Effects of Late Sodium Current Blockade on Ventricular Refibrillation in a Rabbit Model
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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.
- calcium transients
- cardiac arrest
- late sodium current
- ventricular fibrillation
- ventricular refibrillation
- Received June 16, 2016.
- Accepted January 19, 2017.
- © 2017 American Heart Association, Inc.