The hypothesis of lipid depletion for plaque and clinical stability has been established based on observations from animal studies, the relation between human coronary plaque features and unstable clinical episodes, and angiographic regression and clinical event reduction with lipid-lowering therapy. However, the effect of lipid-lowering therapy on human atherosclerotic plaque composition in vivo has not been possible, to date. Magnetic resonance imaging (MRI) is ideal for longitudinal studies of atherosclerotic arteries because it is noninvasive and is superior to other imaging modalities in discriminating tissue contrast. Encouraging results from our pilot study show that prolonged intensive lipid-lowering therapy appears to be associated with a decreased lipid composition in the plaque, which is considered to predict greater plaque stability. We propose to perform carotid MRI studies in 60 CAD patients with a family history of cardiovascular disease and ApoB equal to or greater than 125 mg/dl. These patients will be randomized to triple lipid-lowering therapy (atorvastatin 10-40 mg/day, niacin 2-3 gm/day, and colestipol 20 gm/day) or to mono-statin therapy (atorvastatin 20-80 mg/day), and will undergo MRI examination of both carotid arteries annually for three years, a total of 4 examinations. We will: 1) test the hypothesis that intensive lipid-lowering therapy depletes plaque lipid composition identified by MRI in carotid arteries in CAD patients and examine the relationship between depletion of plaque lipid and other plaque components and plaque regression; 2) determine the time- course of atherosclerotic plaque lipid depletion during lipid- lowering by assessing serial carotid MRI examinations; 3) continue the development of this noninvasive approach to characterize human carotid atherosclerotic plaque composition in vivo by MRI. This study employs a state-of-the art technique to assess both the magnitude and mechanisms of benefit of lipid- lowering. It will be one of the first studies to examine the effects of lipid-lowering therapy on human atherosclerotic plaques in vivo and will provide novel insights into our understanding of atherosclerotic plaque pathology and the mechanisms of lipid-lowering therapy preventing ischemic events.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063895-04
Application #
6629049
Study Section
Special Emphasis Panel (ZRG1-DMG (04))
Program Officer
Wassef, Momtaz K
Project Start
2000-02-01
Project End
2005-01-31
Budget Start
2003-02-01
Budget End
2005-01-31
Support Year
4
Fiscal Year
2003
Total Cost
$233,200
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
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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
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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