Effectiveness of Late I Na Versus Peak I Na Block in the Setting of Ventricular Fibrillation

L ate sodium channel current (late I Na ) 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][2][3] The principal antiarrhythmic mechanisms attributable to late I Na inhibition include (1) suppression of intracellular calcium overload secondary to reduction of intracellular sodium [Na i ], 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 alIn this issue of Circulation: Arrhythmia and Electro physiology, Azam et al 5 report that ranolazine and GS-458967 (GS-967), agents that inhibit late I Na , 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%).Ca 2+ transient duration was reduced in ranolazine-treated but not in GS967-treated hearts compared with controls (Circ Arrhythm