Author + information
- aDepartment of Internal Medicine, Section of Cardiovascular Medicine and Section of Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, North Carolina
- bDepartment of Internal Medicine, Section of Geriatrics and Gerontology, Wake Forest School of Medicine, Winston-Salem, North Carolina
- ↵∗Address for correspondence:
Dr. Dalane W. Kitzman, Section of Cardiovascular Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27012-1045.
- abdominal fat
- heart failure with preserved ejection fraction
- visceral adipose tissue
A major advance in understanding heart failure with preserved ejection fraction (HFpEF) occurred in 2013 when Dr. Walter Paulus proposed the inflammation model of HFpEF pathogenesis (1). There is now a large and growing body of evidence to support this paradigm. Circulating biomarkers of inflammation are elevated in HFpEF and correlate with disease severity, symptoms, objective measurements of physical and cardiac function, and clinical events (2). During 9-year follow-up in a large population-based study, interleukin-6, tumor necrosis factor-α, and C-reactive protein were strong, independent predictors of incident HFpEF but not HF with reduced EF (HFrEF) (2). Inflammation biomarker levels are reduced following interventions that improve outcomes in HFpEF (3).
There are multiple pathways by which inflammation promotes HFpEF (2). However, the most fundamental mechanisms are likely microvascular and mitochondrial dysfunction. HFpEF patients have severe capillary rarefaction in cardiac and skeletal muscle, and measurements of microvascular dysfunction correlate with multiple adverse outcomes (4). HFpEF patients also have reduced mitochondrial content and multiple abnormalities in mitochondrial function, which also correlate with adverse outcomes. These 2 abnormalities impair tissue perfusion (oxygen delivery) and oxygen utilization (aerobic metabolism), which are critical to organ and tissue function.
Where do the inflammatory molecules originate? A recent elegant study showed that the inflammatory markers in HFpEF enter the myocardium through the coronary sinus, and their concentrations are correlated with N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration, indicating that they originate primarily from outside the heart. Dr. Paulus inferred the inflammation was caused by multiple comorbidities, including obesity, that accompany HFpEF and drive most of the clinical events. A plethora of evidence now indicates that excess adipose tissue likely plays the overarching, pivotal role in the development, progression, and adverse outcomes in HFpEF (5). In the United States, >80% of HFpEF patients are overweight or obese, twice that of the general population, and the risk attributable to the HFpEF population of being overweight and obese is similar to that of hypertension. Excess adipose tissue strongly promotes inflammation, hypertension, insulin resistance, and dyslipidemia and impairs diastolic, systolic, arterial, skeletal muscle, and physical functions. Increased body mass index (BMI) is an independent predictor of incident HFpEF and, in established cases of HFpEF, independently predicts more severe symptoms, including exercise intolerance, cardiac dysfunction, and elevations in exercise pulmonary wedge pressures. The highest levels of BMI are associated with worse prognosis, including death. Reducing excess adipose tissue through bariatric surgery prevents development of HF (3). In established HFpEF, reducing excess adipose through dietary caloric restriction reduces symptoms and increases exercise capacity and quality of life and is associated with reduced inflammation (3).
Is some fat worse than others? Adipose tissue is highly heterogeneous. Its location, density, and composition determine its local and systemic effects, including metabolic, endocrine, and inflammatory effects; its mechanical effects; and its overall health impact. For instance, subcutaneous adipose tissue has modest adverse metabolic and systemic effects and correlation with cardiovascular outcomes. In contrast, abdominal visceral (intra-abdominal) adipose tissue (VAT) has profound metabolic and systemic effects and, in clinical studies, including HFpEF, is a strong, independent predictor of adverse outcomes.
Multiple lines of evidence suggest that, among the various fat depots, VAT plays the most pivotal role in the development, pathophysiology, and adverse outcomes of metabolic and obese HFpEF (4). VAT is intensely proinflammatory and metabolically active and produces an array of inflammatory, oxidative, endocrine, vasoactive, and angiogenic substances (4). VAT impairs insulin sensitivity and lipid regulation, increases blood pressure, and is a key mediator of metabolic syndrome. Patients with metabolic syndrome have >50% more VAT than those without it. Furthermore, nonobese persons with increased VAT are at high risk, and obese persons with normal VAT are at normal to low risk for metabolic syndrome. VAT is a strong, independent predictor of diabetes and incident cardiovascular disease, stronger than BMI and total body adipose tissue.
Excess VAT predicts key outcomes in HFpEF as well as their improvement with interventions. A recent study used dual-energy x-ray absorptiometry to quantify total adipose tissue and cardiac magnetic resonance to quantify regional fat depots in obese HFpEF patients and also measured peak exercise VO2, an objective measurement of exercise intolerance in chronic HFpEF, which correlates with their reduced quality of life (4). VAT was a strong independent predictor of peak VO2, independent of total adipose tissue and stronger than for other fat depots. In a trial of dietary weight reduction in obese HFpEF patients, reduced VAT was the strongest predictor of the large improvement in peak VO2 and quality of life. In the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial, where 73% of patients had abdominal obesity, abdominal obesity was an independent predictor (hazard ratio [HR]: 1.5) of all-cause, cardiovascular, and noncardiovascular mortality.
The single piece of missing evidence regarding the role of VAT in HFpEF has been whether VAT specifically and independently predicts incident HFpEF. In this issue of JACC: Heart Failure, Rao et al. (6) fill this key gap with an important study from the MESA (Multi-ethnic Study of Atherosclerosis) trial, a population-based, longitudinal follow-up study that included relatively deep phenotyping of individuals, careful follow-up, and formal adjudication of events. BMI and waist-to-hip ratio measurements were made, and computed tomography scans were obtained in 1,806 participants. During an 11-year follow-up, the authors found that all 3 measurements of adiposity were significant, independent predictors of HFpEF hospitalization, but VAT quantified by computed tomography (HR: 2.24; confidence interval [CI]: 1.44 to 3.49) was much stronger than BMI or waist-to-hip ratio measurements, which had similar HRs. These relationships remained significant even after adjusting for NT-proBNP concentration. Subcutaneous fat was not a predictor of HFpEF.
Rao et al. (6) found that none of the adiposity measurements predicted HFrEF. These results are in accord with those in a study by Savji et al. (7), who showed that increased BMI predicts HFpEF, particularly in women but not HFrEF; and a study by Kalogeropoulos et al. (8) that showed that inflammation biomarkers predict development of HFpEF but not HFrEF (2).
These results from Rao et al. (6) provided the final link that confirms the Paulus paradigm for HFpEF, capping data from the studies discussed here that provided the source of the inflammation (excess VAT), the specific mechanisms whereby excess VAT produces inflammation and metabolic dysregulation, and the final pathways by which these likely cause HFpEF (microvascular and mitochondrial dysfunction).
What is the genesis of the excess VAT? Although sustained excess caloric intake is the primary contributor to obesity and excess VAT, a less recognized factor, cortisol, is a key contributor that disproportionately promotes deposition of VAT. Cortisol is elaborated in response to stress, illness, and comorbidities. This results in catabolism of skeletal muscle tissue, conversion to adipose, and preferential deposition in the abdomen (5). This mechanism has 3 broad, adverse consequences. 1) Even small amounts of excess VAT rapidly exert significant adverse systemic effects that progress and worsen over time. A large amount of VAT can essentially function as an independent organ. 2) Loss of skeletal muscle promotes and worsens exercise intolerance, a hallmark of chronic HFpEF. 3) Along with the liver, skeletal muscle is the key organ helping to regulate insulin sensitivity. As skeletal muscle is lost and VAT accumulates, insulin dysregulation develops and progresses, resulting in metabolic syndrome and often overt diabetes. An accelerated version of this scenario is observed when patients are treated with a high-dose, prolonged regimen of steroids; there is relatively rapid development of muscle wasting, abdominal obesity, insulin resistance or diabetes, and hypertension.
The adverse effects of even a small excess of VAT may help explain the late-life increase in HFpEF among women. After menopause, women gain, on average, 2.5 kg, mostly as adipose tissue, which is disproportionately deposited as VAT, producing the array of adverse consequences discussed here and promoting HFpEF. Estrogen replacement therapy prevents this increase in VAT.
Excess VAT can contribute to HFpEF even when patients are not obese and have normal BMI. For example, in contrast to Western HFpEF populations, most Eastern Asian HFpEF patients have normal weight or are even underweight (9). However, for any given BMI, Asian populations have a significantly higher percentage of VAT than white populations, and this appears to account for their much higher prevalence of diabetes. In asymptomatic Asians with normal EF and relatively low BMI, larger waist circumference is associated with unfavorable left ventricular remodeling, impaired diastolic function, and worse global myocardial deformation (5). These cross-ethnic observations further support the concept that excess VAT plays a key contributory role in HFpEF and highlights the limitations of BMI as a surrogate for body composition.
The central role of excess VAT in HFpEF has important therapeutic implications. Maintaining normal weight and body composition can prevent HFpEF, and removing excess VAT through bariatric surgery or diet can improve established HFpEF (3). Can interventions disproportionately reduce VAT? In a study of dietary weight loss in obese women, where there was a 10% reduction in overall weight, there was a 35% reduction in VAT. In a study where pioglitazone therapy was added to diet and exercise, pioglitazone nearly doubled the amount of VAT that was lost. Trials are planned or underway to examine whether agents aimed at reducing systemic inflammation can benefit HFpEF. It could be that targeting the source of the inflammation (VAT) may be more effective than trying to mitigate the resulting inflammation. The systemic inflammation and VAT hypothesis may also help explain why trial results to date have been negative because they selected agents that were effective in HFrEF, which is not driven by inflammation and VAT, and were focused narrowly on potential cardiac mechanisms rather than broader systemic effects. Because exercise and caloric restriction, the only interventions shown to date to improve HFpEF, appear to do so via reducing VAT, studies directly targeting excess VAT and its numerous adverse consequences may prove more fruitful.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Supported by U.S. National Institutes of Health (NIH) grants R01AG18915, R01AG045551, R01HL107257, U24AG05964, and P30AG021332; and NIH grant R01AG051624 to Dr. Nicklas. Dr. Kitzman holds the Kermit Glenn Phillips II Chair in Cardiovascular Medicine; consults for Abbvie, Relypsa, Corvia Medical, CinRx, Boehringer-Ingelheim, and Bayer; has received research funding from Novartis, Bayer, St. Luke’s Hospital of Kansas City, GlaxoSmithKline; and owns stock in Gilead Sciences. Dr. Nicklas has reported she has no relationships relevant to the contents of this paper to disclose.
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