Late I_NaBlocker GS967 Supresses Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long QT Type 2

Background: Long QT syndrome has been associated with sudden cardiac death likely caused by early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs). Suppressing the late sodium current (I_NaL) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs. Methods: We tested the effects of the selective I_NaLblocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca²⁺imaging, and computer modeling. Results: GS967 reduced ventricular fibrillation induction under a rapid pacing protocol (n=7/14 hearts in control versus 1/14 hearts at 100 nmol/L) without altering action potential duration or restitution and dispersion. GS967 suppressed PVT incidences by reducing Ca²⁺-mediated EADs and focal activity during isoproterenol perfusion (at 30 nmol/L, n=7/12 and 100 nmol/L n=8/12 hearts without EADs and PVTs). Confocal Ca²⁺imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca²⁺transient duration via accelerating Na⁺/Ca²⁺exchanger (I_NCX)-mediated Ca²⁺efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I_NaLpotentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na⁺(Na_i) that decreases the depolarizing I_NCXthereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K⁺channels (I_Ks), suggesting important roles of I_NaLin regulating Na_i.