Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York 10029-6574, USA.
Am J Physiol Heart Circ Physiol. 2011 Aug;301(2):H530-7. doi: 10.1152/ajpheart.01103.2010. Epub 2011 May 6.
A number of promising therapies for ischemic cardiomyopathy are emerging, and the role of translational research in testing the efficacy and safety of these agents in relevant clinical models has become important. The goal of this study was to develop a chronic model of ischemic cardiomyopathy in a large animal model. In this study, 40 consecutive pigs were initially enrolled. To induce progressive stenosis, a plastic occluder with a fixed diameter of 1.0 mm fitted with an 18-gauge copper wire was placed around the proximal left anterior descending (LAD) coronary artery. Coronary angiography, hemodynamic measurements, and echocardiography were performed at 2 wk and 1, 2, and 3 mo. Overall mortality was 26% at 3 mo, and up to 80% of the pigs showed total occlusion of LAD at 1 mo. A significant depression of peak LV pressure rate of rise (+dP/dt(max)) was observed in the animals showing total artery occlusion throughout the study. Left ventricular ejection fraction was also impaired, and the left ventricular volumes tended to be larger in the pigs with occlusion. Approximately 10% of scar tissue was found in the LAD occluded pigs, whereas the coronary flow pattern in the rest of the area took the pattern of hibernating myocardium. At the same time, histological and protein analysis established the presence of fibrosis and ongoing apoptosis in the ischemic area. In this model, the timing and incidence of total occlusion and low mortality offer significant advantages over other ischemic cardiomyopathy models in conducting preclinical studies.
一些有前景的缺血性心肌病治疗方法正在出现，转化研究在测试这些药物在相关临床模型中的疗效和安全性方面的作用变得越来越重要。本研究的目的是在大型动物模型中建立慢性缺血性心肌病模型。在这项研究中，最初有 40 头猪入组。为了诱导进行性狭窄，将一个带有 1.0mm 固定直径的塑料阻塞器和一根 18 号铜丝放置在左前降支（LAD）近端周围。在 2 周和 1、2 和 3 个月时进行冠状动脉造影、血流动力学测量和超声心动图检查。3 个月时的总死亡率为 26%，多达 80%的猪在 1 个月时出现 LAD 完全闭塞。在整个研究过程中，显示完全动脉闭塞的动物的左心室压力上升率峰值（+dP/dt(max)）显著下降。左心室射血分数也受到损害，并且闭塞的猪的左心室容积往往更大。在 LAD 闭塞的猪中发现了大约 10%的疤痕组织，而其余区域的冠状动脉血流模式则呈冬眠心肌模式。同时，组织学和蛋白质分析证实缺血区存在纤维化和持续的细胞凋亡。在这种模型中，完全闭塞的时间和发生率以及低死亡率为进行临床前研究提供了显著优势，优于其他缺血性心肌病模型。
