Decoding Heart Failure: From Mechanisms to Phenotype-Based Management

Abstract

Heart failure (HF) remains a leading cause of morbidity and mortality worldwide, with rising prevalence and substantial heterogeneity in pathophysiology and treatment response. This narrative review focuses on chronic HF in adults, with emphasis on pathophysiological mechanisms and phenotype-based classification. This review provides a comprehensive analysis of the pathophysiology of heart failure, tracing the progression from baseline physiology to the complex mechanisms underlying heart failure. It begins by outlining normal cardiac function, detailing the structure and mechanical determinants of the left and right ventricles, including their helical myocardial fiber orientation, the phases of the cardiac cycle, and the role of torsion and diastolic recoil in maintaining efficient circulation. The review then delves into the pathogenesis of HF, highlighting the interplay among neurohumoral activation, structural remodeling, chronic inflammation, and cardiac aging. Furthermore, this review outlines the classification of HF based on left ventricular ejection fraction, distinguishing HF with preserved ejection fraction, reduced ejection fraction, and HF with mildly reduced ejection fraction. It particularly underscores the heterogeneity of HF with preserved ejection fraction, identifying distinct clinical phenotypes—specifically the metabolic, hypertensive, cardiorenal, pulmonary vascular, and inflammatory/autoimmune subtypes—each characterized by unique pathophysiological mechanisms that provide a framework for personalized therapy, with emerging agents beginning to show phenotype-specific efficacy.