Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Thus, the role of dietary micronutrients in decreasing LDL oxidation assumes considerable significance. The most consistent data with respect to micronutrient antioxidants and atherosclerosis appears to relate to alpha-tocopherol (AT), the predominant lipid-soluble antioxidant in LDL. In addition to decreasing LDL oxidation, data support an effect of ET on critical cells in atherogenesis (monocytes, smooth muscle cells and endothelium) that are potentially anti-atherogenic. The primary aim of the present proposal is to test the effect of AT supplementation (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 coronary artery disease (stable angina pectoris or previous myocardial infarction). Subjects (n=120) recruited would have to be on the American Heart Association Phase II diet and a HMG CoA reductase inhibitor for at least one year and have an LDL cholesterol ,125 mg/dL on 2 visits at least 4 weeks part during the 10 month 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 enzymes, creatinine, complete blood count, lipid profile, antioxidant and fatty acid levels, LDL oxidation, plasma soluble CAMs (cell adhesion molecules) and monocyte activity. Also, an early morning urine sample will be obtained for F2-isoprostanes, a direct measure of lipid peroxidation. IMT will be determined at baseline, 1, 1.5 and 2 years. The mean change in IMT and rate of progression will be compared between the AT and placebo groups. Following isolation, the LDL will be subjected to copper catalyzed oxidation over a 5-hour period. From this will be obtained the lag phase and oxidation rate. Isolated monocytes will be activated with lipopolysaccharide and the following activities assayed: superoxide anion release, interleukin-1beta release and adhesion to human endothelium. F2 isoprostanes and VAM, ICAM, and E-& P-selectin will be quantitated by ELISA. AT levels and the parameters of LDL oxidation and monocyte activity will be correlated with changes in IMT. If this study show that high-dose AT supplementation is beneficial in retarding atherosclerosis this could emerge as an important adjunctive therapy in the management of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
5R01AT000005-02
Application #
6171377
Study Section
Special Emphasis Panel (ZAT1-SRC (99))
Program Officer
Wong, Shan S
Project Start
1999-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
2
Fiscal Year
2000
Total Cost
$181,935
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Devaraj, Sridevi; Leonard, Scott; Traber, Maret G et al. (2008) Gamma-tocopherol supplementation alone and in combination with alpha-tocopherol alters biomarkers of oxidative stress and inflammation in subjects with metabolic syndrome. Free Radic Biol Med 44:1203-8
Devaraj, Sridevi; Tang, Rong; Adams-Huet, Beverley et al. (2007) Effect of high-dose alpha-tocopherol supplementation on biomarkers of oxidative stress and inflammation and carotid atherosclerosis in patients with coronary artery disease. Am J Clin Nutr 86:1392-8
Singh, Uma; Otvos, James; Dasgupta, Amitava et al. (2007) High-dose alpha-tocopherol therapy does not affect HDL subfractions in patients with coronary artery disease on statin therapy. Clin Chem 53:525-8
Singh, U; Devaraj, S; Jialal, I (2005) Vitamin E, oxidative stress, and inflammation. Annu Rev Nutr 25:151-74
Stauffenberg, Michele T; Lange, Richard A; Hillis, L David et al. (2004) Hyperhomocysteinemia measured by immunoassay: a valid measure of coronary artery atherosclerosis. Arch Pathol Lab Med 128:1263-6
Singh, Uma; Jialal, Ishwarlal (2004) Anti-inflammatory effects of alpha-tocopherol. Ann N Y Acad Sci 1031:195-203
Venugopal, Senthil Kumar; Devaraj, Sridevi; Yang, Teddy et al. (2002) Alpha-tocopherol decreases superoxide anion release in human monocytes under hyperglycemic conditions via inhibition of protein kinase C-alpha. Diabetes 51:3049-54
Jialal, I; Devaraj, S; Kaul, N (2001) The effect of alpha-tocopherol on monocyte proatherogenic activity. J Nutr 131:389S-94S
Meira, L B; Devaraj, S; Kisby, G E et al. (2001) Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress. Cancer Res 61:5552-7
Devaraj, S; Hugou, I; Jialal, I (2001) Alpha-tocopherol decreases CD36 expression in human monocyte-derived macrophages. J Lipid Res 42:521-7

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