Abstract 15425: The Novel Late Sodium Current Blocker GS-458967 Suppresses Action Potential Duration Alternans and Early Afterdepolarization in a Transgenic Rabbit Model of Long Qt Syndrome Type 2
Congenital long QT syndrome type 2 (LQT2) is a familial disease, characterized by prolongation of the QT interval and sudden cardiac death caused by polymorphic ventricular tachycardia (PVT) due to IKr. LQT2-related arrhythmias result from the combination of early afterdepolarizations (EADs) as a trigger and increased dispersion of repolarization that promotes reentry formation. One potential therapeutic approach is to mitigate the reduced repolarization reserve by reducing depolarizing currents, such as the late INa (INaL). We determined the effects of the novel, potent (IC50 = 130 nM) and selective INaL inhibitor, GS[[Unable to Display Character: -]]458967 on induction of arrhythmias in a transgenic rabbit model of LQT2 and their littermate controls (LMC) using optical mapping. We investigated the effects of GS-458967 on action potential duration (APD) restitution, dispersion, and vulnerability to EADs and PVTs during sympathetic stimulation following a bolus injection of isoproterenol (140 nM). We found that GS-458967 at 30 nM had the following effects: 1) slightly reduced action potential refractoriness in LMC (15 ms) and LQT2 (12 ms), while not affecting APDs at basic cycle lengths of 250 and 350 ms; 2) stabilized APDs by reducing the amplitude of APD alternans and dispersion during rapid pacing with basic cycle length (BCL) shorter than 200 ms in both LMC and LQT2 (see figure); 3) reduced vulnerability to ventricular fibrillation during ramp pacing; and 4) reduced EADs and PVT in LQT2 (from 75% to 19% at 30 nM, and 13% at 100 nM, n=8). In conclusion, the INaL inhibitor GS-458967 prevented PVT induction in the LQT2 heart model by reducing APD alternans and dispersion during rapid pacing, and by reducing EAD activity during sympathetic stimulation. Thus, inhibition of INaL is a potentially novel therapy for treating LQT2 syndrome or other heart disease(s) whereby increased alternans and formation of EADs are present due to reduced repolarization reserve.
- © 2012 by American Heart Association, Inc.