1. Academic Validation
  2. Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model

  • Circ Arrhythm Electrophysiol. 2017 Mar;10(3):e004331. doi: 10.1161/CIRCEP.116.004331.
Mohammed Ali Azam 1 Nima Zamiri 1 Stéphane Massé 1 Marjan Kusha 1 Patrick F H Lai 1 Govind K Nair 1 Nigel S Tan 1 Christopher Labos 1 Kumaraswamy Nanthakumar 2
Affiliations

Affiliations

  • 1 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.).
  • 2 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.). [email protected].
Abstract

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.

Methods and 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.

Keywords

GS-967; calcium transients; cardiac arrest; late sodium current; ranolazine; ventricular fibrillation; ventricular refibrillation.

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