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Joint Impact of Body Mass Index and Physical Capacity on Mortality in Patients With Systolic Heart Failure
Joint Impact of Body Mass Index and Physical Capacity on Mortality in Patients With Systolic Heart Failure Barak Zafrir, MDa,*, Nabia Salman, MDa, and Offer Amir, MDa,b Obesity paradox is consistently demonstrated in cohorts of patients with systolic heart failure (HF). Recent reports suggest that cardiorespiratory fitness modifies the relation between adiposity measurements and mortality. We aimed to investigate the combined effect of obesity and physical capacity, measured by body mass index (BMI) and 6-minute walk distance (SMWD) test, respectively, on the prognosis of patients with systolic HF. We studied 543 consecutive patients with advanced systolic HF at their initial visit to the HF clinic. SMWD was categorized as low (<300 m) or high (‡300 m) physical capacity and BMI according to standard classification. Association of the BMI 3 SMWD product (kilogram per meter) with total mortality was assessed by Cox proportional hazards analyses. There were 216 deaths during a mean follow-up of 40 months. Obesity paradox was observed in the study cohort but was attenuated in the high physical capacity group. High compared with low physical capacity was associated with significant survival benefit in both the normal-weight and obese patients subgroups (log-rank p [ 0.003 and p [ 0.009, respectively). A progressive inverse relation between quartiles of BMI 3 SMWD product and mortality risk was observed. Compared with the lower quartile (Q1, reference group), Q2 had hazard ratio (HR) of 0.69 (95% confidence interval [CI] 0.49 to 0.97), Q3 had HR of 0.64 (95% CI 0.44 to 0.93), and Q4 had HR of 0.40 (95% CI 0.25 to 0.65). In conclusion, obesity paradox exists in patients with systolic HF but is modified by the degree of physical capacity. Therefore, the combined parameter of BMI 3 SMWD product is more reliable in predicting long-term mortality risk in patients with systolic HF. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:1217e1221)
Emerging data suggest an association among cardiorespiratory fitness level, adiposity, and mortality in heart failure (HF) and cardiovascular diseases.1e6 We aimed to assess the combined prognostic effect of body mass index (BMI) and physical capacity in a cohort of patients with advanced systolic HF, evaluated at their first visit to an outpatient HF clinic. In difference from the aforementioned studies, we used the 6-minute walk distance (SMWD) test as a measure of physical capacity. The SMWD test, a significant prognostic marker in HF, is simple to perform, reflects physical capacity, and was recently reported by Forman et al7 to provide a similar prognostic utility in systolic HF, comparable with the more complex and expensive cardiopulmonary exercise test.8,9 Moreover, it may be more suitable for some of the obese patients to accomplish an SMWD test than regular treadmill testing. Accordingly, we used an innovative index, multiplication product of BMI and SMWD (kilogram per meter), and assessed its joint impact on mortality in patients with systolic HF.
a Heart Failure Unit, Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center & Heart Failure Clinic, Lin Medical Center, Haifa, Israel and bThe Bruce and Ruth Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Manuscript received October 12, 2013; revised manuscript received and accepted December 8, 2013. See page 1221 for disclosure information. *Corresponding author: Tel: (þ972) 48250285; fax: (þ972) 99560390. E-mail address: [email protected] (B. Zafrir).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.030
Methods Study population included 545 consecutive patients with chronic systolic HF (>3-month symptomatic HF disease) defined as left ventricular ejection fraction <40%. Two patients had BMI <18.5 kg/m2 and were excluded from data analysis because of a small group size of underweight patients. All subjects had documented BMI and SMWD measurements, carried out at their first visit to a tertiary outpatient HF clinic. BMI was categorized according to World Health Organization definitions as normal weight (18.5 to 24.9 kg/m2), overweight (25 to 29.9 kg/m2), or obese (30 kg/m2). SMWD test was conducted in a standardized format according to accepted guidelines.10 Low physical capacity was defined as SMWD <300 m, a common prognostic cutoff of reduced functional exercise capacity in HF studies.9,11 Baseline characteristics and co-morbidities were obtained from patients’ computerized medical records and routinely ascertained during the initial visit to the HF clinic in all patients. Data included hypertension, diabetes, coronary artery disease, paroxysmal or permanent atrial fibrillation, New York Heart Association grade, laboratory values of hemoglobin and creatinine, and treatment with b blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists. Two-dimensional echocardiographic studies were performed in all patients. Data concerning all-cause mortality were gathered from patients’ electronic files and computerized records of health maintenance organizations. The study was approved by the Carmel Medical Center Institutional Review Board. www.ajconline.org
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Table 1 Patients characteristics according to body mass index (BMI) and six-minute walk distance (SMWD) categories Variable
SMWD <300 m
Age (yrs) Men BSA BMI (kg/m2) Ejection fraction (%) NYHA class Hypertension Diabetes mellitus Previous myocardial infarction Atrial fibrillation Creatinine level (mg/dl) b-Blocker treatment ACEI/ARB treatment
300 m
Normal Weight
Overweight
Obese
p Value
Normal Weight
Overweight
Obese
p Value
69.8 13.0 72 (84) 1.71 0.13 22.8 1.6 24 7 3.07 0.73 45 (52) 29 (34) 47 (55) 30 (35) 1.51 0.87 76 (88) 72 (84)
68.4 11.6 97 (82) 1.85 0.15 27.1 1.5 24 7 2.95 0.70 80 (68) 59 (50) 85 (72) 44 (37) 1.41 0.78 113 (96) 101 (85)
64.5 12.3 86 (72) 2.05 1.17 34.3 3.8 26 6 2.95 0.73 91 (76) 68 (57) 77 (64) 42 (35) 1.35 0.56 112 (93) 109 (91)
0.01 0.06 <0.001 <0.001 0.09 0.417 0.002 0.004 0.237 0.915 0.323 0.181 0.274
59.9 16.3 52 (81) 1.73 0.13 22.5 1.8 24 6 2.14 0.80 23 (36) 18 (28) 34 (53) 18 (28) 1.20 0.61 58 (91) 53 (83)
60.4 13.8 72 (86) 1.90 0.14 27.1 1.4 25 6 2.04 0.63 37 (45) 28 (34) 50 (60) 15 (18) 1.20 0.59 82 (98) 78 (94)
56.3 10.2 64 (90) 2.16 0.18 33.9 3.4 25 7 2.08 0.58 38 (53) 33 (47) 32 (45) 19 (27) 1.17 0.75 68 (96) 63 (89)
0.144 0.321 <0.001 <0.001 0.658 0.628 0.04 0.03 0.171 0.286 0.940 0.172 0.537
Data are presented as numbers (percentage) or mean SD. ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BSA ¼ body surface area; NYHA ¼ New York Heart Association.
Figure 1. Mortality rates according to BMI categories. Mortality rates during follow-up period according to BMI categories in all the study patients compared with high or low physical capacity determined by the SMWD test. All patients: p ¼ 0.017; SMWD <300 m: p ¼ 0.015; and SMWD 300 m: p ¼ 0.22.
Continuous data are presented as means SD and categorical variables as numbers or percentages. The independent-samples t test and the 1-way analysis of variance were used to compare continuous variables, and the chisquare test was used to compare categorical variables. Survival curves were plotted by the Kaplan-Meier method using the log-rank test for comparison between variables. To assess the joint association of BMI and SMWD at baseline evaluation with the risk of all-cause mortality, the multiplication product of BMI and SMWD (kilogram per meter) was calculated for each patient, and a multivariate analysis was performed by the Cox proportional hazards regression analysis. Hazard ratios (HRs) for death were calculated, with 95% confidence intervals (CIs) in parentheses. Adjustment was made for other risk factors and baseline characteristics including gender, age, hypertension, diabetes mellitus, history of myocardial infarction, paroxysmal or permanent atrial fibrillation, renal dysfunction, and ejection fraction.
The results were considered statistically significant when p value was <0.05. The SPSS statistical software, version 20.0 (IBM Corporation, Armonk, New York), was used to perform all statistical analyses. Results There were 543 patients (81% men) included in the analysis. Mean age was 64 13 years. Most patients had advanced HF, with 53% New York Heart Association functional class III or IV, at their initial index visit to the HF clinic. During a mean follow-up period of 40 26 months (median 35), 216 patients (40%) died. Dividing the patients’ BMI levels according to World Health Organization categories defined 150 patients (28%) as normal weight, 202 (37%) as overweight, and 191 (35%) as obese. Baseline clinical characteristics according to BMI categories in patients with low (SMWD <300 m) and high
Heart Failure/Adiposity and Physical Capacity in HF
Figure 2. Survival according to physical capacity and weight categories. Kaplan-Meier estimates of survival in patients with systolic HF according to physical capacity of obese (BMI 30 kg/m2) and normal-weight (BMI 18.5 to 24.9 kg/m2) patients with HF. PC ¼ physical capacity.
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mortality (p ¼ 0.015) as the overall study population, but this association was significantly attenuated in the high physical capability group (p ¼ 0.22); albeit the tendency for lower mortality rates in overweight and obese patients was retained (Figure 1). In addition, high physical capacity was associated with better survival compared with lower physical capacity in both the obese and the normal-weight groups of patients (log-rank p ¼ 0.009 and p ¼ 0.003, respectively; Figure 2). The multiplication product of BMI and SMWD (kilogram per meter) was used to assess the joint impact of adiposity level and physical capacity on mortality. Mean BMI SMWD product was 7,079 kg/m (range 287 to 19,562 and median 6,797). Figure 3 shows Kaplan-Meier survival curves according to quartiles of BMI SMWD product. Long-term survival rate was significantly better in both of the upper quartiles (Q4 and Q3) compared with each of the lower quartiles (Q2 and Q1; overall log-rank test p <0.001). HRs for all-cause mortality are presented in Table 2 for each quartile of BMI SMWD product, including after adjustment for gender, age, hypertension, diabetes, history of myocardial infarction, paroxysmal or permanent atrial fibrillation, renal function, and ejection fraction (Figure 4). Compared with the lowest quartile (Q1, reference group), patients in the higher quartiles had significantly reduced risk for mortality, in a declining pattern (Q2: HR 0.69, 95% CI 0.49 to 0.97, p ¼ 0.03; Q3: HR 0.64, 95% CI 0.44 to 0.93, p ¼ 0.02; and Q4: HR 0.40, 95% CI 0.25 to 0.65, p <0.001), illustrating a combined protective effect of high BMI and increased SMWD levels on mortality risk. Discussion
Figure 3. Survival according to quartiles of BMI SMWD product. Kaplan-Meier estimates of survival in patients with systolic HF according to quartiles of the product of BMI and physical capacity assessed by the SMWD test. (BMI SMWD [kilogram per meter]: Q1 <3,448; 3,448 Q2 < 6,796; 6,796 Q3 < 10,269; and Q4 10,269.) *Log-rank test for overall comparison, p <0.001. Pairwise comparison: Q4 to Q3, p ¼ 0.002; Q4 to Q2, p <0.001; Q4 to Q1, p <0.001; Q3 to Q2, p ¼ 0.05; and Q3 to Q1, p ¼ 0.002.
(SMWD 300 m) physical capacity are presented in Table 1. Hypertension and diabetes were significantly more prevalent in overweight and obese subjects. Low physical capacity patients tended to be older, with a higher prevalence of comorbidities. In the overall study group, mortality during follow-up was highest in the normal-weight patients (49%), lower in the overweight (39%), and lowest in the obese subjects (30%) demonstrating an obesity paradox (p ¼ 0.017; Figure 1). When taking physical ability into consideration, the lower physical capability group showed the same significant linear inverse relation between BMI categories and
The present study demonstrates that patients with chronic systolic HF with elevated BMI levels have better survival rates than normal-weight subjects. This is despite the fact that co-morbidities such as hypertension and diabetes were more prevalent in the overweight and obese patients. Higher physical capacity was associated with better survival in both normal-weight and obese patients with HF. However, the obesity paradox was significantly attenuated in the group of patients with a higher physical capacity. Accordingly, a better pathophysiological combined parameter, the BMI SMWD product, demonstrated significant and stepwise reduction in mortality risk consistently across all quartiles. Obesity was shown in epidemiologic studies to predispose to the development of HF and may cause adverse effects on left ventricular function.12,13 Despite this, several studies have repeatedly shown an obesity paradox in HF and cardiovascular disorders, demonstrating better prognosis in overweight and obese subjects.14e18 This was evident not only with the use of BMI as a surrogate measure of adiposity but also with measurement of other anthropometric measures.19,20 The present study supports the concept of obesity paradox in HF. Possible reasons for the obesity paradox in this population are suggested in the literature, including better neurohormonal profile and greater metabolic reserve, earlier presentation of the disease course, and, thus, better treatment in the obese subjects, in contrast to cardiac cachexia in patients with advanced HF.13
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Table 2 Hazards ratios (HRs) for all-cause mortality according to quartiles of body mass index six-minute walk distance (BMI SMWD) product in study participants BMI SMWD Quartile Quartile Quartile Quartile
1 2 3 4
No. of Deaths (%) 71 67 51 26
(54) (48) (37) (19)
Model 1, HR (95% CI)* 1 0.78 0.55 0.27
(Reference) (0.56e1.10) (0.38e0.80) (0.17e0.42)
Model 2, HR (95% CI)† 1 0.67 0.56 0.38
(Reference) (0.47e0.94) (0.39e0.80) (0.23e0.62)
Model 3, HR (95% CI)z 1 0.69 0.64 0.40
(Reference) (0.49e0.97) (0.44e0.93) (0.25e0.65)
* Unadjusted. † Adjusted for age. z Adjusted for age plus sex, hypertension, diabetes, myocardial infarction in the past, atrial fibrillation, renal function, and ejection fraction.
Figure 4. Joint impact of BMI SMWD product on mortality. Joint impact of the product of BMI and physical capacity, assessed by the SMWD test, on mortality risk. HRs and 95% CIs (in parentheses) are presented for each quartile of BMI SMWD (kilogram per meter) after adjustment for sex, age, hypertension, diabetes, myocardial infarction in the past, atrial fibrillation, renal function, and ejection fraction.
Cardiorespiratory fitness by itself is a strong independent predictor of prognosis in the general population and in patients with chronic HF, as seen also in the present study cohort.21e24 This evidence supports the need to increase levels of physical fitness in this population, regardless of the level of obesity.25 Similar to recent studies, we observed that the obesity paradox is less prominent in subjects with high physical capacity.1e5 Therefore, it may be that good physical capacity, which is associated with better survival, may mitigate the effect of BMI on HF prognosis, and fitness level may be a possible confounding factor modifying the obesity paradox. Previous studies have shown that increased level of physical activity is associated with improved insulin sensitivity, blood pressure, and lipid profile.26e28 In addition, metabolic risk factors were reported to account for a portion of the increased mortality rate in low-fitness subjects.29 In the present study, the low physical capacity group had a higher rate of diabetes and hypertension compared with the high physical capacity group, across all BMI categories. The combination of lower BMI levels and low physical capacity is associated with poor prognosis in our systolic HF cohort. It may be that these patients have reduced muscular strength, reflecting their lower BMI values and contributing
to their low fitness level. Others have reported that increased adiposity correlates with relatively greater strength in patients with systolic HF, which may explain some of the clinical benefits that result from obesity.30 Because higher BMI levels and increased physical capacity were both shown to be individually associated with better prognosis in HF and may have interrelated interactions, we assessed their joint impact on survival by calculating their multiplication product. BMI SMWD product (kilogram per meter) demonstrated a significant progressive reduction in adjusted all-cause mortality across quartiles, enabling mortality risk stratification by taking into account the impact of both variables in a continuous, quantitative manner. Our study has several limitations. The study was performed in a single center and included predominantly patients with advanced systolic HF; thus, results may not be generalized to other HF populations. The representation of women in the study cohort was relatively low. Other potential modifiers and confounding factors may have affected the association between BMI and physical capacity, and long-term outcomes and might not have been adequately controlled for. In addition, BMI may not be an adequate marker of fat distribution, and the present study did not assess other measures
Heart Failure/Adiposity and Physical Capacity in HF
of adiposity or body composition. Furthermore, underweight patients were excluded because of small group size. Disclosures The authors have no conflicts of interest to disclose. 1. McAuley PA, Artero EG, Sui X, Lee DC, Church TS, Lavie CJ, Myers JN, España-Romero V, Blair SN. The obesity paradox, cardiorespiratory fitness, and coronary heart disease. Mayo Clin Proc 2012;87: 443e451. 2. McAuley PA, Smith NS, Emerson BT, Myers JN. The obesity paradox and cardiorespiratory fitness. J Obes 2012;2012:951582. 3. McAuley PA, Kokkinos PF, Oliveira RB, Emerson BT, Myers JN. Obesity paradox and cardiorespiratory fitness in 12,417 male veterans aged 40 to 70 years. Mayo Clin Proc 2010;85:115e121. 4. Lavie CJ, Cahalin LP, Chase P, Myers J, Bensimhon D, Peberdy MA, Ashley E, West E, Forman DE, Guazzi M, Arena R. Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure. Mayo Clin Proc 2013;88:251e258. 5. Lee DC, Sui X, Church TS, Lavie CJ, Jackson AS, Blair SN. Changes in fitness and fatness on the development of cardiovascular disease risk factors hypertension, metabolic syndrome, and hypercholesterolemia. J Am Coll Cardiol 2012;59:665e672. 6. Uretsky S, Supariwala A, Gurram S, Bonda SL, Thota N, Bezwada P, Manchireddy S, Nair S, Cohen R, Rozanski A. The interaction of exercise ability and body mass index upon long-term outcomes among patients undergoing stress-rest perfusion SPECT imaging. Am Heart J 2013;166:127e133. 7. Forman DE, Fleg JL, Kitzman DW, Brawner CA, Swank AM, McKelvie RS, Clare RM, Ellis SJ, Dunlap ME, Bittner V. 6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol 2012;60:2653e2661. 8. Ingle L, Rigby AS, Carroll S, Butterly R, King RF, Cooke CB, Cleland JG, Clark AL. Prognostic value of the 6 min walk test and self-perceived symptom severity in older patients with chronic heart failure. Eur Heart J 2007;28:560e568. 9. Zafrir B, Goren Y, Paz H, Wolff R, Salman N, Merhavi D, Lavi I, Lewis BS, Amir O. Risk score model for predicting mortality in advanced heart failure patients followed in a heart failure clinic. Congest Heart Fail 2012;18:254e261. 10. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111e117. 11. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J 2009;39:495e501. 12. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med 2002;347:305e313. 13. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. J Am Coll Cardiol HF 2013;1:93e102.
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14. Zafrir B, Adir Y, Shehadeh W, Shteinberg M, Salman N, Amir O. The association between obesity, mortality and filling pressures in pulmonary hypertension patients; the “obesity paradox”. Respir Med 2013;107:139e146. 15. Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin M. An obesity paradox in acute heart failure: analysis of body mass index and in hospital mortality for 108927 patients in the Acute Decompensated Heart Failure National Registry. Am Heart J 2007;153:74e81. 16. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F, Kosiborod M, Portnay EL, Sokol SI, Bader F, Krumholz HM. The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med 2005;165:55e61. 17. Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure: a metaanalysis. Am Heart J 2008;156:13e22. 18. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38:789e795. 19. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol 2003;91:891e894. 20. Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. J Card Fail 2011;17:374e380. 21. Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A, Karasik P, Greenberg M, Papademetriou V, Singh S. Exercise capacity and mortality in black and white men. Circulation 2008;117:614e622. 22. Blair SN, Kohl HW III, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA 1989;262:2395e2401. 23. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009;301:2024e2035. 24. Francis DP, Shamim W, Davies LC, Piepoli MF, Ponikowski P, Anker SD, Coats AJ. Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2) slope and peak VO(2). Eur Heart J 2000;21:154e161. 25. Lavie CJ, De Schutter A, Patel DA, Milani RV. Does fitness completely explain the obesity paradox? Am Heart J 2013;166:1e3. 26. American College of Sports Medicine and American Diabetes Association: joint position statement. Exercise and type 2 diabetes. Med Sci Sports Exerc 2010;42:2282e2303. 27. Durstine JL, Haskell WL. Effects of exercise training on plasma lipids and lipoproteins. Exerc Sport Sci Rev 1994;22:477e521. 28. American College of Sports Medicine. Position stand. Physical activity, physical fitness, and hypertension. Med Sci Sports Exerc 1993;25: iex. 29. Grundy SM, Barlow CE, Farrell SW, Vega GL, Haskell WL. Cardiorespiratory fitness and metabolic risk. Am J Cardiol 2012;109: 988e993. 30. Zavin A, Daniels K, Arena R, Allsup K, Lazzari A, Joseph J, Schulze PC, Lecker SH, Forman DE. Adiposity facilitates increased strength capacity in heart failure patients with reduced ejection fraction. Int J Cardiol 2013;167:2468e2471.
Emerging data suggest an association among cardiorespiratory fitness level, adiposity, and mortality in heart failure (HF) and cardiovascular diseases.1e6 We aimed to assess the combined prognostic effect of body mass index (BMI) and physical capacity in a cohort of patients with advanced systolic HF, evaluated at their first visit to an outpatient HF clinic. In difference from the aforementioned studies, we used the 6-minute walk distance (SMWD) test as a measure of physical capacity. The SMWD test, a significant prognostic marker in HF, is simple to perform, reflects physical capacity, and was recently reported by Forman et al7 to provide a similar prognostic utility in systolic HF, comparable with the more complex and expensive cardiopulmonary exercise test.8,9 Moreover, it may be more suitable for some of the obese patients to accomplish an SMWD test than regular treadmill testing. Accordingly, we used an innovative index, multiplication product of BMI and SMWD (kilogram per meter), and assessed its joint impact on mortality in patients with systolic HF.
a Heart Failure Unit, Department of Cardiovascular Medicine, Lady Davis Carmel Medical Center & Heart Failure Clinic, Lin Medical Center, Haifa, Israel and bThe Bruce and Ruth Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Manuscript received October 12, 2013; revised manuscript received and accepted December 8, 2013. See page 1221 for disclosure information. *Corresponding author: Tel: (þ972) 48250285; fax: (þ972) 99560390. E-mail address: [email protected] (B. Zafrir).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.030
Methods Study population included 545 consecutive patients with chronic systolic HF (>3-month symptomatic HF disease) defined as left ventricular ejection fraction <40%. Two patients had BMI <18.5 kg/m2 and were excluded from data analysis because of a small group size of underweight patients. All subjects had documented BMI and SMWD measurements, carried out at their first visit to a tertiary outpatient HF clinic. BMI was categorized according to World Health Organization definitions as normal weight (18.5 to 24.9 kg/m2), overweight (25 to 29.9 kg/m2), or obese (30 kg/m2). SMWD test was conducted in a standardized format according to accepted guidelines.10 Low physical capacity was defined as SMWD <300 m, a common prognostic cutoff of reduced functional exercise capacity in HF studies.9,11 Baseline characteristics and co-morbidities were obtained from patients’ computerized medical records and routinely ascertained during the initial visit to the HF clinic in all patients. Data included hypertension, diabetes, coronary artery disease, paroxysmal or permanent atrial fibrillation, New York Heart Association grade, laboratory values of hemoglobin and creatinine, and treatment with b blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and aldosterone antagonists. Two-dimensional echocardiographic studies were performed in all patients. Data concerning all-cause mortality were gathered from patients’ electronic files and computerized records of health maintenance organizations. The study was approved by the Carmel Medical Center Institutional Review Board. www.ajconline.org
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Table 1 Patients characteristics according to body mass index (BMI) and six-minute walk distance (SMWD) categories Variable
SMWD <300 m
Age (yrs) Men BSA BMI (kg/m2) Ejection fraction (%) NYHA class Hypertension Diabetes mellitus Previous myocardial infarction Atrial fibrillation Creatinine level (mg/dl) b-Blocker treatment ACEI/ARB treatment
300 m
Normal Weight
Overweight
Obese
p Value
Normal Weight
Overweight
Obese
p Value
69.8 13.0 72 (84) 1.71 0.13 22.8 1.6 24 7 3.07 0.73 45 (52) 29 (34) 47 (55) 30 (35) 1.51 0.87 76 (88) 72 (84)
68.4 11.6 97 (82) 1.85 0.15 27.1 1.5 24 7 2.95 0.70 80 (68) 59 (50) 85 (72) 44 (37) 1.41 0.78 113 (96) 101 (85)
64.5 12.3 86 (72) 2.05 1.17 34.3 3.8 26 6 2.95 0.73 91 (76) 68 (57) 77 (64) 42 (35) 1.35 0.56 112 (93) 109 (91)
0.01 0.06 <0.001 <0.001 0.09 0.417 0.002 0.004 0.237 0.915 0.323 0.181 0.274
59.9 16.3 52 (81) 1.73 0.13 22.5 1.8 24 6 2.14 0.80 23 (36) 18 (28) 34 (53) 18 (28) 1.20 0.61 58 (91) 53 (83)
60.4 13.8 72 (86) 1.90 0.14 27.1 1.4 25 6 2.04 0.63 37 (45) 28 (34) 50 (60) 15 (18) 1.20 0.59 82 (98) 78 (94)
56.3 10.2 64 (90) 2.16 0.18 33.9 3.4 25 7 2.08 0.58 38 (53) 33 (47) 32 (45) 19 (27) 1.17 0.75 68 (96) 63 (89)
0.144 0.321 <0.001 <0.001 0.658 0.628 0.04 0.03 0.171 0.286 0.940 0.172 0.537
Data are presented as numbers (percentage) or mean SD. ACEI ¼ angiotensin-converting enzyme inhibitor; ARB ¼ angiotensin receptor blocker; BSA ¼ body surface area; NYHA ¼ New York Heart Association.
Figure 1. Mortality rates according to BMI categories. Mortality rates during follow-up period according to BMI categories in all the study patients compared with high or low physical capacity determined by the SMWD test. All patients: p ¼ 0.017; SMWD <300 m: p ¼ 0.015; and SMWD 300 m: p ¼ 0.22.
Continuous data are presented as means SD and categorical variables as numbers or percentages. The independent-samples t test and the 1-way analysis of variance were used to compare continuous variables, and the chisquare test was used to compare categorical variables. Survival curves were plotted by the Kaplan-Meier method using the log-rank test for comparison between variables. To assess the joint association of BMI and SMWD at baseline evaluation with the risk of all-cause mortality, the multiplication product of BMI and SMWD (kilogram per meter) was calculated for each patient, and a multivariate analysis was performed by the Cox proportional hazards regression analysis. Hazard ratios (HRs) for death were calculated, with 95% confidence intervals (CIs) in parentheses. Adjustment was made for other risk factors and baseline characteristics including gender, age, hypertension, diabetes mellitus, history of myocardial infarction, paroxysmal or permanent atrial fibrillation, renal dysfunction, and ejection fraction.
The results were considered statistically significant when p value was <0.05. The SPSS statistical software, version 20.0 (IBM Corporation, Armonk, New York), was used to perform all statistical analyses. Results There were 543 patients (81% men) included in the analysis. Mean age was 64 13 years. Most patients had advanced HF, with 53% New York Heart Association functional class III or IV, at their initial index visit to the HF clinic. During a mean follow-up period of 40 26 months (median 35), 216 patients (40%) died. Dividing the patients’ BMI levels according to World Health Organization categories defined 150 patients (28%) as normal weight, 202 (37%) as overweight, and 191 (35%) as obese. Baseline clinical characteristics according to BMI categories in patients with low (SMWD <300 m) and high
Heart Failure/Adiposity and Physical Capacity in HF
Figure 2. Survival according to physical capacity and weight categories. Kaplan-Meier estimates of survival in patients with systolic HF according to physical capacity of obese (BMI 30 kg/m2) and normal-weight (BMI 18.5 to 24.9 kg/m2) patients with HF. PC ¼ physical capacity.
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mortality (p ¼ 0.015) as the overall study population, but this association was significantly attenuated in the high physical capability group (p ¼ 0.22); albeit the tendency for lower mortality rates in overweight and obese patients was retained (Figure 1). In addition, high physical capacity was associated with better survival compared with lower physical capacity in both the obese and the normal-weight groups of patients (log-rank p ¼ 0.009 and p ¼ 0.003, respectively; Figure 2). The multiplication product of BMI and SMWD (kilogram per meter) was used to assess the joint impact of adiposity level and physical capacity on mortality. Mean BMI SMWD product was 7,079 kg/m (range 287 to 19,562 and median 6,797). Figure 3 shows Kaplan-Meier survival curves according to quartiles of BMI SMWD product. Long-term survival rate was significantly better in both of the upper quartiles (Q4 and Q3) compared with each of the lower quartiles (Q2 and Q1; overall log-rank test p <0.001). HRs for all-cause mortality are presented in Table 2 for each quartile of BMI SMWD product, including after adjustment for gender, age, hypertension, diabetes, history of myocardial infarction, paroxysmal or permanent atrial fibrillation, renal function, and ejection fraction (Figure 4). Compared with the lowest quartile (Q1, reference group), patients in the higher quartiles had significantly reduced risk for mortality, in a declining pattern (Q2: HR 0.69, 95% CI 0.49 to 0.97, p ¼ 0.03; Q3: HR 0.64, 95% CI 0.44 to 0.93, p ¼ 0.02; and Q4: HR 0.40, 95% CI 0.25 to 0.65, p <0.001), illustrating a combined protective effect of high BMI and increased SMWD levels on mortality risk. Discussion
Figure 3. Survival according to quartiles of BMI SMWD product. Kaplan-Meier estimates of survival in patients with systolic HF according to quartiles of the product of BMI and physical capacity assessed by the SMWD test. (BMI SMWD [kilogram per meter]: Q1 <3,448; 3,448 Q2 < 6,796; 6,796 Q3 < 10,269; and Q4 10,269.) *Log-rank test for overall comparison, p <0.001. Pairwise comparison: Q4 to Q3, p ¼ 0.002; Q4 to Q2, p <0.001; Q4 to Q1, p <0.001; Q3 to Q2, p ¼ 0.05; and Q3 to Q1, p ¼ 0.002.
(SMWD 300 m) physical capacity are presented in Table 1. Hypertension and diabetes were significantly more prevalent in overweight and obese subjects. Low physical capacity patients tended to be older, with a higher prevalence of comorbidities. In the overall study group, mortality during follow-up was highest in the normal-weight patients (49%), lower in the overweight (39%), and lowest in the obese subjects (30%) demonstrating an obesity paradox (p ¼ 0.017; Figure 1). When taking physical ability into consideration, the lower physical capability group showed the same significant linear inverse relation between BMI categories and
The present study demonstrates that patients with chronic systolic HF with elevated BMI levels have better survival rates than normal-weight subjects. This is despite the fact that co-morbidities such as hypertension and diabetes were more prevalent in the overweight and obese patients. Higher physical capacity was associated with better survival in both normal-weight and obese patients with HF. However, the obesity paradox was significantly attenuated in the group of patients with a higher physical capacity. Accordingly, a better pathophysiological combined parameter, the BMI SMWD product, demonstrated significant and stepwise reduction in mortality risk consistently across all quartiles. Obesity was shown in epidemiologic studies to predispose to the development of HF and may cause adverse effects on left ventricular function.12,13 Despite this, several studies have repeatedly shown an obesity paradox in HF and cardiovascular disorders, demonstrating better prognosis in overweight and obese subjects.14e18 This was evident not only with the use of BMI as a surrogate measure of adiposity but also with measurement of other anthropometric measures.19,20 The present study supports the concept of obesity paradox in HF. Possible reasons for the obesity paradox in this population are suggested in the literature, including better neurohormonal profile and greater metabolic reserve, earlier presentation of the disease course, and, thus, better treatment in the obese subjects, in contrast to cardiac cachexia in patients with advanced HF.13
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The American Journal of Cardiology (www.ajconline.org)
Table 2 Hazards ratios (HRs) for all-cause mortality according to quartiles of body mass index six-minute walk distance (BMI SMWD) product in study participants BMI SMWD Quartile Quartile Quartile Quartile
1 2 3 4
No. of Deaths (%) 71 67 51 26
(54) (48) (37) (19)
Model 1, HR (95% CI)* 1 0.78 0.55 0.27
(Reference) (0.56e1.10) (0.38e0.80) (0.17e0.42)
Model 2, HR (95% CI)† 1 0.67 0.56 0.38
(Reference) (0.47e0.94) (0.39e0.80) (0.23e0.62)
Model 3, HR (95% CI)z 1 0.69 0.64 0.40
(Reference) (0.49e0.97) (0.44e0.93) (0.25e0.65)
* Unadjusted. † Adjusted for age. z Adjusted for age plus sex, hypertension, diabetes, myocardial infarction in the past, atrial fibrillation, renal function, and ejection fraction.
Figure 4. Joint impact of BMI SMWD product on mortality. Joint impact of the product of BMI and physical capacity, assessed by the SMWD test, on mortality risk. HRs and 95% CIs (in parentheses) are presented for each quartile of BMI SMWD (kilogram per meter) after adjustment for sex, age, hypertension, diabetes, myocardial infarction in the past, atrial fibrillation, renal function, and ejection fraction.
Cardiorespiratory fitness by itself is a strong independent predictor of prognosis in the general population and in patients with chronic HF, as seen also in the present study cohort.21e24 This evidence supports the need to increase levels of physical fitness in this population, regardless of the level of obesity.25 Similar to recent studies, we observed that the obesity paradox is less prominent in subjects with high physical capacity.1e5 Therefore, it may be that good physical capacity, which is associated with better survival, may mitigate the effect of BMI on HF prognosis, and fitness level may be a possible confounding factor modifying the obesity paradox. Previous studies have shown that increased level of physical activity is associated with improved insulin sensitivity, blood pressure, and lipid profile.26e28 In addition, metabolic risk factors were reported to account for a portion of the increased mortality rate in low-fitness subjects.29 In the present study, the low physical capacity group had a higher rate of diabetes and hypertension compared with the high physical capacity group, across all BMI categories. The combination of lower BMI levels and low physical capacity is associated with poor prognosis in our systolic HF cohort. It may be that these patients have reduced muscular strength, reflecting their lower BMI values and contributing
to their low fitness level. Others have reported that increased adiposity correlates with relatively greater strength in patients with systolic HF, which may explain some of the clinical benefits that result from obesity.30 Because higher BMI levels and increased physical capacity were both shown to be individually associated with better prognosis in HF and may have interrelated interactions, we assessed their joint impact on survival by calculating their multiplication product. BMI SMWD product (kilogram per meter) demonstrated a significant progressive reduction in adjusted all-cause mortality across quartiles, enabling mortality risk stratification by taking into account the impact of both variables in a continuous, quantitative manner. Our study has several limitations. The study was performed in a single center and included predominantly patients with advanced systolic HF; thus, results may not be generalized to other HF populations. The representation of women in the study cohort was relatively low. Other potential modifiers and confounding factors may have affected the association between BMI and physical capacity, and long-term outcomes and might not have been adequately controlled for. In addition, BMI may not be an adequate marker of fat distribution, and the present study did not assess other measures
Heart Failure/Adiposity and Physical Capacity in HF
of adiposity or body composition. Furthermore, underweight patients were excluded because of small group size. Disclosures The authors have no conflicts of interest to disclose. 1. McAuley PA, Artero EG, Sui X, Lee DC, Church TS, Lavie CJ, Myers JN, España-Romero V, Blair SN. The obesity paradox, cardiorespiratory fitness, and coronary heart disease. Mayo Clin Proc 2012;87: 443e451. 2. McAuley PA, Smith NS, Emerson BT, Myers JN. The obesity paradox and cardiorespiratory fitness. J Obes 2012;2012:951582. 3. McAuley PA, Kokkinos PF, Oliveira RB, Emerson BT, Myers JN. Obesity paradox and cardiorespiratory fitness in 12,417 male veterans aged 40 to 70 years. Mayo Clin Proc 2010;85:115e121. 4. Lavie CJ, Cahalin LP, Chase P, Myers J, Bensimhon D, Peberdy MA, Ashley E, West E, Forman DE, Guazzi M, Arena R. Impact of cardiorespiratory fitness on the obesity paradox in patients with heart failure. Mayo Clin Proc 2013;88:251e258. 5. Lee DC, Sui X, Church TS, Lavie CJ, Jackson AS, Blair SN. Changes in fitness and fatness on the development of cardiovascular disease risk factors hypertension, metabolic syndrome, and hypercholesterolemia. J Am Coll Cardiol 2012;59:665e672. 6. Uretsky S, Supariwala A, Gurram S, Bonda SL, Thota N, Bezwada P, Manchireddy S, Nair S, Cohen R, Rozanski A. The interaction of exercise ability and body mass index upon long-term outcomes among patients undergoing stress-rest perfusion SPECT imaging. Am Heart J 2013;166:127e133. 7. Forman DE, Fleg JL, Kitzman DW, Brawner CA, Swank AM, McKelvie RS, Clare RM, Ellis SJ, Dunlap ME, Bittner V. 6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol 2012;60:2653e2661. 8. Ingle L, Rigby AS, Carroll S, Butterly R, King RF, Cooke CB, Cleland JG, Clark AL. Prognostic value of the 6 min walk test and self-perceived symptom severity in older patients with chronic heart failure. Eur Heart J 2007;28:560e568. 9. Zafrir B, Goren Y, Paz H, Wolff R, Salman N, Merhavi D, Lavi I, Lewis BS, Amir O. Risk score model for predicting mortality in advanced heart failure patients followed in a heart failure clinic. Congest Heart Fail 2012;18:254e261. 10. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111e117. 11. Rasekaba T, Lee AL, Naughton MT, Williams TJ, Holland AE. The six-minute walk test: a useful metric for the cardiopulmonary patient. Intern Med J 2009;39:495e501. 12. Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG, Kannel WB, Vasan RS. Obesity and the risk of heart failure. N Engl J Med 2002;347:305e313. 13. Lavie CJ, Alpert MA, Arena R, Mehra MR, Milani RV, Ventura HO. Impact of obesity and the obesity paradox on prevalence and prognosis in heart failure. J Am Coll Cardiol HF 2013;1:93e102.
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14. Zafrir B, Adir Y, Shehadeh W, Shteinberg M, Salman N, Amir O. The association between obesity, mortality and filling pressures in pulmonary hypertension patients; the “obesity paradox”. Respir Med 2013;107:139e146. 15. Fonarow GC, Srikanthan P, Costanzo MR, Cintron GB, Lopatin M. An obesity paradox in acute heart failure: analysis of body mass index and in hospital mortality for 108927 patients in the Acute Decompensated Heart Failure National Registry. Am Heart J 2007;153:74e81. 16. Curtis JP, Selter JG, Wang Y, Rathore SS, Jovin IS, Jadbabaie F, Kosiborod M, Portnay EL, Sokol SI, Bader F, Krumholz HM. The obesity paradox: body mass index and outcomes in patients with heart failure. Arch Intern Med 2005;165:55e61. 17. Oreopoulos A, Padwal R, Kalantar-Zadeh K, Fonarow GC, Norris CM, McAlister FA. Body mass index and mortality in heart failure: a metaanalysis. Am Heart J 2008;156:13e22. 18. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Woo MA, Tillisch JH. The relationship between obesity and mortality in patients with heart failure. J Am Coll Cardiol 2001;38:789e795. 19. Lavie CJ, Osman AF, Milani RV, Mehra MR. Body composition and prognosis in chronic systolic heart failure: the obesity paradox. Am J Cardiol 2003;91:891e894. 20. Clark AL, Fonarow GC, Horwich TB. Waist circumference, body mass index, and survival in systolic heart failure: the obesity paradox revisited. J Card Fail 2011;17:374e380. 21. Kokkinos P, Myers J, Kokkinos JP, Pittaras A, Narayan P, Manolis A, Karasik P, Greenberg M, Papademetriou V, Singh S. Exercise capacity and mortality in black and white men. Circulation 2008;117:614e622. 22. Blair SN, Kohl HW III, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality: a prospective study of healthy men and women. JAMA 1989;262:2395e2401. 23. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, Sugawara A, Totsuka K, Shimano H, Ohashi Y, Yamada N, Sone H. Cardiorespiratory fitness as a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009;301:2024e2035. 24. Francis DP, Shamim W, Davies LC, Piepoli MF, Ponikowski P, Anker SD, Coats AJ. Cardiopulmonary exercise testing for prognosis in chronic heart failure: continuous and independent prognostic value from VE/VCO(2) slope and peak VO(2). Eur Heart J 2000;21:154e161. 25. Lavie CJ, De Schutter A, Patel DA, Milani RV. Does fitness completely explain the obesity paradox? Am Heart J 2013;166:1e3. 26. American College of Sports Medicine and American Diabetes Association: joint position statement. Exercise and type 2 diabetes. Med Sci Sports Exerc 2010;42:2282e2303. 27. Durstine JL, Haskell WL. Effects of exercise training on plasma lipids and lipoproteins. Exerc Sport Sci Rev 1994;22:477e521. 28. American College of Sports Medicine. Position stand. Physical activity, physical fitness, and hypertension. Med Sci Sports Exerc 1993;25: iex. 29. Grundy SM, Barlow CE, Farrell SW, Vega GL, Haskell WL. Cardiorespiratory fitness and metabolic risk. Am J Cardiol 2012;109: 988e993. 30. Zavin A, Daniels K, Arena R, Allsup K, Lazzari A, Joseph J, Schulze PC, Lecker SH, Forman DE. Adiposity facilitates increased strength capacity in heart failure patients with reduced ejection fraction. Int J Cardiol 2013;167:2468e2471.