基于线粒体功能及葡萄糖代谢核素显像研究非梗死区心肌代谢重构在心肌梗死后心力衰竭中的作用及机制

Myocardial infarction survivors experience high incidence of heart failure and poor long-term prognosis, in which the roles of non-infarcted areas are not clear. Preliminary data by our group indicated that: 1) the wall thickening of myocardium of the non-infarcted areas decreased in myocardial infarction survivors; 2) utilization of the energy substrate (glucose) by myocardium in the non-infarcted areas decreased in minipigs underwent myocardial infarction. We propose that the dysfunction of the myocardium in the non-infarcted areas plays a key role in the occurrence and aggravation of heart failure post myocardial infarction, in which the metabolic remodeling is a critical factor. Our group used nuclear imaging to investigate the dynamic changes of myocardial mitochondrial functions and metabolism of glucose at non-infarcted areas before and after myocardial infarction in minipigs. The critical relationship between myocardial function and metabolic remodeling is demonstrated. Ex vivo studies will be performed to examine the pathological changes in the myocardium at the non-infarcted areas, to determine the levels of metabolic enzymes such as GLUT-1, GLUT-4, PDH, and LDH, to investigate the structure and number changes of mitochondria, and to determine the changes of key enzymes involved in oxidative phosphorylation and Krebs cycles such as PGC-1α, citrate synthase, cytochrome C oxidase, and energy metabolism related factors like AMPK and ATP. These studies will provide critical information on the molecular mechanisms of metabolic remodeling in myocardium at non-infarcted areas post myocardial infarction, which could shed light on new strategies to improve treatment and prognosis of heart failure post myocardial infarction.

心梗幸存者心衰发生率高，长期预后差，非梗死区心肌在其中的作用尚不明确。课题组前期发现：心梗后患者非梗死区心肌室壁增厚减低；小型猪心梗后非梗死区心肌葡萄糖利用减低。我们设想非梗死区心肌功能异常是心梗后心衰发生和加剧的重要原因，心肌代谢重构是其关键机制。课题组拟用核素心肌线粒体功能及葡萄糖代谢显像，活体动态观察小型猪心梗前后多时间点非梗死区心肌线粒体功能、能量底物（葡萄糖）代谢的动态变化，明确非梗死区心肌功能与代谢重构的关系；离体观察非梗死区心肌多时间点的病理改变、心肌糖代谢相关蛋白（GLUT-1、GLUT-4、PDH、LDH）、线粒体结构及数量、线粒体氧化磷酸化及Krebs循环调控的关键酶（PGC-1α、柠檬酸合成酶和细胞色素C氧化酶）、AMPK等能量代谢调节蛋白以及ATP的变化，探索非梗死区心肌代谢重构的分子机制。阐明非梗死区心肌代谢重构在心衰中的作用及机制，为心梗后心衰诊治提供新策略。

心梗幸存者心衰发生率高，长期预后差，非梗死区心肌在其中的作用尚不明确。课题组前期临床研究发现心梗后患者非梗死区心肌室壁增厚率减低且是左室重构的独立预测因素，因此我们设想非梗死区心肌能量代谢及心肌功能异常可能是心梗后心衰发生和加剧的关键机制之一。项目组使用球囊封堵左前降支的方法构建中华小型猪急性心肌梗死（AMI）模型，分析了心梗后非梗死区心肌能量代谢及其病理改变，发现心梗组非梗死区心肌的SUV心/SUV纵隔显著低于假手术组对应心肌节段，表明心梗后非梗死区也存在着心肌能量代谢重构即心肌葡萄糖代谢水平减低，且心梗后4周时远离梗死区心肌细胞存在着明显水肿、肥大、脂肪变性并伴大量炎细胞浸润等一系列病理学改变。项目组分析了心梗后心肌炎症的动态演变及与左室重构的关系，发现心梗后1天梗死心肌即发生炎症反应，并持续约2周，且心梗后梗死心肌18F-FDG摄取强度可预测左室重构。项目组分析了心梗后非梗死区心肌左室收缩不同步的动态演变及其影响因素，发现心梗后梗死区和非梗死区心肌均存在收缩不同步，左室整体收缩不同步主要受瘢痕负荷的影响，非梗死区的局部收缩不同步与其室壁运动及增厚异常密切相关。项目组分析了心梗后左室舒张不同步的动态演变、影响因素及其与左室重构的关系，发现AMI后1天即发生左室舒张不同步，1周时达高峰，4周时有所恢复，AMI后心肌灌注缺损范围与左室舒张不同步参数相位直方图带宽（PBW）、相位直方图标准差（PSD）显著相关，AMI后早期评估左室舒张不同步可用于预测未来左室重构进展。上述研究结果提示心肌梗死后不应只关注梗死心肌，远离梗死区的正常灌注区域的心肌能量代谢重构及功能异常同样发挥着重要作用，阐明了非梗死区心肌能量代谢重构及功能异常在左室重构中的作用及机制，为采取有效措施优化心肌能量代谢模式及改善局部心肌功能以防治心梗后心衰提供了理论依据，指明了方向。