Suppression of Re-Entrant and Multifocal Ventricular Fibrillation by the Late Sodium Current Blocker Ranolazine

Objectives The purpose of this study was to test the hypothesis that the late Na current blocker ranolazine suppresses re-entrant and multifocal ventricular fibrillation (VF). Background VF can be caused by either re-entrant or focal mechanism. Methods Simultaneous voltage and intracellular Ca+2 optical mapping of the left ventricular epicardial surface along with microelectrode recordings was performed in 24 isolated-perfused aged rat hearts. Re-entrant VF was induced by rapid pacing and multifocal VF by exposure to oxidative stress with 0.1 mM hydrogen peroxide (H2O2). Results Rapid pacing induced sustained VF in 7 of 8 aged rat hearts, characterized by 2 to 4 broad propagating wave-fronts. Ranolazine significantly (p < 0.05) reduced the maximum slope of action potential duration restitution curve and converted sustained to nonsustained VF lasting 24 +/- 8 s in all 7 hearts. Exposure to H2O2 initiated early afterdepolarization (EAD)-mediated triggered activity that led to sustained VF in 8 out of 8 aged hearts. VF was characterized by multiple foci, appearing at an average of 6.8 +/- 3.2 every 100 ms, which remained confined to a small area averaging 2.8 +/- 0.85 mm(2) and became extinct after a mean of 43 +/- 16 ms. Ranolazine prevented (when given before H2O2) and suppressed H2O2-mediated EADs by reducing the number of foci, causing VF to terminate in 8 out of 8 hearts. Simulations in 2-dimensional tissue with EAD-mediated multifocal VF showed progressive reduction in the number of foci and VF termination by blocking the late Na current. Conclusions Late Na current blockade with ranolazine is effective at suppressing both pacing-induced re-entrant VF and EAD-mediated multifocal VF. (J Am Coll Cardiol 2011;57:366-75) (C) 2011 by the American College of Cardiology Foundation