Burashnikov Alexander, Di Diego José M, Barajas-Martínez Hector, Hu Dan, Cordeiro Jonathan M, Moise N Sydney, Kornreich Bruce G, Belardinelli Luiz, Antzelevitch Charles
From the Masonic Medical Research Laboratory, Utica, NY (A.B., J.M.D.D., H.B.-M., D.H., A.C.Z., J.M.C., C.A.); Department of Clinical and Biological Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY (N.S.M., B.G.K.); and Gilead Sciences, Foster City, CA (L.B.).
Circ Heart Fail. 2014 Jul;7(4):627-33. doi: 10.1161/CIRCHEARTFAILURE.114.001129. Epub 2014 May 29.
There is a critical need for safer and more effective pharmacological management of atrial fibrillation (AF) in the setting of heart failure (HF).
This study investigates the electrophysiological, antiarrhythmic, and proarrhythmic effects of a clinically relevant concentration of ranolazine (5 μmol/L) in coronary-perfused right atrial and left ventricular preparations isolated from the hearts of HF dogs. HF was induced by ventricular tachypacing (2-6 weeks at 200-240 beats per minute; n=17). Transmembrane action potentials were recorded using standard microelectrode techniques. In atria, ranolazine slightly prolonged action potential duration but significantly depressed sodium channel current-dependent parameters causing a reduction of maximum rate of rise of the action potential upstroke, a prolongation of the effective refractory period secondary to the development of postrepolarization refractoriness, and an increase in diastolic threshold of excitation and atrial conduction time. Ranolazine did not significantly alter these parameters or promote arrhythmias in the ventricles. Ranolazine produced greater inhibition of peak sodium channel current in atrial cells isolated from HF versus normal dogs. A single premature beat reproducibly induced self-terminating AF in 10 of 17 atria. Ranolazine (5 μmol/L) suppressed induction of AF in 7 of 10 (70%) atria. In the remaining 3 atria, ranolazine reduced frequency and duration of AF.
Our results demonstrate more potent suppression of AF by ranolazine in the setting of HF than previously demonstrated in nonfailing hearts and absence of ventricular proarrhythmia. The data suggest that ranolazine may be of benefit as an alternative to amiodarone and dofetilide in the management of AF in patients with HF.
在心力衰竭（HF）的情况下，对心房颤动（AF）进行更安全、更有效的药物治疗至关重要。
本研究调查了临床相关浓度的雷诺嗪（5 μmol/L）对从HF犬心脏分离的冠状动脉灌注右心房和左心室标本的电生理、抗心律失常和促心律失常作用。通过心室快速起搏诱导HF（每分钟200 - 240次，持续2 - 6周；n = 17）。使用标准微电极技术记录跨膜动作电位。在心房中，雷诺嗪略微延长动作电位时程，但显著降低钠通道电流依赖性参数，导致动作电位上升支最大上升速率降低、复极后不应期延长继发有效不应期延长以及舒张期兴奋阈值和心房传导时间增加。雷诺嗪对心室中的这些参数没有显著影响，也不会促进心律失常。与正常犬相比，雷诺嗪对从HF犬分离的心房细胞中的钠通道电流峰值产生更大的抑制作用。17个心房中有10个通过单个早搏可重复性诱导自限性AF。雷诺嗪（5 μmol/L）在10个心房中的7个（70%）抑制了AF的诱导。在其余3个心房中，雷诺嗪降低了AF的频率和持续时间。
我们的结果表明，在HF情况下，雷诺嗪对AF的抑制作用比以前在非衰竭心脏中所证明的更强，并且不存在心室促心律失常作用。数据表明，在HF患者的AF管理中，雷诺嗪可能作为胺碘酮和多非利特的替代品有益。
