Consumption of vitamin E in coronary circulation in patients with variant angina

Transcription

1 Crdiovsculr Reserch 41 (1999) Consumption of vitmin E in coronry circultion in ptients with vrint ngin * Kunihis Miw, Akihiko Igw, Keiko Nkgw, Tdkzu Hiri, Hiroshi Inoue Deprtment of Internl Medicine, Toym Medicl nd Phrmceuticl University, 2630 Sugitni, Toym , Jpn Received 12 Jnury 1998; ccepted 3 June 1998 Abstrct Objectives: The plsm sttus of vitmin E hs been suggested to be linked to the ctivity of coronry rtery spsm. This study ws designed to determine whether vitmin E is ctully consumed in the coronry circultion in ptients with ctive vrint ngin hving repetitive spsm-induced trnsient myocrdil ischemi nd reperfusion. Methods: Blood smples were obtined simultneously from the ortic root, coronry sinus nd right trium in 12 ptients with vrint ngin due to spsm of the left coronry rtery, nine ptients with stble effort ngin nd nine control subjects. Plsm vitmin E (- nd g-tocopherol) concentrtions were determined by use of high-performnce liquid chromtogrphy nd plsm lipid peroxides were mesured s thiobrbituric cid-rective substnces (TBARS). Results: At bseline, both plsm - (p,0.01) nd g- (p,0.05) tocopherol levels were significntly lower in the coronry sinus ( nd mg/l, men6sem) thn in the ortic root ( nd mg/l) nd lso in the right trium ( nd mg/ l) in the vrint ngin group. The TBARS level ws significntly ( p,0.05) higher in the coronry sinus thn in the ortic root in this group. In contrst, these levels were not significntly different between the smples from the coronry sinus nd the ortic root or the right trium in the control group nd lso in the stble effort ngin group. The coronry sinus ortic difference in plsm vitmin E levels in the vrint ngin group ws not significntly ltered fter left coronry rtery spsm induced by intrcoronry injection of cetylcholine. Also, the plsm vitmin E levels in the ortic root, coronry sinus nd right trium ll remined unchnged in the stble effort ngin group fter pcing-induced ngin nd in the control group fter intrcoronry dministrtion of cetylcholine. Conclusions: Trnscrdic reduction in plsm vitmin E concentrtions concomitnt with lipid peroxide formtion ws demonstrted in ptients with ctive vrint ngin, suggesting ctul consumption of this mjor endogenous ntioxidnt. Oxidtive stress nd vitmin E exhustion my be involved in the pthogenesis of coronry rtery spsm Elsevier Science B.V. All rights reserved. Keywords: Vitmin E; Vrint ngin; Coronry spsm; Myocrdil ischemi; Reperfusion 1. Introduction Recent studies lso indicted tht ntioxidnt therpy with vitmin E supplementtion cn be n effective tretment It is generlly believed tht the most importnt bio- for both primry nd secondry prevention ginst corlogicl defence ginst lipid peroxidtion is vitmin E onry hert disese [6 8]. [1,2]. The incorportion of this lipophilic ntioxidnt Vrint ngin is form of unstble ngin chrcterized vitmin into the lipoprotein prticles protects low-density by coronry spsm-induced severe trnsient ischemic lipoprotein (LDL) from the pro-oxidnt environment of the episodes of short durtion, which my be frequently rteril wll by scvenging both oxygen nd lipid free repeted, lthough the precise underlying mechnisms by rdicls [3]. Its level in blood hs been reported to be which coronry spsm is triggered remin to be elucidted inversely relted to the risk of coronry hert disese [4,5]. [9,10]. We hve recently reported tht LDL from ptients with ctive vrint ngin ws highly susceptible to * Corresponding uthor. Tel.: ; fx: e-mil: kmiw@ms.toym-mpu.c.jp Time for primry review 21 dys / 99/ $ see front mtter 1999 Elsevier Science B.V. All rights reserved. PII: S (98)

2 292 K. Miw et l. / Crdiovsculr Reserch 41 (1999) peroxidtive modifiction induced by cupric ion, nd 2.2. Procedures for ctheteriztion nd blood smpling vitmin E levels were significntly lower both in plsm nd LDL frctions from these ptients thn from subjects All drugs were withdrwn.24 h before crdic cthewithout coronry spsm, suggesting n ssocition be- teriztion except for sublingul nitroglycerin. The study tween vitmin E deficiency nd coronry rtery spsm ws performed in the morning while the ptients were in [11,12]. However, the exct cusl reltionship between the fsting stte. For blood smpling, 6F Judkins ctheter them remins unknown. It is possible tht incresed lipid ws dvnced from the femorl rtery nd plced in the oxidtion stress, such s free rdicl production induced by scending ort nd 7.5F Opticthe (Model P7110; frequently repeted ltertion between severe trnsient Oximetrix) ws positioned in the coronry sinus through regionl myocrdil ischemi nd reperfusion, my cuse the internl jugulr vein. The position of the ctheter ws exhustion of vitmin E, resulting in higher susceptibility confirmed by occsionl injection of the contrst medium. of LDL to oxidtion [13]. However, free rdicl formtion Coronry rteriogrphy ws performed using the Judkins nd/ or ntioxidnt vitmin E consumption in the coronry technique. All ptients were given 5000 U of heprin t the circultion during ischemi/ reperfusion by coronry spsm insertion of the Judkins ctheter. A blood smple ws hs not been demonstrted. obtined from the right trium vi the Opticthe before it In the present study, to determine whether vitmin E is ws dvnced into the coronry sinus. Blood smples were ctully consumed in the coronry circultion in the cse then collected from the ortic root nd the coronry sinus of coronry spsm, plsm vitmin E concentrtions nd simultneously. To void rtificil hemolysis, blood smproducts of lipid peroxidtion were determined simul- ples were drwn crefully nd slowly through the ctheter. tneously in the ortic root, coronry sinus nd right trium The time intervl between the blood smpling from the in ptients with vrint ngin before nd fter left right trium nd the coronry sinus through the sme coronry rtery spsm induced by intrcoronry injection ctheter ws few minutes. Written informed consent ws of cetylcholine. obtined from ll the study ptients, nd the study protocol ws pproved by the ethicl committee of our institution. 2. Methods 2.3. Intrcoronry cetylcholine provoctive test 2.1. Study ptients Before coronry rteriogrphy, temporry pcing ctheter ws inserted into the right ventricle vi femorl vein nd connected to pulse genertor with demnd- Ptients included in this study were divided into three driven rte of 50 bets/min, both in the vrint ngin nd groups. The vrint ngin group consisted of 12 ptients control groups. After control blood smpling, 20 to 100 mg (11 men nd womn; men ge, 5763 yers) who hd of cetylcholine ws injected into the left coronry rtery ttcks of chest pin ssocited with ST segment elevtion to induce coronry spsm both in the vrint ngin nd in the precordil leds on the ECG, occurring t rest, nd the control groups [14]. A coronry ngiogrm ws in whom spsm of the left coronry rtery ws induced by obtined when ST segment chnges or chest pin ppered injection of cetylcholine into the left coronry rtery. In or 2 min fter ech injection. The ngin ws relieved the present study, coronry spsm ws defined s totl or promptly by intrcoronry injection of nitroglycerin (0.2 subtotl occlusion of the coronry rtery ssocited with 0.5 mg). After confirming the resolution of the spsm in ischemic ST segment chnges on the ECG with or without the repeted coronry rteriogrm, blood smples were chest pin. The stble effort ngin group consisted of nine tken, gin simultneously from the coronry sinus nd ptients (seven men nd two women; men ge, 5964 the ortic root. yers) with significnt (.75% nrrowing of luminl dimeter) orgnic left coronry rtery stenosis hving exertionl ngin nd positive tredmill exercise stress test 2.4. Pcing stress test but no rest ngin. The control group consisted of nine ptients (seven men nd two women; men ge, 5665 After control blood smpling, tril pcing ws comyers) who were dmitted due to suspected coronry rtery menced in the stble effort ngin group. The pcing rte disese but finlly dignosed to be free from coronry ws begun t 90 bets/ min nd ws incresed until the rtery disese. In these ptients, coronry rteriogrphic ptients experienced ngin tht ws sustined for 3 or 5 findings reveled neither fixed coronry rtery stenosis min. Then, sublingul nitroglycerin ws dministered to (.25% of luminl dimeter) nor coronry rtery spsm relieve ngin. Blood smples then were collected simulinduced by the intrcoronry injection of cetylcholine. tneously from both the coronry sinus nd the ortic root None of them hd positive tredmill exercise stress test fter pcing-induced ngin. results. Ptients receiving ny drugs contining vitmin E In ll of the study ptients, blood smples were lso were excluded. obtined from the right trium through the ctheter, which

3 K. Miw et l. / Crdiovsculr Reserch 41 (1999) ws pulled bck to the right trium from the coronry sinus immeditely fter smpling blood from the coronry sinus Assy of plsm vitmin E concentrtion Ytes correction if one of the frequency tbles ws smller thn five. Differences were considered to be sttisticlly significnt t p,0.05. All of the blood smples were collected into vcutiner 3. Results tubes contining ethylenediminetetrcetic cid. Plsm ws immeditely seprted by centrifugtion nd stored t Tble 1 shows clinicl dt nd plsm lipid profiles in 2208C until use. The vitmin E concentrtion in plsm the study groups. There were no significnt differences ws estimted by the high-performnce liquid chromtog- mong the three groups in ny of the following vribles: rphy method, with vitmin E cette s internl stndrd, ge, sex, hypertension, smoking, dibetes mellitus, obesity, dded before lipid extrction [15]. The plsm vitmin E serum cholesterol nd serum triglycerides. The high-denconcentrtion ws expressed s mg/ l. sity lipoprotein (HDL) cholesterol level ws significntly ( p,0.05) lower both in the vrint ngin nd the stble 2.6. Assy of lipid peroxidtion products effort ngin groups compred with the control group. Plsm lipid peroxidtion products were ssyed s thiobrbituric cid-rective substnces (TBARS), s described previously [11] nd results were expressed s nmol of mlondildehyde equivlents Vitmin E nd TBARS levels in coronry circultion t bseline In the vrint ngin group, five ptients hd spontneously occurring nginl ttcks with ST-segment elev Sttisticl nlysis tion on ECG t night or in the morning prior to coronry rteriogrphy. All of these ptients hd nginl ttcks lso All dt re reported s men6sem. Intergroup com- during coronry rteriogrphic exmintion. The plsm prisons concerning serum lipid levels, plsm tocopherol vitmin E concentrtions in the ortic root, coronry sinus levels nd plsm TBARS levels were mde with nd lso right trium t bseline in the study ptients re Bonferroni multiple comprisons test fter nlysis with shown in Tble 2 nd Fig. 1. Plsm -tocopherol levels in one-wy ANOVA. Student s pired t-test ws used to mke the ortic root, in the coronry sinus nd in the right trium comprison between the tocopherol or TBARS levels in were significntly ( p,0.01 for ech) lower in the vrint the coronry sinus nd in the ortic root or in the right ngin group thn those in the stble effort ngin group trium in the sme subjects. To compre the prevlence nd lso in the control group, respectively. Plsm g- between the groups, chi-squre test ws performed with tocopherol levels in the ortic root, in the coronry sinus Tble 1 Clinicl chrcteristics nd ngiogrphic findings of the study groups Control Vrint Stble effort subjects ngin ngin Number of ptients Age, yers Men6SEM Rnge Mle/ femle 7/ 2 11/ 1 7/ 2 Old myocrdil infrction, n Blood pressure.150/ 90 mmhg, n Smokers, n Dibetes mellitus, n Obesity, n Serum cholesterol, mg/ dl Serum triglycerides, mg/ dl HDL cholesterol, mg/ dl Extent of coronry vessel orgnic stenosis.75% stenosis, n Coronry rtery spsm, n Single-vessel spsm Multivessel spsm Ejection frction,50%, n p,0.05 vs. control subjects.

4 294 K. Miw et l. / Crdiovsculr Reserch 41 (1999) Tble 2 Plsm vitmin E nd TBARS levels in coronry circultion in study ptients Vrint ngin Bseline After ACh Units AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS -Tocopherol b (mg/ l) g-tocopherol (mg/ l) TBARS c (mmol/ l) RA -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS2AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) Stble effort ngin Bseline After pcing AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) RA -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS2AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) Control Bseline After ACh AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) RA -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) CS2AO -Tocopherol (mg/ l) g-tocopherol (mg/ l) TBARS (mmol/ l) p,0.01 vs. AO nd RA. b p,0.05 vs. AO nd RA. c p,0.05 vs. AO. Abbrevitions: AO, ortic root; CS, coronry sinus; RA, right trium. CS2AO, coronry sinus2ortic difference. After ACh, fter intrcoronry injection of cetylcholine in the left coronry rtery. After pcing, fter pcing-induced ngin. TBARS, thiobrbituric cid-rective substnces (mlondildehyde equivlents). nd in the right trium were significntly ( p,0.01 for ech) lower in the vrint ngin group nd lso in the stble effort ngin group compred with those in the control group, respectively. As shown in Tble 2, the vrint ngin group showed significntly ( p,0.05 for ech) higher TBARS when compred to the stble effort ngin group nd the control group, irrespective of the smpling loction, i.e. in the ortic root, in the coronry sinus or in the right trium. In the vrint ngin group, both plsm - nd g-tocopherol levels were significntly

5 K. Miw et l. / Crdiovsculr Reserch 41 (1999) ( p,0.01 for ech) lower in the coronry sinus thn in the ortic root nd in the right trium, respectively. The plsm TBARS level ws significntly ( p,0.05) higher in the coronry sinus thn in the ortic root. In contrst, these levels were not significntly different between the smples from the coronry sinus nd the ortic root or the right trium in the stble effort ngin group or the control group Vitmin E nd TBARS levels in coronry circultion fter spsm Fig. 1. Comprison of the -tocopherol level between the plsm smples simultneously obtined from the ortic root nd the coronry sinus nd lso the coronry sinus nd the right trium t bseline (Bseline) nd fter intrcoronry injection of cetylcholine in the left coronry rtery (ACh) or fter rpid tril pcing-induced ngin (Pcing) in the study ptients. Control: control subjects (); Vrint ngin: ptients with vrint ngin (b); Stble effort ngin: ptients with stble effort ngin (c). The injection of cetylcholine into the left coronry rtery induced left coronry rtery spsm in ll of the ptients of the vrint ngin group. Totl occlusion of the left nterior descending brnch ws induced in nine, nd subtotl or severe diffuse vsoconstriction ws induced in the remining three. In the three ptients, spsm of both the left nterior descending brnch nd the left circumflex brnch ws demonstrted ngiogrphiclly. All of the episodes of induced spsm were ssocited with chest pin nd electrocrdiogrphic ischemic ST-segment chnges. Ten ptients hd ttcks ssocited with ST-segment elevtion in the precordil leds nd the other two hd ST-segment depression. In contrst, coronry rtery spsm ws not induced in the left coronry rtery fter the intrcoronry injection of cetylcholine in the control group. In ll those in the stble effort ngin group, nginl ttcks were induced during rpid tril pcing. The plsm vitmin E concentrtions in the ortic root nd coronry sinus fter injection of cetylcholine or fter rpid tril pcing re shown in Tble 2 nd Fig. 1. In the vrint ngin group, the coronry sinus ortic difference in the plsm -tocopherol levels filed to be ltered significntly fter the left coronry rtery spsm induced by intrcoronry injection of cetylcholine. The plsm -tocopherol level ws still significntly ( p,0.05) lower in the coronry sinus thn in the ortic root nd in the right trium but the g-tocopherol level ws not significntly different fter the spsm. Both - nd g-tocopherol levels remined unchnged nd were not significntly different between the smples from the coronry sinus nd the ortic root or the right trium in the stble effort ngin group fter rpid tril pcing or in the control group fter intrcoronry injection of cetylcholine. Just s demonstrted t bseline, plsm -tocopherol levels in the ortic root, in the coronry sinus nd in the right trium were significntly ( p,0.01 for ech) lower in the vrint ngin group thn those in the stble effort ngin group nd lso in the control group, respectively. Plsm g-tocopherol levels in the ortic root, in the coronry sinus nd in the right trium were significntly ( p,0.01 for ech) lower in the vrint ngin group nd lso in the stble effort ngin group compred with those in the control group, respectively. The coronry sinus ortic difference in the plsm TBARS levels filed to be ltered significntly

6 296 K. Miw et l. / Crdiovsculr Reserch 41 (1999) fter the spsm induced by intrcoronry injection of free rdicls relesed from ctivted neutrophils stying in cetylcholine in ech group (Tble 2). coronry circultion nd/ or possible supplementtion for exhusted vitmin E in cellulr membrnes nd lipoproteins in coronry circultion fter spsm nd reperfusion. It 4. Discussion is possible tht vitmin E-deficient plsm in these ptients my contin intermedite oxidtion products of In our recent reports [11,13], plsm low density tocopherols tht cnnot be detected s n ctive form of lipoprotein in ptients with vrint ngin hs been shown vitmin E nd some of which my be regenerted to ctive to be vitmin E-deficient nd highly susceptible to perox- form by vitmin C elsewhere, such s liver. idtive modifiction compred with tht in ptients without coronry spstic tendency. Also, circulting plsm 4.2. Vitmin E levels in coronry circultion fter vitmin E levels were demonstrted to be significntly spsm lower in ptients with ctive vrint ngin thn in ptients without coronry spsm [12]. In contrst, low level of The coronry sinus ortic difference in plsm vitmin ntioxidnt vitmin E ws not demonstrted in ptients E levels ppered to be unchnged or rther reduced fter with n inctive stge of vrint ngin, suggesting tht the left coronry spsm nd reperfusion compred with plsm sttus of vitmin E is linked to the ctivity of bseline in the ptients with vrint ngin, suggesting no coronry rtery spsm [11,12]. The precise mechnisms for detectble increse of vitmin E uptke in the coronry low plsm levels of vitmin E in ptients with ctive circultion fter single spsm of short durtion nd vrint ngin nd the reltion between the level of reperfusion. Although the uptke of vitmin E in the vitmin E nd coronry rtery spsm hve to be elucidted. coronry circultion ws not quntittively determined, s In the present study, both plsm - nd g-tocopherol the coronry blood flow ws not estimted in the present levels were significntly lower in ptients with vrint study, nd it cnnot be excluded tht the vitmin E ngin compred with ptients without spsm, irrespective consumption might increse immeditely fter spsm nd of the smpling loction, i.e. in the ortic root, in the reperfusion, the ischemi/ reperfusion itself ppered to coronry sinus or in the right trium. In ddition, the cuse no significnt mount of vitmin E consumption in plsm g-tocopherol level ws significntly lower in coronry circultion. Similrly, the pprent uptke of ptients with stble effort ngin compred with control vitmin E in coronry circultion filed to increse fter subjects, results tht re similr to those of our previous the pcing-induced ischemi relted to the incresed report [12]. oxygen demnd in ptients with stble effort ngin. These results suggest tht lower plsm levels of vitmin E in the 4.1. Vitmin E uptke in coronry circultion in vrint coronry sinus t bseline in the ptients with ctive ngin vrint ngin my be the result of exhustion of this mjor endogenous ntioxidnt by incresed lipid peroxid- In the present study, the plsm vitmin E concen- tion stress, such s free rdicl production from vriety trtions (- nd g-tocopherol) were demonstrted to be of cells ctivted during the inflmmtory process trigsignificntly lower in the coronry sinus compred with the gered by frequently repeted ltertions between severe ortic root in ptients with vrint ngin with spsm in trnsient regionl myocrdil ischemi nd reperfusion. the left coronry rtery t bseline, suggesting significnt vitmin E consumption in the coronry circultion in these 4.3. Oxidtive stress in coronry circultion ptients. The TBARS level ws significntly higher in the coronry sinus thn in the ortic root. As mlondildehyde, Recently, Mzzone et l. [16] reported tht neutrophil s estimted by this method, is mesure of lipid nd monocyte CD11b/ CD18 dhesion molecules show peroxidtion, which occurs when polyunsturted ftty higher expression in the coronry sinus blood of ptients cids re ttcked by free rdicls of oxygen, free-rdicl with unstble ngin, indicting tht n inflmmtory ctivity or free rdicl-induced oxidnt stress ppers to be rection tkes plce within their coronry tree. These incresed in coronry circultion in these ptients. In leucocytes, once ctivted, my relese vriety of contrst, no significnt difference in vitmin E concen- potentilly toxic nd vsoctive substnces, in prticulr, trtions between the plsm smples from the ortic root the lipoxygense-derived metbolites of rchidonic cid, nd coronry sinus ws noted in the control subjects or in leucotrienes [17]. These substnces hve been shown to the ptients with n orgnic coronry stenosis nd stble induce coronry vsoconstriction nd decrese coronry effort ngin but without coronry spsm, suggesting tht flow in vriety of preprtions. In ddition, the respirtothere ws no pprent uptke of vitmin E in the coronry ry burst results in the formtion of oxygen-derived free circultion in them. The pprent uptke of vitmin E t rdicls. In their subsequent report [18], mong clinicl bseline in ptients with vrint ngin my be due to nd ngiogrphic findings in ptients with unstble ngin, either n ongoing vitmin E consumption for scvenging only the occurrence of chest pin within 48 h of blood

7 onry spsm. In contrst, no pprent consumption of vitmin E in the coronry circultion ws observed in ptients without coronry rtery disese or in ptients with n orgnic coronry rtery stenosis but without spsm. Incresed oxidtive stress nd depletion of plsm vitmin E, including - nd g-tocopherol, my be involved in the pthogenesis of coronry rtery spsm nd unstble n- gin. smpling ws relted to higher expression of the dhesion molecules in the coronry sinus blood. Mny of our ptients with vrint ngin hd spontneous nginl ttcks during the 12 h prior to blood smpling. When Lfont et l. [19] studied plsm -tocopherol concentrtion before nd fter reperfusion by coronry ngioplsty in ptients with cute myocrdil infrction, reduction of -tocopherol strted immeditely fter brupt reperfusion nd continued for 3 h fter ngioplsty. The underlying hypothesis is tht reperfusion is ssocited with incresed free rdicl production [20 23], which my be indirectly reflected by the cute reductions in mjor endogenous free rdicl scvenger, vitmin E. K. Miw et l. / Crdiovsculr Reserch 41 (1999) Acknowledgements We re grteful to our ctheteriztion tem for blood smpling. We re gretly indebted to Eisi Co., Ltd., Jpn, 4.4. Vitmin E deficiency nd oxidtive stress in the for technicl guidnce in the ssy of vitmin E. genesis of coronry rtery spsm Although vitmin E consumption in the coronry circu- References ltion ws demonstrted in ptients with vrint ngin, the exct cusl reltionship between vitmin E deficiency [1] Burton GW, Joyce A, Ingold KU. First proof tht vitmin E is nd coronry spsm still remins to be elucidted. Vitmin mjor lipid-soluble chin-breking ntioxidnt in humn blood E deficiency s possible cuse of coronry rtery spsm plsm. Lncet 1982;2: cnnot be excluded by the evidence of vitmin E consumpsoluble, chin-breking ntioxidnt in humn blood plsm nd [2] Burton GW, Joyce A, Ingold KU. Is vitmin E the only lipid- tion. It is lso possible tht vitmin E deficiency could be erythrocyte membrnes?. Arch Biochem Biophys 1983;221:281 directly relted to the pthogenesis of coronry spsm Consumption of vitmin E results in reduction in the [3] Witztum JL, Steinberg D. Role of oxidized low density lipoprotein resistnce of low-density lipoprotein to oxidtion. The in therogenesis. J Clin Invest 1991;88: formtion of oxidized low-density lipoprotein hs been [4] Gey KF, Brubcher GB, Sthelin HB. Plsm levels of ntioxidnt vitmins in reltion to ischemic hert disese nd cncer. Am J Clin shown to enhnce gonist-induced coronry vsculr con- Nutr 1987;45: trctions nd reduce endothelium-dependent vsorelx- [5] Riemersm RA, Word DA, Mcintyre CCA, et l. Risk of ngin tions, cusing incresed coronry vsorectivity to gonists pectoris nd plsm concentrtions of vitmin A, C, nd E nd [24 26]. Vitmin E hs other beneficil ctions on vsculr crotene. Lncet 1991;337:1 5. rectivity, such s ntipltelet properties [27], inhibition of [6] Stmpfer MJ, Hennekens CH, Mnson JB, et l. Vitmin E con- sumption nd the risk of coronry disese in women. N Engl J Med vsculr smooth muscle cell prolifertion [28] nd lso 1993;328: inhibition of protein kinse C stimultion [29]. Oxygen- [7] Rimm EB, Stmpfer MJ, Ascherio A, et l. Vitmin E consumption derived free rdicls from ctivted neutrophils nd mono- nd the risk of coronry hert disese in men. N Engl J Med cytes within the coronry vsculture my initite vicious 1993;328: circle by vitmin E consumption, which, in turn, my [8] Stephens NG, Prsons A, Schofield PM, et l. Rndomised con- trolled tril of vitmin E in ptients with coronry disese: Cminhibit endothelium-dependent vsodiltion nd lso poten- bridge Hert Antioxidnt Study (CHAOS). Lncet 1996;347:781 tite gonist-induced vsoconstriction, leding to coronry 786. spsm nd trnsient regionl myocrdil ischemi s well [9] Mseri A, Seven S, DeNes M, et l. Vrint ngin: one spect of s endothelil dmge [13]. The cellulr sources of rec- continuous spectrum of vsospstic myocrdil ischemi. Am J tive oxygen species my lso include endothelil cells, Crdiol 1978;42: [10] Ysue H, Omote S, Tkizw A, et l. Coronry rteril spsm in smooth muscle cells nd fibroblsts within the vessel wll ischemic hert disese nd its pthogenesis: review. Circ Res [30]. Vitmin E deficiency my be involved in this vicious 1983;52(suppl I):I147 I152. circle or chin-rection in the pthogenesis of coronry [11] Miw K, Miygi Y, Fujit M. Susceptibility of plsm low density rtery spsm. lipoprotein to cupric ion-induced peroxidtion in ptients with vrint ngin. J Am Coll Crdiol 1995;26: [12] Miw K, Miygi Y, Igw A, Nkgw K, Inoue H. Vitmin E 5. Conclusion deficiency in vrint ngin. Circultion 1996;94: [13] Miw K, Miygi Y, Fujit M. LDL oxidtion nd vrint ngin: Role of methodologicl procedures in LDL oxidizbility ssessment. In conclusion, n pprent consumption of vitmin E Reply. J Am Coll Crdiol 1996;15: concomitnt with lipid peroxide genertion in the coronry [14] Miw K, Fujit M, Ejiri M, Ssym S. Biphsic chnges (initil increse nd lte decrese) in coronry sinus venous oxygen circultion ws demonstrted t bseline in ptients with sturtion during nginl ttcks induced by intrcoronry cetylvrint ngin, suggesting free rdicl formtion nd choline in ptients with vrint ngin. Crdiology 1992;81:221 incresed lipid oxidtion stress in ssocition with cor- 232.

8 298 K. Miw et l. / Crdiovsculr Reserch 41 (1999) [15] Thompson JN, Htin G. Determintion of tocopherols nd tocot- [23] McMurry J, Chopr M, Abdullh I, Smith WE, Drgie HJ. riennols in food nd tissues by high-performnce liquid chromtog- Evidence for oxidtive stress in unstble ngin. Br Hert J rphy. J Lipid Chromtogr 1979;2: ;68: [16] Mzzone A, De Servi S, Ricevuti G, et l. Incresed expression of [24] Kugiym K, Kerns SA, Morrisett JD, Roberts R, Henry PD. neutrophil nd monocyte dhesion molecules in unstble coronry Impirment of endothelium-dependent rteril relxtion by rtery disese. Circultion 1993;88: lysolecithin in modified low-density lipoproteins. Nture [17] De Servi S, Ricevuti G, Mzzone A, et l. Trnscrdic relese of 1990;344: leucotriene C4 by neutrophils in ptients with coronry rtery [25] Glle J, Bssenge B, Busse R. Oxidized low density lipoproteins disese. J Am Coll Crdiol 1991;17: potentite vsoconstrictions to vrious gonists by direct interction [18] De Servi S, Mzzone A, Ricevuti G, et l. Clinicl nd ngiogrphic with vsculr smooth muscle. Circ Res 1990;66: correltes of leucocyte ctivtion in unstble ngin. J Am Coll [26] Simon BC, Cunninghm LD, Cohen RA. Oxidized low density Crdiol 1995;26: lipoproteins cuse contrction nd inhibit endothelium dependent [19] Lfont A, Mrwick TH, Chisolm GM, et l. Decresed free rdicl relxtion in the pig coronry rtery. J Clin Invest 1990;86: scvengers with reperfusion fter coronry ngioplsty in ptients [27] Steiner M, Anstsi J. Vitmin E: n inhibitor of the pltelet relese with cute myocrdil infrction. Am Hert J 1996;131: rection. J Clin Invest 1976;57: [20] Scrgg R, Jckson R, Holdwy I, Woollrd G, Woollrd D. Chnges [28] Boscoboinik D, Szewczyk A, Hensey C, Azzi A. Inhibition of cell in plsm vitmin levels in the first 48 hours fter onset of cute prolifertion by lph-tocopherol. J Biol Chem 1991;26: myocrdil infrction. Am J Crdiol 1989;64: [29] Mhoney CW, Azzi A. Vitmin E inhibits protein kinse C ctivity. [21] Oldroid KG, Pterson JR, Rumley AG, et l. Coronry venous lipid Biochem Biophys Res Commun 1988;154: peroxide concentrtions fter coronry ngioplsty: correltion with [30] Nunes GL, Robinson K, Klynych A, et l. Vitmins C nd E inhibit biochemicl nd electrocrdiogrphic evidence of myocrdil is- 2 O2 production in the pig coronry rtery. Circultion chemi. Br Hert J 1992;68: ;96: [22] Roberts MJD, Young IS, Trouton TG, et l. Trnsient relese of lipid peroxides fter coronry rtery blloon ngioplsty. Lncet 1990;336: