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

Circ Arrhythm Electrophysiol. 2013 Jun;6(3):546-54. doi: 10.1161/CIRCEP.113.000400. Epub 2013 May 6.


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.

Keywords: Na+ channels; arrhythmias; cardiac resynchronization therapy; electrophysiology; heart failure.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cardiac Resynchronization Therapy / methods*
  • Computer Simulation
  • Disease Models, Animal
  • Dogs
  • Heart Conduction System / metabolism
  • Heart Conduction System / physiopathology
  • Heart Failure / diagnosis
  • Heart Failure / mortality
  • Heart Failure / therapy*
  • Ion Channel Gating / physiology
  • Male
  • Random Allocation
  • Reactive Oxygen Species / metabolism
  • Risk Assessment
  • Sensitivity and Specificity
  • Sodium Channels / metabolism*
  • Survival Rate
  • Treatment Outcome
  • Ventricular Remodeling / physiology*


  • Reactive Oxygen Species
  • Sodium Channels