Episodes of instability caused by plaque disruption often punctuate the course of coronary atherosclerosis. Pathological studies have identified critical features of lesions vulnerable to rupture (thin fibrous cap, large lipid pool, prominent inflammatory component) but routine clinical testing including diagnostic angiography fails to identify structural features of vulnerable plaques.
Specific Aim 1 aims to develop and validate in rabbits with experimental atherosclerosis high resolution magnetic resonance imaging to identify systematically the features of vulnerable plaques and to follow changes and possible improvements in these features with cholesterol lowering. In addition, we will test the hypothesis that lipid lowering improves overexpression of matrix degrading proteinases in the rabbit atheroma, enzymes which accumulate at locations of the human atherosclerotic lesions prone to rupture.
In Specific Aim 2 intravascular ultrasound will be used in patients undergoing cardiac catheterization to examine systematically a) the relationship between intimal growth, compensatory enlargement and lumen size in atherosclerotic lesions and, b) differences in distensibility between normal and diseased coronary segments. Such disparities in distensibility may alter the stress-stain balances within an atherosclerotic lesion, shifting stresses to regions predisposed to rupture. Once again, cholesterol lowering therapy will be used in serial studies to learn which features of the vulnerable plaque improve and need to be monitored when treating patients. These studies may also disclose hitherto unexplored mechanisms whereby cholesterol lowering can promote plaque stability. These studies provide novel approaches to detection of vulnerable atherosclerotic lesions in patients. This much needed information cannot be obtained with conventional angiography or with other current clinical means of testing. This work should provide new mechanistic insights and promote development of therapeutic strategies for further protection from plaque rupture, thrombosis and fatal coronary events.
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