Exercise Increases Age-Related Penetrance and Arrhythmic Risk in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy–Associated Desmosomal Mutation Carriers
Key result
High-volume regular exercise is linked to a ~25-fold higher risk of meeting ARVD/C criteria.
- OR 25.3
- 95% CI 4.21-153
- P<0.0001
- n=87
Why the study?
Animal models and anecdotal evidence suggested exercise is a risk factor for ARVD/C, but systematic human studies were lacking.
Does endurance exercise increase the risk of ventricular arrhythmias, heart failure, and ARVD/C penetrance in desmosomal mutation carriers?
Key Points
- To determine how regular exercise influences disease penetrance, ventricular arrhythmias, and heart failure onset in carriers of ARVD/C-associated desmosomal mutations.
- Interviewed 87 desmosomal mutation carriers (46 male, mean age 44±18 years) from 51 families regarding regular physical activity history starting from age 10.
- Evaluated outcomes including sustained ventricular arrhythmia (VT/VF), stage C heart failure, and fulfillment of 2010 revised Task Force Criteria (TFC) for ARVD/C over a mean follow-up of 8.4±6.7 years.
- Endurance athletes developed symptoms at a younger age (30.1±13.0 vs. 40.6±21.1 years, p=0.05), were more likely to meet TFC (82% vs. 35%, p<0.001), and had lower lifetime survival free from VT/VF (p=0.013) and heart failure (18% vs. 0%, p=0.004).
- Compared with the lowest exercise quartile before presentation, higher exercise quartiles had significantly increased odds of meeting TFC: second quartile (OR=6.64, 95% CI=1.49–29.5, p=0.013), third quartile (OR=16.7, 95% CI=3.21–86.9, p=0.001), and top quartile (OR=25.3, 95% CI=4.21–153, p<0.0001).
- Among 61 subjects without VT/VF at presentation, all 13 first VT/VF events occurred in endurance athletes (34% vs. 0%, p=0.002), and reducing exercise among those in the top quartile decreased VT/VF risk (p=0.04).
Study Design
Type
Cohort (n=87)
Multicenter
No
Structured PICO
Does endurance exercise increase the risk of ventricular arrhythmias, heart failure, and ARVD/C penetrance in desmosomal mutation carriers?
P
Population
87 individuals with a single pathogenic ARVD/C-associated desmosomal mutation, mean age 44, 47% female, evaluated for the impact of exercise history on disease penetrance and arrhythmic risk.
E
Exposure
Endurance athletics (sports with high dynamic demand done for ≥50 hours/year at vigorous intensity) and high duration of annual exercise.
C
Comparator
Non-endurance athletes and lower quartiles of annual exercise duration.
O
Outcome
Meeting diagnostic criteria for ARVD/C (TFC) at last follow-up, first sustained ventricular arrhythmia (VT/VF), and onset of stage C heart failure (HF).hard clinical
Main Result
Odds Ratio: 25.3 (95% CI 4.21–153)
Absolute Event Rate: 86% vs 29%
p-value: p=<0.0001
Endurance and frequent exercise significantly increase the penetrance of ARVD/C and the risk of life-threatening arrhythmias in desmosomal mutation carriers, supporting exercise restriction.
Limitations
- Retrospective interview-based exercise history (recall bias)
- Social desirability bias
- Exclusion of sudden death cases
- Selection bias from tertiary care registry
- Non-independence of observations within families
- Only included desmosomal mutation carriers
Discussion
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The results of this study reveal for the first time that the amount and intensity of exercise among people who carry a mutation increase the likelihood of developing ventricular arrhythmias—a very serious heart rhythm disturbance—and heart failure.”
“Increasing numbers of people are having genetic testing for ARVD/C once they find out that a member of their family has the mutation. This is important information for them and their physicians.”
“Among those who did the most exercise daily, about two hours each day, 75 percent developed their first life-threatening arrhythmia during the course of the study. In contrast, those who heeded advice to cut back to little or no exercise had a much lower, 12 percent, risk within the eight-year follow-up period.”
Implication
May warrant exercise restriction counseling in desmosomal carriers; extends animal models yet leaves prospective confirmation open.
Cite This Study
James et al. (2013) conducted a cohort in Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) desmosomal mutation carriers (n=87). High volume of regular exercise (top quartile) vs. Lowest quartile of regular exercise was evaluated on Meeting diagnostic criteria for ARVD/C (TFC) at last follow-up (OR 25.3, 95% CI 4.21-153, p=<0.0001). High volumes of regular exercise significantly increased the likelihood of meeting ARVD/C diagnostic criteria (OR 25.3 for top vs lowest quartile) and experiencing ventricular arrhythmias.