Bidirectional metabolic-vascular feedback loops in heart failure: From myocardial energetics to multisystem cardiometabolic crosstalk

Abstract

Summary Heart failure (HF) is a multisystem syndrome in which myocardial dysfunction is shaped by metabolic, vascular, and extracardiac abnormalities. Across HFrEF and HFpEF, impaired substrate utilization, mitochondrial function, endothelial signaling, coronary microvascular function, and mechano-energetic coupling disrupt the matching of ATP supply to cardiac demand, while obesity, insulin resistance, inflammation, and vascular stiffness further accentuate cardiometabolic HFpEF. In this Review, we integrate these processes into five self-reinforcing metabolic-vascular circuits: substrate-perfusion mismatch; mitochondrial reactive oxygen species-endothelial dysfunction; endothelial metabolism-nitric oxide-myocardial stiffness; immunometabolic-microvascular inflammation-fibrosis; and afterload-mechano-energetic uncoupling. We also examine how adipose tissue, skeletal muscle, liver, and kidney amplify these circuits. Together, this framework links myocardial energetic dysfunction with systemic vascular-metabolic stress and highlights circuit-directed opportunities for phenotype-informed HF therapy.