From cushion to culprit: pharmacological reversal of epicardial adipose tissue remodeling in obesity-related heart failure with preserved ejection fraction

Obesity is a core driver of heart failure with preserved ejection fraction (HFpEF), yet conventional therapies target hemodynamics and neurohormonal axes rather than this upstream factor. Epicardial adipose tissue (EAT), located between the visceral pericardium and the myocardium, shares the coronary blood supply with the myocardium and lacks a fascial barrier, giving it the most direct, fascia-free interface with its target organ of any visceral fat depot. Healthy EAT maintains cardiac metabolic homeostasis through fatty acid buffering, thermogenesis, and paracrine secretion of protective adipokines. In obesity, however, EAT undergoes pathological remodeling along a “quantity–quality dual axis”: the quantit y axis manifests as expansion in volume and thickness, while the qualit y axis encompasses browning loss, a secretome shift from anti-inflammatory to pro-inflammatory, lipotoxic lipid accumulation, and an imbalanced inflammatory microenvironment, with the two axes progressing asynchronously. Remodeled EAT injures the myocardium through four interconnected mechanisms—mechanical constraint, paracrine–vasocrine inflammatory cascades, cardiomyocyte lipotoxicity, and microvascular dysfunction—that converge on myocardial fibrosis and increased cardiomyocyte stiffness. These changes are associated with left ventricular diastolic dysfunction and HFpEF. Pharmacologically, incretin analogs (semaglutide and tirzepatide) have established the most complete evidence chain, spanning mechanistic, imaging and clinical endpoints, but mediation of their clinical benefit by EAT change has not been established; sodium–glucose cotransporter 2 (SGLT2) inhibitors provide the most systematic structural evidence on the quantit y axis; and statins, thiazolidinediones, metformin, β 3-adrenergic receptor agonists, and microRNA-based therapies also show dual-axis potential. This review synthesizes the mechanisms of quantity–quality remodeling in EAT, evaluates pharmacological strategies for its reversal, and discusses the translational prospects of EAT as both a therapeutic target and a surrogate endpoint.