Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction
Larissa Fabritz,
Lisa Fortmueller,
Katja Gehmlich,
Sebastian Kant,
Marcel Kemper,
Dana Kucerova,
Fahima Syeda,
Cornelius Faber,
Rudolf E. Leube,
Paulus Kirchhof,
Claudia A. Krusche
Affiliations
Larissa Fabritz
University Center of Cardiovascular Science and Department of Cardiology, University Heart and Vascular Center, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany
Lisa Fortmueller
University Center of Cardiovascular Science and Department of Cardiology, University Heart and Vascular Center, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany
Katja Gehmlich
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
Sebastian Kant
Institute for Molecular and Cellular Anatomy (MOCA), RWTH Aachen University, 52074 Aachen, Germany
Marcel Kemper
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
Dana Kucerova
Department of Cardiology, Section of Rhythmology, University Hospital Muenster, 48149 Münster, Germany
Fahima Syeda
Institute of Cardiovascular Sciences, University of Birmingham, Birmingham B15 2TT, UK
Cornelius Faber
Clinic of Radiology, Translational Research Imaging Center (TRIC), University of Muenster, 48149 Münster, Germany
Rudolf E. Leube
Institute for Molecular and Cellular Anatomy (MOCA), RWTH Aachen University, 52074 Aachen, Germany
Paulus Kirchhof
University Center of Cardiovascular Science and Department of Cardiology, University Heart and Vascular Center, University Hospital Hamburg Eppendorf, 20246 Hamburg, Germany
Claudia A. Krusche
Institute for Molecular and Cellular Anatomy (MOCA), RWTH Aachen University, 52074 Aachen, Germany
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.
