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

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 Ca 2+ 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). Ca 2+ transient duration was reduced in ranolazine-treated hearts compared with that in controls (P=0.05) and also Ca 2+ 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 Ca 2+. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models. (Circ Arrhythm Electrophysiol. 2017;10:e004331.

Impact of ranolazine on ventricular arrhythmias – A systematic review

“…An interesting finding was the beneficial impact of ranolazine in post‐VF animal models . Particularly, ranolazine showed to reduce the susceptibility to subsequent refibrillation, but further testing in cardiac arrest models is needed . An interesting finding is that ranolazine has a potent suppressant effect on both re‐entrant and multifocal VF at concentrations considered therapeutic in humans …”

Essential role of ryanodine receptor 2 phosphorylation in the effect of azumolene on ventricular arrhythmia vulnerability in a rabbit heart model

“…During VF, optical mapping was performed to evaluate VF organization at two time‐points (0 and 4 minutes of VF); as a surrogate for VF organization, the number of Ca 2+ wavefronts during VF were quantitated, as described previously …”

“…The detailed methodology for Ca 2+ optical mapping has been described in our previous studies. 3,11 Dye fluorescence was excited using a xenon light source (Moritex, Saitama, Japan) and a 530-nm green filter (Semrock, Rochester, NY) and the emission light was bandpass filtered at 585/40 nm. The fluorescence was recorded with a high-speed CMOS camera (Ultima-L; SciMedia, Costa Mesa, CA).…”

Mechanisms of Ranolazine Pretreatment in Preventing Ventricular Tachyarrhythmias in Diabetic db/db Mice with Acute Regional Ischemia-Reperfusion Injury

“…The Ca i alternans suppression and Ca i TD 80 shortening were reported to reduce the susceptibility to subsequent refibrillation in a long-standing VF rabbit model. [24] Additionally, calsequestrin 2 is the It was reported that cardiac IR injury is accompanied by a marked reduction in SR Ca 2+ -pump ATPase, Ca 2+ -uptake and Ca 2+ -release activities, and the mRNA levels for SR Ca 2+ -handling proteins such as SERCA2a, ryanodine receptor, calsequestrin and phospholamban were decreased in the ischemiareperfused heart as compared with the non-ischemic control. [28] Our data also shows that protein expression of pThr17-phospholamban, calsequestrin 2, and SCN5A was significantly decreased in the IR zone in diabetic mouse hearts, and ranolazine ameliorated the downregulation of these proteins.…”