Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model.
BACKGROUND
After defibrillation of initial ventricular fibrillation (VF), it is crucial to prevent refibrillation to ensure successful resuscitation outcomes. Inability of the late Na+current to inactivate leads to intracellular Ca2+dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na+current, on ventricular refibrillation.


RESULTS
Long-duration VF was induced electrically in Langendorff-perfused rabbit hearts (n=22) and terminated with a defibrillator after 6 minutes. Fibrillating hearts were randomized into 3 groups: treatment with ranolazine, GS-967, or nontreated controls. In the treated groups, hearts were perfused with ranolazine or GS-967 at 2 minutes of VF. In control experiments, perfusion solution was supplemented with isotonic saline in lieu of a drug. Inducibility of refibrillation was assessed after initial long-duration VF by attempting to reinduce VF. Sustained refibrillation was successful in fewer ranolazine-treated (29.17%;P=0.005) or GS-967-treated (45.83%,P=0.035) hearts compared with that in nontreated control hearts (84.85%). In GS-967-treated hearts, significantly more spontaneous termination of initial long-duration VF was observed (66.67%;P=0.01). Ca2+transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca2+alternans (P=0.03).


CONCLUSIONS
Late Na+current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Mohammed Ali
MA
Azam
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Nima
N
Zamiri
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Stéphane
S
Massé
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Marjan
M
Kusha
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Patrick F H
PF
Lai
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Govind K
GK
Nair
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Nigel S
NS
Tan
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.).
Christopher
C
Labos
From the Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, University Health Network, Ontario, Canada (M.A.A., N.Z., S.M., M.K., P.F.H.L., G.K.N., N.S.T., K.N.); and Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada (C.L.). kumar.nanthakumar@uhn.ca.
Kumaraswamy
K
Nanthakumar
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004554:Electric Countershock / Q000379:methods*; D006323:Heart Arrest / Q000628:therapy; D016015:Logistic Models; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D011897:Random Allocation; D000069458:Ranolazine / Q000494:pharmacology*; D012016:Reference Values; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D018709:Statistics, Nonparametric; D014230:Triazoles / Q000494:pharmacology; D014693:Ventricular Fibrillation / Q000175:diagnosis / Q000628:therapy*
C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D015220:Calcium Channels; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D014230:Triazoles; D000069458:Ranolazine; D002118:Calcium
GS-967; calcium transients; cardiac arrest; late sodium current; ranolazine; ventricular fibrillation; ventricular refibrillation