Carotid Plaque Characteristics by MRI in AIM-HIGH (Carotid MRI Substudy)

Although studies have suggested that plaque morphology and composition are important
determinants of plaque stability, 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/Abbott-funded 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 220 subjects enrolled in AIM-HIGH to
investigate the important vascular biological mechanisms of HDL-raising therapy. Image
collection will occur at 3 timepoints. 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 test a hypothesis that LDL-lowering plus HDL-raising, compared to LDL-lowering
alone, will promote more rapid plaque lipid depletion. And determine the time-course of
atherosclerotic plaque lipid depletion during lipid therapy.

- (5) To examine the association of clinical risk factors, lipids, lipoprotein
heterogeneity, inflammatory markers and carotid plaque characteristics.

This 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.

Inclusion Criteria:

- Eligible for main AIM-HIGH study (NCT00120289)

- Medically able to undergo MRI procedure

- Willing to provide informed consent for participation in this substudy

Exclusion Criteria:

- Uses pacemaker or has metallic implants

- History of bilateral carotid endarterectomy

- Glomerular filtration rate less than 60 mL/min/1.73 m^2