心肌梗死的整合素αvβ3受体显像研究

This project is based on the applicants' prior closed project of National Nature Science Foundation, which firstly translated the 68Ga-PRGD2 PET/CT into clinical use for imaging of integrin αvβ3 receptor expression in myocardial infarction. The aim of this study is to resolve the key problems during the traslation of this novel technique and reveal the related mechnism and influence factors. At different time after myocardial infarction, the informed-consented patients may accept 68Ga-PRGD2 PET/CT imaging to evaluate integrin αvβ3 receptor expression, which will be compared to other routine evaluation methods such as 99mTc-MIBI perfusion imaging, 18F-FDG metabolism imaging, coronary artery angiography, cardiac ultrasonography, etc. The role of this novel techinique will be assessed in dynamically monitoring the auto-repair following myocardial infarction and in quantitative evaluation of the treatment effects of anti-mayocardial reconstruction drugs and coronary stent implantation. Its value in guiding the personalized treatment and in prognosis will also be investigated. Preclinical studies using rat myocardial infarction models will also be performed for further investigation of the mechnisms, and for evaluation of those new treatments not yet used clinically, such as stem cell treatment and those using angiogenic drugs (or factors). A novel imaging technique is expected to be established for clinical evaluation of mycardial infarction patients and guiding corresponding treatments. It is also expected that a translational platform based on the molecular imaging techniques will be established to evaluate the effects and in vivo mechnisms of new drugs and treatments for myocardial infarction.

本课题主要建立在前一项结题的国家自然基金项目的基础上，基于课题组前期在国际上率先临床转化的用68Ga-PRGD2 PET/CT技术评估心梗患者的整合素αvβ3受体表达，拟进一步开展相关的应用基础研究，解决这一新的诊断技术在临床转化中的关键基础问题，明确与治疗干预相关的作用机制和调控因素。具体将通过对心梗后不同时期的患者进行68Ga-PRGD2 PET/CT显像，并与其他常用的评估心梗的方法互补结合，明确这一新技术活体、动态监控心梗后心脏修复的价值，对定量评估抗心肌重构药物和支架植入等治疗的作用，以及对指导心梗患者个体化治疗和判断预后的价值。对部分难以通过临床病例研究解决的问题，将用大鼠心梗模型microPET显像实验研究来探索解决。希望最终明确心梗后决定整合素αvβ3受体表达的主要机制，找到相关干预治疗的最佳时机，建立评估针对性治疗新药物和新方法的技术平台。

心肌梗死是威胁人类生命和健康的主要疾病之一。在心梗后的血管新生和心肌重构过程中，整合素αvβ3受体起着重要作用，活体动态评估其变化具有重大意义。本课题通过系统开展大鼠心梗模型实验和临床应用基础研究，探索了整合素素受体显像在临床转化应用中的关键基础问题，取得了以下成果：一是在国际上率先临床转化68Ga-PRGD2 PET/CT，用于评估心梗患者的整合素αvβ3受体表达。研究发现亚急性心梗区周围68Ga-PRGD2摄取明显增高，而陈旧心梗则无明显摄取，相关文章发表在Theranostics 2014;4(8):778-786（影响因子8.9）。二是明确了心梗后心肌整合素αvβ3受体表达的相关规律特点、影响因素和分子机制。临床病例研究发现，心梗后心肌的整合素受体显像迅速升高，1周时68Ga-PRGD2摄取达到高峰，3周后开始缓慢降低；心梗的范围大小与整合素受体表达的程度呈显著正相关(r=0.748,P=0.001)；3～10个月后对部分心梗患者进行68Ga-PRGD2 PET/CT随访，发现治疗后仍有症状者68Ga-PRGD2摄取仍保持在较高水平，而治疗后症状消失者则68Ga-PRGD2很快降低，两组患者摄取值的变化有显著差异（P=0.003），提示68Ga-PRGD2摄取的变化与患者的恢复和预后相关；抗心肌重构药物治疗研究发现，血管紧张素酶抑制剂和血管紧张素Ⅱ受体拮抗剂均可使68Ga-PRGD2摄取显著降低（P分别为0.001和0.002）。三是完善了指导心梗患者针对性进行抗心肌重构、促血管新生治疗的有效检测方法，建立了评估相关治疗药物和方法的技术平台，成为2016年被认定的“核医学分子靶向诊疗北京市重点实验室”的重要部分。课题目前已发表标注SCI文章6篇，总影响因子41.3，最高影响因子12.4；相关研究结果在国际、国内会议交流10余次，部分被选为国际年会的亮点报告。