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

CARNEIRO, JULIANA SARAN; BENTO, AFONSO S. ALVES; BACIC, DANILO; NEARING, BRUCE D.; RAJAMANI, SRIDHARAN; BELARDINELLI, LUIZ; VERRIER, RICHARD L.

GS-967 Suppresses AF. Introduction: The anti-atrial fibrillation (AF) effects of GS-458967 (GS-967), a selective, potent inhibitor of cardiac late Na current (INa), were evaluated in a novelmodel 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 INa 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 INa 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.

ACETYLCHOLINE; ADRENALINE; ANIMAL experimentation; ATRIAL fibrillation; CATECHOLAMINES; ELECTROPHYSIOLOGY; FISHER exact test; PIPERAZINE; SODIUM; SWINE; T-test (Statistics); CHEMICAL inhibitors

Journal of Cardiovascular Electrophysiology, 2015, Vol 26, Issue 12, p1364

1045-3873

Academic Journal

10.1111/jce.12824