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: 7822854
• 负责人: Kevin D. O'Brien
• 金额: $ 44.67万
• 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/7822854
• 关键词: 3-chlorotyrosine; 3-nitrotyrosine; Anti-Inflammatory Agents; Anti-inflammatory; Arterial Fatty Streak; Arts; Atherosclerosis; Carotid Artery Plaques; Cause of Death; Cells; Cholesterol; 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; 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）：这是我们的研究提案（1 R 01 HL 089504 -01）的重新提交申请，标题为：“AIM-HIGH中的斑块炎症和功能障碍性HDL。“这项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试验中独特参与者子集中预防CHD的作用。通过利用完善的AIM HIGH试验招募、临床研究中心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Ktranss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的特征在于HDL的氧化和炎症变化，这些变化与其正常功能受损相关，但可通过他汀类药物+烟酸治疗得到改善。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中特定炎症变化的相对作用的独特机会。基于这些发现，我们提出了一项子研究，该研究将招募120名来自Xue-Qiao Zhao博士的AIM-HIGH患者MR成像子研究的受试者（每个治疗组60名）。我们将对MR图像进行后处理，以获得与颈动脉炎症相关的参数，并测量基线时和辛伐他汀或辛伐他汀+烟酸治疗2年后的血浆HDL氧化和蛋白质组成。在目标1中，我们将检验辛伐他汀+烟酸在2年时比单独使用辛伐他汀导致颈动脉炎症标志物Ktranss更大程度降低的假设。在目标2中，我们将检验辛伐他汀+烟酸治疗2年比单独使用辛伐他汀更能降低HDL氧化和使HDL蛋白组成正常化的假设。在目标3中，我们将检验这一假设，即与单独的HDL水平变化相比，HDL氧化变化在2年内与Ktranss降低的相关性更好。因此，该子研究将使用新的、最先进的、非侵入性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大程度地减少斑块炎症和功能失调的HDL。这些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具有核心重要性的假设提供强有力的支持。 尽管开发了他汀类降脂药物，但冠心病（CHD）仍然是美国死亡的主要原因。CHD事件发生在炎症破坏动脉粥样硬化斑块的结构时。在他汀类药物中加入烟酸可能有助于稳定斑块，但我们不知道烟酸是如何起作用的。我们将检验这一假设，即烟酸通过提高“好”胆固醇（HDL）修复斑块炎症损伤的能力，有助于阻断炎症，从而分解动脉粥样硬化斑块。