The overall goal of Project 2 is to use high-resolution magnetic resonance imaging (MRI) to study mechanisms that may be involved in the progression of carotid atherosclerosis from a sub-clinical lesion to a high-risk plaque. Specifically, we will examine the relationships between neovasculature in the diseased carotid artery, fibrous cap status, and plaque burden. Histological studies suggest that the high-risk plaque is characterized by thinning and rupture of the fibrous cap that ovedies the thrombogenic necrotic core, which in turn may lead to thrombotic occlusion of the vessel or embolization of material downstream. Furthermore, cap rupture with overlying mural thrombus formation may lead to an increase in overall plaque volume. Other studies suggest an important role for plaque neovasculature. Neovessels within plaque are believed to represent a pathway for macrophage infiltration, and these macrophages have been shown to express matrix metalloproteinases that can weaken the fibrous cap. With funding from the NIH, we have shown that MRI is capable of precisely measuring plaque volume, distinguish thick fibrous caps from thin and ruptured caps, and identify regions with plaque neovasculature. We plan to serially examine 275 subjects with early, subclinical carotid atherosclerosis with pre-and postcontrast enhanced MRI.
The specific aims of this study are to test three hypotheses regarding mechanisms of progression to a high-dsk]esion: 1. that fibrous cap thinning and rupture precedes increase in plaque burden; 2. that increased neovasculature in the diseased carotid artery, as identified by MRI, predicts a higher risk for progression in plaque burden; and 3. that plaques with increased neovasculature are more likely progress from a thick cap to a thin or ruptured cap lesion. A better understanding of the mechanisms leading to the development of the high-risk plaque may provide new targets for therapy. Furthermore, identification of additional high-risk plaque features, other than the degree of lumen stenosis, may lead to better selection of patients for intervention, such as carotid endarterectomy, and result in overall reduction in health care costs.
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