Influence of exercise on arrhythmogenic right ventricular cardiomyopathy associated with the p.Ser329Argfs*23 PKP2 variant
G Gonzalez Barbeito, S Huetos Perez, E Martin Alvarez, R Barriales Villa, J M Larranaga MoreiraAbstract
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.Figure.Kaplan-Meier curves