Unlocking metabolic flexibility in heart failure with preserved ejection fraction: Bridging fundamental mechanisms to clinical innovation

Heart failure is often described as a condition of “energy depletion.” However, in heart failure with preserved ejection fraction (HFpEF), particularly when associated with metabolic conditions such as obesity and diabetes, the heart may face a state of fuel overload. This fuel overload disrupts mitochondrial function, leading to the heart’s inability to effectively adjust substrate utilization in response to variations in nutritional status, energy substrate availability, and hemodynamic load, resulting in loss of metabolic flexibility and subsequent adverse effects on cardiac function and structure. Thus, an in-depth analysis of the role of metabolic flexibility in the pathophysiology of HFpEF could pave the way to addressing this clinical challenge. This review addresses: (1) the alterations in metabolic flexibility observed in cardiometabolic disease and HFpEF; (2) the implications of metabolic flexibility in the staging, classification, diagnosis, and prognosis of HFpEF; and (3) current HFpEF therapeutic strategies that improve myocardial metabolic flexibility.