Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy

Cserne Szappanos, Henrietta and Viola, Helena M. and Ito, Danica W. and Lim, Seakcheng and Mangala, Melissa and Holliday, Mira and Barratt Ross, Samantha and Semsarian, Christopher and Hill, Adam and Dixon, Rose E. and Hool, Livia C. (2023) Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy. Scientific Reports, 13 (1). ISSN 2045-2322

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Link to published document: http://doi.org/10.1038/s41598-023-38296-2

Abstract

Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene (MYH6) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the beta-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase Ca(V)1.2 current. We found alterations in Ca(V)1.2-beta1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased Ca(V)1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and beta-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 02 Apr 2024 02:26
Last Modified: 02 Apr 2024 02:26
URI: http://eprints.victorchang.edu.au/id/eprint/1433

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