Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiomyopathy characterized by progressive fibro-fatty replacement of the right ventricular myocardium, predisposing to ventricular arrhythmias, right ventricular failure, and sudden cardiac death. ARVC accounts for approximately 11 to 22% of sudden cardiac death in athletes under age 35 and has an estimated prevalence of 1 in 2,000 to 1 in 5,000 in the general population. The disease is caused primarily by mutations in genes encoding desmosomal proteins, the intercellular junctions that provide mechanical coupling between adjacent cardiomyocytes. Desmosomes are specialized cell-cell adhesion complexes composed of five major proteins: plakoglobin (gamma-catenin), plakophilin-2, desmoplakin, desmoglein-2, and desmocollin-2. These proteins form a structural bridge between the intermediate filament cytoskeletons (desmin in cardiomyocytes) of adjacent cells, transmitting mechanical forces during contraction. In ARVC, mutations (most commonly in plakophilin-2, accounting for 25 to 40% of cases) destabilize desmosomal architecture, weakening mechanical coupling between cardiomyocytes. The weakened junctions cannot withstand the repetitive mechanical stress of cardiac contraction, particularly under conditions of increased wall stress such as vigorous exercise. The pathogenesis proceeds through several interconnected mechanisms. Mechanical uncoupling leads...