title: Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
authors.forename: Norishige
authors.initials: N
authors.lastname: Morita
authors.forename: Jong Hwan
authors.initials: JH
authors.lastname: Lee
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Xie
authors.forename: Ali
authors.initials: A
authors.lastname: Sovari
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Hrayr S
authors.initials: HS
authors.lastname: Karagueuzian
mesh_terms: D000083:Acetanilides / Q000494:pharmacology / Q000627:therapeutic use*; D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology*; D000818:Animals; D008297:Male; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000069458:Ranolazine; D051381:Rats; D011916:Rats, Inbred F344; D026941:Sodium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D014693:Ventricular Fibrillation / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D000083:Acetanilides; D010879:Piperazines; D026941:Sodium Channel Blockers; D000069458:Ranolazine