Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure

Ingrid M. Bonilla, Victor P. Long, Pedro Vargas-Pinto, Patrick Wright, Andriy Belevych, Qing Lou, Kent Mowrey, Jae Yoo, Philip F. Binkley, Vadim V. Fedorov, Sandor Györke, Paulus M.L. Janssen, Ahmet Kilic, Peter J. Mohler, Cynthia A. Carnes

Research output: Contribution to journalArticle

Abstract

The role of IKCa in cardiac repolarization remains controversial and varies across species. The relevance of the current as a therapeutic target is therefore undefined. We examined the cellular electrophysiologic effects of IKCa blockade in controls, chronic heart failure (HF) and HF with sustained atrial fibrillation. We used perforated patch action potential recordings to maintain intrinsic calcium cycling. The IKCa blocker (apamin 100 nM) was used to examine the role of the current in atrial and ventricular myocytes. A canine tachypacing induced model of HF (1 and 4 months, n =5 per group) was used, and compared to a group of 4 month HF with 6 weeks of superimposed atrial fibrillation (n =7). A group of age-matched canine controls were used (n=8). Human atrial and ventricular myocytes were isolated from explanted end-stage failing hearts which were obtained from transplant recipients, and studied in parallel. Atrial myocyte action potentials were unchanged by IKCa blockade in all of the groups studied. IKCa blockade did not affect ventricular myocyte repolarization in controls. HF caused prolongation of ventricular myocyte action potential repolarization. IKCa blockade caused further prolongation of ventricular repolarization in HF and also caused repolarization instability and early afterdepolarizations. SK2 and SK3 expression in the atria and SK3 in the ventricle were increased in canine heart failure. We conclude that during HF, IKCa blockade in ventricular myocytes results in cellular arrhythmias. Furthermore, our data suggest an important role for IKCa in the maintenance of ventricular repolarization stability during chronic heart failure. Our findings suggest that novel antiarrhythmic therapies should have safety and efficacy evaluated in both atria and ventricles.

Original languageEnglish (US)
Article numbere108824
JournalPloS one
Volume9
Issue number10
DOIs
StatePublished - Oct 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Bonilla, I. M., Long, V. P., Vargas-Pinto, P., Wright, P., Belevych, A., Lou, Q., Mowrey, K., Yoo, J., Binkley, P. F., Fedorov, V. V., Györke, S., Janssen, P. M. L., Kilic, A., Mohler, P. J., & Carnes, C. A. (2014). Calcium-activated potassium current modulates ventricular repolarization in chronic heart failure. PloS one, 9(10), [e108824]. https://doi.org/10.1371/journal.pone.0108824