Frommeyer Gerrit, Milberg Peter, Uphaus Timo, Kaiser Dennis, Kaese Sven, Breithardt Günter, Eckardt Lars
Division of Electrophysiology, Department of Cardiovascular Medicine, University Hospital of Münster, Münster, Germany.
Cardiovasc Ther. 2013 Dec;31(6):e63-71. doi: 10.1111/1755-5922.12035.
Ranolazine is evaluated for antiarrhythmic therapy of atrial fibrillation (AF). The electrophysiologic mechanisms of ranolazine in combination with class III drugs were studied in an isolated whole-heart model of stretch-related AF.
Thirty rabbits were fed with amiodarone (50 mg/kg/day, n = 10), dronedarone (50 mg/kg/day, n = 10), or placebo (n = 10) for 6 weeks. Subsequently, in isolated hearts, AF was induced by high-rate atrial pacing and acute atrial dilatation. In placebo-treated hearts, d,l-sotalol (50 μM) was acutely administered. Ranolazine (10 μM) was additionally infused in all groups. Chronic amiodarone (+26 ± 7 ms, P < 0.05) or dronedarone (+22 ± 4 ms, P < 0.05) as well as acute application of d,l-sotalol (+20 ± 3 ms, P < 0.05) increased atrial action potential duration (aAPD90 ). Additional treatment with ranolazine did not significantly change aAPD90 (P = ns). Class III drugs did not affect interatrial conduction time, while ranolazine significantly increased it (amiodarone group: +15 ± 3 ms, dronedarone group: +11 ± 3 ms, sotalol group: +15 ± 6 ms; P < 0.05 each). Ranolazine led to an additional increase in atrial effective refractory period (aERP), thus leading to an enhanced atrial postrepolarization refractoriness (aPRR, +17 ± 6 ms, +21 ± 4 ms and +16 ± 8 ms, P < 0.05, respectively). Acute atrial dilatation increased AF incidence compared with baseline. Amiodarone-pretreated hearts showed a lower incidence of AF. Additional infusion of ranolazine further diminished AF. Dronedarone or acute infusion of sotalol did not significantly suppress AF, while additional treatment with ranolazine in these groups also reduced AF incidence.
In this study, ranolazine on top of class III antiarrhythmic therapy had a beneficial effect. The increase in interatrial conduction time and marked atrial aPRR suppressed AF. These results shed further light on a potential therapeutic benefit of ranolazine on top of conventional antiarrhythmic therapy for rhythm control in AF.
对雷诺嗪用于心房颤动（AF）的抗心律失常治疗进行评估。在一个与牵张相关的AF离体全心模型中研究了雷诺嗪与Ⅲ类药物联合应用的电生理机制。
30只兔子分别接受胺碘酮（50mg/kg/天，n = 10）、决奈达隆（50mg/kg/天，n = 10）或安慰剂（n = 10）治疗6周。随后，在离体心脏中，通过高频率心房起搏和急性心房扩张诱发AF。在接受安慰剂治疗的心脏中，急性给予消旋索他洛尔（50μM）。所有组均额外输注雷诺嗪（10μM）。慢性给予胺碘酮（+26±7ms，P<0.05）或决奈达隆（+22±4ms，P<0.05）以及急性应用消旋索他洛尔（+20±3ms，P<0.05）均增加了心房动作电位时程（aAPD90）。额外给予雷诺嗪并未显著改变aAPD90（P = 无显著性差异）。Ⅲ类药物不影响心房内传导时间，而雷诺嗪显著增加了心房内传导时间（胺碘酮组：+15±3ms，决奈达隆组：+11±3ms，索他洛尔组：+15±6ms；每组P<0.05）。雷诺嗪导致心房有效不应期（aERP）进一步增加，从而导致心房复极后不应期增强（aPRR，分别为+17±6ms、+21±4ms和+16±8ms，P<0.05）。与基线相比，急性心房扩张增加了AF发生率。接受胺碘酮预处理的心脏AF发生率较低。额外输注雷诺嗪进一步降低了AF发生率。决奈达隆或急性输注索他洛尔未显著抑制AF，而在这些组中额外给予雷诺嗪也降低了AF发生率。
在本研究中，Ⅲ类抗心律失常治疗基础上加用雷诺嗪具有有益作用。心房内传导时间的增加和显著的心房aPRR抑制了AF。这些结果进一步揭示了在传统抗心律失常治疗基础上加用雷诺嗪对AF节律控制的潜在治疗益处。
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