Inhibition of the cardiac late sodium current with eleclazine protects against ischemia-induced vulnerability to atrial fibrillation and reduces atrial and ventricular repolarization abnormalities in the absence and presence of concurrent adrenergic stimulation.
Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation.



The purpose of this study was to investigate whether selective inhibition of the cardiac late sodium current (INa) with eleclazine decreases susceptibility to ischemia-induced atrial fibrillation (AF) and atrial and ventricular repolarization abnormalities before and after epinephrine infusion.



In chloralose-anesthetized, open-chest, male Yorkshire pigs (n = 12), atrial and ventricular ischemia was induced by partial occlusion of the left circumflex coronary artery proximal segment to reduce flow by 75%. Epinephrine (0.5 µg/kg IV bolus over 1 minute; n = 6) was infused before and at 2 hours after eleclazine (0.9 mg/kg IV bolus over 15 minutes).



Left circumflex coronary artery occlusion significantly increased ventricular dispersion of repolarization (T-wave alternans [TWA] by 861%, T-wave heterogeneity by 286%, Tpeak-Tend interval by 74%) and atrial repolarization alternans (TWAa) by 2850% and lowered AF threshold by 65%. Eleclazine reduced the ischemia-induced surge in TWA by 81% (P = .007), T-wave heterogeneity by 23% (P = .035), and Tpeak-Tend by 28% (P = .014), suppressed the ischemia-induced surge in atrial TWAa by 64% (P = .002), and reduced the ischemia-induced fall in AF threshold to 20%. It shortened baseline QT interval by 6% (P <.001), JT interval by 8% (P <.001), and atrial action potential duration (PTa) by 8% (P = .002). Similar beneficial effects of eleclazine were observed after epinephrine infusion without reducing contractility (P = .054).



Selective inhibition of cardiac late INa with eleclazine confers dual protection against vulnerability to ischemia-induced AF and reduces atrial and ventricular repolarization abnormalities before and during adrenergic stimulation without negative inotropic effects.
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
Fernanda
F
Justo
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Faculdade de Medicina da Universidade de São Paulo, Sao Paulo, Brazil.
Henrique
H
Fuller
Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Bruce D
BD
Nearing
Gilead Sciences, Inc., Fremont and Foster City, California.
Sridharan
S
Rajamani
Gilead Sciences, Inc., Fremont and 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
D018663:Adrenergic Agents / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D001281:Atrial Fibrillation / Q000175:diagnosis / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000628:therapy; D004562:Electrocardiography; D004837:Epinephrine / Q000494:pharmacology; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications* / Q000503:physiopathology; D010077:Oxazepines / Q000494:pharmacology* / Q000627:therapeutic use; D026941:Sodium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015222:Sodium Channels / Q000187:drug effects*; D013552:Swine
D018663:Adrenergic Agents; D010077:Oxazepines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C000624281:eleclazine; D004837:Epinephrine
Alternans; Atrial fibrillation; Epinephrine; Heterogeneity; Late sodium current; Repolarization