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The Selective Cardiac Late Sodium Current Inhibitor GS‐458967 Suppresses Autonomically Triggered Atrial Fibrillation in an Intact Porcine Model
Author(s) -
CARNEIRO JULIANA SARAN,
BENTO AFONSO S. ALVES,
BACIC DANILO,
NEARING BRUCE D.,
RAJAMANI SRIDHARAN,
BELARDINELLI LUIZ,
VERRIER RICHARD L.
Publication year - 2015
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/jce.12824
Subject(s) - medicine , atrial fibrillation , epinephrine , heart rate , anesthesia , qrs complex , bolus (digestion) , ventricular fibrillation , qt interval , cardiology , blood pressure
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 (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.