Late INa blocker GS967 Suppress Polymorphic VT in a Transgenic Rabbit Model of Long QT Type 2.

Background - Long QT syndrome (LQTS) has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (INaL) may counterbalance the reduced repolarization reserve in LQTS and prevent EADs and PVTs. Methods - We tested the effects of the selective INaL blocker GS967 on PVT induction in a transgenic rabbit model of LQTS type 2 (LQT2) using intact heart optical mapping, cellular electrophysiology and confocal Ca2+ imaging, and computer modeling. Results - GS967 reduced (ventricular fibrillation) VF induction under a rapid pacing protocol (n=7/14 hearts in control vs. 1/14 hearts at 100 nM) without altering APD or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca2+-mediated EADs and focal activity during isoproterenol perfusion (at 30 nM, n=7/12 and 100 nM n=8/12 hearts without EADs and PVTs). Confocal Ca2+ imaging of LQT2 myocytes revealed that GS967 shortened Ca2+ transient duration via accelerating Na+/Ca2+ exchanger (INCX)-mediated Ca2+ efflux from cytosol, thereby reducing EADs. Computer modeling revealed that INaL potentiates EADs in the LQT2 setting through 1) providing additional depolarizing currents during AP plateau phase, 2) increasing intracellular Na+ (Nai) that decreases the depolarizing INCX thereby suppressing the AP plateau and delaying the activation of slowly-activating delayed rectifier K+ channels (IKs), suggesting important roles of INaL in regulating Nai. Conclusions - Selective INaL blockade by GS967 prevents EADs and abolishes PVT in LQT2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Nai.