Exercise Increases Age-Related Penetrance and Arrhythmic Risk in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy–Associated Desmosomal Mutation Carriers
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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.
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Environmental modifiers such as endurance exercise, psychological stress, diet, alcohol, and metabolic dysregulation influence ACM disease penetrance and progression, in part through modulation of inflammatory processes.
“environmental modifiers such as endurance exercise [24,25,26,27,28,29,30], psychological stress [31,32,33], diet [34,35], alcohol [36], and metabolic dysregulation [37,38,39] have been shown to influence disease penetrance and progression, in part, through modulation of inflammatory processes.”
From A Paradigm Shift: Arrhythmogenic Cardiomyopathy Is an Inflammatory Disease (2026) · cites this paper as [26]
The Discussion sections on clinical course and the relationship between exercise and ARVD/C report that endurance exercise is associated with greater disease penetrance and worse outcomes in desmosomal mutation carriers. The proposed inflammatory mechanism is less certain: the paper says exercise “may facilitate” myocyte uncoupling leading to inflammation, rather than showing that modulation of inflammation mediates those outcomes. This citation is attached to endurance exercise, not the other modifiers listed in the sentence. (LLM, conf=0.85)
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- Authors
- James, C. A., Bhonsale, A., Tichnell, C., Murray, B., Russell, S. D., Tandri, H., Tedford, R. J., Judge, D. P., & Calkins, H.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- James, Cynthia A.
- ORCID
- Venue
- Journal of the American College of Cardiology
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 62
- Issue
- 14
- Pages
- 1290-1297
- ISSN
- 0735-1097 (ISSN-L)
- PMC
- PMC3809992
- OpenAlex
- W2089109470
- Cited by
- 710
- References
- 4
- Citations by year
- 2026: 41 · 2025: 57 · 2024: 47 · 2023: 47 · 2022: 62 · 2021: 64 · 2020: 73 · 2019: 53 · 2018: 56 · 2017: 73 · 2016: 43 · 2015: 50 · 2014: 37 · 2013: 6
- FWCI
- 30.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of the American College of Cardiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Bogle Foundation, the Healing Hearts Foundation, the Campanella family, Wilmerding Endowments
- Dr. Francis P. Chiaramonte Private Foundation
- National Heart, Lung, and Blood Institute (K23HL093350)
- Medtronic and St. Jude Medical
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- desmosomal mutations, physical activity, endurance athletes, ventricular arrhythmias, ventricular tachycardia, ventricular fibrillation, penetrance, heart failure, survival, age of onset, genetic carriers, sudden cardiac death
- MeSH terms
- Adult, Arrhythmias, Cardiac, Desmosomes, Electrocardiography, Female, Follow-Up Studies, Humans, Male, Mutation, Prospective Studies, Risk Factors, Exercise, Arrhythmogenic Right Ventricular Dysplasia, Penetrance
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