Modified Late Infarct Reperfusion to Prevent Post MI CHF

改良晚期梗死再灌注以预防 MI 后 CHF

• 批准号: 6611808
• 负责人: Robert C Gorman
• 金额: $ 49.69万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611808
• 关键词: adenosine; anticoagulants; cell death; chemoprevention; congestive heart failure; echocardiography; heart disorder chemotherapy; heart surgery; medical complication; muscle cells; myocardial infarction; reperfusion; sheep; tetracyclines

DESCRIPTION (provided by applicant): Congestive heart failure (CHF) has reached epidemic proportions in the United States. The significant majority of these cases are the result of postinfarction LV remodeling. It is now established that early infarct expansion initiates an inexorable myopathic process in normally perfused myocardium that leads to a CHF. Infarct stiffening can prevent adverse remodeling and reperfusion therapy is currently the best available means to accomplish this. However, reperfusion therapy often fails to influence remodeling especially after long ischemic intervals. Much has been learned about pathophysiology and pathology of myocardial ischemia/reperfusion (I/R) but a comprehensive understanding of this very complex phenomenon has been illusive. It is not the central focus of this proposal to explore the mechanism of myocardial reperfusion injury (although the apoptosis studies will provide new information on how this unique form of cell death contributes to I/R injury) but rather to exploit what is already known to improve the results of reperfusion therapy for acute myocardial infarction. Our hypothesis is that even very limited myocardial salvage (too small to improve contractile function) within the area at risk can alter infarct material properties enough to prevent early infarct expansion, stabilize postinfarction ventricular geometry and prevent the development of CHF. A well-established sheep model of postinfarction ventricular remodeling and progressive CHF will be used. The effect of unmodified and modified reperfusion after varying ischemic intervals on infarct expansion and the outcome of remodeling will be assessed using the imaging techniques of sonomicrometry array localization and quantitative echocardiography. Myocytes are lost at the time of reperfusion due to necrosis, apoptosis and/or microvascular no reflow. Adenosine, abciximab and minocycline have been selected to modify the infarct reperfusate because they have been demonstrated in clinical and/or experimental studies and confirmed in the sheep model to limit infarct size within in the area at risk by affecting one or more of the mechanisms of cell loss that occur during myocardial ischemia/reperfusion.

描述（由申请人提供）： 充血性心力衰竭（CHF）在美国已达到流行病。这些病例中的大部分是引入后左室重塑的结果。现在已经确定，早期的梗塞扩张启动了正常灌注心肌的不可阻挡的肌病过程，导致了CHF。梗塞加强可以防止不良重塑，而再灌注疗法目前是实现这一目标的最佳手段。但是，再灌注疗法通常不会影响重塑，尤其是在长期缺血间隔后。关于心肌缺血/再灌注（I/R）的病理生理学和病理学的知识已经很多，但是对这一非常复杂的现象的全面理解是虚幻的。探索心肌再灌注损伤机制并不是该提案的主要重点（尽管凋亡研究将提供有关这种独特的细胞死亡形式如何有助于I/R损伤的新信息），而是利用已经已知的来改善急性心肌梗死的已知的结果。我们的假设是，在处于危险中的区域内，心肌救助（太小而无法改善收缩功能）也可以改变梗塞材料的特性，以防止早期梗塞扩张，稳定后炎后的心室几何形状并防止CHF的发展。将使用良好的染发后心室重塑和渐进式CHF的绵羊模型。缺血间隔变化后，未修饰和修饰的再灌注对梗塞扩张的影响以及重塑结果将使用Sonomictremitry阵列定位和定量超声心动图的成像技术进行评估。由于坏死，细胞凋亡和/或微血管无回流，在再灌注时肌细胞损失。已经选择了腺苷，阿昔昔单抗和米诺环素以修饰梗塞再生舒适酸盐，因为它们已在临床和/或实验研究中得到证明，并在绵羊模型中证实，以限制在危险中内部的梗塞大小，通过影响一种或多种在心肌局部累积性缺血/再生型中发生的细胞损失机制。