A 48-year-old man with nonischemic cardiomyopathy (left ventricular ejection fraction [LVEF] 20%) presents for subspecialty heart failure evaluation. He has a history of multiple decompensated heart failure hospitalizations (4 within the past year), episodes of ventricular tachycardia, hypertension, hyperlipidemia, hypothyroidism, a thromboembolic stroke with no residual neurological deficit, atrial fibrillation, sleep apnea, and deep vein thrombosis. His weight at the time of evaluation is 162 kg (358 lb); he is volume overloaded in clinic, but after inpatient diuresis his dry weight is established at 156 kg, giving a body mass index (BMI) of 46.8 kg/m². He is receiving full doses of guideline-directed medial therapy and is anticoagulated. What is the potential impact of obesity on his clinical cardiovascular course and what recommendations should the clinician make regarding weight management for this patient?

Obesity is a key determinant of health status and has the potential to affect multiple organ systems (Figure 4-1). The overweight and obese states are commonly defined by BMI, with overweightness diagnosed in the BMI range of 25 to 30 kg/m² and obesity ≥30 kg/m² (Table 4-1). The prevalence of obesity has grown rapidly since the 1960s, with over one-third of adults and 17% of youth in the United States now classified as obese.¹ Obesity has long been known to pose a major threat to cardiovascular population health.² Higher BMI, and other anthropometric measures of obesity such as waist circumference, are independent risk factors for the development of coronary heart disease and heart failure (HF),^3,4 particularly heart failure with preserved ejection fraction (HFpEF),⁵ as well as for cardiovascular death.⁶ There are probably contributions from multiple pathways including the development of hyperlipidemia, insulin resistance, low-level inflammation, and left ventricular hypertrophy, with a potential pathogenic role for the adipokine and gut hormone signaling to the myocardium.

Lifestyle interventions including dietary changes and exercise can help to reduce weight and may improve cardiovascular health.⁷ Bariatric surgery is indicated for treatment of obesity after unsuccessful dietary and exercise interventions in patients with BMI ≥40 kg/m² or BMI ≥35 kg/m² with comorbidities such as type 2 diabetes mellitus or hypertension.^8,9 Bariatric procedures can achieve marked weight loss and remission of diabetes, dyslipidemia, and hypertension.¹⁰ There is growing interest in bariatric surgery for managing severe obesity in patients with coronary artery disease (CAD) and evidence for a reduction in cardiovascular events after bariatric surgery,¹¹ but the role of surgical weight loss in HF remains controversial.^12,13

There are several areas of controversy surrounding obesity in the context of cardiovascular health. One is the recognition that the cardiometabolic impact of excess adipose tissue may be dependent on its location, with visceral adiposity portending worse cardiovascular outcomes than subcutaneous fat deposits, as well as the ratio of brown to white fat.^14-17 Brown fat is rich in mitochondria and predominantly generates body heat, whereas white fat, which predominates in adults, appears to generate the negative metabolic signals leading to obesity-associated diseases. Beige adipocytes have recently been identified, which may promote metabolic health.¹⁸ None of these complexities is adequately captured in the crude measurement of BMI, potentially obscuring the true relationship between differing patterns of adiposity and future cardiovascular risk. Hence the relationship between excessive weight and an abnormal metabolic profile is not absolute; obesity does not always cause a clinical metabolic disease, and not all patients with insulin resistance, hypertension, and hypertriglyceridemia are obese. An additional complicating factor is the so-called obesity paradox observed in some cohorts with established HF, casting doubts upon obesity management recommendations for HF patients.¹⁹

The obese state is proinflammatory, prothrombotic, and proinsulin-resistant. This metabolic milieu promotes endothelial dysfunction and atherosclerotic plaque formation and instability, which are key mechanisms for cardiovascular events such as myocardial infarctions (MI) and strokes. In addition to being an independent predictor of cardiovascular events, obesity is closely associated with other key risk factors such as hypertension, diabetes, hypercholesterolemia, and sleep-disordered breathing.²⁰ In a large standardized case-control study of acute MI in 52 countries, incorporating 15,152 cases and 14,820 controls, abdominal obesity was independently associated with MIs, with a population attributable risk of 20.1% (95% confidence interval, CI; 15.3, 26.0%) for the top 2 tertiles versus the lowest tertile of abdominal obesity, as measured by waist-hip ratios.²¹ Excess weight was an independent predictor of CAD and cardiovascular death over 26 years of follow-up of Framingham Heart Study participants.²²

Obesity is associated with several hemodynamic alterations, including an increased circulating volume, increased cardiac output (mostly through augmented stroke volume rather than increased heart rate), reduced systemic vascular resistance, and a greater degree of sympathetic activation, but a lower maximal oxygen uptake (peak VO₂).^23,24 Various pathophysiological mechanisms have been postulated to explain the relationship between obesity and incident HF, such as increased blood volume or chronically elevated intrathoracic pressure leading to chamber dilatation, hypertension causing left ventricular hypertrophy, the presence of epicardial fat (Figure 4-2) and myocardial fatty infiltration, or a direct cardiotoxic effect of adipose tissue mediated by hormones and inflammatory proteins.²⁵ Elevated BMI, waist circumference, and waist-hip ratio are each associated with incident HF.^26-28 Obese individuals with greater metabolic abnormalities appear to have the greatest risk of HF development.^29,30 Among 59,178 adults followed for mean 18.4 years, the adjusted hazard ratios for HF incidence at BMIs <25, 25 to 29.9, and ≥30 kg/m² were 1.00, 1.25, and 1.99 (p<0.001) for men and 1.00, 1.33, and 2.06 (p<0.001) for women.³¹

The pediatric literature provides some of the clearest evidence for a direct association between obesity and myocardial dysfunction. Obese children have a low prevalence of intermediaries such as diabetes, hypertension, and CAD and so the isolated effect of obesity on myocardial function may be easier to detect in younger individuals. A number of studies have demonstrated that excess adiposity in childhood is strongly associated with increased left ventricular mass both in childhood and into adulthood, independent of the effect of hypertension.^32-34 Abnormal diastolic function has also been reported in obese children, as has abnormal left ventricular circumferential strain imaging.^35-37 These pediatric findings support the hypothesis that there may be a period of left ventricular hypertrophy and increasing diastolic dysfunction, with or without subclinical systolic dysfunction, which precedes the expression of symptomatic HF with either preserved or reduced ejection fraction. Fortunately there is also some evidence that these childhood abnormalities of cardiac structure and function may be reversible with substantial weight loss.^38,39

In obese adults, the relationship between obesity and HF is not only confounded by intermediates such as diabetes, hypertension, and CAD, but also by the impact of obesity on many of our tools for HF diagnosis. Symptoms such as dyspnea, lower extremity edema, orthopnea, and reduced exercise capacity are features of both severe obesity and HF. Physical examination signs of HF may be harder to discern in obese individuals and furthermore the diagnostic markers brain natriuretic peptide (BNP) and N-terminal pro-B natriuretic peptide (NT-proBNP) are affected by the obese state. Multiple investigators have demonstrated an inverse association between BNP/NT-proBNP and BMI.^{3,5,28,31,40,41} The primary imaging tool for determining left ventricular dysfunction, the transthoracic echocardiogram, also has reduced sensitivity in obese patients and access to cardiac magnetic resonance imaging may be limited by equipment weight restrictions. In addition, excess fluid from decompensated HF cannot be distinguished from excess adiposity in the calculation of BMI and so may misrepresent the degree of obesity in HF patients. Through a combination of all these limitations, a clear diagnosis of HF—especially HFpEF—can become challenging among adults with obesity.

Recent research has revealed the role of adipose tissue as an endocrine organ with widespread homeostatic influences, mediated by adipokines, and the potential to adversely affect cardiovascular health (Figure 4-3). The term adiposopathy was adopted to describe the anatomical and functional abnormalities of adipose tissue promoted by positive caloric balance in genetically and environmentally susceptible individuals. These abnormalities of adipose tissue result in adverse endocrine and immune responses that can directly and indirectly contribute to metabolic disease and cardiovascular disease (CVD) risk.⁴² Of particular relevance to the cardiovascular system are the secretion of adiponectin, resistin, leptin, chemerin, visfatin, apelin, and omentin, as well as the inflammatory mediators tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), angiotensinogen, and plasminogen activator inhibitor-1 (PAI-1) from adipose tissue.^43,44

The adipokines can exert both negative and positive effects on the cardiovascular system, depending upon the balance of substances secreted. For example, adiponectin, which is produced both by adipocytes and myocytes, promotes insulin sensitivity, fatty acid breakdown, and normal endothelial function, and is anti-inflammatory and antiatherogenic.^45,46 Furthermore, adiponectin affects myocyte signaling and prevents the negative consequences of myocardial pressure overload and ischemia-reperfusion injury. Adiponectin levels are usually reduced in obesity. In CVD, levels may be elevated with evidence of functional adiponectin resistance at the level of the skeletal muscles.⁴⁷

Conversely, leptin is potentially proinflammatory, atherogenic, thrombotic, and angiogenic and may contribute to the pathogenesis of type 2 diabetes mellitus, hypertension, atherosclerosis, left ventricular hypertrophy, and HF.^48-51 Deficiency caused by leptin gene mutations causes insulin resistance and obesity, but in obese states not associated with this rare gene mutation, circulating leptin levels are high because of leptin resistance.⁵² In a prospective study of 4080 older men, higher circulating leptin was significantly associated with the risk of incident HF in men without preexisting coronary heart disease, independent of BMI and potential mediators, although no association was seen in those with preexisting coronary heart disease.⁵³ Despite the predominantly negative cardiovascular effects of leptin, it may afford some protection against ischemia-reperfusion injury.⁵⁴

The gut hormones may also contribute to the relationship between obesity and HF. The appetite-stimulating hormone ghrelin has been experimentally used as an intravenous HF therapy in 2 small trials, with encouraging results on left ventricular function.^55,56 The incretins, including glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), are a family of gut hormones that stimulate postprandial insulin release, inhibit glucagon, slow gastric emptying rate, and promote weight loss. GLP-1 analogs are used to treat type 2 diabetes mellitus and have attracted attention regarding potentially favorable cardiovascular effects (Figure 4-4). GLP-1 receptors are found on cardiomyocytes, and initial pilot studies indicated positive effects of GLP-1 infusions on left ventricular function for subjects with MI and HF.^57-59 Recognizing that the myocardium becomes increasingly insulin-resistant as HF progresses and that myocardial glucose uptake might be increased by GLP-1 administration, the Functional Impact of GLP-1 for Heart Failure Treatment (FIGHT) study was conceived,⁶⁰ although liraglutide was ultimately found to have no positive effects on HF outcomes. Regardless, there remain biologically plausible endocrine mechanisms linking adiposopathy to abnormalities in ventricular mass and contractility that could contribute to the development of obesity-associated myocardial dysfunction.

Likewise, paracrine signaling from epicardial and perivascular adipose tissue fat may influence local myocardial and coronary function. Epicardial adipose tissue is a normal finding, but fat volume is often increased in obese individuals (Figure 4-2).⁶¹ Epicardial fat has high rates of both lipogenesis and lipolysis and may accommodate local fat storage for the rapid provision of free fatty acids at times of high myocardial substrate demand. Perivascular adipose tissue follows the course of the coronary arteries, and is concentrated in the acute marginal atrioventricular and interventricular sulci. Periventricular adipose tissue secretes mainly beneficial adipokines, predominantly adiponectin.⁶² Despite these putative benefits, epicardial adipose tissue—like visceral adipose tissue—is susceptible to dysfunction in obese individuals and a causative role in local inflammation and cardiovascular pathology has been proposed.⁶³ Epicardial adipose tissue in patients with CAD has shown higher inflammatory cytokine mRNA and protein levels than paired subcutaneous adipose tissue, accompanied by a dense inflammatory infiltrate in the epicardial adipose tissue.⁶⁴ Similarly, higher inflammatory cytokine mRNA and fatty acid levels were observed in the epicardial adipose tissue, compared with paired subcutaneous adipose tissue, in patients with systolic HF.⁶⁵ However, there are some contradictory data in this field and the existing CVD outcomes evidence does not show additive prognostic information for epicardial adipose tissue volume over visceral adipose tissue volume.^66,67

Despite the association between excess adiposity and an elevated risk of incident HF, multiple epidemiology studies suggest that obese subjects with established HF have either no increased mortality risk compared with normal-weight counterparts, or even a lower mortality risk (Figure 4-5).^68-75 This survival paradox has been the source of much uncertainty and debate in the HF literature. For example, all-cause mortality in the Digitalis Investigation Group (DIG) trial decreased in a near linear fashion through increasing BMI groups, from 45.0% in the underweight group to 28.4% in the obese group (p for trend <0.001).⁷⁶ After risk adjustment, overweight and obese subjects maintained a lower mortality than the normal-weight subjects: overweight hazard ratio (HR) 0.88, 95% CI 0.80 to 0.96; obese HR, 0.81, 95% CI 0.72 to 0.92. The highest hazard for mortality was in the underweight group: HR 1.21, 95% CI 0.95 to 1.53. A similar pattern was observed in the Acute Decompensated Heart Failure National Registry (ADHERE) of acute HF hospitalizations across 263 hospitals in the United States. Among 108,927 decompensated HF patients, each incremental 5 kg/m² increase in BMI was associated with a 10% reduction in mortality during the index hospitalization.⁷⁷ A meta-analysis of 28,209 patients across 9 studies, mainly ad hoc analyses of HF therapy trials, compared subjects with normal BMI to those with overweight or obese BMI ranges. The overweight and obese states were both associated with a lower risk of all-cause mortality (adjusted HR 0.88; 95% CI 0.83-0.93 and adjusted HR 0.93; 95% CI 0.89-0.97, respectively) at mean follow-up 2.7 years, which was also consistently seen through the component studies.

The underweight (<18.5 kg/m²) and low-normal weight (<23 kg/m²) subjects had a higher hazard of mortality than normal-weight subjects (adjusted HR 1.11; 95% CI 1.01-1.23). The HF obesity paradox appears to persist when BMI is substituted for anthropometric measurements of obesity, such as waist circumference.⁷⁸

A survival paradox is not universally seen in HF studies, and in some studies the relationship is U-shaped rather than linear. However, even in cohorts without a paradox, investigators have not described as much excess mortality associated with obesity as might be expected from the potential harmful effects that can accompany excess adiposity.^78,79 The paradox does not appear to be unique to HF with reduced ejection fraction (HFrEF) or HFpEF cohorts,^75,80 but among HFrEF patients the phenomenon may be strongest in patients with a nonischemic cardiomyopathy etiology.⁸¹ The paradox does not appear to be restricted to the United States either, with a global analysis of the relationship between BMI and mortality in acutely decompensated HF showing an association between higher BMI and decreased 30-day and 1-year mortality (11% decrease at 30 days; 9% decrease at 1 year per 5 kg/m²; p<0.05), after adjustment for baseline risk.⁸² The risk of HF rehospitalization may also be lower in obese patients.⁸³

Obesity has also been associated with superior short-term, medium-term, and long-term survival in several large cohorts after acute MI,^84-86 and also after coronary artery bypass or valve surgeries.⁸⁷ A similar finding was reported in a large outpatient cohort of patients with hypertension and CAD.⁸⁸ However, the obesity paradox is not universal—1 acute MI cohort showed no independent prediction of mortality by either BMI or waist circumference.⁸⁹ An obesity/overweight paradox has also been observed in the general population without established CVD, for example in a meta-analysis of 97 studies providing a combined sample size of more than 2.88 million individuals. All-cause mortality hazard ratios relative to normal weight (BMI 18.5 to <25 kg/m²) were 0.94 (95% CI 0.91-0.96) for overweight, 1.18 (95% CI 1.12-1.25) for obesity (all grades combined), 0.95 (95% CI 0.88-1.01) for grade 1 obesity, and 1.29 (95% CI 1.18-1.41) for grades 2 and 3 obesity.⁹⁰ These findings caused controversy in their suggestion that even among the general population, modest excess adiposity could be associated with a survival advantage.

POTENTIAL EPIDEMIOLOGICAL EXPLANATIONS FOR THE HEART FAILURE OBESITY SURVIVAL PARADOX

Several methodological considerations may explain the survival paradox, especially given that most data described above were derived from ad hoc analyses of HF medication trials or retrospective cohorts that were not assembled with the intention of analyzing the impact of obesity on survival. Potential epidemiology explanations for erroneously concluding a paradox exists when it does not could include lead-time bias, a healthy survivor effect, or inadequate risk adjustment between obese and nonobese cohorts.^91,92 Lead-time bias describes the scenario where obese patients may present earlier and be diagnosed with HF at a lesser stage of severity than their normal-weight counterparts because of the functional limitations imposed by the obesity. This could then bias the obese cohort toward a milder phenotype of HF with a correspondingly lower mortality risk. A healthy survivor effect describes a situation where the early mortality rate in obese individuals is higher than for normal-weight individuals; thus by the time that the population begins to develop HF with significant frequency, the obese subgroup is biased toward the most healthy individuals who have survived to middle or older age. Also of note the follow-up periods are relatively short in many of these obesity paradox studies, and it is possible that a factor such as obesity may give a short-term advantage but have a detrimental effect over longer periods of exposure.

Inadequate risk adjustment between obese and nonobese cohorts can be challenging to guard against or to prove. For example, changes in cigarette smoking status after baseline data collection or undiagnosed systemic illness could unexpectedly increase the mortality hazard in lower BMI subjects—so-called reverse causality. Neurohumoral medication doses may be higher in the obese subgroups because of higher blood pressures—although medications are adjusted for in some of these studies, individual doses are not. The opposite is also possible, where intermediary factors on a biological pathway from obesity to HF mortality are entered into a multivariable model, nullifying a relationship between higher BMI and higher mortality.