Exercise increases age-related penetrance and arrhythmic risk in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated desmosomal mutation carriers

Abstract

Objectives: This study sought to determine how exercise influences penetrance of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) among patients with desmosomal mutations.

Background: Although animal models and anecdotal evidence suggest that exercise is a risk factor for ARVD/C, there have been no systematic human studies.

Methods: Eighty-seven carriers (46 male; mean age, 44 ± 18 years) were interviewed about regular physical activity from 10 years of age. The relationship of exercise with sustained ventricular arrhythmia (ventricular tachycardia/ventricular fibrillation [VT/VF]), stage C heart failure (HF), and meeting diagnostic criteria for ARVD/C (2010 Revised Task Force Criteria [TFC]) was studied.

Results: Symptoms developed in endurance athletes (N = 56) at a younger age (30.1 ± 13.0 years vs. 40.6 ± 21.1 years, p = 0.05); they were more likely to meet TFC at last follow-up (82% vs. 35%, p < 0.001) and have a lower lifetime survival free of VT/VF (p = 0.013) and HF (p = 0.004). Compared with those who did the least exercise per year (lowest quartile) before presentation, those in the second (odds ratio [OR]: 6.64, p = 0.013), third (OR: 16.7, p = 0.001), and top (OR: 25.3, p < 0.0001) quartiles were increasingly likely to meet TFC. Among 61 individuals who did not present with VT/VF, the 13 subjects experiencing a first VT/VF event over a mean follow-up of 8.4 ± 6.7 years were all endurance athletes (p = 0.002). Survival from a first VT/VF event was lowest among those who exercised most (top quartile) both before (p = 0.036) and after (p = 0.005) clinical presentation. Among individuals in the top quartile, a reduction in exercise decreased VT/VF risk (p = 0.04).

Conclusions: Endurance exercise and frequent exercise increase the risk of VT/VF, HF, and ARVD/C in desmosomal mutation carriers. These findings support exercise restriction for these patients.

Keywords: (stage C) heart failure; 2010 Revised Task Force Criteria; ARVD/C; CI; ECG; HF; ICD; IQR; OR; RV; TFC; VT/VF; arrhythmogenic right ventricular dysplasia; arrhythmogenic right ventricular dysplasia/cardiomyopathy; cardiomyopathy; confidence interval; electrocardiogram; exercise; heart failure; implantable cardioverter-defibrillator; interquartile range; odds ratio; penetrance; right ventricular; ventricular arrhythmias; ventricular tachycardia/ventricular fibrillation.

Figure 1. Cumulative lifetime survival from sustained ventricular arrhythmia and class C heart failure

Cumulative lifetime survival free from (A) sustained ventricular arrhythmias and (B) stage C heart failure (B) stratified by participation in endurance athletics. Event free survival from sustained arrhythmias and stage C heart failure is significantly lower among endurance athletes. Abbreviations: HF - heart failure, VT/VF - sustained ventricular arrhythmia.

Figure 2. Likelihood of ARVD/C diagnosis is associated with exercise history

Likelihood of meeting ARVD/C diagnostic criteria at last follow-up is associated with increasing hours per year of exercise (<0.001) and participation in endurance athletics (p<0.001). Abbreviations: Hrs/yr – hours per year, TFC – 2010 Task Force diagnostic Criteria.

Figure 2. Likelihood of ARVD/C diagnosis is associated with exercise history

Likelihood of meeting ARVD/C diagnostic criteria at last follow-up is associated with increasing hours per year of exercise (<0.001) and participation in endurance athletics (p<0.001). Abbreviations: Hrs/yr – hours per year, TFC – 2010 Task Force diagnostic Criteria.

Figure 3. Cumulative survival free from sustained ventricular arrhythmia in follow-up

Among 61 cases who did not present clinically with a sustained ventricular arrhythmia, survival from a first sustained ventricular arrhythmia during follow-up was significantly lower among (A) endurance athletes and those doing the most (top quartile hours per year) exercise prior to (B) and following (C) clinical presentation. Abbreviations: VT/VF – sustained ventricular arrhythmia.

Figure 4. Change in exercise following clinical presentation influences likelihood of developing a first sustained ventricular arrhythmia

Among 61 cases who did not present clinically with a sustained ventricular arrhythmia, those who did the most (top quartile) exercise both prior to and after clinical presentation were most likely to develop a sustained ventricular arrhythmia in follow-up (p=0.007). Among those doing the most (top quartile) exercise prior to presentation, those who continued to do top quartile exercise were more likely to develop a first sustained ventricular arrhythmia than those who reduced exercise (p=0.04). Abbreviations: VT/VF – sustained ventricular arrhythmia

Figure 4. Change in exercise following clinical presentation influences likelihood of developing a first sustained ventricular arrhythmia

Among 61 cases who did not present clinically with a sustained ventricular arrhythmia, those who did the most (top quartile) exercise both prior to and after clinical presentation were most likely to develop a sustained ventricular arrhythmia in follow-up (p=0.007). Among those doing the most (top quartile) exercise prior to presentation, those who continued to do top quartile exercise were more likely to develop a first sustained ventricular arrhythmia than those who reduced exercise (p=0.04). Abbreviations: VT/VF – sustained ventricular arrhythmia

Figure 4. Change in exercise following clinical presentation influences likelihood of developing a first sustained ventricular arrhythmia

Among 61 cases who did not present clinically with a sustained ventricular arrhythmia, those who did the most (top quartile) exercise both prior to and after clinical presentation were most likely to develop a sustained ventricular arrhythmia in follow-up (p=0.007). Among those doing the most (top quartile) exercise prior to presentation, those who continued to do top quartile exercise were more likely to develop a first sustained ventricular arrhythmia than those who reduced exercise (p=0.04). Abbreviations: VT/VF – sustained ventricular arrhythmia