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

Area of Science:

• Cardiovascular Physiology
• Cardiac Electrophysiology
• Pharmacology

Background:

• Long QT syndrome (LQTS) is linked to sudden cardiac death, primarily due to early afterdepolarizations (EADs) and polymorphic ventricular tachycardias (PVTs).
• Reduced repolarization reserve in LQTS can be counterbalanced by suppressing the late sodium current (I_NaL), potentially preventing EADs and PVTs.

Purpose of the Study:

• To investigate the therapeutic potential of the selective I_NaL blocker GS967 in a rabbit model of LQTS type 2.
• To elucidate the mechanisms by which I_NaL blockade affects cardiac electrophysiology and prevents arrhythmias in LQTS.

Main Methods:

• Utilized a transgenic rabbit model of LQTS type 2.
• Employed intact heart optical mapping, cellular electrophysiology, and confocal Ca²⁺ imaging.
• Conducted computer modeling to simulate electrophysiological effects.

Main Results:

• GS967 significantly reduced ventricular fibrillation induction and suppressed PVTs, particularly during isoproterenol perfusion.
• The drug effectively reduced Ca²⁺-mediated EADs and focal activity without altering action potential duration or restitution.
• GS967 shortened Ca²⁺ transient duration by accelerating Na⁺/Ca²⁺ exchanger (I_NCX)-mediated Ca²⁺ efflux, and computer modeling indicated I_NaL's role in regulating intracellular Na⁺ (Na_i).

Conclusions:

• Selective I_NaL blockade with GS967 is a promising strategy for preventing EADs and PVTs in LQTS type 2.
• GS967 normalizes intracellular Na⁺ levels and counterbalances reduced repolarization reserve, thereby abolishing PVTs in this LQTS model.