Endurance exercise promotes episodes of myocardial injury in individuals with a pathogenic desmoplakin (DSP) variant

Background: Desmoplakin (DSP) variants are associated with left predominant or biventricular arrhythmogenic cardiomyopathy. Exercise promotes penetrance and sustained ventricular arrhythmias (VAs) in right-sided arrhythmogenic right ventricular cardiomyopathy, but its effect is unknown in DSP variant carriers. Objective: The purpose of this study was to assess whether exercise is associated with clinical outcomes in individuals with a pathogenic or likely pathogenic DSP variant. Methods: Adults with a pathogenic or likely pathogenic DSP variant were interviewed about physical activity from age 10. Endurance athletes were defined on the basis of a mean exercise dose >24 metabolic equivalent hours per week of moderate- to vigorous-intensity exercise. Lifetime survival free of VA (ventricular tachycardia/fibrillation or appropriate implantable cardioverter-defibrillator 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, and imaging with nonobstructive coronaries) were examined using the Kaplan-Meier method and Cox regression models. Results: Participants (N=100; 66% female; mean age 36 ± 15 years) were active with a median 28.4 (interquartile range 14.8–46) metabolic equivalent hours per week 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 of VA (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.5–1.98) or clinical HF (HR 0.86; 95% CI 0.36–2.05) but their risk of 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. Conclusion: Endurance exercise may promote progression of DSP cardiomyopathy by increasing the risk of myocardial injury episodes, but the effect on VA and clinical HF is less clear. This study informs shared decision-making exercise and sport participation discussions.