急性心肌缺血时T波电交替及室性心律失常发生机制的研究

急性心肌缺血时T波电交替（TWA）常预示恶性室性心律失常和猝死的发生，其具体机制尚不明确。在本课题组首次成功构建的能够稳定诱发TWA的兔左心室冠脉灌流楔形心肌块急性心肌缺血模型中，我们前期研究发现：TWA出现时触发性室性心律失常发生率显著增高，钙拮抗剂维拉帕米可改善细胞内钙稳态失衡，并有效抑制TWA及心律失常。因此我们提出如下理论假说：急性心肌缺血时细胞内钙稳态失衡可导致TWA和室性心律失常。本研究拟从单个心肌细胞、组织块和在体的不同层面，应用电生理学、激光共聚焦、钙离子成像联合膜片钳检测等技术，深入探究急性心肌缺血时细胞内钙调控在TWA和室性心律失常发生中的关键途径和靶点。并通过药物改构和构效关系研究，进一步探讨维拉帕米等药物的抗心律失常机制，为急性心肌缺血心律失常的防治开辟一条新的途径。

Acute myocardial ischemia is associated with T wave alternans (TWA) that often heralds the development of malignant ventricular arrhythmias and sudden death, but the exact mechanism is unclear. Using arterially perfused rabbit left ventricular preparations, for the first time we made an acute myocardial ischemia model, in which TWA could be stablely induced. Our previous work has shown that TWA is associated with increased incidence of triggered ventricular arrhythmias, and calcium channel blocker verapamil effectively inhibits TWA and arrhythmias by improving abnormal intracellular calcium homeostasis. Therefore, we hypothesize that acute myocardial ischemia could cause abnormal calcium homeostasis, leading to TWA and ventricular arrhythmias. By using the technologies of electrophysiology and laser scanning confocal microscope in single cardiac myocyte, wedge preparation and vivo, the purpose of this study is to clarity the critical underlying mechanisms of the occurrence of TWA and ventricular arrhythmias in acute myocardial ischemia. We will further investigate the antiarrhythmic mechanism of calcium channel blockers, e.g. verapamil, by structure-modified drug design and structure-activity relationship study. This study may provide a novel approach to prevent and treat arrhythmias in the setting of acute myocardial ischemia.