The Metabolic Heart: Reframing Heart Failure With Preserved Ejection Fraction as a Systemic Cardio-Metabolic Syndrome

This review critically reassesses heart failure with preserved ejection fraction (HFpEF) as a systemic cardio-metabolic disorder. Searching PubMed, Scopus, and Web of Science (2000-2025) yielded 108 priority studies, randomized controlled trials (RCTs), prospective cohorts, and mechanistic reports after screening ~800 records. Evidence shows visceral adiposity, insulin resistance, chronic inflammation and mitochondrial dysfunction synergistically impair cardiac energetics. Unlike conventional neuro-hormonal blockade (renin angiotensin aldosterone system or RAAS inhibitors, beta-blockers), which showed neutral outcomes in heterogeneous HFpEF populations, landmark RCTs (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved), Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER)) now demonstrate that sodium-glucose cotransporter-2 inhibitors cut hospitalizations and cardiovascular events, while glucagon-like peptide-1 (GLP-1) receptor agonists improve symptoms, exercise tolerance and weight, validating the metabolic-inflammation paradigm. Persistent phenotypic heterogeneity underscores the need for biomarker-driven phenotyping, advanced imaging and adaptive trial designs to embed metabolic and bioenergetic dimensions into early, precision care.