The Obesity Paradox in Heart Failure With Preserved Ejection Fraction: Untangling Body Composition, Inflammation, and Outcomes

Abstract

Heart failure with preserved ejection fraction (HFpEF) is increasingly recognized as an obesity-driven condition, with excess adiposity serving both as a risk factor and a defining comorbidity. Paradoxically, once HFpEF is established, higher body mass index (BMI) is often associated with improved survival, a phenomenon termed the "obesity paradox." Epidemiological studies, including analyses of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial and large registries, show that overweight and obese HFpEF patients experience lower all-cause mortality compared with normal-weight counterparts, while underweight patients face the worst prognosis due to frailty and cachexia. The survival benefit, however, appears to be shaped by factors beyond BMI. Evidence suggests that favorable body composition, particularly greater lean mass and metabolic reserve, underlies much of the observed advantage. Cardiorespiratory fitness further modifies outcomes, with "fat but fit" individuals driving much of the paradox, while sarcopenic obesity portends poor survival. Inflammatory signaling and adipokine patterns also contribute, with differences in leptin, adiponectin, and cytokine profiles potentially buffering obese patients from catabolic stress. Importantly, fat distribution is critical: visceral and epicardial fat confer risk, whereas subcutaneous fat may be relatively benign, challenging the validity of BMI as a prognostic marker. Critics highlight confounding from cachexia-related weight loss, lead-time bias, and BMI's inability to distinguish fat from muscle. Emerging therapies, including glucagon-like peptide-1 receptor agonists and structured exercise regimens, demonstrate that intentional, controlled weight loss, especially targeting visceral fat while preserving lean mass, can improve symptoms, function, and quality of life. Ultimately, the obesity paradox underscores the need for nuanced, phenotype-specific management rather than complacency toward obesity in HFpEF.

Keywords: body mass index; heart failure; obesity.