Disease progression in arrhythmogenic cardiomyopathy: a cardiac magnetic resonance longitudinal study

AIMS: To evaluate phenotypic progression in a large cohort of patients with arrhythmogenic cardiomyopathy (ACM) using cardiac magnetic resonance (CMR), and to assess the prognostic impact of baseline structural abnormalities and to investigate the impact of exercise performed after diagnosis. METHODS: We retrospectively analysed individuals with a definitive diagnosis of ACM or identified as carriers of pathogenic or likely pathogenic (P/LP) ACM-related genetic variants, all of whom underwent at least one CMR. Longitudinal data on structural remodelling were available for a subset of patients with at least two CMRs. Patients were stratified into higher- and lower-exercise groups based on exercise performed after diagnosis. The primary composite endpoint included major ventricular arrhythmias (MVA), appropriate implantable cardioverter-defibrillator (ICD) interventions, sudden cardiac arrest, and sudden cardiac death. RESULTS: A total of 202 patients (mean age: 41.7 ± 16.4 years, 59% males) were included. Over a mean follow-up of 5.2 years, 32 patients (16%) reached the primary endpoint. Baseline myocardial fibrosis (MF) and reduced right ventricular ejection fraction independently predicted arrhythmic events [HR 4.9, (95% CI: 1.8-12.9), p < 0.001 and HR 2.6, (95% CI: 1.2-5.4), p = 0.002, respectively]. Among the 97 patients with at least 2 CMR scans, 32% developed de novo fibrosis, and 41% showed progression of MF. Patients with longer intervals between CMR scans demonstrated more pronounced structural remodelling, evidenced by greater increases in biventricular end-diastolic volumes and progressive declines in ventricular function. Significant left ventricular dilation was observed in the higher-exercise group, with an increase in indexed end-diastolic volumes. Carriers of PKP2 variants engaging in moderate-to-intense exercise exhibited a higher incidence of arrhythmic events. CONCLUSIONS: MF and right ventricular systolic dysfunction emerge as independent predictors of arrhythmic risk in ACM. Serial CMR assessments demonstrate that structural progression is common, supporting the concept that ACM represents a dynamic rather than a static disease process. Patients carrying PKP2 variants may exhibit heightened susceptibility to exercise-related arrhythmic risk.Arrhythmogenic cardiomyopathy (ACM) is a heart condition that can lead to dangerous arrhythmias and structural remodeling. In this study, we followed one of the largest groups of ACM patients with repeated cardiovascular magnetic resonance (CMR) scans to better understand how the disease evolves and how exercise after diagnosis affects outcomes.