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

Jungmin Hwang, Tae Yun Kim, Dmitry Terentyev, Mingwang Zhong, Anatoli Y. Kabakov, Peter Bronk, Karuppiah Arunachalam, Luiz Belardinelli, Sridharan Rajamani, Yukiko Kunitomo, Zachary Pfeiffer, Yichun Lu, Xuwen Peng, Katja E. Odening, Zhilin Qu, Alain Karma, Gideon Koren, Bum Rak Choi

Research output: Contribution to journalArticlepeer-review

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 (INaL) may counterbalance the reduced repolarization reserve in long QT syndrome and prevent EADs and PVTs. Methods: We tested the effects of the selective INaLblocker 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 (INCX)-mediated Ca2+efflux from cytosol, thereby reducing EADs. Computer modeling revealed that INaLpotentiates EADs in the long QT syndrome type 2 setting through (1) providing additional depolarizing currents during action potential plateau phase, (2) increasing intracellular Na+(Nai) that decreases the depolarizing INCXthereby suppressing the action potential plateau and delaying the activation of slowly activating delayed rectifier K+channels (IKs), suggesting important roles of INaLin regulating Nai. Conclusions: Selective INaLblockade by GS967 prevents EADs and abolishes PVT in long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Nai

Original languageEnglish (US)
JournalCirculation: Arrhythmia and Electrophysiology
DOIs
StatePublished - Aug 1 2020

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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