Modified Late Infarct Reperfusion to Prevent Post MI CHF

描述(由申请人提供)： 充血性心力衰竭(CHF)在美国已经达到流行的程度。这些病例中的大多数是梗死后左室重构的结果。现已证实，早期梗塞扩大在正常灌流的心肌中启动了一个不可阻挡的肌病过程，从而导致心力衰竭。心肌梗死硬化可以防止不利的重构，而再灌注治疗是目前实现这一目标的最有效手段。然而，再灌注治疗往往不能影响重塑，特别是在长时间缺血间隔后。关于心肌缺血/再灌注(I/R)的病理生理学和病理学已有很多研究，但对这一非常复杂的现象的全面理解一直是虚幻的。这项建议的中心焦点不是探索心肌再灌注损伤的机制(尽管细胞凋亡研究将提供关于这种独特的细胞死亡如何导致I/R损伤的新信息)，而是探索已知的改善急性心肌梗死再灌注治疗结果的方法。我们的假设是，即使是危险区域内非常有限的心肌挽救(太小而不能改善收缩功能)也可以改变梗死物质的性质，足以防止早期梗死扩大，稳定梗死后心室几何形状，并防止CHF的发展。我们将使用已建立的梗塞后心室重塑和进行性充血性心力衰竭的绵羊模型。利用声学显微镜阵列定位和定量超声心动图成像技术，评估不同缺血间隔后未修改和修改的再灌注对梗塞扩大和重塑结果的影响。心肌细胞在再灌注时由于坏死、凋亡和/或微血管无复流而丢失。腺苷、阿昔单抗和米诺环素已被用于修饰心肌梗死再灌注液，因为它们已在临床和/或实验研究中得到证实，并在绵羊模型中得到证实，通过影响心肌缺血/再灌注期间发生的一种或多种细胞丢失机制，将心肌梗死范围限制在危险区域内。

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.