Cardiac resynchronization therapy improves altered na channel gating in canine model of dyssynchronous heart failure

Takeshi Aiba, Andreas S. Barth, Geoffrey G. Hesketh, Yasmin L. Hashambhoy, Khalid Chakir, Richard S. Tunin, Joseph L. Greenstein, Raimond L. Winslow, David A. Kass, Gordon F. Tomaselli

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13 Scopus citations

Abstract

Background-Slowed Na+ current (INa) decay and enhanced late INa (INa-L) prolong the action potential duration (APD) and contribute to early afterdepolarizations. Cardiac resynchronization therapy (CRT) shortens APD compared with dyssynchronous heart failure (DHF); however, the role of altered Na+ channel gating in CRT remains unexplored. Methods and Results-Adult dogs underwent left-bundle branch ablation and right atrial pacing (200 beats/min) for 6 weeks (DHF) or 3 weeks followed by 3 weeks of biventricular pacing at the same rate (CRT). INa and INa-L were measured in left ventricular myocytes from nonfailing, DHF, and CRT dogs. DHF shifted voltage-dependence of INa availability by -3 mV compared with nonfailing, enhanced intermediate inactivation, and slowed recovery from inactivation. CRT reversed the DHF-induced voltage shift of availability, partially reversed enhanced intermediate inactivation but did not affect DHF-induced slowed recovery. DHF markedly increased INa-L compared with nonfailing. CRT dramatically reduced DHF-induced enhanced INa-L, abbreviated the APD, and suppressed early afterdepolarizations. CRT was associated with a global reduction in phosphorylated Ca2+/Calmodulin protein kinase II, which has distinct effects on inactivation of cardiac Na+ channels. In a canine AP model, alterations of INa-L are sufficient to reproduce the effects on APD observed in DHF and CRT myocytes. Conclusions-CRT improves DHF-induced alterations of Na+ channel function, especially suppression of INa-L, thus, abbreviating the APD and reducing the frequency of early afterdepolarizations. Changes in the levels of phosphorylated Ca2+/Calmodulin protein kinase II suggest a molecular pathway for regulation of INa by biventricular pacing of the failing heart.

Original languageEnglish (US)
Pages (from-to)546-554
Number of pages9
JournalCirculation: Arrhythmia and Electrophysiology
Volume6
Issue number3
DOIs
StatePublished - Jun 1 2013

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Keywords

  • Arrhythmias
  • Cardiac resynchronization therapy
  • Electrophysiology
  • Heart failure
  • Na+ channels

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Aiba, T., Barth, A. S., Hesketh, G. G., Hashambhoy, Y. L., Chakir, K., Tunin, R. S., Greenstein, J. L., Winslow, R. L., Kass, D. A., & Tomaselli, G. F. (2013). Cardiac resynchronization therapy improves altered na channel gating in canine model of dyssynchronous heart failure. Circulation: Arrhythmia and Electrophysiology, 6(3), 546-554. https://doi.org/10.1161/CIRCEP.113.000400