Effectiveness of Late INa Versus Peak INa Block in the Setting of Ventricular Fibrillation
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Late sodium channel current (late INa) has attracted a great deal of attention over the past 2 decades as a target for development of safe and effective antiarrhythmic therapy for disorders associated with QT prolongation and calcium overload, particularly heart failure, ischemia, and long QT syndrome.1–3 The principal antiarrhythmic mechanisms attributable to late INa inhibition include (1) suppression of intracellular calcium overload secondary to reduction of intracellular sodium [Nai], thus diminishing both early and delayed afterdepolarization activity and (2) suppression of reentrant arrhythmias secondary to reduced dispersion of repolarization.3,4
See Article by Azam et al
In this issue of Circulation: Arrhythmia and Electro physiology, Azam et al5 report that ranolazine and GS-458967 (GS-967), agents that inhibit late INa, abbreviated the duration of ventricular fibrillation (VF) and reduced reinducibility of the arrhythmia in Langendorff-perfused nondiseased rabbit hearts. VF was induced electrically (burst pacing plus 9-V battery) and maintained in the presence of isoproterenol. When VF was first induced, perfusion was stopped for 2 minutes (to simulate global ischemia). Perfusion was then restarted with ranolazine, GS-967, or saline added to the perfusate. VF was terminated at 6 minutes using an external defibrillator, and 4 attempts were subsequently made to electrically reinduce VF. Calcium transients and action potential activity were optically recorded using voltage- and calcium-sanative dyes together with the electromechanical uncoupler, blebbistatin, to suppress contractility and thus prevent motion artifacts.
Ranolazine and GS-967 reduced reinduction of sustained VF to 29% and 46%, respectively, when compared with untreated controls (84.85%). Spontaneous termination of VF after the initial induction of VF was much greater after GS-967 (66.67%, P=0.01) when compared with ranolazine (14.3%) or untreated controls (11.1%).
Ca2+ transient duration was reduced in ranolazine-treated but not in GS967-treated …