Obesity is common in heart failure (HF) and is associated with improved outcomes, a finding often termed the “obesity paradox.” Although fat distribution varies by gender, the role of obesity in the outcomes of women compared to men with HF has not been well studied. In a cohort of patients with advanced systolic HF followed at a single university center, 2,718 patients had body mass indexes (BMIs) measured at baseline, and 469 patients with HF had waist circumferences (WCs) measured at baseline. Elevated BMI was defined as ≥25 kg/m 2 . High WC was defined as ≥88 cm in women and ≥102 cm in men. The primary outcome was death, urgent heart transplantation, or ventricular assist device placement. The mean age was 53.0 ± 12.4 years, 25% of subjects were women, and the mean left ventricular ejection fraction was 22.9 ± 7.19%. In men, 2-year event-free survival was better for high versus normal BMI (63.2% vs 53.5%, p <0.001) and for high versus normal WC (78.8% vs 63.1%, p = 0.01). In women, 2-year event-free survival was better for elevated versus normal BMI (67.1% vs 56.6%, p = 0.01) but similar in the 2 WC groups. In multivariate analyses, normal BMI and normal WC were associated with higher relative risk for the primary outcome in men (BMI 1.34, WC 2.02) and women (BMI 1.38, WC 2.99). In conclusion, in patients with advanced HF, high BMI and WC were associated with improved outcomes in both genders. Further investigation of the interaction between body composition and gender in HF outcomes is warranted.
Heart failure (HF) affects 5.8 million individuals in the United States, including >2.5 million women. Approximately 1/2 to 2/3 of patients with HF are overweight or obese. Obesity, quantified by anthropometric indexes such body mass index (BMI) and waist circumference (WC), is associated with improved outcomes in HF, a finding that has often been termed “the obesity paradox.” Although fat distribution is known to vary by gender, the role of obesity in the outcomes of women compared to men with HF has not been well studied. The primary aims of this study were to (1) assess the relation between BMI and outcomes in men compared to women with HF and (2) assess the relation between WC and outcomes in men and women with HF.
Methods
A total of 4,089 patients were referred to a single university medical center for HF management and heart transplantation evaluation from January 1983 to October 2011. All subjects were followed in a comprehensive HF management program, as previously described. For the purposes of this study, patients were grouped into BMI and WC cohorts, which were not mutually exclusive. Because WC was measured starting only in May 2006, only 613 patients had WC measurements for inclusion in the WC group. Patients with left ventricular ejection fractions >40% (n = 442) were excluded. Those without height or weight recorded (n = 796) at time of initial evaluation were excluded from the BMI group. Furthermore, because underweight HF patients may have “cardiac cachexia,” known to be associated with worse prognosis, those classified as underweight (BMI <18.5 kg/m 2 , n = 133) were excluded as well. Thus, the final study group consisted of 2,718 BMI subjects (the BMI cohort) and 469 WC subjects (the WC cohort). Medical record review was approved by the Medical Institutional Review Board of the University of California, Los Angeles.
Height was recorded at the time of initial referral or at subsequent clinic visits. WC and body weight were measured at time of initial referral or within 3 months unless patients were deemed by physicians to be hypervolemic. In hypervolemic patients, WC and weight were recorded after hemodynamic optimization to remove the confounding effects of edema on these measurements. WC was measured at the midpoint between the lowest rib and the iliac crest; patients were classified as having high or normal WCs on the basis of gender-specific thresholds for increased cardiometabolic risk (≥88 cm in women, ≥102 cm in men). Patients were divided into BMI categories on the basis of World Health Organization and National Institutes of Health guidelines: underweight (BMI <18.5 kg/m 2 [excluded from the study cohort]), healthy weight (BMI 18.5 to 24.9 kg/m 2 ), overweight (BMI 25 to 29.9 kg/m 2 ), and obese (BMI ≥30.0 kg/m 2 ). Hemodynamic parameters and medical treatments were also recorded after invasive hemodynamic monitoring using Swan-Ganz catheterization, when necessary. Laboratory testing, echocardiography, and cardiopulmonary exercise tests all occurred within 3 months of the initial referral. Medical history was extracted from medical record review.
Death, urgent status IA heart transplantation (UT), or ventricular assist device (VAD) placement was the primary end point in this study. UT and VAD placement were analyzed as HF death under the assumption that these patients would have died without intervention. Death rather than UT or VAD implantation represented most events (83%). Nonurgent transplantations were censored and considered as nonfatal at the end of follow-up. All-cause mortality was analyzed as a secondary end point.
For the purposes of analysis, we stratified each cohort by gender and then considered 2 BMI groups: normal BMI (healthy weight, BMI 18.5 to 24.9 kg/m 2 ) and high BMI (overweight and obese, BMI ≥25.0 kg/m 2 ) and 2 WC groups: normal WC (<88 cm in women, <102 cm in men) and high WC (≥88 cm in women, ≥102 cm in men). Actuarial survival curves for the male and female WC and BMI groups were calculated using Kaplan-Meier estimates, and differences between curves were calculated using log-rank statistics. Univariate survival analyses were performed with the likelihood ratio test, using the Cox model for baseline variables of WC and BMI. Multivariate analysis adjusting for known predictors in HF including gender, diabetes history, the left ventricular ejection fraction, cause of HF, and New York Heart Association class was performed using Cox proportional-hazards regression analysis to estimate adjusted odds ratios and 95% confidence intervals for potential predictors of survival. The Cox model retained all independent variables with p values <0.15. Statistics were calculated using SPSS version 19.0 (IBM, Somers, New York).
Results
The BMI and WC cohorts shared similar baseline characteristics: both were approximately 75% male and were similar in terms of age, the left ventricular ejection fraction, WC, BMI, and the prevalence of ischemic heart disease. Patients in the WC cohort were more likely to be managed with aldosterone antagonists (60.0% vs 37.1%) and β blockers (94.5% vs 57.3%), a difference attributable to changes in HF management practices between 1982 (when we began gathering BMI data) and 2006 (when we started to measure WC).
The baseline characteristics of the BMI and WC cohorts when stratified by gender are listed in Table 1 . Male gender was associated with higher WC, higher BMI, older age, ischemic cause of HF, and history of smoking in the BMI and WC cohorts. The baseline characteristics of the subject groups when stratified by gender and high versus normal BMI or WC are listed in Table 2 . In men and women, higher BMI was associated with younger age, increased peak oxygen consumption, increased prevalence of diabetes and smoking history, and decreased high-density lipoprotein.
| Variable | BMI | WC | ||||
|---|---|---|---|---|---|---|
| Men | Women | p Value ⁎ | Men | Women | p Value ⁎ | |
| n (%) | 2,038 (75.0%) | 680 (25.0%) | — | 344 (73.3%) | 125 (26.7%) | — |
| WC (cm) | 104 ± 14.7 | 95.2 ± 17.9 | <0.001 | 103 ± 14.6 | 94.8 ± 18.6 | <0.001 |
| High WC (≥88 cm in women, ≥102 cm in men) | 46.2% | 57.6% | 0.02 | 46.2% | 57.6% | 0.02 |
| BMI (kg/m 2 ) | 27.0 ± 5.2 | 27.5 ± 6.1 | 0.04 | 28.6 ± 5.7 | 27.6 ± 7.6 | 0.20 |
| High BMI (≥25 kg/m 2 ) | 60.2% | 58.7% | 0.3 | 69.5% | 53.5% | 0.004 |
| Age (years) | 53.7 ± 12.1 | 50.5 ± 12.9 | <0.001 | 54.7 ± 12.7 | 51.8 ± 13.3 | 0.03 |
| Left ventricular ejection fraction (%) | 22.6 ± 7.1 | 23.9 ± 7.5 | <0.001 | 22.8 ± 7.7 | 24.5 ± 8.1 | 0.03 |
| Peak oxygen consumption (ml/min) | 1,162 ± 456 | 879 ± 335 | <0.001 | 1,232 ± 503 | 884 ± 384 | 0.20 |
| Peak oxygen consumption (ml/kg/min) | 13.9 ± 4.9 | 12.2 ± 4.3 | <0.001 | 14.0 ± 5.7 | 12.6 ± 5.5 | <0.001 |
| Coronary artery disease | 51.9% | 24.9% | <0.001 | 48.1% | 15.8% | <0.001 |
| Severe mitral regurgitation | 20.7% | 30.3% | <0.001 | 11.6% | 18.6% | 0.049 |
| Severe tricuspid regurgitation | 11.6% | 15.8% | 0.007 | 5.4% | 14.4% | 0.004 |
| Left ventricular end-diastolic dimension (mm) | 70.2 ± 11.0 | 65.2 ± 11.0 | <0.001 | 67.0 ± 11.7 | 59.1 ± 12.9 | <0.001 |
| Left ventricular end-diastolic dimension index (mm/m 2 ) | 35.3 ± 6.53 | 36.5 ± 7.07 | <0.001 | 32.6 ± 6.42 | 33.0 ± 8.0 | 0.70 |
| New York Heart Association class III or IV | 83.4% | 83.2% | 0.5 | 65.9% | 62.0% | 0.30 |
| Hypertension | 42.9% | 35.9% | 0.001 | 41.6% | 36.2% | 0.20 |
| Diabetes | 28.2% | 27.1% | 0.3 | 35.2% | 28.8% | 0.10 |
| Smokers (past and present) | 62.7% | 47.6% | <0.001 | 57.7% | 43.3% | 0.005 |
| Serum sodium (mmol/L) | 136.3 ± 4.6 | 136.5 ± 4.6 | 0.3 | 137.4 ± 3.94 | 136.5 ± 2.27 | 0.20 |
| Serum creatinine (mg/dl) | 1.55 ± 1.38 | 1.26 ± 0.88 | <0.001 | 1.56 ± 1.90 | 1.30 ± 1.20 | 0.20 |
| Total cholesterol (mg/dl) | 166 ± 54.6 | 173 ± 59.3 | 0.02 | 149 ± 48.4 | 170 ± 48.6 | 0.001 |
| High-density lipoprotein cholesterol (mg/dl) | 34.8 ± 13.3 | 41.4 ± 20.2 | <0.001 | 36.5 ± 12.6 | 49.7 ± 29.9 | <0.001 |
| Low-density lipoprotein cholesterol (mg/dl) | 101.8 ± 41.7 | 102.0 ± 43.0 | 0.9 | 83.5 ± 35.0 | 96.9 ± 37.8 | 0.003 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use | 85.2% | 86.2% | 0.3 | 85.4% | 86.4% | 0.50 |
| Aldosterone antagonist use | 36.0% | 40.5% | 0.03 | 60.1% | 60.0% | 0.50 |
| β-blocker use | 58.0% | 55.1% | 0.1 | 95.3% | 92.0% | 0.10 |
⁎ p value determined by independent samples t-test for continuous variables and chi-square for categorical variables.
| Variable | BMI | WC | ||||
|---|---|---|---|---|---|---|
| Elevated | Normal | p Value ⁎ | Elevated | Normal | p Value ⁎ | |
| Men | ||||||
| n (%) | 1,226 (60.2%) | 814 (39.8%) | — | 159 (46.2%) | 185 (53.8%) | — |
| WC (cm) | 110 ± 12.9 | 90.7 ± 8.37 | <0.001 | 115 ± 11.5 | 92.7 ± 6.9 | <0.001 |
| High WC (≥102 cm) | 65.9% | 10.3% | <0.001 | — | — | — |
| BMI (kg/m 2 ) | 30.1 ± 4.29 | 22.4 ± 1.70 | <0.001 | 32.4 ± 5.18 | 25.0 ± 3.44 | <0.001 |
| High BMI (≥25 kg/m 2 ) | — | — | — | 93.8% | 46.3% | <0.001 |
| Age (years) | 52.9 ± 11.4 | 55.0 ± 13.0 | <0.001 | 53.1 ± 11.8 | 56.1 ± 13.3 | 0.03 |
| Left ventricular ejection fraction (%) | 22.9 ± 7.11 | 22.2 ± 6.95 | 0.04 | 23.8 ± 7.59 | 22.0 ± 7.79 | 0.03 |
| Peak oxygen consumption (ml/min) | 1,264 ± 469 | 990 ± 376 | <0.001 | 1,232 ± 503 | 884 ± 384 | 0.04 |
| Peak oxygen consumption (ml/kg per min) | 13.7 ± 4.6 | 14.2 ± 5.3 | 0.1 | 12.9 ± 4.4 | 15.0 ± 6.5 | 0.01 |
| Coronary artery disease | 51.0% | 53.3% | 0.2 | 42.3% | 53.1% | 0.30 |
| Severe mitral regurgitation | 17.0% | 26.0% | <0.001 | 10.9% | 12.3% | 0.40 |
| Severe tricuspid regurgitation | 9.0% | 15.2% | <0.001 | 2.2% | 8.3% | 0.20 |
| Left ventricular end-diastolic dimension (mm) | 70.6 ± 10.9 | 69.7 ± 11.2 | 0.1 | 67.4 ± 12.8 | 66.7 ± 10.8 | 0.60 |
| Left ventricular end-diastolic dimension index (mm/m 2 ) | 33.4 ± 5.8 | 38.1 ± 6.6 | <0.001 | 29.9 ± 5.8 | 35.0 ± 6.0 | <0.001 |
| New York Heart Association class III or IV | 80.3% | 88.1% | <0.001 | 69.2% | 63.0% | 0.20 |
| Hypertension | 47.6% | 35.7% | <0.001 | 50.0% | 34.6% | 0.003 |
| Diabetes | 32.4% | 21.5% | <0.001 | 39.6% | 31.4% | 0.07 |
| Smokers (past and present) | 63.8% | 61.2% | 0.1 | 58.6% | 56.5% | 0.40 |
| Serum sodium (mmol/L) | 136.7 ± 4.4 | 135.7 ± 4.9 | <0.001 | 137.5 ± 3.8 | 137.2 ± 4.1 | 0.50 |
| Serum creatinine (mg/dl) | 1.54 ± 1.44 | 1.56 ± 1.29 | 0.7 | 1.62 ± 1.87 | 1.51 ± 1.93 | 0.60 |
| Total cholesterol (mg/dl) | 169 ± 55.5 | 162 ± 53.0 | 0.004 | 150 ± 45.5 | 148 ± 50.1 | 0.70 |
| High-density lipoprotein cholesterol (mg/dl) | 34.1 ± 12.7 | 35.8 ± 14.2 | 0.01 | 35.4 ± 13.8 | 37.3 ± 11.4 | 0.20 |
| Low-density lipoprotein cholesterol (mg/dl) | 102.6 ± 41.7 | 100.8 ± 41.8 | 0.4 | 84.1 ± 33.6 | 83.0 ± 36.1 | 0.80 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use | 86.2% | 83.5% | 0.7 | 88.6% | 82.7% | 0.08 |
| Aldosterone antagonist use | 39.4% | 30.6% | <0.001 | 62.9% | 57.6% | 0.20 |
| β-blocker use | 62.9% | 50.3% | <0.001 | 97.5% | 93.5% | 0.07 |
| Women | ||||||
| n (%) | 387 (58.7%) | 272 (41.2%) | — | 53 (56.4%) | 41 (43.6%) | — |
| WC (cm) | 104 ± 17.3 | 82.7 ± 8.6 | <0.001 | 107 ± 14.8 | 78.3 ± 6.3 | <0.001 |
| High WC (≥88 cm) | 86.8% | 22.0% | <0.001 | — | — | — |
| BMI (kg/m 2 ) | 31.3 ± 5.0 | 22.1 ± 1.9 | <0.001 | 32.2 ± 7.1 | 22 ± 2.8 | <0.001 |
| High BMI (≥25 kg/m 2 ) | — | — | — | 83.6% | 15.9% | <0.001 |
| Age (years) | 49.3 ± 13.0 | 52.2 ± 12.6 | 0.005 | 50.2 ± 13.1 | 54 ± 13.4 | 0.10 |
| Left ventricular ejection fraction (%) | 24.0 ± 7.4 | 23.9 ± 7.8 | 0.9 | 24.7 ± 8.4 | 24.5 ± 7.8 | 0.90 |
| Peak oxygen consumption (ml/min) | 977 ± 321 | 748 ± 309 | <0.001 | 992 ± 254 | 774 ± 462 | 0.70 |
| Peak oxygen consumption (ml/kg per min) | 11.9 ± 3.7 | 12.5 ± 4.9 | 0.2 | 12 ± 2.8 | 13.2 ± 7.3 | 0.50 |
| Coronary artery disease | 24.6% | 25.4% | 0.4 | 16.2% | 15.4% | 0.60 |
| Severe mitral regurgitation | 31.0% | 29.2% | 0.4 | 21.9% | 14.3% | 0.20 |
| Severe tricuspid regurgitation | 15.5% | 16.1% | 0.5 | 9.7% | 20.4% | 0.10 |
| Left ventricular end-diastolic dimension (mm) | 66.0 ± 11.1 | 64.0 ± 10.7 | 0.04 | 59.1 ± 12.3 | 59.2 ± 13.7 | 0.90 |
| Left ventricular end-diastolic dimension index (mm/m 2 ) | 34.5 ± 6.4 | 39.4 ± 6.9 | <0.001 | 29.9 ± 7 | 36.7 ± 7.7 | <0.001 |
| New York Heart Association class III or IV | 84.9% | 80.8% | 0.1 | 67.2% | 55.3% | 0.10 |
| Hypertension | 41.0% | 28.7% | 0.001 | 38.5% | 33.3% | 0.40 |
| Diabetes | 32.3% | 19.8% | <0.001 | 41.7% | 11.3% | <0.001 |
| Smokers (past and present) | 48.3% | 46.5% | 0.4 | 48.5% | 36.5% | 0.10 |
| Serum sodium (mmol/L) | 136.4 ± 4.1 | 136.6 ± 5.1 | 0.5 | 137.6 ± 4.1 | 134.9 ± 18.4 | 0.30 |
| Serum creatinine (mg/dl) | 1.28 ± 0.82 | 1.22 ± 0.95 | 0.4 | 1.35 ± 1.21 | 1.23 ± 1.18 | 0.60 |
| Total cholesterol (mg/dl) | 178 ± 60.5 | 165 ± 56.9 | 0.1 | 174 ± 46.4 | 164.9 ± 51.6 | 0.40 |
| High-density lipoprotein cholesterol (mg/dl) | 38.9 ± 15.9 | 44.68 ± 24.37 | 0.002 | 43.9 ± 16.8 | 57.1 ± 40 | 0.04 |
| Low-density lipoprotein cholesterol (mg/dl) | 106.7 ± 43.5 | 95.9 ± 41.6 | 0.006 | 103.8 ± 38.3 | 88.4 ± 35.9 | 0.07 |
| Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use | 85.8% | 86.7% | 0.4 | 87.5% | 84.9% | 0.40 |
| Aldosterone antagonist use | 39.6% | 41.7% | 0.3 | 65.3% | 52.8% | 0.10 |
| β-blocker use | 54.5% | 56.1% | 0.4 | 93.1% | 90.6% | 0.40 |
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