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

Exercise has the potential to unmask ventricular arrhythmias in arrhythmogenic cardiomyopathy (ACM). The aim of the study was to assess the prevalence and prognostic significance of exercise-induced ventricular arrhythmias (EIVAs) during exercise tests.

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. EIVAs were adjudicated on revision of the exercise test (exercise tolerance test (ETT) or cardiopulmonary exercise test (CPET)). Peak VO₂ was obtained via CPET or estimated from metabolic equivalents. The primary endpoint was a composite of sustained ventricular tachycardia/fibrillation, appropriate implantable cardioverter-defibrillator therapy, sudden cardiac arrest and sudden death.

Of 202 patients followed at our centre, 157 (mean age 48±16 years, 57% men) underwent ETT or CPET at baseline; 80 (51%) patients harboured a P/LP variant, most commonly in plakophilin-2 (n=43), desmoplakin (n=18) and filamin C (n=11) genes. Mean peak VO₂ was 41.4±10.6 mL/kg/min. EIVAs were observed in 61 (39%) cases. Patients demonstrating EIVA exhibited lower peak VO₂ (38.2 ± 10.2 vs 43.0 ± 10.4 mL/kg/min, p=0.019) and a numerically higher prevalence of myocardial fibrosis (MF) on cardiac magnetic resonance (52% vs 37%, p=0.071) with respect to counterparts. Among 65 patients with a baseline normal ECG, 9 (14%) exhibited EIVA; among 29 genotype-positive individuals with a negative or borderline phenotype, 6 (20%) showed EIVA. The prevalence of EIVA was comparable between the lower-exercise and higher-exercise groups (31% vs 30%, respectively). MF (HR 6.05, 95% CI 1.70 to 21.54; p=0.005) and EIVA (HR 2.8, 95% CI 1.1 to 7.3; p=0.03) were independently associated with the primary arrhythmic endpoint at multivariable analysis, with similar direction of effect after accounting for beta-blocker therapy in sensitivity analyses. 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), p<0.001.

EIVAs occurred in nearly 40% of patients with ACM and were associated with adverse arrhythmic outcomes, alongside MF. These findings support the integration of exercise testing into routine risk stratification.