Endurance Exercise Promotes Episodes of Myocardial Injury in Individuals with a Pathogenic Desmoplakin (DSP) Variant

Desmoplakin (DSP) variants are associated with left-predominant or biventricular arrhythmogenic cardiomyopathy. Exercise promotes penetrance and sustained ventricular arrhythmias (VA) in right-sided arrhythmogenic right ventricular cardiomyopathy, but its effect is unknown in DSP variant carriers. To assess whether exercise is associated with clinical outcomes among individuals with a pathogenic or likely pathogenic (P/LP) DSP variant. Adults with P/LP DSP variants were interviewed about physical activity from age 10. Endurance athletes were defined based on a mean exercise dose >24 metabolic equivalent hours/week (METhr/wk) of moderate to vigorous intensity exercise. Lifetime survival free from VA (ventricular tachycardia/fibrillation or appropriate ICD therapy), clinical heart failure (HF) (presentation to the emergency department or hospitalization with HF), and myocardial injury events characteristic of DSP-cardiomyopathy (symptoms, elevated troponin, imaging with non-obstructive coronaries) were examined with the Kaplan-Meier method and Cox regression models. Participants (N=100, 66% female, age 36 ± 15 years) were active with a median 28.4 METhr/wk (IQR 14.8-46) of pre-baseline evaluation exercise, and just 8 individuals continued athlete level exercise post-baseline evaluation. In multivariable analyses, endurance athletes (60%) had no worse survival free from VA [HR 1.00 (95% CI 0.5-1.98)] or clinical HF [HR 0.86 (95% CI 0.36-2.05)] but their risk for myocardial injury was elevated [HR 2.37 (95% CI 1.11-5.05)]. Furthermore, myocardial injury episodes were strongly associated with an elevated risk of both VA [HR 7.86 (95% CI 3.56-17.33)] and clinical HF [HR 10.28 (95% CI 2.95-35.83)] thereafter. Endurance exercise may promote progression of DSP-cardiomyopathy by increasing risk of myocardial injury episodes, but the effect on VA and clinical HF is less clear. This study informs shared decision-making exercise and sports participation discussions.