Eleclazine, a new selective cardiac late sodium current inhibitor, confers concurrent protection against autonomically induced atrial premature beats, repolarization alternans and heterogeneity, and atrial fibrillation in an intact porcine model

BACKGROUND The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eledazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias. OBJECTIVE We tested whether late INa inhibition by eledazine confers protection against atrial premature beats (APBs) and AF. METHODS In dosed-chest anesthetized Yorkshire pigs, epinephrine (2.0 mu g/kg, intravenous, bolus over 1 minute) was administered alone to induce APBs (n = 6) or in combination with intrapericardial acetylcholine (0.5-4 mL of 12.5 mM solution) to induce spontaneous AF (n = 11). Effects of eledazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined. RESULTS Epinephrine-induced APBs were reduced >3-fold (P <.04) after eledazine (0.9 mg/kg) infusion. The combined administration of epinephrine and acetylcholine resulted in AF in all animals tested, which was invariably preceded by APBs. Eledazine pretreatment suppressed AF in all 7 animals in at least 1 test episode during the 60- to 150-minute observation period (P =.04). The plasma eledazine level at 120 minutes was 828 45.8 nM, within exposure range evaluated clinically. Eledazine shortened ventricular QT and atrial PTa intervals by 7% (P <.001 for both) and reduced atrial repolarization alternans (P =.003) and heterogeneity (P =.021) without attenuation of the inotropic response to catecholamine (P =.56). The drug inhibited the enhanced late INa of single atrial myocytes with a potency of 736 67 nM. CONCLUSION Selective cardiac late INa inhibition with eledazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.