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June 21, 1995, Vol 273, No. 23 >
ARTICLE | June 21, 1995

Serial Coronary Angiographic Evidence That Antioxidant Vitamin Intake Reduces Progression of Coronary Artery Atherosclerosis FREE

Howard N. Hodis, MD; Wendy J. Mack, PhD; Laurie LaBree, MS; Linda Cashin-Hemphill, MD; Alex Sevanian, PhD; Ruth Johnson, RD, MA; Stanley P. Azen, PhD
[+] Author Affiliations

Reprint requests to Atherosclerosis Research Unit, Division of Cardiology, University of Southern California School of Medicine, 2250 Alcazar St, CSC 132, Los Angeles, CA 90033 (Dr Hodis).


JAMA. 1995;273(23):1849-1854. doi:10.1001/jama.1995.03520470057032
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Article
References

Objective.  —To explore the association of supplementary and dietary vitamin E and C intake with the progression of coronary artery disease.

Design.  —A subgroup analysis of the on-trial antioxidant vitamin intake database acquired in the Cholesterol Lowering Atherosclerosis Study, a randomized, placebo-controlled, serial angiographic clinical trial evaluating the risk and benefit of colestipol-niacin on coronary artery disease progression.

Setting.  —Community- and university-based cardiac catheterization laboratories.

Subjects.  —A total of 156 men aged 40 to 59 years with previous coronary artery bypass graft surgery.

Intervention.  —Supplementary and dietary vitamin E and C intake (nonrandomized) in association with cholesterol-lowering diet and either colestipol-niacin or placebo (randomized).

Outcome.  —Change per subject in the percentage of vessel diameter obstructed because of stenosis (%S) determined by quantitative coronary angiography after 2 years of randomized therapy on all lesions, mild/moderate lesions (<50%S), and severe lesions (≥50%S).

Results.  —Overall, subjects with supplementary vitamin E intake of 100 IU per day or greater demonstrated less coronary artery lesion progression than did subjects with supplementary vitamin E intake less than 100 IU per day for all lesions (P=.04) and for mild/moderate lesions (P=.01). Within the drug group, benefit of supplementary vitamin E intake was found for all lesions (P=.02) and mild/moderate lesions (P=.01). Within the placebo group, benefit of supplementary vitamin E intake was not found. No benefit was found for use of supplementary vitamin C exclusively or in conjunction with supplementary vitamin E, use of multivitamins, or increased dietary intake of vitamin E or vitamin C.

Conclusions.  —These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.(JAMA. 1995;273:1849-1854)

REFERENCES

1 +
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med . 1989;;320:915-924.
2 +
Parthasarathy S, Young SF, Witztum JL, Pittman RC, Steinberg D.  Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest . 1986;;77:641-644.
3 +
Morel DW, Di Corleto PE, Chisolm GM.  Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis . 1984;;4:357-364.
4 +
Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D.  Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A . 1984;;81:3883-3887.
5 +
Kita T, Nagano Y, Yokode M, et al.  Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Nati Acad Sci U S A . 1987;;84:5928-5931.
6 +
Bjorkhem I, Henriksson-Freyschuss A, Breuer O, Diczfalusy U, Berglund L, Henriksson P.  The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler Thromb . 1991;;11:15-22.
7 +
Hodis HN, Chauhan A, Hashimoto S, Crawford DW, Sevanian A.  Probucol reduces plasma and aortic wall oxysterol levels in cholesterol-fed rabbits independently of its plasma cholesterol lowering effect. Atherosclerosis . 1992;;96:125-134.
8 +
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC.  Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med . 1993;;328:1450-1456.
9 +
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC.  Vitamin E consumption and the risk of coronary disease in women. N Engl J Med . 1993;;328:1444-1449.
10 +
Gey KF, Puska P, Jordan P, Moser UK.  Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr . 1991;;53:326S-334S.
11 +
Riemersma RA, Wood DA, Maclntyre CCA, Elton RA, Gey KF, Oliver MF.  Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet . 1991;;337:1-5.
12 +
Enstrom JE, Kanim LE, Klein MA.  Vitamin C intake and mortality among a sample of the United States population. Epidemiology . 1992;;3:194-202.
13 +
Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L.  Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA . 1987;;257:3233-3240.
14 +
Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH.  The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results. Control Clin Trials . 1987;;8:354-387.
15 +
Blankenhorn DH, Johnson RL, Mack WJ, el Zain HA, Vailas LI.  The influence of diet on the appearance of new lesions in human coronary arteries. JAMA . 1990;;263:1646-1652.
16 +
Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH.  Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up. JAMA . 1990;;264:3013-3017.
17 +
Blankenhorn DH, Selzer RH, Mack WJ, et al.  Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures: a comparison of different measures of treatment effect. Circulation . 1992;;86:1701-1709.
18 +
Selzer RH, Hagerty C, Azen SP, et al, and the CLAS Investigators and Staff.  Precision and reproducibility of quantitative coronary angiography with applications to controlled clinical trials: a sampling study. J Clin Invest . 1989;;83:520-526.
19 +
Johnson RL, Selzer R, Blankenhorn DH, et al.  Nutrient Analysis System: a computerized seven-day food record system. J Am Diet Assoc . 1983;; 83:667-671.
20 +
Cashin-Hemphill L, Mack W, LaBree L, et al.  Coronary progression predicts future cardiac events. Circulation . 1993;;88( (suppl) ):I363.
21 +
 Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA . 1993;;269:3015-3023.
22 +
McDowell MA, Briefel RR, Alaimo K, et al. Energy and micronutrient intakes of persons ages two months and older in the United States: third National Health and Nutrition Examination Survey, phase 1,1988-91 . Advance data from vital and health statistics; No. 255. Hyattsville, Md: National Center for Health Statistics; 1994;.
23 +
Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, Esterbauer H.  Effect of oral supplementation with d-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J Lipid Res . 1991;;32:1325-1332.
24 +
Princen HMG, Duyvenvoorde W, Butenhek R, et al.  Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women. Arterioscler Thromb Vascular Biol . 1995;; 15:325-333.
25 +
Jialal I, Grundy SM.  Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res . 1992;;33:899-906.
26 +
Reaven PD, Witztum JL.  Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans: effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscl Thromb . 1993;;13:601-608.
27 +
Rengström J, Nilsson J, Tornvall P, Landou C, Hamsten A.  Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet . 1992;;339:1183-1186.
28 +
Verlangieri AJ, Bush MK.  Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr . 1992;;11:131-138.
29 +
Williams RJ, Motteram JM, Sharp CH, Gallagher PJ.  Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis . 1992;;94:153-159.
30 +
Janero DR.  Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Radic Biol Med . 1991;;11:129-144.
31 +
Carpenter KLH, Taylor SE, Ballantine JA, Fussell B, Halliwell B, Mitchinson MJ.  Lipids and oxidised lipids in human atheroma and normal aorta. Biochim Biophys Acta . 1993;;1167:121-130.
32 +
Buchwald H, Matts JP, Fitch LL, et al, for the Surgical Control of the Hyperlipidemias (POSCH) Group.  Changes in sequential coronary arteriograms and subsequent coronary events. JAMA . 1992;;268: 1429-1433.
33 +
Waters D, Craven TE, Lesperance J.  Prognostic significance of progression of coronary atherosclerosis. Circulation . 1993;;87:1067-1075.

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1 +
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL.  Beyond cholesterol: modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med . 1989;;320:915-924.
2 +
Parthasarathy S, Young SF, Witztum JL, Pittman RC, Steinberg D.  Probucol inhibits oxidative modification of low density lipoprotein. J Clin Invest . 1986;;77:641-644.
3 +
Morel DW, Di Corleto PE, Chisolm GM.  Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis . 1984;;4:357-364.
4 +
Steinbrecher UP, Parthasarathy S, Leake DS, Witztum JL, Steinberg D.  Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proc Natl Acad Sci U S A . 1984;;81:3883-3887.
5 +
Kita T, Nagano Y, Yokode M, et al.  Probucol prevents the progression of atherosclerosis in Watanabe heritable hyperlipidemic rabbit, an animal model for familial hypercholesterolemia. Proc Nati Acad Sci U S A . 1987;;84:5928-5931.
6 +
Bjorkhem I, Henriksson-Freyschuss A, Breuer O, Diczfalusy U, Berglund L, Henriksson P.  The antioxidant butylated hydroxytoluene protects against atherosclerosis. Arterioscler Thromb . 1991;;11:15-22.
7 +
Hodis HN, Chauhan A, Hashimoto S, Crawford DW, Sevanian A.  Probucol reduces plasma and aortic wall oxysterol levels in cholesterol-fed rabbits independently of its plasma cholesterol lowering effect. Atherosclerosis . 1992;;96:125-134.
8 +
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC.  Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med . 1993;;328:1450-1456.
9 +
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC.  Vitamin E consumption and the risk of coronary disease in women. N Engl J Med . 1993;;328:1444-1449.
10 +
Gey KF, Puska P, Jordan P, Moser UK.  Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am J Clin Nutr . 1991;;53:326S-334S.
11 +
Riemersma RA, Wood DA, Maclntyre CCA, Elton RA, Gey KF, Oliver MF.  Risk of angina pectoris and plasma concentrations of vitamins A, C, and E and carotene. Lancet . 1991;;337:1-5.
12 +
Enstrom JE, Kanim LE, Klein MA.  Vitamin C intake and mortality among a sample of the United States population. Epidemiology . 1992;;3:194-202.
13 +
Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L.  Beneficial effects of combined colestipol-niacin therapy on coronary atherosclerosis and coronary venous bypass grafts. JAMA . 1987;;257:3233-3240.
14 +
Blankenhorn DH, Johnson RL, Nessim SA, Azen SP, Sanmarco ME, Selzer RH.  The Cholesterol Lowering Atherosclerosis Study (CLAS): design, methods, and baseline results. Control Clin Trials . 1987;;8:354-387.
15 +
Blankenhorn DH, Johnson RL, Mack WJ, el Zain HA, Vailas LI.  The influence of diet on the appearance of new lesions in human coronary arteries. JAMA . 1990;;263:1646-1652.
16 +
Cashin-Hemphill L, Mack WJ, Pogoda JM, Sanmarco ME, Azen SP, Blankenhorn DH.  Beneficial effects of colestipol-niacin on coronary atherosclerosis: a 4-year follow-up. JAMA . 1990;;264:3013-3017.
17 +
Blankenhorn DH, Selzer RH, Mack WJ, et al.  Evaluation of colestipol/niacin therapy with computer-derived coronary end point measures: a comparison of different measures of treatment effect. Circulation . 1992;;86:1701-1709.
18 +
Selzer RH, Hagerty C, Azen SP, et al, and the CLAS Investigators and Staff.  Precision and reproducibility of quantitative coronary angiography with applications to controlled clinical trials: a sampling study. J Clin Invest . 1989;;83:520-526.
19 +
Johnson RL, Selzer R, Blankenhorn DH, et al.  Nutrient Analysis System: a computerized seven-day food record system. J Am Diet Assoc . 1983;; 83:667-671.
20 +
Cashin-Hemphill L, Mack W, LaBree L, et al.  Coronary progression predicts future cardiac events. Circulation . 1993;;88( (suppl) ):I363.
21 +
 Summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA . 1993;;269:3015-3023.
22 +
McDowell MA, Briefel RR, Alaimo K, et al. Energy and micronutrient intakes of persons ages two months and older in the United States: third National Health and Nutrition Examination Survey, phase 1,1988-91 . Advance data from vital and health statistics; No. 255. Hyattsville, Md: National Center for Health Statistics; 1994;.
23 +
Dieber-Rotheneder M, Puhl H, Waeg G, Striegl G, Esterbauer H.  Effect of oral supplementation with d-alpha-tocopherol on the vitamin E content of human low density lipoproteins and resistance to oxidation. J Lipid Res . 1991;;32:1325-1332.
24 +
Princen HMG, Duyvenvoorde W, Butenhek R, et al.  Supplementation with low doses of vitamin E protects LDL from lipid peroxidation in men and women. Arterioscler Thromb Vascular Biol . 1995;; 15:325-333.
25 +
Jialal I, Grundy SM.  Effect of dietary supplementation with alpha-tocopherol on the oxidative modification of low density lipoprotein. J Lipid Res . 1992;;33:899-906.
26 +
Reaven PD, Witztum JL.  Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans: effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscl Thromb . 1993;;13:601-608.
27 +
Rengström J, Nilsson J, Tornvall P, Landou C, Hamsten A.  Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man. Lancet . 1992;;339:1183-1186.
28 +
Verlangieri AJ, Bush MK.  Effects of d-alpha-tocopherol supplementation on experimentally induced primate atherosclerosis. J Am Coll Nutr . 1992;;11:131-138.
29 +
Williams RJ, Motteram JM, Sharp CH, Gallagher PJ.  Dietary vitamin E and the attenuation of early lesion development in modified Watanabe rabbits. Atherosclerosis . 1992;;94:153-159.
30 +
Janero DR.  Therapeutic potential of vitamin E in the pathogenesis of spontaneous atherosclerosis. Free Radic Biol Med . 1991;;11:129-144.
31 +
Carpenter KLH, Taylor SE, Ballantine JA, Fussell B, Halliwell B, Mitchinson MJ.  Lipids and oxidised lipids in human atheroma and normal aorta. Biochim Biophys Acta . 1993;;1167:121-130.
32 +
Buchwald H, Matts JP, Fitch LL, et al, for the Surgical Control of the Hyperlipidemias (POSCH) Group.  Changes in sequential coronary arteriograms and subsequent coronary events. JAMA . 1992;;268: 1429-1433.
33 +
Waters D, Craven TE, Lesperance J.  Prognostic significance of progression of coronary atherosclerosis. Circulation . 1993;;87:1067-1075.

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