From the VA WNY Health Care System and the Departments of Medicine, Pharmacology and Toxicology, Physiology and Biophysics, and Biomedical Engineering, and the Clinical and Translational Research Center of the University at Buffalo, NY.
Circ Res. 2018 Sep 28;123(8):986-995. doi: 10.1161/CIRCRESAHA.118.313341.
Metformin has been demonstrated to decrease infarct size (IS) and prevent postinfarction left ventricular (LV) remodeling in rodents when given intravenously at the time of reperfusion. It remains unclear whether similar cardioprotection can be achieved in a large animal model.
The objective of this study was to determine whether intravascular infusion of metformin at the time of reperfusion reduces myocardial IS in a porcine model of acute myocardial infarction.
In a blinded and randomized preclinical study, closed-chest swine (n=20) were subjected to a 60-minute left anterior descending coronary artery occlusion to produce myocardial infarction. Contrast-enhanced computed tomography was performed during left anterior descending coronary artery occlusion to assess the ischemic area-at-risk. Animals were randomized to receive either metformin or vehicle as an initial intravenous bolus (5 mg/kg) 8 minutes before reperfusion, followed by a 15-minute left coronary artery infusion (1 mg/kg per minute) commencing with the onset of reperfusion. Echocardiography and computed tomographic imaging of LV function were performed 1 week later, at which time the heart was removed for postmortem pathological analysis of area-at-risk and IS (triphenyltetrazolium chloride). Baseline variables including hemodynamics and LV function were similar between groups. Peak circulating metformin concentrations of 374±35 µmol/L were achieved 15 minutes after reperfusion. There was no difference between the area-at-risk as a percent of LV mass by computed tomography (vehicle: 20.7%±1.1% versus metformin: 19.7%±1.3%; P=0.59) or postmortem pathology (22.4%±1.2% versus 20.2%±1.2%; P=0.21). IS relative to area-at-risk averaged 44.5%±5.0% in vehicle-treated versus 38.2%±6.8% in metformin-treated animals ( P=0.46). There was no difference in global function 7 days after myocardial infarction as assessed by echocardiography or computed tomographic ejection fraction (56.2%±2.6% versus 56.3%±2.4%; P=0.98).
In contrast to rodent hearts, postconditioning with high-dose metformin administered immediately before reperfusion does not reduce IS or improve LV function 7 days after myocardial infarction in swine. These results reinforce the importance of rigorously testing therapies in large animal models to facilitate clinical translation of novel cardioprotective therapies.
在再灌注时静脉内给予二甲双胍已被证明可减少啮齿动物的梗死面积（IS）并预防梗死后左心室（LV）重构。目前尚不清楚是否可以在大型动物模型中获得类似的心脏保护作用。
本研究旨在确定再灌注时血管内输注二甲双胍是否可减少猪急性心肌梗死模型中的心肌 IS。
在一项盲法和随机的临床前研究中，对 20 只闭胸猪进行了 60 分钟的左前降支冠状动脉闭塞以产生心肌梗死。在左前降支冠状动脉闭塞期间进行对比增强 CT 以评估缺血危险区的面积。动物随机接受二甲双胍或载体作为初始静脉推注（5mg/kg），在再灌注前 8 分钟，然后在再灌注开始时开始 15 分钟的左冠状动脉输注（1mg/kg/分钟）。1 周后进行超声心动图和 LV 功能的 CT 成像，此时取出心脏进行危险区和 IS（氯化三苯基四氮唑）的死后病理分析。组间基线变量包括血流动力学和 LV 功能相似。再灌注后 15 分钟达到 374±35µmol/L 的峰值循环二甲双胍浓度。通过 CT（载体：20.7%±1.1%与二甲双胍：19.7%±1.3%；P=0.59）或死后病理学（22.4%±1.2%与 20.2%±1.2%；P=0.21）测量的危险区面积作为 LV 质量的百分比没有差异。载体治疗的 IS 相对于危险区平均为 44.5%±5.0%，而二甲双胍治疗的动物为 38.2%±6.8%（P=0.46）。7 天后通过超声心动图或 CT 射血分数评估，心肌梗死后的整体功能无差异（56.2%±2.6%与 56.3%±2.4%；P=0.98）。
与啮齿动物心脏相反，在再灌注前立即给予大剂量二甲双胍进行后处理不会减少猪 7 天后的 IS 或改善 LV 功能。这些结果强调了在大型动物模型中严格测试治疗方法的重要性，以促进新型心脏保护疗法的临床转化。
