Phenotypic differences in Obese Patients with Heart Failure with Preserved Ejection Fraction (HFpEF) - A Mini Review

The incidence of heart failure with preserved ejection fraction (HFpEF) continues to rise, and obesity continues to be a predominant comorbid condition affecting patients with HFpEF. Recent research sheds light on the important pathophysiologic role that obesity plays in the development of HFpEF, with many areas of opportunity existing for future developments in understanding the etiology and management of the disease. Crucial in these pathophysiologic developments are studies that clearly characterize the obesity phenotype in HFpEF and compare it to presentations of HFpEF in patients without obesity. This paper reviews the existing literature on the obesity phenotype within HFpEF and discusses some of the prevailing ideas behind the pathophysiologic interplay between the conditions, as well as the existing treatments demonstrating improved outcomes in HFpEF.

Heart failure (HF) is a leading cause of hospitalization and cardiovascular mortality in the United States [1,2]. An estimated 8 million people will be impacted by HF in 2030, with one-third of Americans having at least one HF risk factor [3]. About half of patients with HF have heart failure with preserved ejection fraction (HFpEF) [3], defined by an ejection fraction of 50% or greater at the time of diagnosis with evidence of increased cardiac filling pressures, elevated natriuretic peptides, or other clinical evidence of congestion [4]. A shift from an initial understanding involving solely diastolic dysfunction, the diagnosis of HFpEF now incorporates multiple comorbid metabolic conditions as well as echocardiographic, imaging, laboratory, genetic, or invasive catheterization findings; two primary diagnostic scoring systems are recommended: H2FPEF and HFA-PEFF [5]. Echocardiographic measures remain the most common noninvasive diagnostic technique, with both of these scores including left ventricular (LV) filling pressure, estimated by a ratio of peak mitral inflow velocity during early diastole (E) to averaged mitral annular peak velocities in early diastole (e’), and pulmonary artery systolic pressure or pulmonary hypertension via right ventricular (RV) pressure [6,7]. The incidence of HFpEF has continued to increase despite improvements in treatment for HF overall [1] and patients with HFpEF often experience multiple cardiac and extra-cardiac comorbidities. The primary cardiac comorbidities associated with HFpEF include atrial fibrillation, hypertension, and coronary artery disease. Common noncardiac comorbidities include obstructive or restrictive pulmonary disease, type 2 diabetes, anemia, sleep apnea, chronic kidney disease, and obesity [8]. These comorbidities complicate the diagnosis and treatment of HFpEF as they concurrently result in dyspnea with exercise intolerance, the most common presenting symptom of HFpEF [9].

Data suggests comorbid rates of overweight/obesity in up to 85% of individuals with HFpEF [10,11]. Obesity accounts for a significant portion of attributable risk in HFpEF development and as such has become a popular topic of investigation in HFpEF patients [11-17]. Obesity is largely defined by body mass index (BMI) derived from a person’s weight in kilograms divided by the square of the height in meters. A BMI of 25 or greater is classified as overweight, while a BMI of 30 or greater is classified as obese [18]. Two in every five US adults have obesity and 9% of adults have severe obesity, classified as a BMI of 40 or greater [19]. Given the prevalence of obesity in HFpEF and the increasing number of affected individuals with HFpEF, there have been efforts to further characterize an obesity phenotype with a delineated pathophysiology and tailored treatment plan [9-15,17,20].

Mechanisms of obesity and HFpEF

Multiple mechanisms have been proposed to explain the role of obesity in HFpEF, though the pathophysiology is incompletely understood. The cardiac abnormalities seen in patients with HFpEF are likely the result of multifactorial changes at the systemic, organ, and genetic levels [13,21-23]. At the systemic level, obesity contributes to a chronic inflammatory state in patients with HFpEF reflected by higher C-reactive protein [24], interleukin 6, and tumor necrosis factor-alpha [25]. Downstream, the inflammatory state increases the activation of fibrotic pathways leading to cardiomyocyte stiffening and causing endothelial and microvascular dysfunction leading to pulmonary vasoconstriction, inadequate skeletal muscle perfusion, and renal hyperfiltration, among other organ pathologies [13,22]. Increased production of reactive oxygen species, neurohormonal activation, and autonomic dysfunction mediate the multi-organ changes seen in HFpEF [23]. Increased body mass, particularly visceral fat deposition [26,27], contributes to adverse cardiac and extra-cardiac manifestations via metabolic derangements such as insulin resistance and impaired free fatty acid storage [13,27], as well as expanded total blood volume which drives elevated cardiac filling pressures and ventricular remodeling [28]. Additional cardiomyocyte dysfunction occurs through proinflammatory epicardial adipose tissue deposition as well as impaired myocardial energetics affecting cardiac function during both systole and diastole [13]. Mechanistic compression is thought to contribute to cardiac remodeling via bi-ventricular interdependence, dilation, and wall stress, as well as increased stiffness of the chambers over time [29]. New data continue to emerge further exploring the interplay between obesity and HFpEF and better understanding the pathophysiologic mechanisms essential to optimizing treatment plans for obese patients with HFpEF.

The obesity phenotype: A review of the literature

Though there are few direct comparison studies, a review of the evidence suggests demographic, hemodynamic, and structural differences in HFpEF patients with obesity compared to those without obesity. As a group, obese patients with HFpEF carry increased rates of comorbidities including type 2 diabetes and sleep apnea compared to their non-obese counterparts [30]. Obese patients with HFpEF are younger [24] and have significantly increased intra-abdominal fat distribution [27]. Further, evidence suggests that obese patients have worse quality of life measures and heart failure functional class compared to nonobese patients [24].

In hemodynamic analysis and cardiopulmonary function testing, multiple studies reveal greater dysfunction and worse functional outcomes in obese patients. Analyses demonstrate increased right atrial (RA) pressures, higher pulmonary capillary wedge pressures (PCWP) [29], and elevated left heart filling pressures in obese patients [30]. Further, Sorimachi et al. note inadequate cardiac output increase with exercise and reduced venous compliance in patients with HFpEF compared to healthy controls; these effects were directly associated with BMI [31]. Evidence additionally reveals decreased oxygen consumption calculated through VO2 in obese patients with HFpEF, as well as lower peak exercise tolerance [30]. Studies additionally suggest decreased six-minute walk test distance in obese patients with HFpEF [24]. 

Echocardiographic measures further differentiate patients with obesity and HFpEF. In patients with HFpEF, minor impairments in systolic function lead to early diastolic recoil and elevated LV filling pressures [32]. Measures of LV systolic function include EF and global longitudinal strain, a measure of the longitudinal shortening of myocardial fibers. In a comparison of systolic myocardial tissue Doppler velocity (Sm global) and early diastolic myocardial tissue Doppler velocity (Em global) between obese and non-obese individuals, results revealed that both Sm global and Em global were significantly lower in obese women [33]. Interestingly, analyses revealed that BMI was an independent predictor when adjusted for co-morbidities, of systolic and diastolic dysfunction [33]. Measures of diastolic function include filling pressures estimated via E/e’ and LV lengthening velocities. Specifically, tissue Doppler imaging (TDI) can measure LV lengthening velocities, early-diastolic (e’), and atrial-induced myocardial lengthening (a’), which act as proxies for LV relaxation rate [34]. Recently, there has been interest in left atrial (LA) longitudinal strain as a marker of diastolic function. In a study comparing contractility indices, obese individuals had increased late diastolic filling velocity (A) and stable early diastolic filling velocity (E), leading to a significantly lower E/A ratio [35]. This is likely due to inappropriate LV relaxation in obese people and the tendency to rely on LA contraction for LV filling. Similarly, cohort studies showed that obese individuals experienced a significant decrease in mitral filling velocity (E) [36].

In further echocardiographic analysis and structural assessment, obese patients with HFpEF have increased cardiomegaly with abnormalities including all cardiac chambers as well as increased ventricular interdependence with septal distortion [29,30]. In the left heart, obese patients with HFpEF have increased left ventricular concentric remodeling [30], increased LA stiffness, and decreased LA strain [37] the left atrial dysfunction was independently associated with worse peak VO2 and quality of life measures [37]. In the right heart, obese patients have larger RV size, decreased RV systolic function, and higher RA pressures [29,30]. In a longitudinal assessment of HFpEF patients, higher body weight was associated with the progression of RV disease and dysfunction; patients with progression of RV disease had higher mortality than those without RV disease progression [38]. In tissue biopsy analysis, Aslam et al. found that in patients with HFpEF, those with class II obesity or greater had more depressed systolic RV sarcomere function, possibly explaining the decreased RV function seen in other studies [39]. Finally, increased epicardial adipose tissue EAT) is noted in obese patients with HFpEF [29,30]; EAT has been found to be associated with elevated mean pulmonary artery pressures, elevated right-sided diastolic pressure, elevated PCWP, and decreased peak oxygen consumption on cardiopulmonary testing [29,40]. Increased EAT has been noted to be associated with increased all-cause mortality and HF hospitalizations [41], in addition to increased cardiovascular mortality specifically as well as overall hospitalizations [42].

HFpEF treatments

Recent years have produced some of the first treatments with positive outcomes for patients with HFpEF, though many areas of opportunity remain unexplored. The successful treatments to date involve pathways pertaining to the pathophysiology linking obesity and HFpEF including direct weight loss itself, as well as medication classes that moderate volume status, inflammation, and insulin resistance. In initial trials exploring caloric restriction and intentional weight loss in obese patients with HFpEF, outcomes significantly improved post-treatment period with measures including increased peak VO2 [43], reduced LA volume, improved diastolic function, and lower LV mass [44]. Further, as bariatric surgery has become an increasingly popular treatment option for obese patients, multiple analyses have been conducted exploring the hemodynamic and structural outcomes post-procedure [45]. In analyses of patients with HFpEF who underwent bariatric surgery, data revealed that patients had a significant decrease in LV mass and wall thickness, LA diameter, and improvement in LV diastolic function, offering important long-term cardioprotective benefits [44,46,47]. Pivotal studies on medication classes including sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists have been the first to show significant benefit for patients with HFpEF. SGLT2 inhibitors, in patients with HFpEF with or without T2DM, resulted in decreased rates of death from cardiovascular causes and hospitalization for HF [48-50]. In the recent STEP-HFpEF trial, treatment with semaglutide, a GLP-1 receptor agonist, for patients with obesity and HFpEF improved HF-related symptoms and exercise limitations; this benefit was seen across the spectrum of obesity categories and the magnitude of the benefit was directly related to the degree of weight loss [51]. GLP-1 receptor agonists are proposed to mediate a number of processes including natriuresis, blood pressure, inflammation, insulin resistance, and lipolysis, in addition to their direct effect on weight, lending support to the notion that obesity plays a critical role in HFpEF.

The understanding of HFpEF has evolved over time, from a disease initially thought to solely involve cardiac diastolic dysfunction to a now multi-organ system disease process with a variety of phenotypes contributing to symptomology, optimal treatment course, and outcomes. Obesity has become an increasingly relevant comorbidity, now thought to contribute to a significant portion of disease progression in affected patients. Patients with obesity and HFpEF have uniquely worsened outcomes pertaining to hemodynamics, cardiac structure, and associated comorbid organ system involvement resulting in exercise intolerance, poor functional performance, and decreased quality of life. Evidence suggests that weight loss, whether through targeted diet or surgical intervention, and medication management with drug classes including SGLT2 inhibitors and GLP-1 receptor agonists, can improve structural, hemodynamic, and mortality outcomes for obese patients with HFpEF. Further research into the pathophysiologic mechanisms underlying HFpEF development and progression, particularly for obese patients, is needed to better identify, diagnose, and treat the disease in patients with an obesity phenotype. 

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