Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction
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 phen...
| Hauptverfasser: | , , , , , , , , , , |
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| Format: | Journal article |
| Sprache: | English |
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MDPI
2024
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| _version_ | 1826313566294114304 |
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| author | Fabritz, L Fortmueller, L Gehmlich, K Kant, S Kemper, M Kucerova, D Syeda, F Faber, C Leube, RE Kirchhof, P Krusche, CA |
| author_facet | Fabritz, L Fortmueller, L Gehmlich, K Kant, S Kemper, M Kucerova, D Syeda, F Faber, C Leube, RE Kirchhof, P Krusche, CA |
| author_sort | Fabritz, L |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-09-25T04:16:58Z |
| format | Journal article |
| id | oxford-uuid:5a3dfbd2-dac3-4076-8eea-5cc2f543d9a0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:16:58Z |
| publishDate | 2024 |
| publisher | MDPI |
| record_format | dspace |
| spelling | oxford-uuid:5a3dfbd2-dac3-4076-8eea-5cc2f543d9a02024-07-20T14:57:19ZEndurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload ReductionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5a3dfbd2-dac3-4076-8eea-5cc2f543d9a0EnglishJisc Publications RouterMDPI2024Fabritz, LFortmueller, LGehmlich, KKant, SKemper, MKucerova, DSyeda, FFaber, CLeube, REKirchhof, PKrusche, CADesmoglein-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. |
| spellingShingle | Fabritz, L Fortmueller, L Gehmlich, K Kant, S Kemper, M Kucerova, D Syeda, F Faber, C Leube, RE Kirchhof, P Krusche, CA Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title | Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title_full | Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title_fullStr | Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title_full_unstemmed | Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title_short | Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction |
| title_sort | endurance training provokes arrhythmogenic right ventricular cardiomyopathy phenotype in heterozygous desmoglein 2 mutants alleviation by preload reduction |
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