Heart Failure with Reduced versus Preserved Ejection Fraction: Molecular Mechanisms, Immunologic Pathways, Current Therapies, and Future Directions

Abstract

Heart failure remains a major clinical and public health challenge due to its rising prevalence, heterogeneous biology, and persistent burden of morbidity, mortality, and healthcare utilization. Although left ventricular ejection fraction remains central to classification and treatment selection, it incompletely captures the molecular and clinical diversity of heart failure syndromes. Heart failure with reduced ejection fraction is commonly characterized by cardiomyocyte injury, impaired systolic force generation, neurohormonal activation, and adverse ventricular remodeling, which has enabled development of a standardized guideline-directed medical therapy framework. In contrast, heart failure with preserved ejection fraction is driven by more heterogeneous and overlapping mechanisms, including cardiometabolic stress, endothelial dysfunction, coronary microvascular disease, inflammation, myocardial fibrosis, and impaired physiologic reserve. This narrative review synthesizes current evidence on the fundamental pathophysiology, cellular and molecular mechanisms, immunologic pathways, and contemporary therapeutic strategies in HFrEF and HFpEF. Emphasis is placed on the translational gap between mechanistic discovery and clinically actionable treatment selection. Emerging evidence suggests that future progress, especially in HFpEF, may depend on integrating molecular phenotyping with biomarkers, imaging, hemodynamics, comorbidity profiles, and social determinants of health. A more precise and equitable approach to heart failure care may improve risk stratification, therapeutic selection, and patient-centered outcomes across the full spectrum of disease.