Plaque Inflammation and Dysfunctional HDL in AIM-HIGH

AIM-HIGH 中的斑块炎症和 HDL 功能障碍

• 批准号: 8067139
• 负责人: Kevin D. O'Brien
• 金额: $ 44.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8067139
• 关键词: 3-chlorotyrosine; 3-nitrotyrosine; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Atherosclerosis; Carotid Artery Plaques; Cause of Death; Cells; Cholesterol; Clinical Data; Coronary heart disease; Data Collection; Derivation procedure; Development; Enrollment; Event; Evolution; Goals; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Image; Impairment; Inflammation; Inflammatory; Inflammatory Response; Intervention; Isotope Labeling; Lesion; Lipids; Magnetic Resonance Imaging; Mass Spectrum Analysis; Measures; Monitor; Nicotinic Acids; Participant; Patients; Peptides; Pharmaceutical Preparations; Plasma; Play; Process; Proteins; Proteomics; Randomized; Relative (related person); Research Infrastructure; Research Proposals; Risk; Role; Rupture; Screening procedure; Simvastatin; Stenosis; Structure; Testing; Tissues; Ultrasonography; Work; analytical tool; base; candidate marker; clinical research site; cohort; cost effective; experience; improved; improved functioning; in vivo; inflammatory marker; macrophage; novel; oxidation; particle; prevent; repaired

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.

描述（由申请人提供）：这是我们的研究建议（1 R01 HL089504-01）的重新提交，标题为“ AIM-HIGH中的斑块炎症和功能失调的HDL”。该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在防止CHD中的作用，以防止CHD在AIM-HIGH试验中可用的独特参与者中。通过利用良好的AIM高试验招聘，临床部位和数据收集基础设施，该子女将比独立的多中心试验更有效和成本效益。在初步研究中，我们发现动态对比度增强（DCE-MRI）参数，ktrans和斑块炎症之间存在很强的相关性，并且还获得了初步证据，表明CHD具有HDL的氧化和炎症性变化的特征，与其正常功能相关，但与NiCin+Niacin+Niacin therapy相关。在这种情况下，AIM-HIGH队列代表了研究辛伐他汀或辛伐他汀+烟酸对动脉粥样硬化斑块特定炎症变化的相对影响的独特机会。基于这些发现，我们提出了一种典型，将从Xue-Qiao Zhao博士的MR成像中招募120名参与者（每个治疗组60组）。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+烟酸蛋白上测量血浆HDL氧化和蛋白质组成。在AIM 1中，我们将检验以下假设：辛伐他汀+烟酸会导致颈动脉炎症标志物KTRAN的降低比单独的辛伐他汀的降低。在AIM 2中，我们将检验以下假设：辛伐他汀+烟酸的2年导致HDL氧化和HDL蛋白组成的归一化降低要比单独使用辛伐他汀的降低。在AIM 3中，我们将检验以下假设：HDL氧化在2年内的变化与KTRAN的降低相比，与单独的HDL水平的变化相比，KTRAN的降低更好。因此，这种质谱将使用新颖的，最先进的，非侵入性成像和蛋白质分析工具来确定与他汀类药物相比，与他汀类药物相比，与他汀类药物相比，与他汀类药物相比，与他汀类药物相比，是否会减少斑块炎症和功能障碍的HDL。结果将为假说提供强烈的支持，即烟酸诱导的HDL改变在减少动脉粥样硬化斑块炎症方面至关重要。 尽管降低脂质的药物（如他汀类药物）的发展，但当炎症破坏动脉粥样硬化斑块的结构时，冠状动脉心脏病（CHD）仍然是美国冠心病事件的主要死亡原因。将烟酸添加到他汀类药物中可能有助于稳定斑块，但我们不知道烟酸可能会如何做到这一点。我们将检验以下假设：烟酸通过提高“良好”胆固醇HDL修复对斑块的炎症损害的能力来帮助阻断炎症，从而阻止炎症。