Mapping the electrical impact of exercise on disease trajectory in arrhythmogenic cardiomyopathy: a longitudinal ECG study

Abstract Background Retrospective studies suggest that exercise may play a significant role in modulating the pathogenesis of arrhythmogenic cardiomyopathy (ACM), potentially influencing its phenotypic expression and clinical course Purpose To assess ECG progression in a cohort of patients with ACM, with particular focus on the potential impact of exercise. Methods Clinical data of 202 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 analyzed. Patients were stratified into "lower" and "higher" exercise groups based on exercise intensity after the diagnosis. The ECGs of 163 patients with complete data at baseline and follow-up were considered. The primary composite endpoint included major ventricular arrhythmia, appropriate implantable cardioverter-defibrillator interventions, sudden cardiac arrest and sudden cardiac death. Results A total of 163 (mean age 47.4 ± 16.0 years, 92 (56%) males) patients were included; P/LP variants were found in 77 (47%) individuals, most commonly PKP2 (n=42, 26%), DSP (n=16, 10%) and FLNC (n=12, 7%). Almost a third (n=52, 32%) of the cases continued to exercise at moderate and intense levels after diagnosis (higher-exercise group). The first ECG was abnormal in 66% of the total cohort at baseline (anterior T-wave inversion (ATWI) was the most common abnormality (n=42, 26%)). Low QRS voltages (LQRSV) were found in 12%. At an average follow-up of 4.6±2.5 years, 11 (9%) patients developed new ATWI. Among patients with ATWI at baseline, 45% demonstrated progression (deepening and/or extension of TWI). Among patients with normal QRSV at baseline, 6% developed new LQRSV at follow-up and a substantial decline in QRSV was observed in 23% of cases. Whilst progression of specific ECG variables did not differ significantly between the lower- and higher-exercise groups, a greater rise in the prevalence of abnormal ECGs at follow-up was observed among those with higher exercise exposure after diagnosis (p=0.027). Inferior T-wave inversion and total limb lead QRS voltages 3mV emerged as independent predictors of arrhythmic risk. Conclusions ECG abnormalities in ACM patients commonly progress over time, with inferior T-wave inversion and low QRS voltages emerging as independent predictors of arrhythmic risk. Although specific ECG changes did not differ significantly between exercise groups, patients with higher post-diagnosis exercise exposure showed a greater prevalence of abnormal ECGs at follow-up. These findings support regular ECG surveillance and suggest that exercise intensity may influence disease expression, warranting individualized exercise recommendations.Abstract IllustrationFor image description, please refer to the figure legend and surrounding text.