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.
The cardiac late sodium current (INa) has been increasingly implicated in the initiation of atrial fibrillation (AF). Eleclazine (formerly known as GS-6615) is a new selective late INa inhibitor and is undergoing clinical testing for the treatment of cardiac arrhythmias.



We tested whether late INa inhibition by eleclazine confers protection against atrial premature beats (APBs) and AF.



In closed-chest anesthetized Yorkshire pigs, epinephrine (2.0 µg/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 eleclazine (0.3 and 0.9 mg/kg, intravenous, over 15 minutes) on APBs and AF were determined.



Epinephrine-induced APBs were reduced >3-fold (P < .04) after eleclazine (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. Eleclazine 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 eleclazine level at 120 minutes was 828 ± 45.8 nM, within exposure range evaluated clinically. Eleclazine 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.



Selective cardiac late INa inhibition with eleclazine suppresses autonomically mediated atrial repolarization alternans and heterogeneity, APBs, and AF in an intact porcine model.
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Henrique
H
Fuller
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil.
Fernanda
F
Justo
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Bruce D
BD
Nearing
Gilead Sciences, Inc., Foster City, California.
Kristopher M
KM
Kahlig
Gilead Sciences, Inc., Foster City, California.
Sridharan
S
Rajamani
Gilead Sciences, Inc., Foster City, California.
Luiz
L
Belardinelli
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address: rverrier@bidmc.harvard.edu.
Richard L
RL
Verrier
D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000503:physiopathology; D018880:Atrial Premature Complexes / Q000188:drug therapy* / Q000503:physiopathology; D001341:Autonomic Nervous System / Q000187:drug effects / Q000503:physiopathology*; D004195:Disease Models, Animal; D004562:Electrocardiography; D006325:Heart Atria / Q000187:drug effects / Q000503:physiopathology*; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D010077:Oxazepines / Q000494:pharmacology*; D013552:Swine
D010077:Oxazepines; C000624281:eleclazine
Acetylcholine; Alternans; Atrial fibrillation; Atrial premature beats; Epinephrine; Heterogeneity; Late sodium current; Repolarization