基于多模态成像的心肌梗死后微循环代谢稳态失衡的机制研究

Myocardial infarction is a major disease that threatens human health. Although revascularization can restore infarct-related coronary blood flow, the inability of myocardium to achieve effective perfusion could aggravate myocardial injury due to the injured myocardial microcirculation homeostasis. Recent studies have shown that a variety of small metabolic molecules may be involved in the homeostasis regulation of microcirculation, but the molecular mechanism is still unclear. How to elucidate the key regulating molecule of microcirculatory metabolism homeostasis in vivo is key to precision therapy of myocardial infarction. Previously, the applicant team has successfully constructed a stable and reliable model of acute and chronic myocardial infarction in large animals and performed multimodal imaging of angiogenesis, and found five arachidonic acid metabolites were independently associated with death after coronary revascularization. This study intends to integrate the research advantages of both sides based on previous studies, and apply metabolomics techniques to clarify the changes of myocardial microcirculatory metabolism. Besides, the functional and structural alterations of microcirculation are to be evaluated by multi-modal molecular imaging in large animal and radiomic technology systematically based on multi-modal imaging platform of nuclides/MRI/ultrasound/CTA and construction of various molecular imaging probes such as RGD2 and FDG. Finally, the associated mechanism between key metabolic molecules and cardiovascular dynamic remodeling after myocardial infarction will be analyzed and clinical transformation studies will be carried out in order to achieve precise regulation of cardiac microcirculation homeostasis.

心肌梗死是危害人类健康的重大疾病，尽管血运重建术可恢复梗死相关冠脉血流，但由于梗死后心肌微循环稳态失衡，使得心肌不能得到有效灌注，加重心肌损伤。近年来研究显示多种代谢小分子可能参与微循环的稳态调节，但分子机制尚不明确。如何从在体水平阐明心肌微循环代谢稳态调控的关键分子是心肌梗死精准治疗的关键。申请团队前期成功构建了稳定可靠的大动物急慢性冠脉闭塞心肌梗死模型并进行血管新生的多模态成像，并发现5种花生四烯酸代谢产物与冠脉血运重建术后的死亡独立相关。本研究拟于在前期基础上集成双方科研优势，应用代谢组学技术阐明心肌微循环代谢产物水平变化；基于核素/MRI/超声/CTA 的多模态成像平台及RGD2、FDG等多种分子影像探针的构建，利用大动物多模态分子影像及影像组学技术系统评估微循环结构功能变化，从而对关键代谢分子与心梗后心血管动态重塑进行关联性机制分析，并开展临床转化研究，以期实现心脏微循环稳态的精准调控。

心肌梗死是危害人类健康的重大疾病，尽管血运重建术可恢复梗死相关冠脉血流，但由于梗死后心肌微循环稳态失衡，使得心肌不能得到有效灌注，加重心肌损伤。近年来研究显示多种代谢小分子可能参与微循环的稳态调节，但分子机制尚不明确。本项目针对如何从在体水平阐明心肌微循环代谢稳态调控的关键分子这一关键科学问题，开展了系列研究。主要研究内容及重要成果包括：1）：通过冠脉序贯球囊栓塞法/开胸Ameroid 缩窄环法成功构建小型猪急性/慢性冠脉闭塞心梗模型和缺血再灌注模型，并进行验证；2）建立了大动物多模态影像对心肌梗死后微循环、心肌细胞代谢水平及心脏收缩功能变化的定量分析技术，通过心肌梗死后RGD2、FDG血管新生的多模态成像，建立组织病理学与影像学特征的关联及3D打印模型，并将该模型成功应用于临床心肌梗死患者的预后评估；3）基于多模态影像指导对大动物不同微循环状态病理组织进行代谢组学分析，发现83中代谢物存在差异，确定微循环障碍的特征代谢途径为花生四烯酸代谢，其主要核心代谢分子为前列腺素B2和前列腺素J2；4）通过对关键代谢分子在临床患者中的验证，联合临床基线数据和CMR影像学特征，采用机器学习及数据建模的方法，结合分析心肌微循环障碍的关键代谢分子，建立基于微循环障碍代谢分子、临床特征和影像学特征相关联的微循环障碍风险评估模型，最终为实现心脏微循环稳态的精准调控提供新策略。课题组已发表标注基金号的文章20篇，其中SCI收录文章11篇，10分以上2篇；授权国家发明及实用新型专利4项，获批计算机软件著作权1项。