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: 7462430
• 负责人: Kevin D. O'Brien
• 金额: $ 44.81万
• 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/7462430
• 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; Invasive; 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; clinical research site; cohort; cost; experience; improved; improved functioning; in vivo; 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）：这是我们研究计划（1 R01 HL089504-01）的重新提交申请，标题为：“AIM-HIGH 中的斑块炎症和 HDL 功能障碍”。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 AIM-HIGH 试验中的一部分独特参与者中预防冠心病的作用。通过利用完善的 AIM HIGH 试验招募、临床站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加高效且更具成本效益。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的特征是HDL中的氧化和炎症变化，这些变化与其正常功能受损相关，但通过他汀类药物+烟酸治疗可以得到改善。在这种情况下，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定炎症变化的相对影响。基于这些发现，我们提出一项亚组研究，将招募赵雪桥博士的 AIM-HIGH 患者 MR 成像亚组研究中的 120 名参与者（每个治疗组 60 名）。我们将对 MR 图像进行后处理，以获得与颈动脉炎症相关的参数，并测量辛伐他汀或辛伐他汀+烟酸治疗基线和 2 年后的血浆 HDL 氧化和蛋白质组成。在目标 1 中，我们将检验以下假设：与单独使用辛伐他汀相比，辛伐他汀+烟酸在 2 岁时可更大程度地减少颈动脉炎症标志物 Ktrans。在目标 2 中，我们将检验以下假设：与单独使用辛伐他汀相比，2 年辛伐他汀+烟酸可更大程度地减少 HDL 氧化并使 HDL 蛋白质组成正常化。在目标 3 中，我们将检验以下假设：两年内 HDL 氧化变化与 Ktrans 减少的相关性比单独 HDL 水平的变化更好。因此，本子研究将使用新颖、最先进的非侵入性成像和蛋白质分析工具来确定烟酸与他汀类药物联合治疗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。这些结果将为烟酸诱导的 HDL 改变对于减少动脉粥样硬化斑块炎症至关重要的假设提供强有力的支持。 尽管开发了他汀类药物等降脂药物，但冠心病 (CHD) 仍然是美国死亡的主要原因。当炎症破坏动脉粥样硬化斑块的结构时，就会发生冠心病事件。在他汀类药物中添加烟酸可能有助于稳定斑块，但我们并不确切知道烟酸如何发挥作用。我们将检验这样的假设：烟酸通过提高“好”胆固醇（HDL）修复斑块炎症损伤的能力，有助于阻止炎症分解动脉粥样硬化斑块。