Effect of Intracoronary Metformin on Myocardial Infarct Size in Swine.
Effect of Intracoronary Metformin on Myocardial Infarct Size in Swine.
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DOI：
10.1161/circresaha.118.313341
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发表时间：
2018-09-28
影响因子：
20.1
通讯作者：
Canty JM Jr
中科院分区：
文献类型：
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作者：
Techiryan G;Weil BR;Palka BA;Canty JM Jr
二甲双胍在啮齿类动物再灌注时静脉给予二甲双胍可以减少梗死面积（IS）并防止梗死后左心室（LV）重构。目前尚不清楚在大型动物模型中是否能实现类似的心脏保护。在猪急性心肌梗死（MI）模型中，确定再灌注时血管内输注二甲双胍是否能降低心肌IS。在一项盲法随机临床前研究中，对20头闭胸猪（n=20）进行60分钟的LAD闭塞以产生心肌梗死。在LAD闭塞期间进行对比增强CT以评估缺血危险区域（AAR）。动物在再灌注前8分钟随机接受二甲双胍或载药作为初始静脉注射（5mg /kg），然后在再灌注开始时进行15分钟左冠状动脉输注（1mg /kg/min）。1周后行超声心动图和左室功能CT成像，同时取心进行死后病理分析AAR和IS （TTC）。包括血流动力学和左室功能在内的基线变量在两组之间相似。再灌注15分钟后二甲双胍循环浓度达到峰值374±35µmol/L。CT显示AAR占左室质量的百分比（Vehicle: 20.7±1.1% vs. Metformin: 19.7±1.3%;p=0.59）或死后病理（22.4±1.2% vs. 20.2±1.2%;p=0.21）无差异。车辆组相对于AAR平均为44.5±5.0%，二甲双胍组为38.2±6.8% （p=0.46）。超声心动图和CT射血分数评估心肌梗死后7天的整体功能无差异（56.2±2.6% vs 56.3±2.4%,p=0.98）。与啮齿类动物心脏相比，猪心肌梗死后7天，在再灌注前立即给予大剂量二甲双胍后适应并不能减少梗死面积或改善左室功能。这些结果强化了在大型动物模型中严格测试治疗的重要性，以促进新型心脏保护疗法的临床转化。
Metformin has been demonstrated to decrease infarct size (IS) and prevent post-infarction 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. To determine whether intravascular infusion of metformin at the time of reperfusion reduces myocardial IS in a porcine model of acute myocardial infarction (MI). In a blinded and randomized pre-clinical study, closed-chest swine (n=20) were subjected to a 60-minute LAD occlusion to produce MI. Contrast-enhanced CT was performed during LAD occlusion to assess the ischemic area-at-risk (AAR). Animals were randomized to receive either metformin or vehicle as an initial IV bolus (5 mg/kg) 8-minutes before reperfusion, followed by a 15-minute left coronary artery infusion (1 mg/kg/min) commencing with the onset of reperfusion. Echocardiography and CT imaging of LV function were performed 1-week later, at which time the heart was removed for post-mortem pathologic analysis of AAR and IS (TTC). 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 AAR as a percent of LV mass by CT (Vehicle: 20.7±1.1% vs. Metformin: 19.7±1.3%; p=0.59) or post-mortem pathology (22.4±1.2% vs 20.2±1.2%; p=0.21). IS relative to AAR averaged 44.5±5.0% in vehicle-treated vs. 38.2±6.8% in metformin-treated animals (p=0.46). There was no difference in global function 7-days after MI as assessed by echocardiography or CT ejection fraction (56.2±2.6% vs. 56.3±2.4%, p=0.98). In contrast to rodent hearts, postconditioning with high-dose metformin administered immediately before reperfusion does not reduce infarct size or improve LV function 7-days after MI in swine. These results reinforce the importance of rigorously testing therapies in large animal models to facilitate clinical translation of novel cardioprotective therapies.