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

This review synthesizes evidence from approximately 108 priority studies—including RCTs, prospective cohorts, and mechanistic reports—identified through a systematic search of PubMed, Scopus, and Web of Science (2000–2025) to reframe heart failure with preserved ejection fraction (HFpEF) as a systemic cardio-metabolic syndrome rather than a purely cardiac condition. The authors argue that visceral adiposity, insulin resistance, chronic inflammation, and mitochondrial dysfunction collectively impair cardiac energetics and drive HFpEF pathophysiology. The review notes that conventional neurohormonal therapies (RAAS inhibitors, beta-blockers) showed neutral outcomes in heterogeneous HFpEF populations, whereas the landmark EMPEROR-Preserved and DELIVER RCTs demonstrated that SGLT-2 inhibitors reduced hospitalizations and cardiovascular events. GLP-1 receptor agonists were also reported to improve symptoms, exercise tolerance, and body weight, further supporting a metabolic-inflammation framework. The authors call for biomarker-driven patient phenotyping, advanced imaging, and adaptive trial designs to enable precision care. Limitations include the inherent heterogeneity of HFpEF populations and the reliance on synthesized rather than primary data, with mechanistic claims drawn partly from preclinical and observational sources.

Why this grade: This is a narrative/systematic review synthesizing existing RCTs, cohorts, and mechanistic studies rather than generating new primary human data, warranting a "review" evidence grade.