Pathophysiology of HFpEF: Insights from a Metabolic-Mitochondrial Perspective.

Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic-mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients.