Restrictive cardiomyopathy Jens Mogensena and Eloisa Arbustinib a Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, Aarhus N, Denmark and b Academic Hospital, IRCCS Foundation Policlinico San Matteo, Pavia, Italy
Correspondence to Jens Mogensen, MD, PhD, Department of Cardiology, Skejby University Hospital, Brendstrupgaardsvej, 8200 Aarhus N, Denmark Tel: +45 89 49 61 99; fax: +45 89 49 60 02; e-mail:
[email protected] Current Opinion in Cardiology 2009, 24:214–220
Purpose of review Restrictive cardiomyopathy (RCM) is an uncommon myocardial disease characterized by impaired filling of the ventricles in the presence of normal wall thickness and systolic function. Most affected individuals have severe signs and symptoms of heart failure. A large number die shortly after diagnosis unless they receive a cardiac transplant. Controversy has existed about the exact definition of the condition and diagnostic criteria that will be discussed along with an update on recent findings. Recent findings Previously, RCM was believed to be of idiopathic origin unless otherwise associated with inflammatory, infiltrative or systemic disease. Recent investigations have shown that the condition may be caused by mutations in sarcomeric disease genes and even may coexist with hypertrophic cardiomyopathy in the same family. However, most sarcomeric RCM mutations appear to be de novo and associated with a severe disease expression and an early onset. Summary Recent reports suggest that mutations in sarcomeric contractile protein genes are not uncommon in RCM. These findings imply that RCM may be hereditary, and that clinical assessment of relatives should be considered in addition to genetic investigations when systemic disease has been excluded. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death. Keywords genetic investigations, inheritance, restrictive cardiomyopathy Curr Opin Cardiol 24:214–220 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 0268-4705
Introduction Restrictive cardiomyopathy (RCM) is characterized by increased stiffness of the ventricles leading to compromised diastolic filling with preserved systolic function. These changes may develop in association with local inflammatory or systemic, infiltrative or storage disease (Fig. 1) [1]. Usually, patients develop severe symptoms of heart failure over a short period of time, and the majority die within a few years following diagnosis unless they receive a cardiac transplant [2]. The results of recent molecular genetic investigations have revealed that a substantial proportion of RCM without associated systemic disease is caused by mutations in sarcomeric disease genes that have been associated with hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and noncompaction cardiomyopathy [3–5,6]. Controversy exists on how to define the condition because restrictive filling patterns of the ventricles occur in a wide range of different diseases [7–9]. It is the purpose of this review to demonstrate that a variety of 0268-4705 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
myocardial and systemic diseases are associated with RCM. Therefore, the definition of RCM should be descriptive rather than categorical and reflect that many conditions may ultimately lead to RCM.
Clinical characteristics Adult RCM patients present with dyspnea, fatigue and limited exercise capacity. They may experience palpitation accompanied by dizziness due to supraventricular arrhythmia (SVT). Thromboembolic complications are common and may be the initial presentation of the condition. In children, RCM may present with failure to thrive, fatigue and even syncope [8,9]. In advanced cases, patients develop raised jugular venous pressures, peripheral edema, liver enlargement and ascites. Chest radiograph usually shows a normal-sized heart with enlarged atria and variable degrees of pulmonary congestion. The ECG exhibits large P waves indicating biatrial enlargement accompanied by various ST segment and T wave abnormalities (Fig. 2b). Echocardiography typically reveals biatrial enlargement, a normal or slightly DOI:10.1097/HCO.0b013e32832a1d2e
Restrictive cardiomyopathy Mogensen and Arbustini 215 Figure 1 Restrictive cardiomyopathy
Restrictive cardiomyopathy
Inflammatory
Infiltrative
Storage
Idiopathic
Endomyocardial fibrosis
Amyloidosis
Hemochromatosis
Loeffler cardiomyopathy
Sarcoidosis
Glycogen storage disease
Postirradiation therapy
Fabry disease
Patients need to be assessed in relation to familial involvement and the potential genetic basis. Adapted from [1].
impaired systolic function and mitral inflow Doppler velocities indicative of severe diastolic dysfunction (Fig. 2a). These include increased ratio of early diastolic filling to atrial filling, decreased E-deceleration time and decreased isovolumic relaxation time (IVRT) (Fig. 3). Invasive pressure measurements within the ventricles during cardiac catheterization are characterized by an early diastolic dip quickly followed by a plateau, also called the ‘square-root sign’. Usually, the diastolic pressure of both ventricles is elevated with the highest plateau being in the left ventricle [2]. However, when diagnosing RCM, it is important to realize that pressure measurements obtained during cardiac catheterization as well as Doppler velocities vary according to preload, which in turn is highly dependent on the current medication of individual patients. For instance, aggressive diuretic therapy will tend to normalize filling pressures and diastolic volumes. Furthermore, pressures and velocities also vary in response to heart rate and rhythm [7].
Diagnosis
RCM in patients with mild systolic dysfunction or mild left ventricular hypertrophy or both, the specific values for Doppler velocities and diastolic volumes and whether systemic diseases such as amyloidosis and glycogen storage diseases should be classified as RCM [7,10]. Recently, a working group of the European Society of Cardiology (ESC) proposed revised classification of cardiomyopathies reflecting the clinical disease expression of the conditions focusing on ventricular morphology and function and the familial/genetic background [11]. Specifically, the classification characterizes cardiomyopathies in relation to the familial background. In this context, RCM is defined as a condition presenting with restrictive ventricular physiology in the presence of normal or reduced diastolic volumes and normal ventricular wall thickness in the absence of ischemic heart disease, hypertension, valvular heart disease and congenital heart disease. This broad definition should help physicians to identify the condition and consider further diagnostic investigations to reveal the cause that may include cardiac biopsies, family screening and genetic investigations.
It has been difficult to obtain consensus about uniform diagnostic criteria of RCM. From a historical perspective, there has been general agreement that RCM should be considered in patients presenting with heart failure in the presence of a nondilated, nonhypertrophic left ventricle with preserved contractility but abnormal diastolic function. There is uncertainty regarding the diagnosis of
Differentiation of RCM from constrictive pericarditis is important, as patients suffering from the latter condition may recover completely following surgical removal of the fibrotic pericardium. However, the distinction between the two conditions may be difficult. Noninvasive realtime imaging with echo Doppler and respirometry provides
216 Molecular genetics Figure 2 Restrictive cardiomyopathy
Clinical characteristics of restrictive cardiomyopathy in a 19-year-old male who was diagnosed at the age of 16 years following a stroke as previously reported [7]. (a) Apical four-chamber echocardiogram in systole with marked biatrial dilatation, normal-sized ventricles and normal wall thickness. (b) Twelve-lead ECG in sinus rhythm with prominent P waves, T wave inversion and incomplete right bundle branch block. (c) Microscopy of heart tissue obtained postmortem with myocyte hypertrophy, abundant fibrosis and myofibrillar disarray characteristic of the histological findings in HCM (hematoxylin–eosin staining, x40). aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right; HCM, hypertrophic cardiomyopathy. Part (a) adapted from [3]. Parts (b) and (c) reproduced from [3].
the mainstay of diagnosis. Patients with restriction will not have sufficient respiratory variation. Cardiac magnetic resonance and computed tomography (CT) may be useful to assess pericardial thickness, whereas MRI with late enhancement may facilitate diagnosis of infiltrative myocardial disease, for example, amyloidosis. During invasive investigation, it is possible to obtain simultaneous pressure measurements in the ventricles, and both conditions are characterized by rapid early diastolic filling with diastolic dip and plateau waveform. There may be a pressure difference between left ventricular end-diastolic pressure (LVEDP) and right ventricular end-diastolic pressure (RVEDP) in RCM, which is considered significant if diastolic pressure is
more than 5–7 mmHg, in contrast to constrictive pericarditis, in which the pressures tend to be equal in both ventricles. Nonetheless, no technique is totally reliable, and in some patients it is necessary to perform a diagnostic pericardiectomy [2,7,12,13].
Outcome RCM carries a poor prognosis, particularly in children, despite optimal medical treatment. Several studies [14,15] have reported that 66–100% die or receive a cardiac transplant within a few years of diagnosis. In one study of 18 RCM children, five died suddenly without signs of heart failure. However, they had severe angina
Restrictive cardiomyopathy Mogensen and Arbustini 217 Figure 3 Doppler velocities in restrictive cardiomyopathy
Typical restrictive Doppler findings including increased E to A ratio (2.1), decreased E-deceleration time (90 ms) and decreased isovolumetric relaxation time (40 ms). A, atrial filling; E, early diastolic filling.
and ECG evidence of ischemia. Four hearts of children who died suddenly were available for autopsy and revealed acute myocardial infarcts, subendocardial ischemic necrosis or chronic ischemic scarring, despite normal appearance of their coronary arteries. These findings led the authors to suggest that pediatric patients with RCM represent a population of children who are at high risk for ischemiarelated complications and death in addition to heart failure. In adults, two studies [16,17] have reported that 32–44% suffered a cardiovascular-related death within 5 years following diagnosis. The outcome is highly correlated to symptoms and signs of heart failure. Embolic stroke is a common complication as a consequence of large atria and SVT. Therefore, prophylactic anticoagulant therapy should be considered in all RCM patients with enlarged atria even before SVT has developed.
Familial restrictive cardiomyopathy associated with sarcomeric gene mutations In 1992, Feld and Caspi [18] reported a family with a mixed appearance of RCM and HCM. The cardiac morphology of a deceased individual with RCM showed typical features of HCM with myocyte disarray. Angelini et al. [19] reported similar histomorphological features of seven patients with a clinical diagnosis of RCM and suggested that RCM and HCM may represent two different phenotypes of the same basic sarcomeric disease, although no genetic investigations were performed. We investigated a large family in which the proband and two additional individuals were diagnosed with RCM,
nine individuals had clinical features of HCM and 12 individuals died suddenly. Linkage analysis for selected sarcomeric contractile protein genes identified troponin I [troponin I (TNNI3)] as the likely disease gene [3]. Subsequent mutation analysis revealed a missense mutation, which segregated with the disease in the family (lod score: 4.8). To elucidate whether TNNI3 mutations were common in RCM, mutation analysis was performed in nine unrelated RCM patients with unexplained restrictive filling patterns, gross atrial dilatation, normal systolic function and normal wall thickness. Histology of heart tissue from several individuals showed myofibril disarray characteristic of HCM (Fig. 2c). TNNI3 mutations were identified in seven of 10 patients including the index family of the study. Two of the mutations identified in young individuals were de-novo mutations. All mutations were novel missense mutations and appeared in conserved and functionally important domains of the gene. We concluded that mutations in cardiac troponin I were responsible for the development of RCM in a significant proportion of patients diagnosed with RCM. Additional TNNI3 mutations have been reported in RCM, as well as mutations in other sarcomeric genes including troponin T (TNNT2), b-myosin heavy chain (MYH7) and a-cardiac actin (ACTC) [15,20–22]. Most of the mutations reported appeared de novo with a severe disease expression and onset of symptoms in childhood leading to premature death or cardiac transplantation shortly after diagnosis. These findings imply that RCM is part of the clinical expression of hereditary sarcomeric contractile protein disease, and familial evaluation should be
218 Molecular genetics Figure 4 Cardiac amyloidosis
considered whenever an individual has been diagnosed with RCM.
Familial restrictive cardiomyopathy, atrioventricular block and desmin accumulation Desmin-related myopathies are very rare disorders characterized by intracytoplasmatic accumulation of desmin caused by mutations in the gene for either desmin (DES) or a-B-crystallin (CRYAB). Diagnosis requires ultrastructural investigation and immunohistochemistry of cardiac or skeletal muscle biopsy to reveal desmin deposits [23]. The disease expression may involve skeletal muscle only, affect both cardiac and skeletal muscle simultaneously or have an isolated impact on the heart [24–27]. Very few families have been reported with isolated RCM and cardiac-specific accumulation of desmin. In one large four-generation family, no disease gene was identified, whereas another report identified four independent individuals with RCM, atrioventricular block and mutations of the DES gene [23,28]. Genetic investigations and clinical assessment of relatives revealed one de-novo mutation, one mutation with recessive inheritance and two dominant mutations with a total number of three affected relatives. Penetrance was 100%, and all but one had advanced atrioventricular block. Recognizing that this disease expression is extremely rare, the authors suggested that desmin accumulation might be considered in patients presenting with RCM and atrioventricular block.
Cardiac amyloidosis By tradition, cardiac amyloidosis has been classified as a RCM, as deposits of amyloid within the heart typically result in restrictive filling patterns [10,11]. However, this condition is also characterized by increased ventricular wall thickness and impaired systolic function. Echocardiography often reveals a remarkable homogeneous granular sparkling of the myocardium, and valves are often thickened due to amyloid infiltration. In addition, the ECG of patients with cardiac amyloidosis often shows low voltage in standard leads. Cardiac biopsies show typical features of amyloid deposits (Fig. 4a–c). A variety of diseases are associated with sporadic occurrence of Figure 4 (continued)
Clinical characteristics of a 46-year-old male who was diagnosed with cardiac amyloidosis at the age of 42 years because of heart failure symptoms. (a) Apical four-chamber view in systole with biatrial dilatation, normal-sized ventricles and significant thickening of ventricular walls that
appears bright and sparkling. (b) Twelve-lead ECG in sinus rhythm with low voltage in standard leads. (c) Microscopy of cardiac biopsies stained with hematoxylin–eosin showing extensive infiltration of amyloid between myocytes (x40). The small picture inserted shows cardiac tissue from the same patient stained with Congo red, which defines amyloid deposits by its green refringence under polarized light. aVF, augmented vector foot; aVL, augmented vector left; aVR, augmented vector right.
Restrictive cardiomyopathy Mogensen and Arbustini 219
cardiac amyloidosis, whereas hereditary appearances most often are caused by mutations in the genes for transthyretin and apolipoprotein A1 [29,30].
Other rare familial diseases associated with restrictive cardiomyopathy Hemochromatosis is an autosomal recessive disorder leading to iron deposition in multiple organs resulting in widespread damage. Although clinical disease expression in many cases is unpredictable, most patients present with a variety of symptoms from different organ systems, whereas only few patients have isolated cardiac manifestations and very rarely RCM [29]. Anderson–Fabry’s disease is an X-linked lysosomal storage disorder caused by mutations in the gene for a-galactosidase A (GLA). Glycosphingolipids accumulate in multiple organs and cause substantial morbidity and mortality, especially in men. In women, isolated affection of the heart is more frequent than in men, and affected women most often present with symptoms late in life. Typical echocardiographic findings include left ventricular hypertrophy, modest diastolic filling abnormalities and thickening of the valves [31–33]. RCM in the context of Fabry’s disease with normal ventricular wall thickness is extremely rare [34]. The same seems to be the case with a variety of rare hereditary glycogen storage diseases exhibiting different modes of transmission.
Nonfamilial restrictive cardiomyopathy Sporadic RCM may be diagnosed in patients affected by systemic diseases including scleroderma and sarcoidosis [29]. Patients who previously have undergone radiotherapy of the chest, as in Hodgkin’s disease, have an increased risk of developing myocardial and endocardial fibrosis many years later leading to RCM. Restrictive ventricular physiology can also be caused by endocardial fibrosis in association with hypereosinophilic syndromes or induced by exposure to various drugs and parasitic infections [30].
Conclusion RCM is an uncommon condition with a poor outcome unless patients receive a cardiac transplant. RCM is generally seen in association with local inflammatory or systemic diseases. The finding of TNNI3 mutations in a substantial proportion of patients fulfilling diagnostic criteria of idiopathic RCM suggested a causal relationship between gene abnormality and disease. This has prompted genetic investigations of other RCM patients and confirmed that RCM in many instances is part of the clinical expression of sarcomeric contractile protein disease. De-novo mutations appear to be prevalent findings especially in children and young adults, suggesting that they are associated with a more severe disease expression
and early onset in comparison with mutations that have been inherited through many generations. As RCM, HCM, DCM and even noncompaction cardiomyopathy may be caused by mutations in the same genes, previous perceptions of cardiomyopathies as separate and distinct clinical and pathophysiological entities are difficult to sustain. It is important to realize that transitional forms of the conditions frequently appear even within the same family affected by the same mutation. Therefore, the diagnosis of any condition likely to be a cardiomyopathy should lead to family screening for a potential hereditary disorder. Identification and risk stratification of affected relatives is important to avoid adverse disease complications and diminish the rate of sudden death.
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