Review
Ten-year retrospective on the antioxidant hypothesis of arteriosclerosis: Threshold plasma levels of antioxidant micronutrients related to minimum cardiovascular risk

https://doi.org/10.1016/0955-2863(95)00032-UGet rights and content

Abstract

The antioxidant hypothesis postulates that suboptimal levels of principal antioxidant micronutrients are hitherto underrated risk factors for cardiovascular diseases. Complementary observational data consistently suggest optimal, i.e., potentially protective plasma levels of approximately >50 μmol/L of vitamin C, >30 μmol/L of lipid-standardized vitamin E (α-tocopherol/cholesterol ratio >5.2 μmol/mmol), and >0.4 μmol/L β (>0.5 μmol/L total)-carotene. Relative risks are doubled at >25 to 50% lower values. Suboptimal levels of each factor increase the risk singly, or in combination risk increases multiplicatively. They can be stronger predictors of coronary heart disease than classical risk factors such as hypercholesterolemia and hypertension, at least in Northern Europe. In male Americans, the relative risk of cardiovascular diseases was substantially reduced by daily intake of >130 mg of vitamin C, >100 IU of vitamin E (100 mg of d,l- or 74 mg of d-α-acetyl-tocopherol) in all subjects, and by >9 mg of β-carotene, but only in smokers—in comparison with a suboptimal intake that very probably permits only suboptimal plasma levels. Antioxidant deficits can be avoided by “prudent diets” rich in fruits/vegetables, and net vitamin E (high vitamin E/polyunsaturated fatty acids ratio) as is common in European communities where premature cardiovascular death is low. These essential antioxidants may be crucial components of such protective diets but other, presumably synergistic constituents await evaluation, e.g., carotenoids other than β-carotene, phenols/bioflavonoids, minerals such as potassium and selenium, fibers, mono- and n-3 polyenic fatty acids, and oxygen-sensitive B vitamins such as folate.

References (259)

  • A.J. Verlangieri et al.

    Effects of d-alphatocopherol supplementation on experimentally induced primate atherosclerosis

    J. Am. Coll. Nutr.

    (1992)
  • J.T. Mao et al.

    Attenuation of atherosclerosis in an modified strain of hypercholesterolemic Watanabe rabbits with use of a probucol analogue (MDL 29,311) that does not lower serum cholesterol

    Arteriosclerosis

    (1991)
  • Y. Stein et al.

    Lack of effect of probucol on atheroma formation in cholesterol-fed rabbits kept at a comparable plasma cholesterol levels

    Atherosclerosis

    (1989)
  • H. Yoshida et al.

    Effect of dietary vitamin E on the toxicity of autoxidized oil to rats

    Ann. Nutr. Metab.

    (1989)
  • K.F. Gey et al.

    Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C

    Am. J. Clin. Nutr.

    (1993)
  • K.F. Gey et al.

    Plasma levels of antioxidant vitamins in relation to ischemic heart disease and cancer

    Am. J. Clin. Nutr.

    (1987)
  • K.F. Gey et al.

    Plasma vitamins E and A inversely related to mortality from ischemic heart disease in cross-cultural epidemiology

    Ann. NY Acad. Sci.

    (1989)
  • D.I. Thurnham

    Antioxidants and prooxidants in malnourished populations

  • V.E. Kagan et al.

    Recycling of vitamin E in human low density lipoproteins

    J. Lipid Res.

    (1992)
  • G.R. Buettner

    The pecking order of free radicals and antioxidants: lipid peroxidation, α-tocopherol and ascorbate

    Arch. Biochem. Biophys.

    (1993)
  • M. Sharma et al.

    Interaction of vitamin C and vitamin E during free radical stress in plasma

    Free Radical Biol. Med.

    (1993)
  • O. Igarashi et al.

    Synergistic action of vitamin E and vitamin E in vivo using a new mutant of Wistar-strain rats, ODS, unable to synthesize vitamin C

    J. Nutr. Sci. Vitamol.

    (1991)
  • B.B. Frei et al.

    Relative importance of vitamin E in antiperoxidative defenses in human blood plasma and low-density lipoprotein (LDL)

  • P. Palozza et al.

    Antioxidant effects of carotenoids in vitro and in vivo: an overview

    Meth. Enzymol.

    (1992)
  • H. Chen et al.

    Protection by vitamin E, selenium and β-carotene against oxidative damage in rat liver slices and homogenate

    Free Radical Biol. Med.

    (1993)
  • M.L. Bierenbaum et al.

    Relationship between serum lipid peroxidation products in hypercholesterolemic subjects and vitamin E status

    Biochem. Int.

    (1992)
  • J. Martensson et al.

    Glutathion ester delays the onset of scurvy in ascorbate-deficient guinea pigs

  • C. Costagliola et al.

    Effects of vitamin E on the oxidative state of glutathione in plasma

    Clin. Physiol. Biochem.

    (1990)
  • A. Nègre-Salvayre et al.

    Protection of Ca2+ channel blockers (nifedipine, diltiazem and verapamil) against the toxicity of oxidized low density lipoprotein to cultured lymphoid cells

    Brit. J. Pharmacol

    (1992)
  • P.A. Sobotka et al.

    Elevated breath pentane in heart failure reduced by free radical scavenger

    Free Radical Biol. Med.

    (1993)
  • H.J.M. Kempen et al.

    Vastatins inhibit cholesterol ester accumulation in human monocyte-derived macrophages

    Arteriosclerosis

    (1991)
  • L.M. Giroux et al.

    Simvastatin inhibits the oxidation of low-density lipoproteins by activated human monocyte-derived macrophages

    Biochim. Biophys. Acta

    (1993)
  • M. Naruszewicz et al.

    Modification of low-density lipoproteins from hypertriglyceridemic patients by macrophages in vitro and the effect of bezafibrate treatment

    Atherosclerosis

    (1989)
  • K.D. Croft et al.

    Low density lipoprotein and oxidizability in coronary disease—apparent favourable effect of beta blockers

    Atherosclerosis

    (1992)
  • B. Halliwell

    Drug antioxidant effects. A basis for drug selection?

    Drugs

    (1991)
  • J. Regnström et al.

    Susceptibility to low-density lipoprotein oxidation and coronary atherosclerosis in man

    Lancet

    (1992)
  • R.A. Riemersma et al.

    Risk of angina pectoris and plasma concentrations of vitamins A, C and E and carotene

    Lancet

    (1991)
  • J.K. Crombie et al.

    Geographic clustering of risk factors and lifestyle for coronary heart disease in the Scottish Heart Health Study

    Brit. Heart J.

    (1990)
  • K.F. Gey

    On the antioxidant hypothesis with regard to arteriosclerosis

    Bibl. Nutr. Diet.

    (1986)
  • K.F. Gey

    The antioxidant hypothesis of cardiovascular disease: Epidemiology and mechanisms

    Biochem. Soc. Trans.

    (1990)
  • K.F. Gey

    Vitamin E and other essential antioxidants regarding coronary heart disease: risk assessment studies. Epidemiological basis of the antioxidant hypothesis of cardiovascular disease

  • K.F. Gey

    Prospects for the prevention of free radical disease, regarding cancer and cardiovascular disease

  • National Research Council et al.
  • H. Sies

    Strategies of antioxidative defense

    Eur. J. Biochem.

    (1993)
  • B. Halliwell et al.
  • B.N. Ames et al.

    Oxidants, antioxidants, and the degenerative diseases of aging

  • A.C. Arntzenius et al.

    Diet, lipoproteins and the progression of coronary atherosclerosis: The Leyden Intervention Trial

    N. Engl. J. Med.

    (1985)
  • D. Ornish et al.

    Can life-style changes reverse coronary heart disease? The Lifestyle Heart Trial

    Lancet

    (1990)
  • Cited by (0)

    View full text