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Grant Abstract

Grant Number: 3R01AT000005-06S1
PI Name: Ishwarlal Jialal
Project Title: High Dose Alpha Tocopherol and Carotid Atherosclerosis

Abstract: DESCRIPTION (provided by applicant): Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Both oxidative stress and inflammation appear to be crucial in atherogenesis. The most consistent data with respect to micronutrient antioxidants and atherosclerosis appears to relate to alpha tocopherol (AT). Studies to date have shown that AT supplementation results in both an antioxidant and anti-inflammatory effect, especially at higher doses (>-800 IU/day). The aim of the present study (RO1AT00005) is to test the effect of supplementation with 1200 IU/day of RRR-AT in a placebo-controlled, randomized double blind trial over 2 years on the progression of carotid atherosclerosis in patients with stable coronary artery disease (angina pectoris or previous myocardial infarction). Subjects (n = 120), as determined by our power calculations, will have to be on the AHA Phase II diet and have an LDL cholesterol <125 mg/dL on diet alone or diet and hypolipidemic drug therapy on at least 2 visits at least 4 weeks apart during the lead in phase. Intimal-medial thickness (IMT) of both carotids, including the common carotid, the bulb and the proximal internal carotid will be determined by high-resolution B-mode sonography. At six month intervals blood samples will be obtained for liver function, creatinine, complete blood count, lipid profile, antioxidants and fatty acid levels, LDL oxidation, plasma soluble cell adhesion molecules (CAMs), C-reactive protein (CRP) and monocyte activity. Also, a 24-hour urine sample will be obtained for F2 -isoprostanes, a measure of in-vivo oxidative stress. IMT will be determined at baseline, 1, 1.5 and 2 years. The mean change in IMT and the rate of progression will be compared between the AT and placebo groups. Isolated LDL will be subjected to copper catalyzed oxidation and the kinetics studied. Isolated monocytes will be activated with lipopolysaccharide and the following activities assayed: superoxide anion release, interleukin-1 beta, TNF-alpha and interleukin-6 release and adhesion to human endothelium. Soluble CAMs will be quantitated by ELISA and CRP will be assayed by a high sensitive assay. AT levels and the parameters of oxidative stress and inflammation will be correlated with changes in IMT. This study has the additional novelty of correlating biomarkers of oxidative stress and inflammation with a cardiovascular endpoint and will establish whether high dose AT decreases atherosclerosis progression.

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