Carotid plaque characteristics by MRI in AIM-HIGH

描述（由申请人提供）：这是我们的研究申请（1 R01 HL088214- 01）题为“颈动脉斑块特征的MRI在AIM-HIGH”的再提交申请。尽管研究表明斑块的形态和组成是斑块稳定性的重要决定因素，然而，我们对斑块组织成分的理解主要来自组织学研究，直到最近MRI技术的发展。低水平的HDL与心血管事件的高风险和颈动脉斑块中脂质含量的增加有关。与单独降低ldl相比，降低ldl +升高hdl治疗更有效地预防动脉粥样硬化的进展。人们普遍认为，HDL或其载脂蛋白介导外周细胞中多余的游离胆固醇的清除，胆固醇通过LDL或HDL传递到肝脏并排泄到胆汁中。然而，它尚未在人体动脉粥样硬化条件下进行体内试验和批准。NIH/ koss支持的多中心AIM-HIGH试验旨在比较他汀类药物单独降低ldl与他汀类药物加烟酸联合治疗降低ldl加升高HDL在血管疾病、高甘油三酯和低HDL患者中的临床疗效。我们建议在AIM-HIGH的300名受试者中进行颈动脉MRI亚研究，以探讨hdl升高治疗的重要血管生物学机制。假设和具体目的是：(1)验证主要假设，即与单独降低ldl相比，强化降ldl加升高hdl治疗降低了MRI评估的颈动脉平均斑块脂质组成。(2)为了验证与单独降ldl相比，强化降ldl +升高hdl治疗可减少斑块负担，包括体积和壁厚。(3)验证MRI显示斑块脂质组成或血管壁厚度增加与心血管事件风险增加相关的假设。(4)探讨临床危险因素、血脂、脂蛋白异质性、炎症标志物与颈动脉斑块特征的相关性。这项拟议的MRI亚研究提供了一个独特的机会来研究降低ldl和提高hdl治疗在体内对人类动脉粥样硬化斑块的有效性，检查斑块特征（MRI评估的脂质组成和体积）与心血管结局的关系，并在我们对动脉粥样硬化斑块病理和强化脂质管理预防心血管事件的机制的理解中获得新的见解。在美国，由不稳定的动脉粥样硬化斑块引起的心脏病和中风仍然是导致死亡的主要原因。不稳定斑块通常比稳定斑块含有更多的脂肪。这项拟议的研究将调查降低低密度脂蛋白和升高高密度脂蛋白的治疗是否比单独降低低密度脂蛋白更有效地减少磁共振成像（MRI）评估的斑块脂肪含量，从而进一步减少心脏病发作和中风。

DESCRIPTION (provided by applicant): This is a resubmission application of our research application (1 R01 HL088214- 01) entitled 'Carotid plaque characteristics by MRI in AIM-HIGH.' Although studies have suggested that plaque morphology and composition are important determinants of plaque stability, however, our understanding on plaque tissue components is mainly from histological studies until recent development in MRI technique. A low level of HDL is associated with higher risk of cardiovascular events and increased amount of lipid content in the carotid plaques. Treatment with LDL-lowering plus HDL-raising compared with LDL-lowering alone more effectively protects against atherosclerosis progression. It is widely believed that HDL or its apolipoproteins mediate the removal of excess free cholesterol from peripheral cells and the cholesterol is delivered via either LDL or HDL to the liver for excretion into the bile. However, it has not been tested and approved in human atherosclerotic condition in vivo. The NIH/KOS-supported multi-center AIM-HIGH trial is designed to compare the clinical efficacy of LDL-lowering alone with statin versus LDL-lowering plus HDL-raising with statin plus nicotinic acid combination therapy in patients with established vascular disease and high triglycerides and low HDL. We propose to conduct a carotid MRI sub-study in 300 subjects enrolled in AIM-HIGH to investigate the important vascular biological mechanisms of HDL-raising therapy. The hypotheses and specific aims are: (1) To test the primary hypothesis that compared with LDL-lowering alone, intensive LDL-lowering plus HDL-raising therapy decreases the mean plaque lipid composition in carotid arteries assessed by MRI. (2) To test the hypothesis that compared with LDL-lowering alone, intensive LDL-lowering plus HDL-raising therapy decreases the plaque burden including volume and wall thickness. (3) To test the hypothesis that increased plaque lipid composition or vessel wall thickness by MRI is associated with increased risk of cardiovascular events. (4) To examine the association of clinical risk factors, lipids, lipoprotein heterogeneity, inflammatory markers and carotid plaque characteristics. This proposed MRI sub-study offers a unique opportunity to investigate the effectiveness of LDL-lowering plus HDL-raising therapy on human atherosclerotic plaque in vivo, to examine the association of plaque characteristics both lipid composition and volume assessed by MRI and cardiovascular outcome, and to gain novel insights in our understanding of atherosclerotic plaque pathology and the mechanisms of intensive lipid management in preventing cardiovascular events. Heart attacks and strokes caused by the unstable atherosclerotic plaques remain the leading cause of death in the United States. Unstable plaques often have more fat than stable plaques. The proposed study will investigate if a treatment with LDL-lowering plus HDL-raising compared with LDL-lowering alone would more effectively reduce the plaque fat content assessed by magnetic resonance imaging (MRI), therefore, further reducing heart attacks and strokes.