Leptin in Obesity‐Related Heart Failure: Pathophysiological Mechanisms and Therapeutic Implications

Obesity is a major and potentially modifiable risk factor for heart failure (HF); however, the biological mediators linking excess adiposity to adverse cardiac remodeling and HF progression remain incompletely defined. Among adipose-derived factors, leptin has emerged as a candidate mediator because of its associations with neurohormonal activation, vascular dysfunction, inflammation, oxidative stress, and myocardial remodeling. This review synthesizes contemporary evidence regarding the role of leptin in the pathophysiology of obesity-related heart failure and examines its clinical and translational ramifications. Data indicate that hyperleptinemia and leptin resistance may facilitate HF progression via interconnected mechanisms, including sympathetic nervous system activation, dysregulation of the renin-angiotensin-aldosterone system, endothelin-1 and reactive oxygen species signaling, diminished nitric oxide bioavailability, endothelial dysfunction, and myocardial hypertrophy and fibrosis. These pathways may be particularly pertinent to obesity-related HF phenotypes characterized by diastolic dysfunction and detrimental remodeling. Leptin may facilitate biomarker-driven phenotyping and risk stratification, especially in obesity-related heart failure with preserved ejection fraction (HFpEF). Nonetheless, the majority of mechanistic evidence is sourced from animal and cellular studies, with substantial human data still lacking. Taken together, current evidence supports leptin as a mechanistically informative biomarker candidate in obesity-related HF, particularly HFpEF, rather than as an established causal mediator or therapeutic target.