Azam Mohammed Ali, Zamiri Nima, Massé Stéphane, Kusha Marjan, Lai Patrick F H, Nair Govind K, Tan Nigel S, Labos Christopher, Nanthakumar Kumaraswamy
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.).
Circ Arrhythm Electrophysiol. 2017 Mar;10(3). doi: 10.1161/CIRCEP.116.004331.
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 dysregulation and arrhythmias. Our aim was to determine the effects of ranolazine and GS-967, inhibitors of the late Na current, on ventricular refibrillation.
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%; =0.005) or GS-967-treated (45.83%, =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%; =0.01). Ca transient duration was reduced in ranolazine-treated hearts compared with that in controls (=0.05) and also Ca alternans (=0.03).
Late Na current inhibition during long-duration VF reduces the susceptibility to subsequent refibrillation, partially by mitigating dysregulation of intracellular Ca. These results suggest the potential therapeutic use of ranolazine and GS-967 and call for further testing in cardiac arrest models.
在初始室颤（VF）除颤后，预防再发室颤对于确保复苏成功至关重要。晚钠电流无法失活会导致细胞内钙调节异常和心律失常。我们的目的是确定晚钠电流抑制剂雷诺嗪和GS-967对心室再发室颤的影响。
在Langendorff灌注兔心脏（n = 22）中电诱导长时程室颤，并在6分钟后用除颤器终止。颤动的心脏被随机分为3组：用雷诺嗪治疗、用GS-967治疗或未治疗的对照组。在治疗组中，在室颤2分钟时用雷诺嗪或GS-967灌注心脏。在对照实验中，灌注液中补充等渗盐水以代替药物。在初始长时程室颤后，通过尝试再次诱导室颤来评估再发室颤的诱导性。与未治疗的对照心脏（84.85%）相比，接受雷诺嗪治疗的心脏（29.17%；P = 0.005）或接受GS-967治疗的心脏（45.83%，P = 0.035）中持续再发室颤成功的较少。在接受GS-96-7治疗的心脏中，观察到初始长时程室颤的自发终止明显更多（66.67%；P = 0.01）。与对照组相比，接受雷诺嗪治疗的心脏中钙瞬变持续时间缩短（P = 0.05），钙交替变化也减少（P = 0.03）。
长时程室颤期间抑制晚钠电流可降低随后再发室颤的易感性，部分原因是减轻细胞内钙的调节异常。这些结果表明雷诺嗪和GS-967具有潜在的治疗用途，并呼吁在心脏骤停模型中进行进一步测试。
