Gene-elusive arrhythmogenic cardiomyopathy: Roles of sports, inflammation, and beyond

Arrhythmogenic cardiomyopathy (ACM) represents a leading cause of sudden cardiac death in young adults and in athletes. Although inherited cases typically involve genetic variants in desmosomal proteins, impairing cardiac tissue’s capacity to withstand mechanical stress, approximately one-third of patients with ACM harbor no identifiable genetic variant and are classified as gene elusive. Even if some gene-elusive cases may be caused by yet undiscovered variants, the striking observation that gene-elusive ACM predominantly affects high-level endurance athletes without familial disease has generated the concept of exercise-induced ACM, a form of desmosomal damage caused by excessive endurance exercise in the absence of a causal variant, most probably in the presence of a polygenic predisposition. Through mechanical stress and transcriptional pathways, endurance exercise may prompt the upregulation of desmosomal proteins before reaching a threshold where chronic stress leads to inflammatory and autoimmune reactions, further destabilizing the intercalated disc and exacerbating cardiomyocyte damage. According to the current understanding, inflammatory and mechanical effects of exercise may thus act synergistically, accelerating the transition from physiological adaptations to pathologic remodeling with irreversible structural and arrhythmic manifestations. This comprehensive review examines the evolving understanding of gene-elusive ACM, exploring mechanical and transcriptional explanations and inflammatory triggers to autoimmune responses, while addressing the critical clinical challenge of differentiating pathologic remodeling from physiological athletic adaptation.