFH and immediately reverses the anticoagulation e ect. Heparin-induced thrombocytopenia (HIT) is another potential major adverse e ect and can occur in two orms. The more common type, thought to result rom direct heparin-induced platelet aggregation, occurs in up to 15% o patients and is usually asymptomatic, dose dependent, and sel -limited. This mild HIT rarely causes severe reductions in platelet counts and usually does not require cessation o heparin. The less common, much more dangerous orm o HIT is immune-mediated, a condition that a ects 3% o UFH-treated patients. It can lead to li e-threatening bleeding and, paradoxically, to thrombosis. Thrombosis is caused by the ormation o antibodies directed against heparin–platelet complexes, resulting in platelet activation, aggregation, and clot production. In the immune-mediated orm o HIT, the platelet count can all markedly and is not dependent on the dose o heparin. Therapy requires immediate cessation o heparin and substitution by alternate antithrombotic therapy to prevent urther clotting (e.g., a direct thrombin inhibitor, described later in the chapter). Patients receiving long-term UFH therapy are also prone to a dose-dependent orm o osteoporosis through an unclear mechanism.
Low Molecular Weight Heparins Some o the shortcomings o UFH (e.g., short hal -li e and unpredictable bioavailability) have been addressed by the development o LMWHs, examples o which are enoxaparin, dalteparin, and tinzaparin. As the name implies, LMWH molecules are smaller than UFH (approximately one third the size). These agents also interact with AT, but unlike UFH, the LMWH–AT complex pre erentially inhibits actor Xa more than thrombin (thrombin inhibition requires heparin molecules larger than those in LMWHs). Selectively inhibiting actor Xa upstream in the coagulation cascade has a multiplier e ect in preventing downstream ormation o thrombin. Advantages o LMWHs over UFH include (1) inhibition o platelet-bound actor Xa, contributing to a more prominent anticoagulant e ect; (2) less binding to plasma proteins and endothelial cells, resulting in more predictable bioavailability and a longer hal -li e; (3) ewer bleeding complications; and (4) a lower incidence o immune-mediated HIT. From a practical standpoint, the major advantages o LMWH ormulations are the ease o use and more consistent level o anticoagulation. They can be administered as subcutaneous injections once or twice a day in f xed doses, without the requent blood monitoring required or UFH. In rare cases in which monitoring the anticoagulant e ect is necessary (e.g., in patients with renal dys unction, because LMWHs are cleared via the kidneys), a actor Xa inhibition assay is used. In clinical trials, LMWH therapy is at least as e ective as UFH in preventing DVT and treating unstable angina. It also has a better sa ety prof le than UFH, with lower rates o bleeding, thrombocytopenia, and osteoporosis. LMWHs should not, however, be used in patients with a history o HIT, and unlike UFH, the e ects o LMWHs cannot be completely reversed by protamine. Current clinical indications or LMWH therapy are (1) prophylaxis against DVT ollowing hip, knee, or abdominal surgery; (2) treatment o DVT (with or without pulmonary embolism); and (3) management o acute coronary syndromes.
Direct Thrombin Inhibitors The anticoagulation e ects o UFH and LMWH are limited because their activity depends, at least in part, on AT, and they inhibit only circulating thrombin. The large heparin–AT complex cannot inactivate thrombin that is already bound to f brin within a clot. In contrast, the direct
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thrombin inhibitors (e.g., lepirudin, bivalirudin, argatroban) inhibit thrombin activity independently o AT and are e ective against both circulating and clot-bound thrombin. They do not cause thrombocytopenia and are used to maintain anticoagulation and prevent thrombosis in patients with HIT. Bivalirudin is approved or use as an anticoagulant in patients with unstable angina undergoing percutaneous coronary intervention. All direct thrombin inhibitors are potent anticoagulants and the major adverse e ect is bleeding.
Factor Xa Inhibitor The anticoagulant fondaparinux is a synthetic pentasaccharide that specif cally inhibits actor Xa, thereby reducing thrombin activation. Like heparin, ondaparinux binds to AT with high a f nity, greatly increasing AT’s ability to inactivate actor Xa. Unlike UFH, ondaparinux does not inactivate ormed thrombin, nor does it inter ere with platelet actions or cause HIT. It is administered by subcutaneous injection, and its hal -li e is su f ciently long (17 to 21 hours) that it can be prescribed just once a day. There are no known antidotes to its anticoagulant e ect. Fondaparinux is approved or prevention o DVT a ter certain surgical procedures and as treatment or DVT and pulmonary embolism.
Anticoagulant Drugs: Oral Agents Warfarin War arin is an oral agent prescribed or long-term anticoagulation. It acts by antagonizing the enzyme vitamin K epoxide reductase that is required in usual vitamin K metabolism. Normally, the reduced orm o vitamin K promotes the carboxylation o a glutamic acid residue within specif c coagulation actors ( actors II, VII, IX, and X), an action that is necessary or the actors Ca rboxyla te d fa ctors II, VII, IX, X Pre curs ors of to subsequently bind calcium, become unctional, and ++ fa ctors II, VII, IX, X (a b le to b ind Ca ) participate in coagulation (Fig. 17-19). By inter ering with the ormation o reduced vitamin K, war arin indirectly inhibits carboxylation o the coagulation actors, rendering them inactive. Because certain natural coagulation inhibitors (protein C and protein S) are also vitamin K dependent, war arin impairs their unctions Re duce d Oxidize d as well, which in some cases may counteract the drug’s vita min K vita min K anticoagulant e ect. Vita min K War arin’s action has a delayed onset o 2 to 7 e p oxid e days; thus, i immediate anticoagulation is needed, re d uc ta s e UFH or LMWH must be prescribed concurrently at – f rst (known as anticoagulant “bridging”). The hal -li e o war arin is long (37 hours), and the drug’s dosage WARFARIN must be individualized to achieve a therapeutic e ect while minimizing the risk o bleeding complications. FIGURE 17-19. Mechanism of action of warfarin. The extent o anticoagulation is monitored by measurNormally, coagulation factors II, VII, IX, and X are ing the prothrombin time in blood samples, reported converted to functional forms by carboxylation in the liver, in the presence of reduced vitamin K. During as an international normalized ratio (INR). There this reaction, vitamin K undergoes oxidation and are two target ranges o anticoagulant intensity. For must be regenerated back to the reduced state for patients at greatest risk o pathologic thrombosis (e.g., the sustained synthesis of functional clotting factors. those with certain types o mechanical heart valves), Warfarin inhibits the formation of reduced vitamin K the desired INR is 2.5 to 3.5. For others (e.g., those by antagonizing the enzyme epoxide reductase, such with uncomplicated atrial f brillation), the target INR that the conversion of the coagulation factors does is usually 2.0 to 3.0. not occur and they remain nonfunctional.
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TABLE 17-17
Examples o Drugs that Alter the Anticoagulation E ect o War arin
Reduced Anticoagulation E ect
Increased Anticoagulation E ect
Hepatic enzyme induction Barbiturates Ri ampin Carbamazepine Na cillin War arin malabsorption Cholestyramine Sucral ate
Hepatic enzyme inhibition Amiodarone Cephalosporins Cimetidine Erythromycin Fluconazole Isoniazid Ketoconazole Metronidazole Propa enone Trimethoprim–sul amethoxazole Displacement rom protein-binding sites Allopurinol Gem brozil Phenytoin Altered vitamin K production by gut f ora Ciprof oxacin Piperacillin
Many actors inf uence the anticoagulation e ect o war arin and require alterations in its dosage. For example, liver disease and heart ailure each reduce the war arin requirement, whereas a high dietary ingestion o oods containing vitamin K (e.g., green lea y vegetables) increases the required dose. Similarly, many pharmaceuticals alter war arin’s anticoagulation e ect (Table 17-17). Finally, the combined use o war arin with aspirin or other antiplatelet agents increases the risk o a bleeding complication. I serious bleeding arises during war arin therapy, the drug’s e ect can be reversed within hours by the administration o vitamin K (or even more quickly by trans using resh rozen plasma or prothrombin complex concentrates, which directly replenish unctional circulating clotting actors). In patients with mechanical heart valves, vitamin K should be avoided unless li e-threatening bleeding occurs, because o the possibility o rebound valve thrombosis. War arin is teratogenic and should not be taken during pregnancy, especially during the rst trimester. Given the many limitations and inconvenience o war arin therapy, much e ort has been directed toward the development o newer oral anticoagulants endowed with more predictable pharmacologic properties and ease o use.
Newer Oral Anticoagulants The direct thrombin inhibitor dabigatran and the actor Xa inhibitors rivaroxaban, apixaban, and edoxaban are oral anticoagulants that were initially approved by the FDA or the prevention o stroke in patients with atrial brillation in the absence o valvular heart disease. Each o these drugs is as e ective, or superior, to war arin in e cacy and sa ety. Advantages o these agents over war arin include a xed dosing regimen (so there is no need to monitor laboratory tests to assess the degree o anticoagulation), a rapid onset o action (such that “bridging” with UFH or LMWH is not necessary), ew interactions with other drugs, and no important ood interactions. Disadvantages compared to war arin include higher costs, lack o a laboratory test to accurately monitor a patient’s compliance, and di culty in reversing the anticoagulant e ect
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in case o bleeding, as unlike war arin, no antidotes or these agents are currently approved or use. In addition, the dose o each o these agents must be reduced in the presence o renal dys unction. The mechanism o action o dabigatran is the same as the parenteral direct thrombin inhibitors described earlier in the chapter. Rivaroxaban, apixaban, and edoxaban di er rom the parenteral anti– actor Xa agent ondaparinux described earlier in that they directly inhibit actor Xa, without requiring AT as an intermediary. In addition to their indication in patients with nonvalvular atrial f brillation, these newer oral anticoagulants have also gained approval or the treatment o DVT and pulmonary embolism.
LIPID-REGULATING DRUGS As described in Chapter 5, abnormal serum lipid levels play a critical role in the pathogenesis o atherosclerosis. Specif c groups o drugs that improve lipid abnormalities are cardioprotective; they inhibit the progression o atherosclerosis, improve cardiovascular outcomes, and, especially in high-risk patients, reduce mortality rates.
HMG-CoA Reductase Inhibitors The HMG-CoA reductase inhibitors, commonly known as “statins,” are the most e ective drugs or reducing LDL cholesterol. By virtue o their potency, tolerability, and mortality benef ts, they represent the pre erred orm o lipid-altering therapy. The most commonly used agents o this group, in increasing order o potency, are lovastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (Table 17-18).
TABLE 17-18
Lipid-Regulating Drugs LDL Effect ( %)
HDL Effect ( %)
Triglyceride Effect ( %)
Adverse Effects
HMG-CoA reductase inhibitors Atorvastatin Fluvastatin Lovastatin Pitavastatin Pravastatin Rosuvastatin Simvastatin Bile acid–binding agents Cholestyramine Colestipol Colesevelam Cholesterol absorption inhibitor Ezetimibe Niacin
↓ 20–55
↑ 5–15
↓ 7–30
Transaminitis, myopathy
↓ 15–30
↑ 3–5
May ↑
Constipation, bloating
↓ 15–20
↑ 1–2
↓ 0–5
Rare allergic reaction
↓ 5–25
↑ 15–35
↓ 20–50
Fibric acid derivatives Fenof brate Gemf brozil
↓ 0–20 or ↑ 0–10
↑ 10–20
↓ 20–50
Flushing, hepatotoxicity, hyperglycemia, hyperuricemia, exacerbation o peptic ulcer disease Nausea, gallstones
Class
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Chapter 17 Statins are competitive inhibitors o the enzyme HMG-CoA reductase, a rate-controlling actor in cholesterol biosynthesis (Fig. 17-20). By inhibiting cholesterol production in the liver, statins lower serum LDL cholesterol through three mechanisms: (1) the reduced intrahepatic cholesterol content induces increased expression o the LDL receptor gene, causing a greater number o LDL receptors to appear on the sur ace o the hepatocyte, which acilitates the binding and clearance o LDL rom the circulation; (2) circulating LDL precursors (known as very low density lipoprotein [VLDL] remnants and intermediate-density lipoprotein particles) are cleared more rapidly rom the circulation because o their cross-recognition with the hepatic LDL receptor; and (3) hepatic VLDL production alls due to the reduced availability o intracellular cholesterol or lipoprotein assembly. Because the catabolism o VLDL in the circulation ultimately orms LDL, lowering VLDL production also decreases circulating LDL levels. The reduced production o VLDL is also likely responsible or the triglyceride-lowering e ect o statins, because this lipoprotein is the major carrier o triglycerides in the circulation. The overall e ect is that statins reduce serum LDL levels by 20% to 55% , depending on the specif c drug and dose. Statins also decrease plasma triglyceride levels by 7% to 30% , and by an unclear mechanism, HDL levels increase by 5% to 15% .
LDL
Live r HMG CoA S ta tins
Fib ra te s
VLDL re mna nts
LDL + LP L Triglyce ride s
Chole s te rol
Ad ip os e tis s ue
FFA
Nia c in VLDL (mos tly TG)
Mus c le
Bile a cids
Chylomicrons Inte s tine Eze timib e Chole s te rol
Bile a c id – b ind ing a g e nts
FIGURE 17-20. Major sites of action of lipid-regulating drugs. The statins inhibit cholesterol biosynthesis in the liver by competing with the enzyme HMG-CoA reductase. This action depletes intrahepatic cholesterol stores, which results in increased expression of surface low-density lipoprotein (LDL) receptors. The latter enhance clearance of LDL and very low density lipoprotein (VLDL) remnants from the circulation. The lower intrahepatic cholesterol content leads to reduction in VLDL synthesis. Ezetimibe selectively inhibits cholesterol uptake in the small intestine, thereby reducing chylomicron production and cholesterol delivery to the liver. Bile acid–binding agents interrupt the enterohepatic circulation of bile acids in the intestine, causing more hepatic cholesterol to be diverted to new bile acid production; the reduced availability of intrahepatic cholesterol augments LDL receptor expression and LDL clearance increases. Among its effects, niacin inhibits VLDL production. It also increases lipoprotein lipase (LPL) activity, thus promoting triglyceride (TG) clearance from circulating VLDL particles. Niacin raises circulating high-density lipoprotein (HDL) by impairing hepatic uptake of apo AI, the HDL apoprotein (not shown). Fibrates enhance VLDL catabolism by increasing the synthesis of lipoprotein lipase via peroxisome proliferator–activated receptor-α (PPAR-α), a nuclear transcription factor. They also raise HDL by stimulating the production of HDL-associated apoproteins (not shown). FFA, free fatty acids.
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The lowering o LDL reduces the lipid content o atherosclerotic lesions and promotes plaque stability. This lessens the vulnerability o plaque to rupture, thus decreasing the likelihood o thrombus ormation and vascular occlusion. In addition to their lipid-modulating properties, statins have other potentially cardioprotective e ects. They improve endothelial unction as evidenced by enhanced synthesis o nitric oxide. They urther promote plaque stability by inhibiting monocyte penetration into the arterial wall and reducing macrophage secretion o metalloproteinases, enzymes that degrade and weaken the brous caps o plaques. Statins also diminish the vulnerability o lipoproteins to oxidation, thus inhibiting the unregulated uptake o modi ed LDL cholesterol by macrophages (see Chapter 5). Finally, they appear to suppress inf ammation, a key component o atherogenesis. Statins are widely prescribed or patients with CAD, because major trials have shown that they substantially reduce mortality, cardiac events, and strokes in this population, whether LDL cholesterol is elevated or even in the “normal” range. In studies o patients not known to have CAD, statin therapy has been shown to reduce coronary events in high-risk individuals— those with elevated LDL cholesterol levels or those with average total cholesterol but low HDL values. Statins are well-tolerated drugs. The most signi cant potential adverse e ects are hepatotoxicity and myopathy (skeletal muscle toxicity). Hepatotoxicity is dose related and occurs in ewer than 1% o patients. Those a ected may experience atigue, anorexia, and weight loss. More commonly, the patient is asymptomatic, but laboratory studies show an increase in transaminase levels (ALT, AST). Symptoms disappear almost immediately a ter the drug is discontinued, but transaminase levels may remain elevated or weeks. The risk o statinassociated hepatic toxicity is higher in patients who drink excessive amounts o alcohol. Myopathy, typically involving the proximal leg or arm muscles symmetrically, can range rom vague aches to intense myalgias and muscle weakness and rarely may lead to rhabdomyolysis (destruction o muscle) with myoglobinuria and renal ailure. While benign muscle aches are reported in 2% to 10% o patients on statins, signi cant myositis (de ned as an elevated serum level o muscle-derived creatine kinase greater than 10 times the upper limit o normal) develops in less than 0.5% . However, the incidence o muscle injury is increased by concomitant therapy with certain other drugs, including other lipid-lowering agents (i.e., niacin and the bric acid derivatives) and drugs that inhibit the 3A4 iso orm o cytochrome P450, which is responsible or the hepatic metabolism o many statins. Such agents include macrolide antibiotics (e.g., erythromycin, clarithromycin), azole anti ungal drugs (e.g., ketoconazole, itraconazole), and many HIV protease inhibitors. Notably, pravastatin, rosuvastatin, and f uvastatin are not substantially dependent on the cytochrome P450 3A4 iso orm or their metabolism and may be less likely to cause myopathy in combination with these other drugs. As described in Chapter 5, statins orm the oundation o lipid-lowering drug therapy. The ollowing sections describe other lipid-lowering agents that are sometimes prescribed to patients who are intolerant o statins, to patients who cannot achieve desired LDL reduction on statin therapy alone, or in other special circumstances.
Bile Acid–Binding Agents This group includes the resins cholestyramine and colestipol and the hydrophilic polymer colesevelam. These drugs are large, highly positively charged molecules that bind bile acids (which are negatively charged) in the intestine and prevent their normal reabsorption to the liver through the enterohepatic circulation (see Fig. 17-20). As a consequence, more hepatic cholesterol is converted into newly produced bile acids. This action depletes intrahepatic cholesterol stores, thus stimulating the production o LDL receptors. Similar to the e ect o the statins, an increased number o hepatic LDL receptors bind a greater amount o circulating LDL, reducing the circulating concentration o that lipoprotein. However, unlike statins,
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Chapter 17 new hepatic cholesterol production is also stimulated by the reduced intrahepatic cholesterol content. The boost in cholesterol synthesis augments VLDL production, which likely explains the commonly observed rise in serum triglyceride levels during therapy with a bile acid–binding agent. In one o the f rst drug trials o patients with hypercholesterolemia, cholestyramine signif cantly reduced the risk o atal and non atal myocardial in arctions. However, drugs o this class are di f cult or patients to take (e.g., cholestyramine and colestipol are unappealing gritty powders that must be mixed with liquids), and their potency is much less than that o statins. Thus, the bile acid–binding agents are only occasionally used, mainly as second-line lipid-regulating drugs, in patients who cannot tolerate statins. Because they can elevate the serum triglyceride level, they should be avoided in patients with hypertriglyceridemia. The bile acid–binding agents inter ere with the absorption o at-soluble vitamins and certain drugs (e.g., war arin, digoxin, propranolol, and thyroid hormones). Thus, other medications should be consumed 1 hour be ore or 3 to 4 hours a ter these agents. The main side e ects are gastrointestinal: bloating, constipation, and nausea. Because bile acid–binding agents are not absorbed into the circulation, they do not cause systemic side e ects.
Cholesterol Absorption Inhibitors Ezetimibe, the f rst member o this class, is a selective inhibitor o cholesterol uptake at the brush border o epithelial cells in the small intestine. It acts by competitively inhibiting a transporter known as the Niemann–Pick C1–like 1 protein. Normally, a portion o dietary and biliary cholesterol taken up in this manner is esterif ed and incorporated into chylomicrons, which then enter into the circulation and are transported to the liver (see Box 5-1). By inhibiting cholesterol uptake (see Fig. 17-20), ezetimibe results in reduced chylomicron production and there ore less cholesterol delivery to the liver. The reduced cholesterol content stimulates compensatory hepatic production o LDL receptors, which augment clearance o circulating LDL particles. The net result is lowering o circulating LDL. Used alone, ezetimibe reduces LDL cholesterol by about 18% . When combined with a statin, much more potent LDL lowering results. A recent prospective clinical trial o patients soon a ter experiencing an acute coronary syndrome showed that the combination o ezetimibe plus a statin was modestly superior to statin therapy alone at preventing subsequent cardiovascular events. Unlike bile acid–binding agents, side e ects rom ezetimibe therapy are rare. When combined with a statin, the incidence o transaminase elevation is only slightly greater than that o statin therapy alone. The addition o ezetimibe to a statin regimen does not appear to signif cantly increase the risk o statin-associated myopathy.
Niacin Niacin is one o the oldest lipid-regulating drugs and has avorable e ects on all the circulating lipid ractions. It is the most e ective currently approved agent or raising HDL cholesterol (by 15% to 35% ), and it reduces LDL cholesterol (by 5% to 25% ) and triglyceride levels (by 20% to 50% ). Furthermore, unlike most other lipid-lowering drugs, niacin reduces the circulating level o lipoprotein(a), an LDL-like lipoprotein that carries an independent risk o cardiovascular disease (see Chapter 5). Niacin modif es lipid levels through multiple mechanisms. It inhibits the release o atty acids rom adipose tissue. As a result, ewer atty acids are transported to the liver and hepatic triglyceride synthesis declines. Impaired triglyceride production by the liver reduces VLDL secretion into the circulation; consequently, less LDL is ormed (see Fig. 17-20). Niacin also enhances the clearance o triglycerides rom circulating VLDL by promoting the
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activity o lipoprotein lipase at adipose and muscle cells. The net e ect o these actions is a reduction in serum triglyceride and LDL levels. Niacin is thought to raise circulating HDL cholesterol levels by decreasing the hepatic uptake o its apoprotein, apo AI, thus reducing clearance o HDL particles rom the circulation. This mechanism does not disturb hepatic retrieval (and disposal) o cholesterol rom the HDL particles. In the 1970s, prior to the introduction o statins, a study o men with prior myocardial in arction showed that niacin reduced the risk o uture cardiac events, and lowered the mortality rate, in long-term ollow-up. However, more recent large clinical trials have demonstrated no signi cant bene t o niacin on cardiovascular outcomes when the drug is added to patients whose LDL levels are already well controlled on statin therapy. There ore, the use o niacin is in decline. Niacin has several common side e ects. Transient cutaneous f ushing episodes occur in most patients. These episodes are prostaglandin mediated and can be minimized by taking aspirin prior to the daily niacin dose. Gastrointestinal side e ects include nausea and exacerbation o peptic ulcer disease. Hepatotoxicity can occur, mani ested by atigue, weakness, and elevated serum transaminases (ALT, AST). Niacin should be used cautiously in diabetic patients because it can contribute to insulin resistance and hyperglycemia. It also raises serum uric acid levels and can precipitate gout in susceptible patients. Rare cases o myopathy have been reported with niacin; the incidence is increased when niacin is prescribed concurrently with a statin.
Fibrates The bric acid derivatives (“ brates”) gemf brozil and enof brate are used primarily to treat marked hypertriglyceridemia. They are the most power ul available agents to reduce serum triglyceride levels (by up to 50% ), and they raise HDL cholesterol levels (by up to 20% ). However, their e ect on LDL cholesterol is more variable and less bene cial than other lipidaltering drugs (see Table 17-18). A large study o men with hypercholesterolemia, but no known coronary disease, showed that gem brozil reduced the number o subsequent myocardial in arctions, without lowering the total death rate. In another study o men with CAD, normal LDL levels, and low HDL levels, the rate o coronary events on gem brozil declined, but again, total mortality was not a ected. In a 5-year study o patients with type 2 diabetes, eno brate reduced the incidence o non atal myocardial in arction but not total cardiovascular mortality. Fibrates are thought to exert their antilipid e ects through interactions with peroxisome proli erator–activated receptor-α (PPAR-α), a nuclear transcription actor. Activation o PPAR-α leads to a decrease in triglycerides, at least in part by augmenting atty acid oxidation and increasing the synthesis o lipoprotein lipase (see Fig. 17-20). The latter results in increased VLDL catabolism, which may actually ra ise the circulating LDL level, especially in patients with baseline hypertriglyceridemia. Fibrates are believed to augment HDL cholesterol levels via PPAR-α activation o the gene or apoprotein AI, a key constituent o HDL particles. Fibrates are primarily used to lower elevated triglyceride levels. They are metabolized by hepatic glucuronidation with subsequent renal excretion. Thus, they should be avoided or prescribed at lower dosages or patients with impaired liver or kidney unction. Fibrates are generally well tolerated. Potential side e ects include dyspepsia, gallstones, and myalgias. When used in combination with a statin, the risk o rhabdomyolysis is increased. There ore, i these drugs are prescribed concurrently, it is recommended that the serum creatine kinase (a marker o muscle inf ammation or necrosis) be monitored routinely. Fibrates augment the e ect o war arin by displacing it rom albumin-binding sites, possibly necessitating a decrease in the anticoagulant dosage. They also enhance the potency o oral hypoglycemic drugs.
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Chapter 17
SUMMARY • Inotropic drugs increase the orce o ventricular contraction when myocardial systolic unction is impaired and include the cardiac glycosides (digitalis), sympathomimetic amines, and phosphodiesterase-3 inhibitors. • Vasodilator therapy (e.g., ACE inhibitors, angiotensin receptor blockers, nitrates, hydralazine) or heart ailure is directed at modulating the excessive constriction o veins and arterioles that occurs during physiologic compensation or the all in CO, thus reducing pulmonary congestion and augmenting orward CO; in hypertension, vasodilator therapy decreases arteriolar resistance and lowers blood pressure. • Antiadrenergic drugs inter ere with the sympathetic nervous system. • Centrally acting antiadrenergic agents (e.g., methyldopa) stimulate CNS α2-adrenergic receptors and thereby reduce systemic sympathetic outf ow, peripheral vascular resistance, and cardiac stimulation, resulting in a all in blood pressure and heart rate. • Peripheral α-antagonists are divided into those that act on both α1- and α2-receptors (e.g., phentolamine and phenoxybenzamine) and those that inhibit α1 alone (e.g., prazosin, terazosin, doxazosin), the latter resulting in reduced norepinephrine release and blunted ref ex sympathetic side e ects. • β-Blockers are distinguished by their speci c properties: (1) the relative a nity o the drug or β1- and β2-receptors, (2) whether partial β-agonist activity is present, (3) whether the drug also has vasodilator properties, and (4) di erences in pharmacokinetic properties. • Antiarrhythmic drugs can be grouped according to their primary electrophysiologic mechanisms o action: (1) Class I drugs primarily block the ast sodium channel responsible or phase 0 depolarization o the action potential in cardiac muscle cells and Purkinje bers (and are urther subdivided into classes IA, e.g., quinidine; IB, e.g., lidocaine; and IC, e.g., f ecainide); (2) class II drugs are β-adrenergic receptor antagonists (β-blockers); (3) class III drugs (e.g., amiodarone) predominantly block potassium channels responsible or repolarization, thereby prolonging the action potential with little e ect on the rise o phase 0 depolarization; and (4) class IV drugs (e.g., verapamil and diltiazem) block the L-type calcium channel. • Diuretics (e.g., loop, thiazide, and potassium-sparing diuretics), which eliminate excess sodium and water through renal excretion, are a cornerstone o therapy or hypertension and heart ailure. • Antithrombotic drugs inhibit platelet unction (e.g., aspirin, thienopyridines, ticagrelor, GP IIb/ IIIa receptor inhibitors, dipyridamole) or inhibit the coagulation cascade (e.g., UFH, low molecular weight heparin, direct thrombin inhibitors, actor Xa inhibitors, war arin), thereby modulating key pathways in the pathogenesis o acute coronary syndromes, DVT, and thrombi that may complicate atrial brillation, dilated cardiomyopathy, or mechanical prosthetic heart valves. • Lipid-regulating drugs include HMG-CoA reductase inhibitors (the “statins,” e.g., atorvastatin, rosuvastatin, simvastatin); bile acid–binding agents (e.g., cholestyramine and colestipol); cholesterol absorption inhibitors (e.g., ezetimibe); niacin; and bric acid derivatives (e.g., gem brozil and eno brate). • O the lipid-altering agents, statins are the most e ective to lower LDL cholesterol and reduce coronary events.
Ack n ow le d gm en t s Contributors to previous editions o this chapter were Christopher A. Miller, MD; Cyrus K. Yamin MD; Martin W. Schoen, MD; Mark Friedberg, MD; Chiadi E. Ndumele, MD; Steven N. Kalkanis, MD; David Sloane, MD; Andrew C. Hecht, MD; Steven P. Leon, MD; and Ralph A. Kelly, MD.
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Ad d i t i o n a l Rea d i n g Antman EM, Sabatine MS. Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease. 4th ed. Philadelphia, PA: Elsevier Saunders; 2013. Barrese V, Taglialatela M. New advances in beta-blocker therapy in heart ailure. Fron t Physiol. 2013;4:323. Bruton LL, Chabner BA, Knollmann BC. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill; 2011. DeBacker D, Biston P, Devriendt J, et al. Comparison o dopamine and norepinephrine in the treatment o shock. N Engl J Med. 2010;362:779–789. Ernst ME, Moser M. Use o diuretics in patients with hypertension. N Engl J Med. 2009;361:2153–2164. Kalantzi KI, Tsoumani ME, Goudevenos IA, et al. Pharmacodynamic properties o antiplatelet agents. Expert Rev Clin Pharmacol. 2012;5:319–336. Layland J, Carrick D, Lee M, et al. Adenosine: physiology, pharmacology, and clinical applications. J Am Coll Cardiol Intv. 2014;7:581–591.
Maron BA, Leopold JA. Aldosterone receptor antagonists: e ective but o ten orgotten. Circulation. 2010;121: 934–939. Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention o atherothrombotic events. N Engl J Med. 2012;366:1404–1413. Opie LH, Gersh BJ, eds. Drugs for the Heart. 8th ed. Philadelphia, PA: Elsevier Saunders; 2013. Rubin LJ. Endothelin receptor antagonists or the treatment o pulmonary artery hypertension. Life Sci. 2012;91: 517–521. Ru CT, Giugliano RP, Braunwald E, et al. Comparison o the e f cacy and sa ety o the new oral anticoagulants with war arin in patients with atrial f brillation: a meta-analysis o randomized trials. Lancet. 2014;383: 955–962. Wong J. Is there a benef t in dual renin-angiotensin-aldosterone system blockage? No, yes and maybe: a guide or the perplexed. Diab Vasc Dis Res. 2013;10(3):193–201.
Index Note: Page numbers ollowed by t indicate tables; those ollowed by b indicate boxes; page numbers in italics re er to igures.
A ABCA1 gene, 119b ABCG1 gene, 119b Abciximab, 444 Abdominal aorta, 351 Abdominal aortic aneurysm, 325 Aberrant conduction, 294 Abnormal automaticity, 275 Accelerated-malignant hypertension, 327 Accessory pathway, 279–280, 280. See also Bypass tract concealed, 300 impulse conduction and, 298 ACE inhibitors, Angiotensin–converting enzyme (ACE) inhibitors Acetylcholine (ACh), 137b Acoustic shadowing, 50 Actin, 22 Action potential cardiac conduction system, 17–18 cardiac muscle cell, 17–18 digitalis e ect, 404 early a terdepolarizations-triggered, 275 pacemaker cells, 18–19 re ractory periods, 19–20 specialized conduction system, 18 spontaneous, 275 triggered activity, 275–276 Acute arterial occlusion, 361–362, 361t Acute bacterial endocarditis (ABE), 212 Acute cholecystitis, 175t Acute coronary syndromes (ACS) acute myocardial in arction (See Acute myocardial in arction (AMI)) angina pectoris (See Angina pectoris) clinical eatures o , 173–177 clotting actors inactivation, 163–164, 164 cocaine abuse and, 167 complications o arrhythmias, 185–186 conduction blocks, 186 recurrent ischemia, 184, 185 supraventricular arrhythmias, 186 ventricular f brillation, 186 diagnosis o creatine kinase levels, 177 ECG, 175, 176, 176 echocardiography, 177 troponins levels, 176, 177 endogenous platelet inhibition, 164 ibrin clots lysis, 164 hemostasis, 163 ischemic heart disease (See Ischemic heart disease) myocardial dys unction, 186–187 myocardial in arction (See Myocardial in arction) pathogenesis o , 162–168 pathology and pathophysiology contractility and compliance, 172 description o , 168 early changes, 169, 169t, 170, 170, 171 unctional alterations, 172–173 ischemic preconditioning, 172 late changes, 170, 171 ventricular remodeling, 172–173
456
right ventricular in arction, 187 thrombosis (See Thrombosis) treatment o adjunctive therapy, 183–184 anti-ischemic therapy, 178 anticoagulant drugs, 180–181 antiplatelet drugs, 180 antithrombotic therapy, 179–181 descriptions o , 178 f brinolytic therapy, 183 initial management strategies in, 179 primary percutaneous coronary intervention, 182–183 ST-elevation myocardial in arction, 182–183 Acute intramural hematoma, 353 Acute myocardial in arction (AMI) arrhythmias in, 185t causes o , 168t clinical presentation o , 173–174, 174t nonatherosclerotic causes o , 167–168 with pericarditis, 336 Acute non–ST-segment elevation MI, 99–101 Acute pulmonary edema, 246–247 Acute rheumatic ever (ARF), 193b Adenosine, 434, 434–435 Adenosine diphosphate, 136, 166 Adenosine triphosphate, 136, 169 Adrenergic nervous system, 232–233 Adrenocortical hormone excess, 321–322 Adventitia, 112 A terdepolarization, 275–276 A terload, 224 alterations in, 226–227, 227 de inition, 222, 223t e ect o , 227 Agatston score, 66 Aggregation o platelets, 157 Akinetic, o wall motion abnormalities, 172 Alcohol intake, hypertension management, 328 Alcoholic cardiomyopathy, 251 Aldosterone antagonist therapy or acute MI, 184 therapy or heart ailure, 244 α2-adrenergic agonists, or hypertension, 330 Altered automaticity, 273–275 Ambrisentan, 419 Amiloride, 436t, 439 Amiodarone, 254, 424t, 431 Amyloidosis, as cause or restrictive cardiomyopathy, 262 Aneurysms, aortic. See Aortic aneurysms Angina pectoris, 205. See also Stable angina; Unstable angina de inition, 135t ixed-threshold, 145 with hypertrophic cardiomyopathy, 259 medical treatment, 154 Prinzmetal, 145
stable (See Stable angina) unstable (See Unstable angina) variable-threshold, 145 variant, 145–146 Anginal equivalents, 147 Angioblastic cords, 374, 374 Angiogram, 60 Angiography contrast, 60–62, 61, 62 coronary, 152, 152–153 magnetic resonance, 69 Angiotensin-converting enzyme (ACE), 233 Angiotensin-converting enzyme (ACE) inhibitors or acute cardiac events, 157 in adjunctive therapy or MI, 183 description o , 408 or hypertension, 331 indication heart ailure, 410 hypertension, 409 renal blood low e ects, 409 renin–angiotensin system interactions, 410 side e ect o , 410 sites o action, 408 vasodilators in heart ailure, 242 Angiotensin II (AII), 233, 318, 318, 411–412 Angiotensin II receptor blocker (ARB), 242 characteristics o , 411 or hypertension, 331 indications, 411–412 renin–angiotensin system interactions, 410t types, 410t Ankle–brachial index (ABI), 359, 360b Anterior intervention groove, 8 Anti-ischemic therapy, or acute coronary syndromes, 178 Antiadrenergic drugs β-blockers (See β-Blockers) central adrenergic inhibitors, 421 description o , 419, 420 indications, 419 peripheral α-adrenergic receptor antagonists, 421–422, 421t sympathetic nerve-ending antagonists, 421 Antiarrhythmic drugs, 261 class IA clinical uses, 427, 427t disopyramide, 428 electrocardiogram e ects, 426, 426t electrophysiologic e ects o , 426 mechanism o action, 425–426 procainamide, 427, 428 quinidine, 427 types, 424t class IB clinical uses, 429 electrophysiologic e ects o , 426 lidocaine, 429 mechanism o action, 428–429, 428b mexiletine, 429 types, 424t
Index 457 class IC clinical uses, 429–430 electrophysiologic e ects o , 426 f ecainide, 430 mechanism o action, 429 propa enone, 430 types, 424t class II clinical uses, 431 description o , 430 mechanism o action, 430, 430–431 types, 424t class III amiodarone, 431–432 do etilide, 433 dronedarone, 432 electrophysiologic e ects o , 431 ibutilide, 433 mechanism o action, 431, 431 sotalol, 433 types, 424t class IV clinical uses, 434 diltiazem, 433 electrophysiologic e ects o , 433 mechanism o action, 433 types, 424t verapamil, 433 description o , 424 goal o , 425 mechanisms o action, 424 reentrant rhythms inhibited by, 425 triggered activity treated using, 425 Antiarrhythmic therapy or bradyarrhythmias electronic pacemakers, 282–283 pharmacologic therapy, 282 or tachyarrhythmias catheter ablation, 285 de brillation, 284 electric cardioversion, 284 implantable cardioverter– de brillators, 285 pharmacologic therapy, 283–284 vagotonic maneuvers, 284 Anticholinergic drugs, or bradyarrhythmias, 282 Anticoagulants acute coronary syndromes, 180–181 description, 445 direct thrombin inhibitors, 446–447 heparin (See Heparin) ST-elevation myocardial in arction treatment, 182 war arin, 447, 447–448, 448t Antidiuretic hormone, 234 Antidromic AVRT, 301 Antihypertensive therapy, 129–130, 438 Antiplatelet drugs acute coronary syndromes, 180 aspirin clinical uses, 441–443, 442t description o , 441 side e ects o , 443 glycoprotein IIb/ IIIa receptor antagonists, 444–445 thienopyridines, 443–444 ticagrelor, 444 Antiplatelet therapy, or acute cardiac events, 157 Antitachycardia pacing, 284 Antithrombin, 163
Antithrombotic drugs anticoagulants (See Anticoagulants) description o , 439 platelet inhibitors (See Antiplatelet drugs) Antithrombotic properties, loss o , 142 Antithrombotic therapy, or acute coronary syndromes, 179–181 Aorta. See also Coarctation o the aorta anatomy, 351 aortic aneurysms clinical presentation, 353 conditions associated with, 352t CTA o , 353 diagnosis, 353–354 etiology, 352 pathogenesis, 352–353 treatment, 354 aortic dissection classi cation, 355 clinical presentation, 355 complications o , 356t diagnosis, 355–356 etiology, 355 pathogenesis, 355 treatment, 356–357 coarctation o , secondary hypertension, 320 and peripheral vasculature, 325 Aortic arch, 351 Aortic closure sound (A2), 33–34 Aortic dissection CT, 67 Aortic ejection click, 33 Aortic insu iciency. See Aortic regurgitation Aortic regurgitation acute, 208 assessment o , 209 charactestics o , 218t chronic, 208 clinical mani estations o , 209, 209t early diastolic murmurs, 38 etiology o , 207 pathophysiology o , 208, 208–209, 209 radiographic indings, 209 severity o , 209 treatment o , 209, 210 Aortic rupture, 353 Aortic stenosis cardiac catheterization, 207 causes o , 217 charactestics o , 218t clinical mani esdation o , 388 clinical mani estations o , 206–207 electrocardiogram indings, 207 etiology o , 204 evaluation o , 206–207 hemodynamic pro ile o , 205 laboratory studies, 390 pathology o , 204–205 pathophysiology o , 205, 205–206, 206t, 389, 389 physical examination, 389 severity a ects heart sounds, 38 symptoms o , 389 systolic ejection murmur o , 37, 37 treatment o , 207, 390 Aortic valve anatomy o , 5 aortic valve replacement with severe aortic stenosis, 207 development o , 378 Apoproteins, 118 Apoptosis in heart ailure, 235 Argatroban, 447
Arrhythmias. See also Bradycardias; Impulse; Tachycardias acute coronary syndromes, 185–186 atrial ibrilation (See Atrial ibrilation) development, mechanisms o , 281t genetic causes o , 304b–305b heart ailure secondary to, 244–245 myocardial in arction, 185 supraventricular, 186 treatment, 254–255 treatment or, 282–285 Arrhythmogenic right ventricular cardiomyopathy (ARVC), 265 Arterial wall anatomy o , 112–113, 113 atherosclerotic, 115–124 endothelial cells, 113–114, 114 extracellular matrix, 114 vascular smooth muscle cells, 114 Arteries, nitrate-induced dilation o , 417 Arteriolar vasodilators, 242 Arterioles anatomy o vascular supply, 141 constriction, 233 vasodilators, 242 Arteriovenous oxygen di erence, 59 Arti icial hearts, 245 Ascending aorta, 351 Ascending thoracic aortic aneurysms, 352 Ascho body, 193b Aspirin, 180, 182 or acute cardiac events, 157 clinical uses, 441–443, 442t description o , 441 side e ects o , 443 Asymmetric hypertrophy, 256 Atheroembolism, 362 Atherosclerosis arterial wall (See Arterial wall) clinical presentation, 358–359 complications o , 124–125, 125 diagnosis, 358–360 etiology, 357–358 pathogenesis, 357–358 pathological stages atty streaks, 115–120 plaque disruption, 121–124 plaque progression, 120–121 risk actors C-reactive protein (CRP), 131–132 diabetes mellitus, 130 dyslipidemia, 127–129 estrogen status, 130–131 genetics, 126 hypertension, 129–130 lipoprotein (a), 131 physical activity, lack o , 130 tobacco smoking, 129 treatment, 360–361 Atherosclerotic plaque calci ication, 124 developmental stages, 116 disruption plaque integrity, 121–122 thrombogenic potential, 122–124, 123 embolization, 124 evolution o , 115 hemorrhage, 124 plaque progression extracellular matrix metabolism, 121 smooth muscle cell migration, 120–121, 121
458
Index
Atherosclerotic plaque (Continued) rupture/ ulceration, 124 stable versus vulnerable, 123 Atherothrombotic CVAs, 324 Atorvastatin, 449, 449t Atria atrial ibrillation, 196, 259, 296, 296–297 def nition o , 296 mechanism o , 296 mitral stenosis, 196 treatment o , 261 atrial gallop, 34 digitalis e ects, 403 le t, 5, 6 right, 4–5, 5 septal de ect, 45, 46 septation o , 376, 376 Atrial lutter, 294–296, 295 Atrial natriuretic peptide (ANP), 234 Atrial premature beats, 294, 294 Atrial septal de ect incidence o , 382 laboratory studies, 384 ostium primum, 382 ostium secundum, 382, 383 pathophysiology o , 383–384 physical examination, 384 sinus venosus, 382 site o , 382 symptoms o , 384 treatment o , 384–385 Atrioventricular block, 77 Atrioventricular canal, 375, 375 Atrioventricular dissociation, 292 Atrioventricular nodal artery, 9 Atrioventricular nodal cells, 270 Atrioventricular nodal reentrant tachycardia, 298–300, 299 Atrioventricular (AV) node anatomy o , 7 Atrioventricular node, digitalis e ects, 402, 403t Atrioventricular reentrant tachycardias, 300, 402 Atrioventricular valve development, 379 Atrioventricular (AV) valves, anatomy o , 2 Austin Flint murmur, 209 Automaticity abnormal, 275 altered escape rhythms, 274 latent pacemakers, 274–275 in sinus node, 273–274 arrhythmias caused by increases in, 426 de inition, 269 ionic basis o , 269–270 triggered activity, 275–276 aVF lead, 77, 82 aVL lead, 77, 82 aVR lead, 77
B Bacterial endocarditis, 212 Bacterial pericarditis, 335–336 Barlow syndrome, 203 Baroreceptor re lex, 313 Bernoulli equation, 52 β-adrenergic agonists, 243 β-adrenergic stimulation, 24–25 β-blockers, 422–424 in acute coronary syndromes, 182 or anginal attacks, 154, 155t characteristics o , 422 description o , 422 in heart ailure, 244 or hypertension, 330
or hypertrophic cardiomyopathy, 260 indication heart ailure, 423 hypertension, 423 ischemic heart disease, 423 side e ects, 424 tixicity o , 424 types, 422t vasospasm precipitated by, 423 β1-antagonists, or hypertension, 330 β1-receptor agonists, bradyarrhythmias, 282 Bigeminy, 303 Bile acid–binding agents, 448t, 451–452 Biliary colic, diagnosis o , 148t Bis eriens pulse, 209t Bisoprolol, 244 Bivalirudin, 181, 182, 447 Blood low measurement, cardiac catheterization, 59–60 Blood, oxygen-carrying capacity o , 379–381 Blood pool imaging. See Radionuclide ventriculography Blood pressure Ankle-brachial index (ABI), 359, 360b diastolic, 130 elevated (See Hypertension) re lexes, 312 regulation, 312–313 systolic, 344 Blood vessel tone, 311 Blood vessels BP regulation in, 314 coronary artery low in, 136 unctions, 315 Bosentan, 419 Bradyarrhythmias atrioventricular conduction system f rst-degree AV block, 290, 290–291 second-degree AV block, 291, 291–292 third-degree AV block, 292, 292 escape rhythms, 289, 289–290 impulse ormation and conduction, 281t sinoatrial node sick sinus syndrome, 288–289, 289 sinus bradycardia, 287–288, 288 treatment or electronic pacemakers, 282–283 pharmacologic therapy, 282 Bradycardia–tachycardia syndrome, 289 Bronchospasm, 152 Brugada syndrome, 304b–305b Buerger disease, 363 Bulbus cordis, 375 Bumetanide, 436t, 437 Bundle branch, 7 Bundle branch blocks indings, by ECG, 91–96 Bundle o His, 7 Bundle o Kent, 280 Bypass tract, 279–280, 280
C C-reactive protein (CRP), risk or atherosclerosis, 131–132 Cachexia, 238 Calcium channel, 415 Calcium channel antagonists, or hypertrophic cardiomyopathy, 260 Calcium channel blockers. See also Antiarrhythmic drugs, class IV or anginal attacks, 155t, 156
cardiac cells e ects, 415 clinical uses, 416, 417, 417t description o , 414 diltiazem, 415 or hypertension, 330 indication, 414–415, 415t mechanism o action, 414–415 ni edipine, 415 side e ects o , 416 sites o action, 408 types o , 415t verapamil, 415 Calcium-induced calcium release (CICR), 22–24 Calcium, intracellular, 404 Carbonic anhydrase inhibitors, 436 Carcinoid syndrome, 210 Cardiac asthma, 239 Cardiac catheterization blood low measurement, 59–60 contrast angiography, 60–62 dilated cardiomyopathy, 253 indications aortic stenosis, 390 atrial septal de ect, 374 tetralogy o Fallot, 396 ventricular septal de ect, 386 pressure measurement pulmonary artery, 58–59 right atrial, 57 right ventricular, 57 vascular resistance calculation, 60 Cardiac conduction pathway, 80, 81 Cardiac conduction system action potential, 17–18 blood supply o , 186t components o , 7 conduction pathway, 80, 81 impulse conduction, 20 ion movement and channels energetic avorability, 12–13 permeability, 13–15 normal sequence o depolarization, 20–21 pacemaker cells, 18–19 re ractory periods, 19–20 resting potential, 15–16 specialized conduction system, 18 Cardiac cycle. See also Heart murmurs; Heart sounds jugular venous pulsations, 28b–29b pressure relationships, 26–28, 27 a wave, 26 Cardiac unction determinants pressure–volume loops, 225, 225–228, 227 stroke volume (See Stroke volume) Cardiac imaging. See specific types Cardiac index, 60 Cardiac jelly, 374 Cardiac MRI (CMR), 68–69, 69 Cardiac muscle cell action potential, 17–18 electrical excitation, 12 permeability, 13–15 resting potential, 15–16 transmembrane potential, 12–13 Cardiac output (CO) calculation o , 222 de inition o , 223t heart ailure e ects, 230, 410 mediators o , 223 Cardiac resynchronization therapy (CRT), 245, 255
Index 459 Cardiac rhythm, 102 Cardiac signaling systems β-adrenergic stimulation, 24, 24–25 cholinergic signaling, 24, 25 Cardiac silhouette, 44–45 Cardiac skeleton, 2 Cardiac tamponade clinical eatures, 343–344 diagnostic studies, 344 etiology, 342 pathophysiology, 342–343 treatment, 344–345 Cardiac transplantation, 245, 255 Cardiac vessels coronary arteries, 8–10, 9 coronary veins, 10 lymphatic vessels, 10 Cardiogenic shock, in myocardial dys unction, 187 Cardiomegaly, 240 Cardiomyopathy, 54 anatomic appearance o , 250 arrhythmogenic right ventricular cardiomyopathy, 265 dilated (See Dilated cardiomyopathy (DCM)) echocardiography, 54 hypertrophic (See Hypertrophic cardiomyopathy (HCM)) le t ventricular noncompaction, 264–265 restrictive (See Restrictive cardiomyopathy) Cardiothoracic ratio, 44 Cardiovascular system development description o , 374 heart loop, 374–375, 375 heart tube, 374, 374 septation, 375 Cardioversion, 284 Carotid sinus massage, 284 Carvedilol, 244 Catecholaminergic polymorphic ventricular arrhythmias, amilial, 305b Catecholamines, 24 Catheter ablation o AV node, 297 or tachyarrhythmias, 285 Central adrenergic inhibitors, 421 Cephalization o vessels, 45 Cerebral ischemic, 51 Cerebrovascular accidents (CVAs), 324 Cerebrovascular system, damage caused by hypertension, 324–325 Cervical radiculitis, diagnosis o , 148t CHARGE syndrome, 395b Chemokines, 117 Chest leads, 80, 80, 84 Chest pain, causes o , 148t. See also Angina pectoris Chest radiograph. See Radiography Cheyne–Stokes respiration, 238 Chlorothiazide, 436t, 438 Chlorthalidone, 436t, 438 Cholesterol absorption inhibitors, 452 homeostasis, 119b Cholestyramine, 449t, 451–452 Cholinergic signaling, 25 Chordae tendineae, 4, 5 Chronic venous insu iciency, 366 Cine/ angiogram, 60 Circulation etal, 379–381, 380 transitional, 381–382 Circum lex artery, 8
Claudication, 358 Clopidogrel, 180, 443 Coarctation o the aorta incidence o , 392 laboratory studies, 393 pathophysiology o , 392, 392 physical examination, 392–393 postductal, 392 preductal, 392 symptoms o , 392 treatment o , 393 Colesevelam, 449t, 451–452 Colestipol, 449t, 451–452 Compensatory vasodilatation, 141 Compliance, 223t Computed tomography (CT) o aortic dissection, 67 coronary angiography, 68 EBCT, 66 multidetector row CT, 66 spiral/ helical, 66, 67 Concealed accessory pathways, 302 Concentric hypertrophy, 235, 324 Conduction blocks, 186 Conduction system action potential, 17–18 blood supply o , 186t components o , 7 conduction pathway, 80, 81 impulse conduction, 20 ion movement and channels energetic avorability, 12–13 permeability, 13–15 normal sequence o depolarization, 20–21 pacemaker cells, 18–19 re ractory periods, 19–20 resting potential, 15–16 specialized conduction system, 18 Congenital heart disease acyanotic, 382 aortic atenosis (See Aortic atenosis) atrial septal de ect (See Atrial septal de ect) circulations, 379–382 classi ication o , 382 coarctation o the aorta (See Coarctation o the aorta) cyanotic, 393–398 in DiGeorge syndrome, 395b in Down syndrome, 394b Eisenmenger syndrome, 382, 398 genetic abnormalities in, 394b–395b heart development aorticopulmonary septum, 378 atrial septation, 376, 376 atrioventricular canal sepdation, 376, 377, 377 heart loop ormation, 374–375, 375 heart tube, 374, 374 septation, 375 valves, 378 ventricular outf ow tracts sepdation, 377, 378, 378 ventricular sepdation, 377, 378, 378 in Holt–Oram syndrome, 395b incidence o , 373 patent oramen ovale, 376 pulmonic stenosis (See Pulmonic stenosis) survival rates, 373 tetralogy o Fallot, 393–394, 394 transitional circulation, 381–382 transposition o the great arteries, 396, 396–398 in Turner syndrome, 394b
ventricular septal de ect (See Ventricular septal de ect) in Williams syndrome, 394b Congenital long QT syndromes, 305b Conn syndrome, 321 Connectin. See Titin Constrictive pericarditis clinical eatures, 346–347 diagnostic studies, 347–348 etiology, 346 pathogenesis, 346 pathology, 346 pathophysiology, 346 symptoms and signs, 346–347 treatment, 349 Continuity equation, 53, 53 Continuous murmurs, 39–40 Contractile cycle, 22–24 Contractility, 222, 224–225 alterations in, 227–228 de inition, 223t e ect o , 227 Contractility, myocardial, 140 Contraction bands, 170 Contrast angiography, 60–62, 61, 62 Contrast echocardiography, 51–52 Contrast-enhanced MRI, 69, 70 Coronary angiography, 152, 152–153 with CT, 68 stable angina diagnosis, 152–153 Coronary arteries, 8–10 anatomy o , 9 angiography, 61 Coronary artery bypass gra t (CABG) surgery, 159, 159 Coronary artery calci ication, 153 Coronary artery disease, 324 cardiac catheterization, 62t echocardiography, 53 and hypertension, 324 statins or, 451 Coronary blood low, 136 Coronary magnetic resonance angiography (coronary MRA), 69 Coronary MRA, 69 Coronary stents, during percutaneous coronary intervention, 158, 158 Coronary vascular resistance, 136 endothelial actors, 137–139 metabolic actors, 136–137 neural actors, 139 Coronary veins, 10 Corrected QT interval, 86 Corrigan pulse, 209t Costochondral syndrome, diagnosis o , 148t Couplets, 303 Creatine kinase, 177 CT angiography, 153 Cushing syndrome, 322 Cyclooxygenase, 441 CYP2C19, 180 Cystic medial degeneration, 352 Cytochrome P450, 451 Cytokines, 174 Cytosol, 24
D 3D echocardiography, 51 Deep venous thrombosis clinical presentation, 368 diagnosis, 368 epidemiology, 366 etiology, 367 pathophysiology, 367–368 treatment, 368–369
460
Index
De ibrillation external, 284 or tachyarrhythmias, 284 Delayed a terdepolarizations, 276 Depolarization o cardiac cell, 74–75, 75 cardiac cells, 20–21 in rontal plane, 82 nonpacemaker cell, 272 in transverse (horizontal) plane, 84 Descending aorta, 351 Diabetes mellitus, risk or atherosclerosis, 130 Diastole, 26 Diastolic current theory, 99, 100 Diastolic dys unction, 324 unctional myocardial cells, 172 heart ailure in, 228, 228 Diastolic murmurs, 38–39 Diastolic rumble, 197 Diet or hypertension management, 328 lipoprotein reductions, 131 DiGeorge syndrome, 395b Digitalis, 243 action potential e ect, 404 atrioventricular node e ects, 402, 403t automaticity e ects, 404 clinical uses o , 402 contractility e ects, 401, 402 electrical e ects, 402, 403t hypokalemia e ects, 403 mechanical e ect, 401–402, 402 mechanism o action, 401–402 pharmacokinetics o , 402, 403–404 Purkinje cell e ects, 404 sodium levels a ected by, 402 toxicity, 402, 403–404 Digoxin, 401, 402, 407 Dilated cardiomyopathy (DCM) clinical indings, 253 diagnostic studies, 253–254 etiology, 250–251 examples o , 250t pathology, 252, 252 pathophysiology, 252, 252–253 physical examination, 253 treatment, 254–255 ventricular morphology, 266t Diltiazem, 156, 424t, 433 Dipyridamole, 445 Direct renin inhibitor, or hypertension, 331 Disopyramide, 424t, 428 Diuretics, 241, 241–242 description o , 435 or hypertension, 329 loop, 436t, 437 mechanism o action, 436 potassium-sparing, 436t, 438–439 thiazide, 436t, 437–438 types, 436t Dobutamine, 152, 405t, 406 Do etilide, 424t, 433 Dopamine, 405–406, 405t Doppler echocardiography, 49, 50, 209 Doppler tissue imaging, 52 Down syndrome, 394b Doxazosin, 421, 421t Dressler syndrome, 189 Dronedarone, 424t, 432 Drug-eluting stents, during percutaneous coronary intervention, 158 Drug-induced pericarditis, 337
Ductus arteriosus de inition o , 381 patent (See Patent ductus arteriosus) Ductus venosus, 379 Dys unctional endothelium, 166 Dyskinetic, o wall motion abnormalities, 172 Dyslipidemia, risk or atherosclerosis, 127–129 Dyspnea heart ailure, 236 with hypertrophic cardiomyopathy, 258 Dysrhythmias. See Arrhythmias
E Early a terdepolarizations, 275 Early diastolic murmurs, 38 Early diastolic sound (S3), 239 EBCT, 66 Eccentric hypertrophy, 235 ECG. See Electrocardiogram (ECG) Echocardiography acute coronary syndromes, 177 cardiac tamponade, 338 cardiomyopathy, 54 contrast echocardiography, 51–52 coronary artery disease, 53 3D echocardiography and intracardiac echocardiography, 51 dilated cardiomyopathy, 253 Doppler, 49 indications atrial septal de ect, 384 coarctation o the aorta, 393 patent ductus arteriosus, 388 pulmonic stenosis, 391 tetralogy o Fallot, 396 transposition o the great arteries, 397 ventricular septal de ect, 386 M-mode, 48 mitral regurgitation in, 202 in mitral stenosis, 197 mitral stenosis in, 197 pericardial disease, 54 pericarditis, 338 transesophageal, 50–51 two-dimensional (2D), 48–49 valvular lesions, 52–53, 53 ventricular assessment, 52, 52 Ectopic beat, 274 Ectopic pacemakers, 271 Ectopic rhythms, 274 digitalis e ects, 404 Edema acute pulmonary, 246–247 peripheral, 237, 263 Ehlers–Danlos type IV syndrome, 352 Eisenmenger syndrome, 382, 398 Ejection clicks, 33 Ejection raction, 52, 223t Ejection type systolic murmur, 36–37 Elastic laminae, 112 Electric cardioversion, or tachyarrhythmias, 284 Electrocardiogram (ECG) class IA antiarrhythmic e ects, 426, 426t dilated cardiomyopathy, 253 electrical measurement, single cardiac muscle cell, 74–76, 75, 76 electrode placement, 77 in endocarditis, 215 heart rate calculation, 86, 87 heart rhythm, 85
indications atrial septal de ect, 384 coarctation o the aorta, 393 congenital aortic stenosis, 390 Eisenmenger syndrome, 398 patent ductus arteriosus, 388 pulmonic stenosis, 391 transposition o the great arteries, 397 ventricular septal de ect, 386 lead re erence system aVF, 77, 82 aVL, 77, 82 aVR, 77 chest leads, 80, 80, 84 limb leads, 78, 78–80, 78t, 79 unipolar lead, 77 in mitral stenosis, 197 non–ST-segment elevation, 99–101 P wave abnormalities, 90–91, 91 def nition, 80–83 pericarditis, 338 PR interval, 85, 86, 88t QRS complex abnormalities o , 91–97 bundle branch blocks f ndings, 91–96 def nition, 80 mean QRS axis calculation, 86–90 myocardial in arction f ndings, 96–97 shapes, 81, 81 ventricular hypertrophy f ndings, 91–92, 92 QRS interval, 86, 88t QT interval, 85, 86, 88t sequence o cardiac activation, 80–83 ST-segment elevation, 97–99 stable angina, 149–150, 150 T wave abnormalities o , 97 def nition, 80 U wave, 80 voltage calibration o machine, 85 Electronic pacemakers, or bradyarrhythmias, 282–283 End-diastolic pressure, 223 End-diastolic volume, 223, 227, 231 End-systolic pressure–volume relation (ESPVR), 227 End-systolic volume, 226 Endocarditis acute, 214 antibiotic prophylaxis or, 217t cardiac examination o , 214 classi ication, 212–213 clinical mani estations, 214–215 clinical use, 212 criteria or diagnosis o , 216t electrocardiogram indings, 215 epidemiology o , 214 microbiology o , 214t pathogenesis, 213–214 peripheral stigmata o , 215 prevention o , 216 Staphylococcus epidermidis, 212 subacute, 214 systemic in lammatory response by, 215 treatment o , 216 Endocardium, 2 Endogenous (hepatic) pathway, 118b–119b
Index 461 Endothelial cell in arterial wall, 113–114, 114 dysfunction antithrombotic properties loss, 142, 143 fatty streaks, 116, 116–117 inappropriate vasoconstriction, 141–142 Endothelin 1, 139, 234 Endothelium-derived hyperpolarizing factor (EDHF), 138–139 Endothelium-derived NO, 137, 137b–138b Endothelium-derived relaxing factor (EDRF), 137b–138b Epicardium, 4 Epinephrine, 405t, 406 Eplerenone, 244 Eptifibatide, 444 Escape beat, 274 Escape rhythms, 274, 289, 289–290 Esmolol, 424t Esophageal spasm, diagnosis of, 148t Esophageal varices, 365 Essential hypertension epidemiology, 314 genetics, 313–314 insulin resistance, 315 metabolic syndrome, 315 natural history, 315–316 obesity, 315 systemic abnormalities, 314, 315 Estrogen status, risk for atherosclerosis, 130–131 Ethacrynic acid, 436t, 437 Everolimus, 158 Excitation–contraction coupling calcium-induced calcium release, 22–24 contractile proteins in myocyte, 21–22 Exercise for hypertension management, 327 lipoprotein reductions, 131 Exercise echocardiography, stable angina diagnosis, 151 Exogenous (intestinal) pathway, 118b External cardioversion, 284 External defibrillation, 284 Extra diastolic heart sounds, 33–35 Extra systolic heart sounds, 32–33 Extracellular matrix metabolism, 121 Ezetimibe, 452
F False aneurysm, 351 Familial catecholaminergic polymorphic VT, 305b Familial hypercholesterolemia, 127 Familial thoracic aortic aneurysms, 352 Fascicular blocks, 94, 95, 96 Fast sodium channel, 14–15, 14f Fast sodium ion channel, 14, 14, 19 Fatty streaks endothelial dysfunction, 116, 116–117 foam cell formation, 117, 120 leukocyte recruitment, 117 lipoprotein entry and modification, 117 Fenofibrate, 449t, 453 Fenoldopam, 412t, 414 Fetal circulation description of, 379–381 schematic diagram of, 380 transition of normal circulation, 381–382 Fibrates, 453 Fibrinoid necrosis, 325
Fibrinolytic therapy, 183. See also Thrombolytic therapy acute coronary syndromes, 183 Fick technique, 59 First-degree atrioventricular block, 290, 290–291 First heart sound (S1), 29, 29–30, 30t Fixed splitting of S2, 32 Fixed vessel narrowing anatomy of vascular supply, 141 fluid mechanics, 140–141 Flecainide, 424t, 430 Floppy mitral valve, 203 Fluid mechanics, 140–141 Fluoro-18 deoxyglucose ( 18FDG), 65 Fluvastatin, 449t, 451 Foam cell formation, 117, 120 Focal atrial tachycardia, 302–303 Fondaparinux, 181, 447 Foramen ovale definition of, 376 patent, 383 Fourth heart sound, 34 Fractional flow reserve (FFR), 152–153 Framingham heart study, 126 Frank–Starling mechanism, 252 Frank–Starling relationship, 222, 231, 231 Free fatty acids, 118b Friction rub, pericarditis, 338 Furosemide, 436t, 437 Fusiform aneurysm, 351
G G protein system (Gs), 24 Gadolinium-enhanced magnetic resonance imaging, 70 Gastroesophageal reflux, diagnosis of, 148t GATA4, 395b Gemfibrozil, 448t, 453 Genetic abnormalities arrhythmias and, 304b–305b in congenital heart disease, 394b–395b essential hypertension, 313–314 Giant cell arteritis, 362–363 Glucocorticoid-remediable aldosteronism (GRA), 321 Glucocorticoids, 321–322 Glycoprotein, 180 Glycoprotein IIb/ IIIa receptor antagonists, 444–445 Great vessels, transposition of, 396–398 Guanylate cyclase, 414 Guanylyl cyclase (G-cyclase), 137b
H Heart, 1–2, 2 arteries, 8–10, 9 BP regulation, 314 congenital disorders of (See Congenital heart disease) damage caused by hypertension, 323–324 impulse (See Impulse) impulse-conducting system, 7, 7–8 innervation of, 8 internal structure, 2, 4 interventricular septum, 5, 6, 7 ion movement and channels, 12 left atrium, 5, 6 left ventricle, 5, 6 lymphatic vessels, 10 right atrium, 4–5, 5 right ventricle, 4–5, 5 surface anatomy, 2, 3 veins, 10 ventricles (See Ventricles of heart)
Heart development aorticopulmonary septum, 378 atrial septation, 376, 376 atrioventricular canal sepdation, 376, 377, 377 heart loop formation, 374–375, 375 heart tube, 374, 374 septation, 375 valves, 378 ventricular outflow tracts sepdation, 377, 378, 378 ventricular sepdation, 377, 378, 378 Heart failure aortic stenosis in, 206 apoptosis, 235 cardiac function determinants pressure–volume loops, 225, 225–228, 227 stroke volume (See Stroke volume) cardiac output decreases caused by, 231, 232, 232 Cheyne–Stokes respiration associated with, 238 classification of, 238t clinical manifestations, 236–240 compensatory mechanisms adrenergic nervous system, 232–233 antidiuretic hormone, 233–234 description of, 231 Frank–Starling mechanism, 231, 231 natriuretic peptides, 234 neurohormonal alterations, 231, 232, 232–234 renin–angiotensin–aldosterone system, 233 ventricular hypertrophy and remodeling, 234–235 definition of, 220 description of, 220 laboratoty tests and findings, 239–240 left-sided acute pulmonary edema, 246–247 characteristics of, 238 mitral regurgitation associated with, 239 in myocardial dysfunction, 186 myocyte loss and cellular dysfunction, 235 New York Heart Association classification, 238t orthopnea associated with, 237 pathophysiology of description of, 228 diastolic dysfunction, 228, 228, 230 systolic dysfunction, 228, 228, 229, 229 physiology, 221–228 precipitating factors, 235–236, 236t prevalence of, 220 prognosis, 240 radiographs, 47 right-sided, 230, 230t signs and symptoms, 236–238, 237t, 238t sinus tachycardia findings, 239 stages of, 238t tachyarrhythmias effect, 235 treatment of, 240–241 aldosterone antagonist therapy, 244 arrhythmia management, 244–245 β-blockers, 244, 423 cardiac mechanical circulatory support, 245
462
Index
Heart ailure (Continued) cardiac resynchronization therapy, 245 digitalis, 402 diuretic drugs, 241, 241–242 positive inotropic drugs, 243 with preserved ejection raction, 245 replacement therapy, 245 vasodilators, 242–243 tricuspid regurgitation associated with, 239 vasoconstriction, 407 wall stress increases, 224 Heart loop, 374–375, 375 Heart murmurs causes, 35 continuous murmurs, 39–40 diastolic murmurs, 38–39 location, 36, 42 pitch, 35 shape, 36 systolic murmurs, 36–38 timing and intensity o , 35 Heart rate, 140 calculation o , 86, 87 Heart rhythm, 85 Heart sounds extra diastolic heart sounds, 33–35 extra systolic heart sounds, 32–33 irst heart sound (S1), 29, 29–30, 30t gallop, 34 myocardial in arction, 186 pericardial knock, 35 second heart sound (S2), 30–32, 31 Heart transplantation dilated cardiomyopathies, 255 heart ailure treated using, 245 Heart valves, embryonic development o , 374 Hemorrhagic CVAs, 324 Hemorrhagic pericarditis, 337 Hemorrhoids, 365 Hemostasis, in acute coronary syndromes, 163 Heparin low molecular weight, 446 un ractionated, 445–446 Heparin-induced thrombocytopenia, 446 Hepatic pathway, 118b–119b Hereditary amyloidosis, 262 Hibernating myocardium, 64, 144 High-grade AV block, 291–292 Hill sign, 209t HMG-CoA reductase, 119b HMG-CoA reductase inhibitors, 157. See also Statins description o , 449–450 mechanism o action, 450, 450 types, 449, 449t Holt–Oram syndrome, 395b Hydralazine, 243, 412–413, 412t or hypertension, 331 induced pericarditis, 337 Hydrochlorothiazide, 436t, 438 Hyperglycemia, 438 Hyperkalemia, 411 Hyperpolarization, pacemaker cell, 272, 272–273 Hypertension BP regulation by blood pressure ref exes, 313 hemodynamic actors, 312–313 consequences o , 322–326 description, 311 essential epidemiology, 314 genetics, 313–314
insulin resistance, 315 metabolic syndrome, 315 natural history, 315–316 obesity, 315 pulmonary, 418 systemic abnormalities, 314, 315 organ damage caused by aorta and peripheral vasculature, 325 cerebrovascular system, 324–325 heart, 323–324 kidney, 325 retina, 325–326 risk or atherosclerosis, 129–130 secondary adrenocortical hormone excess, 321–322 aorta, coarctation o , 320 clinical conditions, 317, 317t exogenous causes, 318–319 patient evaluation, 317–318 pheochromocytoma, 321 renal parenchymal disease, 319 renovascular hypertension, 319–320 thyroid hormone abnormalities, 322 signs and symptoms, 322 treatment o ACE inhibitors, 331 angiotensin II receptor blockers, 331 β2-adrenergic agonists, 330 β1-antagonists, 330 β-blockers, 330 calcium channel blockers, 330 diet, 328 direct renin inhibitor, 331 diuretics, 329 exercise, 327 hydralazine, 331 minoxidil, 331 nonpharmacologic, 327–329 relaxation therapy, 328–329 smoking cessation, 328 thiazides, 329 vasodilators, 330 weight reduction, 327 Hypertensive crisis, 326–327 Hypertensive encephalopathy, 326 Hypertensive retinopathy, 325 Hypertrophic cardiomyopathy (HCM) clinical indings, 258–259 diagnostic studies, 260 etiology, 255 LVOT obstruction in, 52 pathology, 256, 256 pathophysiology, 256–258, 257, 258 physical examination, 259–260, 259t prognosis, 261–262 treatment, 260–261 ventricular morphology, 266t Hyperuricemia, 438 Hypokalemia, 403, 438 Hypokinetic, o wall motion abnormalities, 172 Hypomagnesemia, 437 Hyponatremia, 438 Hypotension, 410–411
I Ibutilide, 433 Idiopathic pericarditis, 335 Idiopathic VT, 306
Implantable cardioverter-de ibrillator (ICD), 245, 254, 285 Impulse conduction accessory pathways, 279 altered, 276–279 permanent, 276 reentry, 277–280 unidirectional, 278 ormation automaticity, 269–270, 275–276 electrotonic interactions, 272–273 escape rhythms, 274 overdrive suppression, 271–272 pacemakers, native and latent, 270–271, 275–276 sinus node automaticity, 273–274 triggered activity, 275–276 Indapamide, 436t, 438 In ectious pericarditis, 335–336 In ective endocarditis (IE). See Endocarditis In erior vena cava, 379, 380, 381 Inotropic drugs, 243 digitalis (See Digitalis) hemodynamic e ect, 401, 401 mechanism o action, 401–402 phosphodiesterase-3 inhibitors, 407, 407t sympathomimetic amines (See Sympathomimetic amines) Inotropic state, 139. See also Contractility Insulin resistance, 315 Insulin resistance syndrome. See Metabolic syndrome Intercalated disk, 11 Intermediate-density lipoproteins (IDL), 119b Internal mammary artery (IMA) gra ts, 159 Intestinal pathway, 118b Intima, 112 Intra-aortic balloon pump, 187 Intracardiac echocardiography, 51 Intracardiac pressure tracings, 56b–57b Intravenous nitroglycerin, 418 Ion channels energetic avorability, 12–13 ast sodium channel, 14–15, 14 permeability, 13–15 Ischemic heart disease. See also Angina pectoris causes o , 142, 148t clinical presentation, 134 consequences o , 143–146 de inition, 135t myocardial oxygen demand, 139–140 myocardial oxygen supply endothelial actors, 137–139 external compression, 136 metabolic actors, 136–137 neural actors, 139 pathophysiology o endothelial cell dys unction, 141–142 xed vessel narrowing, 140–141 myocardial ischemia, causes, 142 treatment acute cardiac events, 157 or acute episode o angina, 154 medical versus revascularization therapy, 159–160 pharmacologic agents, 155t recurrent ischemic episodes, 154–156 revascularization therapy, 157–159
Index 463 Ischemic preconditioning, myocardial in arction, 172 Ischemic syndromes, 143–146 Isoelectric complex, 90 Isometric contraction, 222 Isoproterenol, 405t, 406 Isosorbide dinitrate, 243, 417 Isosorbide mononitrate, 415, 417 Isotonic contraction, 222 Isovolumetric contraction, 226
J Janeway lesions, 215 Jones criteria, 193b Jones criteria or rheumatic ever, 193b Jugular venous pulsations/ pressure, 28b–29b Junctional escape rhythm, 289
K Kerley B lines, 45, 239 Kidney BP regulation in, 314 damage caused by hypertension, 325 tubules o , 435, 435 Krüppel-like actor 2 (KLF2), 116 Kussmaul sign, 263
L Lactate dehydrogenase, 345 Lacunae, 324 Late diastolic sound (S4), 239 Late systolic murmur, 38 Latent pacemakers, 271 altered automaticity, 274–275 Lead re erence system aVF, 77, 82 aVL, 77, 82 aVR, 77 chest leads, 80, 80, 84 limb leads, 78, 78–80, 78t, 79 unipolar lead, 77 Lecithin cholesterol acyltrans erase (LCAT), 119b Le t anterior descending (LAD) coronary artery, 8 Le t anterior ascicular block (LAFB), 94 Le t atrial appendage (LAA) ligation or occlusion, 297 Le t atrial pressure elevation o , 195 in mitral stenosis, 194 Le t atrium, 5, 6 Le t axis deviation, 86 Le t bundle branch, 7–8 Le t bundle branch block (LBBB), 32, 94 Le t dominant coronary circulation, 9 Le t main coronary artery, 8 Le t posterior ascicular block (LPFB), 94 Le t-to-right shunting, 382 Le t ventricle, 5, 6 dilatation o , 208 Le t ventricular assist device (LVAD), 187 Le t ventricular hypertrophy, 91, 324 Le t ventricular noncompaction (LVNC), 264–265 Le t ventricular out low tract (LVOT), 48 Leg ulcers, 359 Lepirudin, 447 Leukocyte adhesion molecules (LAMs), 117 Leukocyte recruitment, atty streaks, 117 Levine sign, 147 Lidocaine, 424t, 429 Limb leads, 78, 78–80, 78t, 79
Lipid-regulating drugs bile acid–binding agents, 451–452 description o , 449 ibrates, 453 HMG-CoA reductase inhibitors (See HMG-CoA reductase inhibitors) niacin, 449t, 452–453 sites o action, 420, 450 Lipid-regulating therapy, or acute cardiac events, 157 Lipoprotein entry and modi ication, atty streaks, 117 lipoprotein (a), risk or atherosclerosis, 131 very low-density, niacin e ects, 453 Lipoprotein transport system cholesterol homeostasis, 119b endogenous (hepatic) pathway, 118b–119b exogenous (intestinal) pathway, 118b reverse cholesterol transport, 119b Loeys–Dietz syndrome, 352 Loop diuretics, 329 Lovastatin, 449, 449t Low-density lipoproteins (LDL), 117, 119b, 127 ezetimibe e ects on, 452 lowering o , 452 statins e ects, 452 Low molecular weight heparins (LMWHs), 181, 368, 442t, 446 Lown–Ganong–Levine syndrome, 302 Lymphatic vessels, 10
M M-mode echocardiography, 48 Macitentan, 419 Magnetic resonance imaging (MRI) cardiac, 68–69, 69 contrast-enhanced, 69, 70 coronary MRA, 69 dilated cardiomyopathy, 253 Mar an syndrome, 352 Matrix metalloproteinases (MMP), 121, 122 Media, 112 Mesenchymal tissue, 379 Metabolic alkalosis, 437, 438 Metabolic syndrome, 130, 315 Metolazone, 436t, 438 Metoprolol, 244, 424t Mexiletine, 424t, 429 Mid-to-late diastolic murmurs, 38–39 Mild mitral stenosis, 30 Milrinone, 407 Mineralocorticoids, 321 Minoxidil, 412t, 413 or hypertension, 331 Mitral regurgitation (MR), 198–203 acute, 199, 200, 201 cardiac catheterization, 202 charactestics o , 218t chronic, 199, 201 clinical mani estations o , 201–202 Doppler color low mapping o , 50 echocardiography in, 202 electrocardiogram in, 202 etiology o , 198, 198–199 evaluation o , 201–202 in heart ailure, 239 pansystolic murmur, 37 pathophysiology, 199, 199–201, 200 radiographic indings, 202 regurgitant raction in, 200
severity o , 200 treatment o , 202–203 Mitral stenosis (MS), 193–198 charactestics o , 218t clinical mani estations o , 196–197 echocardiography indings, 197 electrocardiogram in, 197 etiology, 193, 193b–194b, 194 evaluation o , 196–197 hemodynamic pro ile o , 195 pathology, 194 pathophysiology, 194–196, 195 percutaneous balloon valvuloplasty in, 207 posteroanterior chest radiograph, 45, 45 treatment o , 197–198 Mitral valve, 5 development o , 379 prolapse, 38, 203, 203, 203–204 repair, 203 replacement, 198 Moderator band, 4 Monocyte chemotactic protein-1 (MCP-1), 117 Monomorphic VT, 306 99m Tc-sestamibi, 64 Multidetector row CT, 66 Multi ocal atrial tachycardia, 303 Murmurs, heart. See Heart murmurs Mycotic aneurysm, 215 Myocardial cells histology o , 10–12 tubular systems o , 11 ultrastructure o , 11 Myocardial dys unction, heart ailure in, 186 Myocardial in arction acute (See Acute myocardial in arction (AMI)) clinical presentation o , 173–174 complications o , 184 arrhythmias, 185 conduction blocks, 186 Dressler syndrome, 189 myocardial dys unction, 186–187 papillary muscle rupture, 187 pericarditis, 188 recurrent ischemia, 184, 185 right ventricular in arction, 187 supraventricular arrhythmias, 186 thromboembolism, 189 ventricular aneurysm, 188 ventricular f brillation, 186 ventricular ree wall rupture, 187–188 ventricular septal rupture, 188 de inition, 135t indings, by ECG, 96–97 ischemic preconditioning, 172 nonatherosclerotic causes o , 167–168, 168t pathologic evolution o , 169–171 pathologic Q waves in, 94–97 physical indings, 174 risk strati ication and management ollowing, 189 signs and symptoms o , 174t subendocardial in arcts, 168 thrombolysis in, 181 transmural in arcts, 168 Myocardial ischemia. See Ischemic heart disease Myocardial metabolism assessment, 65 Myocardial oxygen demand, 139–140 Myocardial oxygen supply endothelial actors, 137–139 external compression, 136
464
Index
Myocardial oxygen supply (Continued) metabolic factors, 136–137 neural factors, 139 Myocardial perfusion, nuclear imaging, 63–65 Myocardial viability, 65 Myocardium, 2, 4 stunned, 172 Myocyte. See Myocardial cells contractile proteins in, 21–22 Myofibrils, 10 Myomectomy, 261 Myopathy, 451 Myosin, 21 Myxomatous mitral valve, 203
N Native pacemaker, 271 Natriuretic peptides, 234 Neoplastic pericarditis, 336 Nesiritide, 243, 418 Neurohormonal compensatory mechanisms, 231, 232, 232 adrenergic nervous system, 232–233 antidiuretic hormone, 233–234 natriuretic peptides, 234 Renin–angiotensin–aldosterone system, 233 New York Heart Association (NYHA) classification, 238t Niacin, 452–453 Niemann–Pick C1–like 1 protein, 452 Nitrates agents, 417–418 hemodynamic effects, 416, 417 mechanism of action, 416, 417 nitroglycerin (See Nitroglycerin) pharmacokinetics of, 417–418 sildenafil, 418 sites of action, 408 vascular smooth muscle effects, 417 Nitric oxide (NO), 164 Nitroglycerin, 154 intravenous, 418 sublingual hemodynamic effects, 416–417 pharmacokinetics of, 417–418 transdermal, 417 Nkx2.5., 395b Nocturnal cough, 237 Non-ST-elevation myocardial infarction (NSTEMI), 99–101, 162 Nonbacterial thrombotic endocarditis (NBTE), 213 Nondihydropyridine calcium channel blockers, 156 Noninfectious pericarditis, 336–337 Norepinephrine, 405t, 406 Normal sinus rhythm, 85, 109–111 Nuclear imaging in cardiac disorders, 66t myocardial metabolism assessment, 65 myocardial perfusion assessment, 63–65 radionuclide ventriculography, 65 stable angina diagnosis, 151
O Open mitral valve commissurotomy, 198 Organic nitrates, for anginal attacks, 155–156, 155t Orthodromic AVRT, 300 Orthopnea, 237 Ostium primum, 376 Ostium secundum, 376, 376, 382 Ototoxicity, 437
Overdrive suppression, 271–272 Oxidation, 117 Oxygen content, 136
P P wave abnormalities, 90–91, 91 definition, 80–83 Pacemaker ectopic, 271 latent, 270–271, 275–276 native, 270–271, 275–276 permanent, 282–283 temporary, 282 Pacemaker cells, 18–19 definition, 269 Pacemaker current (If), 19, 269 Paclitaxel, 158 Pansystolic/ holosystolic murmur, 37–38 Papillary muscles, 4, 5 Paradoxical embolism, 361 Paradoxical splitting of S2, 32 Parietal pericardium, 1, 334 Paroxysmal nocturnal dyspnea (PND), 237 Paroxysmal supraventricular tachycardias (PSVTs) atrioventricular reentrant tachycardias, 300 AV nodal reentrant tachycardia, 298–300 concealed accessory pathways, 302 ventricular preexcitation syndrome, 300–302 Patent ductus arteriosus incidence of, 386 laboratory studies, 388 pathophysiology of, 387 physical examination, 388 risk factors, 386 symptoms of, 387–388 treatment of, 388 Pathologic Q waves, in myocardial infarction, 94–97 PCSK9 (proprotein convertase subtilisin/ kexin type 9), 126 Penetrating atherosclerotic ulcer, 353 Pentoxifylline, 361 Peptic ulcer disease, diagnosis of, 148t Percutaneous balloon mitral valvuloplasty, 198 Percutaneous balloon valvuloplasty, 207 Percutaneous catheter ablation, 297 Percutaneous septal ablation, 261 Percutaneous transluminal coronary angioplasty (PTCA), 157 Perfusion pressure, 136 Pericardial disease, echocardiography for, 54 Pericardial effusion clinical features, 341 diagnostic studies, 341–342 etiology, 340 pathophysiology, 340–341 treatment, 342 Pericardial knock, 35 Pericardiocentesis, 338 Pericarditis with acute myocardial infarction, 336 clinical history, 338 with connective tissue diseases, 336–337 diagnosis of, 148t diagnostic studies, 338–339 drug-induced, 337
etiology, 335–337 idiopathic, 335 infectious, 335–336 myocardial infarction, 188 neoplastic, 336 noninfectious, 336–337 pathogenesis, 337 pathology, 337 physical examination, 338 purulent, 335–336, 336 radiation-induced, 336 treatment, 339 tuberculous, 335 uremic, 336 viral, 335 Pericardium anatomy, 334 anatomy of, 1–2, 2 function, 334 parietal, 334 visceral, 334 Peripartum cardiomyopathy, 251 Peripheral α-adrenergic receptor antagonists, 421–422, 421t Peripheral artery disease (PAD) acute arterial occlusion, 361–362 angiogram, 358 atherosclerosis clinical presentation, 358–359 diagnosis, 358–360 etiology, 357–358 pathogenesis, 357–358 treatment, 360–361 giant cell arteritis, 362–363 takayasu arteritis, 362 thromboangiitis obliterans, 363 vasculitic syndromes, 362–363 Peripheral pruning, 47 Peripheral stigmata of endocarditis, 215 Peripheral vascular disease. See also Peripheral artery diseases; Venous disease aortic aneurysms, 351–354 aortic dissection, 354–357 Raynaud phenomenon, 364 vascular lumen narrowing, 350 vessel wall, structural changes in, 350 Permanent pacemakers, 282–283 Pharmacologic therapy for bradyarrhythmias, 282 for tachyarrhythmias, 283–284 Phenoxybenzamine, 421t, 422 Phentolamine, 421t, 422 Pheochromocytoma, 321 Phosphodiesterase 3 inhibitors, 243, 407, 407t Phospholamban (PL), 25 Phospholipase A2, 441 Physiologic splitting, heart sound, 30, 31 Plaque rupture, 165 Platelet(s) activation of, 441 aggregation of, 440 antiplatelet drugs effects, 441 function of, 441 substances released from, 441 Platelet-derived growth factor (PDGF), 120 Platelet P2Y12 ADP receptor antagonists, 157 Poiseuille equation, 357 Poiseuille’s law, 141 Polymorphic ventricular tachycardia, 279, 306 Posterior descending artery, 8 Potassium channels, 15–16, 16 Potassium equilibrium potential, 16
Index 465 Potassium, dietary, in hypertension, 328 Potassium-sparing diuretics, 329, 436t, 438–439 PR interval, 85, 86, 88t Prasugrel, 180 Pravastatin, 449, 449t Prazosin, 421, 421t Preload, 222 alterations in, 226 concept of, 223 definition, 223t effect of, 227 Pressure measurement, by cardiac catheterization pulmonary artery, 58–59 right atrial, 57 right ventricular, 57 Pressure natriuresis, 312 Pressure–volume loops cardiac function determinants, 225, 225–226 effect of, 227 in systolic and diastolic dysfunction, 229 Presystolic accentuation, 197 Primary aldosteronism, 321 Primary pulmonary hypertension, 409 Prinzmetal angina, 145 Proarrhythmia, 283 Proarrhythmic effect, 425 Procainamide, 424, 424t, 427 induced pericarditis, 337 Propafenone, 424t, 430 Propranolol, 424t Prostacyclin, 138, 164 Prosthetic valves bioprosthetic device, 211, 211–212 mechanical device, 211, 211 Protein C/ S, 163 Protein kinases (PKAs), 24–25 Proximal isovelocity surface area (PISA) method, 53 Pseudoaneurysm, 187, 351 Pulmonary artery (PA), 57, 57b Pulmonary capillary wedge (PCW) tracing, 57b Pulmonary embolism clinical presentation, 370 diagnosis, 370 epidemiology, 369 etiology, 369–370 pathophysiology, 370 treatment, 370–371 Pulmonary hypertension, primary, 409 Pulmonary valves, development of, 378 Pulmonary vascular resistance perinatal, 385 postnatal changes, 387 Pulmonic ejection click, 33 Pulmonic regurgitation (PR), 211 early diastolic murmurs, 38 Pulmonic stenosis, 210–211 clinical features of, 391 heart sound associated with, 391 laboratory studies, 391 murmur of, 37 pathophysiology of, 391 physical examination of, 391 radiograph findings, 391 symptoms of, 391 treatment of, 391 Pulmonic valve, 4 Pulmonic valve disease pulmonic regurgitation, 211 pulmonic stenosis, 210–211 Pulsus paradoxus, 344, 344b Purkinje cell, 404, 426
Purkinje fibers, 8 Purulent pericarditis, 335–336 P2Y12 receptor inhibitor, 182
Q QRS complex abnormalities of, 91–97 bundle branch blocks findings, 91–96 definition, 80 mean QRS axis calculation, 86–90 myocardial infarction findings, 96–97 shapes, 81, 81 ventricular hypertrophy findings, 91–92, 92 QRS interval, 86, 88t QT interval, 85, 86, 88t Quadruple rhythm, 34 Quincke sign, 209t Quinidine, 424, 427
R Radiation-induced pericarditis, 336 Radiography cardiac silhouette, 44–45 frontal view, 44, 44 for heart disease, 45–47, 48t indications atrial septal defect, 384 coarctation of the aorta, 393 congenital aortic stenosis, 390 Eisenmenger syndrome, 398 patent ductus arteriosus, 388 pulmonic stenosis, 391 tetralogy of Fallot, 396 transposition of the great arteries, 397 ventricular septal defect, 386 lateral view, 44, 44 posteroanterior view, 45, 45 x-rays and tissue density., 43 Radionuclide ventriculography, 65 Ranolazine, anti-ischemic therapy, 155t, 156 Raynaud phenomenon, 364 primary, 364 secondary, 364 treatment of, 364 Reentry, 277–279 Refractory periods, 19–20 Relaxation therapy, for hypertension, 328–329 Renal parenchymal disease, hypertension secondary, 319 Renin–angiotensin–aldosterone system, 233, 234, 318 drug interactions, 410 schematic diagram of, 409 Renovascular hypertension, 319–320 Repolarization of cardiac cell, 75–76, 76 of pacemaker cells, 19 Reserpine, 421 Resting potential, 15–16, 16 Restrictive cardiomyopathy causes of, 262, 262t clinical findings, 263 diagnostic studies, 263–264 etiology, 266t pathophysiology, 263 physical examination, 263 treatment, 264 ventricular morphology, 266t Retina, damage caused by hypertension, 325–326 Revascularization therapy, 157–159 Rheumatic fever, 194b
Rheumatic heart disease (RHD), 193b Right atrium, 4–5, 5 pressure measurement, 57, 57b Right axis deviation, 86 Right bundle branch, 7 Right bundle branch block (RBBB), 92 Right coronary artery (RCA), 8–9 Right coronary artery (RCA) stenoses, 62 Right dominant coronary circulation, 9 Right-sided heart failure, 230, 230t Right ventricle (RV), 4–5, 5 infarction, 187 pressure tracings, 57, 57b Right ventricular hypertrophy, 91 Ryanodine receptors, 22, 22
S S1. See First heart sound S2. See Second heart sound Sarcolemma, 11 electrical stimulation in, 12 Sarcomeres, 10 Sarcoplasmic reticulum (SR), 12 Sarco(endo)plasmic reticulum Ca+ + ATPase (SERCA), 23 Second-degree atrioventricular block, 291, 291–292, 292 Second heart sound in atrial septal defect, 384 splitting of, 389 Second heart sound (S2), 30–32, 31 Secondary aldosteronism, 321 Secondary hypertension adrenocortical hormone excess, 321–322 aorta, coarctation of, 320 clinical conditions, 317, 317t exogenous causes, 318–319 patient evaluation, 317–318 pheochromocytoma, 321 renal parenchymal disease, 319 renovascular hypertension, 319–320 thyroid hormone abnormalities, 322 Senile amyloidosis, 262 Septum primum, 376, 376 Septum secundum, 376 Serofibrinous pericarditis, 337 Serous pericarditis, 337 Sick sinus syndrome, 288–289, 289 Silent ischemia, 134 definition, 135t pathophysiologic findings, 144, 146 Simvastatin, 449, 449t Single cardiac muscle cell, electrical measurement, 74–76, 75, 76 Sinoatrial node, 271 digitalis effects, 403t Sinoatrial (SA) node, 7 Sinus bradycardia, 287–288, 288 Sinus bradycardia rhythm, 85, 107–108 Sinus node automaticity, 273–274 Sinus rhythm, 85 Sinus tachycardia, 85, 239, 293, 294 Sirolimus, 158 Smoking cessation, effect on hypertension, 328 Smooth muscle cells in arterial wall, 114 migration and proliferation, 120–121, 121 Sodium channel, 14–15, 14f Sodium, dietary, in hypertension, 328 Sodium nitroprusside, 412t, 413–414 Sotalol, 424t, 433 Spiral/ helical computed tomography, 66, 67 Spironolactone, 244, 436t, 439
466
Index
ST-segment elevation, 97–99 ST-segment elevation myocardial in arction (STEMI), 163 diastolic current theory o , 99, 100 ECG evolution during, 97–99 systolic current theory o , 99, 100 Stable angina accompanying symptoms, 147 coronary angiography, 152–153 coronary artery calci ication, 153 coronary CT angiography, 153 de inition, 135t diagnostic studies, 149–150 di erential diagnosis, 148, 148t electrocardiographic studies, 149–150, 150 exercise echocardiography, 151 requency, 147 history, 146–147 location, 147 natural history, 153 nuclear imaging studies, 151 pathophysiologic indings, 144, 145 pharmacologic stress tests, 151–152 physical examination, 149 precipitants, 147 quality o , 146–147 risk actors, 147 standard exercise testing or, 150–151 stress testing, 150–152 Standard exercise testing, 150–151 Staphylococcus aureus endocarditis, 212 Statin therapy, 127–128, 128t Statins, 183 or acute cardiac events, 157 Stenotic mitral/ tricuspid valve, 38 Sterol regulatory element–binding protein (SREBP), 119b Stress echocardiography, 53 Stress testing, stable angina diagnosis, 150–152 Stroke volume (SV) a terload, 223t, 224, 226–227, 227 contractility, 223t, 224–225, 227–228 de inition, 223 de inition o , 223t preload, 223, 223t, 226 Stunned myocardium, 144 Subacute bacterial endocarditis (SBE), 212 Sudden cardiac death, with hypertrophic cardiomyopathy, 259, 261 Summation gallop, 34 Super icial thrombophlebitis, 371 Suppurative (or purulent) pericarditis, 337 Supraventricular arrhythmias, 186 atrial ibrillation, 296, 296–297 atrial lutter, 294–296, 295 atrial premature beats, 294, 294 ocal atrial tachycardia, 302–303 multi ocal atrial tachycardia, 303 paroxysmal supraventricular tachycardias, 297–302 sinus tachycardia, 293, 294 Supraventricular tachycardias, paroxysmal, 298–302 Sustained-release nitroglycerin, 417 SVT with aberrancy, 306 Swan–Ganz catheter, 56 Sympathetic receptors, 139 Sympatholytic agents, 330 Sympathomimetic amines cAMP ormation e ects, 404–405 de inition o , 405 dobutamine, 405t, 406
dopamine, 405, 405t epinephrine, 405t, 406 isoproterenol, 405t, 406–407 norepinephrine, 405t, 406 Syncope, 206 with hypertrophic cardiomyopathy, 259 Syndrome X, 146 Systemic lupus-like syndrome, 337 Systole, 26 Systolic current theory, 99, 100 Systolic dys unction, 324 unctional myocardial cells, 172 heart ailure in, 228, 228 Systolic murmur classi ication, 36 ejection type, 36–37 late systolic, 38 pansystolic/ holosystolic, 37–38 Systolic murmurs, 36–38
T T cells, in plaque evolution, 121 T wave abnormalities o , 97 de inition, 80 Tachyarrhythmias impulse ormation and conduction, 281t supraventricular arrhythmias atrial brillation, 296, 296–297 atrial f utter, 294–296, 295 atrial premature beats, 294, 294 ocal atrial tachycardia, 302–303 multi ocal atrial tachycardia, 303 paroxysmal supraventricular tachycardias, 297–302 sinus tachycardia, 293, 294 treatment or catheter ablation, 285 de brillation, 284 electric cardioversion, 284 implantable cardioverter– de brillators, 285 pharmacologic therapy, 283–284 vagotonic maneuvers, 284 ventricular arrhythmias torsades de pointes, 307–308 ventricular brillation, 308 ventricular premature beats, 303–304 ventricular tachycardia, 304, 306–307 Tachycardia atrioventricular reentrant, 300 AV nodal reentrant, 298–300, 299 ocal atrial, 302–303 multi ocal atrial, 303 paroxysmal supraventricular, 297–302 sinus, 293, 294 ventricular, 304, 306–307 Takayasu arteritis, 362 TBX1, 395b Temporal arteritis, 362–363 Temporary pacemakers, 282 Tetralogy o Fallot, 393–396 Thebesian veins, 10 Thermodilution method, or cardiac output, 59 Thiazide diuretics, 329, 436t, 437–438 Thiazides, 329 Thienopyridines, 443–444 Third-degree atrioventricular block, 292, 292 Third heart sound, 34 Thromboangiitis obliterans, 363, 363 Thrombocytopenia, heparin-induced, 446
Thromboembolic complications, treatment or, 255 Thromboembolic CVAs, 324 Thromboembolism, 189 Thrombomodulin, 163 Thrombosis consequences o , 167 dys unctional endothelium, 166 pathogenesis o , 165–166 plaque rupture, 165 signi icance o , 166–167, 167 Thyroid hormone abnormalities, 322 Ticagrelor, 180, 444 Ticlopidine, 443 Tiro iban, 444 Tissue actor pathway inhibitor (TFPI), 164 Tissue plasminogen activator (tPA), 164 Titin, 22 Tobacco smoking, risk or atherosclerosis, 129 Torsades de pointes, 307–308 Torsemide, 436t, 437 Trabeculae carneae, 4 Transcatheter aortic valve replacement (TAVR), 207 Transdermal nitroglycerin patches, 417 Transesophageal echocardiography (TEE), 50–51 Transient myocardial ischemia, 97 Transmembrane potential, 12–13 Transthoracic echocardiography (TTE), 48–49 Transverse tubular system (T tubules), 11, 11 Triamterene, 436t, 439 Tricuspid regurgitation (TR), 210, 239 Tricuspid stenosis (TS), 210 Tricuspid valve, 4 Tricuspid valve disease, 210 Tricuspid valve regurgitation, 38 Trigeminy, 303 Triplets, 303 Tropomyosin, 22 Troponin, 22, 176, 177 troponin C (TnC), 22 troponin I (TnI), 22 troponin T (TnT), 22 True aneurysm, 351 Tuberculous pericarditis, 335 Turner syndrome, 394b Two-dimensional (2D) echocardiography, 48–49, 49
U U wave, 80 Ulcers, leg, 359 Un ractionated heparin (UFH), 180, 445–446 Unipolar lead, 77 Unstable angina, 162 clinical diagnosis o , 174 clinical presentation o , 173 de inition, 135t laboratory indings, 173 pathophysiologic indings, 144, 145 treatment o anti-ischemic therapy, 178 antithrombotic therapy, 179–181 β-blockers, 178 calcium channel antagonists, 178 conservative vs. early invasive management, 181 nitrates, 178 Upper-zone vascular redistribution, 239 Uremic pericarditis, 336
Index 467 V Vagotonic maneuver, for tachyarrhythmias, 284 Valsalva maneuver, 260 Valvular heart disease aortic regurgitation (See Aortic regurgitation (AR)) aortic stenosis (See Aortic stenosis (AS)) mitral regurgitation (See Mitral regurgitation (MR)) mitral stenosis (See Mitral stenosis (MS)) mitral valve prolapse, 203–204, 204 pulmonic regurgitation, 211 pulmonic stenosis, 210–211 tricuspid regurgitation, 210 tricuspid stenosis, 210 Variant angina definition, 135t pathophysiologic findings, 144, 145–146 Varicocele, 365 Varicose veins, 365–366 Vascular cell adhesion molecule-1 (VCAM-1), 117 Vascular smooth muscle cells, 120–121, 121, 417 Vasculitic syndromes, 362–363 Vasoconstriction, 138, 139 inappropriate, 142 Vasodilatation, 138, 142 acute coronary syndromes, 164 in acute coronary syndromes, 164 Vasodilator drugs angiotensin-converting enzyme inhibitors (See Angiotensinconverting enzyme inhibitors) angiotensin II type 1 receptor antagonists (See Angiotensin II type 1 receptor antagonists) direct-acting, 412–414, 412t, 413
Vasodilators, 137 direct-acting, 412–413, 412t fenoldopam, 412t, 414 heart failure treated using, 242–243 hydralazine, 412, 412t for hypertension, 330 minoxidil, 412t, 413 nesiritide, 408 nitrates (See Nitrates) sites of action, 408 sodium nitroprusside, 412t, 413–414 Vasopressin, 233, 407 Vasospasm, 364 Venae cavae, superior and inferior, 4, 5 Venodilatation, 154, 156 Venous disease chronic venous insufficiency, 366 varicose veins, 365–366 venous thromboembolism, 366–371 Venous vasodilators, 242 Ventricle fibrillation, 186 interventricular septum, 5, 6, 7 left, 5, 6 right, 4–5, 5 septal rupture, 188 ventricular gallop, 34 Ventricular arrhythmias torsades de pointes, 307–308 ventricular fibrillation, 308 ventricular premature beats, 303–304 ventricular tachycardia, 304, 306–307 Ventricular assist devices (VADs), 245 Ventricular escape rhythms, 290 Ventricular fibrillation, 308 Ventricular hypertrophy, and remodeling, 234–235 Ventricular hypertrophy findings, by ECG, 91–92, 92
Ventricular preexcitation syndrome, 300–302 Ventricular premature beats, 303–304 Ventricular septal defect clinical features of, 385, 385 incidence of, 385 laboratory studies, 386 left-to-right shunting associated with, 386 pathophysiology of, 385–386 physical examination of, 386 symptoms of, 386 treatment of, 386 Ventricular tachycardia, 304, 306–307 Verapamil, 156, 424t, 433 Very-low-density lipoproteins (VLDL), 118b–119b, 452–453 Viral myocarditis, 251 Viral pericarditis, 335 Visceral pericardium, 1, 334 Voltage-sensitive gating, 13–14
W Wall stress (σ), 139 Warfarin, 368 Weight reduction, for hypertension management, 327 Wenckebach block, 291 Westermark sign, 47 Widened splitting of S2, 32 Williams syndrome, 394b Wolff–Parkinson–White (WPW) syndrome, 279–280, 280, 300–302
X X-ray. See Radiography
Y Yellow softening, 169t, 170
Z Zona glomerulosa, 418
