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）在美国已达到流行病的程度。这些病例中的绝大多数是梗死后LV重构的结果。现在已经确定，早期梗死扩展在正常灌注的心肌中启动了一个不可阻挡的肌病过程，导致CHF。血管硬化可以防止不良重塑，再灌注治疗是目前实现这一目标的最佳方法。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经了解了很多，但对这一非常复杂的现象的全面理解一直是虚幻的。这不是这个建议的中心焦点，以探讨心肌再灌注损伤的机制（虽然细胞凋亡的研究将提供新的信息，这种独特的形式的细胞死亡如何有助于I/R损伤），而是利用什么是已知的，以改善急性心肌梗死再灌注治疗的结果。我们的假设是，即使在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）也可以改变梗死材料的性质，足以防止早期梗死扩展，稳定梗死后心室几何形状并防止CHF的发展。将使用完善的梗死后心室重构和进行性CHF绵羊模型。将使用声测微阵列定位和定量超声心动图的成像技术评估不同缺血间隔后未经修改和修改的再灌注对梗死扩展和重构结果的影响。由于坏死、凋亡和/或微血管无复流，心肌细胞在再灌注时丢失。腺苷、阿昔单抗和米诺环素已被选择来改变梗塞再灌注液，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/再灌注期间发生的细胞损失的一种或多种机制来限制危险区域内的梗塞大小。

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.