This is a revised application of continuation of R01HL63895 entitled CAROTID PLAQUE COMPOSITION BY MRI DURING LIPID-LOWERING, which is a randomized, double blind, and partial placebo controlled study. In this study, 123 patients with CAD or carotid disease and with apolipoprotein B greater to or equal to 120 mg/dl (LDL levels 100-190 mg/dl) were randomized to one of three treatment groups: (1) single therapy - atorvastatin alone, placebos for niaspan and colesevelam;(2) double therapy - atorvastatin plus niaspan (2 g/day), and placebo for colesevelam;(3) triple therapy - atorvastatin, niaspan plus colesevelam (3.8 g/day). The treatment target for LDL is less than or equal to 80 mg/dl for the single and double therapy and less than or equal to 60 mg/dl for the triple therapy. The HDL target for the two niacin-treated groups is to increase 10 mg/dl from baseline. The patient recruitment is completed, and patient clinical/laboratory follow-up is on-going. All patients are undergoing MRI examination of both carotid arteries annually for three years, a total of 4 examinations. This proposed research is the first study to examine plaque lipid depletion, volume reduction, enhancement decrease by contrast-enhanced MRI in vivo during intensive lipid modification among patients with carotid atherosclerosis. The hypotheses and specific aims of the original grant plus this proposed continuation are: (1) to test the hypothesis that intensive lipid-lowering therapy decreases carotid plaque lipid content assessed by contrast-enhanced MRI. (2) To test the secondary and exploratory hypotheses that intensive lipid therapy is associated with plaque regression and decreased plaque enhancement assessed by contrast-enhanced MRI. (3) To examine the association of clinical risk factors, lipids, lipoprotein heterogeneity, inflammatory markers, oxidative stress markers with carotid plaque characteristics. (4) To investigate the effects of HDL-raising and very intensive LDL-lowering, comparing to LDL-lowering alone, on carotid lipid content, volume, and enhancement over 3 years. (5) To determine if carotid plaque characteristics (lipid content, volume, and enhancement) or its change predicts future major cardiovascular events. The primary MRI endpoint is carotid plaque lipid content. The secondary endpoints are plaque volume, other tissue contents. The exploratory endpoint is plaque enhancement assessed by contrast- enhanced MRI. This study employs a state-of-the art technique to examine the effects of lipid-lowering therapy on human atherosclerotic plaque characteristics in vivo and will provide novel insights into our understanding of atherosclerotic plaque pathology and the mechanisms of intensive lipid modification in preventing ischemic events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063895-09
Application #
7878717
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Fleg, Jerome
Project Start
2000-02-01
Project End
2011-08-31
Budget Start
2010-07-01
Budget End
2011-08-31
Support Year
9
Fiscal Year
2010
Total Cost
$286,707
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Zhao, Xue-Qiao; Phan, Binh An P; Davis, Joseph et al. (2016) Mortality reduction in patients treated with long-term intensive lipid therapy: 25-year follow-up of the Familial Atherosclerosis Treatment Study-Observational Study. J Clin Lipidol 10:1091-7
Phan, Binh An P; Moore, Andrew B; Davis, Joseph et al. (2014) Prolonged combination lipid therapy is associated with reduced carotid intima-media thickness: a case-control study of the 20-year Familial Atherosclerosis Treatment - Observational Study (FATS-OS). J Clin Lipidol 8:489-93
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Zhao, Xue-Qiao; Dong, Li; Hatsukami, Tom et al. (2011) MR imaging of carotid plaque composition during lipid-lowering therapy a prospective assessment of effect and time course. JACC Cardiovasc Imaging 4:977-86
Dong, Li; Kerwin, Williams S; Chen, Huijun et al. (2011) Carotid artery atherosclerosis: effect of intensive lipid therapy on the vasa vasorum--evaluation by using dynamic contrast-enhanced MR imaging. Radiology 260:224-31
Zhao, Xue-Qiao; Brown, B Greg (2008) ApoA-I(Milano)/phospholipid complex: clinical implications of dose-response studies in rabbit atherosclerosis with intravascular ultrasound and magnetic resonance imaging. J Am Coll Cardiol 51:1110-1
Zhao, Xue-Qiao; Phan, Binh An P; Chu, Baocheng et al. (2007) Testing the hypothesis of atherosclerotic plaque lipid depletion during lipid therapy by magnetic resonance imaging: study design of Carotid Plaque Composition Study. Am Heart J 154:239-46