Imaging of Aortic Atherosclerosis and Inflammation in the Metabolic Syndrome

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Despite advances in both identification and risk reduction, atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Atherosclerosis primarily affects large and medium sized vessels with autopsy data demonstrating that the abdominal aorta offers a valuable early window for the study of atherosclerosis. Coronary heart disease (CHD) risk factors include age, male gender, family history of premature CHD, hypertension, smoking, diabetes, elevated LDL-C, and low HDL-C. The Metabolic Syndrome [obesity, insulin resistance, hypertension, impaired glucose tolerance, hyperinsulinemia, and dyslipidemia), highly prevalent in the United States and implicated in CHD and inflammation, is increasingly accepted as a major contributor to the pathogenesis both of atherosclerosis and of insulin resistance. Non-invasive vascular imaging techniques, including cardiovascular magnetic resonance (CMR) and multidetector computed tomography (MDCT) offer the opportunity to identify, quantify, and characterize atherosclerosis. CMR and MDCT are complementary in providing information about plaque volume and characterization, with increased sensitivity of CMR for providing information regarding plaque components, including inflammation in a non-ionizing radiation environment and in the absence of iodinated contrast. Contrast-enhanced CMR (CE-CMR) is a new CMR application that has been shown to be useful for the evaluation of aortic plaque for fibrosis and for identification of focal inflammation in the fibrous cap. A Specialized Center of Clinically Oriented Research (SCCOR) program in Vascular Injury, Repair, and Remodeling with the central theme "Metabolic Syndrome, Inflammation and Vascular Remodeling" was recently funded by the NHLBI at our insitution. This parent SCCOR will randomize 720 subjects with CHD and Metabolic Syndrome to 30 months of 1) usual care 2) novel anti-inflammatory salsalates or 3) intensive lifestyle modification with monitoring inflammatory markers and baseline/30 month coronary MDCT to monitor atherosclerosis. This parent SCCOR offers the timely and cost-effective opportunity to expand our knowledge regarding the atherosclerotic process including the impact of these novel therapies on focal plaque inflammation by applying advanced CMR methods to characterize aortic atherosclerosis and inflammation in the Metabolic Syndrome, its relationship to biochemical inflammatory markers, and the response of the plaque and plaque components (including inflammation) to usual and novel treatment. We will also have the opportunity to compare these findings with coronary MDCT measures of soft and calcified plaque. We propose to recruit a subset of 420 subjects (n=140 in each treatment group) of the 720 parent SCCOR subjects with Metabolic Syndrome. The primary and secondary aims include relating quantitative CMR measures of aortic plaque volume, plaque components, vessel wall area, vessel inflammation with MDCT plaque measures and systemic biochemical measures of systemic inflammation and to characterize the response of these CMR measures to 30 months of conventional and novel antiinflammatory therapies with correlation with changes in systemic biochemical measures of inflammation. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page Principal Investigator/Program Director (Last, First, Middle): Manning, Warren J. Despite advances in both identification and risk reduction, atherosclerotic cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in the United States. Atherosclerosis primarily affects large and medium sized vessels with autopsy data demonstrating that the abdominal aorta offers a valuable early window for the study of atherosclerosis. Non-invasive vascular imaging techniques, including cardiovascular magnetic resonance (CMR) and multidetector computed tomography (MDCT) offer the opportunity to identify, quantify, and characterize atherosclerosis. A Specialized Center of Clinically Oriented Research (SCCOR) program in Vascular Injury, Repair, and Remodeling with the central theme "Metabolic Syndrome, Inflammation and Vascular Remodeling" was recently funded by the NHLBI at our insitution. This parent SCCOR will randomize 720 subjects with CHD and Metabolic Syndrome to 30 months of 1) usual care 2) novel anti-inflammatory salsalates or 3) intensive lifestyle modification with monitoring inflammatory markers and baseline/30 month coronary MDCT to monitor atherosclerosis. In this study, the primary and secondary aims include relating CMR measures of aortic plaque volume, vessel wall area, vessel inflammation with MDCT plaque measures and measures of biochemical markers of systemic inflammation and to characterize the response of these CMR measures to 30 months of conventional and novel antiinflammatory therapies with correlation with systemic biochemical markers of inflammation.