Lim, Seakcheng and Mangala, Melissa M. and Holliday, Mira and Cserne Szappanos, Henrietta and Barratt-Ross, Samantha and Li, Serena and Thorpe, Jordan and Liang, Whitney and Ranpura, Ginell N. and Vandenberg, Jamie I. and Semsarian, Christopher and Hill, Adam P. and Hool, Livia C. (2024) Reduced connexin-43 expression, slow conduction and repolarisation dispersion in a model of hypertrophic cardiomyopathy. Disease Models & Mechanisms, 17 (8). ISSN 1754-8403
Full text not available from this repository.Abstract
Hypertrophic cardiomyopathy (HCM) is an inherited heart muscle disease that is characterised by left ventricular wall thickening, cardiomyocyte disarray and fibrosis, and is associated with arrhythmias, heart failure and sudden death. However, it is unclear to what extent the electrophysiological disturbances that lead to sudden death occur secondary to structural changes in the myocardium or as a result of HCM cardiomyocyte electrophysiology. In this study, we used an induced pluripotent stem cell model of the R403Q variant in myosin heavy chain 7 (MYH7) to study the electrophysiology of HCM cardiomyocytes in electrically coupled syncytia, revealing significant conduction slowing and increased spatial dispersion of repolarisation - both well-established substrates for arrhythmia. Analysis of rhythmonome protein expression in MYH7 R403Q cardiomyocytes showed reduced expression of connexin-43 (also known as GJA1), sodium channels and inward rectifier potassium channels - a three-way hit that reduces electrotonic coupling and slows cardiac conduction. Our data represent a previously unreported, biophysical basis for arrhythmia in HCM that is intrinsic to cardiomyocyte electrophysiology. Later in the progression of the disease, these proarrhythmic phenotypes may be accentuated by myocyte disarray and fibrosis to contribute to sudden death.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 27 Dec 2024 07:38 |
| Last Modified: | 27 Dec 2024 07:38 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1588 |
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