Recreational and occupational physical activity and risk of adverse events in truncating MYBPC3 founder variant carriers

Background: MYBPC3 founder variants cause hypertrophic cardiomyopathy (HCM) leading to heart failure (HF) and malignant ventricular arrhythmias (MVA). Exercise is typically regarded a risk factor for disease expression, although evidence is conflicting. Stratifying by type of exercise may discriminate low- from high-risk activities in these patients. Objective(s): Evaluate effects of exercise, stratified by high-static and high-dynamic component, on risk of major cardiomyopathy-related events (MCE) and cardiomyopathy penetrance among MYBPC3 founder variant carriers. Methods: We interviewed 188 carriers (57% male, 43.4±14.8 years) on exercise participation since age ten. Exercise was quantified as metabolic equivalent task (MET)-hours/week before presentation. MCE was defined as a composite of MVA (sustained ventricular tachycardia/fibrillation), HF (HF hospitalizations or transplantation), and septal reduction therapy. Static and dynamic exercise were defined per Bethesda classification. Associations of exercise with MCE and cardiomyopathy penetrance were adjusted for sex and assessed using Cox regression. Results: Overall, 40 (21%) subjects experienced MCE and 139 (74%) were diagnosed with cardiomyopathy. No association was found for overall physical activity and high-static activity with MCE (p=0.900 overall; p=0.274 high-static) or cardiomyopathy penetrance (p=0.787 overall; p=0.774 high-static). In contrast, high-dynamic activity was associated with MVA (dichotomized at 75th percentile: adjusted hazard ratio 2.70, 95% confidence interval 1.01-7.24, p=0.049). Conclusions: Overall exercise participation does not generally increase the risk of adverse events among MYBPC3 founder variant carriers. Nonetheless, an increased risk of MVA was observed among those engaged in the highest quartile of high-dynamic-sports, suggesting that high-level high-intensity exercise activities should be entertained with caution. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Netherlands Cardiovascular Research Initiative with the support of the Dutch Heart Foundation (CVON2014-40 DOSIS, Dutch Cardiovascular Alliance 2020B005 DoubleDose to A.F.B, F.W.A., J.P.v.T., M.M. and R.A.d.B.; CVON2015-12 e-Detect to F.W.A, J.P.v.T. A.S.J.M.t.R. and I.C.), the Dutch Heart Foundation (Dekker 2015T041 to A.F.B. and M.J), ZONMw Off Road 2021 to ASJMtR, European Research Counsil HORIZON IMPACT (grant no. #101115536 to A.S.J.M.t.R.), University College London Hospitals National Institute for Health and Care Research Biomedical Research Centre (to F.W.A.), and British Heart Foundation (PG/18/5033837, PG/22/10989 and University College London/British Heart Foundation Research Accelerator AA/18/6/34223 to A.F.S.). Dr. de Boer is supported by the Netherlands Heart Foundation (grants 2017-21; 2017-11; 2018-30;), by the leDucq Foundation (Cure-PLaN), and by the European Research Council (ERC CoG 818715). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board, Medical Ethics Committee of UMC Utrecht gave ethical approval for this work, with local approval at the Amsterdam UMC and UMC Groningen. All individuals provided written informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data that support the findings of this study are available from the corresponding author upon reasonable request.