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

Henrietta Cserne Szappanos1, Helena M Viola1, Danica W Ito2

  • 1School of Human Sciences, University of Western Australia, Crawley, WA, Australia.

Scientific Reports
|July 12, 2023
PubMed

Insights

Familial hypertrophic cardiomyopathy (FHC) mouse models show that altered ion channel function and beta-adrenergic signaling contribute to heart arrhythmias. These findings highlight potential therapeutic targets for FHC patients at risk of sudden cardiac events.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Genetics

Background:

  • Familial hypertrophic cardiomyopathy (FHC) is linked to an increased risk of arrhythmias, particularly with strenuous exercise.
  • A mouse model with the MYH6 R403Q mutation mimics FHC, displaying cytoskeletal disarray and arrhythmia susceptibility.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying electrical instability in the R403Q FHC mouse model.
  • To explore the role of ion channel function and beta-adrenergic signaling in FHC-related arrhythmias.

Main Methods:

  • In vivo administration of isoproterenol to induce arrhythmias in mutant and wild-type mice.
  • Pharmacological interventions using atenolol (a beta-blocker) and PKI (a protein kinase A inhibitor).
  • Electrophysiological assessments of cardiac myocytes, including action potential recordings and analysis of connexin 43 expression. Super-resolution nanoscopy was used to assess CaV1.2 and beta-1 adrenergic receptor colocalization.

Main Results:

  • Mutant mice exhibited exacerbated tachyarrhythmias, poor recovery, and fatigue upon isoproterenol challenge.
  • Arrhythmias were significantly reduced by atenolol and PKI treatment.
  • Mutant myocytes displayed prolonged action potentials and triggered automaticity, linked to reduced repolarization reserve and connexin 43 levels.
  • While isoproterenol did not alter CaV1.2 current, it increased CaV1.2 phosphorylation and altered CaV1.2-beta-1 adrenergic receptor colocalization in mutant hearts.

Conclusions:

  • Altered ion channel expression, co-localization, and beta-adrenergic receptor signaling contribute to cardiac electrical instability in the R403Q FHC model.
  • These molecular changes, in conjunction with myocyte disarray, are key factors in the increased arrhythmia susceptibility observed in FHC.
  • The findings provide novel insights into FHC pathophysiology and suggest potential therapeutic strategies targeting ion channel and receptor signaling pathways.

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