Cheung MC, Zhao XQ, Chait A, et al. Antioxidant supplements block the response of HDL to simvastatin-niacin therapy in patients with coronary artery disease and low HDL. Arterioscl Thromb Vasc Biol 2001; 21: 1320–26.
Sir—James Fang and colleagues1 show that although vitamins C and E reduce the progression of transplant-associated atherosclerosis, they do not affect the frequency of episodes of acute parenchymal rejection. They suggest that transplantasscociated atherosclerosis and parenchymal rejection are mediated by different parts of the immune system, and that treatment that eliminates transplant-asscociated atherosclerosis may not affect acute parenchymal rejection. We think that a possibility for cross-talk between the two mechanisms exists, and that vitamins C and E may act as mediators of both. Unfortunately, dependent on doses, opposite and paradoxical effects can arise.2 Vitamins C and E are powerful antioxidants, more so in combination, but they also have immunostimulating effects;3 therefore, it is not surprising that they do not prevent parenchymal rejection in the host. Moreover, they can affect host immune reactivity by different and opposite mechanisms, and the final effect is unpredictable. At least three important cross-linked targets for vitamins C and E exist in the area of graft: marcophage activation; endothelial-cell activation and cytokine expression; and nitric-oxide (NO) and prostanoids synthesis and regulation of microcirculation. Vitamin E inhibits protein-kinase C-dependent oxidative burst of macrophages, and thus suppresses macrophage-mediated oxidative stress. Vitamin C regenerates vitamin E from tocopheroxyl-radical, which keeps its study-state concentration in the host. Both mechanisms are widely discussed by Fang and colleagues. However, the two vitamins have many other effects on the host immune system. Supplementation with vitamins C and E increases cytokine production in healthy adults.4 The same effect might occur in transplant recipients. Endothelial activation and cytokine expression is postulated as a probable component of the host response in acute allograft rejection and cardiac transplant-asscociated atherosclerosis, and, therefore, the advisability of vitamin C and E supplementation becomes disputable. Vitamin E enrichment also lowers the synthesis of NO and potentiates the release of prostacyclin through direct interaction with NO radicals or up-regulation of the expression of NO synthase,
phospholipase A2, and cyclo-oxygenase isoenzymes.5 Collectively, these biological functions of vitamin E may account for regulation of microcirculation in the graft area. It should be borne in mind that NO and prostacyclin are endogenous vasodilators necessary to transplant recipients, and the final effect of vitamin E on vascular resistance is unclear. Therefore, to eliminate potentially unacceptable effects of vitamins C and E on the host immune system and on microcirculation, and to make progress in prevention of acute parenchymal rejection, potential targets for therapeutic interventions should be identified and natural and synthetic substances with multidiractional effects combined. Zhivko Zhelev, *Rumiana Bakalova Functional Organic Materials Section, National Institute of Advanced Industrial Science and Technology, AIST Kyushu, Saga-ken 841-0052, Japan (e-mail: [email protected]
Fang JC, Kinlay S, Beltrame J, et al. Effects of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002; 359: 1108–13. Halliwell B. The antioxidant paradox. Lancet 2000; 355: 1179–80. Beharka A, Redican S, Leka L, et al. Vitamin E status and immune function. Meth Enzymol 1997; 282: 247–63. Jeng KC, Yang CS, Siu WY, et al. Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults. Am J Clin Nutr 1996; 64: 960–65. Bruckner G. Microcirculation, vitamin E and omega 3 fatty acids: an overview. Adv Exp Med Biol 1997; 415: 195–208.
Authors’ reply Sir—We noted no correlation between the antioxidant vitamin concentrations and the progression of coronary atherosclerosis. This lack of correlation may be due to our sample size or due to the inability of the plasma concentrations of these antioxidant vitamins to fully characterise the oxidant environment, especially at the tissue level. Although we have previously reported a relation between plasma vitamin C and coronary endothelial responses, this correlation was before vitamin supplementation.1 We are currently investigating other measures of oxidant stress in this population and there is a suggestion that, for example, autoantibodies to oxidised LDL cholesterol also correlate with the degree of coronary endothelial dysfunction.2 Michel de Lorgeril and Patricia Salen suggest that the mechanism of the vitamin effect in our study may have been mediated by improvements in platelet biology, increased immunosuppression, or both. We did not
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prospectively collect information on platelet function but agree that improvements in platelet function can be seen after vitamin supplementation. We did not examine the relation between lymphocyte counts, serum creatinine, and vitamin concentrations because of the number of confounding variables (ie, purine antagonist doses, antihypertensive drugs, fluctuating cyclosporine concentrations, diuretic use, diabetes, etc). These inter-related factors could probably not be examined adequately in a study of our size. de Lorgeril and Salen also suggest that the lack of vitamin effect on coronary endothelial function in our study might be explained by decreases in HDL cholesterol induced by vitamin supplementation, which has been observed in other populations. Our data do not allow us to draw such conclusions, but we would suggest that the lack of antioxidant effect on coronary endothelial function in our study results from the beneficial use of pravastatin in the active drug and placebo groups.3 Finally, they question the use of ultrasonographic measurements of coronary arteriosclerosis as a valid surrogate for post-transplant heart disease. Several studies4,5 have shown that such measurements do indeed predict clinical outcomes. Therefore, we are comfortable in the implications of our work for the routine clinical management of the cardiac transplant recipient, but await large-scale longterm clinical trials for further confirmation. *James C Fang, Scott Kinlay, Peter Ganz Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA 02115, USA (e-mail: [email protected]
Fang JC, Kinlay S, Hikita H, et al. Relation of nitric oxide dependent coronary vasomotor function to plasma vitamin C concentration in cardiac transplant recipients. Am J Cardiol 2000; 86: 460–62. Fang JC, Kinlay S, Hikita H, Witztum JL, Selwyn AP, Ganz P. An IgG auto-antibody to oxidized LDL is related to impaired coronary endothelial function in patients after cardiac transplantation. Circulation 1999; 100: I–834. Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol lowering and antioxidant therapy on endothelium dependent coronary vasomotion. N Engl J Med 1995; 332: 488–93. Mehra MR, Ventura HO, Stapleton DD, Smart FW, Collins TC, Ramee SR. Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy. J Heart Lung Transplant 1995; 14: 632–39. Rickenbacher PR, Pinto FJ, Lewis NP, et al. Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation. Circulation 1995; 92: 1445–2452.
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