Exercise and Arrhythmic Risk in TMEM43 p.S358L Arrhythmogenic Right Ventricular Cardiomyopathy

Abstract Background High level exercise has been associated with a malignant phenotype in desmosomal and genotype negative forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). This is the first study to examine this issue with ARVC secondary to the TMEM43 p.S358L mutation. Objective To evaluate the impact of exercise on arrhythmic risk and cardiac death in TMEM43 p.S358L ARVC. Methods Individuals with the TMEM43 p.S358L mutation enrolled in a prospective registry that had received a primary prevention implantable cardioverter defibrillator (ICD) were invited to complete the modified Paffenbarger Physical Activity Questionnaire (PPAQ) to assess their physical activity in the year preceding their ICD. Time-to-event analyses using unadjusted and adjusted Cox proportional hazards models evaluated associations between physical activity and first appropriate ICD discharge secondary to a malignant ventricular arrhythmia or cardiac death. Results In 80 subjects with the TMEM43 p.S358L mutation exercise ≥9.0 MET-hours/day (high level) in the year prior to ICD was associated with an adjusted 9.1-fold increased hazard of first appropriate ICD discharge (there were no deaths) relative to physical activity Conclusions Exercise ≥9.0 MET-hours/day is associated with an increased risk of malignant ventricular arrhythmias in the TMEM43 p.S358L subtype of ARVC. Extrapolating this data we suggest molecular testing be offered in early childhood to inform exercise choices reflective of genotype.