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(R01HL089504-01)的重新提交申请，标题为：AIM-HIGH中的斑块炎症和功能失调的高密度脂蛋白。这项建议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高密度脂蛋白在从AIM-HIGH试验中获得的独特参与者中预防冠心病方面的作用。通过利用成熟的AIM高试验招募、临床站点和数据收集基础设施，这项子研究将比独立的多中心试验更有效率和成本效益。在初步研究中，我们发现动态对比增强(DCE-MRI)参数KTRANS与斑块炎症之间有很强的相关性，也获得了初步证据，即CHD的特征是高密度脂蛋白的氧化和炎症变化，这些变化与其正常功能受损有关，但他汀类药物+烟酸治疗可以改善这些变化。在此背景下，AIM-HIGH队列代表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中特定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患者磁共振成像子研究中招募120名参与者(每个治疗组60名)。我们将对MR图像进行后处理，以得出与颈动脉炎症相关的参数，并在基线和辛伐他汀或辛伐他汀+烟酸治疗2年后测量血浆高密度脂蛋白氧化和蛋白质组成。在目标1中，我们将检验这一假设，即辛伐他汀+烟酸在2年内导致颈动脉炎症标记物KTRANS的下降幅度大于单独使用辛伐他汀。在目标2中，我们将检验这一假设，即辛伐他汀+烟酸治疗2年比单独服用辛伐他汀更能减少高密度脂蛋白氧化和使高密度脂蛋白组成正常化。在目标3中，我们将检验这一假设，即两年内高密度脂蛋白氧化的变化与Ktras的减少比仅高密度脂蛋白水平的变化更好地相关。因此，这项子研究将使用新颖、最先进的非侵入性成像和蛋白质分析工具来确定烟酸疗法与他汀类药物联合治疗是否比单独使用他汀类药物在更大程度上减少斑块炎症和高密度脂蛋白功能障碍。这一结果将有力地支持烟酸诱导的高密度脂蛋白改变在减轻动脉粥样硬化斑块炎症中的核心重要性的假说。 尽管开发了他汀类降脂药物，但在美国，冠心病(CHD)仍然是主要的死亡原因。当炎症破坏动脉粥样硬化斑块的结构时，就会发生CHD事件。在他汀类药物中加入烟酸可能有助于稳定斑块，但我们不清楚烟酸是如何做到这一点的。我们将验证这样一种假设，即烟酸通过提高“好”胆固醇高密度脂蛋白修复斑块炎症损伤的能力来帮助阻止破坏动脉粥样硬化斑块的炎症。

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.