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

Journal of Cardiovascular Electrophysiology
Juliana Saran CarneiroRichard L Verrier

Abstract

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. 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. Selec...Continue Reading

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Aug 5, 2016·Nature Reviews. Cardiology·Stanley Nattel, Dobromir Dobrev
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May 7, 2020·Frontiers in Pharmacology·Balázs HorváthTamás Bányász
Jul 28, 2020·Circulation Research·Dominik SchüttlerWilliam J Hucker
Dec 2, 2020·Channels·Kornél KistamásPéter P Nánási

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