心肌梗死模型在体凋亡显像研究

Coronary artery disease (CAD), which most lead to myocardial infarction, is the leading cause of morbidity and mortality in china. As we know, the prognosis of myocardial infarction depends on the severity of myocardium cell injury. Two main factors determine the myocardium cell injury, which includes myocardium cell necrosis and apoptosis. Detection and quantification of the myocardium cell necrosis such as CK-MB and cTNT has been applied for many years. However, the methods to detect and quantify the myocardium cell apoptosis in vivo are still limited. Cysteine-aspartic acid protease (Caspase) family is essential for cell apoptosis. Caspase-3 is a member of caspase family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. So it's reasonable detect caspase-3 to represent the cell apoptosis. In our previous study, we have demonstrated that it is feasible to detect the tumor cell apoptosis with PET tracer 18F-CP-18 which were synthesized by our labs in vivo. At meantime, it is successful to used to detect myocardium cell apoptosis in myocardial infarction model in dogs. So we designed the study to answer the following questions.1. Quantitive analyze the caspase-3 imaging of myocardium cell apoptosis in vivo with the serum caspase-3 protein level. 2. The relationships of myocardium cell necrosis severity and caspse-3 labeled myocardium cell apoptosis in vivo. 3. The relationships of imaging strength of the Caspase-3 pet imaging afford with applicable 18F -CP-18 dose.4)Establish the relationships of imaging strength and prognosis in dog infarction-repufusion models.

急性心肌梗死引起的心肌细胞坏死和凋亡是缺血心肌损伤的主要原因。尽管目前认为心肌凋亡在急性心肌梗死预后中有重要作用，但心肌凋亡的在体监测仍没有有效的方法。Caspase-3是细胞凋亡的核心酶和标志物。我们前期用自己合成的PET示踪剂（18F-CP-18）可在体有效监测肿瘤细胞和犬心肌梗死模型中Caspase-3。在此基础上，本研究拟在犬心肌梗死模型（球囊阻断）中探讨：1）定量分析caspase-3凋亡显像与caspase-3活性蛋白水平的相关性；2）定量分析caspase-3凋亡显像与心肌梗死体积的对应关系，以及最适18F-CP-18剂量的选择；3）使用最适剂量的18F-CP-18，然后研究给药不同时间与显像强度的关系，选择最佳时间；4）对犬心肌梗死模型球囊阻断－再通的caspase-3显像，研究信号强度与预后的关系。在体评估心肌凋亡对临床指导冠心病治疗选择干预手段和评价预后有重要指导价值。

心肌梗死是危及人民健康的重要致死、致残疾病之一。心肌梗死及其后再灌注损伤使心肌细胞发生凋亡导致心功能受损，远期多发展至心功能不全，影响患者的生存和生活质量。目前心肌细胞凋亡的在体监测仍没有有效的方法。因此本研究就在体凋亡显像进行初步探讨。本项目通过在犬心肌梗死-再灌注模型（球囊阻断）中探讨：最适18F-ML-10剂量的选择和定量分析凋亡显像与caspase-3 活性蛋白水平的相关性；发现PET扫描显示在缺血-再灌注模型中，2h即可在相应缺血部位出现明显凋亡，在6h时凋亡达到最大强度，缺血部位ROI最大SUV与未缺血部位SUV比值为17.5。在48h时凋亡显像可见凋亡强度显著下降。Caspase-3免疫组化检测显示凋亡部位与梗死部位一致。不同时间点caspase-3表达强度有显著差异，与PET检测18F-ML-10信号强度呈正相关。提示在体PET显像检测心肌细胞凋亡是可行的，为进一步定量研究再灌注损伤与预后的关系及临床检测打下基础。