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Natural antioxidants and restenosis after percutaneous transluminal coronary angioplasty
EDITORIAL
Natural antioxidants and restenosis after percutaneous transluminal coronary angioplasty Susan L. Godfried, MD, and Lawrence I. Deckelbaum, MD West Haven and N e w Haven, Conn.
Percutaneous transluminal coronary angioplasty (PTCA) has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977.1 Despite the increase in case complexity the primary success rate for PTCA has improved. Restenosis, however, remains a problem after successful angioplasty, occurring in --<57% of patients within the first 6 months 2 after the procedure. Many interventions, both mechanic and pharmacologic, have been attempted to reduce the rate of restenosis. None have been conclusively successful to date. Mechanical approaches include long inflations with autoperfusion devices, postprocedure implantation of coronary stents, and plaque removal by atherectomy and laser angioplasty. Pharmacologic approaches include antiplatelet agents, prostacyclin analogs, calcium channel blockers, anticoagulants, cholesterol-lowering agents, and ~ 3 fatty acids. Of the interventions tested, only lovastatin and ~ 3 fatty acids have been shown to reduce restenosis rates in some, although not all, clinical trials. 37 Given the variation in study design and results of these trials, their results must be interpreted with caution. Restenosis appears to be the result of two processes: an accelerated form of atherosclerosis induced by arterial injury 8 and a wound-healing response to severe intimal and medial damage. 9 Antioxidants may attenuate the process of restenosis after anglo-
From the Departments of Internal Medicine, Veterans Administration Medical Center, West Haven, and Yale University School of Medicine, New Haven. Received for publication Jan. 6, 1994; accepted May 2, 1994. Reprint requests: Lawrence I. Deckelbaum, MD, Section of Cardiology, III B, West Haven VAMC, 950 Campbell Ave., West Haven, CT 06516. AM HEART J 1995;129:203-10. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/1/59126
plasty through their ability to both reduce the progression of atherosclerotic plaque formation and to favorably influence wound healing. Either alone or in combination, the natural antioxidants, vitamin E (a, ~, 7, and 5 tocopherol), vitamin C (ascorbic acid), and beta-carotene, prevent oxidation of low-density lipoproteins (LDL) and cellular constituents, reduce platelet aggregation, modulate prostaglandin and leukotriene synthesis, and reduce inflammation. The following discussion reviews natural antioxidants and their effects on the processes involved in restenosis in support of the hypothesis that these antioxidants may decrease the incidence of restenosis after PTCA. Antioxidants and atherosclerosis. Alone or in combination, natural antioxidants have been shown to reduce the progression of atherosclerotic plaque in animal models. Further, dietary vitamin E, vitamin C, and f~-carotene intake appears to be inversely correlated with vascular disease and its complications in population and clinical studies. Several trials have examined the relation between vitamins E and C and atherosclerosis in hypercholesterolemic animal models. Vitamin E supplementation significantly reduced atherosclerotic plaque formation in 5 of 11 trials. 1°-2° The effects of high dietary vitamin E on atherogenesis appeared to depend on the cholesterol status of the diet and/or plasma. Wilson et al. 1° and Westrope et al. 11reported that the ability of vitamin E to inhibit plaque formation was inversely related to the degree of hypercholesterolemia produced in a rabbit experimental model. In trials that showed an acceleration of atherosclerotic plaque formation diets that produced severe hypercholesterolemia (900 to 1400 mg/dl serum cholesterol) were used. 19, 2o The studies that showed a significant reduction 1°14 in atherosclerotic plaque formation were performed in animals with total serum cholesterol levels of <750 mg/dl. Vitamin C supple203
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mentation has been shown to significantly reduce atherosclerotic plaque formation in rabbits in two studies.21, 22 Two other animal studies have shown either a trend toward a beneficial effect or no effect. 23,24 No animal trials evaluated the effect of S-carotene on atherogenesis. Several epidemiologic trials suggest that populations with a high intake of vitamin E have a lower risk of cardiovascular heart disease even after correction for other known risk factors. 25-27 Intake of #-carotene 27-29 and vitamin C 3°, Sl also appear to be negatively correlated with the incidence of vascular disease. Two prospective epidemiologic studies, the Nurses' Health Study 26 and the Health Professionals Follow-up Study, 27 recently reported an inverse correlation between vitamin E intake and cardiovascular disease. A cross-sectional survey in Europe and Israel, the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA) Project, reported a significant inverse relation between lipid standardized serum vitamin E levels and ischemic heart disease mortality (p = 0.0003) in men. 25 Indirect evidence of a benefit of vitamin E on atherogenesis in human beings has been reported in clinical trials involving patients with intermittent claudication. A significant increase both in symptom-free walking distance 32-37 and lower extremity arterial blood flow32 has been demonstrated in vitamin E-supplemented treatment groups as compared to controls treated with placebo33,35 or anticoagulants and vasodilatory agents. 34' 36 The Physicians Health Study found a statistically significant reduction in major vascular events by/~-carotene in a subgroup of patients with a history of stable angina and/or coronary revascnlarization. 2s Taken as a whole, these data suggest that antioxidants may effectively retard that part of the restenosis process that represents accelerated atherosclerosis. Antioxidants and LDL. Areas of intima that are denuded by angioplasty have a dramatically increased rate of lipid uptake and deposition in hyperlipidemic animal models. 3s Tissue damage, such as that produced by angioplasty, leads to rapid increases in the production of oxidative products caused by platelet aggregation, phagocytosis, synthesis of prostaglandins, and rapid increases or changes in cellular metabolic activities. These reactive oxidative products can oxidize LDL. Once oxidized, LDL promotes plaque formation in several ways. It accelerates foam-cell formation by enhancing LDL uptake into macrophages 39 and smooth-muscle cells. It is chemotactic for blood monocytes 4° and inhibits macrophage motility, thereby augmenting monocyte recruitment into intimal lesions. It stimulates monocyte
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adherence to the arterial intima and differentiation of monocytes into macrophages. 41 It promotes cellular necrosis and endothelial injury within the arterial wall resulting from direct cytotoxicity, 42 and it stimulates smooth-muscle cell proliferation by increasing release of interleukin-1 from macrophagesJ 3 Although the role of oxidized LDL in restenosis has not been definitively resolved, vitamin E, vitamin C, and S-carotene prevent oxidative modification of LDL42, 44-52 and may therefore slow oxidized L D L mediated plaque growth after angioplasty. Antioxidants and inflammation and wound healing.
Angioplasty causes substantial vascular damage by denuding endothelium and creating intimal and medial dissections. As a result, the vessel undergoes a healing response with three characteristic phases: inflammation, granulation, and extracellular matrix deposition. Oxidative cytotoxic products produced by vessel injury may enhance the inflammatory process by (1) promoting free radical-related membrane peroxidation, destabilization, and destruction53; (2) promoting interaction of free radicals with deoxyribonucleic acid 54 and cellular proteins, 55 thus impairing cellular repair and accelerating cell death; and (3) promoting platelet aggregation and prostaglandin and leukotriene synthesis. 56-59The severity of the inflammatory stage predicts the severity of subsequent stages of wound healing 6° and therefore the total amount of collagen and matrix formation produced as a result of an injury. Reduction of the inflammatory response after angioplasty could theoretically reduce the amount of neointimal formation. Vitamin E has been shown in several studies to reduce inflammation, 61, 62 facilitate wound healing, 63, 64 and reduce collagen and scar tissue formation. 65-67Although vitamin C is essential to wound healing via its effects on collagen synthesis and extracellular matrix formation, 6s, 69 it has not been shown to significantly accelerate wound healing. The role of S-carotene in wound healing is unclear at this time. Antioxidants and platelets. The vessel injury of angioplasty results in platelet aggregation, thrombosis, and release of platelet-derived vasoactive and mitogenic agents. 7° Vitamin E, vitamin C, and S-carotene may mediate the inflammatory process via their effects on platelet aggregation and the arachidonic acid cascade. Vitamin E is a potent inhibitor of platelet aggregation in vitro 71"76 and platelet adhesion in viv0.77, 7s It interferes with the synthesis of vitamin K-dependent coagulation factors.79 The antioxidants vitamin E and vitamin C and, to a less well-investigated extent, S-carotene, regulate prostaglandin synthesis by enhancing or inhibiting the activity of sev-
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Phospholipids in membranes Phospholipase A2 Oxidants
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eral enzymes in the arachidonic cascade (Fig. 1). Natural antioxidants appear to be able to adjust the ratio of prostacyclin to thromboxane in favor of a reduction in platelet aggregation and vasoconstriction. Vitamins E and C reduce arachidonate release from phospholipids. Phospholipase A2 releases arachidonic acid from membranes to make it available for conversion into prostaglandins via the cyclooxygenase pathway, and leukotrienes via the lipooxygenase pathway. Phospholipase A2 is activated by oxidants 56 and inhibited by vitamin E and possibly vitamin C. 57, 58 Lipooxygenase and cyclooxygenase also require oxidants (fatty acid hydroperoxides) for activation. 59 Both enzymes cause the formation of lipid peroxides. 59 Vitamin E has been shown to have an inhibitory effect on lipooxygenase 59 and cyclooxygenase. 8° fl-Carotene has been shown to inhibit both prostaglandin and leukotriene production in vitro. 81 Arachidonic acid is metabolized by cyclooxygenase
to endoperoxide, which in turn is metabolized to prostacyclin and thromboxane A2. Prostacyclin synthetase metabolizes endoperoxide to. prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. The prostacyclin pathway predominates in blood vessel walls, particularly endothelial cells. 82 Lipid peroxides inhibit prostacyclin synthetase. 83 Vitamins E and C have been shown to increase the synthesis of prostacyclin. 23, 84-86 Vitamin C has also been shown to decrease the inhibitory effects of hyperlipidemia on prostacyclin production. 23, s6 Thromboxane synthetase metabolizes endoperoxide to thromboxane A2, a potent vasoconstrictor and proaggregatory agent. The thromboxane pathway predominates in activated platelets. 82 Vitamins E and C have been shown to reduce thromboxane synthesis in both animal and human experimental in vitro mode!s, 5s, 87, 88 although the mechanism is unclear. As a result of these multiple sites of action, the
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Angioplasty (Arterial Tissue Injury)
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Restenosis Fig. 2. Relation between natural antioxidants and restenosis after angioplasty.
natural antioxidants may decrease platelet aggregation and platelet mediated-thrombosis and vasoconstriction after angioplasty. Antioxidants and smooth-muscle cell proliferation.
Postangioplasty restenotic lesions often contain a predominance of smooth-muscle cells, s9 Interleukin-l, which is produced by endothelial cells, smoothmuscle cells and monocyte/macrophages, stimulates proliferation of smooth-muscle cells. 43, 90 Oxidized LDL 43 and oxidants such as superoxide and hydrogen peroxide 91 are known cell mitogens and have been shown to stimulate interleukin-1 production. Platelet-derived growth factor (PDGF) and endothelin, both inflammatory mediators, also promote vascular smooth-muscle cell proliferation. 92 This may be the result of their ability to activate protein kinase C,92-94 a calcium- and phospholipid-dependent enzyme that controls many cellular processes and may play a predominant role in cellular proliferation. 95 Antioxidants may be effective inhibitors of the smooth-muscle cell proliferation that occurs after angioplasty. ~ Tocopherol, the most biologically active tocopherol, 96 has been shown to inhibit proliferation of vascular smooth-muscle cells in vitro at physiologically relevant concentrations. 92,97 It ap-
pears to inhibit the production of interleukin-191, 98 via its inhibitory effect on the activation of the interleukin-lB gene2 s a Tocopherol has been shown to completely inhibit the proliferation of vascular smooth-muscle cells by PDGF and endothelin in vitro. 92 a-Tocopherol has also been shown to significantly reduce LDL-mediated smooth-muscle cell proliferation in vitro, 99 possibly inhibition of protein kinase C activation by alpha-tocopherol. 92,97 Because protein kinase C can be activated in vivo by mild oxidative conditions 1°° and lipid oxidation products, 1°1 the effect of a tocopherol on protein kinase C may in part be antioxidant mediated. Other antioxidants (trolox, phytol, butylated hydroxytoluene (BHT)) and compounds structurally similar to a tocopherol (a-tocopherol acetate), however, have been unable to inhibit vascular smooth-muscle cell proliferation in a similar in vitro experimental model. 92, 97 a-Tocopherol may act as a site specific ligand for protein kinase C and prevent translocation of protein kinase C to the membrane, a step that is necessary for the enzyme's activation. 92 Antioxidants and restenosis. Few studies at present specifically investigate the effect of antioxidants on restenosis. 1°2-1°7Probucol, a potent synthetic antiox-
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idant, significantly reduced restenosis in one of two animal models. 1°2-1°3 Probucol reduced neointimal formation in a swine model of restenosisl°2; however, it had no effect on restenosis after laser thermal angioplasty in rabbits, l°3 BHT, a synthetic antioxidant with a chemical structure similar to that of probucol, effectively inhibited the accumulation of intimal smooth-muscle cells and the development of intimal thickening in the aorta of hypercholesterolemic rabbits after balloon injury. 1°4 Vitamins E and C are the only natural antioxidants to date that have been used in animal 1°5, 107 or human 1°6 restenosis studies. Vitamin E significantly reduced restenosis after femoral artery angioplasty in a rabbit model. 1°5 Nunes et al. 1°7 demonstrated a significant improvement in the vascular response to injury after balloon angioplasty in pigs treated with a combination of vitamins E and C; either vitamin alone had no effect even though oxidized LDL was reduced in all treatment groups. Superoxide anion (02_) production in the vessel wall was significantly decreased only by the combination of vitamins E and C. l°s This finding is consistent with the ability of natural antioxidants to act synergistically to prevent oxidative damage of intracellular and extracellular constituents by reactive oxygen species and free-radical chain reactions. Synergy between antioxidant vitamins is demonstrated by the ability of vitamin C to regenerate tocopherol from the tocopherol radical 1°9 and of a tocopherol to regenerate the fl, 7, and 5 tocopherol radicals. 11° Therefore it is not unexpected that natural antioxidant combination treatment would be more effective than monotherapy. In all animal trials that showed a beneficial effect of antioxidants on restenosis, the experimental animals were premedicated with the relevant antioxidant for at least 2 days before angioplasty. 1°2, lo4, t05 Premedication with antioxidants before angioplasty may be essential to the ability of the antioxidants to modify the restenosis process. Premedication allows time for incorporation of lipid soluble antioxidants (vitamin E and fl-carotene) into lipoproteins and membranes and for maximization of plasma and cytosol water-soluble antioxidant (vitamin C) concentrations. To date, only one clinical trial has investigated the effect of antioxidants on restenosis. Demaio et al. 1°6 supplemented angioplasty patients with 1200 IU of vitamin E per day starting the day of angioplasty and found a trend toward a reduction in restenosis as measured by repeat angiogram, thallium test, or exercise stress test. Follow-up angiograms were obtained in only 86 % of patients receiving vitamin E and in 83 % of patients receiving placebo. Restenosis,
Uodfried and Deckelbaum 207
defined as a _>50% loss of the initial gain in luminal diameter after angioplasty, was 35.5 % in the vitamin E-treated patients as compared to 47.5 % in the controls (p = 0.2). The overall incidence of restenosis as defined by abnormal stress test or angiogram was 34.6% in patients receiving vitamin E and 50% in patients receiving placebo (p = 0.06). The study was limited by the inconsistent definition of restenosis and a small sample size. In summary, antioxidants may favorably alter the progression of restenosis after angioplasty by several mechanisms (Fig. 2). They may inhibit inflammation, smooth-muscle cell proliferation, and thrombus formation after arterial injury, with a net resultant inhibition of neointimal formation. Vitamin E has been shown to be antiinflammatory and to reduce collagen formation during wound healing. Vitamins E and C inhibit platelet aggregation and/or adhesion, reduce thromboxane A2 synthesis, and increase prostacyclin synthesis. These actions appear to be only partly the result of their antioxidant properties. a-Tocopherol, the most biologically active tocopherol in vitamin E, inhibits smooth-muscle cell proliferation stimulated or mediated by PDGF, endothelin, interleukin-1, and LDL. The combination of these effects supports the hypothesis that natural antioxidants may decrease restenosis. Preliminary animal and clinical trials are suggestive of a beneficial effect. Clearly the magnitude of the problem and the relatively low cost and morbidity of the agents mandate further investigation of this hypothesis. Natural antioxidants, either alone or in combination, may prove to be a safe and cost-effective means of preventing restenosis after PTCA. We t h a n k Sonja L. Godfried for t h e graphic design of Figs. 1 a n d 2 a n d J o h n Scott for technical assistance.
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Godfried and Deckelbaum 209 78. Jandak J, Steiner M, Richardson PD. Alpha-tocopherol, an effective inhibitor of platelet adhesion. Blood 1989;73:141-9. 79. Corrigan James J, Jr. The effect of vitamin E on Warfarin induced vitamin K deficiency. NY Acad Sci 1982;393:361-8. 80. Sterner M, Mower R. Mechanism of action of vitamin E on platelet function. Ann NY Acad Sci 1982;393:289-99. 81. Halevy O, Sklan D. Inhibition of arachidonic acid oxidation by betacarotene, retinol and alpha- tocopherol. Biochemica et Biophysica Acta 1987;918:304-7. 82. Gryglewski RJ, Dembinska K, Zmuda A, Gryglewska T. Prostacyclin and Thromboxane A2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atherosclerosis in rabbits. Atherosclerosis 1978;31:385-94. 83. Moncada S, Gryglewsh RJ, Bunting S, Vane JR. A lipid peroxide inhibits the enzyme in blood vessel microsomes that generate from prostaglandin endoperoxides the substance (prostaglandin x) which prevents platelet aggregation. Prostaglandins 1976;12:715-37. 84. Tran K, Chan AC. R,R,R-alpha-tocopherol potentiates prostacyclin release in human endothelial cells. Evidence for structural specificity of the tocopherol molecule. Biochimica et Biophysica Acta 1990;1043:189-97. 85. Breetens JR, Herman AG. Vitamin C increased the formation of prostacyclin by aortic rings from various species and neutralizes the inhibitory effect of 15-hydroperoxyl-arachidonic acid. Br J Pharmac 1983:80:249-54. 86. Wang J, Zhen E, Guo Z, Lu Y. Effect of hyperlipidemic serum on lipid peroxidation, synthesis of prostacyclin and thromboxane by cultured endothelial cells: protective effect of antioxidants. Free Radical Biol Med 1989;7:243-9. 87. Forester W. In vivo and ex vivo studies of the effect of vitamin E pretreatment of PGI2 and TxA2 synthesis. Acta Med Scan 1980 (suppl);642:47-8. 88. Karpen CW, Merola AJ, Trewyn RW, Cornwell DG, PanganamaIa RV. Modulation of platelet thromboxane A2 and arterial prostacyclin by dietary vitamin E. Prostaglandins 1981:22:651-61. 89. Ip JH, Fuster V, Badimon L, Badimon J, Tanbman MB, Chesbro JH. Syndromes of accelerated atherosclerosis: Role of vascular injury and smooth muscle cell proliferation. J Am Coll Cardiol 1990;15:1667-87. 90. Raines EW, Dower SK, Ross R. Interleuken-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science 1989;243:393-5. 91. Kasama T, Kobayashi K, Fukushima T, Tabata M, Ohno I, Negishi M, Ide H, Takahashi T, Niwa Y. Production of interleukin 1 like factor from human peripheral blood monocytes and polymorphonuclear leukocytes by a superoxide anion: The role of interleukin 1 and reactive oxygen species in inflammed sites. Clin Immunol Immunopath 1989;53:439-88. 92. Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C. J Biol Chem 1991;266:6188-94. 93. Kariya KI, Kawahara Y, Tsuda T, Fukuzaki H, Takal Y. Possible involvement of protein kinase C in platelet-derived growth factor-stimulated DNA synthesis in vascular smooth muscle cells. Atherosclerosis 1987;63:251-5. 94. Kawahara Y, Kariya K, Araki S, Fukuzaki H, Takai Y. Platetet-derived growth factor (PDGF)-induced phosphohpose C mediated hydrolysis of phosphoinositides in vascular smooth muscle cells-different sensitivity of PDGF and Angiotension II induced phospholipose C reactions to protein kinase C activating phorbol esters. Biochem Biophys Res Comm 1988;156:846-54. 95. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 1988;335:661-5. 96. Machlin LJ, Bendich A. Free radical tissue damage: Protective role of antioxidant nutrients. FASEB J 1987;1:441-5. 97. Boscoboinik D, Szewczyk A, Azzi A. Alpha tocopherol regulates vascular smooth muscle cell proliferation and protein kinase C activity. Arch Biochem Biophys 1991;286:264-9. 98. Akeson A, Woods CW, Mosher LB, Thomas CE, Jackson RL. Inhibition of IL-1B expression in THP-1 cells by probucol and tocopherol. Atherosclerosis 1991;86:261-70.
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99. Ozer, Nk, Palozza P, Boscoboinik D, Azzi A. D-alpha-tocopherol inhibits low density lipoprotein-induced proliferation and protein kinase C activity in vascular smooth muscle cells. FEBS 1993;322:30710. 100. Gopalakrishna R, Anderson WB. Calcium and phospholipid-indepandent activation of protein kinase C by selective oxidative modifications of regulatory domain. Proc Natl Acad Sci USA 1989;86:6758-62. 101. O'Brien CA, Ward NE, Weinstein IB, Bull AW, Marnett LJ. Activation of rat brain protein kinase C by lipid oxidation products. Biochem Biophys Res Commun 1988;155:1374-80. 102. Schneider JE, Berk BC, Santoian EC, Gravanis MB, Cipolla GD, Tarazona N, King SB. Oxidative stress is important in restenosis: reduction of neointimal formation by the antioxidant probucol in a swine model of restenosis [Abstract 0744]. Circulation 1992;86:I186. 103. Hsiang Y, White RA, Kopchok GE, Rosenbaum D, Guthrie C, Kao J, Zhen E, Peng S, Fragoso M. Stenosis following laser thermal angioplasty. A blinded controlled randomized study between aspirin against probucol. J Surg Res 1991;50:252-8. 104. Freyschuss A, Stiko-Rahm A, Swedenborg J, Henriksson P, Bjorkhem I, Bergltmd L, Nilsson J. Antioxidant treatment inhibits the develop-
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ment of intimal thickening after balloon injury of the aorta in hypercholesterolemic rabbits. J Clin Invest 1993;91:1282-8. Lafont AM, Whitlow PL, Cornhill JF, Chisolm GM. Alpha tocopherol reduced restenosis after femoral artery angioplasty in a rabbit model of experimental atherosclerosis [Abstract 2970]. Circulation 1992;86:I747. DeMalo SJ, King SB, Lembo NJ, Roubin GS, Hearn JA, Bhagavan HN, Sgoutas DS. Vitamin E supplementation, plasma lipids and incidence of restenosis after percutaneous transtuminal coronary angioplasty (PTCA). J Am Coil Nutr 1992;11:68-73. Nunes GL, Sgoutas DS, Sigman SR, Britt B, Gravanis MB, King SB, Berk BC. Vitamins C and E improve the response to coronary balloon injury in the pig: effect of vascular remodeling [Abstract 1994]. Circulation 1993;88:I-372. Nunes GL, Redden RA, Sgoutas DS, Berk BC. Vitamins C and E improve the response to balloon injury: effect on redox state [Abstract 0174]. Circulation 1993;88:I-35. Niki E. Interaction of ascorbate and alpha tocopherol. Ann N Y Acad Sci 1987;498:186-99. Niki E. Antioxidants in relation to lipid peroxidation. Chem Phys Lipids 1987;44:227-53.
1-800-55-MOSBY This number links you to the full text of literally every article published in Mosby journals. M O S B Y Doeument Express TM, a rapid-response information retrieval service, provides quick turnaround, 24-hour availability, and speedy delivery methods. For inquiries and pricing information call our toll-free 24-hour order line: 1-800-55-MOSBY; outside the United States: (415)259-5046; fax: (4t5)259-4019; E-mall: [email protected]. MOSBY Document Express T M is offered in cooperation with Dynamic Information Corp.
Natural antioxidants and restenosis after percutaneous transluminal coronary angioplasty Susan L. Godfried, MD, and Lawrence I. Deckelbaum, MD West Haven and N e w Haven, Conn.
Percutaneous transluminal coronary angioplasty (PTCA) has become a successful and widely used treatment for patients with coronary artery disease since its first clinical application in 1977.1 Despite the increase in case complexity the primary success rate for PTCA has improved. Restenosis, however, remains a problem after successful angioplasty, occurring in --<57% of patients within the first 6 months 2 after the procedure. Many interventions, both mechanic and pharmacologic, have been attempted to reduce the rate of restenosis. None have been conclusively successful to date. Mechanical approaches include long inflations with autoperfusion devices, postprocedure implantation of coronary stents, and plaque removal by atherectomy and laser angioplasty. Pharmacologic approaches include antiplatelet agents, prostacyclin analogs, calcium channel blockers, anticoagulants, cholesterol-lowering agents, and ~ 3 fatty acids. Of the interventions tested, only lovastatin and ~ 3 fatty acids have been shown to reduce restenosis rates in some, although not all, clinical trials. 37 Given the variation in study design and results of these trials, their results must be interpreted with caution. Restenosis appears to be the result of two processes: an accelerated form of atherosclerosis induced by arterial injury 8 and a wound-healing response to severe intimal and medial damage. 9 Antioxidants may attenuate the process of restenosis after anglo-
From the Departments of Internal Medicine, Veterans Administration Medical Center, West Haven, and Yale University School of Medicine, New Haven. Received for publication Jan. 6, 1994; accepted May 2, 1994. Reprint requests: Lawrence I. Deckelbaum, MD, Section of Cardiology, III B, West Haven VAMC, 950 Campbell Ave., West Haven, CT 06516. AM HEART J 1995;129:203-10. Copyright © 1995 by Mosby-Year Book, Inc. 0002-8703/95/$3.00 + 0 4/1/59126
plasty through their ability to both reduce the progression of atherosclerotic plaque formation and to favorably influence wound healing. Either alone or in combination, the natural antioxidants, vitamin E (a, ~, 7, and 5 tocopherol), vitamin C (ascorbic acid), and beta-carotene, prevent oxidation of low-density lipoproteins (LDL) and cellular constituents, reduce platelet aggregation, modulate prostaglandin and leukotriene synthesis, and reduce inflammation. The following discussion reviews natural antioxidants and their effects on the processes involved in restenosis in support of the hypothesis that these antioxidants may decrease the incidence of restenosis after PTCA. Antioxidants and atherosclerosis. Alone or in combination, natural antioxidants have been shown to reduce the progression of atherosclerotic plaque in animal models. Further, dietary vitamin E, vitamin C, and f~-carotene intake appears to be inversely correlated with vascular disease and its complications in population and clinical studies. Several trials have examined the relation between vitamins E and C and atherosclerosis in hypercholesterolemic animal models. Vitamin E supplementation significantly reduced atherosclerotic plaque formation in 5 of 11 trials. 1°-2° The effects of high dietary vitamin E on atherogenesis appeared to depend on the cholesterol status of the diet and/or plasma. Wilson et al. 1° and Westrope et al. 11reported that the ability of vitamin E to inhibit plaque formation was inversely related to the degree of hypercholesterolemia produced in a rabbit experimental model. In trials that showed an acceleration of atherosclerotic plaque formation diets that produced severe hypercholesterolemia (900 to 1400 mg/dl serum cholesterol) were used. 19, 2o The studies that showed a significant reduction 1°14 in atherosclerotic plaque formation were performed in animals with total serum cholesterol levels of <750 mg/dl. Vitamin C supple203
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mentation has been shown to significantly reduce atherosclerotic plaque formation in rabbits in two studies.21, 22 Two other animal studies have shown either a trend toward a beneficial effect or no effect. 23,24 No animal trials evaluated the effect of S-carotene on atherogenesis. Several epidemiologic trials suggest that populations with a high intake of vitamin E have a lower risk of cardiovascular heart disease even after correction for other known risk factors. 25-27 Intake of #-carotene 27-29 and vitamin C 3°, Sl also appear to be negatively correlated with the incidence of vascular disease. Two prospective epidemiologic studies, the Nurses' Health Study 26 and the Health Professionals Follow-up Study, 27 recently reported an inverse correlation between vitamin E intake and cardiovascular disease. A cross-sectional survey in Europe and Israel, the World Health Organization Multinational Monitoring of Trends and Determinants in Cardiovascular Diseases (MONICA) Project, reported a significant inverse relation between lipid standardized serum vitamin E levels and ischemic heart disease mortality (p = 0.0003) in men. 25 Indirect evidence of a benefit of vitamin E on atherogenesis in human beings has been reported in clinical trials involving patients with intermittent claudication. A significant increase both in symptom-free walking distance 32-37 and lower extremity arterial blood flow32 has been demonstrated in vitamin E-supplemented treatment groups as compared to controls treated with placebo33,35 or anticoagulants and vasodilatory agents. 34' 36 The Physicians Health Study found a statistically significant reduction in major vascular events by/~-carotene in a subgroup of patients with a history of stable angina and/or coronary revascnlarization. 2s Taken as a whole, these data suggest that antioxidants may effectively retard that part of the restenosis process that represents accelerated atherosclerosis. Antioxidants and LDL. Areas of intima that are denuded by angioplasty have a dramatically increased rate of lipid uptake and deposition in hyperlipidemic animal models. 3s Tissue damage, such as that produced by angioplasty, leads to rapid increases in the production of oxidative products caused by platelet aggregation, phagocytosis, synthesis of prostaglandins, and rapid increases or changes in cellular metabolic activities. These reactive oxidative products can oxidize LDL. Once oxidized, LDL promotes plaque formation in several ways. It accelerates foam-cell formation by enhancing LDL uptake into macrophages 39 and smooth-muscle cells. It is chemotactic for blood monocytes 4° and inhibits macrophage motility, thereby augmenting monocyte recruitment into intimal lesions. It stimulates monocyte
AmericanHeartJournal
adherence to the arterial intima and differentiation of monocytes into macrophages. 41 It promotes cellular necrosis and endothelial injury within the arterial wall resulting from direct cytotoxicity, 42 and it stimulates smooth-muscle cell proliferation by increasing release of interleukin-1 from macrophagesJ 3 Although the role of oxidized LDL in restenosis has not been definitively resolved, vitamin E, vitamin C, and S-carotene prevent oxidative modification of LDL42, 44-52 and may therefore slow oxidized L D L mediated plaque growth after angioplasty. Antioxidants and inflammation and wound healing.
Angioplasty causes substantial vascular damage by denuding endothelium and creating intimal and medial dissections. As a result, the vessel undergoes a healing response with three characteristic phases: inflammation, granulation, and extracellular matrix deposition. Oxidative cytotoxic products produced by vessel injury may enhance the inflammatory process by (1) promoting free radical-related membrane peroxidation, destabilization, and destruction53; (2) promoting interaction of free radicals with deoxyribonucleic acid 54 and cellular proteins, 55 thus impairing cellular repair and accelerating cell death; and (3) promoting platelet aggregation and prostaglandin and leukotriene synthesis. 56-59The severity of the inflammatory stage predicts the severity of subsequent stages of wound healing 6° and therefore the total amount of collagen and matrix formation produced as a result of an injury. Reduction of the inflammatory response after angioplasty could theoretically reduce the amount of neointimal formation. Vitamin E has been shown in several studies to reduce inflammation, 61, 62 facilitate wound healing, 63, 64 and reduce collagen and scar tissue formation. 65-67Although vitamin C is essential to wound healing via its effects on collagen synthesis and extracellular matrix formation, 6s, 69 it has not been shown to significantly accelerate wound healing. The role of S-carotene in wound healing is unclear at this time. Antioxidants and platelets. The vessel injury of angioplasty results in platelet aggregation, thrombosis, and release of platelet-derived vasoactive and mitogenic agents. 7° Vitamin E, vitamin C, and S-carotene may mediate the inflammatory process via their effects on platelet aggregation and the arachidonic acid cascade. Vitamin E is a potent inhibitor of platelet aggregation in vitro 71"76 and platelet adhesion in viv0.77, 7s It interferes with the synthesis of vitamin K-dependent coagulation factors.79 The antioxidants vitamin E and vitamin C and, to a less well-investigated extent, S-carotene, regulate prostaglandin synthesis by enhancing or inhibiting the activity of sev-
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Phospholipids in membranes Phospholipase A2 Oxidants
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eral enzymes in the arachidonic cascade (Fig. 1). Natural antioxidants appear to be able to adjust the ratio of prostacyclin to thromboxane in favor of a reduction in platelet aggregation and vasoconstriction. Vitamins E and C reduce arachidonate release from phospholipids. Phospholipase A2 releases arachidonic acid from membranes to make it available for conversion into prostaglandins via the cyclooxygenase pathway, and leukotrienes via the lipooxygenase pathway. Phospholipase A2 is activated by oxidants 56 and inhibited by vitamin E and possibly vitamin C. 57, 58 Lipooxygenase and cyclooxygenase also require oxidants (fatty acid hydroperoxides) for activation. 59 Both enzymes cause the formation of lipid peroxides. 59 Vitamin E has been shown to have an inhibitory effect on lipooxygenase 59 and cyclooxygenase. 8° fl-Carotene has been shown to inhibit both prostaglandin and leukotriene production in vitro. 81 Arachidonic acid is metabolized by cyclooxygenase
to endoperoxide, which in turn is metabolized to prostacyclin and thromboxane A2. Prostacyclin synthetase metabolizes endoperoxide to. prostacyclin, a potent vasodilator and inhibitor of platelet aggregation. The prostacyclin pathway predominates in blood vessel walls, particularly endothelial cells. 82 Lipid peroxides inhibit prostacyclin synthetase. 83 Vitamins E and C have been shown to increase the synthesis of prostacyclin. 23, 84-86 Vitamin C has also been shown to decrease the inhibitory effects of hyperlipidemia on prostacyclin production. 23, s6 Thromboxane synthetase metabolizes endoperoxide to thromboxane A2, a potent vasoconstrictor and proaggregatory agent. The thromboxane pathway predominates in activated platelets. 82 Vitamins E and C have been shown to reduce thromboxane synthesis in both animal and human experimental in vitro mode!s, 5s, 87, 88 although the mechanism is unclear. As a result of these multiple sites of action, the
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Angioplasty (Arterial Tissue Injury)
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Restenosis Fig. 2. Relation between natural antioxidants and restenosis after angioplasty.
natural antioxidants may decrease platelet aggregation and platelet mediated-thrombosis and vasoconstriction after angioplasty. Antioxidants and smooth-muscle cell proliferation.
Postangioplasty restenotic lesions often contain a predominance of smooth-muscle cells, s9 Interleukin-l, which is produced by endothelial cells, smoothmuscle cells and monocyte/macrophages, stimulates proliferation of smooth-muscle cells. 43, 90 Oxidized LDL 43 and oxidants such as superoxide and hydrogen peroxide 91 are known cell mitogens and have been shown to stimulate interleukin-1 production. Platelet-derived growth factor (PDGF) and endothelin, both inflammatory mediators, also promote vascular smooth-muscle cell proliferation. 92 This may be the result of their ability to activate protein kinase C,92-94 a calcium- and phospholipid-dependent enzyme that controls many cellular processes and may play a predominant role in cellular proliferation. 95 Antioxidants may be effective inhibitors of the smooth-muscle cell proliferation that occurs after angioplasty. ~ Tocopherol, the most biologically active tocopherol, 96 has been shown to inhibit proliferation of vascular smooth-muscle cells in vitro at physiologically relevant concentrations. 92,97 It ap-
pears to inhibit the production of interleukin-191, 98 via its inhibitory effect on the activation of the interleukin-lB gene2 s a Tocopherol has been shown to completely inhibit the proliferation of vascular smooth-muscle cells by PDGF and endothelin in vitro. 92 a-Tocopherol has also been shown to significantly reduce LDL-mediated smooth-muscle cell proliferation in vitro, 99 possibly inhibition of protein kinase C activation by alpha-tocopherol. 92,97 Because protein kinase C can be activated in vivo by mild oxidative conditions 1°° and lipid oxidation products, 1°1 the effect of a tocopherol on protein kinase C may in part be antioxidant mediated. Other antioxidants (trolox, phytol, butylated hydroxytoluene (BHT)) and compounds structurally similar to a tocopherol (a-tocopherol acetate), however, have been unable to inhibit vascular smooth-muscle cell proliferation in a similar in vitro experimental model. 92, 97 a-Tocopherol may act as a site specific ligand for protein kinase C and prevent translocation of protein kinase C to the membrane, a step that is necessary for the enzyme's activation. 92 Antioxidants and restenosis. Few studies at present specifically investigate the effect of antioxidants on restenosis. 1°2-1°7Probucol, a potent synthetic antiox-
Volume 129, Number 1 American Heart Journal
idant, significantly reduced restenosis in one of two animal models. 1°2-1°3 Probucol reduced neointimal formation in a swine model of restenosisl°2; however, it had no effect on restenosis after laser thermal angioplasty in rabbits, l°3 BHT, a synthetic antioxidant with a chemical structure similar to that of probucol, effectively inhibited the accumulation of intimal smooth-muscle cells and the development of intimal thickening in the aorta of hypercholesterolemic rabbits after balloon injury. 1°4 Vitamins E and C are the only natural antioxidants to date that have been used in animal 1°5, 107 or human 1°6 restenosis studies. Vitamin E significantly reduced restenosis after femoral artery angioplasty in a rabbit model. 1°5 Nunes et al. 1°7 demonstrated a significant improvement in the vascular response to injury after balloon angioplasty in pigs treated with a combination of vitamins E and C; either vitamin alone had no effect even though oxidized LDL was reduced in all treatment groups. Superoxide anion (02_) production in the vessel wall was significantly decreased only by the combination of vitamins E and C. l°s This finding is consistent with the ability of natural antioxidants to act synergistically to prevent oxidative damage of intracellular and extracellular constituents by reactive oxygen species and free-radical chain reactions. Synergy between antioxidant vitamins is demonstrated by the ability of vitamin C to regenerate tocopherol from the tocopherol radical 1°9 and of a tocopherol to regenerate the fl, 7, and 5 tocopherol radicals. 11° Therefore it is not unexpected that natural antioxidant combination treatment would be more effective than monotherapy. In all animal trials that showed a beneficial effect of antioxidants on restenosis, the experimental animals were premedicated with the relevant antioxidant for at least 2 days before angioplasty. 1°2, lo4, t05 Premedication with antioxidants before angioplasty may be essential to the ability of the antioxidants to modify the restenosis process. Premedication allows time for incorporation of lipid soluble antioxidants (vitamin E and fl-carotene) into lipoproteins and membranes and for maximization of plasma and cytosol water-soluble antioxidant (vitamin C) concentrations. To date, only one clinical trial has investigated the effect of antioxidants on restenosis. Demaio et al. 1°6 supplemented angioplasty patients with 1200 IU of vitamin E per day starting the day of angioplasty and found a trend toward a reduction in restenosis as measured by repeat angiogram, thallium test, or exercise stress test. Follow-up angiograms were obtained in only 86 % of patients receiving vitamin E and in 83 % of patients receiving placebo. Restenosis,
Uodfried and Deckelbaum 207
defined as a _>50% loss of the initial gain in luminal diameter after angioplasty, was 35.5 % in the vitamin E-treated patients as compared to 47.5 % in the controls (p = 0.2). The overall incidence of restenosis as defined by abnormal stress test or angiogram was 34.6% in patients receiving vitamin E and 50% in patients receiving placebo (p = 0.06). The study was limited by the inconsistent definition of restenosis and a small sample size. In summary, antioxidants may favorably alter the progression of restenosis after angioplasty by several mechanisms (Fig. 2). They may inhibit inflammation, smooth-muscle cell proliferation, and thrombus formation after arterial injury, with a net resultant inhibition of neointimal formation. Vitamin E has been shown to be antiinflammatory and to reduce collagen formation during wound healing. Vitamins E and C inhibit platelet aggregation and/or adhesion, reduce thromboxane A2 synthesis, and increase prostacyclin synthesis. These actions appear to be only partly the result of their antioxidant properties. a-Tocopherol, the most biologically active tocopherol in vitamin E, inhibits smooth-muscle cell proliferation stimulated or mediated by PDGF, endothelin, interleukin-1, and LDL. The combination of these effects supports the hypothesis that natural antioxidants may decrease restenosis. Preliminary animal and clinical trials are suggestive of a beneficial effect. Clearly the magnitude of the problem and the relatively low cost and morbidity of the agents mandate further investigation of this hypothesis. Natural antioxidants, either alone or in combination, may prove to be a safe and cost-effective means of preventing restenosis after PTCA. We t h a n k Sonja L. Godfried for t h e graphic design of Figs. 1 a n d 2 a n d J o h n Scott for technical assistance.
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