Cardiac hypertrophy at the crossroads: Mechanistic insights and emerging multimodal therapeutic strategies

Cardiovascular diseases (CVDs) remain the leading cause of mortality worldwide, accounting for approximately 17.9 million deaths annually. Among their diverse manifestations, cardiac hypertrophy is a clinically significant condition that predisposes patients to heart failure, arrhythmias, and and sudden cardiac death. Clinically, hypertrophy can be classified into three forms: physiological (adaptive) hypertrophy, which supports cardiac performance and is reversible, pathological hypertrophy most often secondary to hypertension, valvular disease, hemodynamic stress, or sustained neurohumoral activation; and hypertrophic cardiomyopathy (HCM) represents a primary genetic disorder, most often caused by mutations in sarcomeric proteins. These distinct etiologies have important therapeutic implications, as they determine how efficiently pharmacological agents can target underlying mechanisms. Conventional pharmacological treatments are widely used in clinical practice, yet they provide limited reversal of established remodeling. This therapeutic gap has driven the development of innovative modalities such as RNA-based therapeutics, exosome-mediated interventions, stem cell-derived therapies, and genome-editing technologies, which aim to modulate maladaptive signaling and restore myocardial integrity. This review integrates clinical perspectives with mechanistic insights, delineating the drivers of pathological hypertrophy while evaluating both established therapies and emerging strategies that hold promise for precision cardiology and improved patient outcomes.