Current Atherosclerosis Reports

, Volume 5, Issue 2, pp 83–87

Clinical trials of vitamin E in coronary artery disease: Is it time to reconsider the low-density lipoprotein oxidation hypothesis?

  • Jay W. Heinecke
Invited Commentary

Abstract

A wide range of structurally unrelated antioxidants inhibit atherosclerosis in animal models of hypercholesterolemia, implicating oxidation of low-density lipoprotein (LDL) in the pathogenesis of atherosclerosis. However, most prospective, randomized trials of one proposed antioxidant, vitamin E, have failed to demonstrate any reduction in cardiovascular events in humans with established coronary artery disease. Recent clinical studies suggest that vitamin E is also ineffectual in the primary prevention of atherosclerosis. These observations have led many to question the relevance of LDL oxidation to the pathogenesis of human cardiovascular disease. However, vitamin E’s ineffectiveness in clinical trials might result from its failure to act as a physiologically relevant antioxidant. Indeed, vitamin E does not consistently inhibit atherosclerosis in hypercholesterolemic animals, and there is remarkably little evidence that clinically relevant doses of vitamin E result in inhibition of lipid peroxidation in vivo. Collectively, these observations indicate that there is little rationale for using vitamin E to prevent coronary artery disease in humans. They also strongly suggest that it will be critically important to establish that compounds with antioxidant activity in vitro actually prevent oxidative reactions in vivo before embarking on any new clinical trials.

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References and Recommended Reading

  1. 1.
    Brown MS, Goldstein JL: Koch’s postulates for cholesterol. Cell 1992, 71: 187–189.PubMedCrossRefGoogle Scholar
  2. 2.
    Goldstein JL, Ho YK, Basu SK, Brown MS: Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition. Proc Natl Acad Sci U S A 1979, 76: 333–336.PubMedCrossRefGoogle Scholar
  3. 3.
    Fogelman AM, Shechter I, Seager J, et al.: Malondialdehyde alteration of low density lipoproteins leads to cholesteryl ester accumulation in human monocyte-macrophages. Proc Natl Acad Sci U S A 1980, 77: 2214–2217.PubMedCrossRefGoogle Scholar
  4. 4.
    Henriksen T, Mahoney EM, Steinberg D: Enhanced macrophage degradation of low density lipoprotein previously incubated with cultured endothelial cells: recognition by receptors for acetylated low density lipoproteins. Proc Natl Acad Sci U S A 1981, 78: 6499–6507.PubMedCrossRefGoogle Scholar
  5. 5.
    Heinecke JW, Rosen H, Chait A: Iron and copper promote modification of low density lipoprotein by human arterial smooth muscle cells in culture. J Clin Invest 1984, 74: 1890–1893.PubMedGoogle Scholar
  6. 6.
    Morel DW, DiCorleto PE, Chisolm GM: Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation. Arteriosclerosis 1984, 4: 357–363.PubMedGoogle Scholar
  7. 7.
    Steinbrecher UP, Parthasarathy S, Leake DS, et al.: 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: 3883–3886.PubMedCrossRefGoogle Scholar
  8. 8.
    Witztum JL, Steinberg D: Role of oxidized low density lipoprotein in atherogenesis. J Clin Invest 1991, 88: 1785–1791.PubMedGoogle Scholar
  9. 9.
    Diaz MN, Frei B, Vita JA, Keaney JF: Antioxidants and atherosclerotic heart disease. N Engl J Med 1997, 337: 408–413.PubMedCrossRefGoogle Scholar
  10. 10.
    Heinecke JW: Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidized low density lipoprotein hypothesis. Atherosclerosis 1998, 141: 1–15.PubMedCrossRefGoogle Scholar
  11. 11.
    Carew TE, Schwenke DC, Steinberg D: Antiatherogenic effect of probucol unrelated to its hypercholesterolemic effect: evidence that antioxidants in vivo can selectively inhibit low density lipoprotein degradation in macrophage-rich fatty streaks and slow the progression of atherosclerosis in the Watanabe Heritable hyperlipidemic rabbit. Proc Natl Acad Sci U S A 1987, 84: 7725–7729.PubMedCrossRefGoogle Scholar
  12. 12.
    Sparrow CP, Deobber TW, Olszewski J, et al.: Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N-diphenyl-phenylenediamine. J Clin Invest 1992, 89: 1885–1893.PubMedGoogle Scholar
  13. 13.
    Kleinveld HA, Demacker PN, Stalenhoef AF: Comparative study on the effect of low-dose vitamin E and probucol on the susceptibility of LDL to oxidation and the progression of atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits. Arterioscler Thromb 1994, 14: 1386–1364.PubMedGoogle Scholar
  14. 14.
    Lynch SM, Frei B: Antioxidants as anti-atherogens: animal studies. In Natural Antioxidants in Human Health and Disease. Edited by Frei, B. Orlando FL: Academic Press; 1994.Google Scholar
  15. 15.
    Shaish A, Daugherty A, O’Sullivan F, et al.: Beta-carotene inhibits atherosclerosis in hypercholesterolemic rabbits. J Clin Invest 1995, 96: 2075.PubMedGoogle Scholar
  16. 16.
    Kleinveld HA, Hak-Lemmers HL, Hectors MP, et al.: Vitamin E and fatty acid intervention does not attenuate the progression of atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits. Arterioscler Thromb Vasc Biol 1995, 15: 290.PubMedGoogle Scholar
  17. 17.
    Thomas SR, Leichtweis SB, Pettersson K, et al.: Dietary cosupplementation with vitamin e and coenzyme q(10) inhibits atherosclerosis in apolipoprotein e gene knockout mice. Arterioscler Thromb Vasc Biol 2001, 21: 585–593.PubMedGoogle Scholar
  18. 18.
    Pratico D, Tangirala RK, Rader DJ, et al.: Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nature Med 1998, 4: 1189–1192.PubMedCrossRefGoogle Scholar
  19. 19.
    Morrow JD, Roberts LJ: The isoprostanes: current knowledge and directions for future research. Biochem Pharm 1996, 51: 1–12.PubMedCrossRefGoogle Scholar
  20. 20.
    Patrono C, FitzGerald GA: Isoprostanes: potential markers of oxidant stress in atherothrombotic disease. Arterioscler Thromb Vasc Biol 1997, 17: 2309–2317.PubMedGoogle Scholar
  21. 21.
    Terasawa Y, Ladha Z, Leonard SW, et al.: Increased atherosclerosis in hyperlipidemic mice deficient in alpha-tocopherol transfer protein and vitamin E. Proc Natl Acad Sci U S A 2000, 97: 13830–13834.PubMedCrossRefGoogle Scholar
  22. 22.
    Baynes JW: Role of oxidative stress in development of complications in diabetes. Diabetes 1991, 40: 405–412.PubMedCrossRefGoogle Scholar
  23. 23.
    Stadtman ER: Protein oxidation and aging. Science 1992, 257: 1220–1224.PubMedCrossRefGoogle Scholar
  24. 24.
    Burton GW, Ingold KU: Vitamin E as an in vitro and in vivo antioxidant. Ann N Y Acad Sci 1989, 570: 7–22.PubMedCrossRefGoogle Scholar
  25. 25.
    Bowry VW, Ingold KU, Stocker R: Vitamin E in human low density lipoprotein. When and how this antioxidant becomes a pro-oxidant. Biochem J 1992, 288(Pt 2): 341–344.PubMedGoogle Scholar
  26. 26.
    Davi G, Alessandrini P, Mezzetti A, et al.: In vivo formation of 8-Epi-prostaglandin F2 alpha is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997, 17: 3230–3235.PubMedGoogle Scholar
  27. 27.
    Meagher EA, Barry OP, Lawson JA, et al.: Effects of vitamin E on lipid peroxidation in healthy persons. JAMA 2001, 285: 1178–1182.PubMedCrossRefGoogle Scholar
  28. 28.
    Stampfer M, Hennekens CH, Manson JE, et al.: Vitamin E consumption and the risk of coronary disease in women. N Engl J Med 1993, 328: 1444–1449.PubMedCrossRefGoogle Scholar
  29. 29.
    Rimm EB, Stampler MJ, Ascherio A, et al.: Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med 1993, 328: 1450–1455.PubMedCrossRefGoogle Scholar
  30. 30.
    Stephens NG, Parsons A, Schofield PM, et al.: Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996, 347: 781–786.PubMedCrossRefGoogle Scholar
  31. 31.
    Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999, 354:447–455.Google Scholar
  32. 32.
    Yusuf S, Dagenais G, Pogue J, et al.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000, 342: 154–160.PubMedCrossRefGoogle Scholar
  33. 33.
    MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360:23–33.Google Scholar
  34. 34.
    Brown BG, Zhao XQ, Chait A, et al.: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001, 345: 1583–1592.PubMedCrossRefGoogle Scholar
  35. 35.
    Cheung MC, Zhao XQ, Chait A, et al.: Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscler Thromb Vasc Biol 2001, 21: 1320–1326.PubMedGoogle Scholar
  36. 36.
    de Gaetano G: Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project. Lancet 2001, 357: 89–95.PubMedCrossRefGoogle Scholar
  37. 37.
    Boaz M, Smetana S, Weinstein T, et al.: Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet 2000, 356: 1213–1218.PubMedCrossRefGoogle Scholar
  38. 38.
    Fang JC, Kinlay S, Beltrame J, et al.: Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002, 359: 1108–1113.PubMedCrossRefGoogle Scholar
  39. 39.
    Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994, 344:1383–1389.Google Scholar
  40. 40.
    Heinecke JW: Mass spectrometric quantification of amino acid oxidation products in proteins: insights into pathways that promote LDL oxidation in the human artery wall. FASEB J 1999, 13: 1113–1120.PubMedGoogle Scholar
  41. 41.
    Daugherty A, Rateri DL, Dunn JL, Heinecke JW: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 1994, 94: 437.PubMedCrossRefGoogle Scholar
  42. 42.
    Savenkova ML, Mueller DM, Heinecke JW: Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein. J Biol Chem 1994, 269: 20394–20400.PubMedGoogle Scholar
  43. 43.
    Hazell LJ, Stocker R: Alpha-tocopherol does not inhibit hypochlorite-induced oxidation of apolipoprotein B-100 of low-density lipoprotein. FEBS Lett 1997, 414: 541–544.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2003

Authors and Affiliations

  • Jay W. Heinecke
    • 1
  1. 1.Division of Metabolism, Endocrinology and NutritionUniversity of WashingtonSeattleUSA

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