Abstract 18260: Association of Physical Activity History With Disease Penetrance in a Disease-Based Cohort Does Not Replicate in a Healthcare-Based Genomic Screening Population

Abstract

Background: Physical activity (PA) restriction is a recommended intervention for patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), due to strong associations of PA history with disease, and the known risk of arrhythmic events in affected patients from tertiary referral centers. However, in patients with secondary findings of genetic risk for ARVC, the association of PA exposure with disease expression is unknown. Hypothesis: Among individuals with incidentally identified pathogenic or likely pathogenic (P/LP) variants in desmosome genes (PKP2, DSP, DSG2, DSC2), clinical evidence of disease will be associated with higher pre-diagnostic PA exposure. Methods: The MyCode (MC) cohort included individuals with P/LP variants in desmosome genes, discovered via population genomic screening of 175,000 individuals; the Johns Hopkins (JH) disease-based cohort included ARVC probands and family members with single P/LP variants enrolled in the JH ARVC Registry. The ARVC task force criteria (TFC) status of each patient was defined based on most recent clinical evaluation. Recreational PA history from age 10 to time of diagnosis (TFC+) or survey (TFC-) was self-reported through structured phone interview and each activity was assigned a metabolic equivalent score. Results: The MC cohort was older, more female-predominant, had a lower proportion of PKP2 variants, and had less disease than the JH cohort (Figure; all p<0.001). As expected, MET-hrs/year of exercise prior to presentation was significantly higher in affected vs. unaffected patients in the JH cohort. In contrast, no association between PA history and disease expression was observed in MC (p=0.42). Conclusions: The MyCode cohort demonstrated both a paucity of clinically evident disease and a lack of obvious association of exercise with disease expression. These findings may be seen as reassuring in the management of patients with secondary ARVC genetic findings, but additional data are needed.