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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Cardiovascular and Sleep Epidemiology (CASE)
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Fleg, Jerome
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Hippe, Daniel S; Phan, Binh An P; Sun, Jie et al. (2018) Lp(a) (Lipoprotein(a)) Levels Predict Progression of Carotid Atherosclerosis in Subjects With Atherosclerotic Cardiovascular Disease on Intensive Lipid Therapy: An Analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/ Arterioscler Thromb Vasc Biol 38:673-678
Sun, Jie; Zhao, Xue-Qiao; Balu, Niranjan et al. (2017) Carotid Plaque Lipid Content and Fibrous Cap Status Predict Systemic CV Outcomes: The MRI Substudy in AIM-HIGH. JACC Cardiovasc Imaging 10:241-249
O'Brien, Kevin D; Hippe, Daniel S; Chen, Huijun et al. (2016) Longer duration of statin therapy is associated with decreased carotid plaque vascularity by magnetic resonance imaging. Atherosclerosis 245:74-81
Sun, Jie; Zhao, Xue-Qiao; Balu, Niranjan et al. (2015) Carotid magnetic resonance imaging for monitoring atherosclerotic plaque progression: a multicenter reproducibility study. Int J Cardiovasc Imaging 31:95-103
Chen, Huijun; Sun, Jie; Kerwin, William S et al. (2014) Scan-rescan reproducibility of quantitative assessment of inflammatory carotid atherosclerotic plaque using dynamic contrast-enhanced 3T CMR in a multi-center study. J Cardiovasc Magn Reson 16:51
Zhao, Xue-Qiao; Hatsukami, Thomas S; Hippe, Daniel S et al. (2014) Clinical factors associated with high-risk carotid plaque features as assessed by magnetic resonance imaging in patients with established vascular disease (from the AIM-HIGH Study). Am J Cardiol 114:1412-9
Zhao, Xue-Qiao; Kerwin, William S (2012) Utilizing imaging tools in lipidology: examining the potential of MRI for monitoring cholesterol therapy. Clin Lipidol 7:329-343
Qiao, Y; Etesami, M; Malhotra, S et al. (2011) Identification of intraplaque hemorrhage on MR angiography images: a comparison of contrast-enhanced mask and time-of-flight techniques. AJNR Am J Neuroradiol 32:454-9
Balu, Niranjan; Yarnykh, Vasily L; Chu, Baocheng et al. (2011) Carotid plaque assessment using fast 3D isotropic resolution black-blood MRI. Magn Reson Med 65:627-37
Kosior, Robert K; Hill, Michael D; Frayne, Richard (2010) Less could be more when it comes to diffusion imaging of acute stroke. Neurology 74:1936-7

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