Abstract 15811: A Novel, Potent, and Selective Inhibitor of Cardiac Late Sodium Current Suppresses Experimental Arrhythmias
Background - Slowly inactivating or late sodium current (late INa) 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 INa, and demonstrates its effectiveness to suppress ventricular arrhythmias.
Methods and Results - The effects of GS-458967 to inhibit cardiac late INa 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 INa in ventricular myocytes with an IC50 of 0.13 µM and did not prolong action potential duration or the QRS interval (surrogates for inhibitions of IKr and peak INa) in rabbit heart. GS-458967 prevented and reversed proarrhythmic effects (afterdepolarizations, torsades de pointes) of the late INa enhancer ATX-II (Figure 1A) and the IKr inhibitors E-4031 (isolated heart) and clofilium (in vivo). GS-458967 was many-fold more potent and selective to inhibit late INa, 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 INa 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.
- © 2012 by American Heart Association, Inc.