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

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

Author information

1
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
2
Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
3
Harvard Medical School, Boston, Massachusetts, USA.
4
Gilead Sciences, Inc, Foster City, California, USA.

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

PMID:
26331943
DOI:
10.1111/jce.12824
[Indexed for MEDLINE]

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