The incidence of heart failure (HF) is constantly increasing in the Western world. Treatment with statins is well established for the primary and secondary prevention of cardiac events by lowering low-density lipoprotein (LDL) cholesterol levels. There are conflicting reports on the role of LDL cholesterol as an adverse prognostic predictor in patients with advanced HF. The aim of this study was to investigate the association between LDL cholesterol levels and clinical outcomes in 297 patients with severe HF (average New York Heart Association class 2.8). The mean follow-up period was 3.7 years (range 8 months to 11.5 years), and 37% of the patients died during follow-up. The mean time to first hospital admission for HF was 25 ± 17 months. The study group was divided according to plasma LDL level ≤89, >89 to ≤115, >115 mg/dl. Patients with the highest baseline LDL cholesterol levels had significantly improved outcomes, whereas those with the lowest LDL cholesterol levels had the highest mortality. When analyzed with respect to statin use, it emerged that the negative association between LDL cholesterol level and mortality was present only in the patients with HF who were treated with statins. In conclusion, lower LDL cholesterol levels appear to predict less favorable outcomes in patients with HF, particularly those taking statins, raising questions about the need for aggressive LDL cholesterol–lowering strategy in patients with HF, regardless of its cause.
Treatment with statins is well established for the primary and secondary prevention of coronary events. Several preclinical and clinical studies advocated the use of statins in patients with heart failure (HF), assuming that there will be pleiotropic effects (e.g., improvement in endothelial dysfunction, downregulation of the inflammatory process) that are involved in the pathogenesis of HF, irrespective of cholesterol reduction. The reduction of cholesterol by statins, however, may also be hazardous in patients with HF. Ubiquinone (coenzyme Q 10 ), a vital product of the cardiac mitochondrial respiration chain involved in adenosine triphosphate production and harboring antioxidant properties, is reduced in patients with congestive HF. Treatment with statins was shown to reduce ubiquinone levels and thus could be potentially harmful. Moreover, according to the endotoxin-lipoprotein hypothesis, low-density lipoprotein (LDL) cholesterol– and triglyceride-rich particles are capable of buffering endotoxins that are powerful promoters of inflammatory cytokine release. LDL reduction could thus result in increased susceptibility to infections, which is already increased in patients with congestive HF. In the large Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA), rosuvastatin treatment did not improve survival from cardiovascular causes in patients with systolic HF, and there is still no consensus with regard to the management goals of hyperlipidemia in this growing population of patients. We examined the role of baseline LDL cholesterol levels as a prognostic predictor in patients with severe but clinically controlled HF who were or were not receiving statin treatment.
Methods
All the patients in this prospective study were recruited from the special HF unit at Tel Aviv Sourasky Medical Center. Baseline blood samples for lipid profiles, renal function tests, and hemoglobin levels were obtained from January 2000 to July 2001. Consecutive patients with HF were enrolled. Systolic HF was defined as a left ventricular ejection fraction <40% by echocardiography. At their first visits, all participants were examined by physicians, and the following information was obtained: medical history, medications, physical examination results, blood pressure at rest, heart rate, weight, New York Heart Association (NYHA) classification, and the results of echocardiography or isotopic ventriculography. Ischemic heart disease was defined according to a history of proved myocardial infarction, coronary artery bypass grafting, or coronary angiography. Hyperlipidemia was defined according to treatment using hypolipidemic medicines such as statins, fibrates, and ezetimibe or levels of total cholesterol >200 mg/dl, LDL >100 mg/dl, or triglycerides >150 mg/dl. Patients were followed up by a HF specialist at least once every 3 months and, not uncommonly, much more often.
Exclusion criteria were malignant disease with diffuse metastases and severe cerebral vascular disease. The end point of the study was all-cause mortality. The study was approved by the institutional ethics committee, and each subject provided informed consent to participate.
All data were summarized and are expressed as mean ± SD for normally distributed continuous variables, as medians and interquartile ranges for non-normally distributed continuous variables, and as number (percentage) in each group for dichotomous variables. To evaluate the importance of different lipid values, we divided our cohort into tertiles and compared the outcomes data among them. The comparisons of basic parameters among the tertiles was done using 1-way analysis of variance for continuous variables and the chi-square test for categorical variables. For continuous variables, we further calculated the p value for linear trend among tertiles using linear regression analysis. We then compared mortality, adjusting for age, gender, histories of diabetes mellitus and hypertension, NYHA functional class, creatinine clearance, and the left ventricular ejection fraction among the tertiles using Cox regression. Significance was set at p <0.05 (2 tailed). SPSS was used to perform all statistical evaluations (SPSS, Inc., Chicago, Illinois).
Results
A total of 324 consecutive outpatients with congestive HF–related symptoms were eligible for participation in this prospective study according to the exclusion and inclusion criteria. Twenty-seven were excluded for technical reasons, noncompliance, or a lack of follow-up information. The remaining 297 patients constituted the study cohort. Their mean follow-up duration was 3.7 years (range 8 months to 11.5 years). The general characteristics of the study patients are listed in Table 1 . Their mean age was 71.2 years (range 30 to 90), 73% were men, 74% had ischemic cardiomyopathy, 26% had valvular disease, and 72% had systolic dysfunction. Their mean left ventricular ejection fraction was 37.7%, and their mean NYHA class was 2.8. The mean number of clinical visits during follow-up was 15.3. Thirty-seven percent had confirmed diagnoses of non-insulin-dependent diabetes mellitus, 58% had hypertension, and 29% were current or past smokers.
| Variable | Value |
|---|---|
| Age (years) | 71.2 ± 11.31 (range 30–95) |
| Men | 216 (73%) |
| Women | 81 (27%) |
| New York Heart Association class | 2.8 ± 0.61 |
| LVEF (%) | 37.7 ± 14.31 |
| Admissions | 100 (34%) |
| Mortality | 109 (37%) |
| Mean follow-up duration (years) | 3.7 |
| Hypertension | 173 (58%) |
| Smokers | 85 (29%) |
| Hyperlipidemia | 173 (58%) |
| Diabetes mellitus | 111 (37%) |
| Systolic dysfunction (LVEF ≤40%) | 214 (72%) |
| Heart failure with preserved LVEF (>40%) | 83 (28%) |
| Valvular disease | 77 (26%) |
| Ischemic heart disease | 220 (74%) |
| Chronic atrial fibrillation | 68 (24%) |
| Cerebrovascular accident and transient ischemic attack | 37 (13%) |
| Percutaneous transluminal coronary angiography and coronary artery bypass grafting | 136 (48%) |
The distribution of NYHA class for the 297 study patients was 1.4% in class I, 23.9% in class II, 53.9% in class III, and 20.7% in class IV. There were no interclass differences between the number of patients classes I and II (p = 0.078), class III (p = 0.077), and class IV (p = 0.073).
To explore the predictive value of LDL on mortality, we divided our cohort (tertiles) according to LDL cholesterol levels group 1, ≤89 mg/dl; group 2, >89 to ≤115 mg/dl; and group 3, >115 mg/dl. Table 2 lists the distributions of various clinical characteristics (risk factor–related diseases, revascularization procedures, and NYHA class) according to tertiles. The patients in the highest tertile (LDL cholesterol >115 mg/dl) were slightly younger, and the prevalence of non-insulin-dependent diabetes mellitus, hypertension, and ischemic heart disease was lower in this tertile, although there were more patients in advanced NYHA classes (III and IV). There were no differences in the left ventricular ejection fraction between the groups (35% for group 1, 39% for group 2, and 37% for group 3, p = 0.423).
| Variable | LDL Cholesterol (mg/dl) | Chi-Square p Value | ||
|---|---|---|---|---|
| ≤89 (n = 98) | >89 to ≤115 (n = 100) | >115 (n = 99) | ||
| Mean age (years) | 73 | 72 | 69 | 0.058 ⁎ |
| Men | 84 (85.7%) | 69 (69.0%) | 69 (69.7%) | 0.009 |
| Body mass index (kg/m 2 ) | 24 | 23 | 25 | 0.23 ⁎ |
| Hyperlipidemia | 58 (59.2%) | 60 (60.0%) | 63 (63.6%) | 0.792 |
| Smokers | 35 (35.7%) | 23 (23.0%) | 31 (31.3%) | 0.139 |
| Hypertension | 60 (61.2%) | 67 (67.0%) | 49 (50.0%) | 0.047 |
| Diabetes mellitus | 47 (48.0%) | 38 (38.0%) | 32 (32.3%) | 0.076 |
| Ischemic heart disease | 78 (79.6%) | 80 (80.0%) | 68 (68.7%) | 0.106 |
| Chronic atrial fibrillation | 24 (24.5%) | 21 (21.0%) | 25 (25.3%) | 0.753 |
| Cerebrovascular accident or transient ischemic attack | 15 (15.3%) | 11 (11.0%) | 11 (11.0%) | 0.580 |
| Percutaneous transluminal coronary angiography or coronary artery bypass grafting | 47 (48.0%) | 53 (53.0%) | 49 (49.5%) | 0.767 |
| New York Heart Association class | ||||
| I and II | 27 (27.8%) | 26 (26.0%) | 21 (21.2%) | 0.782 |
| III | 53 (54.6%) | 55 (55.0%) | 55 (55.6%) | 0.774 |
| IV | 17 (17.5%) | 19 (19.0%) | 23 (23.2%) | 0.726 |
The use of medications in the 3 groups is listed in Table 3 . The prevalence of angiotensin-converting enzyme inhibitor use was significantly lower in group 1, whereas digoxin and antiarrhythmic drugs were used more frequently in group 3. Table 4 lists the main laboratory data for the 3 groups: group 3 had significantly higher levels of total cholesterol and triglycerides but lower levels of N-terminal pro–B-type natriuretic peptide. The levels of hemoglobin, glucose albumin, creatinine, and creatinine clearance were approximately equal among the groups. Although C-reactive protein levels were slightly elevated in all 3 groups, they were higher in group 3 (p = 0.402).
| Medicine | LDL Cholesterol (mg/dl) | Chi-Square p Value | ||
|---|---|---|---|---|
| ≤89 (n = 98) | >89 to ≤115 (n = 100) | >115 (n = 99) | ||
| Warfarin | 19 (19.4%) | 17 (17.0%) | 23 (23.2%) | 0.539 |
| Aspirin | 56 (57.1%) | 56 (56.0%) | 61 (61.6%) | 0.698 |
| Statins | 54 (55.1%) | 57 (57.0%) | 50 (50.5%) | 0.640 |
| ACE inhibitors | 40 (40.8%) | 53 (53.0%) | 51 (51.5%) | 0.175 |
| ARBs | 20 (20.4%) | 26 (26.0%) | 21 (21.2%) | 0.594 |
| Clopidogrel | 4 (4.1%) | 6 (6.0%) | 6 (6.1%) | 0.783 |
| Nitrates | 34 (34.7%) | 36 (36.0%) | 38 (38.4%) | 0.861 |
| Calcium channel blockers | 17 (17.3%) | 18 (18.0%) | 13 (13.1%) | 0.600 |
| β blockers | 59 (60.2%) | 62 (62.0%) | 56 (56.6%) | 0.729 |
| Insulin | 10 (10.2%) | 9 (9.0%) | 2 (2.0%) | 0.053 |
| Oral hypoglycemic agents | 26 (26.5%) | 21 (21.0%) | 22 (22.2%) | 0.627 |
| α blockers | 18 (18.4%) | 21 (21.0%) | 13 (13.1%) | 0.332 |
| Fibrates | 4 (4.1%) | 5 (5.0%) | 9 (9.1%) | 0.291 |
| Antiarrhythmic agents | 16 (16.3%) | 13 (13.0%) | 22 (22.2%) | 0.218 |
| Digoxin | 17 (17.3%) | 21 (21.0%) | 28 (28.3%) | 0.171 |
| Spironolactone | 48 (49.0%) | 54 (54.0%) | 55 (55.6%) | 0.627 |
| Diuretics | 76 (77.6%) | 79 (79.0%) | 77 (77.8%) | 0.965 |
| Laboratory Parameter | LDL Cholesterol (mg/dl) | Analysis of Variance | |||
|---|---|---|---|---|---|
| ≤89 (n = 98) | >89 to ≤115 (n = 100) | >115 (n = 99) | p Value | p Value for Trend | |
| Hemoglobin (g) | 12.8 ± 1.6 | 12.9 ± 1.5 | 13.0 ± 1.5 | 0.700 | 0.402 |
| Glucose (mg/dl) | 133 ± 54 | 134 ± 64 | 131 ± 66 | 0.951 | 0.813 |
| Creatinine clearance (ml/minutes) | 41 ± 2 | 42 ± 2 | 45 ± 2 | 0.607 | 0.332 |
| Total cholesterol (mg/dl) | 150 ± 25 | 177 ± 29 | 213 ± 44 | <0.001 | <0.001 |
| High-density lipoprotein (mg/dl) | 40 ± 11 | 45 ± 11 | 45 ± 9 | <0.001 | <0.001 |
| Triglycerides (mg/dl) | 125 ± 2 | 132 ± 2 | 158 ± 2 | 0.003 | 0.001 |
| Aspartate aminotransferase (mg/dl) | 23 ± 10 | 24 ± 19 | 24 ± 13 | 0.820 | 0.558 |
| Alkaline phosphatase (mg/dl) | 67 ± 47 | 67 ± 36 | 64 ± 41 | 0.873 | 0.631 |
| Albumin (g/l) | 4.0 ± 0.5 | 4.0 ± 0.9 | 3.9 ± 1.0 | 0.486 | 0.244 |
| Alanine aminotransferase (mg/dl) | 21 ± 15 | 21 ± 15 | 24 ± 16 | 0.333 | 0.205 |
| Total bilirubin (mg/dl) | 0.7 ± 0.5 | 0.7 ± 0.4 | 0.7 ± 0.3 | 0.529 | 0.260 |
| Weight (kg) | 78 ± 17 | 75 ± 14 | 80 ± 16 | 0.161 | 0.398 |
| Left ventricular ejection fraction (%) | 35 ± 14 | 39 ± 14 | 37 ± 14 | 0.186 | 0.423 |
| N-terminal pro–B-type natriuretic peptide (pg/ml) | 1991 ± 5 | 1358 ± 4 | 1499 ± 4 | 0.180 | 0.193 |
| High-sensitivity C-reactive protein (mg/dl) | 3.8 ± 3.1 | 3.4 ± 3.4 | 4.3 ± 3.4 | 0.402 | 0.525 |
| Red blood cell count (×10 6 ) | 4.3 ± 0.6 | 4.4 ± 0.6 | 4.5 ± 0.6 | 0.132 | 0.044 |
| White blood cell count (×10 3 ) | 7.2 ± 2.0 | 7.3 ± 2.6 | 8.0 ± 2.4 | 0.038 | 0.019 |
| Neutrophil count (×10 3 ) | 4.5 ± 1.6 | 4.7 ± 2.2 | 5.3 ± 2.2 | 0.031 | 0.010 |
| Platelet count (×10 3 ) | 222 ± 86 | 214 ± 62 | 234 ± 78 | 0.237 | 0.328 |
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