THE EFFECT OF EXERCISE ON TIME TO APPROPRIATE IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR THERAPY OR DEATH IN SUBJECTS WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY SECONDARY TO A TMEM43 P.S358L MUTATION

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) can lead to malignant ventricular arrhythmias, right ventricular and occasionally left ventricular dysfunction as well as sudden cardiac death (SCD). Competitive sports have been associated with SCD in ARVC presumably by accelerating the disease process and triggering terminal arrhythmias during the elevated adrenergic state. The purpose of this study was to assess the effect of exercise on expression of the disease phenotype in a genetically homogeneous cohort of ARVC patients with a TMEM43 p.S358L mutation. Subjects with implantable cardioverter-defibrillators (ICD) were identified from fifteen families shown to have ARVC caused by a p.S358L mutation in TMEM43. Consecutive patients with the p.S358L mutation were ascertained (n=110). Of these, 24 who received ICDs for secondary prevention were excluded; of the remaining 86 eligible patients, 83 were enrolled, following informed consent, in this study. All participants were administered the Paffenbarger Physical Activity Questionnaire to assess their level of physical activity in the 12 month period prior to receiving their ICD. This was used to estimate the number of MET-hours/day these participants were expending prior to ICD implantation. The primary outcome measure was a composite of first appropriate ICD discharge for VT/VF or death. Quartiles of physical activity were categorized as ≤9.9, 10-13.6 and ≥13.7 MET-hours/day. The mean times to first appropriate ICD discharge or death were 7.22, 5.08 and 2.63 years respectively (p=0.003). Survival curves are shown in Figure 1. This study demonstrates a clear dose-response relationship between level of physical activity in the year preceding ICD implantation for ARVC caused by TMEM43 p.S358L and progression to first appropriate ICD shock or death. This is consistent with with the hypothesis that exercise modifies the phenotype expression in ARVC patients. Data from others assessing the effects of physical activity on ARVC studied heterogeneous desmosomal mutations patient cohorts and demonstrated increased phenotypic expression of Task Force Criteria in “endurance athletes”. Our study demonstrates the novel finding of increased arrhythmic burden in a genetically homogeneous group of ARVC ICD patients associated with increased physical activity level. These results should inform physicians when advising subjects with this mutation on appropriate levels of physical activity.