Skip to main content
Log in

Antioxidants and cardiovascular disease: Still a topic of interest

  • Review Article
  • Published:
Environmental Health and Preventive Medicine Aims and scope

Abstract

Cardiovascular disease constitutes a major public health concern in industrialised nations. Over recent decades, a large body of evidence has accumulated indicating that free radicals play a critical role in cellular processes implicated in atherosclerosis. Herein, we present a mechanism of oxidative stress, focusing mainly on the development of an oxidised low density lipoprotein, and the results of a clinical trial of antioxidant therapy and epidemiological studies on the relationships between nutrient antioxidants, such as vitamin E, vitamin C, β-carotene, coenzyme Q, flavonoids and L-arginine, and coronary events. These studies indicated that a diet high in antioxidants is associated with a reduced risk of cardiovascular disease, but did not confirm a strong causality link. With regard to vitamin E, observational studies suggested that the daily use of at least 400 International Units of vitamin E is associated with beneficial effects on coronary events. However, it is apparently too early to define the clinical benefits of vitamin E for cardiovascular disease. From the results of several randomised interventional trials, it appears that no single antioxidant given to subjects at high doses has substantial benefits, and the question of whether nutrient antioxidants truly protect against cardiovascular disease remains open. This article provides an overview of the epidemiological and clinical studies related to antioxidants and cardiovascular disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Wagakunino Hoken Tokei (H13). Tokyo: Health and Welfare Statistics Association, 2001 (Magazine in Japanese).

  2. Weisburger JH. Lifestyle, health and disease prevention: the underlying mechanisms. Eur J Cancer Prev. 2002; 11: S1–7.

    Article  PubMed  Google Scholar 

  3. Hu FB, Willett WC. Optimal diets for prevention of coronary heart disease. JAMA. 2002; 288: 2569–2578.

    Article  PubMed  CAS  Google Scholar 

  4. National Research Council, USA. Committee on Diet and Health, Implication for reducing Chronic Disease risk. Washington, DC: National Academy of Sciences, 1989.

    Google Scholar 

  5. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford: Clarendon Press, 2nd end, 1989.

    Google Scholar 

  6. Hirvonen T, Pietinen P, Virtanen M, et al. Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology, 2001; 12: 62–67.

    Article  PubMed  CAS  Google Scholar 

  7. De Bree A, Verschuren WM, Kromhout D, Kluijtmans LA, Blom HJ. Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev. 2002; 54: 599–618.

    Article  PubMed  Google Scholar 

  8. Hinderliter AL, Caughey M. Assessing endothelial function as a risk factor for cardiovascular disease. Curr Atheroscler Rep. 2003; 5: 506–513.

    Article  PubMed  Google Scholar 

  9. Samman S, Sivarajah G, Man JC, Ahmad ZI, Petocz P, Caterson ID. A mixed fruit and vegetable concentrate increases plasma antioxidant vitamins and folate and lowers plasma homocysteine in men. J Nutr. 2003; 133: 2188–2193.

    PubMed  CAS  Google Scholar 

  10. Gey KF. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Acta Cardiol. 1989; 44: 493–494.

    PubMed  CAS  Google Scholar 

  11. Gey KF. The antioxidant hypothesis of cardiovascular disease: epidemiology and mechanisms. Biochem Soc Trans. 1990; 18: 1041–1045.

    PubMed  CAS  Google Scholar 

  12. Gaziano JM, Manson JE, Ridker PM, Buring JE, Hennekens CH. beta carotene therapy for chronic stable angina. Circulation. 1990; 82: Abstract 0796.

  13. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992; 3: 194–202.

    Article  PubMed  CAS  Google Scholar 

  14. Gey KF, Stahelin HB, Eichholzer M. Poor plasma status of carotene and vitamin C is associated with higher mortality from ischemic heart disease and stroke: Basel Prospective study. Clin Investig. 1993; 71: 3–6.

    Article  PubMed  CAS  Google Scholar 

  15. Hennekens CH, Gaziano JM, Manson JE, Buring JE. Antioxidant vitamin-cardiovascular disease hypothesis is still promising, but still unproven: the need for randomized trials. Am J Clin Nutr. 1995; 62: 1377S-1380S.

    PubMed  CAS  Google Scholar 

  16. Gaziano JM. Antioxidants in cardiovascular disease: randomized trials. Nutrition. 1996; 12: 583–588.

    Article  PubMed  CAS  Google Scholar 

  17. Rimm EB, Stampfer MJ. The role of antioxidants in preventive cardiology. Curr Opin Cardiol. 1997; 12: 188–194.

    Article  PubMed  CAS  Google Scholar 

  18. Steinbrecher UP. Dietary antioxidants and cardioprotection—fact or fallacy? Can J Physiol Pharmacol. 1997; 75: 228–233.

    Article  PubMed  CAS  Google Scholar 

  19. Manson JE, Bassuk SS, Stampfer MJ. Does vitamin E supplementation prevent cardiovascular events? J Womens Health (Larchmt). 2003; 12: 123–136.

    Google Scholar 

  20. Davies KJ. Oxidative stress: the paradox of aerobic life. Biochem Soc Symp. 1995; 61: 1–31.

    PubMed  CAS  Google Scholar 

  21. Griendling KK, FitzGerald GA. Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation. 2003; 108: 1912–1916.

    Article  PubMed  Google Scholar 

  22. Loscalzo J. Oxidant stress: a key determinant of atherothrombosis. Biochem Soc Trans. 2003; 31: 1059–1061.

    PubMed  CAS  Google Scholar 

  23. Maxwell SR, Lip GY. Free radicals and antioxidants in cardiovascular disease. Br J Clin Pharmacol. 1997; 44: 307–317.

    Article  PubMed  CAS  Google Scholar 

  24. Chen K, Thomas SR, Keaney JF Jr. Beyond LDL oxidation: ROS in vascular signal transduction. Free Radic Biol Med. 2003; 35: 117–132.

    Article  PubMed  CAS  Google Scholar 

  25. Fri B. Cardiovascular disease and nutrient antioxidants: role of low-density lipoprotein oxidation. Crit Rev Food Sci Nutr. 1995; 35: 83–98.

    Google Scholar 

  26. Napoli C, de Nigris F, Palinski W. Multiple role of reactive oxygen species in the arterial wall. J Cell Biochem. 2001; 82: 674–682.

    Article  PubMed  CAS  Google Scholar 

  27. Ruef J, Peter K, Nordt TK, Runge MS, Kubler W, Bode C. Oxidative stress and atherosclerosis: its relationship to growth factors, thrombus formation and therapeutic approaches. Thromb Haemost 1999; 82: 32–37.

    PubMed  Google Scholar 

  28. Keaney JF Jr, Vita JA. Atherosclerosis, oxidative stress, and antioxidant protection in endothelium-derived relaxing factor action. Prog Cardiovasc Dis. 1995; 38: 129–154.

    Article  PubMed  Google Scholar 

  29. Halliwell B. Albumin—an important extracellular antioxidant? Biochem Pharmacol. 1988; 15: 569–571.

    Article  Google Scholar 

  30. Rush JW, Sandiford SD. Plasma glutathione peroxidase in healthy young adults: influence of gender and physical activity. Clin Biochem. 2003; 36: 345–351.

    Article  PubMed  CAS  Google Scholar 

  31. Martin A, Frei B. Both intracellular and extra cellular vitamin C inhibits atherogenic modification of LDL by human vascular endothelial cells. Arterioscler Thromb Vasc Biol. 1997; 17: 1583–1590.

    PubMed  CAS  Google Scholar 

  32. May JM, Cobb CE, Mendiratta S, Hill KE, Burk RF. Reduction of the ascorbyl free radical to ascorbate by thioredoxin reductase. J Biol Chem. 1998; 273: 23039–23045.

    Article  PubMed  CAS  Google Scholar 

  33. Giugliano D. Dietary antioxidants for cardiovascular prevention. Nutr Metab Cardiovasc Dis. 2000; 10: 38–44.

    PubMed  CAS  Google Scholar 

  34. Rice-Evans CA, Miller NJ, Bolwell PG, et al. The relative antioxidant activities of plant-derived polyphenolic flavonoids. Free Radic Res. 1995; 22: 375–383.

    Article  PubMed  CAS  Google Scholar 

  35. Sanz MJ, Ferrandiz ML, Cejudo M, et al. Influence of a series of natural flavonoids on free radical generating systems and oxidative stress. Xenobiotica. 1994; 24: 689–699.

    PubMed  CAS  Google Scholar 

  36. Kessler M, Ubeaud G, Jung L. Anti- and pro-oxidant activity of rutin and quercetin derivatives. J Pharm Pharmacol. 2003; 55: 131–142.

    Article  PubMed  CAS  Google Scholar 

  37. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet. 1992; 339: 1523–1526.

    Article  PubMed  CAS  Google Scholar 

  38. Cooke JP. Nutriceuticals for cardiovascular health. Am J Cardiol. 1998; 82: 43S-46S.

    PubMed  CAS  Google Scholar 

  39. Basu TK, Dickerson JWT. In: Vitamins ad Human Health and Disease. Oxford: Cab International, 1996.

    Google Scholar 

  40. Daily Reference Intakes for vitamin C, vitamin E, Selenium, and Carotenoids. Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of DRIs, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board. Washington DC: National Academy of Sciences, 2000.

  41. Dietary Reference Values for food energy and nutrients for the United Kingdom, 41. London: HMSO, 1991.

  42. COMA, Department of Health Report on Health and Social Subjects no 41. Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report of the Panel on Dietary Reference Values of the Committee on the Medical Aspects of Food Policy (COMA). Department of Health RHSS 41. London: HMSO, 1991.

    Google Scholar 

  43. Human vitamin and mineral requirements. Report of a joint FAO/WHO expert consultation, Bankok, Thailand, Genova: World Health Organization Food and Agriculture Organization of the United Nations, 2002.

  44. Recommended Daily Allowances for Japan. Tokyo: Ministry of Health and Welfare, 2000.

  45. 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.

    PubMed  CAS  Google Scholar 

  46. Hertog MG, Kromhout D, Aravanis C, et al. Flavonoid intake and long-term risk of coronary heart disease and cancer in the seven countries study. Arch Intern Med. 1995; 155: 381–386.

    Article  PubMed  CAS  Google Scholar 

  47. Matilainen T, Vartiainen E, Puska P, et al. Plasma ascorbic acid concentrations in the Republic of Karelia, Russia and in North Karelia, Finland. Eur J Clin Nutr. 1996; 50: 115–120.

    PubMed  CAS  Google Scholar 

  48. Rimm EB, Stampfer MJ, Ascherio A, et al. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993; 328: 1450–1456.

    Article  PubMed  CAS  Google Scholar 

  49. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994; 139: 1180–1189.

    PubMed  CAS  Google Scholar 

  50. Morris DL, Kritchevsky SB, Davis CE. Serum carotenoids and coronary heart disease. The Lipid Research Clinics Coronary Primary Prevention Trial and Follow-up Study. JAMA. 1994; 272: 1439–1441.

    Article  PubMed  CAS  Google Scholar 

  51. Gaziano JM, Manson JE, Branch LG, Colditz GA, Willett WC, Buring JE. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann Epidemiol. 1995; 5: 255–260.

    Article  PubMed  CAS  Google Scholar 

  52. Pandey DK, Shekelle R, Selwyn BJ, et al. Dietary vitamin C and beta-carotene and risk of death in middle-aged men. The Western Electric Study. Am J Epidemiol. 1995; 142: 1269–1278.

    PubMed  CAS  Google Scholar 

  53. Klipstein-Grobusch K, Geleijnse JM, den Breeijen JH, et al. Dietary antioxidants and risk of myocardial infarction in the elderly: the Rotterdam Study. Am J Clin Nutr. 1999; 69: 261–266.

    PubMed  CAS  Google Scholar 

  54. Ford ES, Giles WH. Serum vitamins, carotenoids, and angina pectoris: findings from the National Health and Nutrition Examination Survey III. Ann Epidemiol. 2000; 10: 106–116.

    Article  PubMed  CAS  Google Scholar 

  55. Osganian SK, Stampfer MJ, Rimm E, et al. Dietary carotenoids and risk of coronary artery disease in women. Am J Clin Nutr. 2003; 77: 1390–1399.

    PubMed  CAS  Google Scholar 

  56. Kritchevsky SB, Shimakawa T, Tell GS, et al. Dietary antioxidants and carotid artery wall thickness. Atherosclerosis Risk in Communities Study. The ARIC Study. Circulation. 1995; 92: 2142–2150.

    PubMed  CAS  Google Scholar 

  57. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996; 334: 1156–1162.

    Article  PubMed  CAS  Google Scholar 

  58. Nyyssonen K, Parviainen MT, Salonen R, et al. Vitamin C deficiency and risk of myocardial infarction: prospective population study of men from eastern Finland. BMJ. 1997; 314: 634–638.

    PubMed  CAS  Google Scholar 

  59. Simon JA, Hudes ES. Serum ascorbic acid and cardiovascular disease prevalence in U.S. adults: the Third National Health and Nutrition Examination Survey (NHANES III). Ann Epidemiol. 1999; 9: 358–365.

    Article  PubMed  CAS  Google Scholar 

  60. Simon JA, Hudes ES, Tice JA. Relation of serum ascorbic acid to mortality among US adults. J Am Coll Nutr. 2001; 20: 255–263.

    PubMed  CAS  Google Scholar 

  61. Muntwyler J, Hennekens CH, Manson JE, Buring JE, Gaziano JM. Vitamin supplement use in a low-risk pepulation of US male physicians and subsequent cardiovascular mortality. Arch Intern Med. 2002; 162: 1472–1476.

    Article  PubMed  Google Scholar 

  62. Osganian SK, Stampfer MJ, Rimm E, et al. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol. 2003; 42: 246–252.

    Article  PubMed  CAS  Google Scholar 

  63. Stampfer MJ, Hennekens CH, Manson JE, et al. Vitamin E consumption and the risk of coronary disease in women. N Eng J Med. 1993; 328: 1444–1449.

    Article  CAS  Google Scholar 

  64. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996; 64: 190–196.

    PubMed  CAS  Google Scholar 

  65. Evans RW, Shaten BJ, Day BW, Kuller LH. Prospective association between lipid soluble antioxidants and coronary heart disease in men. The Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1998; 147: 180–186.

    PubMed  CAS  Google Scholar 

  66. Brubacher D, Moser U, Jordan P. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res. 2000; 70: 226–237.

    Article  PubMed  CAS  Google Scholar 

  67. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003; 361: 2017–2023.

    Article  PubMed  CAS  Google Scholar 

  68. van’t Veer P, Jansen MC, Klerk M, Kok FJ. Fruits and vegetables in the prevention of cancer and cardiovascular disease. Public Health Nutr. 2000; 3: 103–107.

    Google Scholar 

  69. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet. 1993; 342: 1007–1011.

    Article  PubMed  CAS  Google Scholar 

  70. Knekt P, Jarvinen R, Reunanen A, Maatela J. Flavonoid intake and coronary mortality in Finland: a cohort study. BMJ. 1996; 312: 478–481.

    PubMed  CAS  Google Scholar 

  71. Jarvinen R, Seppanen R, Knekt P. Short-term and long-term reproducibility of dietary history interview data. Int J Epidemiol. 1993; 22: 520–517.

    Article  PubMed  CAS  Google Scholar 

  72. Joshipura KJ, Hu FB, Manson JE, et al. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann Intern Med. 2001; 134: 1106–1114.

    PubMed  CAS  Google Scholar 

  73. Hertog MG, Sweetnam PM, Fehily AM, Elwood PC, Kromhout D. Antioxidant flavonols and ischemic heart disease in a Welsh population of men: the Caerphilly Study. Am J Clin Nutr. 1997; 65: 1489–1494.

    PubMed  CAS  Google Scholar 

  74. Fraser GE, Shavlik DJ. Risk factors for all-cause and coronary heart disease mortality in the oldest-old. The Adventist Health Study. Arch Intern Med. 1997; 157: 2249–2258.

    Article  PubMed  CAS  Google Scholar 

  75. Sesso HD, Gaziano JM, Liu S, et al. Flavonoid intake and the risk of cardiovascular disease in women. Am J Clin Nutr. 2003; 77: 1400–1408.

    PubMed  CAS  Google Scholar 

  76. Kritchevsky SB. beta-Carotene, carotenoids and the prevention of coronary heart disease. J Nutr. 1999; 129: 5–8.

    PubMed  CAS  Google Scholar 

  77. Rissanen TH, Voutilainen S, Nyyssonen K, Salonen R, Kaplan GA, Salonen JT. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2003; 77: 133–138.

    PubMed  CAS  Google Scholar 

  78. Rissanen T, Voutilainen S, Nyyssonen K, Salonen JT. Lycopene, atherosclerosis, and coronary heart disease. Exp Biol Med (Maywood). 2002; 227: 900–907.

    CAS  Google Scholar 

  79. Meydani M. Nutrition interventions in aging and age-associated disease. Ann NY Acad Sci. 2001; 928: 226–235.

    Article  PubMed  CAS  Google Scholar 

  80. McKay DL, Blumberg JB. The role of tea in human health: an update. J Am Coll Nutr. 2002; 21: 1–13.

    PubMed  CAS  Google Scholar 

  81. Rietveld A, Wiseman S. Antioxidant effects of tea: evidence from human clinical trials. J Nutr. 2003; 133: 3285S-3292S.

    PubMed  CAS  Google Scholar 

  82. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC. Reproducibility and validity of an expanded self-administered semi-quantitive food frequency questionnaire among male health professionals. Am J Epidemiol. 1992; 135: 1114–1126.

    PubMed  CAS  Google Scholar 

  83. Heitmann BL, Lissner L, Osler M. Do we eat less fat, or just report so? Int J Obes Relat Metab Disord. 2000; 24: 435–442.

    Article  PubMed  CAS  Google Scholar 

  84. Yokoi H, Daida H, Kuwabara Y, et al. Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: the Probucol Angioplasty Restenosis Trial. J Am Coll Cardiol. 1997; 30: 855–862.

    Article  PubMed  CAS  Google Scholar 

  85. Daida H, Kuwabara Y, Yokoi H, et al. Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART]). Am J Cardiol. 2000; 86: 550–552.

    Article  PubMed  CAS  Google Scholar 

  86. Tardif JC, Cote G, Lesperance J, et al. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. N Engl J Med. 1997; 337: 365–372.

    Article  PubMed  CAS  Google Scholar 

  87. Tardif JC, Cote G, Lesperance J, Gosselin G, et al. Impact of residual plaque burden after balloon angioplasty in the Multi-Vitamins and Probucol (MVP) trial. Can J Cardiol. 2001; 17: 49–55.

    PubMed  CAS  Google Scholar 

  88. Wayner DD, Burton GW, Ingold KU, Locke S. Quantitative measurement of the total, peroxyl radical-trapping antioxidant capability of human blood plasma by controlled peroxidation. The important contribution made by plasma proteins. FEBS Lett. 1985; 187: 33–37.

    Article  PubMed  CAS  Google Scholar 

  89. Cao G, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med. 1993; 14: 303–311.

    Article  PubMed  CAS  Google Scholar 

  90. Rice-Evans C, Miller NJ. Total antioxidant status in plasma and body fluids. Methods Enzymol. 1994; 234: 279–293.

    Article  PubMed  CAS  Google Scholar 

  91. Ghiselli A, Serafini M, Ferro-Luzzi A. New approaches for measuring plasma or serum antioxidant capacity: a methodological note. Free Radic Biol Med. 1994; 16: 135–137.

    Article  PubMed  CAS  Google Scholar 

  92. Benzie IF, Strain JJ. The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay. Anal Biochem. 1996; 239: 70–76.

    Article  PubMed  CAS  Google Scholar 

  93. Rigatteri S, Bufon A, Ramazotti V, et al. Oxidative stress inschemia-reperfusion injury: assessment by three independent biochemical markers. Ital Heart J. 2000; 1: 68–72.

    Google Scholar 

  94. Tomasetti M, Alleva R, Piva R, et al. Evaluation of ischemia-reperfusion damage during coronary angioplasty. Electrocardiographic assessment and biochemical modifications in blood from the coronary sinus. Ital Heart J. 2000; 1: 216–220.

    PubMed  CAS  Google Scholar 

  95. Kummerow FA, Olinescu RM, Fleischer L, Handler B, Shinkareva SV. The relationship of oxidazed lipids to coronary artery stenosis. Atherosclerosis. 2000; 149: 181–190.

    Article  PubMed  CAS  Google Scholar 

  96. Nojiri S, Daida H, Mokuno H, et al. Association of serum antioxidant capacity with coronary artery disease in middle-aged men. Jap Heart J. 2001; 42: 677–690.

    Article  PubMed  CAS  Google Scholar 

  97. Blot WJ, Li JY, Taylor PR, Guo W, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993; 85: 1483–1492.

    Article  PubMed  CAS  Google Scholar 

  98. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med. 1994; 330: 1029–1035.

    Article  Google Scholar 

  99. Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and beta carotene on the incidence of angina pectoris. A randomized, double-blind, controlled trial. JAMA. 1996; 275: 693–698.

    Article  PubMed  CAS  Google Scholar 

  100. Virtamo J, Rapola JM, Ripatti S, et al. Effect of vitamin E and beta carotene on the incidence of primary nonfatal myocardial infarction and fatal coronary heart disease. Arch Intern Med. 1998; 158: 668–675.

    Article  PubMed  CAS  Google Scholar 

  101. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996 2; 334: 1150–1155.

    Article  PubMed  CAS  Google Scholar 

  102. Redlich CA, Chung JS, Cullen MR, Blaner WS, Van Bennekum AM, Berglund L. Effect of long-term beta-carotene and vitamin A on serum cholesterol and triglyceride levels among participants in the Carotene and Retinol Efficacy Trial (CARET). Atherosclerosis. 1999; 145: 425–432.

    Article  PubMed  Google Scholar 

  103. Manson JE, Buring JE, Satterfield S, Hennekens CH. Base-line characteristics of participants in the Physicians’ Health Study: a randomized trial of aspirin and beta-carotene in U.S. physicians. Am J Prev Med. 1991; 7: 150–154.

    PubMed  CAS  Google Scholar 

  104. No author, Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med. 1999; 321: 129–135.

    Google Scholar 

  105. Christen WG, Gaziano JM, Hennekens CH. Design of Physicians’ Health Study II—a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol. 2000; 10: 125–134.

    Article  PubMed  CAS  Google Scholar 

  106. Hereberg S, Preziosi P, Briancon S, et al. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristies. SUpplementation en VItamines et Mineraux AntioXydants. Control Clin Trials. 1998; 19: 336–351.

    Article  Google Scholar 

  107. Lee IM, Cook NR, Manson JE, Buring JE, Hennekens CH. Beta-carotene supplementation and incidence of cancer and cardiovascular disease: the Women’s Health Study. J Natl Cancer Inst. 1999; 91: 2102–2106.

    Article  PubMed  CAS  Google Scholar 

  108. Arad Y, Newstein D, Roth M, Guerci AD. Rationale and design of the St. Francis Heart Study: a randomized clinical trial of atorvastatin plus antioxidants in asymptomatic persons with elevated coronary calcification. Control Clin Trials. 2001; 22: 553–572.

    Article  PubMed  CAS  Google Scholar 

  109. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003; 107: 947–953.

    Article  PubMed  CAS  Google Scholar 

  110. The WACS Research Group. A secondary prevention trial of antioxidant vitamins and cardiovascular disease in women. Rationale, design, and methods. Ann Epidemiol. 1995; 5: 261–269.

    Article  Google Scholar 

  111. Mason PJ, Manson JE, Sesso HD, et al. Blood pressure and risk of secondary cardiovascular events in women: the Women’s Antioxidant Cardiovascular Study (WACS). Circulation. 2004; 109: 1623–1629.

    Article  PubMed  Google Scholar 

  112. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996; 347: 781–786.

    Article  PubMed  CAS  Google Scholar 

  113. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and beta-carotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997; 349: 1715–1720.

    Article  PubMed  CAS  Google Scholar 

  114. Angiotensin-converting enzyme (ACE) inhibition in the secondary prevention of vascular disease: the Heart Outcomes Prevention Evaluation (HOPE) Trial and its substudies. Curr Atheroscler Rep. 2000; 2: 361–362

  115. Lonn E, Yusuf S, Dzavik V, et al. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultrasound changes in patients treated with ramipril and vitamin E (SECURE). Circulation. 2001; 103: 919–925.

    PubMed  CAS  Google Scholar 

  116. Marchioli R, Schweiger C, Tavazzi L, Valagussa F. Efficacy of n-3 polyunsaturated fatty acids after myocardial infarction: results of GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. Lipids. 2001; 36: S119-S116.

    Article  PubMed  CAS  Google Scholar 

  117. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation. 2002 23; 105: 1897–1903.

    Article  PubMed  CAS  Google Scholar 

  118. Hsia J, Alderman EL, Verter JI, et al. Women’s angiographic vitamin and estrogen trial: design and methods. Control Clin Trials. 2002; 23: 708–727.

    Article  PubMed  Google Scholar 

  119. Heart Protection Collaborative Group. 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.

    Article  Google Scholar 

  120. Hennekens CH, Buring JE. Epdemiology in medicine. Philadelphia: Lippincott Williams & Wilkins, 1987.

    Google Scholar 

  121. Hodis HN, Mack WJ, LaBree L, et al. VEAPS Research Group, Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002; 106: 1453–1459.

    Article  PubMed  CAS  Google Scholar 

  122. Leeson CP, Mann A, Kattenhorn M, Deanfield JE, Lucas A, Muller DP. Plasma vitamin E, total antioxidant status and vascular function in young adults. Eur J Clin Invest. 2002; 32: 889–894.

    Article  PubMed  CAS  Google Scholar 

  123. Halliwell B. Lipid peroxidation, antioxidants and cardiovascular disease: how should we move forward? Cardiovasc Res. 2000; 47: 410–418.

    Article  PubMed  CAS  Google Scholar 

  124. Eastwood MA. Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease? QJM. 1999; 92: 527–530.

    Article  PubMed  CAS  Google Scholar 

  125. Patrick L. Beta-carotene: the controversy continues. Altern Med Rev. 2000; 5: 530–545.

    PubMed  CAS  Google Scholar 

  126. Jialal I, Fuller CJ, Huet BA. The effect of α-tocopherol supplementation on LDL oxidation: a dose-response study. Arteriscler Thromb Vasc Biol. 1995; 15: 190–198.

    CAS  Google Scholar 

  127. Gey KF. Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer. Biofactors. 1998; 7: 113–174.

    PubMed  CAS  Google Scholar 

  128. Parthasarathy S, Khan-Merchant N, Penumetcha M, Khan BV, Santanam N. Did the antioxidant trials fail to validate the oxidation hypothesis? Curr Atheroscler Rep. 2001; 3: 392–398.

    Article  PubMed  CAS  Google Scholar 

  129. Heinecke JW. Clinical trials of vitamin E in coronary artery disease: is it time to reconsider the low-density lipoprotein oxidation hypothesis? Curr Atheroscler Rep. 2003; 5: 83–87.

    Article  PubMed  Google Scholar 

  130. Lampe JW. Health effects of vegetables and fruit: assessing mechanisms of action in human experimental studies. Am J Clin Nutr. 1999; 70: 475S-490S.

    PubMed  CAS  Google Scholar 

  131. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999; 69: 1086–1107.

    PubMed  CAS  Google Scholar 

  132. Bakalova RA, Hadzhimitova V, Ribarov S. Relationships between serum levels of autoantibodies against oxidized low density lipoproteins, lipid-soluble antioxidants and apolipo-protein B in patients with coronary heart disease. Gen Physiol Biophys. 2000; 19: 103–113.

    PubMed  CAS  Google Scholar 

  133. Ottonello L, Frumento G, Arduino N, Dapino P, Tortolina G, Dallegri F. Immune complex stimulation of neutrophil apoptosis: investigating the involvement of oxidative and nonoxidative pathways. Free Radic Biol Med. 2001; 30: 161–169.

    Article  PubMed  CAS  Google Scholar 

  134. Meydani M. Soluble adhesion molecules: surrogate markers of cardiovascular disease? Nutr Rev. 2003; 61: 63–68.

    Article  PubMed  Google Scholar 

  135. Calder PC, Kew S. The immune system: a target for functional foods? Br J Nutr. 2002; 88: S165-S177.

    Article  PubMed  CAS  Google Scholar 

  136. Hasler CM, Kundrat S, Wool D. Functional foods and cardiovascular disease. Curr Atheroscler Rep. 2000; 2: 467–475.

    Article  PubMed  CAS  Google Scholar 

  137. Meraji S, Abuja PM, Hayn M, et al. Relationship between classic risk factors, plasma antioxidants and indicators of oxidant stress in angina pectoris (AP) in Tehran. Atherosclerosis. 2000; 150: 403–412.

    Article  PubMed  CAS  Google Scholar 

  138. Kristenson M, Kucinskiene Z, Schafer-Elinder L, Leanderson P, Tagesson C. Lower serum levels of beta-carotene in Lithuanian men are accompanied by higher urinary excretion of the oxidative DNA adduct, 8-hydroxydeoxyguanosine. The LiVicordia study. Nutrition. 2003; 19: 11–15.

    Article  PubMed  CAS  Google Scholar 

  139. Howitz KT, Bitterman KJ, Cohen HY, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425: 191–196.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nojiri, S., Daida, H. & Inaba, Y. Antioxidants and cardiovascular disease: Still a topic of interest. Environ Health Prev Med 9, 200–213 (2004). https://doi.org/10.1007/BF02898101

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02898101

Key words

Navigation