Pericardial Fat and the Risk of Heart Failure.

BACKGROUND: Obesity is a well-established risk factor for heart failure (HF). However, implications of pericardial fat on incident HF is unclear. OBJECTIVES: This study sought to examine the association between pericardial fat volume (PFV) and newly diagnosed HF. METHODS: This study ascertained PFV using cardiac computed tomography in 6,785 participants (3,584 women and 3,201 men) without pre-existing cardiovascular disease from the MESA (Multi-Ethnic Study of Atherosclerosis). Cox proportional hazards regression was used to evaluate PFV as continuous and dichotomous variable, maximizing the J-statistic: (Sensitivity + Specificity - 1). RESULTS: In 90,686 person-years (median: 15.7 years; interquartile range: 11.7 to 16.5 years), 385 participants (5.7%; 164 women and 221 men) developed newly diagnosed HF. PFV was lower in women than in men (69 ± 33 cm3 vs. 92 ± 47 cm3; p < 0.001). In multivariable analyses, every 1-SD (42 cm3) increase in PFV was associated with a higher risk of HF in women (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.21 to 1.71; p < 0.001) than in men (HR: 1.13; 95% CI: 1.01 to 1.27; p = 0.03) (interaction p = 0.01). High PFV (≥70 cm3 in women; ≥120 cm3 in men) conferred a 2-fold greater risk of HF in women (HR: 2.06; 95% CI: 1.48 to 2.87; p < 0.001) and a 53% higher risk in men (HR: 1.53; 95% CI: 1.13 to 2.07; p = 0.006). In sex-stratified analyses, greater risk of HF remained robust with additional adjustment for anthropometric indicators of obesity (p ≤ 0.008), abdominal subcutaneous or visceral fat (p ≤ 0.03) or biomarkers of inflammation and hemodynamic stress (p < 0.001) and was similar among Whites, Blacks, Hispanics, and Chinese (interaction p = 0.24). Elevated PFV predominantly augmented the risk of HF with preserved ejection fraction (p < 0.001) rather than reduced ejection fraction (p = 0.31). CONCLUSIONS: In this large, community-based, ethnically diverse, prospective cohort study, pericardial fat was associated with an increased risk of HF, particularly HF with preserved ejection fraction, in women and men.

Cocaine Use and Pulmonary Hypertension.

Evidence linking cocaine to the risk of pulmonary hypertension (PH) is limited and inconsistent. We examined whether cocaine use, in the absence of other known causes of PH, was associated with elevated systolic pulmonary artery pressure (sPAP) and increased probability of PH. We compared patients with documented cocaine use to a randomly selected age, sex, and race-matched control group without history of cocaine use. All participants had no known causes of PH and underwent echocardiography for noninvasive estimation of sPAP. We used routinely reported echocardiographic parameters and contemporary guidelines to grade the probability of PH. In 88 patients with documented cocaine use (mean age ± standard deviation 51.7 ± 9.5 years), 33% were women and 89% were of Black race. The commonest route of cocaine use was smoking (74%). Cocaine users compared with the control group had significantly higher sPAP (mean ± standard deviation, 30.1 ± 13.1 vs 22.0 ± 9.8 mm Hg, p <0.001) and greater likelihood of PH (25% vs 10%, p = 0.012). In multivariable analyses adjusted for potential confounders including left ventricular diastolic dysfunction, cocaine use conferred a fivefold greater odds of echocardiographic PH (p = 0.006). Additionally, a stepwise increase in the likelihood of PH was noted across cocaine users with negative or no drug screen on the day of echocardiography to cocaine users with a positive drug screen (multivariable p for trend = 0.008). In conclusion, cocaine use was associated with a higher sPAP and an increased likelihood of echocardiographic PH with a probable acute-on-chronic effect.

The Current Focus of Heart Failure Clinical Trials.

BACKGROUND: Heart failure (HF) is a major global health problem. Clinical trials test efficacy, effectiveness, and safety of novel and emerging therapies in HF. We sought to determine the salient features of ongoing interventional clinical trials in HF. METHODS AND RESULTS: We accessed the ClinicalTrials.gov registry of the National Institutes of Health (NIH) and the International Clinical Trials Registry Platform of the World Health Organization on January 1, 2017, and extracted pertinent information on current HF clinical trials for systematic review. Of 794 HF trials that met our inclusion criteria, almost one-half (49.1%) evaluated clinical end points and one-third (32.8%) examined imaging end points as primary outcomes. One-fourth (24.8%) were industry sponsored and one-third (35.6%) were university sponsored. The NIH and other United States federal agencies funded only 14 trials (1.8% of all trials; 10.7% of trials in the US). Among 536 HF trials with specified left ventricular ejection fraction status, 434 (81.0%) focused on HF with reduced ejection fraction (HFrEF) and only 102 (19.0%) trials targeted HF with preserved ejection fraction (HFpEF). CONCLUSIONS: Ongoing HF trials are predominantly sponsored by nongovernmental funding agencies. Although HFpEF occurs as commonly as HFrEF in the community, the number of clinical trials targeting HFpEF is substantially lower compared with HFrEF.

Heart Failure in Women--Insights from the Framingham Heart Study.

In the latter half of the 20th century, among participants of the Framingham Heart Study, incidence of heart failure (HF) has declined by about a third in women but not in men and survival after the onset of HF has improved in both sexes; however, HF remains highly lethal with over 50% dying within 5 years after onset of HF. Overall, the 8-year relative risk of HF is 24% lower in women compared with men. The 8-year incidence rates of HF with preserved ejection fraction (HFPEF; EF >45%) and HF with reduced EF (HFREF; EF ≤ 45%) in women and HFPEF in men are similar; however, men have a 2-fold higher cumulative incidence of HFREF than HFPEF. The lifetime risk of HF is about 20% in both women and men at 40, 50, 60, 70, and 80 years of age. Contribution of hypertension and diabetes mellitus to the risk of HF was more prominent in women than in men. Serum levels of several biomarkers were distinctly different in women compared with men and had differential effects on left ventricular structure and function; however, the strength and direction of the association between biomarkers levels and HF risk were generally similar in women and men. In individuals with HF, about two-thirds of the underlying cause of death and about one-half of the immediate cause of death were due to cardiovascular causes. Non-cardiovascular underlying and immediate causes of death were more evident in HFPEF.

Atherosclerotic biomarkers and aortic atherosclerosis by cardiovascular magnetic resonance imaging in the Framingham Heart Study.

BACKGROUND: The relations between subclinical atherosclerosis and inflammatory biomarkers have generated intense interest but their significance remains unclear. We sought to determine the association between a panel of biomarkers and subclinical aortic atherosclerosis in a community-based cohort. METHODS AND RESULTS: We evaluated 1547 participants of the Framingham Heart Study Offspring cohort who attended the 7th examination cycle and underwent both cardiovascular magnetic resonance imaging (CMR) and assays for 10 biomarkers associated with atherosclerosis: high-sensitivity C-reactive protein, fibrinogen, intercellular adhesion molecule-1, interleukin-6, interleukin-18, lipoprotein-associated phospholipase-A2 activity and mass, monocyte chemoattractant protein-1, P-selectin, and tumor necrosis factor receptor-2. In logistic regression analysis, we found no significant association between the biomarker panel and the presence of aortic plaque (global P=0.53). Using Tobit regression with aortic plaque as a continuous variable, we noted a modest association between biomarker panel and aortic plaque volume in age- and sex-adjusted analyses (P=0.003). However, this association was attenuated after further adjustment for clinical covariates (P=0.09). CONCLUSIONS: In our community-based cohort, we found no significant association between our multibiomarker panel and aortic plaque. Our results underscore the strengths and limitations of the use of biomarkers for the identification of subclinical atherosclerosis and the importance of traditional risk factors.

Secular trends in echocardiographic left ventricular mass in the community: the Framingham Heart Study.

OBJECTIVE: To investigate secular trends in echocardiographically determined left ventricular mass (LVM). DESIGN, SETTING AND PARTICIPANTS: Longitudinal community-based cohort study in Framingham, Massachussetts. LVM was calculated from routine echocardiography in 4320 participants (52% women) of the Framingham offspring cohort at examination cycles 4 (1987-1991), 5 (1991-1995), 6 (1995-1998) and 8 (2005-2008), totalling 13 971 person-observations. MAIN OUTCOME MEASURES: Sex-specific trends in mean LVM (and its components, LV diastolic diameter (LVDD) and LV wall thickness (LVWT)), and LVM indexed to body surface area (BSA). RESULTS: In men, age-adjusted LVM modestly increased from examination 4 to 8 (192 g to 198 g, p-trend=0.0005), whereas, in women it decreased from 147 g at examination 4 to 140 g at examination 8 (p-trend<0.0001). The trend for increasing LVM in men tracked with an increasing LVDD (p-trend=0.0002), whereas the decline in LVM in women was accompanied by a decrease in LVWT (p-trend<0.0001). Indexing LVM to BSA abolished the increasing trend in men (p-trend=0.49), whereas, the decreasing trend in women was maintained. CONCLUSIONS: In our longitudinal analysis of a large community-based sample spanning two decades, we observed sex-related differences in trends in LVM, with a modest increase of LVM in men (likely attributable to increasing body size), but a decrease in women. Additional studies are warranted to elucidate the basis for these sex-related differences.

Usefulness of biventricular volume as a predictor of mortality in patients with diabetes mellitus (from the Diabetes Heart Study).

Patients with type 2 diabetes mellitus are at increased risk for cardiovascular disease (CVD) and mortality. Beyond traditional CVD risk factors, novel measures reflecting additional aspects of disease pathophysiology, such as biventricular volume (BiVV), may be useful for risk stratification. The aim of this study was to examine the relationship between BiVV and risk for mortality in European Americans with type 2 diabetes mellitus from the Diabetes Heart Study (DHS). BiVV was calculated from 771 noncontrast computed tomographic scans performed to image coronary artery calcified plaque. Relationships between BiVV and traditional CVD risk factors were examined. Cox proportional-hazards regression was performed to determine risk for mortality (all-cause and CVD mortality) associated with increasing BiVV. Area under the curve analysis was used to assess BiVV utility in risk prediction models. During 8.4 ± 2.4 years of follow-up, 23% of the patients died. In unadjusted analyses, BiVV was significantly associated with increasing body mass index, height, coronary artery calcified plaque, history of hypertension, and previous myocardial infarction (p <0.0001 to 0.012). BiVV was significantly associated with all-cause (hazard ratio 2.45, 95% confidence interval 1.06 to 5.67, p = 0.036) and CVD (hazard ratio 4.36, 95% confidence interval 1.36 to 14.03, p = 0.014) mortality in models adjusted for other known CVD risk factors. Area under the curve increased from 0.76 to 0.78 (p = 0.04) and from 0.74 to 0.77 (p = 0.02) for all-cause and CVD mortality with the inclusion of BiVV. In conclusion, in the absence of echocardiography or other noninvasive imaging modalities to assess ventricular volumes, or when such methods are contraindicated, BiVV from computed tomography may be considered a tool for the stratification of high-risk patients, such as those with type 2 diabetes mellitus.

Cardiac magnetic resonance imaging: infarct size is an independent predictor of mortality in patients with coronary artery disease.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) can accurately determine infarct size. Prior studies using indirect methods to assess infarct size have shown that patients with larger myocardial infarctions have a worse prognosis than those with smaller myocardial infarctions. OBJECTIVES: This study assessed the prognostic significance of infarct size determined by CMR. METHODS: Cine and contrast CMR were performed in 100 patients with coronary artery disease (CAD) undergoing routine cardiac evaluation. Infarct size was determined by planimetry. We used Cox proportional hazards regression analyses (stepwise forward selection approach) to evaluate the risk of all-cause death associated with traditional cardiovascular risk factors, symptoms of heart failure, medication use, left ventricular ejection fraction, left ventricular mass, angiographic severity of CAD and extent of infarct size determined by CMR. RESULTS: Ninety-one patients had evidence of myocardial infarction by CMR. Mean follow-up was 4.8±1.6 years after CMR, during which time 30 patients died. The significant multivariable predictors of all-cause mortality were extent of myocardial infarction by CMR, extent of left ventricular systolic dysfunction, symptoms of heart failure, and diabetes mellitus (P<.05). The presence of infarct greater than or equal to 24% of left ventricular mass and left ventricular ejection fraction less than or equal to 30% were the most optimal cut-off points for the prediction of death with bivariate adjusted hazard ratios of 2.11 (95% confidence interval 1.02-4.38) and 4.06 (95% confidence interval 1.73-9.54), respectively. CONCLUSIONS: The extent of myocardial infarction determined by CMR is an independent predictor of death in patients with CAD.

Fatal myocardial rupture after acute myocardial infarction complicated by heart failure, left ventricular dysfunction, or both: the VALsartan In Acute myocardial iNfarcTion Trial (VALIANT).

BACKGROUND: Myocardial rupture is a relatively rare and usually fatal complication of myocardial infarction (MI). Early recognition of patients at greatest risk of myocardial rupture provides an opportunity for early intervention. METHODS: VALIANT was a double-blind, randomized, controlled trial comparing valsartan, captopril, and their combination in high-risk patients post-MI. Myocardial rupture was identified by autopsy (available in 138/589 patients dying within 30 days of index MI), echocardiography, direct surgical visualization, or presence of hemopericardium. An independent clinical end points committee reviewed medical records for all deaths or suspected nonfatal cardiovascular events. RESULTS: Rupture was identified in 45 (0.31%) patients enrolled in VALIANT, occurring 9.8 +/- 6.0 days after the qualifying MI. Rupture accounted for 7.6% (45/589) of all deaths occurring in the first 30 days of follow-up and 24% (33/138) of deaths in which autopsies were obtained. Compared with survivors, rupture was associated with increased age, hypertension, increased Killip class, lower estimated glomerular filtration rate, and Q wave MI, and inversely related to beta-blocker and diuretic use. Compared with patients who died of other causes within 30 days, patients with myocardial rupture were more likely to have had an inferior MI, Q wave MI, or hypertension; to have used oral anticoagulants; or to have received thrombolytic therapy. CONCLUSIONS: Although rare, myocardial rupture accounted for nearly one fourth of all deaths within the first 30 days after high-risk MI, suggesting an estimated incidence of approximately 1% within the first 30 days. A number of clinical characteristics may identify post-MI patients at higher risk of myocardial rupture.

Epidemiology of left ventricular false tendons: clinical correlates in the Framingham Heart Study.

OBJECTIVE: The study objective was to describe the echocardiographic characteristics and investigate the clinical correlates and prognostic significance of left ventricular false tendons (LVFTs). Although LVFTs are generally considered as anatomic variants, they have been associated with innocent precordial murmurs and electrocardiographic abnormalities in small case series. The correlates of LVFTs in the community are unknown. METHODS: We compared 101 Framingham Study participants with LVFTs (mean age 56 years, 45% were women) on routine two-dimensional echocardiograms with 151 referents without LVFTs (mean age 57 years, 44% were women). We examined the cross-sectional clinical, electrocardiographic (rest and ambulatory), and echocardiographic correlates of LVFTs using logistic regression models and evaluated the prospective association between LVFTs and all-cause mortality using Cox proportional hazards regression models. RESULTS: A total of 107 LVFTs (94 simple with 2 points of attachment and 13 complex/branching type with 3 or more points of attachment) were identified in 101 participants. LVFTs were most commonly visualized in the apical 4-chamber view (81%) and predominantly localized to the apical third of the left ventricular cavity (78%). LVFTs were associated with the presence of innocent precordial murmurs (multivariable adjusted odds ratio [OR] 5.55, 95% confidence interval [CI], 1.40-21.94) and electrocardiographic left ventricular hypertrophy (OR 4.43; 95% CI, 1.08-18.25). Body mass index was inversely related to the presence of LVFTs (per kilogram/meters squared increment; OR 0.94; 95% CI, 0.88-0.99). LVFTs were not associated with QRS axis deviation, ventricular premature beats, or repolarization abnormalities (all P values > .20). During a mean (+/- standard deviation) follow-up of 7.7 (+/-1.6) years, 15 participants with LVFTs and 19 participants without LVFTs died. In multivariable analyses, the presence of LVFTs was not associated with the risk of death (P = .92). CONCLUSION: In our community-based sample of middle-aged to elderly white women and men, LVFTs were more likely to be identified in individuals with lower body mass index and cross-sectionally associated with the presence of innocent precordial murmurs and electrocardiographic left ventricular hypertrophy, but they were not associated with the risk of mortality.

Body mass index and vigorous physical activity and the risk of heart failure among men.

BACKGROUND: Elevated body mass index (BMI; weight in kilograms divided by height in meters squared) in the obese range (> or =30 kg/m(2)) is associated with an excess risk of heart failure (HF). However, the impact of overweight or preobese (BMI, 25 to 29.9 kg/m(2)) status and physical activity on HF risk is unclear. METHODS AND RESULTS: In a prospective cohort of 21,094 men (mean age, 53 years) without known coronary heart disease at baseline in the Physicians' Health Study, we examined the individual and combined effects of BMI and vigorous physical activity (exercise to the point of breaking a sweat) on HF incidence from 1982 to 2007. We evaluated BMI as both a continuous (per 1-kg/m(2) increment) and a categorical (lean, <25 kg/m(2); overweight, 25 to 29.9 kg/m(2); and obese, > or =30 kg/m(2)) variable; we evaluated vigorous physical activity primarily as a dichotomous variable (inactive [rarely/never] versus active [> or =1 to 3 times a month]). During follow-up (mean, 20.5 years), 1109 participants developed new-onset HF. In multivariable analyses, every 1-kg/m(2) increase in BMI was associated with an 11% (95% confidence interval [CI], 9 to 13) increase in HF risk. Compared with lean participants, overweight participants had a 49% (95% CI, 32 to 69) and obese participants had a 180% (95% CI, 124 to 250) increase in HF risk. Vigorous physical activity conferred an 18% (95% CI, 4 to 30) decrease in HF risk. No interaction was found between BMI and vigorous physical activity and HF risk (P=0.96). Lean active men had the lowest and obese inactive men had the highest risk of HF. Compared with lean active men, the hazard ratios were 1.19 (95% CI, 0.94 to 1.51), 1.49 (95% CI, 1.30 to 1.71), 1.78 (95% CI, 1.43 to 2.23), 2.68 (95% CI, 2.08 to 3.45), and 3.93 (95% CI, 2.60 to 5.96) in lean inactive, overweight active, overweight inactive, obese active, and obese inactive men, respectively. CONCLUSIONS: In this cohort of men, elevated BMI, even in the preobese range, was associated with an increased risk of HF, and vigorous physical activity was associated with a decreased risk. Public health measures to curtail excess weight, to maintain optimal weight, and to promote physical activity may limit the scourge of HF.

Multidetector computed tomography shows intramyocardial fat deposition.

BACKGROUND: Intramyocardial fat deposition occurs as an age-related process and in multiple pathologic processes. OBJECTIVE: We evaluated the presence of left ventricular (LV) and right ventricular (RV) intramyocardial fat with 64-slice multidetector computed tomography (MDCT). METHODS: One hundred persons with no history of coronary artery disease (47 women, 53 men; mean age [+/- SD], 53 +/- 12.2 years) and 25 patients with CT findings of myocardial infarction (17 men, 8 women; mean age, 71.3 +/- 9.6 years) were studied for intramyocardial fat in defined segments of the ventricles (17 LV and 10 RV segments) at 3 levels. Fat deposition was defined as density range of -30 to -190 Hounsfield units on images both before and after contrast. RESULTS: In healthy persons, LV intramyocardial fat was primarily located in the basal segments (5% anteroseptal, 5% inferior), and RV intramyocardial fat was primarily located in the anterolateral (24% of base, 23% of mid) and inferolateral (27% base, 27% mid) segments. Older age was associated with an increased odds of RV (sex-adjusted odds ratio [OR] per decade increment, 1.61; 95% confidence interval [CI], 1.11-2.33; P = 0.012) but not LV (OR, 0.97; 95% CI, 0.67-1.40; P = 0.85) intramyocardial fat. Compared with women, men had a lower risk of LV (95% CI, 0.1-0.64; P = 0.004) but not RV (95% CI, 0.35-1.87; P = 0.62) intramyocardial fat. Patients with old myocardial infarction (>3 years) had increased percentage of fat in infarcted left ventricles at all 3 levels (P

Differential effects of lipids on the risk of heart failure and coronary heart disease: the Physicians' Health Study.

BACKGROUND: It is understood that coronary heart disease (CHD) is one cause of heart failure, and many risk factors are common to both entities. Hypercholesterolemia, however, being a well-recognized risk factor for CHD, has an unclear association with incident heart failure. METHODS: We evaluated the relations of total and high-density lipoprotein (HDL) cholesterol to incident heart failure and CHD in 10,813 US male physicians (mean age, 68 years). Total and HDL cholesterol were analyzed both as continuous and as categorical (in quartiles) variables. RESULTS: There were 222 incident heart failure cases on follow-up (mean, 6 years). In Cox models, after adjusting for traditional coronary risk factors, 1-SD increase in total cholesterol (36.7 mg/dL) and HDL cholesterol (15.3 mg/dL) was not related to incident heart failure with a hazard ratio and 95% CI of 0.91 (0.79-1.05) for total cholesterol and 0.95 (0.82-1.11) for HDL cholesterol. In categorical models, heart failure risk in second, third, and fourth quartiles of total and HDL cholesterol was statistically not different from those in the lowest quartile; hazard ratios with 95% CI were 0.72 (0.49-1.05), 0.76 (0.52-1.11), 0.73 (0.50-1.09) for total cholesterol, and 0.78 (0.53-1.15), 0.66 (0.43-1.00), and 1.03 (0.69-1.54), for HDL cholesterol. Further adjustment for CHD on follow-up or exclusion of individuals with CHD at baseline did not alter the results. In contrast, high total cholesterol and low HDL cholesterol increased the risk of incident CHD (P < .001). CONCLUSION: In healthy males, total and HDL cholesterol levels were not related to incident heart failure.

Antecedent blood pressure, body mass index, and the risk of incident heart failure in later life.

Higher blood pressure and body mass index (BMI) are risk factors for heart failure. It is unknown whether the presence of these risk factors in midadulthood affect the future development of heart failure. In the community-based Framingham Heart Study, we examined the associations of antecedent blood pressure and BMI with heart failure incidence in later life. We studied 3362 participants (57% women; mean age: 62 years) who attended routine examinations between 1969 and 1994 and examined their systolic and diastolic blood pressure, pulse pressure, and BMI at current (baseline), recent (average of readings obtained 1 to 10 years before baseline), and remote (average of readings obtained 11 to 20 years before baseline) time periods. During 67 240 person-years of follow-up, 518 participants (280 women) developed heart failure. Current, recent, and remote systolic pressure; pulse pressure; and BMI were individually associated with incident heart failure (all P<0.001). Recent systolic pressure (hazards ratio [HR] per 1-SD increment: 1.31; 95% CI: 1.11 to 1.55), pulse pressure (HR per 1-SD increment: 1.33; 95% CI: 1.14 to 1.54), and BMI (HR per unit increase: 1.15; 95% CI: 1.08 to 1.23) were associated with heart failure risk even after adjusting for current measures. Similarly, remote systolic pressure (HR per 1 SD: 1.17; 95% CI: 1.04 to 1.31), pulse pressure (HR per 1 SD: 1.17; 95% CI: 1.06 to 1.31), and BMI (HR per unit: 1.09; 95% CI: 1.05 to 1.14) remained associated with incident heart failure after adjusting for current measurements. Higher blood pressure and BMI in midlife are harbingers of increased risk of heart failure in later life. Early risk factor modification may decrease heart failure burden.

Body mass index and prognosis in patients with chronic heart failure: insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program.

BACKGROUND: In individuals without known cardiovascular disease, elevated body mass index (BMI) (weight/height2) is associated with an increased risk of death. However, in patients with certain specific chronic diseases, including heart failure, low BMI has been associated with increased mortality. METHODS AND RESULTS: We examined the influence of BMI on prognosis using Cox proportional hazards models in 7599 patients (mean age, 65 years; 35% women) with symptomatic heart failure (New York Heart Association class II to IV) and a broad spectrum of left ventricular ejection fractions (mean, 39%) in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. During a median follow-up of 37.7 months, 1831 patients died. After adjustment for potential confounders, compared with patients with BMI between 30 and 34.9, patients in lower BMI categories had a graded increase in the risk of death. The hazard ratios (95% confidence intervals) were 1.22 (1.06 to 1.41), 1.46 (1.24 to 1.71), and 1.69 (1.43 to 2.01) among those with BMI of 25 to 29.9, 22.5 to 24.9, and < 22.5, respectively. The increase in risk of death among patients with BMI > or = 35 was not statistically significant (hazard ratio, 1.17; 95% confidence interval, 0.95 to 1.43). The association between BMI and mortality was not altered by age, smoking status, or left ventricular ejection fraction (P for interaction >0.20). However, lower BMI was associated with a greater risk of all-cause death in patients without edema but not in patients with edema (P for interaction <0.0001). Lower BMI was associated with a greater risk of cardiovascular death and noncardiovascular death. Baseline BMI did not influence the risk of hospitalization for worsening heart failure or due to all causes. CONCLUSIONS: In patients with symptomatic heart failure and either reduced or preserved left ventricular systolic function, underweight or low BMI was associated with increased mortality, primarily in patients without evidence of fluid overload (edema).