PET/CT心肌代谢动态显像评价二甲双胍对冬眠心肌的保护作用及其相关分子机制研究

To protect hibernating myocardium is an very important target for treatment of patients with ischemic cardiomyopathy and heart failure.Metformin (MF) has been suggested as the preferred drug by the guideline of American Diabetes, Association for the treatment of diabetic patient complicated with heart failure. Previous animal studies demonstrated that MF has a protective effect for reducing acute myocardial ischemia-reperfusion injury. However,related mechanism is not clear now, and it is considered that MF can inhibit myocardial mitochondrial respiratory function, reduce aerobic metabolism, and increase anaerobic glycolysis to keep the balance of energy supplying and consumpation. So far, no previous study has been reported to evaluate the effects of MF on chronic hibernation myocardium in swine hibernating myocardium (HB) model by FDG PET metabolic imaging. treatment. In addition, the drug concentration in myocardium is significantly lower than that in liver and small intestine. Therefore, we speculate that MF can reduce the oxygen consumption of tissue in peripheral organ and it could relatively increase the oxygen supply in myocardium,then it may prevent HB to become apopsis or scar tissue. We can successfully establish the swine HB model.So the aim of this study is to evaluate the effects of MF on HB in swine HB model by gated SPECT myocardial perfusion imaging and gated FDG PET / CT metabolic imaging, including the effects of MF on regional myocardial perfusion, myocardial metabolism, myocardial viability and global left ventricular function and remodeling. We also evaluate the effects of MF on the function of mitochondrial respiratory,energy metabolism, apoptosis, myocardial viability by molecular biology technique and pathology. In order to clarify the protective effects of MF on HB and its related molecular mechanism.It can also provide some important evidence for treatment of heart failure in patient with ischemic cardiomyopathy and heart failure. It can also provide some clue for developing new drugs in order to improve the myocardial metabolism of HB.

保护冬眠心肌治疗缺血性心衰是心血管领域的重要目标。二甲双胍（MF）已被指南列为糖尿病合并心衰首选药物。既往主要针对MF对急性缺血灌注损伤模型有保护作用，机制尚不明确，主要认为MF抑制心肌的线粒体呼吸功能，减少有氧代谢，增加无氧糖酵解。尚无PET代谢显像对猪慢性冬眠心肌模型（HB）治疗的研究。针对该药在心肌的浓度分布远低于肝脏、小肠，推测该药可通过减少外周脏器的氧耗量，相对增加心肌供氧而延缓心肌损伤，减轻左心室重构并改善左心室功能。在既往成功建立猪HB模型基础上，给予MF治疗，采用门控心肌灌注+门控代谢PET/CT活体分子显像动态评价MF对HB局部心肌灌注、代谢、存活性以及对心肌局部和整体心功能及心室重构的作用。辅以线粒体呼吸功能、能量代谢、病理学、分子生物学等相关指标的检测，深入探讨MF对HB的保护作用及其分子机制，为其治疗缺血性心肌病心衰提供重要依据，为研制针对心肌代谢药物提供新思路。

保护冬眠心肌阻止其发展为梗死心肌治疗缺血性心衰是心血管领域的重要目标。二甲双胍（MF）被指南列为糖尿病合并心衰患者的首选药物。既往研究发现MF对急性缺血灌注损伤（MIRI）有保护作用，机制尚不明确。期望通过本项目的系列研究，对临床实践中对于冬眠心肌的诊断和治疗提供重要的理论基础。首先，通过结扎大鼠左前降支（LAD），建立大鼠心肌缺血－再灌注损伤模型，给予MF干预治疗，与未治疗组对比，分别在术前1天，术后1天、7天、14天、30天行门控18F-FDG代谢PET/CT显像，分别评价缺血中心区、周边区和远端区不同部位心肌葡萄糖代谢的变化特点，以及左心室整体心功能（LVEF），心室重构（左心室舒张末期容积， LVEDV）的变化特点，从多角度，综合评估MF对心肌缺血再灌注心肌是否具有保护作用。结果1）在建模后30天，MF干预组（n=6），心肌缺血中心区与远端区SUVmax比值（TBR）较对照组明显升高 (0.81±0.06 vs. 0.65±0.09，p<0.05)。2）同一时期，MF干预组LVEDV358.21±22.62（mm3），明显小于对照组457.53±29.91（mm3）（p<0.05）。其次，采用LAD放置环缩环的方法，成功建立了猪冬眠心肌模型（n=19），分别在术前，术后1周、4周、8周对动物模型行门控99mTc-MIBI SPECT/CT心肌灌注显像+门控18F-FDG PET/CT心肌代谢显像，多角度动态评价心肌灌注缺损范围（TPD，% LV）、冬眠心肌 （HM，LV%）、梗死心肌（scar，LV%），左心室心肌的局部功能（室壁运动和室壁增厚率），左心室整体功能（LVEF）、心室重构（LVEDV、LVESV）及）等的变化规律和特点，评价冬眠心肌与心功能与心室重构变化之间的关系和特点。采用冠状动脉造影评价是否有侧枝循环，比较两组间不同参数变化特点是否有差异，我们发现建立侧枝循环的猪，心肌灌注受损的范围随着术后时间延长逐步减小，左心室功能逐步改善，而没有侧枝循环形成的猪，心肌灌注受损的范围逐步增加，左心室功能逐步恶化。心肌代谢显像在活体研究证实MF可以保护缺血再灌注损伤心肌，并延缓左心室重构的发展。后续将采用同样的冬眠心肌模型，采用同样的影像学参数，评估MF干预治疗的研究。并对病理组织进行深入的免疫组化的基础研究。