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  • Title: 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.
    Author: Justo F, Fuller H, Nearing BD, Rajamani S, Belardinelli L, Verrier RL.
    Journal: Heart Rhythm; 2016 Sep; 13(9):1860-7. PubMed ID: 27317981.
    Abstract:
    BACKGROUND: Myocardial ischemia carries dual risk for initiating atrial and ventricular arrhythmias that can be exacerbated by adrenergic stimulation. OBJECTIVE: 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. METHODS: 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). RESULTS: 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). CONCLUSION: 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.
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