Abstract 15811: A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias

Background - Slowly inactivating or late sodium current (late I Na ) in the mammalian ventricle is pro-arrhythmic. Inhibition of it is a strategy to suppress afterdepolarizations and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. This study introduces GS-458967, a potent and selective inhibitor of late I Na , and demonstrates its effectiveness to suppress ventricular arrhythmias. Methods and Results - The effects of GS-458967 to inhibit cardiac late I Na versus other ion currents were determined using rabbit isolated ventricular myocytes and perfused hearts. Anti-arrhythmic actions of GS-458967 were characterized in ex vivo and in vivo models of reduced repolarization reserve and ischemia. GS-458967 inhibited late I Na in ventricular myocytes with an IC 50 of 0.13 µM and did not prolong action potential duration or the QRS interval (surrogates for inhibitions of I Kr and peak I Na ) in rabbit heart. GS-458967 prevented and reversed proarrhythmic effects (afterdepolarizations, torsades de pointes) of the late I Na enhancer ATX-II (Figure 1A) and the I Kr inhibitors E-4031 (isolated heart) and clofilium ( in vivo ). GS-458967 was many-fold more potent and selective to inhibit late I Na , and more effective to reduce arrhythmias in myocytes, isolated hearts and intact rabbits than either flecainide or ranolazine. GS-458967 suppressed cardiac arrhythmias caused by acute ischemia (ligation of the left circumflex coronary artery) in the anesthetized rabbit, whereas flecainide increased ischemia-induced ventricular arrhythmias and mortality (Figure 1B). Conclusions - Our results establish a role of late I Na in mammalian ventricular rhythm disturbances and demonstrate that a selective inhibitor of this current is not proarrhythmic and is superior to flecainide or ranolazine for suppression of ventricular arrhythmias in experimental models.