Relation of Obesity to Heart Failure Hospitalization and Cardiovascular Events in Persons With Stable Coronary Heart Disease (from

the Heart and Soul Study)

Christian Spies, MDa, Ramin Farzaneh-Far, MDb,c,*, Beeya Na, MPHb, Alka Kanaya, MDc, Nelson B. Schiller, MDc, and Mary A. Whooley, MDb,c,d
Obesity is an independent risk factor for recurrent events among patients with established coronary heart disease (CHD). The goal of the present study was to identify potential mechanisms underlying this association. We measured the waist-to-hip ratio and body mass index in 979 outpatients with stable CHD and followed them for a mean of 4.9 years. We used proportional hazards models to evaluate the extent to which the association of obesity with subsequent heart failure (HF) hospitalization or cardiovascular (CV) events (myocardial infarction, stroke, or CHD death) was explained by baseline co-morbidities, cardiac disease severity, inammation, insulin resistance, neurohormones and adipokines. Of the 979 participants, 128 (13%) were hospitalized for HF and 152 (16%) developed a CV event. Each standard deviation (SD) increase in the waist-to-hip ratio was associated with a 30% increased risk of HF hospitalization (unadjusted hazard ratio [HR] 1.3, 95% condence interval [CI] 1.1 to 1.6). This association was not attenuated after adjustment for potential mediators (HR 1.6, 95% CI 1.2 to 2.1). Likewise, each SD increase in the waist-to-hip ratio was associated with a 20% greater risk of CV events (unadjusted HR 1.2, 95% CI 1.0 to 1.4), and this remained unchanged after adjustment for potential mediators (adjusted HR 1.3, 95% CI 1.0 to 1.5). The body mass index was not associated with the risk of HF or CV events. In conclusion, abdominal obesity is an independent predictor of HF hospitalization and recurrent CV events in patients with stable CHD. This association does not appear to be mediated by co-morbid conditions, cardiac disease severity, insulin resistance, inammation, neurohormones, or adipokines. 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:883 889) Obesity is an independent risk factor for heart failure (HF) and cardiovascular (CV) events in the general population,1 patients with established CV disease,2 and elderly persons.3 Many potential mechanisms have been proposed to explain the association of obesity with CV events including increased severity of CV disease,4 systemic inammation,5 insulin resistance,6 neurohormonal activation,7 and abnormalities in adipokine pathways.8 To date, no single study has evaluated all of these potential mechanisms simultaneously. To identify potential mediators of the association between obesity and CV events in patients with
a Queens Medical Center, Honolulu, Hawaii; bSan Francisco Veterans Affairs Medical Center, cDepartment of Medicine, University of California, San Francisco, and dDepartment of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Manuscript received January 24, 2009; revised manuscript received and accepted May 18, 2009. The Heart and Soul Study was funded by the Department of Veterans Affairs, Washington, DC; the National Heart Lung and Blood Institute, Grant RO 1 HL079235, Bethesda, Maryland; the American Federation for Aging Research (Paul Beeson Scholars Program), New York, New York; the Robert Wood Johnson Foundation (Faculty Scholars Program), Princeton, New Jersey; and the Nancy Kirwan Heart Research Fund, San Francisco, California. Dr. Farzaneh-Far was supported by an American Heart Association Fellow-to-Faculty Transition Award (Dallas, Texas). *Corresponding author: Tel: (617) 642-8373; fax: (415) 376-1175. E-mail address: rfarzanehfar@medicine.ucsf.edu (R. Farzaneh-Far).

stable coronary heart disease (CHD), we performed a prospective cohort study with high-resolution phenotyping of obesity, CV events, and putative mediating variables. Methods The Heart and Soul Study is a prospective cohort study investigating how psychosocial factors inuence the outcomes of patients with CHD. The methods have been previously described.9 In brief, we recruited outpatients with CHD who were identied through administrative databases from 2 Department of Veterans Affairs Medical Centers (San Francisco and Palo Alto, California), 1 University Medical Center (University of California, San Francisco, California), and 9 public health clinics in the Community Health Network of San Francisco. Eligible participants had 1 of the following: (1) history of myocardial infarction, (2) angiographic evidence of 50% stenosis in 1 coronary vessels, (3) evidence of exercise-induced ischemia by treadmill electrocardiogram or stress nuclear perfusion imaging, or (4) a history of coronary revascularization. A total of 15,438 eligible patients were invited by mail to make an appointment for a baseline study visit. The patients were excluded if they were unable to walk 1 block, had had an acute coronary syndrome in the previous 6 months, or were planning to move out of the local area within 3 years. From September 2000 and December 2002, 1,024 participants were enrolled, and 995 of these provided waist-to-hip
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0002-9149/09/$ see front matter 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.05.027

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Table 1 Baseline characteristics stratied by tertile of waist-to-hip ratio (WHR) Variable Tertile 1 (n 327; Minimum 0.73; Maximum 0.92) 65 11 199 (61%) 168 (52%) 219 (67%) 173 (53%) 73 (22%) 67 (20%) 183 (56%) 189 (58%) 153 (47%) 242 (74%) 13.7 1.4 81.8 30.2 8.1 3.7 133.5 21.9 86 (26%) 67 (20%) 0.62 0.10 95.2 26.7 28 (13%) 62 (27%) 5.2 1.3 0.4 1.3 0.8 0.7 1.3 0.9 113.9 34.4 5.6 0.9 50.2 25.0 35.6 25.2 17.1 0.8 9.0 0.6 8.8 1.3 Tertile 2 (n 326; Minimum 0.92; Maximum 0.99) 68 10 296 (91%) 191 (59) 229 (70%) 147 (46%) 84 (26%) 54 (17%) 187 (57%) 215 (66%) 173 (53%) 256 (79%) 13.9 1.4 80.3 26.5 7.4 3.2 133.8 21.4 101 (31%) 65 (20%) 0.61 0.10 100.2 27.7 48 (13%) 91 (24%) 5.3 1.4 0.8 1.2 1.0 0.7 1.3 0.9 119.7 46.8 5.7 0.6 52.0 28.7 38.9 34.4 16.8 0.8 9.0 0.5 8.9 1.0 Tertile 3 (n 326; Minimum 0.99; Maximum 1.25) 68 10 313 (96%) 225 (69) 247 (76%) 199 (61%) 100 (31%) 94 (29%) 204 (63%) 231 (71%) 174 (53%) 263 (81%) 14.0 1.4 80.9 28.5 6.5 2.9 131.9 19.7 91 (28%) 57 (17%) 0.62 0.09 98.9 23.6 35 (13%) 61 (22%) 5.2 1.3 0.9 1.3 1.1 0.6 1.2 0.9 123.9 41.7 5.8 0.7 53.2 25.7 40.8 28.1 16.8 0.8 9.1 0.6 9.2 1.0 p Value (ANOVA or Chi-Square) 0.0001 0.0001 0.0001 0.04 0.0004 0.05 0.0005 0.20 0.002 0.16 0.11 0.004 0.80 0.0001 0.44 0.37 0.58 0.65 0.04 1.0 0.38 0.81 0.0001 0.0001 0.88 0.008 0.002 0.35 0.11 0.0001 0.01 0.0001

Age (years) Men White Hypertension Myocardial infarction Diabetes mellitus NYHA III/IV -Blocker use Statin use ACE inhibitor use Aspirin use Hemoglobin (g/dl) Creatinine clearance (ml/min) Exercise capacity (Mets) Systolic blood pressure (mm Hg) Regular alcohol use (4/wk) Current smoker Ejection fraction LV mass index (g/m2) Diastolic dysfunction Inducible ischemia Log NT-proBNP Log CRP Log IL-6 Log TNF- Fasting glucose (mg/dl) Log insulin 24-Hour urine norepinephrine (g) 24-Hour urine cortisol (g) Log adiponectin Log resistin Log leptin

Data are presented as mean SD for continuous variables or numbers (%). ACE angiotensin-converting enzyme; ANOVA analysis of variance; CRP C-reactive protein; IL-6 interleukin-6; LV left ventricular; NT-proBNP prohormone brain-type natriuretic peptide; NYHA New York Heart Association; TNF- tumor necrosis factor-.

measurements. Of these, 979 participants (98%) were available for follow-up. The institutional review board at each of the sites approved this protocol, and all participants provided written informed consent. The waist and hip circumferences were measured with a exible plastic measure to the nearest 0.1 cm. The waist circumference was measured midway between the lower rib margin and the iliac crest. The hip circumference was measured at the level of the greater trochanters. The waist-to-hip ratio (WHR) was calculated as the waist circumference divided by the hip circumference. Participants were stratied into tertiles according to their WHR. The body mass index (BMI) was calculated as the weight in kilograms divided by the height squared in meters. The participants were categorized as normal weight (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25 to 29.9 kg/m2), or obese (BMI 30 kg/m2).10 A complete, at rest, 2-dimensional echocardiogram using an Acuson Sequoia Ultrasound System (Mountain View, California) with a 3.5-MHz transducer and Doppler ultrasound examination, including all standard views and subcostal imaging of the inferior vena cava, was performed just

before and immediately after exercise. All echocardiograms were interpreted by 1 cardiologist (NBS). We obtained standard 2-dimensional parasternal short-axis and apical 2and 4-chamber views during held inspiration; these were planimetered using a computerized digitization system to determine the end-diastolic and end-systolic left ventricular volume. We calculated the left ventricular ejection fraction as (end-diastolic volume end-systolic volume)/end-diastolic volume. We categorized participants as having diastolic dysfunction if the velocitytime integral in the pulmonary vein was greater during diastole than during systole.11,12 The left ventricular mass index was measured on the echocardiogram at rest using the truncated ellipsoid method.13 We performed a symptom-limited, graded exercise treadmill test according to the standard Bruce protocol.14 To achieve the maximal heart rate, the participants who were unable to continue the standard Bruce protocol were switched to lower settings on the treadmill and encouraged to exercise for as long as possible. The participants underwent echocardiography immediately after exercise, and inducible ischemia was dened as the presence of echocar-

Coronary Artery Disease/Relation of Obesity to Heart Failure Table 2 Baseline characteristics stratied according to body mass index (BMI) Variable Age (years) Men White Hypertension Myocardial infarction Diabetes mellitus NYHA III/IV -Blocker use Statin use ACE inhibitor use Aspirin use Hemoglobin (g/dl) Creatinine clearance (ml/min) Exercise capacity (Mets) Systolic blood pressure (mm Hg) Regular alcohol use (4/wk) Current smoking Ejection fraction LV mass index (g/m2) Diastolic dysfunction Inducible ischemia Log NT-proBNP Log CRP Log IL-6 Log TNF- Fasting glucose (mg/dl) Log insulin 24-Hour urine norepinephrine (g) 24-Hour urine cortisol (g) Log adiponectin Log resistin Log leptin Normal (BMI 18.524.9 kg/m2; n 249) 68 11 213 (86%) 147 (60%) 169 (68%) 138 (55%) 54 (22%) 49 (20%) 134 (54%) 142 (57%) 116 (47%) 188 (76%) 13.7 1.4 75.5 28.2 7.8 3.7 132.4 21.9 76 (31%) 65 (26%) 0.61 0.11 98.9 29.7 28 (13) 62 (27) 5.4 1.4 0.5 1.4 0.8 0.8 1.3 0.9 115.1 47.9 5.4 0.8 48.1 26.9 37.2 36.7 17.1 0.9 9.1 0.6 8.1 1.0 Overweight (BMI 2529.9 kg/m2; n 415) 68 10 351 (85%) 247 (60%) 280 (68%) 219 (53%) 97 (23%) 82 (20%) 254 (61%) 288 (69%) 220 (53%) 321 (77%) 13.9 1.4 80.3 26.5 7.7 3.3 133.0 21.8 116 (28%) 64 (15%) 0.62 0.09 96.5 24.1 48 (13) 91 (24) 5.2 1.3 0.6 1.3 0.9 0.7 1.2 0.8 114.0 32.8 5.7 0.6 48.6 20.9 37.9 26.1 16.9 0.8 9.0 0.6 9.0 0.9 Obese (BMI 30 kg/m2; n 306) 65 10 237 (77%) 187 (61%) 238 (78%) 155 (51%) 106 (35%) 80 (26%) 181 (59%) 202 (66%) 162 (53%) 245 (80%) 13.9 1.4 86.4 29.2 6.5 2.9 133.9 19.1 83 (27%) 54 (18%) 0.62 0.09 99.4 25.7 35 (13) 61 (22) 5.0 1.3 1.0 1.2 1.1 0.6 1.2 0.9 130.2 44.6 5.9 0.6 59.1 31.3 40.2 27.7 16.7 0.8 9.0 0.6 9.7 1.0

885

p Value (ANOVA or Chi-Square Test) 0.0001 0.02 0.88 0.005 0.61 0.0004 0.08 0.17 0.005 0.22 0.42 0.17 0.0001 0.0001 0.70 0.62 0.003 0.12 0.28 1.0 0.38 0.003 0.0001 0.0001 0.34 0.0001 0.0001 0.0001 0.49 0.0001 0.32 0.0001

Data are presented as mean SD for continuous variables or numbers (%). BMI body mass index; other abbreviations as in Table 1.

Figure 1. Kaplan-Meier plot for survival free of HF hospitalization by tertile of WHR (p 0.03, log-rank test).

Figure 2. Kaplan-Meier plot for survival free of CV events (myocardial infarction, stroke, CHD death) by tertile of WHR (p 0.10, log-rank test).

diographic wall motion abnormalities at peak exercise that were not present on the at rest echocardiogram. Before the study appointment, the participants completed an overnight fast, except for taking their regularly pre-

scribed medications. Venous blood samples were obtained, and the plasma and serum samples were stored at 70C. The details of the analyses for prohormone brain-type natriuretic peptide, C-reactive protein, and 24-hour urine nor-

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Table 3 Association of waist-to-hip ratio (WHR) and body mass index (BMI) with subsequent heart failure (HF) among all participants Model BMI per SD Increase HR (95% CI)* Unadjusted Plus demographics Above plus medical history Above plus medications Above plus behaviors Above plus cardiac function Above plus inammatory markers# Above plus glucose intolerance** Above plus neurohormones Above plus Adipokines Above plus hemoglobin Above plus creatinine clearance Above plus BMI

WHR per SD Increase p Value 0.49 0.13 0.65 0.60 0.83 0.47 0.51 0.80 0.90 0.61 0.52 0.37 HR (95% CI)* 1.3 (1.11.6) 1.3 (1.11.6) 1.2 (1.01.4) 1.2 (1.01.5) 1.3 (1.11.6) 1.5 (1.11.9) 1.5 (1.11.9) 1.5 (1.22.0) 1.6 (1.22.1) 1.7 (1.22.3) 1.6 (1.22.1) 1.6 (1.22.1) 1.6 (1.22.1) p Value 0.0007 0.002 0.03 0.02 0.009 0.003 0.004 0.0007 0.002 0.001 0.002 0.001 0.002

1.1 (0.91.3) 1.1 (1.01.4) 1.0 (0.91.3) 1.1 (0.91.3) 1.0 (0.81.2) 1.1 (0.91.4) 1.1 (0.91.3) 1.0 (0.81.3) 1.0 (0.81.3) 0.9 (0.71.3) 0.9 (0.71.2) 0.9 (0.61.2)

* Adjusted for variables associated with HF (at p 0.05) from previous step plus the variables as listed. Age, male gender, and white race. Hypertension, myocardial infarction, diabetes, NYHA class III/IV. Blocker, statin, ACE inhibitor, and aspirin. Exercise capacity, systolic blood pressure, regular alcohol use, and smoking. Ejection fraction, left ventricular mass index, diastolic dysfunction, inducible ischemia, total cholesterol, and log NT-proBNP. # CRP, IL-6, and TNF-. ** Fasting glucose and log insulin. 24-Hour urine norepinephrine and cortisol. Log adiponectin, log resistin, and log leptin. CI condence interval; HR hazard ratio; other abbreviations as in Tables 1 and 2.

epinephrine and cortisol levels have been previously published.1518 Tumor necrosis factor-, interleukin-6, insulin, adiponectin, resistin, and leptin levels were determined using immunoassays (LINCOplex System, Millipore, St. Charles, Missouri). We used the Human Serum Adipokine Panel A to measure adiponectin and resistin and the Human Serum Adipokine Panel B to measure leptin, tumor necrosis factor-, and insulin. The R&D Systems (Minneapolis, Minnesota) Quantikine HS interleukin-6 immunoassay was used to determine the concentration of interleukin-6. The laboratory technicians who performed the assays were unaware of the patient characteristics and echocardiographic results. Self-reported age, gender, ethnicity, medical history, and smoking status were determined by questionnaire. We assessed the New York Heart Association Classication as the self-reported limitation of physical activity because of CV symptoms (i.e., fatigue, shortness of breath, or chest pain). The responses were dichotomized into New York Heart Association class I or II (no or slight limitation) versus New York Heart Association class III or IV (marked limitation or symptoms present at rest). To assess medication use, we performed a detailed interview. The participants were instructed to bring their medication bottles to the study appointment, and the study personnel recorded all current medications. The medications were categorized using Epocrates Rx. (San Mateo, California). The outcomes were hospitalization for HF or CV events (i.e., myocardial infarction, stroke, or cardiac death). We conducted annual telephone follow-up interviews with the participants (or their proxy) to ask about death or hospitalization for heart trouble. For any reported event, the

medical records, electrocardiograms, death certicates, and coroners reports were retrieved and reviewed by 2 independent and blinded adjudicators. If the adjudicators agreed on the outcome classication, their classication was binding. In the event of a disagreement, the adjudicators conferred, reconsidered their classication, and requested consultation from a third blinded adjudicator. HF was dened as hospitalization for a clinical syndrome involving 2 of the following: paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary rales, third heart sound, and cardiomegaly or pulmonary edema on a chest radiograph. These clinical signs and symptoms must have represented a clear change from the normal clinical status of the participant and must have been accompanied by either decreased cardiac output as determined by peripheral hypoperfusion (in the absence of other causes such as sepsis or dehydration) or peripheral or pulmonary edema. Supportive documentation of reduced cardiac output, elevated pulmonary capillary wedge pressure, decreased oxygen saturation, and a symptomatic response to diuretic therapy were assessed.19 We also examined incident HF as an outcome among the 806 patients who did not report a history of HF. Nonfatal myocardial infarction was dened using the American Heart Association diagnostic criteria.20 Cardiac death was dened as (1) death during the same hospitalization in which an acute myocardial infarction was documented, or (2) death not explained by other etiologies that occurred within 1 hour of the onset of terminal symptoms.21 Stroke was dened as a new neurologic decit not known to be secondary to brain trauma, tumor, infection, or another cause.

Coronary Artery Disease/Relation of Obesity to Heart Failure Table 4 Association of body mass index and waist-to-hip ratio (WHR) with hospitalization for heart failure (HR) among 806 participants without a history of heart failure (HF) Model Body Mass Index per SD Increase HR (95% CI)* Unadjusted Plus demographics Above plus medical history Above plus medications Above plus behaviors Above plus cardiac function Above plus inammatory markers# Above plus glucose Intolerance** Above plus neurohormones Above plus adipokines Above plus hemoglobin Above plus creatinine clearance Above plus body mass index 1.1 (0.91.3) 1.2 (1.01.5) 1.1 (0.91.4) 1.1 (0.91.4) 1.1 (0.81.3) 1.1 (0.81.4) 1.1 (0.91.4) 1.1 (0.81.3) 1.0 (0.71.3) 0.8 (0.51.0) 0.7 (0.51.0) 0.7 (0.51.0) p Value 0.45 0.09 0.46 0.35 0.61 0.69 0.53 0.61 0.80 0.09 0.06 0.04 WHR per SD Increase HR (95% CI)* 1.5 (1.21.9) 1.4 (1.11.8) 1.4 (1.11.7) 1.4 (1.11.7) 1.4 (1.11.8) 1.7 (1.22.3) 1.5 (1.12.0) 1.5 (1.12.0) 1.5 (1.12.2) 1.7 (1.22.3) 1.7 (1.22.3) 1.7 (1.22.3) 1.8 (1.32.5)

887

p Value 0.0001 0.003 0.004 0.003 0.005 0.002 0.005 0.005 0.01 0.001 0.002 0.002 0.0005

* Adjusted for variables associated with HF (at p 0.05) from previous step plus variables as listed. Age, male gender, and white race. Hypertension, myocardial infarction, diabetes, NYHA class III/IV. Blocker, statin, ACE inhibitor, and aspirin. Exercise capacity, systolic blood pressure, regular alcohol use, and smoking. Ejection fraction, left ventricular mass index, diastolic dysfunction, inducible ischemia, total cholesterol, and log NT-proBNP. # CRP, IL-6, and TNF-. ** Fasting glucose and log insulin. 24-Hour urine norepinephrine and cortisol. Log adiponectin, log resistin, and log leptin. Abbreviations as in Tables 1 to 3.

Table 5 Association of waist-to-hip ratio (WHR) and body mass index to cardiovascular (CV) events (myocardial infarction, stroke, or coronary heart disease [CHD] death) among all participants Model Body Mass Index per SD Increase HR (95% CI) Unadjusted Plus demographics Above plus medical history Above plus medications Above plus behaviors Above plus cardiac function Above plus inammatory markers# Above plus glucose intolerance** Above plus neurohormones Above plus Adipokines Above plus hemoglobin Above plus creatinine clearance Above plus body mass index

WHR per SD Increase HR (95% CI) 1.2 (1.01.4) 1.2 (1.01.4) 1.1 (0.91.3) 1.1 (1.01.3) 1.2 (1.01.4) 1.2 (1.01.4) 1.2 (1.01.4) 1.2 (1.01.4) 1.2 (1.01.5) 1.2 (1.01.4) 1.2 (1.01.4) 1.2 (1.01.4) 1.2 (1.01.5) p Value 0.02 0.06 0.23 0.16 0.06 0.10 0.10 0.08 0.14 0.08 0.10 0.10 0.05

p Value 0.57 0.86 0.48 0.53 0.24 0.19 0.05 0.06 0.26 0.17 0.05 0.24

1.0 (0.81.1) 1.0 (0.91.2) 0.9 (0.81.1) 0.9 (0.81.1) 0.9 (0.71.1) 0.9 (0.71.1) 0.8 (0.71.0) 0.8 (0.71.0) 0.9 (0.71.1) 0.9 (0.71.1) 0.8 (0.71.0) 0.9 (0.71.1)

Adjusted for variables associated with HF (at p 0.05) from previous step plus variables as listed. Age, male gender, and white race. Hypertension, myocardial infarction, diabetes, NYHA class III/IV. Blocker, statin, ACE inhibitor, and aspirin. Exercise capacity, systolic blood pressure, regular alcohol use, and smoking. Ejection fraction, left ventricular mass index, diastolic dysfunction, inducible ischemia, total cholesterol, and log NT-proBNP. # CRP, IL-6, and TNF-. ** Fasting glucose and log insulin. 24-Hour urine norepinephrine and cortisol (loss of signicance owing to smaller sample size because not all participants were able to complete 24-hour urine collection). Log adiponectin, log resistin, and log leptin. Abbreviations as in Tables 1 to 3.

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Differences in the participant characteristics by WHR tertile and BMI category were compared using chi-square tests for dichotomous variables and analysis of variance for continuous variables. We excluded 9 participants with a BMI 18.5 kg/m2 from the BMI (but not the WHR) analysis because previous reports have demonstrated a Ushaped association between BMI and mortality.22 We used multivariate Cox proportional hazards analyses to examine the association of WHR and BMI with HF and CV events. To evaluate the role of potential confounders and mediators, we sequentially added each group of variables (demographic factors, co-morbid conditions, medications, behaviors, cardiac function, general laboratory tests, inammatory markers, glucose intolerance markers, neurohormones, and adipokines) to the models. Variables associated with the outcome (at p 0.05) in each model were included in the subsequent models. We log transformed prohormone braintype natriuretic peptide, insulin, adiponectin, leptin, and resistin levels because they were not normally distributed among the study participants. We also examined the association of WHR and BMI with incident HF among patients who did not report a history of HF. All analyses were performed using Statistical Analysis Software (Version 9.1, SAS Institute, Cary, North Carolina). Results The baseline characteristics according to the WHR and BMI are summarized in Tables 1 and 2, respectively. During a mean follow-up of 4.9 years, 128 participants (13%) were hospitalized for HF and 152 (16%) developed other CV events (e.g., myocardial infarction, stroke, or CHD death). Figure 1 shows the Kaplan-Meier plot of survival free of HF hospitalization by tertile of WHR (p 0.03 for logrank test). Figure 2 shows the Kaplan-Meier plot of survival free of CV events by tertile of WHR (p 0.10 for log-rank test). In regression analysis, each standard deviation (SD 0.078) increase in WHR ratio was associated with a 30% increased rate of HF hospitalization (unadjusted HR 1.3; 95% CI 1.1 to 1.6; p 0.0007). This association was stronger after adjustment for potential mediators (adjusted HR 1.6; 95% CI 1.2 to 2.1; p 0.002) (Table 3). We observed no association between BMI and HF hospitalization (unadjusted HR 1.1; 95% CI 0.9 to 1.3; p 0.49). These results were unchanged when participants with a self-reported history of HF were excluded from the analysis (Table 4). A positive association between the WHR and CV events was observed (unadjusted hazard ratio [HR] per SD increase 1.2; 95% condence interval [CI] 1.0 to 1.4; p 0.02) which was attenuated after adjustment for potential confounders (all p 0.05; Table 5). We observed no association between the BMI and the occurrence of CV events (unadjusted HR 1.0; 95% CI 0.8 to 1.1, p 0.57). Discussion In an ambulatory cohort of 979 patients with known CHD, we found that abdominal obesity, as assessed by the WHR, is a superior predictor of subsequent HF hospitaliza-

tion and CV events than BMI. Furthermore, the excess risk of HF hospitalization incurred by abdominal obesity did not appear to be mediated by co-morbidities, cardiac disease severity, insulin resistance, systemic inammation, neurohormonal activation, or adipokine abnormalities. In contrast, the association of abdominal obesity with CV events was attenuated by multivariate adjustment, suggesting that different mechanisms might be operating. Several previous studies have demonstrated that the WHR is more strongly associated with traditional CV risk factors, and a better predictor of adverse CV events and death, than the BMI.2,10,2325 Our study has extended these ndings by demonstrating that the WHR is also a stronger predictor of HF hospitalization than the BMI. In a post hoc analysis of the Heart Outcomes Prevention Evaluation (HOPE) study, Dagenais et al2 showed that the WHR, unlike the BMI, was an independent predictor of HF. Nicklas et al3 also identied an association between the WHR and HF in a cohort of adults 70 years old. Although these investigators were able to adjust for several potential mediators, including fasting insulin and tumor necrosis factor- levels, the question of why the WHR, but not the BMI, predicts HF remained unanswered, because several other important potential mediators were not measured. Most recently, Kenchaiah et al26 found an association between an increasing BMI, even in the overweight range (BMI 25 to 30 kg/m2), and incident HF, with an attenuation of this relation by physical activity. The participants in that analysis of the Physicians Health Study were healthy volunteers, in contrast to our cohort of patients with established coronary artery disease. A critical distinction between abdominal fat and general obesity tissue is the increased endocrine activity of abdominal adipocytes.27 Hence, one can speculate that it is possible for adipokines such as leptin, adiponectin, and resistin to mediate the association between the WHR and HF. Support for such a theory comes from reports showing a relation between leptin and adiponectin and adverse outcome in patients with established HF.28 Our results, however, did not conrm this theory, because an adjustment for those adipokines did not alter the identied association of WHR with HF. We also observed discordance in the associations of the WHR (p 0.04) and BMI (p 0.28) with the left ventricular mass index. This discrepancy has not been previously reported and warrants additional study. In seeking to identify the underlying mechanisms accounting for the association of abdominal obesity and HF, Ingelsson et al29 analyzed data from the Uppsala Longitudinal Study of Adult Men, a prospective study including almost 1,200 men 70 years old. They demonstrated an increased risk of HF with increasing waist circumference. After adjustment for the parameters of insulin resistance, this association was lost; hence, the investigators concluded that insulin resistance mediates the association between abdominal obesity and HF. We did not replicate this nding in the present study, because the association of the WHR with HF was not attenuated after adjustment for the fasting glucose or insulin levels. It is possible that differences in the denition of abdominal obesity (waist circumference vs WHR) or insulin resistance (oral glucose tolerance test and the homeostasis model assessment-estimated insulin resis-

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tance vs fasting glucose and insulin levels) might account for these divergent ndings. The main strength of the present study was the collection of detailed phenotypic data, including measurement of an extensive list of possible mediators of the association between abdominal obesity and adverse CV events. However, several important limitations should be considered in the interpretation of our results. First, a large proportion of our study population was male; thus, we could not generalize our ndings to women. Second, other potential mediators of the association between obesity and CV events might exist, such as common genetic variants, which were not assessed in the present study.30 Third, the validity of New York Heart Association Classication to evaluate functional capacity in obese patients is questionable, because other mechanisms of exertional limitation often coexist.
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