氟西汀对心肌梗死后抑郁大鼠室性心律失常的影响及其机制研究

Ventricular arrhythmias(VAs) have been associated with increased mortality in patients during and after episodes of acute myocardial infarction (MI), and Ventricular arrhythmias(VAs) after MI is the main cause of sudden cardiac death..There is compelling evidence that depression,which is especially common in cardiac patients, is also a risk factor for fatal and nonfatal events in coronary heart disease (CHD) patients.The morbidity and mortality of VAs in MI patients with depression is significantly increased,which may be related to the excessive activation of N-methyl-d-aspartate receptor(NMDAR). Reducing the incidence of depression can improve the prognosis of MI. .In this project, we attempt to investigate the signal pathway of NMDAR/Ca2+/KChIPs as the breakthrough point in the occurrence of VAs in MI rats with depression with the help of new antidepressant drug -Fluoxetine.In a rat model of post-MI depression, we examine the expression and distribution of NMDAR、Cav1.2、KchIPs and Kv4.2 in cardiac myocytes by way of confoca laser scanning microscope and molecular biotechnology. Meanwhile,examing cardiac electrophysiology change in vivo/vitro is by means of electrophysiology technology.The influence of Fluoxetine on these indexes were also analysed..Through the above researches, we try to explore the mechanism that may be involved in VAs induced by depression and the improvement of Fluoxetine for outcomes in MI rats, in order to study the relationship among MI, depression and ventricular arrhythmia, and to clarify the influence of Fluoxetine on the cardiac electrophysiology in post-MI depression and the potential mechanisms.In addition, our study will develop the research on the effects of antidepressants on CHD patients with depression, and get the findings of the psychological and pharmacological intervention trial seeking to improve outcomes for depressed cardiac patients. The project is helpful in developing clinical practice guidelines and pathways which support the implementation of best practice in the assessment and management of co-morbid depression in people with and at risk of CHD.

心肌梗死（简称心梗）后室性心律失常是心脏性猝死的主要因素，心梗合并抑郁患者室性心律失常发生率及死亡率明显增加，其机制可能与N-甲基-D-天门冬氨酸受体(NMDAR)过度激活相关，降低抑郁发生可以改善冠心病预后。本项目以NMDAR/Ca2+/KChIPs（Kv通道交互作用蛋白）信号通路为突破口，借助新型抗抑郁药物氟西汀，用激光共聚焦显微镜和分子生物学技术研究心梗后抑郁大鼠心肌细胞NMDAR、Cav1.2、KchIPs和Kv4.2等指标的表达与分布；结合电生理技术研究在体、离体灌流心脏电生理变化并观察氟西汀对上述指标的影响，探讨抑郁增加心梗后室性心律失常的发生机制，搭建心梗、抑郁、室性心律失常三者间的研究桥梁；并初步阐明氟西汀对心梗后心脏电生理学的作用效果及途径，以拓展抗抑郁药治疗冠心病合并抑郁的机制研究，为临床应用提供参考依据。

心肌梗死（简称心梗）后室性心律失常是心脏性猝死的主要因素，心梗合并抑郁患者室性心律失常发生率及死亡率明显增加，本课题旨在探讨新型抗抑郁药物氟西汀对心梗后抑郁大鼠行为学的影响，以及室性心律失常和组织重构的影响，并通过分子生物学和心脏电生理研究探讨其作用机制。我们的研究发现：（1）通过结扎冠状动脉左前降支结合慢性不可预见性温和应激的方法可以建立稳定的心梗后抑郁大鼠模型；与心梗组、抑郁组相比，心梗+抑郁组大鼠糖水偏好百分比有进一步降低；氟西汀干预后，糖水偏好百分比及心脏功能、行为学指标有所改善。（2）与正常组相比，心梗组、抑郁组及心梗+抑郁组大鼠的MAPD50、MAPD90及心室肌ERP时间明显延长，室颤阈值明显降低, 氟西汀组可以增加室颤阈值。（3）抑郁大鼠心肌细胞NMDAR1表达量增加，Kv4.2表达量减少，而氟西汀可以逆转这种趋势，心梗和心梗后抑郁模型大鼠Cx43表达量显著减少，但是氟西汀对其表达没有影响。（4）与正常组相比，抑郁组、心梗组及心梗后抑郁组ICa-L峰值密度均显著下降，稳态激活曲线右移；与正常组相比，心梗组及心梗后抑郁组的稳态失活曲线明显左移，失活后恢复曲线明显下移，通道失活后恢复时间会延长；同时，抑郁能导致心梗后大鼠心室肌细胞Ito电流密度显著下降，Ito通道的失活后恢复减慢。抑郁增加大鼠室性心律失常发生。. 我们的研究结果表明： NMDAR/Ca2+/KchIP2信号信号通路在心梗后抑郁大鼠室性心律失常发生中扮演重要角色，氟西汀干预有助于改善心肌梗死后室性心律失常和心脏重构。