Exercise-induced ventricular arrhythmias: a marker of risk in arrhythmogenic cardiomyopathy

Abstract Background Exercise has the potential to unmask ventricular arrhythmias in arrhythmogenic cardiomyopathy (ACM). The aim of the study was to assess the prevalence and the prognostic significance of exercise-induced ventricular arrhythmias (EIVA) during exercise test. Methods Clinical data of patients with a definitive diagnosis of ACM as well as individuals harbouring a pathogenic or likely pathogenic (P/LP) gene variant associated with ACM who exhibited a negative or borderline phenotype were retrospectively analysed. Patients were stratified into "lower" and "higher" exercise groups based on exercise intensity performed after the diagnosis. Exercise-induced ventricular arrhythmias were graded during exercise tolerance test (ETT) or cardiopulmonary test (CPET) on a 0-3 scale (Classification on Figure 1.). EIVA was defined as grade ≥2. Peak VO2 was obtained via CPET or estimated from METs. The primary endpoint was a composite of sustained ventricular tachycardia/fibrillation, appropriate implantable cardioverter-defibrillator therapy, sudden cardiac arrest and sudden death. Results Of 202 ACM patients followed in our center 157 (mean age 48.3 ± 16.8 years, 56.7% males), underwent ETT or CPET at baseline; 80 (51%) patients harboured a P/LP variant, most commonly in PKP2 (n=41), DSP (n=17) and FLNC (n=11) genes. Mean peak VO2 was 41.6±10.5 ml·kg−¹·min−¹. EIVA were observed in 61 (30%) cases. Patients demonstrating EIVA exhibited significantly reduced peak oxygen uptake (VO2peak: 38.2 ± 10.2 vs 43.0 ± 10.4 ml·kg·min, p=0.019) and and a higher prevalence of myocardial fibrosis (MF) on cardiac magnetic resonance, (93% vs 74%, p=0.001). Among 56 patients with a baseline normal ECG, 8 (14%) exhibited EIVA; among 23 genotype-positive individuals with a negative or borderline phenotype, 4 (17%) showed EIVA. The prevalence of EIVA was comparable between patients who continued higher levels of physical activity and those who reduced their exercise after the diagnosis (31% vs 30%, respectively). During follow-up, the primary arrhythmic endpoint occurred in 22 (14%) patients, with events more frequent among those with EIVA. Myocardial fibrosis (HR 6.0, 95% CI 1.7-21.5; p=0.006) and EIVA (HR 2.8, 95% CI 1.1-7.3; p=0.03) were independently associated with the primary arrhythmic endpoint at multivariate analysis. The combination of the two risk factors EIVA and MF (score 2) significantly stratified prognosis, in comparison to none or one risk factor (score 0-1), p0.001 (Figure 2.). Conclusion Exercise-induced ventricular arrhythmias occurred in nearly one-third of ACM patients and were independently associated with adverse arrhythmic outcomes, alongside myocardial fibrosis. These findings support the integration of exercise testing into routine risk stratification.Figure 1.Classification of EIVAFor image description, please refer to the figure legend and surrounding text. Figure 2.EIVA-Myocardial FibrosisFor image description, please refer to the figure legend and surrounding text.