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

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 ) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs. We tested the effects of the selective I blocker GS967 on PVT induction in a transgenic rabbit model of long QT syndrome type 2 using intact heart optical mapping, cellular electrophysiology and confocal Ca imaging, and computer modeling. 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 Ca -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 Ca imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca transient duration via accelerating Na /Ca exchanger (I )-mediated Ca efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I potentiates 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 ) that decreases the depolarizing I thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K channels (I ), suggesting important roles of I in regulating Na . Selective I blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na . Graphic Abstract: A graphic abstract is available for this article.