Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a rare cardiomyopathy but significantly contributes to sudden cardiac death in young otherwise healthy patients, especially endurance athletes. 5-10% of patients with ARVC harbour mutations in the extracellular domains of the Desmoglein (DSG) 2 gene. To assess the role of DSG2 in ARVC pathomechanism, mice lacking exons 4-6 of the endogenous DSG2 gene (DSG2mt/wt) were generated. Homozygous DSG2 mutant mice (DSG2mt/mt, loss-of-function) developed dilatation of ventricles and pronounced fibrosis. Heterozygous DSG2 mutants (DSG2mt/wt) did not show such morphological alterations. Objective: To study whether physical exercise provokes a cardiac phenotype in DSG2wt/mt mice, they were subjected to endurance training and compared with Wild-Type (WT) littermates. Methods/Results:ÿTraining sessions were performed 6 times a week, incrementing to 90 minutes per day for 7 weeks. Echocardiography was performed before and after training using a small animal ultrasound unit. Rightÿventricular dimensions were increased in DSG2wt/mt after training compared to WT after training andÿto DSG2wt/mt pre-training (see table for values). Electrophysiological studies in isolated Langendorff DSG2wt/mtÿhearts showed that DSG2 mutation correlated with increased arrhythmia inducibility after endurance training. Ventricular arrhythmias were induced by a single extrastimulus during right ventricular stimulation in 5 of 8 DSG2wt/mt, but in none of the 7 WT hearts (p<0.05). In conclusion, endurance training reveals an ARVC-like phenotype in otherwise healthy and morphologically inconspicuous DSG2wt/mt mice. |