Effect of vitamins E and C on transplant-associated atherosclerosis

Effect of vitamins E and C on transplant-associated atherosclerosis

CORRESPONDENCE COMMENTARY CORRESPONDENCE e-mail submissions to [email protected] Effect of vitamins E and C on transplant-associated athero...

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CORRESPONDENCE

COMMENTARY

CORRESPONDENCE e-mail submissions to [email protected]

Effect of vitamins E and C on transplant-associated atherosclerosis Sir—James C Fang and colleagues (March 30, p 1108)1 report their analysis of the effect of two antioxidants, vitamins E and C, on the progression of transplant-associated atherosclerosis. They show that, compared with placebo, supplementation with these vitamins retards the progression of coronary atherosclerosis. This finding is apparently at variance with previous studies, in which no effect of antioxidant vitamin in coronary atherosclerosis was noted. Fang and colleagues argue that the beneficial effect they saw could be dependent on oxidative stress playing a major part in the pathogenesis of transplant-associated atherosclerosis. This hypothesis is consistent with the results of the secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE) trial,2 in which a reduced risk of cardiovascular events was seen in patients with renal insufficiency treated with 800 IU daily vitamin E. Despite the small sample size of Fang and colleagues’ trial and the SPACE trial, the converging results raise the question of whether antioxidant treatment could be of clinical benefit, especially in patients with increased oxidative stress and accelerated atherosclerosis. To substantiate the protective role of antioxidant vitamins on atherosclerotic progression, Fang and colleagues should provide more information. Contrary to most clinical trials with they report the antioxidants,3 bioavailability of vitamin C and E after supplementation. However, they do not show whether or not there is a correlation between plasma concentrations of the vitamins and progression of coronary atherosclerosis. In an experimental model, there was an inverse correlation between antioxidant plasma concentrations and atherosclerotic lesions.4 This information may be useful to interpret the role of antioxidant vitamins on coronary atherosclerotic progression. *Francesco Violi, Lorenzo Loffredo, Marianna Maranghi Division IV Clinica Medica, Policlinico Umberto I, University of Rome “La Sapienza”, Viale del Policlinico, 00161 Rome, Italy (e-mail: [email protected])

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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. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebocontrolled trial. Lancet 2000; 356: 1213–18. Violi F, Micheletta F, Iuliano L. Clinical trials with vitamin E in cardiovascular disease: are they meaningful? Thromb Haemost 2001; 86: 1121–22. Praticò D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reduces atherosclerosis in ApoEdeficient mice. Nat Med 1998; 4: 1189–92.

Sir—The mechanism of protection discussed by James Fang and colleagues1 remains unknown, since in that study the benefit of antioxidants they show seems to be independent of any change in endothelial function. However, vitamin E (500 IU orally per day) was shown in a randomised trial2 to decrease in-vitro platelet aggregation, and platelet aggregation was shown3 to be predictive of complications of coronary heart disease (CHD) in heart-transplant recipients. Findings from pathological studies4 also suggest a major role of platelet thrombosis in the accelerated form of CHD that develops after heart transplantation. Thus, the benefit noted by Fang and colleagues might be related to an effect on platelets. Although there is no question about the association of cardiac transplantation and oxidant stress and the benefit of supplementing patients with antioxidants,1,2 we report some other features of dietary antioxidant supplementation after transplantation. First, in addition to reducing platelet aggregation, we noted that vitamin E generally improved immunosuppression (by reducing lymphocyte count, p=0·009) and decreased cyclosporine nephrotoxic effects, since we saw a significant decrease in blood creatinine concentrations, whereas cyclosporine trough concentrations (and dose) remained stable.2 These two effects are very important for the every-day management of such patients, and should be known by the physicians. Thus, we ask Fang and colleagues whether they noted the same

favourable factors with their antioxidant regimen (800 IU vitamin E, 1000 mg vitamin C). Our second comment concerns the effects of antioxidant supplementation on HDL cholesterol. We actually saw a slight but significant decrease in HDL cholesterol in our trial,2 which has been confirmed in a study of nontransplanted CHD patients who received simvastatin and niacin.5 Beyond the present controversy about the potential benefit of antioxidants to prevent CHD, and the effect of antioxidants on HDLcholesterol concentration, Fang and colleagues also report a decrease, although not a significant one, probably because of the small sample size, in HDL cholesterol in their supplemented group.1 Whether this finding explains the lack of effect of antioxidants on endothelial function warrants further investigation. Nevertheless, antioxidants actually retarded the progression of atherosclerosis after transplantation, which also emphasises the need for clinical rather than surrogate endpoints to assess the protective effect of any treatment. The main question in the context of post-transplant CHD, and in the absence of clinical warning such as chest pain, is whether intravascular ultrasonographic measurements can substitute for true clinical endpoints. *Michel de Lorgeril, Patricia Salen Laboratoire du Stress Cardiovasculaire et des Pathologies Associées, UFR de Médecine et Pharmacie, Domaine de la Merci, 38706 La Tronche, Grenoble, France (e-mail: [email protected]) 1

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Fang JC, Kinlay S, Beltrame J, et al. Effects of vitamin C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet 2002; 359: 1108–13. de Lorgeril M, Boissonnat P, Salen P, et al. The beneficial effect of dietary antioxidant supplementation on platelet aggregation and cyclosporine treatment in heart transplant recipients. Transplantation 1994; 58: 193–94. de Lorgeril M, Boissonnat P, Mamelle N, et al. Platelet aggregation and HDL cholesterol are predictive of acute coronary events in heart transplant recipients. Circulation 1994; 89: 2590–94. de Lorgeril M, Loire R, Guidollet J, et al. Accelerated coronary artery disease after heart transplantation: the role of enhanced platelet aggregation and thrombosis. J Intern Med 1993; 233: 343–50.

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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]) 1

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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]) 1

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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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