左心室收缩功能障碍家兔模型可评估药物诱发心律失常的风险
Evaluation of cardiac arrhythmic risks using a rabbit model of left ventricular systolic dysfunction
背景与目的：心脏病患者自发或药物诱发心律失常的风险较高。本研究拟通过心肌梗死（MI）伴左心室收缩功能障碍(LVSD)家兔模型，观察药物对心脏病患者心律失常发生风险的影响
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方法：选取23周龄雄性新西兰白兔(3-4kg)，并随机分为两组：假手术组(n = 12)：进行开放式胸部手术，但不对心脏进行干预；MI组(n = 34)：通过结扎冠脉左侧回旋支，诱导心肌梗塞。与假手术组相比，MI组术后7周会出现大面积MI以及中度或重度LVSD。根据左心室梗塞面积大小和心肌收缩功能障碍的严重程度，通过cMRI分为三种不同的MI亚组:无左心室收缩功能障碍亚组(Group MI_NO_LVSD)，中度左心室收缩功能障碍亚组(Group MI_M_LVSD)及重度左心室收缩功能障碍亚组(Group MI_S_LVSD)。随后，实验组家兔注射抗心律失常药物氟卡尼（0.25-4 mg/kg）且剂量逐渐加大，对照组只注射溶剂(1N HCl含20%环糊精)。分别于术前、术后1周、术后7周及药物治疗期间记录各组家兔的ECG。计算心电图的心脏-电生理平衡指数（QT/QRS）。
结果：ECG显示术后第1周及第7周实验组家兔无自发性心律失常发生。当给家兔注射氟卡尼时，2/5的Group MI_M_LVSD家兔出现了心律失常：室性心动过速/室颤，而经溶剂处理的家兔均未出现心律失常。并且在出现心律失常之前，家兔的心脏电生理平衡指数显著降低（分别从4.09降到2.42，从5.56降到2.25）。此外，在注射氟卡尼后，1/5MI_S_LVSD组家兔和1/7MI_S_LVSD组家兔出现了完全性房室传导阻滞并最终死亡。
结论：MI伴重度LVSD的家兔模型有助于可诱发心律失常风险类药物(类似于氟卡尼机理)的临床前评价，并且可用心脏电生理平衡指数（QT/QRS）预测。
ABSTRACT
Patients with heart disease have a higher risk to develop cardiac arrhythmias, either spontaneously or drug-induced. In this study, we have used a rabbit model of myocardial infarction (MI) with severe left ventricular systolic dysfunction (LVSD) to study potential druginduced cardiac risks with N-(piperidin-2-ylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide
(flecainide). Upon ligation of the left circumflex arteries, male New Zealand White rabbits developed a large MI and moderate or severe LVSD 7 weeks after surgery, in comparison to SHAM-operated animals. Subsequently, animals were exposed to escalating doses of flecainide (0.25-4 mg/kg) or solvent. Electrocardiograms (ECG) were recorded before surgery, 1 and 7 weeks after surgery and continuously during the drug protocol. The ECG biomarker iCEB (index of Cardio-Electrophysiological Balance = QT/QRS ratio) was calculated. During the ECG recording at week 1 and week 7 post MI, rabbits had no spontaneous cardiac arrhythmias. When rabbits were exposed to escalating doses of flecainide, 2 out of 5 rabbits with MI and moderate LVSD versus 0 out of 5 solvent-treated rabbits developed arrhythmias,such as ventricular tachycardia/ventricular fibrillation. These were preceded by a marked decrease of iCEB just before the onset (from 4.09 to 2.42 and from 5.56 to 2.25, respectively). Furthermore, 1 out of 5 MI rabbits with moderate LVSD and 1 out of 7 MI rabbits with severe LVSD developed total atrioventricular block after flecainide infusion and died. This rabbit model of MI and severe LVSD may be useful for preclinical evaluation of drug (similar mechanism as flecainide)-induced arrhythmic risks, which might be predicted by iCEB.
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