What Should We Advise Our Patients About Taking Antioxidants?

Thomas G. Pickering, MD, DPhil

Introduction

Increasing numbers of our patients are taking supplements, among the most popular of which are antioxidants, such as vitamins C, E, and ß carotene. These are the "big three" antioxidants, which have received the most attention, but they are by no means the only ones. There are many others in fruits and vegetables, with less familiar names such as lycopene and quercetin, whose clinical significance is less well studied. The rationale for this attention is two-fold. First, there are numerous basic science studies showing that these antioxidants, which act by "scavenging" free radicals such as the reactive oxygen species (ROS), cannot only antagonize the harmful effects of ROS, but also delay the progression of the atherosclerotic process.[1] Second, there are also a number of epidemiologic studies that have shown inverse correlations between the intake of these antioxidants and the prevalence of cancer and heart disease.[2] However, when the clinical studies progressed from observational studies to randomized controlled intervention trials, the results have been mostly disappointing.[3] Hence, the paradox.

The Basic Science Findings

The most important oxidants are the ROS, which have three major constituents: superoxide radicals, hydroxyl radicals, and hydrogen peroxide. They are generated by a number of cytosolic enzymes, most importantly nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Another enzyme that may be implicated is xanthine oxidase, which is markedly increased in patients with heart failure.[4] ROS are produced in small amounts by normal vascular endothelium cells, but production can be markedly increased in the presence of inflammation, when it is stimulated by the presence of neutrophils and other phagocytes. ROS do a number of bad things, including promoting endothelial dysfunction and apoptosis, the formation of foam cells, the activation of platelets, and the expression of leucocyte adhesion molecules. One of the key interactions is with nitric oxide, which not only produces vasodilation, but also has antiatherogenic effects. Cardiovascular risk factors such as smoking may do some of their damage by increasing production of ROS such as superoxide, which reacts rapidly with nitric oxide and inactivates it.[5] Endothelial dysfunction, a generally accepted surrogate measure for impaired availability of nitric oxide, is now entering the clinical arena, as it has been shown in at least four prospective studies that endothelial dysfunction is an independent predictor of cardiovascular events.[5] In one of these studies[6] it was found that the patients at highest risk of events were also those whose endothelial dysfunction was reversed by the intra-arterial administration of vitamin C.

Increased production of ROS is characteristic of several models of hypertension, including the spontaneously hypertensive rat (SHR), the Dahl salt-sensitive rat, and hypertension induced by angiotensin infusion.[7] Since increased ROS production is observed in the pre-hypertensive SHR, it is unlikely that it is a consequence of the increased blood pressure. Furthermore, antioxidants can reduce the blood pressure of SHRs.[7] Angiotensin is a special case here. NADPH oxidase (the enzyme that boosts ROS production) is stimulated by angiotensin, and angiotensin infusion increases superoxide levels in the blood, as well as increasing blood pressure. In contrast, norepinephrine infusions that cause the same increase of blood pressure do not have any effect on superoxide.[7] The superoxide resulting from the actions of angiotensin scavenges nitric oxide and removes its vasodilating effects, so this may be one mechanism by which angiotensin raises the blood pressure.[8] Indeed, in mice in which the NADPH oxidase is deficient, both the pressor response to angiotensin and the production of superoxide are greatly diminished.[5]

The Clinical Findings

Studies of the effects of antioxidants on the progression of atherosclerosis have mostly proved disappointing.[5] Examples are the Heart Outcomes Prevention Evaluation (HOPE)[9] and Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)[10] trials, in which vitamin E was found to be no better than placebo at preventing cardiovascular morbid events. A substudy of HOPE, the Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E (SECURE),[11] found that vitamin E had no effect on preventing the progression of carotid atherosclerosis, evaluated by ultrasound, while the angiotensin-converting enzyme (ACE) inhibitor ramipril did have a protective effect. Another study, Antioxidant Supplementation for Atherosclerosis Prevention (ASAP),[12] found that vitamins E and C did not delay the progression of carotid atherosclerosis when given on their own, although the combination of the two did. However, combination treatment may not always be the answer since the Heart Protection Study[13] found no benefit from the combination of vitamins C (250 mg/day), E (600 mg/day), and ß carotene (20 mg/day) given to a population of more than 20,000 people at high risk for cardiovascular events.

Other modalities of treatment that have antioxidant effects have provided more positive results, however. Two treatments that have been shown to prevent cardiovascular events are statins and ACE inhibitors. Both inhibit the actions of NADPH oxidase, and hence, prevent the formation of ROS, which may be a more effective strategy than trying to scavenge them after they have been formed (the mechanism of action of vitamins E and C).[5]

Increased production of superoxide and hydrogen peroxide has also been found in patients with untreated hypertension, and plasma hydrogen peroxide levels correlate with the height of the blood pressure.[7] Lymphocytes taken from hypertensive subjects show increased ROS production that can be attributed to NADPH oxidase activity.[14] Studies of antioxidants in hypertensive patients have given mixed results. Intravenous administration of vitamin C and glutathione have been reported to lower blood pressure acutely in hypertensive patients,[15] and some studies[16] have reported an antihypertensive effect of chronic administration. However, others[17] have failed to confirm this. The effects of both vitamins E and C on blood pressure have been investigated using ambulatory monitoring. Administration of 300 mg/day of vitamin E to 142 treated hypertensives for 12 weeks had no significant effect on ambulatory blood pressure,[18] and giving vitamin C (500 mg/day) to 40 elderly hypertensives for 3 months resulted in a small (2 mm Hg) but just significant fall of systolic pressure.[19] At least two randomized trials of the effects of coenzyme Q10 (another antioxidant) on blood pressure have been reported. In the first,[20] 59 treated hypertensives were randomized to either coenzyme Q10 (60 mg twice daily) or vitamin B (placebo); after 8 weeks, clinic blood pressure was 14/7 mm Hg lower in the treated group. In the second,[21] 83 patients with isolated systolic hypertension were treated with coenzyme Q10 (using the same dose as the earlier study) for 12 weeks. The mean reduction of blood pressure was 17.8/7.3 mm Hg.

The increased ROS production in hypertension can to some extent be reversed by controlling the hypertension with ACE inhibitors, ß blockers, and calcium channel blockers; additionally, ACE inhibitors have been shown to have antioxidant properties in vitro.[7] Carvedilol, a combined and ß blocker, decreases low-density lipoprotein oxidation in hypertensive patients.

Another antioxidant beginning to attract more attention is lycopene, the acyclic and more potent form of ß carotene, which is found mainly in tomatoes. It is not only resistant to the heat of cooking, but also has a greater bioavailability in processed than in fresh tomatoes. In the Kuopio Ischemic Heart Disease Risk Factor study[22] of Finnish men it has been found that men with the lowest circulating levels of lycopene had the most advanced carotid atherosclerosis.

Another major group of antioxidants is the flavonoids, which are present in several vegetable sources, including grapes, red wine, tea, broccoli, onions, and apples. Chemically, they are polyphenols; they are effective scavengers of ROS, and can inhibit lipid peroxidation through chelation of transition metal ions or their action as chain-breaking antioxidants.[23] Quercetin is a flavonoid that makes up about 60% of the total intake. In rats made hypertensive by the administration of NG-nitro-L-arginine methyl ester (L-NAME), which raises blood pressure by inhibiting nitric oxide synthesis (and also causes endothelial dysfunction), the addition of quercetin in the diet prevented the hypertension and related vascular damage.[24]

At the present time, there appears to be no justification for recommending that our patients take antioxidants on a routine basis, either to lower their blood pressure or to prevent its consequences. The situation was well summarized in a report from the American Heart Association/American College of Cardiology,[25] which stated: "...the most prudent and scientifically supportable recommendation for the general population is to consume a balanced diet with emphasis on antioxidant-rich fruits and vegetables and whole grains...the absence of efficacy and safety data from randomized trials precludes the establishment of population-wide recommendations regarding vitamin E supplementation." In other words, as our mothers told us, we must eat our broccoli, and advise our patients to do the same.

References

  1. Diaz MN, Frei B, Vita JA, et al. Antioxidants and atherosclerotic heart disease. N Engl J Med. 1997;337(6):408-416.

  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(11):860-872.

  3. Hooper L, Ness AR, Smith GD. Antioxidant strategy for cardiovascular diseases. Lancet. 2001;357(9269):1705-1706.

  4. Landmesser U, Spiekermann S, Dikalov S, et al. Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine-oxidase and extracellular super-oxide dismutase. Circulation. 2002;106(24):3073-3078.

  5. Landmesser U, Harrison DG. Oxidant stress as a marker for cardiovascular events: ox marks the spot. Circulation. 2001; 104(22):2638-2640.

  6. Heitzer T, Schlinzig T, Krohn K, et al. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001;104(22): 2673-2678.

  7. Kitiyakara C, Wilcox CS. Antioxidants for hypertension. Curr Opin Nephrol Hypertens. 1998;7(5):531-538.

  8. Hilgers KF, Stumpf C. Angiotensin II, the endothelium and superoxide anions. J Hypertens. 2002;20(7):1271-1273.

  9. 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(3):154-160.

  10. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSIPrevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico. Lancet. 1999; 354(9177):447-455.

  11. 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(7):919-925.

  12. 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(7):947-953.

  13. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):23-33.

  14. Pettit AI, Wong RK, Lee V, et al. Increased free radical production in hypertension due to increased expression of the NADPH oxidase subunit p22(phox) in lymphoblast cell lines. J Hypertens. 2002;20(4):677-683.

  15. Ceriello A, Giugliano D, Quatraro A, et al. Antioxidants show an anti-hypertensive effect in diabetic and hypertensive subjects. Clin Sci (Lond). 1991;81(6):739-742.

  16. Galley HF, Thornton J, Howdle PD, et al. Combination oral antioxidant supplementation reduces blood pressure. Clin Sci (Lond). 1997;92(4):361-365.

  17. Ghosh SK, Ekpo EB, Shah IU, et al. A double-blind, placebo-controlled parallel trial of vitamin C treatment in elderly patients with hypertension. Gerontology. 1994;40(5): 268-272.

  18. Palumbo G, Avanzini F, Alli C, et al. Effects of vitamin E on clinic and ambulatory blood pressure in treated hypertensive patients. Collaborative Group of the Primary Prevention Project (PPP) -- Hypertension study. Am J Hypertens. 2000; 13(5 pt 1):564-567.

  19. Fotherby MD, Williams JC, Forster LA, et al. Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons. J Hypertens. 2000;18(4):411-415.

  20. Singh RB, Niaz MA, Rastogi SS, et al. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens. 1999;13(3):203-208.

  21. Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J. 2001;94(11):1112-1117.

  22. Rissanen TH, Voutilainen S, Nyyssonen K, et al. Serum lycopene concentrations and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr. 2003;77(1):133-138.

  23. Cosentino F, Volpe M. Antihypertensive effect and end-organ protection of flavonoids: some insights, more questions. J Hypertens. 2002;20(9):1721-1724.

  24. Duarte J, Jimenez R, O'Valle F, et al. Protective effects of the flavonoid quercetin in chronic nitric oxide deficient rats. J Hypertens. 2002;20(9):1843-1854.

  25. Tribble DL. AHA Science Advisory. Antioxidant consumption and risk of coronary heart disease: emphasis on vitamin C, vitamin E, and beta-carotene: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;99(4):591-595.