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Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e139-e140
doi: 10.1161/01.ATV.0000131259.97572.99
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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:e139.)
© 2004 American Heart Association, Inc.

Letters to the Editor

Vitamin E Is Not Deficient in Human Atherosclerotic Plaques

Anatol Kontush; M. John Chapman

Dyslipoproteinemia and Atherosclerosis Research Unit (U.551), National Institute for Health and Medical Research (INSERM), Paris, France

Roland Stocker

Centre for Vascular Research, University of New South Wales, Department of Haematology, Prince of Wales Hospital, Sydney, Australia

To the Editor:

With great interest, we recently read the article entitled "Vitamin E supplementation in patients with carotid atherosclerosis: reversal of altered oxidative stress status in plasma but not in plaque" published in the January 2004 issue of Arterioscler Thromb Vasc Biol.1 This article addresses the endogenous vitamin E status of candidates for carotid endarterectomy as compared with healthy controls and evaluates the effect of supplemental vitamin E on markers of oxidative stress in the circulation and in atherosclerotic plaques. These questions are important in light of several large-scale clinical trials documenting a lack of benefit of dietary vitamin E supplementation relative to the risk of coronary heart disease2–4 (reviewed by Kritharides et al5). The authors reported plasma vitamin E/cholesterol ratios to be lower in patients than in controls, and 7ß-hydroxycholesterol/vitamin E ratios to be substantially higher in carotid plaque than plasma.1 Based on these findings, the authors concluded "vitamin E levels are reduced in... atherosclerotic plaques of patients with advanced atherosclerosis."1

In our opinion, this conclusion is not justified, for the following reasons. First, it is based on comparison of vitamin E/cholesterol ratios in plaques versus control plasma1 (Table). Second, 7ß-hydroxycholesterol/vitamin E ratios reflect the extent of cholesterol oxidation relative to the concentration of the vitamin, so that changes in either or both compound(s) affect the ratio. Analysis of the data reported1 clearly shows that higher levels of 7ß-hydroxycholesterol (330±170 versus 2.1±0.4 nmol/mmol cholesterol for plaque and plasma, respectively) rather than lower concentrations of vitamin E (2.06±0.7 versus 3.05±0.6 µmol/mmol cholesterol for plaque and plasma, respectively) are responsible for the difference in the 7ß-hydroxycholesterol/vitamin E ratios. Third, the authors’ data in fact show that the concentrations of vitamin E in plaques and normal vessels are comparable (2.06±0.7 versus 0.54±0.3 µmol/mmol cholesterol for plaques and normal vessels, respectively)1 (Table). Indeed, the lack of a deficit in {alpha}-tocopherol in human atherosclerotic plaques has been documented previously (Table).6–8 Moreover, the intra-plaque levels of {alpha}-tocopherol do not differ between early, intermediate, and advanced lesions and are comparable to plasma levels of the vitamin (Table).6,8,9 Similar results have been reported for the vitamin E content of lipoproteins isolated from human lesions corresponding to different developmental stages.9,10 In addition, gas chromatography–mass spectrometry analysis suggests that only a fraction (<20%) of vitamin E is oxidized in the lesions.9 Thus, the data of Micheletta at el1 and others6–10 have consistently documented the absence of a deficit of vitamin E in human plaque tissue, even at advanced stages of atherosclerosis.


View this table:
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  		Lipid-Adjusted Concentrations of Vitamin E in Arterial Tissue and Plasma from Atherosclerotic Patients and Control Subjects

It is also relevant that a decrease in plasma vitamin E levels in atherosclerotic patients versus controls, as reported by Micheletta at el,1 is not observed consistently. For example, lipid-adjusted plasma levels of vitamin E have been reported to be lower in subjects with myocardial infarction as compared with their respective controls.11,12 By contrast, patients with advanced atherosclerosis,13 unstable coronary syndrome,14 coronary heart disease,15 peripheral vascular disease,16 or hyperlipidemia17 were reported to display normal plasma vitamin E levels (Table).

Interestingly, Micheletta at el.1 reported that supplementation of candidates for carotid endarterectomy with {alpha}-tocopherol (450 IU/d for 6 weeks) led to elevation in its concentration in plasma but not in carotid plaques. The reasons for this difference are not clear at present. Based on the observed increased circulating concentrations of {alpha}-tocopherol,1 and the fact that the vitamin is transported by and enters the vessel wall via lipoproteins, one might expect lesion vitamin E levels to increase with increasing severity of the disease in subjects displaying atherogenic dyslipidemia. However, at advanced stages of plaque development, accumulation of lipoprotein-derived lipids and antioxidants may no longer be substantial, particularly over the relatively short period of six weeks examined,1 or vitamin E may be metabolized faster than (and independently of) lipoprotein-derived lipids. Regarding the latter possibility, it is known that oxidation does not appear to contribute significantly to a putative increase in metabolism of vitamin E in endarterectomy specimens.8 In any case, the findings of Micheletta et al1 suggest that supplemental vitamin E may not have reached its target tissue, and that plasma {alpha}-tocopherol is not a suitable surrogate measure for vessel wall vitamin E.

Concomitant with the increased plasma concentration of {alpha}-tocopherol, 7ß-hydroxycholesterol levels decreased in plasma but not in lesions. The authors concluded that {alpha}-tocopherol supplementation beneficially influenced oxidative stress in plasma but not in atherosclerotic plaques. The apparent inability of therapeutic amounts of supplemental vitamin E to decrease oxidative stress in human atherosclerotic lesions is consistent with earlier studies (reviewed by Upston et al18) and with the observation that vitamin E is not deficient in human lesions.1,6–8 In contrast, much higher pharmacological doses of the vitamin have been reported to decrease both aortic lipid oxidation and lesion formation in some19 but not all20 animal studies (see Neuzil et al21 and Upston et al22 for review).

The study by Micheletta at el1 confirms previous reports6,8,9 that atherosclerotic lesions contain elevated levels of oxidized lipids as compared with that in normal arteries and plasma (reviewed by Upston et al18). Therefore, the available data suggests that in diseased vessels, oxidation of lipids, including those in lipoproteins, occurs in the presence of {alpha}-tocopherol.8,18 Mechanistically, such oxidation can be explained readily by the model of tocopherol-mediated peroxidation.23

Oxidative stress is believed to play a key role in the initiation and progression of atherosclerosis, and supplementation with antioxidants is believed to beneficially influence the disease.24 Quantitatively, {alpha}-tocopherol is the major antioxidant in organic extracts of LDL,25 and it is therefore not surprising that it was first chosen for large-scale clinical trials.2–4 However, there is accumulating evidence to suggest a major role for two-electron oxidants (such as hypochlorite and peroxynitrite) in lipoprotein oxidation and in other oxidative events in the arterial wall.9,18,26 Importantly, {alpha}-tocopherol does not provide protection against these oxidants.27,28 Rather than casting doubt on the concept that antioxidants may be beneficial in the treatment of atherosclerosis, these findings shift attention from vitamin E to agents that could provide protection against physiologically relevant oxidants. The latter may include HDL-associated proteins,29,30 such as those whose precise mechanism of action and relevance to atherosclerosis deserve detailed investigation.

References

  1. Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E supplementation in patients with carotid atherosclerosis: reversal of altered oxidative stress status in plasma but not in plaque. Arterioscler Thromb Vasc Biol. 2004; 24: 136–140.[Abstract/Free Full Text]
  2. 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.[CrossRef][Medline] [Order article via Infotrieve]
  3. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. 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.[Abstract/Free Full Text]
  4. Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP. {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.[Abstract/Free Full Text]
  5. Kritharides L, Stocker R. The use of antioxidant supplements in coronary heart disease. Atherosclerosis. 2002; 164: 211–219.[CrossRef][Medline] [Order article via Infotrieve]
  6. Suarna C, Dean RT, May J, Stocker R. Human atherosclerotic plaque contains both oxidized lipids and relatively large amounts of {alpha}-tocopherol and ascorbate. Arterioscler Thromb Vasc Biol. 1995; 15: 1616–1624.[Abstract/Free Full Text]
  7. Upston JM, Niu X, Brown AJ, Mashima R, Wang H, Senthilmohan R, Kettle AJ, Dean RT, Stocker R. Disease stage-dependent accumulation of lipid and protein oxidation products in human atherosclerosis. Am J Pathol. 2002; 160: 701–710.[Abstract/Free Full Text]
  8. Upston JM, Terentis AC, Morris K, Keaney Jr JF, Stocker R. Oxidized lipid accumulates in the presence of {alpha}-tocopherol in atherosclerosis. Biochem J. 2002; 363: 753–760.[CrossRef][Medline] [Order article via Infotrieve]
  9. Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic lesions. Circ Res. 2002; 90: 333–339.[Abstract/Free Full Text]
  10. Niu X, Zammit V, Upston JM, Dean RT, Stocker R. Coexistence of oxidized lipids and {alpha}-tocopherol in all lipoprotein density fractions isolated from advanced human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 1999; 19: 1708–1718.[Abstract/Free Full Text]
  11. Regnstrom J, Nilsson J, Moldeus P, Strom K, Bavenholm P, Tornvall P, Hamsten A. Inverse relation between the concentration of low-density-lipoprotein vitamin E and severity of coronary artery disease. Am J Clin Nutr. 1996; 63: 377–385.[Abstract/Free Full Text]
  12. Ruiz Rejon F, Martin Pena G, Lopez Manglano C, Seijas Martinez V, Ruiz Galiana J. [Plasma levels of vitamins A and E and the risk of acute myocardial infarct]. Rev Clin Esp. 1997; 197: 411–416.(In Spanish)[Medline] [Order article via Infotrieve]
  13. Cleary J, Mohr D, Adams MR, Celermajer DS, Stocker R. Plasma and LDL levels of major lipophilic antioxidants are similar in patients with advanced atherosclerosis and age-matched controls. Free Radic Res. 1997; 26: 175–182.[Medline] [Order article via Infotrieve]
  14. Vita JA, Keaney JF Jr, Raby KE, Morrow JD, Freedman JE, Lynch S, Koulouris SN, Hankin BR, Frei B. Low plasma ascorbic acid independently predicts the presence of an unstable coronary syndrome. J Am Coll Cardiol. 1998; 31: 980–986.[Abstract/Free Full Text]
  15. Kontush A, Spranger T, Reich A, Baum K, Beisiegel U. Lipophilic antioxidants in blood plasma as markers of atherosclerosis: the role of {alpha}-carotene and {gamma}-tocopherol. Atherosclerosis. 1999; 144: 117–122.[CrossRef][Medline] [Order article via Infotrieve]
  16. Sanderson KJ, van Rij AM, Wade CR, Sutherland WH. Lipid peroxidation of circulating low density lipoproteins with age, smoking and in peripheral vascular disease. Atherosclerosis. 1995; 118: 45–51.[CrossRef][Medline] [Order article via Infotrieve]
  17. Kontush A, Reich A, Baum K, Spranger T, Finckh B, Kohlschutter A, Beisiegel U. Plasma ubiquinol-10 is decreased in patients with hyperlipidaemia. Atherosclerosis. 1997; 129: 119–126.[CrossRef][Medline] [Order article via Infotrieve]
  18. Upston JM, Kritharides L, Stocker R. The role of vitamin E in atherosclerosis. Prog Lipid Res. 2003; 42: 405–422.[CrossRef][Medline] [Order article via Infotrieve]
  19. Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med. 1998; 4: 1189–1192.[CrossRef][Medline] [Order article via Infotrieve]
  20. Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. 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.[Abstract/Free Full Text]
  21. Neuzil J, Weber C, Kontush A. The role of vitamin E in atherogenesis: linking the chemical, biological and clinical aspects of the disease. Atherosclerosis. 2001; 157: 257–283.[CrossRef][Medline] [Order article via Infotrieve]
  22. Upston JM, Terentis AC, Stocker R. Tocopherol-mediated peroxidation of lipoproteins: implications for vitamin E as a potential antiatherogenic supplement. FASEB J. 1999; 13: 977–994.[Abstract/Free Full Text]
  23. Bowry VW, Stocker R. Tocopherol-mediated peroxidation. The prooxidant effect of vitamin E on the radical-initiated oxidation of human low-density lipoprotein. J Am Chem Soc. 1993; 115: 6029–6044.[CrossRef]
  24. Steinberg D, Witztum JL. Is the oxidative modification hypothesis relevant to human atherosclerosis? Do the antioxidant trials conducted to date refute the hypothesis? Circulation. 2002; 105: 2107–2111.[Free Full Text]
  25. Esterbauer H, Gebicki J, Puhl H, Jurgens G. The role of lipid peroxidation and antioxidants in oxidative modification of LDL. Free Radic Biol Med. 1992; 13: 341–390.[CrossRef][Medline] [Order article via Infotrieve]
  26. Gaut JP, Heinecke JW. Mechanisms for oxidizing low-density lipoprotein. Insights from patterns of oxidation products in the artery wall and from mouse models of atherosclerosis. Trends Cardiovasc Med. 2001; 11: 103–112.[CrossRef][Medline] [Order article via Infotrieve]
  27. 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.[CrossRef][Medline] [Order article via Infotrieve]
  28. Thomas SR, Davies MJ, Stocker R. Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite. Chem Res Toxicol. 1998; 11: 484–494.[CrossRef][Medline] [Order article via Infotrieve]
  29. Van Lenten BJ, Navab M, Shih D, Fogelman AM, Lusis AJ. The role of high-density lipoproteins in oxidation and inflammation. Trends Cardiovasc Med. 2001; 11: 155–161.[CrossRef][Medline] [Order article via Infotrieve]
  30. Kontush A, Chantepie S, Chapman MJ. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler Thromb Vasc Biol. 2003; 23: 1881–1888.[Abstract/Free Full Text]




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