Clinical Investigation
Low Serum Triglyceride Levels as Predictors of Cardiac Death in Heart Failure Patients
Guliz Kozdag, MD Gokhan Ertas, MD Ender Emre, MD Yasar Akay, MD Umut Celikyurt, MD Tayfun Sahin, MD Gozde Gorur, MD Kurtulus Karauzum, MD Irem Yilmaz, MD Dilek Ural, MD Mira Sarsekeyeva, MD
Understanding the influence of sex differences on predictors of cardiac mortality rates in chronic heart failure might enable us to lengthen lifetimes and to improve lives. This study describes the influence of sex on cardiovascular mortality rates among chronic heart failure patients. From January 2003 through December 2009, we evaluated 637 consecutive patients (409 men and 228 women) with chronic heart failure, who ranged in age from 18 through 94 years (mean age, 64 ± 13 yr) and ranged in New York Heart Association (NYHA) functional class from II through IV. The mean follow-up period was 38 ± 15 months, the mean age was 64 ± 13 years, and the mean left ventricular ejection fraction was 0.27 ± 0.11. By the end of the study, both sexes had similar cardiovascular mortality rates (36% men vs 37% women, P=0.559). In Cox regression analysis, NYHA functional class, triglyceride level, and history of coronary artery disease were independent predictors of cardiovascular death for women with chronic heart failure. For men with chronic heart failure, the patient’s age, ejection fraction, and sodium level were independent predictors of cardiovascular death. In a modern tertiary referral heart failure clinic, decreased triglyceride levels were, upon univariate analysis, predictors of poor outcomes for both men and women. However, upon Cox regression analysis, reduced triglyceride levels were independent predictors of cardiac death only in women. (Tex Heart Inst J 2013;40(5):521-8)
Key words: Cachexia/ blood; chronic disease; heart failure/mortality; female; follow-up studies; male; predictive value of tests; prognosis; risk assessment; sex factors; survival analysis; triglycerides/blood; univariate analysis From: Departments of Cardiology (Drs. Akay, Celikyurt, Emre, Ertas, Karauzum, Kozdag, Sahin, Ural, and Yilmaz) and Nuclear Medicine (Dr. Gorur), Faculty of Medicine, Kocaeli University, 41300 Kocaeli, Turkey; and Charles E. Schmidt College of Medicine (Dr. Sarsekeyeva), Florida Atlantic University, Boca Raton, Florida 33431 Address for reprints: Gokhan Ertas, MD, Department of Cardiology, Istanbul Dr. Siyami Ersek Thoracic and Cardiovascular Surgery Training and Research Hospital, Tibbiye St., Haydarpasa-Kadikoy, 34710 Istanbul, Turkey E-mail: drgokhanertas@ yahoo.com.tr © 2013 by the Texas Heart ® Institute, Houston
Texas Heart Institute Journal
T
he 5-year survival rate for chronic heart failure (CHF) remains at 50%, with mortality rates higher for men than for women (relative risk=1.33, P <0.001). After diagnosis with heart failure, women tend to have a better prognosis and to survive longer than men.1 Given the greater life expectancy of women in the developed world, the overall impact of heart failure is still very important for them.2 Although the CHF death rate seems to be lower or the same in women, most available scientific evidence regarding the influence of male versus female sex on the prognosis of CHF patients derives from observational studies and retrospective analyses, and women are known to be underrepresented in clinical trials.3 These studies report divergent findings concerning the prognosis of CHF patients according to sex, mainly attributable to the study characteristics, the cause of the heart failure, and the type of population studied.2,4-6 Few reports deal with the differences between men and women in specialized heart failure clinics or units. Chronic heart failure can lead to a catabolic state and eventually to cachexia in advanced cases. There is preferential loss of fat but also a decline in lean body mass. Reduced efficiency of adenosine triphosphate production by mitochondria, reduced appetite, malabsorption, and reduced levels of anabolic steroids might play a role.7 Patients with advanced heart failure have severe symptoms, a high mortality rate, and a low cholesterol level.8 This can be due to inflammation, endotoxins, adrenergic activation, oxidative stress, tissue injury, and cachexia.9,10 Liver-function abnormalities are most commonly seen in patients with low cardiac indices and resolve with compensation of heart failure; they are not associated with clinically apparent hepatic disease.11 It has been determined that liver dysfunction is frequent in CHF and is characterized by a predominantly cholestatic enzyme profile that worsens with disease severity.12 Functional liver mass was significantly decreased in New York Heart Association (NYHA) functional class IV patients, in comparison with NYHA II and III patients and with subjects in a control group. The funcLow Serum Triglycerides as Predictors of Cardiac Death
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tional liver mass in patients with systolic CHF did not show any correlations with left ventricular ejection fraction (LVEF), but it did correlate strongly with left atrial diameter.13 Dysfunction of the liver during heart failure syndrome can be another explanation of decreased cholesterol level in CHF. Triglycerides are neutral lipids consisting of a glycerol backbone and 3 long-chain fatty acids. These molecules are a major source of stored energy in such diverse tissues as adipose tissue and skeletal muscle, and they are integral components of lipoprotein particles synthesized by the liver and small intestine.14 In advanced heart failure, mechanisms similar to those that cause low cholesterol levels might cause low triglyceride levels. It seems that heart failure might alter both the production and the storage of triglycerides. Loss of a major energy source can adversely affect the survival of patients with CHF. The aim of this study was to determine the prognostic significance of triglyceride levels for both men and women who have CHF.
Patients and Methods From January 2003 through December 2009, we evaluated 637 patients (409 men and 228 women) who ranged in age from 18 through 94 years (mean age, 64 ± 13 yr) and in NYHA functional class from II through IV. They had been admitted for worsening of heart failure: either ischemic or nonischemic dilated cardiomyopathy. Dilated cardiomyopathy was diagnosed on the basis of transthoracic echocardiographic (TTE) findings of left ventricular (LV) end-diastolic diameter >56 mm and LVEF <0.45. All patients who had not undergone diagnostic coronary angiography were so evaluated to determine the cause of the heart failure (Table I). In patients who had symptoms of decompensated heart failure, the criteria for exclusion from the study were malignancy, the concomitant presence of any predominant severe systemic illness, acute coronary syndrome, pericardial tamponade, hypertrophic cardiomyopathy, restrictive cardiomyopathy, right-sided heart failure due to chronic obstructive pulmonary disease, severe aortic stenosis, and mitral stenosis. This study was conducted in accordance with the Declaration of Helsinki and approved by our institutional ethics committee. All patients gave written informed consent before entry into the study. Echocardiographic and Clinical Evaluation
A detailed medical history and physical examination were obtained for each patient, along with a baseline electrocardiogram and chest radiograph. All participants underwent TTE by means of an echocardiograph equipped with a Vivid 7 ® broadband transducer (GE VingMed Ultrasound AS; Horten, Norway). Measurements of the left atrium, left ventricle, and right ventri522
Low Serum Triglycerides as Predictors of Cardiac Death
cle were obtained from parasternal long-axis and apical 4-chamber views, in accordance with standard criteria. The LVEF was calculated by means of the modified Simpson rule, in the apical 2- and 4-chamber views. Mitral flow was measured from the apical 4-chamber view with pulsed-wave Doppler by placing the sample volume at the tips of the mitral leaflets. Right ventricular systolic pressure was determined by continuouswave Doppler study of the tricuspid regurgitation jet. If tricuspid regurgitation was mild and right atrial size was normal, right atrial pressure was assumed to be 5 mmHg. For moderate tricuspid regurgitation with mild or no right atrial enlargement, we assumed a constant pressure of 10 mmHg. When tricuspid regurgitation was severe and was observed in the presence of a dilated right atrium, we assumed a constant pressure of 15 mmHg. Blood Samples
Fasting blood samples were drawn from a large antecubital vein in each patient for determination of biochemical and hemostatic values during the first 1 to 3 days of hospitalization. Brain natriuretic peptide (BNP) levels were measured with the Triage® BNP test (Biosite Incorporated; San Diego, Calif ), which is a fluorescence immunoassay for the quantification of BNP in 24 hours. Serum high-sensitivity C-reactive protein (hs-CRP) was measured by means of a sensitive nephelometric assay. Sedimentation rate, albumin, creatinine, hemoglobin, and lipid levels were measured by standard methods. Follow-Up of Patients
Clinical follow-up was done by telephone contact and periodic examination of outpatients. All patients were followed for a mean duration of 38 ± 15 months (range, 3–82 mo). The primary endpoint of the study was cardiac death, including sudden death and death attributable to advanced heart failure. Statistical Analysis
All statistical analyses were performed with the SPSS 13.0 statistical software package (IBM Corporation; Armonk, NY). Results are presented as mean ± SD or, for categorical data, as number and percentage. In comparing patients with and without study endpoints, normally distributed continuous variables were analyzed with the 2-tailed t test, and unequally distributed variables were analyzed with the Mann-Whitney U test. Categorical data and proportions were analyzed by means of the c2 test. Correlations between triglyceride and echocardiographic or biochemical values were determined by Spearman correlation analysis. A P value of less than 0.05 was considered statistically significant. During the follow-up period, the clinical and laboratory values of patients with and without study endpoints were compared. The resulting values (as evaluated in the Volume 40, Number 5, 2013
TABLE I. Baseline Characteristics of the Patients
Characteristic
Mean age (yr)
All Patients (n=637)
Women (n=228)
Men (n=409)
P Value
64 ± 13
63 ± 14
64 ± 12
0.72
26.8 ± 5.5
26.7 ± 4.1
0.788 <0.001
Body mass index (kg/m ) 26.7 ± 4.6 2
Coronary artery disease
402 (63)
LVEF 0.27 ± 0.11
111 (49)
291 (71)
0.28 ± 0.12
0.26 ± 0.11
0.007
NYHA functional class
2.8 ± 0.5
2.8 ± 0.5
2.8 ± 0.5
0.601
SBP (mmHg)
125 ± 18
125 ± 20
124 ± 18
0.499
DBP (mmHg)
76 ± 11
76 ± 12
76 ± 11
0.764
12 ± 8
13 ± 2
1,155 ± 980
Hemoglobin (g/dL)
12.6 ± 2
1,238 ± 2,191
0.931
hs-CRP (pg/mL)
2.6 ± 4.3
2.67 ± 4.85
2.60 ± 3.97
0.844
Creatinine (mg/dL)
1.4 ± 1.2
1.4 ± 1.3
1.5 ± 1.14
0.533
Triglycerides (mg/dL)
129 ± 69
136 ± 68
125 ± 69
0.017
Cholesterol (mg/dL)
BNP (pg/mL)
1,208 ± 1,249
<0.001
168 ± 47
178 ± 55
162 ± 41
<0.001
HDL cholesterol (mg/dL)
36 ± 11
39 ± 12
35 ± 11
<0.001
LDL cholesterol (mg/dL)
105 ± 38
112 ± 45
102 ± 34
0.004
Albumin (mg/dL)
3.8 ± 0.5
3.8 ± 0.6
3.8 ± 0.5
0.725
Hypertension
463 (73)
180 (79)
283 (70)
0.008
Diabetes mellitus
223 (35)
88 (39)
135 (34)
0.156
443 (70)
163 (71)
280 (70)
0.425
ACEI/ARB
522 (82)
176 (77)
346 (85)
0.02
Spironolactone
289 (45)
118 (52)
171 (43)
0.016
Loop diuretic
513 (81)
191 (84)
228 (57)
0.123
Comorbidities
Medications β-Blockers
Digitalis
118 (19)
70 (31)
71 (17)
<0.001
Nitrates
258 (41)
79 (35)
179 (45)
0.023
Aspirin
564 (89)
197 (84)
367 (91)
0.206
ACEI/ARB = angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers; BNP = brain natriuretic peptide; DBP = diastolic blood pressure; HDL = high-density lipoprotein; hs-CRP = high sensitivity C-reactive protein; LDL = low-density lipoprotein; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SBP = systolic blood pressure Values are expressed as mean ± SD or as number and percentage. P <0.05 was considered statistically significant.
model) were significantly different between cardiovascular death-positive and death-negative patient groups. The values of triglycerides, LVEF, and sodium levels that were predictors of cardiovascular death were detected via receiver operating characteristic (ROC) curve analysis by using the SPSS statistical software package. Cox proportional hazard analysis was used to arrive at the independent predictors of survival. Coronary artery disease, age, NYHA functional class, body mass index, LVEF <0.145, BNP levels, hs-CRP levels, triglyceride levels <70.5 mg/dL, triglyceride levels <150 mg/dL, and sodium levels <128.5 mEq/L were studied via Cox reTexas Heart Institute Journal
gression analysis as possible independent predictors of cardiac death. The Kaplan-Meier method was used to analyze the timing of events during follow-up.
Results The cardiovascular mortality rates of men (143; 36%) and women (85; 37%) were similar, P=0.559. Upon univariate analysis, histories of coronary artery disease, diabetes mellitus, and hypertension were not predictors of cardiovascular death in either sex. On the other hand, older age, worse NYHA functional status, and Low Serum Triglycerides as Predictors of Cardiac Death
523
lower triglyceride levels were important determinants of cardiovascular death in both sexes, upon univariate analysis. In both sexes, surviving patients had higher triglyceride levels than nonsurviving patients (in women, 147 ± 70 vs 119 ± 62 mg/dL, P=0.001; in men, 130 ± 74 vs 116 ± 57 mg/dL, P=0.038) (Table II). Although increased hs-CRP level was a predictor of cardiovascular death in women (4.19 ± 6.51 vs 1.77 ± 3.22 mg/dL, P <0.001), its level was not an important predictor in men (Table II). In men, surviving patients had higher LVEFs, increased hemoglobin levels, higher sodium levels, and lower BNP levels, compared with nonsurviving patients in univariate analysis (Table II). One hundred fifty mg/dL was accepted as a cutoff value for triglycerides. A triglyceride level of <150 mg/ dL, in accordance with the ATP III guidelines,15 was accepted as normal. Patients were divided into 2 different groups, according to triglyceride level. One group comprised patients who had triglyceride levels <150 mg/dL, and the other group comprised patients who had triglyceride levels ≥150 mg/dL. Of the 458 patients whose triglyceride levels were <150 mg/dL, 179 (39%) died, and of the 179 patients whose triglyceride levels were ≥150 mg/dL, 48 (27%) died (P=0.005). We found no statistically significant difference between men whose tri-
glyceride levels were <150 mg/dL and men whose levels were ≥150 mg/dL: of 307 men whose triglyceride levels were <150 mg/dL, 110 (36%) died; and of 101 whose triglyceride levels were ≥150 mg/dL, 32 (32%) died (P=0.448). However, of 151 women whose triglyceride levels were <150 mg/dL, 69 (46%) died; and of 75 whose triglyceride levels were ≥150 mg/dL, 16 (21%) died (P <0.001) (Fig. 1). Cutoff Values of Triglycerides for Predicting Cardiovascular Death in Women
To define the predictor level in the study population, we used ROC curve analysis to detect the predictive cutoff values of triglyceride level for the occurrence of cardiovascular death in women (area under the curve [AUC]=0.363; 95% confidence interval [CI], 0.289– 0.437; P=0.001). The ROC curves showed that the best cutoff value for predicting cardiovascular death in women was a triglyceride level of <70.5 mg/dL (79% sensitivity and 91% specificity). There were 31 women with triglyceride levels of <70.5 mg/dL, 18 (58%) of whom died during the follow-up period. There were 197 women with triglyceride levels of >70.5 mg/dL, 67 (34%) of whom died due to cardiovascular reasons during the study period (P=0.01).
TABLE II. Comparison of the Clinical, Echocardiographic, and Laboratory Values among Men and Women
Women
Men
Variable
Surviving Nonsurviving Surviving Nonsurviving Patients Patients Patients Patients (n=144) (n=84) P Value (n=270) (n=139) P Value
Mean age (yr)
59.8 ± 11
69.4 ± 11.5
<0.001
61.6 ± 12.2
68 ± 11.6
<0.001
2.68 ± 0.48
2.98 ± 0.46
<0.001
2.7 ± 0.52
3.03 ± 0.46
<0.001
NYHA functional class
Body mass index (kg/m ) 27 ± 5.9
26.5 ± 4.6
0.464
27 ± 4.1
12 ± 1.8
11.8 ± 1.7
0.548
13.3 ± 1.9
2
Hemoglobin (mg/dL) Creatinine (mg/dL)
1.41 ± 1.44
1.4 ± 0.88
26.1 ± 4.1
0.044
12.6 ± 2
0.002
0.928
1.4 ± 1.08
1.6 ± 1.24
1,119 ± 2,572
1,456 ± 1,194
2.36 ± 3.55
3.04 ± 4.63
0.086
1,124 ± 986
1,206 ± 974
0.545
hs-CRP (mg/dL)
1.77 ± 3.22
4.19 ± 6.51
<0.001
Triglycerides (mg/dL)
147 ± 70
119 ± 62
0.002
130 ± 74
116 ± 57
Cholesterol (mg/dL)
183 ± 57
170 ± 51
0.086
164 ± 41
159 ± 42
0.334
LDL cholesterol (mg/dL)
114 ± 46
108 ± 42
0.322
102 ± 34
101 ± 33
0.703
HDL cholesterol (mg/dL)
39 ± 12
38 ± 12
0.369
35 ± 10
36 ± 12
0.526
BNP (pg/mL)
Sodium (mEq/L)
137.7 ± 5.2
LVDD (mm)
60 ± 6.5
LVSD (mm)
46.4 ± 7.3
LVEF 0.29 ± 0.12
137.8 ± 4.8
0.887
0.001 0.13 0.038
137.8 ± 4.5
136.2 ± 6.2
0.006
61 ± 7
NS
61.7 ± 7.4
63.9 ± 7.7
0.004
47.7 ± 7.9
NS
48.3 ± 8.4
50.8 ± 8.8
0.003
0.27 ± 0.11
0.12
0.27 ± 0.1
0.23 ± 0.11
0.013
BNP = brain natriuretic peptide; HDL = high-density lipoprotein; hs-CRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; LV = left ventricular; LVDD = left ventricular diastolic diameter; LVEF = left ventricular ejection fraction; LVSD = left ventricular systolic diameter; NS = not significant; NYHA = New York Heart Association Values are expressed as mean ± SD. P <0.05 was considered statistically significant.
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Fig. 1 Cumulative survival rate in women, in accordance with triglyceride level (P <0.001).
Fig. 2 Cumulative survival rate in men, in accordance with ejection fraction (P=0.011).
Cutoff Values of Ejection Fraction for Predicting Cardiovascular Death in Men
TABLE III. Cox Regression Analysis for Cardiovascular Death in Chronic Heart Failure Patients
As determined by ROC curve analysis (AUC=0.42; 95% CI, 0.361–0.479; P=0.008), the cutoff value of LVEF for cardiovascular death was <0.145 in men (84% sensitivity and 92% specificity) . There were 44 men with LVEFs of <0.145, 23 (52%) of whom died during the follow-up period. There were 365 men with LVEFs of >0.145; 67 (33%) of whom died due to cardiovascular reasons during the study period (P=0.011) (Fig. 2). Cutoff Values of Sodium for Predicting Cardiovascular Death in Men
As determined by ROC curve analysis (AUC=0.427; 95% CI, 0.369–0.496; P=0.018), the cutoff value of sodium that predicted cardiovascular death was <128.5 mEq/L in men, with 92% sensitivity and 97% specificity. There were 21 men with sodium levels of <128.5 mEq/L, 12 (57%) of whom died during the followup period. There were 388 men with sodium levels of >128.5 mEq/L, 131 (34%) of whom died due to cardiovascular reasons during the follow-up period (P=0.029). Cox Regression Analysis
In Cox regression analysis, NYHA functional class, triglyceride level <150 mg/dL, and history of coronary artery disease were independent predictors of cardiovascular death in women with CHF (Table III). The NYHA functional class had a 95% CI of 2.002 (range, 1.147–3.494; P=0.015); history of coronary artery disease had a 95% CI of 1.608 (range, 1.033– Texas Heart Institute Journal
Variable
Hazard Ratio
95% CI
P Value
Women NYHA functional class
2.002
1.147–3.494
0.015
Triglyceride level <150 mg/dL
1.995
1.142–3.487
0.015
Coronary artery disease
1.608
1.033–2.504
0.035
Men Age
1.057 1.039–1.075 <0.001
Ejection fraction <0.145
3.208
1.966–5.234
<0.001
Sodium <128.5 mEq/L
2.674
1.416–5.048
0.002
CI = confidence interval; NYHA = New York Heart Association P <0.05 was considered statistically significant.
2.504; P=0.035); and triglyceride level <150 mg/dL had a 95% CI of 1.995 (range, 1.142–3.487; P=0.015) (Table III). Patients’ age, LVEFs of <0.145, and sodium levels of <128.5 mEq/L were independent predictors of cardiovascular death in men with CHF. Age had a 95% CI of 1.057 (range, 1.039–1.075; P <0.001); LVEF of <0.145 had a 95% CI of 3.208 (range, 1.966–5.234; P <0.001); and sodium levels of <128.5 mEq/L had a 95% CI of 2.674 (range, 1.416–5.048; P=0.002) (Table III). Low Serum Triglycerides as Predictors of Cardiac Death
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Correlations between Triglyceride Levels and Other Values
In women, significant negative correlations were found between triglyceride levels and left atrial dimensions, right ventricular dimensions, pulmonary artery pressures, and grades of mitral regurgitation and tricuspid regurgitation (Table IV).
Discussion Higher NYHA functional class, older age, and reduced triglyceride levels were important prognostic markers for cardiovascular death in both sexes in the presented study. Besides those factors, increased hs-CRP level was another indicator of poor prognosis in women. In men, poor prognosis was indicated by such factors as lower body mass index, decreased hemoglobin levels, and reduced sodium levels, and higher creatinine and BNP levels. Decreased LVEF was a significant echocardiographic factor associated with a poor prognosis in men. In Cox regression analysis, older age, history of coronary artery disease, and triglyceride level <150 mg/ dL were important predictors in women, but older age, LVEF <0.145, and sodium levels <128.5 mEq/L were significant predictors in men. Before our study, it was known that higher functional class,16,17 increased hs-CRP levels,18,19 higher BNP levels,20,21 lower hemoglobin levels,22 lower LVEFs, and decreased sodium levels23,24 were prognostic markers in heart failure patients. It has also been reported25 that, in CHF patients, a higher body mass index is associated with a better prognosis independently of other clinical variables. The risk of death due to progressive heart failure was 3.4-fold higher in underweight than in obese patients. Normal weight, overweight, and obese patients had lower risk
of death, compared with underweight patients.25 In fact, a paradox between decreased total cholesterol levels and prognosis has been confirmed: lower cholesterol levels predicted significantly worse clinical outcomes in CHF patients. These findings imply that the classic risk profile should not apply in patients once CHF is established. Rauchhaus and colleagues10 observed a relationship between lower cholesterol levels, higher cytokine levels, and increased mortality rates. They found that triglyceride levels were lower in cachectic heart failure patients than in noncachectic heart failure patients (P=0.04).10 It has been suggested that cholesterol levels in stable mild-to-moderate CHF patients are an indicator of nutritional status, because cholesterol levels correlate closely with prealbumin levels.26 Some investigators conclude that higher total cholesterol might represent a greater metabolic reserve to deal with heart failure syndrome and that the cholesterol could limit the production of harmful cytokines.8 Low triglyceride levels might be merely a consequence of advanced heart failure. Kato and colleagues27 showed that both glucose and insulin levels were lower in CHF rats than in control rats in “fed” condition. The amount of glycogen in the liver was decreased, and the level of triglycerides was increased in CHF rats. Metabolome analysis revealed that levels of some metabolites of glycolysis increased, whereas some metabolites in the Krebs cycle, such as acyl coenzyme A (acetyl-CoA) and citrate, decreased. Overall, these results might suggest that hepatic lipogenesis is increased and that acetyl-CoA is used for the synthesis of triglycerides and cholesterol. Plasma levels of cholesterol and triglycerides were increased, and free fatty acids (FFAs) were decreased in Dahl salt-sensitive rats with CHF. Kato and colleagues27 concluded that the animals’ decreased food intake, in
TABLE IV. Related Values with Triglycerides in Patients with Congestive Heart Failure
Women
Variable
Correlation of Estimates (r) P Value
Men Correlation of Estimates (r)
P Value
Cholesterol
0.52 <0.001
0.41 <0.001
LDL cholesterol
0.35
<0.001
0.11
0.028
Left atrial dimension
–0.25
<0.001
–0.01
0.067
RV dimension
–0.16
0.021
–0.09
0.09
Mitral regurgitation
–0.16
0.014
–0.09
0.068
Tricuspid regurgitation
–0.3
<0.001
–0.14
0.004
RV systolic pressure
–0.24
0.001
–0.18
<0.001
Albumin
0.23 0.027
0.12 0.15
CHF = chronic heart failure; LDL = low-density lipoprotein; RV = right ventricular P <0.05 was considered statistically significant.
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association with lower glucose and insulin levels, suggested starvation. However, the plasma level of FFAs was decreased and that of triglycerides increased, which is not consistent with a starved condition.27 Acyl-coenzyme A:diacylglycerol acyltransferase (DGAT) is the enzyme that catalyzes the final step in triglyceride synthesis. In states of energy excess, hepatic DGAT activity increases triglyceride synthesis. These triglycerides are exported from the liver in lipoprotein particles and delivered to extrahepatic adipose depots for storage. Within adipose tissue, lipoprotein lipase hydrolyzes liver-derived triglycerides to liberate FFAs, which are then transported into adipocytes. Adipocyte DGAT catalyzes the esterification of these FFAs to regenerate triglycerides.14 Congestion of the liver secondary to congestive heart failure results in elevation of hepatic venous pressure; in fact, the close relationship between elevated venous pressure and elevated serum levels of transaminases can be seen as a measure of hepatic dysfunction.28 In CHF rats compared with control-group rats, liver weight (corrected by body weight) was found to be higher.27 The increase in liver weight was most likely due to congestion, because venous dilation in liver tissue was reported in their model.29 It is of interest that increased right atrial pressure has been reported to indicate malnutrition in CHF patients.30 During cancer cachexia in mice bearing an experimental colon adenocarcinoma (MAC16), Briddon and colleagues31 studied the effect of weight loss on plasma levels of FFAs and triglycerides, and on tissue levels of lipoprotein lipase (LPL). They found that plasma levels of triglycerides were reduced despite extensive mobilization of host body-fat reserves and regardless of weight loss. The plasma levels of FFA also showed an initial decrease with weight loss, followed by an increase, which peaked at a weight loss of about 2 g; thereafter, the levels decreased with increasing weight loss. The level of LPL in both heart and adipose tissue showed an initial rise with increasing weight loss, which peaked at a weight loss of approximately 2.5 g, followed by a decrease upon further weight loss. The increased LPL would provide an increased level of fatty acids for oxidation in the cachectic state and would account for the effect on plasma FFAs and triglycerides.31 Although it might be assumed that increased triglyceride levels serve the human body as a compensatory mechanism against starvation during CHF, this mechanism would not raise triglyceride levels enough during an advanced stage of starvation in CHF. Lower levels of triglycerides might therefore be a sign of the more advanced stages of starvation in CHF. Although a triglyceride level of <150 mg/dL has been accepted as normal in the general population, it seemed to us, in view of this study’s results, that such a level could not be used as normal in CHF patients. This is Texas Heart Institute Journal
the first report of low triglyceride level as a predictor of poor outcomes in both sexes. In Cox regression analysis, that triglyceride level (<150 mg/dL) was an independent predictor of cardiovascular death in women with CHF. In this study, we found that negative correlations between triglyceride levels and pulmonary artery pressure, tricuspid regurgitation, and right-sided heart dimension can show impaired biosynthetic function of the liver, due to the failure of the right side of the heart in CHF. Repeated states of hepatic congestion during decompensation episodes of CHF could have negative effects on biosynthetic processes of the liver. In advanced stages of CHF, the liver could lose its ability to synthesize. “Cardiac cirrhosis,” a liver condition characterized by chronic venous congestion and caused by right-sided heart failure, could be a signal for the end stage of CHF.32 Reduced triglyceride levels might be the consequence of associated factors during CHF: advanced states of congestion in the gastrointestinal system and liver, decreased food intake, increased cachexia, and increased levels of inflammation. Conclusion
Although decreased serum triglyceride levels are predictors of cardiovascular death in patients with heart failure, the reasons for the low triglyceride levels are unknown and require further investigation.
References 1. Gustafsson F, Torp-Pedersen C, Burchardt H, Buch P, Seibaek M, Kjoller E, et al. Female sex is associated with a better longterm survival in patients hospitalized with congestive heart failure. Eur Heart J 2004;25(2):129-35. 2. Ng AC, Wong HS, Yong AS, Sindone AP. Impact of gender on outcomes in chronic systolic heart failure. Int J Cardiol 2007;117(2):214-21. 3. Pina IL. A better survival for women with heart failure? It’s not so simple. J Am Coll Cardiol 2003;42(12):2135-8. 4. Opasich C, Tavazzi L, Lucci D, Gorini M, Albanese MC, Cacciatore G, Maggioni AP. Comparison of one-year outcome in women versus men with chronic congestive heart failure. Am J Cardiol 2000;86(3):353-7. 5. Varela Roman A, Grigorian Shamagian L, Bandin Dieguez MA, Rigueiro Veloso P, Gonzalez-Juanatey JR. Influence of sex on mortality in hospitalized patients with congestive heart failure and preserved or depressed systolic function [in Spanish]. Rev Esp Cardiol 2005;58(10):1171-80. 6. McCullough PA, Philbin EF, Spertus JA, Sandberg KR, Sullivan RA, Kaatz S. Opportunities for improvement in the diagnosis and treatment of heart failure. Clin Cardiol 2003;26(5): 231-7. 7. Berry C, Clark AL. Catabolism in chronic heart failure. Eur Heart J 2000;21(7):521-32. 8. Rauchhaus M, Clark AL, Doehner W, Davos C, Bolger A, Sharma R, et al. The relationship between cholesterol and survival in patients with chronic heart failure. J Am Coll Cardiol 2003;42(11):1933-40. 9. Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet 2000;356(9233):930-3.
Low Serum Triglycerides as Predictors of Cardiac Death
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10. Rauchhaus M, Koloczek V, Volk H, Kemp M, Niebauer J, Francis DP, et al. Inflammatory cytokines and the possible immunological role for lipoproteins in chronic heart failure. Int J Cardiol 2000;76(2-3):125-33. 11. Naschitz JE, Slobodin G, Lewis RJ, Zuckerman E, Yeshurun D. Heart diseases affecting the liver and liver diseases affecting the heart. Am Heart J 2000;140(1):111-20. 12. Poelzl G, Ess M, Mussner-Seeber C, Pachinger O, Frick M, Ulmer H. Liver dysfunction in chronic heart failure: prevalence, characteristics and prognostic significance. Eur J Clin Invest 2012;42(2):153-63. 13. Malek F, Hendrichova M, Kratka K, Sedlakova M, Vranova J, Horak J. Correlation of the functional liver mass with left ventricular ejection fraction and left atrial diameter in patients with congestive heart failure. Int J Cardiol 2008;127(2):2713. 14. Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 2008;19(3):295300. 15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19):2486-97. 16. Ponikowski P, Anker SD, Chua TP, Szelemej R, Piepoli M, Adamopoulos S, et al. Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1997;79(12):1645-50. 17. Shi C, Wang LJ, Hu DF, Li JP, Zhu TQ, Shan Y, et al. Prevalence, clinical characteristics and outcome in patients with chronic heart failure and diabetes. Chin Med J (Engl) 2010; 123(6):646-50. 18. Kozdag G, Ertas G, Kilic T, Acar E, Agir A, Sahin T, et al. Elevated level of high-sensitivity C-reactive protein is important in determining prognosis in chronic heart failure. Med Sci Monit 2010;16(3):CR156-61. 19. Tang WH, Shrestha K, Van Lente F, Troughton RW, Martin MG, Borowski AG, et al. Usefulness of C-reactive protein and left ventricular diastolic performance for prognosis in patients with left ventricular systolic heart failure. Am J Cardiol 2008;101(3):370-3. 20. Balion C, Santaguida PL, Hill S, Worster A, McQueen M, Oremus M, et al. Testing for BNP and NT-proBNP in the diagnosis and prognosis of heart failure. Evid Rep Technol Assess (Full Rep) 2006(142):1-147.
528
Low Serum Triglycerides as Predictors of Cardiac Death
21. Kozdag G, Ertas G, Kilic T, Acar E, Sahin T, Ural D. Triiodothyronine and brain natriuretic peptide: similar long-term prognostic values for chronic heart failure. Tex Heart Inst J 2010;37(5):538-46. 22. Jindrich S, Ondrej L, Viktor M, Zbynek P, Tomas P, Ladislav D, et al. The profile and prognosis of patients hospitalised with heart failure. The value of discharge blood pressure and cholesterol. Int Heart J 2008;49(6):691-705. 23. Stevenson LW. Patient selection for mechanical bridging to transplantation. Ann Thorac Surg 1996;61(1):380-7. 24. Kawahara C, Tsutamoto T, Nishiyama K, Yamaji M, Sakai H, Fujii M, et al. Prognostic role of high-sensitivity cardiac troponin T in patients with nonischemic dilated cardiomyopathy [published erratum appears in Circ J 2011;75(5):1284]. Circ J 2011;75(3):656-61. 25. Cicoira M, Maggioni AP, Latini R, Barlera S, Carretta E, Janosi A, et al. Body mass index, prognosis and mode of death in chronic heart failure: results from the Valsartan Heart Failure Trial. Eur J Heart Fail 2007;9(4):397-402. 26. Araujo JP, Frioes F, Azevedo A, Lourenco P, Rocha-Goncalves F, Ferreira A, Bettencourt P. Cholesterol--a marker of nutritional status in mild to moderate heart failure. Int J Cardiol 2008;129(1):65-8. 27. Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Kawamoto A, et al. Analysis of liver metabolism in a rat model of heart failure. Int J Cardiol 2012;161(3):130-6. 28. Shibayama Y. The role of hepatic venous congestion and endotoxaemia in the production of fulminant hepatic failure secondary to congestive heart failure. J Pathol 1987;151(2):133-8. 29. Inoko M, Kihara Y, Morii I, Fujiwara H, Sasayama S. Transition from compensatory hypertrophy to dilated, failing left ventricles in Dahl salt-sensitive rats. Am J Physiol 1994;267(6 Pt 2):H2471-82. 30. Carr JG, Stevenson LW, Walden JA, Heber D. Prevalence and hemodynamic correlates of malnutrition in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1989;63(11):709-13. 31. Briddon S, Beck SA, Tisdale MJ. Changes in activity of lipoprotein lipase, plasma free fatty acids and triglycerides with weight loss in a cachexia model. Cancer Lett 1991;57(1):4953. 32. Pillarisetti J, Nath J, Berenbom L, Lakkireddy D. Cardiac cirrhosis: a rare manifestation of an uncorrected primum atrial septal defect. J Cardiovasc Med (Hagerstown) 2010;11(9): 689-91.
Volume 40, Number 5, 2013
