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

Circ Arrhythm Electrophysiol. 2020 Aug;13(8):e006875. doi: 10.1161/CIRCEP.118.006875. Epub 2020 Jul 6.

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 INaL 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 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 INaL 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+ (Nai) that decreases the depolarizing INCX thereby suppressing the action potential 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 long QT syndrome type 2 rabbits by counterbalancing the reduced repolarization reserve and normalizing Nai. Graphic Abstract: A graphic abstract is available for this article.

Keywords: electrophysiology; long QT syndrome; potassium channels; sodium channels; ventricular fibrillation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Animals, Genetically Modified
  • Anti-Arrhythmia Agents / pharmacology*
  • Calcium Signaling / drug effects
  • Computer Simulation
  • Delayed Rectifier Potassium Channels / metabolism
  • Disease Models, Animal
  • Female
  • Heart Rate / drug effects*
  • Long QT Syndrome / drug therapy*
  • Long QT Syndrome / genetics
  • Long QT Syndrome / metabolism
  • Long QT Syndrome / physiopathology
  • Male
  • Models, Cardiovascular
  • Myocytes, Cardiac / drug effects*
  • Myocytes, Cardiac / metabolism
  • Pyridines / pharmacology*
  • Rabbits
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / drug effects*
  • Sodium Channels / metabolism
  • Sodium-Calcium Exchanger / metabolism
  • Tachycardia, Ventricular / genetics
  • Tachycardia, Ventricular / metabolism
  • Tachycardia, Ventricular / physiopathology
  • Tachycardia, Ventricular / prevention & control*
  • Time Factors
  • Triazoles / pharmacology*
  • Ventricular Fibrillation / genetics
  • Ventricular Fibrillation / metabolism
  • Ventricular Fibrillation / physiopathology
  • Ventricular Fibrillation / prevention & control

Substances

  • 6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine
  • Anti-Arrhythmia Agents
  • Delayed Rectifier Potassium Channels
  • Pyridines
  • Sodium Channel Blockers
  • Sodium Channels
  • Sodium-Calcium Exchanger
  • Triazoles

Supplementary concepts

  • Long Qt Syndrome 2