Exercise has a disproportionate role in the pathogenesis of arrhythmogenic right ventricular dysplasia/cardiomyopathy in patients without desmosomal mutations

Background: Exercise is associated with age-related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)-associated desmosomal mutations; however, its role in patients without desmosomal mutations (gene-elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of geneelusive ARVD/C and (2) has a differential impact in desmosomal and gene-elusive patients. Methods and Results: Eighty-two ARVD/C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity (MET-Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene-elusive ARVD/C. All gene-elusive patients were endurance athletes. Gene-elusive patients were more likely to be endurance athletes (P < 0.001) and had done significantly more intense (MET-Hrs/year) exercise prior to presentation (P < 0.001), particularly among cases presenting < age 25 (P=0.027). Family history was less prevalent among gene-elusive patients (9% versus 40% desmosomal, P < 0.001), suggesting a greater environmental influence. Gene-elusive patients without family history did considerably more intense exercise than other ARVD/C patients (P=0.004). Gene-elusive patients who had done the most intense (top quartile MET-Hrs/year) exercise prior to presentation had a younger age of presentation (P=0.025), greater likelihood of meeting ARVD/C structural Task Force Criteria (100% versus 43%, P=0.02), and shorter survival free from a ventricular arrhythmia in follow-up (P=0.002). Conclusions: Gene-elusive, non-familial ARVD/C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted.