Key result
Exercise volume is linked to ~27% higher ARVC risk per 10 MET-h/wk in female PKP2 probands.
Why the study?
Exercise is associated with disease onset and progression in PKP2 pathogenic variant carriers, but its impact on ARVC phenotype development and MACE in carriers of the p.Ser329Argfs*23 PKP2 variant remained unclear.
Does a higher exercise burden increase the risk of ARVC diagnosis and major adverse cardiovascular events in carriers of the p.Ser329Argfs*23 PKP2 variant?
Observational (n=89)
Does a higher exercise burden increase the risk of ARVC diagnosis and major adverse cardiovascular events in carriers of the p.Ser329Argfs*23 PKP2 variant?
In carriers of the p.Ser329Argfs*23 PKP2 variant, higher exercise volume increased the probability of ARVC diagnosis in probands (especially women) but was not associated with ARVC diagnosis in relatives or overall MACE risk, suggesting exercise restriction in asymptomatic carriers may warrant individualized consideration.
Exercise restriction in asymptomatic PKP2 variant carriers should not yet change practice; leaves open how physical activity modifies penetrance in genotype-positive relatives across larger prospective cohorts.
Background/Introduction Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterised by fibrofatty myocardial replacement and a high incidence of ventricular arrhythmias. Exercise has been associated with disease onset and progression, particularly in carriers of pathogenic variants in plakophilin-2 (PKP2)1. The impact of exercise on phenotype development in carriers of the p.Ser329Argfs*23 PKP2 variant remains unclear2. Purpose To assess the influence of exercise burden on ARVC diagnosis and major adverse cardiovascular events (MACE) in carriers of the p.Ser329Argfs*23 PKP2 variant. Methods A retrospective observational study was conducted in carriers of this variant from 19 families. ARVC diagnosis was established according to 2010 criteria. Structural involvement was defined by morphofunctional abnormalities and/or late gadolinium enhancement. Physical activity was quantified in metabolic equivalent hours per week (MET-h/week); ≥15 MET-h/week defined significant exercise. Kaplan–Meier analysis evaluated penetrance and MACE-free survival (cardiovascular death, heart failure hospitalisation, sustained ventricular arrhythmia or appropriate implantable cardioverter-defibrillator therapy). Cox regression assessed associations between exercise (per 10 MET-h/week increment) and ARVC diagnosis or MACE, adjusting for sex, proband status and presence of an additional pathogenic or likely pathogenic cardiomyopathy-related variant. Results Eighty-nine carriers were identified; 24 (26.7%) fulfilled ARVC criteria at last follow-up. Among relatives only, penetrance at 80 years was 32.3%. Nearly half (49.4%) reported a sedentary lifestyle. Patients performing >15 MET-h/week were diagnosed at a younger age (29.3±13.7 vs 50.5±16.3 years, p=0.013) and had higher ventricular ectopy burden, without differences in structural involvement or MACE incidence. In multivariable analysis, ARVC diagnosis was independently associated with proband status (HR 4.61, p=0.007) and an additional pathogenic/likely pathogenic variant (HR 6.02, p<0.001). Exercise volume modified risk among probands: each 10 MET-h/week increment predicted ARVC in men (HR 1.11, p=0.023) and women (HR 1.27, p=0.003), but not in relatives. No association was observed between exercise burden and MACE after diagnosis; male sex was the only independent predictor of events (HR 5.3, p=0.046). Conclusions In carriers of the p.Ser329Argfs*23 PKP2 variant, exercise burden was not associated with increased MACE risk nor with ARVC diagnosis among relatives. Exercise volume increased diagnostic probability only in probands, with a stronger effect observed in women. These findings suggest that exercise restriction in asymptomatic carriers of this variant may warrant individualised consideration.
No takes yet. Share an insight, caveat, or question.
Barbeito et al. (2026) conducted an observational in Arrhythmogenic right ventricular cardiomyopathy (ARVC) / p.Ser329Argfs*23 PKP2 variant carriers (n=89). Exercise burden (MET-h/week; significant exercise defined as ≥15 MET-h/week) vs. <15 MET-h/week or per 10 MET-h/week increment was evaluated on ARVC diagnosis (2010 criteria) and major adverse cardiovascular events (MACE: cardiovascular death, heart failure hospitalisation, sustained ventricular arrhythmia, or appropriate ICD therapy) (HR 1.11 (male probands) / HR 1.27 (female probands), p=0.023 (men) / 0.003 (women)). Exercise volume (per 10 MET-h/wk) predicted ARVC in male (HR 1.11, p=0.023) and female (HR 1.27, p=0.003) probands with p.Ser329Argfs*23 PKP2, but was not associated with ARVC in relatives or MACE.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: