Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

Heart Rhythm. 2016 Aug;13(8):1679-86. doi: 10.1016/j.hrthm.2016.04.015. Epub 2016 Apr 21.


Background: The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias.

Objective: We tested whether late INa inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF.

Methods: In closed-chest anesthetized Yorkshire pigs, epinephrine (2.0 µg/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5-4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eleclazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined.

Results: Epinephrine-induced APBs were reduced >3-fold (P < .04) after eleclazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eleclazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P = .04). The plasma eleclazine level at 120 minutes was 828 ± 45.8 nM, within exposure range evaluated clinically. Eleclazine shortened ventricular QT and atrial PTa intervals by 7% (P < .001 for both) and reduced atrial repolarization alternans (P = .003) and heterogeneity (P = .021) without attenuation of the inotropic response to catecholamine (P = .56). The drug inhibited the enhanced late INa of single atrial myocytes with a potency of 736 ± 67 nM.

Conclusion: Selective cardiac late INa inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.

Keywords: Acetylcholine; Alternans; Atrial fibrillation; Atrial premature beats; Epinephrine; Heterogeneity; Late sodium current; Repolarization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Fibrillation / drug therapy*
  • Atrial Fibrillation / physiopathology
  • Atrial Premature Complexes / drug therapy*
  • Atrial Premature Complexes / physiopathology
  • Autonomic Nervous System / drug effects
  • Autonomic Nervous System / physiopathology*
  • Disease Models, Animal
  • Electrocardiography
  • Heart Atria / drug effects
  • Heart Atria / physiopathology*
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology*
  • Male
  • Oxazepines / pharmacology*
  • Swine


  • Oxazepines
  • eleclazine