Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction.
Larissa FabritzLisa FortmuellerKatja GehmlichSebastian KantMarcel KemperDana KucerovaFahima SyedaCornelius FaberRudolf E. LeubePaulus F KirchhofClaudia A KruschePublished in: Biomedicines (2024)
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 ( Dsg2 mt/wt ) or haploinsufficient ( Dsg2 0/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 Dsg2 mt/wt and Dsg2 0/wt mice and in young Dsg2 mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg2 0/wt and Dsg2 mt/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 Dsg2 mt/wt mice but not in wild types. Dsg2 mt/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 Dsg2 mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2 mt/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.
Keyphrases
- high fat diet induced
- skeletal muscle
- wild type
- heart failure
- left ventricular
- mycobacterium tuberculosis
- resistance training
- virtual reality
- young adults
- physical activity
- insulin resistance
- end stage renal disease
- oxidative stress
- type diabetes
- mesenchymal stem cells
- risk assessment
- endothelial cells
- chronic kidney disease
- metabolic syndrome
- bone marrow
- catheter ablation
- adipose tissue
- atrial fibrillation
- pluripotent stem cells