DETECTION AND MODULATION OF THE VULNERABLE ATHEROSCLEROTIC PLAQUE

由斑块破裂引起的不稳定发作经常是点状的， 冠状动脉粥样硬化的过程。 病理学研究 确定了易破裂病变的关键特征（薄 纤维帽，大脂质池，突出的炎症成分） 但包括诊断性血管造影术在内的常规临床测试未能 识别易损斑块的结构特征。 具体目标1 目的是在兔子身上开发和验证实验性 动脉粥样硬化高分辨率磁共振成像， 系统地识别易损斑块的特征， 跟踪这些功能中的更改和可能的改进， 降低胆固醇。 此外，我们还将检验以下假设： 降脂改善基质降解的过度表达 蛋白酶在兔动脉粥样硬化，酶的积累， 人类动脉粥样硬化病变易于破裂的位置。 在 Specific Aim 2血管内超声将用于患者 接受心导管插入术，以系统地检查a） 内膜生长、代偿性增大和 动脉粥样硬化病变中的管腔尺寸，和，B） 正常和病变冠状动脉节段之间的扩张性。 这种扩张性的差异可能会改变应力-应变平衡 在动脉粥样硬化病变内， 容易破裂 再一次，降低胆固醇的治疗 将用于系列研究，以了解 易损斑块改善，治疗时需要监测 患者 这些研究也可能揭示迄今尚未探索的 降低胆固醇可促进斑块形成的机制 稳定 这些研究提供了新的方法来检测 易受动脉粥样硬化损害的患者。 这种急需 常规血管造影无法获得信息， 与其他现有的临床测试方法相结合。 这项工作应 提供新的机制见解，促进 用于进一步保护免于斑块破裂的治疗策略， 血栓形成和致命的冠状动脉事件。

Episodes of instability caused by plaque disruption often punctuate the course of coronary atherosclerosis. Pathological studies have identified critical features of lesions vulnerable to rupture (thin fibrous cap, large lipid pool, prominent inflammatory component) but routine clinical testing including diagnostic angiography fails to identify structural features of vulnerable plaques. Specific Aim 1 aims to develop and validate in rabbits with experimental atherosclerosis high resolution magnetic resonance imaging to identify systematically the features of vulnerable plaques and to follow changes and possible improvements in these features with cholesterol lowering. In addition, we will test the hypothesis that lipid lowering improves overexpression of matrix degrading proteinases in the rabbit atheroma, enzymes which accumulate at locations of the human atherosclerotic lesions prone to rupture. In Specific Aim 2 intravascular ultrasound will be used in patients undergoing cardiac catheterization to examine systematically a) the relationship between intimal growth, compensatory enlargement and lumen size in atherosclerotic lesions and, b) differences in distensibility between normal and diseased coronary segments. Such disparities in distensibility may alter the stress-stain balances within an atherosclerotic lesion, shifting stresses to regions predisposed to rupture. Once again, cholesterol lowering therapy will be used in serial studies to learn which features of the vulnerable plaque improve and need to be monitored when treating patients. These studies may also disclose hitherto unexplored mechanisms whereby cholesterol lowering can promote plaque stability. These studies provide novel approaches to detection of vulnerable atherosclerotic lesions in patients. This much needed information cannot be obtained with conventional angiography or with other current clinical means of testing. This work should provide new mechanistic insights and promote development of therapeutic strategies for further protection from plaque rupture, thrombosis and fatal coronary events.