Is there a Threshold for Safe Exercise for Desmosomal Mutation Carriers?

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Summary

Is there a Threshold for Safe Exercise for Desmosomal Mutation Carriers?

If, as the model suggests, exercise and genetic predisposition have an additive effect towards a threshold for ARVD/C pathogenesis, there may be a level of exercise at least some at-risk mutation carriers can participate in without triggering ARVD/C onset. Based on their finding of a dose–response relationship of exercise with the extent of LV and RV dysfunction, Saberniak and colleagues²² postulated that there may be no threshold value for recommendations for physical activity in at-risk mutation carriers to prevent negative effects on myocardial function. However, given the indisputable benefits of exercise for overall health, complete exercise restriction in young, otherwise healthy mutation carriers is not without risk. Unfortunately, there are few clinical recommendations for appropriate exercise for at-risk carriers. The recent ARVD/C treatment consensus statement concludes only that restriction from competitive sports may be considered in healthy gene carriers (Class IIa).⁵⁷

Therefore, we recently completed a study⁶⁵ assessing a threshold for disease onset based on the American Heart Association (AHA) minimum recommended exercise (450–750 MET-minutes weekly)⁶⁶  for maintenance of overall health in adults. In this study we interviewed members of families segregating heterozygous radical mutations in plakophilin-2. This study design allowed us to control for genotype and other genetic and environmental variables clustering in families as the interaction of exercise and genetic predisposition likely differs based on genotype.

Unsurprisingly, probands had done more exercise than family members and athletic family members had poor outcomes. However, family members who restricted exercise at or below the upper bound of the AHA minimum were significantly less likely to be diagnosed and had no sustained ventricular arrhythmias. (These family members were not sedentary; their median exercise was 80 % of the lower AHA bound.) Furthermore, when family members were diagnosed and had a first sustained ventricular arrhythmia they had accumulated 2.8- and 3.5-fold, respectively, greater MET-hours exercise (from age 10) than the AHA-recommended minimum. By contrast, median exercise for family members who did not develop disease was close to the AHA recommended levels across the lifespan.

These results suggest that at least for many unaffected PKP2 carriers, the AHA-recommended minimum exercise level may fall below the threshold required to promote disease onset. This points to restricting these carriers from endurance and high-intensity athletics, but potentially not from AHA-minimum recommended levels of exercise for healthy adults. It is likely the threshold for healthy versus risky exercise will differ based on genotype and will almost certainly be much lower for carriers of multiple mutations. The findings also support the concept of the additive model of genetic predisposition and exercise intensity in ARVD/C pathogenesis. Future research to improve understanding of the interaction of genotype and exercise ‘dose’ as well as other environmental factors in triggering disease onset is key to improving care for families affected with ARVD/C. Additionally, improved understanding of the molecular mechanism through which exercise interacts with expression of abnormal protein or reduced protein expression to cause the pathological features of ARVD/C is critical.

Clinical Perspective

• Carriers of multiple mutations typically have a more severe ARVD/C phenotype with more frequent and earlier onset arrhythmias, structural dysfunction, heart failure and need for transplant.
• DSP and PLN carriers are at significant risk of developing LV dysfunction. Their risk is significantly higher than that of the large proportion of ARVD/C patients with PKP2 mutations for whom the risk is relatively low.
• The data support restricting ARVD/C patients from competitive, frequent, high-intensity exercise regardless of genotype.
• Unaffected PKP2 carriers of heterozygous mutations may be able to participate in exercise based on AHA-minimum guidelines for exercise in healthy adults, thus avoiding risks of a sedentary lifestyle so long as they are complying with regular ongoing clinical follow-up to detect any early signs of ARVD/C onset.