Experimental evidence is emerging implicating cellular and inflammatory processes in the development and characteristics of atherosclerotic plaque and the clinical course of cardiovascular disease. We propose to examine an informative subset of the bi-ethnic Atherosclerosis Risk in Communities (ARIC) cohort to identify cellular, metabolic and genomic correlates of atherosclerotic plaque characteristics and of early changes in the vascular wall. The longitudinal follow-up and stored DNA in ARIC will allow us to test the ability of the genomic correlates of plaque characteristics to predict incident coronary heart disease and stroke. One thousand two hundred individuals with high (>85th percentile) carotid artery wall thickness documented by B-mode ultrasound and 800 individuals sampled from the remainder of the carotid artery wall thickness distribution (<85th percentile) will receive a contrast-enhanced carotid MRI examination. Standardized MRI measures will include carotid artery wall thickness, T2 signal intensity changes and percent contrast enhancement indicative of endothelial dysfunction, and for those with plaque, fibrous cap thickness, lipid core volume, and calcification. Novel cellular, metabolic and genomic measures will be collected and will be related to MRI-measurable plaque characteristics. In particular, flow cytometry will be used to measure monocyte and platelet presentation of cytokines, growth factors and adhesion molecules, and cell-cell aggregation. High throughput genotyping methods will be used to measure 5 to 7 polymorphic sites in each of 150 positional, expressional and biologic candidate genes, permitting multilocus and haplotype genomic analyses. The depth and breadth of existing risk factor and lifestyle data, extensive follow-up since 1986-89, and accumulation of clinical outcomes, including coronary heart disease, stroke and arteriolosclerosis, contribute additional strengths to the laboratory and MRI investigations. Inferences will be made both cross-sectionally and longitudinally, with a special emphasis on genotype x environment interaction. The ARIC cohort is in an ideal age range for the proposed research because of the frequent and documented occurrence of plaque and the spectrum of clinically relevant stages from plaque initiation to mature fibrosis, calcification and even erosion and near-rupture. The significance of the proposed research is its potential to identify correlates of, and therefore potential mechanisms affecting, carotid artery endothelium and plaque characteristics, which in turn will lead to a better understanding of the etiology of the vulnerable plaque and the conversion of the stable to the vulnerable plaque.
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