Abstract
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(NaL) 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(2+) 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 Ca(2+)-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(2+) imaging of long QT syndrome type 2 myocytes revealed that GS967 shortened Ca(2+) transient duration via accelerating Na(+)/Ca(2+) exchanger (I(NCX))-mediated Ca(2+) efflux from cytosol, thereby reducing EADs. Computer modeling revealed that I(NaL) 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(i)) that decreases the depolarizing I(NCX) thereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K(+) channels (I(Ks)), suggesting important roles of I(NaL) in regulating Na(i). CONCLUSIONS: Selective I(NaL) blockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Na(i). Graphic Abstract: A graphic abstract is available for this article.