Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction

Journal article

Desmoglein-2 mutations are detected in 5–10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2mt/wt) or haploinsufficient (Dsg20/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2mt/wt and Dsg20/wt mice and in young Dsg2mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg20/wt and Dsg2mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2mt/wt mice but not in wild types. Dsg2mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.

Authors: Fabritz, L; Fortmueller, L; Gehmlich, K; Kant, S; Kemper, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Biomedicines
• Volume: 12
• Issue: 5
• Article number: 985
• Publication date: 2024-04-30
• Acceptance date: 2024-04-23
• DOI: 10.3390/biomedicines12050985
• EISSN: 2227-9059
• Language: English
• Keywords: endurance exercise; desmosome; preload-reducing therapy; intercalated disk; arrhythmogenic right ventricular cardiomyopathy (ARVC); desmoglein 2; mouse model; arrhythmogenic cardiomyopathy