Abstract
Obesity is a chronic, highly prevalent disease affecting nearly one-third of the global population and represents a major independent risk factor for heart failure (HF), particularly heart failure with preserved ejection fraction (HFpEF). Excess adiposity-especially visceral and epicardial adipose tissue (EAT)-acts as an active endocrine and immune organ, promoting chronic low-grade inflammation, oxidative stress, endothelial dysfunction, and adverse myocardial remodeling. Expanded EAT exerts both paracrine inflammatory effects and mechanical constraint on the myocardium, contributing to diastolic dysfunction, microvascular impairment, atrial arrhythmogenesis, and elevated filling pressures despite preserved systolic function. Evidence demonstrates a dose-response relationship between increasing body mass index and incident HF. Clinically, obesity-related HFpEF is characterized by concentric left ventricular hypertrophy, impaired relaxation, increased plasma volume, reduced exercise tolerance, and relatively low natriuretic peptide levels, complicating diagnosis. HF management includes traditional treatment with diuretics, renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor-neprilysin inhibitors. These agents widely remain foundational as they primarily target hemodynamic and neurohormonal pathways in HF. In contrast, sodium-glucose cotransporter 2 inhibitors consistently reduce HF hospitalizations across the ejection fraction spectrum, while glucagon-like peptide-1 receptor agonists and dual incretin therapies (e.g., tirzepatide) promote substantial weight loss, improve symptoms, and demonstrate promising anti-remodeling effects in obesity-related HFpEF. Recognizing obesity-driven HF as a distinct cardiometabolic entity supports an integrated therapeutic strategy combining structured weight reduction with guideline-directed HF polypharmacotherapy to address both hemodynamic burden and upstream adiposity-related mechanisms.