Objectives-The relationship between specific gene regulation and subsequent development and progression of atherosclerosis is incompletely understood. We hypothesized that genes in the vasculature related to cholesterol metabolism, inflammation, and insulin signaling pathways are differentially regulated in a site-specific and time-dependent manner. Methods and Results-Expression of 59 genes obtained from coronary, carotid, and thoracic aortic arteries were characterized from diabetic (DM)/hypercholesterolemic (HC) swine (nϭ52) 1, 3, and 6 months after induction. Lesion development in the 3 arterial beds was quantified and characterized at 1, 3, 6, and 9 months. Progressive lesion development was observed in the coronaryϾthoracic aortaϾ Ͼcarotid arteries. Genes involved in cholesterol metabolism and insulin pathways were upregulated in coronariesϾthoracic aortaeϾcarotids. Inflammatory genes were more markedly upregulated in coronary arteries than the other 2 arteries. Genes implicated in plaque instability (eg, matrix metalloproteinase-9, CCL2 and Lp-PLA 2 mRNAs) were only upregulated at 6 months in coronary arteries. Key Words: atherosclerosis Ⅲ diabetes Ⅲ hypercholesterolemia Ⅲ animal models Ⅲ mRNA A therosclerosis is a multi-factorial pathological process resulting from environmental and genetic influences involving multiple vascular territories. Patients with diabetes mellitus (DM) have an increased risk of developing accelerated cardiovascular disease which is potentiated by hypercholesterolemia (HC). 1 Although gene expression of atherosclerotic genes is associated with the presence of atherosclerosis, the sequence of specific gene regulation and the relationship to subsequent development of atherosclerosis is incompletely understood. Also unclear is whether development of atherosclerosis in separate vascular beds is associated with differential gene expression. Conclusions-VariableWe hypothesized that genes relating to vascular cholesterol metabolism, insulin pathways, and inflammatory responses are differentially regulated in a site-specific and time-dependent manner. We tested this hypothesis in the atherosclerotic DM/HC swine model which develops advanced coronary lesions within 6 months. 2 We chose genes that had previously (1) shown differential expression in stable and unstable human atherosclerotic plaques, (2) demonstrated involvement in the atherosclerotic process, and (3) had a pig ortholog. 3 MethodsDiabetes mellitus was induced in male pigs (nϭ52) weighing 25 to 30 kg by 125 mg/kg of intravenous streptozotocin (Sicor Pharmaceuticals). Exogenous insulin was administered to insure that glucose levels did not exceed 350 mg/dL. The animals were fed chow containing 0.5% to 2% cholesterol, 5% to 20% lard, and 1.5% sodium cholate (Animal Specialties) to achieve a cholesterol level of 250 to 1000 mg/dL. Animals were euthanized at 1, 3, 6, or 9 months after induction. The protocol followed institutional guidelines. Histological EvaluationPlease see supplemental methods, available online at http://atvb....

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Objective-To prospectively evaluate whether the development of fibroatheromas exhibiting features of potential instability can be detected and predicted by serial invasive imaging. Methods and Results-Multivessel intravascular ultrasound and near infrared spectroscopy (NIRS) were performed in diabetic/hypercholesterolemic pigs 3, 6, and 9 months after induction. Animals were euthanized at 9 months and histological/immunohistochemical evaluation of the arteries was performed (n=304 arterial segments). Intravascular ultrasound demonstrated, over time, a progressive increase in plaque + media and necrotic core areas and positive vascular remodeling. By histology, NIRS+ lesions were significantly more likely to be a high-risk fibroatheroma (P=0.0001) containing larger plaque (P<0.0001) and necrotic core areas (P<0.0019) and thinner fibrous caps (P=0.04). NIRS + fibroatheromas possessed a greater concentration of inflammatory cells demonstrating protease activity (P=0.006), and proliferating (P=0.016), and apoptotic cells (P=0.04) within the fibrous cap. Eighty-eight percent of NIRS+ lesions at 3 and 6 months subsequently developed into a fibroatheroma at 9 months (P<0.01). By multivariate analysis NIRS positivity at 6 months predicted the subsequent presence of a fibroatheroma at 9 months (P=0.005; odds ratio, 2.71). Conclusion-The