Inflammation, metabolism, and aging in heart failure with preserved ejection fraction: Mechanisms and treatment perspectives

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent clinical syndrome with limited effective therapies, representing a major unmet need in cardiovascular medicine. A comorbidity-driven systemic proinflammatory state, together with coronary microvascular endothelial inflammation, has emerged as a central paradigm in HFpEF pathogenesis. Accumulating evidence over the past decade has highlighted the extensive crosstalk between inflammation, metabolic dysregulation, and aging-related processes. In this review, we summarize key advances defining the roles of systemic and microvascular inflammation, metabolic abnormalities, and cellular senescence, and integrate these findings into an interconnected inflammation-metabolism-aging axis in HFpEF. We further discuss the current clinical and emerging preclinical therapeutic strategies targeting these pathways. By linking mechanistic insights with translational perspectives, this review provides a conceptual framework to guide precise therapeutic development for this complex and heterogeneous syndrome.