Metabolic Heterogeneity of Chronic Heart Failure with Preserved Ejection Fraction: Phenotyping and Personalized Approaches to Treatment

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in which comparable symptoms and elevations in cardiac filling pressures may arise from substantially different combinations of cardiovascular, metabolic, renal, inflammatory, and age-related abnormalities. The increasing prevalence of obesity, type 2 diabetes mellitus, chronic kidney disease, physical inactivity, and population aging has shifted the contemporary HFpEF population toward a predominantly cardiometabolic phenotype. Nevertheless, metabolic dysfunction is not uniform across patients. Visceral adiposity, insulin resistance, myocardial substrate inflexibility, mitochondrial dysfunction, systemic inflammation, coronary microvascular impairment, skeletal muscle bioenergetic abnormalities, and renal metabolic disturbances occur in overlapping patterns and with variable severity. This heterogeneity may partly explain the limited effectiveness of historically uniform treatment strategies and the marked variability in clinical presentation, exercise capacity, congestion, treatment response, and prognosis. Phenotyping offers a framework for moving beyond classification based primarily on left ventricular ejection fraction. Clinically applicable approaches may integrate comorbidities, body composition, hemodynamic characteristics, imaging findings, exercise physiology, circulating biomarkers, and selected metabolomic or proteomic signatures. Data-driven phenomapping and mechanistically informed endotyping have identified reproducible patient clusters, but their stability, treatment predictiveness, and generalizability remain incompletely established. Personalized treatment therefore requires a pragmatic combination of broadly effective disease-modifying therapy and targeted management of dominant pathophysiological drivers, including obesity, diabetes, hypertension, atrial fibrillation, renal dysfunction, congestion, and physical deconditioning. https://doi.org/10.52783/jchr.v16.i4.15789