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Relevance of calmodulin/CaMKII activation for arrhythmogenesis in the AV block dog

Vincent J A Bourgonje1, Marieke Schoenmakers, Jet D M Beekman

  • 1Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. v.j.a.bourgonje@umcutrecht.nl

Heart Rhythm
|August 1, 2012
PubMed
Abstract

Insights

Calcineurin is not involved in long-term cardiac remodeling in dogs. While CaMKII is chronically activated, acute overactivation initiates arrhythmias, highlighting its role in triggered activity.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Biochemistry

Background:

  • Calcineurin and CaMKII are calcium-dependent signaling molecules implicated in cardiac hypertrophy and arrhythmias.
  • CaMKII is also involved in the acute regulation of ion channels.

Purpose of the Study:

  • To investigate the roles of calcineurin and CaMKII in a canine model of compensated cardiac hypertrophy and a long QT syndrome phenotype.

Main Methods:

  • Atrioventricular (AV) block was induced in dogs to promote ventricular remodeling and susceptibility to dofetilide-induced torsades de pointes.
  • Cyclosporin A treatment reduced calcineurin activity but did not prevent remodeling or arrhythmias.
  • Western blotting assessed levels of phosphorylated CaMKII, phospholamban, Akt, and HDAC4.

Main Results:

  • Chronic AV block increased phosphorylation of Akt, CaMKII, and phospholamban, but not HDAC4.
  • Dofetilide induced torsades de pointes and early afterdepolarizations, with increased intracellular calcium and CaMKII autophosphorylation.
  • Pharmacological inhibition of CaMKII (W-7 and KN-93) counteracted these effects.

Conclusions:

  • The calcineurin pathway does not appear to contribute to long-term cardiac remodeling in this chronic AV block model.
  • Chronic CaMKII activation does not lead to HDAC4 phosphorylation, but acute CaMKII overactivation triggers arrhythmias via triggered activity.

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