Heart failure with preserved ejection fraction (HFpEF): translational mechanisms, diagnostic evolution and therapeutic frontiers

Abstract

Heart failure with preserved ejection fraction (HFpEF) is responsible for approximately half of global heart failure cases and is characterized by marked symptom burden, frequent hospitalization and limited disease-modifying options. Its biology extends beyond the ventricle into vascular, myocardial, metabolic and inflammatory pathways that converge to produce diastolic dysfunction and systemic remodeling. Diagnostic inconsistency and frequent need for exertional testing to unmask elevated filling pressures underscore residual gaps in recognition and targeted therapy. This review synthesizes contemporary evidence spanning epidemiology, mechanisms, diagnostic strategies and phenotype-directed management. Therapeutic advances comprise sodium glucose cotransporter-2 (SGLT2) inhibitors as foundational disease-modifying therapy, Glucagon-like peptide-1 receptor agonists (GLP-1RAs) as emerging adjunctive therapy for cardiometabolic HFpEF, structured exercise and lifestyle programs, hemodynamic-guided decongestion and ongoing evaluation of soluble guanylate cyclase (sGC) stimulators. Integrating these insights, HFpEF represents a family of endotypes unified by diastolic dysfunction but driven by distinct systemic mechanisms accounting for variable biomarker profiles and treatment responses. The priorities ahead center on linking human tissue biology with multi-omics and deep clinical phenotyping, standardization of diagnostic criteria, refinement of representative preclinical models and execution of biomarker-enriched, endotype-stratified trials to enable precision prevention and therapy in HFpEF.