Leptin and heart failure: the chicken or the egg?

Leptin plays a dual role in heart failure (HF), acting as either a primary driver or a secondary phenomenon depending on the HF subtype. In HF with preserved ejection fraction (HFpEF), chronic hyperleptinemia is a primary mediator of disease initiation and progression, closely linked to obesity and metabolic dysfunction. Elevated leptin levels promote systemic inflammation, sympathetic nervous system activation, arterial stiffness, myocardial hypertrophy, fibrosis, and sodium retention, culminating in diastolic dysfunction and elevated ventricular filling pressures. Conversely, in HF with reduced ejection fraction (HFrEF), elevated leptin levels arise as a secondary response to myocardial dysfunction, systemic inflammation, and tissue hypoperfusion. Here, leptin exacerbates cardiac dysfunction by amplifying neurohormonal activation, inflammation, and cardiac remodeling. Understanding these distinct roles has potential therapeutic implications. In HFpEF, interventions such as weight loss, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and mineralocorticoid receptor antagonists can improve symptoms and prognosis, partly by mitigating chronic hyperleptinemia. Furthermore, leptin-specific therapies should be investigated in clinical trials as potential approach in managing cardiometabolic HFpEF. In HFrEF, management focuses on guideline-directed therapies targeting neurohormonal activation—the key mechanism driving disease progression. However, future research should explore whether modulating leptin signaling could provide additional benefits translated in hard clinical endpoints. By framing leptin as the initiator (“chicken”) in HFpEF and a consequence (“egg”) in HFrEF, this manuscript highlights the need for individualized, integrated treatment strategies. Addressing both metabolic and cardiovascular components could potentially further improve patient outcomes and quality of life.