The Selective Cardiac Late Sodium Current Inhibitor GS-458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model

J Cardiovasc Electrophysiol. 2015 Dec;26(12):1364-9. doi: 10.1111/jce.12824. Epub 2015 Oct 30.

Abstract

Introduction: The anti-atrial fibrillation (AF) effects of GS-458967 (GS-967), a selective, potent inhibitor of cardiac late Na(+) current (I(Na)), were evaluated in a novel model of AF induction that does not require electrical stimuli.

Methods and results: In 6 closed-chest anesthetized pigs, AF was induced by intrapericardial acetylcholine (1 mL of 100 mM solution) followed within 1 minute by epinephrine (20 μg/kg, i.v., bolus over 1 min). Effects of GS-967 (0.4 mg/kg, i.v., infused over 30 min) on inducibility and duration of AF were analyzed. Administration of acetylcholine followed by epinephrine elicited spontaneous AF that persisted for 12.03 ± 1.22 minutes (mean ± SEM) in all 6 pigs. Following GS-967, AF did not occur in 5 of 6 pigs when plasma concentration was 383 ± 150 nM. In the single animal in which AF could still be induced, the arrhythmia lasted 6.3 minutes. Partial return of AF inducibility occurred in 2 of 6 animals at 90 minutes, when plasma concentration of GS-967 was 228 ± 35 nM. GS-967 reduced the QT interval (P = 0.004), consistent with cardiac late I(Na) inhibition, but did not affect heart rate, mean arterial pressure, QRS duration, or PR interval. Epinephrine infusion alone, tested in a separate group (N = 6), did not provoke AF.

Conclusion: Selective cardiac late I(Na) inhibition with GS-967 suppresses spontaneous induction of AF in a novel model that does not require provocative electrical stimuli. Because this mode of action has only a mild on effect on contractility, it offers an advantage over contemporary anti-AF agents, which can have negative inotropic actions.

Keywords: QT interval; acetylcholine; atrial fibrillation; cardiac late sodium current; catecholamines; epinephrine; ranolazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine
  • Animals
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / therapeutic use*
  • Arterial Pressure / drug effects
  • Atrial Fibrillation / chemically induced
  • Atrial Fibrillation / physiopathology
  • Atrial Fibrillation / prevention & control*
  • Autonomic Nervous System Diseases / complications
  • Autonomic Nervous System Diseases / physiopathology
  • Autonomic Nervous System Diseases / prevention & control*
  • Electric Stimulation
  • Electrocardiography / drug effects
  • Epinephrine
  • Heart Rate / drug effects
  • Male
  • Pyridines / pharmacokinetics
  • Pyridines / therapeutic use*
  • Sodium Channel Blockers / pharmacokinetics
  • Sodium Channel Blockers / therapeutic use*
  • Sus scrofa
  • Swine
  • Triazoles / pharmacokinetics
  • Triazoles / therapeutic use*

Substances

  • 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
  • Anti-Arrhythmia Agents
  • Pyridines
  • Sodium Channel Blockers
  • Triazoles
  • Acetylcholine
  • Epinephrine