Exploration of the Pathogenesis and Treatment of Heart Failure

Heart failure remains a major cause of morbidity and mortality worldwide despite substantial advances in pharmacological and device-based therapies. Distinct phenotypes, including heart failure with reduced ejection fraction, mildly reduced ejection fraction, and preserved ejection fraction, differ markedly in underlying pathophysiology, clinical presentation, and therapeutic responsiveness. Therefore, a deeper understanding of disease mechanisms is essential for guiding evolving management strategies and identifying novel therapeutic targets. This narrative review synthesizes contemporary evidence on the pathogenesis and management of heart failure, integrating mechanistic biology with phenotype-specific treatment effects and acute-chronic disease transitions to provide a translational framework for care. Key clinical trials, guideline documents, and mechanistic studies were identified through structured searches of major medical databases and review of international guideline updates, with emphasis on recent advances in disease-modifying therapies, inflammatory mechanisms, and emerging treatment strategies across heart failure phenotypes. Heart failure with reduced ejection fraction is characterized predominantly by myocyte loss, adverse ventricular remodeling, and neurohormonal activation, with robust evidence supporting combined disease-modifying pharmacotherapy and selected device-based interventions. In contrast, heart failure with preserved ejection fraction is driven largely by systemic comorbidities, endothelial dysfunction, and myocardial fibrosis, contributing to impaired ventricular compliance and limited evidence-based treatment options. Sodium-glucose cotransporter 2 inhibitors have demonstrated consistent reductions in symptoms and hospitalizations across the spectrum of ejection fractions, representing a major advance in management. However, translation of mechanistic insights into effective therapies has been variable. Broad anti-inflammatory strategies targeting cytokine pathways have yielded mixed or neutral outcomes. In contrast, more targeted approaches, including interleukin-1 inhibition, inflammasome modulation, and mitochondrial-directed therapies, show emerging but heterogeneous signals that warrant phenotype-specific evaluation. Heart failure is a heterogeneous syndrome that requires biologically informed, phenotype-specific approaches. Thus, by linking dominant mechanisms to therapeutic response and highlighting the limitations of current evidence, this review aims to advance understanding beyond descriptive summaries and to outline priorities for future precision-oriented heart failure care.