Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Centre, Maastricht, The Netherlands.
Circ Arrhythm Electrophysiol. 2012 Feb;5(1):201-9. doi: 10.1161/CIRCEP.111.963025. Epub 2011 Nov 11.
AZD1305 is an investigational antiarrhythmic agent for management of atrial fibrillation. It blocks various cardiac ion currents at different potencies and has atrial-predominant electrophysiological effects. We investigated the electrophysiological and proarrhythmic effects of AZD1305 versus dofetilide in dogs with chronic complete atrioventricular block and myocardial hypertrophic remodeling.
AZD1305 was administered to anesthetized mongrel dogs before and >2 weeks after the induction of atrioventricular block and ventricular and atrial electrophysiological parameters were assessed. In all dogs, the selective I(Kr) blocker dofetilide was used to examine susceptibility to acquired torsades de pointes in chronic atrioventricular block and for comparison. At normal sinus rhythm, AZD1305 increased QT and RR intervals from 290±7 to 397±15 ms (+37%, P<0.0001) and from 603±22 to 778±32 ms (+29%, P=0.002), respectively. In the same animals at chronic atrioventricular block, AZD1305 increased the QT interval from 535±28 to 747±36 ms (+40%, P<0.0001), similar to the QT prolongation by dofetilide (511±22 to 703±45 ms [+38%, P<0.0001]). AZD1305 slightly slowed the idioventricular rhythm. Whereas all (n=14) chronic atrioventricular block animals exhibited torsades de pointes on dofetilide, the arrhythmia was induced in only 4 of 11 dogs after AZD1305. Beat-to-beat variability of left-ventricular monophasic-action-potential duration increased after dofetilide (2.3±0.2 to 6.3±0.7 ms; P<0.0001) but not after AZD1305 (2.8±0.3 to 3.7±0.3 ms; P=0.20) despite similar left-ventricular monophasic-action-potential duration prolongations.
Despite causing similar degrees of repolarization delay as the selective I(Kr) blocker dofetilide, the combined ion-channel blocker AZD1305 induces less repolarization instability and has a lower ventricular proarrhythmic potential in the remodeled dog heart.
AZD1305 是一种用于治疗心房颤动的新型抗心律失常药物。它以不同的效力阻断各种心脏离子电流，具有以心房为主的电生理效应。我们研究了 AZD1305 与多非利特在患有慢性完全性房室传导阻滞和心肌肥厚重塑的犬中的电生理和致心律失常作用。
在诱导房室传导阻滞前后，麻醉杂种犬给予 AZD1305，并评估心室和心房电生理参数。在所有犬中，使用选择性 I(Kr)阻滞剂多非利特检查慢性房室传导阻滞中的获得性尖端扭转型室性心动过速易感性，并进行比较。在正常窦性节律下，AZD1305 将 QT 和 RR 间期分别从 290±7 增加到 397±15 ms（增加 37%，P<0.0001）和从 603±22 增加到 778±32 ms（增加 29%，P=0.002）。在同一动物处于慢性房室传导阻滞时，AZD1305 将 QT 间期从 535±28 增加到 747±36 ms（增加 40%，P<0.0001），与多非利特的 QT 延长相似（511±22 至 703±45 ms [增加 38%，P<0.0001]）。AZD1305 略微减慢了自身的室性节律。虽然所有（n=14）慢性房室传导阻滞动物在多非利特上均出现尖端扭转型室性心动过速，但在 AZD1305 后仅 11 只犬中的 4 只诱发了心律失常。多非利特后左室单相动作电位持续时间的逐搏变异性增加（2.3±0.2 至 6.3±0.7 ms；P<0.0001），而 AZD1305 后不变（2.8±0.3 至 3.7±0.3 ms；P=0.20），尽管左室单相动作电位持续时间延长相似。
尽管 AZD1305 引起的复极延迟程度与选择性 I(Kr)阻滞剂多非利特相似，但在重塑的犬心中，联合离子通道阻滞剂 AZD1305 引起的复极不稳定和致心律失常的心室潜在风险较低。
