Plaque Inflammation and Dysfunctional HDL in AIM-HIGH

描述（由申请人提供）：这是我们的研究计划（1 R01 HL089504-01）的再提交申请，题为：“AIM-HIGH中的斑块炎症和功能失调的HDL”。本提案的总体目标是使用最先进的成像和蛋白质组学方法来了解巨噬细胞和HDL在AIM-HIGH试验中预防冠心病的作用。通过利用完善的AIM HIGH试验招募、临床地点和数据收集基础设施，该子研究将比独立的多中心试验更有效和更具成本效益。在初步研究中，我们发现动态对比增强（DCE-MRI）参数、Ktrans与斑块炎症之间存在很强的相关性，并获得了初步证据，表明冠心病的特征是HDL的氧化和炎症变化，这些变化与其正常功能的损害有关，但他汀类药物+烟酸治疗可改善这种变化。在此背景下，AIM-HIGH队列提供了一个独特的机会来研究辛伐他汀或辛伐他汀+烟酸对动脉粥样硬化斑块特异性炎症变化的相对影响。基于这些发现，我们提出了一项子研究，将从赵雪乔博士的AIM-HIGH患者MR成像亚研究中招募120名参与者（每个治疗组60名）。我们将对磁共振图像进行后处理，以获得与颈动脉炎症相关的参数，并在基线和服用辛伐他汀或辛伐他汀+烟酸2年后测量血浆HDL氧化和蛋白质组成。在Aim 1中，我们将检验辛伐他汀+烟酸导致颈动脉炎症标志物Ktrans在2年内比单独辛伐他汀更大的降低的假设。在Aim 2中，我们将检验假设，即2年的辛伐他汀+烟酸治疗比单独使用辛伐他汀更能降低HDL氧化和使HDL蛋白组成正常化。在目标3中，我们将验证假设，即2年内HDL氧化变化与Ktrans减少的相关性优于单独的HDL水平变化。因此，本亚研究将使用新颖的、最先进的、非侵入性的成像和蛋白质分析工具来确定烟酸治疗与他汀类药物联合使用是否比单独使用他汀类药物更能减少斑块炎症和功能失调的HDL。结果将为烟酸诱导的HDL改变在减少动脉粥样硬化斑块炎症中起核心作用的假设提供强有力的支持。

Description (provided by applicant): This is a resubmission application of our research proposal (1 R01 HL089504-01), entitled: "Plaque Inflammation and Dysfunctional HDL in AIM-HIGH." The overall goal of this proposal is to use state-of-the-art imaging and proteomic approaches to understand the roles of macrophages and HDL in preventing CHD in a subset of the unique participants available from the AIM-HIGH Trial. By utilizing the well-established AIM HIGH trial recruitment, clinical site and data collection infrastructure, this Substudy will be much more efficient and cost-effective than would a stand-alone, multi-center trial. In preliminary studies, we have found a strong correlation between a dynamic contrast enhanced (DCE-MRI) parameter, Ktrans, and plaque inflammation, and also have obtained preliminary evidence that CHD is characterized by oxidative and inflammatory changes in HDL that are associated with impairment of its normal function but that are improved with statin+niacin therapy. In this context, the AIM-HIGH cohort represents a unique opportunity to investigate the relative effects of simvastatin or simvastatin+niacin on specific inflammatory changes in atherosclerotic plaques. Based on these findings, we propose a Substudy that will enroll 120 participants (60 per treatment group) from Dr. Xue-Qiao Zhao's Substudy of MR imaging in AIM-HIGH patients. We will perform post processing of MR images to derive parameters associated with carotid inflammation and measure plasma HDL oxidation and protein composition at baseline and after 2 years on either simvastatin or simvastatin+ niacin. In Aim 1, we will test the hypothesis that simvastatin+niacin results in greater reduction in the carotid inflammation marker, Ktrans, at 2 years than does simvastatin alone. In Aim 2, we will test the hypothesis that 2 years of simvastatin+niacin results in greater reduction in HDL oxidation and normalization of HDL protein composition than does simvastatin alone. In Aim 3, we will test the hypothesis that HDL oxidation changes over 2 years correlate better with reduction in Ktrans than do changes in HDL levels alone. Thus, this Substudy will use novel, state-of-the-art, non-invasive imaging and protein analytical tools to determine whether niacin therapy in concert with a statin reduces plaque inflammation and dysfunctional HDL to a greater extent than does a statin alone. The results would provide strong support for the hypothesis that niacin-induced alterations in HDL are of central importance in decreasing atherosclerotic plaque inflammation. Despite the development of lipid-lowering drugs like statins, coronary heart disease (CHD) remains the leading cause of death in the U.S. CHD events occur when inflammation breaks down the structure of atherosclerotic plaques. Adding niacin to statins might help stabilize plaques, but we don't know exactly how niacin might work to do this. We will test the hypothesis that niacin helps to block the inflammation that breaks down atherosclerotic plaques by improving the ability of "good" cholesterol, HDL, to repair inflammatory damage to the plaque.