Should antioxidant status be considered in interventional trials with antioxidants?
Journal: 2004/June - Heart
ISSN: 1468-201X
PUBMED: 15145850
Abstract:
The last decade has seen many trials with antioxidants in patients with cardiovascular disease, with equivocal results. One possible explanation for the disappointing findings is the lack of identification criteria of patients who are potential candidates for antioxidant treatment. Several studies have been carried out in patients at risk of cardiovascular disease, indicating that enhanced oxidative stress is associated with the presence of diabetes, hypercholesterolaemia, hypertension, and smoking. This review analyses the data reported so far to determine whether they clearly support the premise that patients at risk of cardiovascular events may be candidates for antioxidant treatment.
Relations:
Content
Citations
(7)
References
(46)
Diseases
(5)
Conditions
(1)
Chemicals
(1)
Organisms
(1)
Processes
(1)
Affiliates
(1)
Similar articles
Articles by the same authors
Discussion board
Heart 90(6): 598-602

Should antioxidant status be considered in interventional trials with antioxidants?

IV Divisione di Clinica Medica, Viale del Policlinico, University “La Sapienza”, Roma, Italy
Correspondence to:
Professor Francesco Violi
IV Divisione di Clinica Medica, Viale del Policlinico, 155, Roma, 00161, Italy; ti.1amorinu@iloiv.ocsecnarf
Correspondence to:
Professor Francesco Violi
IV Divisione di Clinica Medica, Viale del Policlinico, 155, Roma, 00161, Italy; ti.1amorinu@iloiv.ocsecnarf

Abstract

The last decade has seen many trials with antioxidants in patients with cardiovascular disease, with equivocal results. One possible explanation for the disappointing findings is the lack of identification criteria of patients who are potential candidates for antioxidant treatment. Several studies have been carried out in patients at risk of cardiovascular disease, indicating that enhanced oxidative stress is associated with the presence of diabetes, hypercholesterolaemia, hypertension, and smoking. This review analyses the data reported so far to determine whether they clearly support the premise that patients at risk of cardiovascular events may be candidates for antioxidant treatment.

Keywords: antioxidants, atherosclerosis, oxidative stress, vitamin C, vitamin E
Abstract

Oxidative stress is believed to play a crucial role in the initiation and progression of atherosclerosis disease. Oxidation of low density lipoprotein (LDL) within the vessel wall represents a key step in the accumulation of LDL by resistant macrophages that ultimately become the foam cells of atherosclerotic plaque.1 Enzymatic and non-enzymatic oxidation of LDL seems to be involved in this process but its relevance in the evolution of human atherosclerosis is still unclear.1 An important consideration is the evident discrepancy between experimental and clinical trials with antioxidants, which have provided divergent results. Most trials with antioxidants in experimental models of atherosclerosis have demonstrated that this treatment is able to retard the progression of atherosclerosis, while the results of clinical trials are conflicting,1 inasmuch as positive as well as negative effects have been reported. Investigation of antioxidants for prevention of atherosclerosis stems from observational trials that demonstrated the existence of an inverse relation between the consumption of antioxidant vitamins and the risk of cardiovascular events. However, meta-analysis of the observational studies indicated that among antioxidant vitamins, vitamin E was the only one that exerted a beneficial effect against atherosclerotic complications.2

On the basis of these data almost all the trials have been planned on the assumption that supplementation with vitamin E would represent a useful approach in preventing cardiovascular disease.

However, candidates for antioxidant treatment were not accurately defined probably for the application of the following syllogism:

  • oxidant stress is a common pathway for initiation and progression of atherosclerosis

  • cardiovascular complications are secondary to atherosclerosis

  • all patients with or at risk of cardiovascular complications have enhanced oxidant stress and could obtain beneficial effects from antioxidant treatment.

That this syllogism has been applied to almost all trials with antioxidants is demonstrated by the fact that any patient at risk of cardiovascular events has been indiscriminately enrolled in those trials. We argue on the contrary that, as antioxidant status represents an important marker of oxidative stress,3 its determination may be useful in better identifying candidates for antioxidant treatment. In order to substantiate this hypothesis, data inherent to oxidative stress and antioxidant status in patients at risk of cardiovascular disease, and in patients included in observational and interventional trials, have been reviewed. As antioxidant vitamins, such as vitamins E and C, are major determinants of antioxidant status and have been the object of the most important research in this field, our analysis essentially focuses on the clinical relevance of these vitamins in patients with cardiovascular disease.

REFERENCES

REFERENCES

References

  • 1. 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;105:2107–11. [[PubMed]
  • 2. Jha P, Flather M, Lonn E, et al. The antioxidant vitamins and cardiovascular disease. A critical review of epidemiologic and clinical trial data. Ann Intern Med 1995;123:860–72. [[PubMed]
  • 3. Violi F, Micheletta F, Iuliano L. How to select patient candidates for antioxidant treatment? Circulation 2002;106:e195. [[PubMed]
  • 4. Mezzetti A, Cipollone F, Cuccurullo F. Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm. Cardiovasc Res 2000;47:475–88. [[PubMed]
  • 5. Timimi FK, Ting HH, Haley EA, et al. Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. J Am Coll Cardiol 1998;31:552–7. [[PubMed]
  • 6. Cosentino F, Hishikawa K, Katusic ZS, et al. High glucose increases nitric oxide synthase expression and superoxide anion generation in human aortic endothelial cells. Circulation 1997;96:25–8. [[PubMed]
  • 7. Wolin MS. Interactions of oxidants with vascular signaling systems. Arterioscler Thromb Vasc Biol 2000;20:1430–42. [[PubMed]
  • 8. Guzik TJ, Mussa S, Gastaldi D, et al. Mechanisms of increased vascular superoxide production in human diabetes mellitus: role of NAD(P)H oxidase and endothelial nitric oxide synthase. Circulation 2002;105:1656–62. [[PubMed]
  • 9. Ohara Y, Peterson TE, Sayegh HS, et al. Dietary correction of hypercholesterolemia in the rabbit normalizes endothelial superoxide anion production. Circulation 1995;92:898–903. [[PubMed]
  • 10. Davì G, Alessandrini P, Mezzetti A, et al. In vivo formation of 8-epi-prostaglandin F2α is increased in hypercholesterolemia. Arterioscler Thromb Vasc Biol 1997;17:3230–35. [[PubMed]
  • 11. Ting HH, Timimi FK, Haley EA, et al. Vitamin C improves endothelium-dependent vasodilation in forearm resistance vessels of humans with hypercholesterolemia. Circulation 1997;95:2617–22. [[PubMed]
  • 12. Sanguigni V, Pignatelli P, Caccese D, et al. Increased superoxide anion production by platelets in hypercholesterolemic patients. Thromb Haemost 2002;87:796–801. [[PubMed]
  • 13. Ferro D, Parrotto S, Basili S, et al. Simvastatin inhibits the monocyte expression of proinflammatory cytokines in patients with hypercholesterolemia. J Am Coll Cardiol 2000;36:427–31. [[PubMed]
  • 14. Beswick RA, Dorrance AM, Leite R, et al. NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat. Hypertension 2001;38:1107–11. [[PubMed]
  • 15. Berry C, Hamilton CA, Brosnan MJ, et al. Investigation into the sources of superoxide in human blood vessels: angiotensin II increases superoxide production in human internal mammary arteries. Circulation 2000;101:2206–12. [[PubMed]
  • 16. Sanguigni V, Germanò G, Pignatelli P, et al. Role of AT1 receptors in enhancing oxidative stress in patients with hypertension. AHA Scientific Sessions. 2002, Abstract ID, 102176.
  • 17. Taddei S, Virdis A, Ghiadoni L, et al. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation 1998;97:2222–9. [[PubMed]
  • 18. Miller ER, Appel LJ, Jiang L, et al. Association between cigarette smoking and lipid peroxidation in a controlled feeding study. Circulation 1997;96:1097–101. [[PubMed]
  • 19. Morrow JD, Frei B, Longmire AW, et al. Increase in circulating products of lipid peroxidation (F2-isoprostanes) in smokers. Smoking as a cause of oxidative damage. N Engl J Med 1995;332:1198–203. [[PubMed]
  • 20. Davi G, Guagnano MT, Ciabattoni G, et al. Platelet activation in obese women: role of inflammation and oxidant stress. JAMA 2002;288:2008–14. [[PubMed]
  • 21. Wen Y, Killalea S, McGettigan P, et al. Lipid peroxidation and antioxidant vitamins C and E in hypertensive patients. Ir J Med Sci 1996;165:210–2. [[PubMed]
  • 22. Duffy SJ, Gokce N, Holbrook M, et al. Effect of ascorbic acid treatment on conduit vessel endothelial dysfunction in patients with hypertension. Am J Physiol Heart Circ Physiol 2001;280:H528–34. [[PubMed]
  • 23. Pierdomenico SD, Costantini F, Bucci A, et al. Low-density lipoprotein oxidation and vitamins E and C in sustained and white-coat hypertension. Hypertension 1998;31:621–6. [[PubMed]
  • 24. Liu CS, Chen HW, Lii CK, et al. Alterations of small-molecular-weight antioxidants in the blood of smokers. Chem Biol Interact 1998;116:143–54. [[PubMed]
  • 25. Tsuchiya M, Asada A, Kasahara E, et al. Smoking a single cigarette rapidly reduces combined concentrations of nitrate and nitrite and concentrations of antioxidants in plasma. Circulation 2002;105:1155–7. [[PubMed]
  • 26. Mol MJ, de Rijke YB, Demacker PN, et al. Plasma levels of lipid and cholesterol oxidation products and cytokines in diabetes mellitus and cigarette smoking: effects of vitamin E treatment. Atherosclerosis 1997;129:169–76. [[PubMed]
  • 27. Sinclair AJ, Taylor PB, Lunec J, et al. Low plasma ascorbate levels in patients with type 2 diabetes mellitus consuming adequate dietary vitamin C. Diabet Med 1994;11:893–8. [[PubMed]
  • 28. Maxwell SR, Thomason H, Sandler D, et al. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. Eur J Clin Invest 1997;27:484–90. [[PubMed]
  • 29. Leonhardt W, Hanefeld M, Muller G, et al. Impact of concentrations of glycated hemoglobin, alpha-tocopherol, copper, and manganese on oxidation of low-density lipoproteins in patients with type I diabetes, type II diabetes and control subjects. Clin Chim Acta 1996;254:173–86. [[PubMed]
  • 30. Gòde P, Poulsen HE, Parving HH, et al. Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in type 2 diabetic patients Diabet Med 2001;18:756–60. [[PubMed]
  • 31. Seghieri G, Martinoli L, di Felice M, et al. Plasma and platelet ascorbate pools and lipid peroxidation in insulin-dependent diabetes mellitus. Eur J Clin Invest 1998;28:659–63. [[PubMed]
  • 32. Jain SK, McVie R, Jaramillo JJ, et al. The effect of modest vitamin E supplementation on lipid peroxidation products and other cardiovascular risk factors in diabetic patients. Lipids 1996;31 (suppl):S87–90. [[PubMed]
  • 33. Porkkala-Sarataho E, Nyyssonen K, Salonen JT. Increased oxidation resistance of atherogenic plasma lipoproteins at high vitamin E levels in non-vitamin E supplemented men. Atherosclerosis 1996;124:83–94. [[PubMed]
  • 34. Salonen RM, Nyyssonen K, Kaikkonen J, et al. Antioxidant supplementation in atherosclerosis prevention study. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the antioxidant supplementation in atherosclerosis prevention (ASAP) study. Circulation 2003;107:947–53. [[PubMed]
  • 35. Nourooz-Zadeh J, Smith CCT, Betteridge DJ. Measures of oxidative stress in heterozygous familial hypercholesterolaemia. Atherosclerosis 2001;156:435–41. [[PubMed]
  • 36. Pryor WA. Vitamin E and heart disease: basic science to clinical intervention trials. Free Radic Biol Med 2000;28:141–64. [[PubMed]
  • 37. Pratico D, Tangirala RK, Rader DJ, et al. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoE-deficient mice. Nat Med 1998;4:1189–92. [[PubMed]
  • 38. Van der Loo B, Labugger R, Abeischer CC. Cardiovascular aging is associated with vitamin E increase. Circulation 2002;105:1635–8. [[PubMed]
  • 39. Gotto AM. Antioxidants, statins, and atherosclerosis. J Am Coll Cardiol 2003;41:1205–10. [[PubMed]
  • 40. Iuliano L, Micheletta F, Maranghi M, et al. Bioavailability of vitamin E as function of food intake in healthy subjects: effects on plasma peroxide-scavenging activity and cholesterol-oxidation products. Arterioscler Thromb Vasc Biol 2001;21:E34–7. [[PubMed]
  • 41. Carroll MF, Schade DS. Timing of antioxidant vitamin ingestion alters postprandial proatherogenic serum markers. Circulation 2003;108:24–31. [[PubMed]
  • 42. Gey KF. Vitamin E and other essential antioxidants regarding coronary heart disease: risk assessment studies. Epidemiological basis of the antioxidant hypothesis of cardiovascular disease. In: Packer L, Fuchs J, eds. Vitamin E in health and disease. New York: Marcel Dekker, Inc, 1993:589–633.
  • 43. Riemersma RA, Wood DA, Macintyre CC, et al. Risk of angina pectoris and plasma concentration of vitamins A, C, and E and carotene. Lancet 1991;337:1–5. [[PubMed]
  • 44. Mezzetti A, Zuliani G, Romano F, et al. Vitamin E and lipid peroxide plasma levels predict the risk of cardiovascular events in a group of healthy very old people. J Am Geriatr Soc 2001;49:533–7. [[PubMed]
  • 45. Hodis HN, Mack WJ, La Bree L, et al. for 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;106:1453–9. [[PubMed]
  • 46. Violi F, Micheletta F, luliano L. Vitamin E supplementation. Lancet 2000;357:632–3. [[PubMed]
  • 47. Inoue T, Uchida T, Kamishirado H, et al. Antibody against oxidized low density lipoprotein may predict progression or regression of atherosclerotic coronary artery disease. J Am Coll Cardiol 2001;37:1871–6. [[PubMed]
  • 48. Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet 2003;361:2017–23. [[PubMed]
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.