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 wavefronts. 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 mm² 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.