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1 Original ORIGINAL Article ARTICLE Korean Circulation J 26;36:39-45 ISSN c 26, The Korean Society of Circulation 성공적인일차관동맥중재술을시행받은급성심근경색환자에서혈중 Thioredoxin 과심근손상의관계 충북대학교의과대학순환기내과학교실, 1 제주대학교의과대학순환기내과학교실 2 김기석 2 한혜숙 1 이영신 1 배장환 1 황경국 1 김동운 1 주승재 2 조명찬 1 Plasma Thioredoxin Level and Its Correlation to Myocardial Damage in Patients with Acute Myocardial Infarction who Underwent Successful Primary Angioplasty Ki-Seok Kim, MD 2, Hyeo-Sook Han, MD 1, Yeong-Shin Lee, MS 1, Jang-Whan Bae, MD 1, Kyeong-Kuk Hwang, MD 1, Dong-Woon Kim, MD 1, Seung-Jae Joo, MD 2 and Myeong-Chan Cho, MD 1 1 Department of Internal Medicine, Chungbuk National University, Cheongju, 2 Department of Internal Medicine, Cheju National University, Jeju, Korea ABSTRACT Backgroud and Objectives:Oxidative stress is thought to play important role in cardiovascular disease. Thioredoxin is an important biomarker for determining the degree of oxidative stress. However, the relationship between the plasma thioredoxin levels and myocardial damage has not been investigated. Subjects and Methods:We measured the plasma thioredoxin levels in the patients suffering with acute myocardial infarction and who also underwent successful primary angioplasty. We then compared the plasma thioredoxin levels and the clinical parameters in acute myocardial infarction patients (n=37) in order to examine the relationship between oxidative stress and myocardial damage. Results:The plasma thioredoxin level was significantly related with the initial WBC count (r=.349, p<.5) and the myocardial damage, the peak CK level (r=.489, p<.1), the CK increment (r=.452, p<.5), the peak MB level (r=.417, p<.5), and the MB increment (r=.364, p<.5). We divided the patients into two groups according to the plasma thioredoxin levels. There was a significant difference in myocardial damage between the low and high plasma thoiredoxin levels at the initial WBC count (1174.2±338.4/uL vs 135±374.7/uL, respectively; p<.1) and the cardiac enzyme, the peak CK level (2565.2± IU/L vs 445.9± IU/L, respectively; p=.2), the CK increment (239.6± IU/L vs ±279.7 IU/L, respectively; p=.3), the peak MB level (28.7±127.5 IU/L vs 322.7±146.3 IU/L, respectively; p=.2), and the MB increment (173.8±128.4 IU/L vs 277.7±158.9 IU/L, respectively; p=.5). Conclusion:High thioredoxin levels were associated with the degree of oxidative stress and the extent of myocardial damage. Thioredoxin levels may be used as a new surrogate biomarker for the severity of oxidative stress and the extent of myocardial damage in the patients suffering with acute myocardial infarction. (Korean Circulation J 26;36:39-45) KEY WORDS:Thioredoxin;Oxidative stress;myocardial infarction;angioplasty. 서 활성산소종 (Reactive Oxygen Species; ROS) 의과잉생 론 논문접수일 :25 년 17 월 21 일수정논문접수일 :25 년 11 월 1 일심사완료일 :25 년 11 월 15 일교신저자 : 조명찬, 충북청주시개신동 62 충북대학교의과대학순환기내과학교실전화 :(43) 전송 :(43) mccho@cbnu.ac.kr 39 산과이로인한산화스트레스의발생은여러가지심장질환의발생과진행에있어중요한역할을하는것으로알려지고있다. 1) 지금까지다양한방면의연구에서활성산소종

2 4 Korean Circulation J 26;36:39-45 의과잉생산으로인한세포손상에관한연구가진행되고있으며, 특히이에따른산화스트레스의증가는생체내의산화환원계의불균형을초래하여세포기능의소실과세포고사및괴사를일으키는것으로알려져있다. 2) 또한동맥경화의발생과진행, 허혈재관류손상, 심비후등의심혈관질환과관련됨이알려져있으며, 3) 특히허혈후재관류손상의과정에서산화스트레스가중요한역할을하는것으로알려져있다. 4) 이러한산화스트레스에대한세포방어기전으로는세포내완충계의작용과여러가지효소들이관련되어있으며, 카탈라아제, 과산소디스뮤타제, 과산소산화환원효소, 글루타티온 / 글루타티온과산화효소가알려져있고, 최근에알려진 thioredoxin/thioredoxin 산화환원효소가있다. Thioredoxin 은 1974년 adult T cell leukemia 에서처음으로존재가알려진 12 kda 의단백질로여러가지스트레스상황에대한세포수준의반응을도모하며, 세포외작용으로는산화스트레스에대한세포보호작용을하고세포성장과분열을촉진하는것으로알려져있고, 세포내작용으로는단백질들과의상호작용및단백질과핵산간의작용에관여하는것으로알려져있다. 3) 지금까지 thioredoxin 에관한연구는산화스트레스에의하여세포에서분비가증가하며, 5) 심부전환자에서혈중농도가증가함이보고되어있고, 6)7) 바이러스성심근염환자에서 thioredoxin 의혈중농도가증가하고치료후감소함이보고되어있으며, 8) 급성관동맥증후군에서의연구로는불안정성협심증환자와급성심근경색환자에서혈중 thioredoxin 의농도가증가한다는연구결과는있다. 9)1) 산화스트레스와심혈관질환에관한국내일부연구가있으나 11)12) 매우미비한상태이며특히 thioredoxin 과급성심근경색환자에서심근손상정도와의연관성에관한연구는전무한상태이다. 따라서본연구에서는급성심근경색증으로응급실을내원하여성공적인일차적관동맥중재술을시행받은환자에서혈중 thioredoxin 의발현양상과이에관련된산화스트레스를반영하는임상적인인자와의관계를알아보고, thioredoxin 의발현정도가심근손상의정도와연관이있는지를알아보고자하였다. 대상및방법 한환자, 간경화, 만성신부전, 악성종양있었거나새로이진단된환자, 그리고감염등의교란요인 (confounding factor) 이있는환자는본연구에서제외하였다. 성공적인중재술은스텐트삽입후급성혈전증이나처치되지않은동맥박리등의급성합병증이없으며잔존협착이 2% 이하이며 TIMI 3 관류를유지한환자로정의하였다. 실험실검사응급실내원당시의백혈구수치는 Coulter Gen S automated hematology analyzer(beckman Coulter, Miami, USA) 를이용하여측정하였다. 그외임상적인인자로응급실내원시 WBC, glucose, uric acid, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglyceride 를측정하였다. 심근손상의평가 CK 및 CK-MB 는내원당시와재관류치료후 4시간간격으로 automatic analyzer(model 718, Hitachi, Tokyo, Japan) 로측정하여 CK와 CK-MB 의최고치를구하였고, CK와 CK-MB 의상승치는최고치에서내원시수치를뺀값으로하였다. 경색관련혈관및혈관내병변의위치는심전도와관동맥조영술의결과로판정하였다. 심근손상의정도는기존의연구들에서사용되어진바와같은방법으로추정하였다. 재관류치료전의 초기심근손상 의정도는응급실도착시의 CK 및 CK-MB 수치로추정하였고, 치료후의심근손상 의정도는 CK 및 CK-MB 의최고치및상승치로추정하였다. 혈중 Thioredoxin의측정혈중 Thioredoxin 농도의측정을위하여혈액은 Heparin 을첨가한주사기를이용하여관동맥조영술직전에혈액채혈한후즉시원심분리 (1,5 rpm, 15분 ) 를실시하여혈장을분리하고영하 72 에서냉동보관하였다. Sandwich ELISA kit (Redox Bioscience Inc. Kyoto, Japan.) 를이용하여 ELISA reader 로 45/6 nm에서흡광도를 3회측정한후평균하여혈중농도를구하였다. 대상 23 년 4월에서 24 년 3월까지충북대학교병원응급실을방문하여 ST 분절상승급성심근경색증으로진단받고성공적인일차적관동맥중재술을시행받은 37명의환자를대상으로하였다. 급성심근경색증의진단은 ST 분절상승심근경색은심전도에서 2개이상사지유도에서 1 mv 이상의 ST 분절의상승이있거나, 2개이상의연속되는흉부유도에서 2 mv 이상의 ST 분절상승이있고, 3분이상의전형적인흉통이있는경우로하였다. 성공적인중재술을시행하지못한환자, 입원기간중 24시간내에사망 심혈관조영술모든환자는응급실내원후일차적관동맥중재술을시행하였다. 관동맥조영술에서혈관협착의정도는 Philips Omtimus 2 system 에내장된 Quantitative Coronary Arteriography(QCA) 프로그램을이용하여측정하였다. 급성심근경색에연관된혈관은풍선확장술과스텐트삽입술로치료하였다. 분석방법 ST 분절상승급성심근경색환자 37명을대상으로산화스

3 Ki-Seok Kim, et al:thioredoxin Level in Acute Myocardial Infarction 41 트레스의발현정도와심근손상의정도의연관성을알아보기위하여 thioredoxin 의혈중농도와 CK 및 CK-MB 의최고치및상승치를비교하였다. 또한혈중 thioredoxin 결과의 7 percentile 인 25 ng/ml 을기준으로 2군으로나누어양군간의임상적인자와심근손상의차이를알아보았다. 통계분석통계적인분석은 SPSS 1. 프로그램을이용하여분석하였고, 모든수치는평균 ± 표준편차로표시하였다. 연속변수들간의상관관계분석은 Pearson 상관계수로검증하였고, 비교가능한변수는연속변수인경우모수검증법인 Student T test 를시행하여분석하였다. 비연속변수일경우에는 χ 2 test 로결과를분석하였다. 모든결과는 p<.5 인경우를통계적으로유의한결과로해석하였다. 결과 ±228.6 분에응급실을내원하였고, 응급실도착후성공적인관동맥재개통을마칠때까지걸린시간은 132.4±64. 분이었다. 내원당시백혈구수치는 ±3815.2/uL 로증가되어있었고, 혈중 thioredoxin 수치는 232.2±211.1 ng/ml 로정상치 (2~3 ng/ml) 에 13)14) 비하여현저히증가된결과를보였다 (Table 1). 37명의환자에서성공적으로관상동맥재개통술이시행되었으며, 시술및입원기간중합병증과사망한환자는없었다. 혈중 Thioredoxin 과임상적인자의비교혈중 thioredoxin 농도와 pain to door time, pain to ballon time 과는통계적으로유의한상관관계를보이지않았다. 내원당시의백혈구수치와혈중 thioredoxin 농도는통계적으로유의한상관관계를 (r=.349, p=.34) 보였다 (Fig. 1). 혈중요산농도와혈중 glucose 농도는 thioredoxin 농도와상관관계를보이지않았다. 임상적특징대상환자의평균연령은 61.1±14.1 세였고남자 27명, 여자 1명있었다. 관동맥질환의위험인자로고혈압 (n=16), 당뇨 (n=9), 흡연력 (n=22) 이있었다. 흉통발생후평균 281 Table 1. Clinical characteristics in patients with acute myocardial infarction Acute myocardial Characteristics infarction (n=37) Age (years) 61.1±14.1 Sex (Men/Women) 27/1 Smoking 22(59.5%) Hypertension 16(43.2%) Diabetes 9(24.3%) Total cholesterol (mg/dl) 196.1±51.2 HDL cholesterol (mg/dl) 43.1±1.9 LDL cholesterol (mg/dl) 128.4±42.9 Triglyceride (mg/dl) 144.6±85.3 Uric acid (mg/dl) 4.7±1.8 Glucose (mg/dl) 19.8±14.2 Initial WBC (/ul) ± ±211.1 Pain to admission time (min) 281.±228.6 Door to balloon time (min) 132.4±64. Initial CK (IU/L) 327.6±338.4 Peak CK (IU/L) 393.8± Increment of CK (IU/L) 286.8±178.2 Balloon to CK peak time (min) 527.1±443.8 Initial CK-MB (IU/L) 36.33±29.5 Peak CK-MB (IU/L) ±143.3 Increment of CK-MB (IU/L) 28.5±145.6 Balloon to CK-MB peak time (min) 416.8±234.6 WBC: white blood cell, CK: creatin kinase, CK-MB: creatine kinase- MB, HDL: high dencity lipoprotein, LDL: low density lipoprotein 혈중 Thioredoxin 과심근손상과의관계 Thioredoxin 수치와심근경색후심근손상의정도를비교하기위하여 CK 와 CK-MB 의최고치와 CK, CK-MB 의변화량과의상관관계를분석하였다. 혈중 thioredoxin 농도와 CK의최고치 (r=.489, p<.1), CK의변화량 (r=.452, p=.14) 은유의한상관관계 (Fig. 2) 를보였으며, CK-MB 의최고치 (r=.417, p=.14), CK-MB 의변화량 (r=.364, p=.37) 과도유의한상관관계 (Fig. 3) 를보였다. Thioredoxin 혈중농도에따른비교대상환자를혈중 thioredoxin 농도가 25 ng/ml 이상인군과미만인 2군으로나누어임상적인자와심근손상 WBC (/mm 3 ) r=.349 p=.34 Fig. 1. Correlation between initial WBC count and plasma thioredoxin levels. WBC: white blood cell.

4 42 Korean Circulation J 26;36: CK peak level (IU/L) 4 CK-MB peak level (IU/L) r=.489 p<.1 r=.417 p=.14 A A Increment of CK (IU/L) Increment of CK-MB (IU/L) r=.452 p=.14 r=.364 p=.37 B B Fig. 2. Correlation between plasma thioredoxin levels and peak CK and increment of CK levels. A: correlation between plasma thioredoxin levels and peak CK levels. B: correlation between plasma thioredoxin levels and increment of CK levels. CK: creatine kinase. 의정도를비교하였다. 양군에서혈중지질농도및요산농도, glucose 농도의차이는없었다. 혈중농도가 25 ng/ml 이상인군에서내원당시백혈구수치가유의하게높았다 (1174.2±338.4/uL vs 135±374.7/uL; p<.1). 심근손상정도를반영하는심근효소의최고치역시 (CK: ± IU/L vs 445.9± IU/L; p=.2, CK- MB: 28.7±127.5 IU/L vs 322.7±146.3 IU/L; p=.2) 높은결과를보였고, 심근효소의변화량 (CK: 239.6± IU/L vs ±279.7 IU/L; p=.3, CK-MB: ±128.4 IU/L vs 277.7±158.9 IU/L; p=.5) 또한높았다 (Table 2). 경색관련혈관을재개통한후심근효소의최고치에이르는시간은양군간의차이가없었다. Fig. 3. Correlation between plasma thioredoxin levels and peak CK-MB and increment of CK-MB levels. A: correlation between plasma thioredoxin levels and peak CK-MB levels. B: correlation between plasma thioredoxin levels and increment of CK-MB levels. CK-MB: creatine kinase-mb. 고 산화스트레스의유발은동맥경화의발생과진행, 고혈압, 관동맥재협착, 관동맥증후군등다양한심혈관질환의발생과밀접한관계가있는것으로알려지고있다. 3)15) Thioredoxin 은 Cys-Gly-Pro-Cys 의생물학적활성부위를가지며 disulfied bond 를형성하여산화환원반응에관여하는물질로최근그생물학적역할에관한다양한연구가진행되고있다. Thioredoxin 은심근세포는물론혈관내피세포, 혈관평활근세포의증식, 비후, 세포자멸사 (apoptosis) 등에관여하며, 3) nuclear factor-kappa B(NF-kB), activating protein-1(ap-1), serine-threonine kinase(akt), extracel- 찰

5 Ki-Seok Kim, et al:thioredoxin Level in Acute Myocardial Infarction 43 Table 2. Comparison of the high thioredoxin group and the low thioredoxin group in patients with acute myocardial infarction Characteristics Low thioredoxin (Trx<25 ng/ml) (n=24) High thioredoxin (Trx 25 ng/ml) (n=13) Age (years) 63.3± ±12.4 NS Sex (Men/Women) 19/5 8/4 NS Hypertension 11 (46%) 5 (38%) NS Diabetes 3 (13%) 6 (46%).4 Smoking 16 (67%) 6 (46%) NS Total cholesterol (mg/dl) 195.7± ±31.6 NS HDL cholesterol (mg/dl) 43.9± ±1.5 NS LDL cholesterol (mg/dl) 128.4± ±21.1 NS Triglyceride (mg/dl) 127.7± ±115.7 NS Uric acid (mg/dl) 4.2±1. 5.6±2.6 NS Glucose (mg/dl) 178.4± ±141.6 NS Initial WBC (/mm 3 ) ± ± Extent of myocardial injury Pain to admission time (min) 31.9± ±151.6 NS Door to balloon time (min) 83.9± ±79.1 NS Initial CK (IU/L) 321.9± ±292.2 NS Peak CK (IU/L) ± ± Increment of CK (IU/L) 239.6± ± Balloon to CK peak time (min) 533.7± ±357.3 NS Initial CK-MB (IU/L) 36.6± ±21.7 NS Peak CK-MB (IU/L) 28.7± ± Increment of CK-MB (IU/L) 173.8± ± Balloon to CK-MB peak time (min) 4.1± ±91.9 NS Trx: thioredoxin, WBC: white blood cell, CK: creatin kinase, CK-MB: creatine kinase-mb, HDL: high density lipoprotein, LDL: low density lipoprotein, NS: not significant p lular signal-regulated protein kinase(erk), apoptosis signal-regulated kinase 1(ASK1) 등의다양한신호전달체계의발현에관여하는것으로알려지고있다. 16) Thioredoxin 과심부전과의연관성에관한연구로는, Kishimoto 등 7) 과 Jekell 등 17) 의연구에서심부전환자에서혈중농도가증가되어있으며이는심부전의정도와연관이있다는결과와 Miyamoto 등 6) 의심부전환자에서혈관에서발현이증가한다는보고가있다. Shioji 등 8) 은심근염환자에서혈중 thioredoxin 의발현이증가하며치료후혈중농도가감소함을보고하였고, 심근염마우스모델에서심근손상의정도와 thioredoxin 의발현이비례함을보고하여, 5) thioredoxin 이심근질환에서심근손상과연관이있음을시사하는결과들이있다. 심혈관질환과산화스트레스의과잉의연관성에관한연구로는, Guan 등 18) 의연구에서급성심근경색환자에서산화스트레스의발현을대변하는 8-epi prostaglandin F2가정상인에비하여발현이증가함을보고하여심근경색발생시에과도한산화스트레스가발생됨을보고하였고, Ide 등 19) 은심부전동물모델에서활성산소종의일환인 superoxide anion(. O - 2 ) 의발생이증가함을보고하였으며, Tsutsui 등 2) 의연구에서생쥐심근경색모델에서활성산소종의급격한발생이일어남을보고하였다. 급성관동맥증후군에서 thioredoxin 의발현에관한연구로는불안정성협심증환자에 서혈중 thioredoxin 이안정성협심증환자에비하여현저히증가하며이는질환의중증도와비례한다는보고가있고, 9) Seojima 등 1) 은급성심근경색환자에서혈중 thioredoxin 농도가증가되며, 재관류실패군에서혈중농도가높았다는결과가있다. 이들의연구결과를종합하면관동맥의폐쇄에의한심근경색의발생시심근손상으로인한과다한산화스트레스의발생이일어남을알수있으며, 이에따라 thioredoxin 과같은항산화계의발현이증가하여심근보호작용에관여하고, 그발현정도는산화스트레스의발생정도와연관이있음을알수있다. 하지만아직까지심근경색환자에서심근손상의정도와혈중 thioredoxin 농도의연관성에관한연구결과는없었다. 본연구에서도혈중 thioredoxin 의발현이심근경색환자에서정상치 (2~3 ng/ml) 에 13)14) 비하여현저히증가 (232.2±211.1 ng/ml) 되어있는결과를보여심근경색환자에서과다한산화스트레스의발생이일어나며, 이에따른항산화기전의발현의증가로혈중 thiredoxin 의농도가증가하는결과를보였다. 또한일차적관동맥중재술후심근손상의정도와 thioredoxin 의발현을비교한결과에서혈중 thioredoxin 농도와 CK의최고치 (r=.489, p<.1), CK의변화량 (r=.452, p=.14) 은유의한상관관계 (Fig. 2) 를보였으며, CK-MB 의최고치 (r=.417, p=.14), CK-MB 의변화량 (r=.364, p=

6 44 Korean Circulation J 26;36: ) 과도유의한상관관계 (Fig. 3) 를보였다. 이는산화스트레스의발생정도와이를대변하는혈중 thioredoxin 농도가심근경색후심근손상의정도를대변하는지표의가능성을시사하는결과이며, 또한산화스트레스와심근손상간의연관성이있음을시사한다. 급성심근경색및불안정성협심증환자에서혈중백혈구수치는관동맥질환의중증도와사망률, 심부전및재경색등환자의예후와연관이있음이여러임상연구에서보고되고있으며, 21) 국내연구에서한등 22) 의보고에서혈중백혈구수치가심근손상의정도와비례한다는보고가있다. 또한백혈구수치의상승으로인하여혈관벽에염증세포의부착이증가하고염증매개물질의분비증가및활성산소종의증가가일어나고결과적으로경색부위의확장에관여하고성공적인재관류의실패와 No reflow 현상의발생과연관이있다는보고가있다. 23) 따라서재관류과정에서막혔던혈관이재개통되면서재관류가일어날때급격한활성산소종의증가가발생하며이로인한재관류손상에서산화스트레스의과발현이관련이있음을알수있다. 이를시사하는연구결과로는항산화제를투여한심근경색동물모델에서경색부위가감소하였고, 24) Turoczi 등 25) 의연구에서는 thioredoxin 과발현마우스모델에서대조군에비하여심근경색부위가감소함을보고하였다. 또한 ischemic preconditioning 으로전처치한동물심근경색모델에서대조군에비하여항산화물질의분비가증가하며경색부위의감소가관찰되고, 산화환원반응에민감한신호전달체계인 NFkB가관련되어있음이보고한연구가있다. 26)27) 따라서심근경색의발생시백혈구수치의증가는그기전이명확히밝혀지지는않았지만산화스트레스의과발현에의하여발생하게되고, thioredoxin 혈중농도가산화스트레스의과잉생산과연관이있으며심근손상및심근경색의크기와연관이있을뿐아니라재관류과정에서재관류손상과도연관이있음을알수있다. 본연구에서도혈중백혈구수치와 thioredoxin 수치는통계적으로유의한상관관계를 (r=.349, p=.34) 보였으며 (Fig. 1) 혈중 thioredoxin 농도가높은환자군 (>25 ng/ ml) 에서내원당시백혈구수치가유의하게높았고 ( ±338.4 IU/L vs 135±374.7 IU/L; p<.1), 심근손상정도를반영하는심근효소의최고치가 (CK: ± IU/L vs 445.9± IU/L; p=.2, CK-MB: 28.7±127.5 IU/L vs 322.7±146.3 IU/L; p=.2) 높은결과를보였으며, 심근효소의변화량 (239.6± IU/L vs ±279.7 IU/L; p=.3, CK-MB: 173.8±128.4 IU/L vs 277.7±158.9 IU/L; p=.5) 또한높았다 (Table 2). 따라서본연구에서혈중 thioredoxin 농도가백혈구수치와심근경색에따른심근손상의정도와연관이있었으며, 이는산화스트레스의과발현과관련이있음을시사하는결과이다. 본연구의제한점으로는이미알려진산화스트레스의생화학적인자와 thioredoxin 의발현을비교하지못하였고, 관동맥재개통술후모든환자에서 TIMI 3 혈류는얻었지만, Blush score 의분석을통한조직순환의정도를평가하지못한점, 염증반응의정도를평가하기위하여 hs-crp 등을측정하지못한점과재관류후혈중 thioredoxin 의농도변화를측정하지못한점을들수있다. 앞으로이에관한추가적인연구가필요할것으로생각된다. 본연구의결과를요약하면급성심근경색환자에서심근경색의발생에의하여급격한산화스트레스의증가가발생하게되고, 혈중백혈구수치및 thioredoxin 농도가산화스트레스의발현정도와연관이있으며, 혈중 thioredoxin 농도는심근경색의정도와연관이있는새로운산화스트레스를반영하는지표로의가능성을확인하였다. 앞으로많은환자를대상으로한전향적연구와 thioredoxin 발현이심근손상에미치는기전에관한연구가필요할것으로생각된다. 요약 배경및목적 : 산화스트레스는심혈관질환의발생과진행에있어중요한역할을하는인자로알려지고있으며, thioredoxin 은산화스트레스를반영하는생화학적인자이다. 하지만급성심근경색환자에서 thioredoxin 의발현양상과심근손상의연관성에관한국내외연구는매우미비한상태이다. 본연구에서는급성심근경색증으로응급실을내원하여성공적인일차적관동맥중재술을시행받은환자에서혈중 thioredoxin 의발현양상과이에관련된산화스트레스를반영하는임상적인인자와의관계를알아보고, thioredoxin 의발현정도가심근손상의정도와연관이있는지를알아보고자한다. 방법 : ST 분절상승급성심근경색증으로진단받고성공적인일차적관동맥중재술을시행받은 37명의환자를대상으로혈중 thioredoxin 의발현양상과이에연관된임상적인자를비교하였다. 심근손상정도와의연관성을알아보기위하여심근효소의최고치및상승치의변화와 thioredoxin 혈중농도와의연관성을비교하였다. 결과 : 혈중 thioredoxin 의발현이심근경색환자에서정상치 (2~3 ng/ml) 에비하여현저히증가 (232.2±211.1 ng/ ml) 되었다. 내원당시의백혈구수치와혈중 thioredoxin 수치는통계적으로유의한상관관계를 (r=.349, p=.34) 보였다. 혈중 thioredoxin 농도와 CK의최고치 (r=.489, p<.1), CK의변화량 (r=.452, p=.14) 은유의한상관관계를보였으며, CK-MB 의최고치 (r=.417, p=.14), CK-MB 의변화량 (r=.364, p=.37) 과도유의한상관관

7 Ki-Seok Kim, et al:thioredoxin Level in Acute Myocardial Infarction 45 계를보였다. 혈중 thioredoxin 농도가높은환자군 (>25 ng/ml) 에서내원당시백혈구수치가유의하게높았고 (1174.2±338.4/uL vs 135±374.7/uL; p<.1), 심근손상정도를반영하는심근효소의최고치가 (CK: ± IU/L vs 445.9± IU/L; p=.2, CK- MB: 28.7±127.5 IU/L vs 322.7±146.3 IU/L; p=.2) 높은결과를보였으며, 심근효소의변화량 (239.6± IU/L vs ±279.7 IU/L; p=.3, CK-MB: ±128.4 IU/L vs 277.7±158.9 IU/L; p=.5) 또한높았다. 결론 : 급성심근경색환자에서혈중 thioredoxin 은산화스트레스와심근손상의정도를반영하는새로운생화학적인자로의가능성이있을것으로생각된다. 중심단어 :Thioredoxin; 산화스트레스 ; 심근경색 ; 혈관성형술. 이논문은 24 년도충북대학교학술연구지원사업의연구비지원에의하여연구되었음. REFERENCES 1) Nordberg J, Arner ES. Reactive oxygen species, antioxidants, and the mammalian thioredoxin system. Free Radic Biol Med 21; 31: ) Ueda S, Masutani H, Nakamura H, Tanaka T, Ueno M, Yodoi J. Redox control of cell death. Antioxid Redox Signal 22;4: ) Nakamura H, Nakamura K, Yodoi J. Redox regulation of cellular activation. Annu Rev Immunol 1997;15: ) Kaminski KA, Bonda TA, Korecki J, Musial WJ. Oxidative stress and neutrophil activation: the two keystones of ischemia/reperfusion injury. Int J Cardiol 22;86: ) Miyamoto M, Kishimoto C, Shioji K, et al. Difference in thioredoxin expression in viral myocarditis in inbred strains of mice. Jpn Circ J 21;65: ) Miyamoto M, Kishimoto C, Shioji K, et al. Cutaneous arteriolar thioredoxin expression in patients with heart failure. Circ J 23; 67: ) Kishimoto C, Shioji K, Nakamura H, Nakayama Y, Yodoi J, Sasayama S. Serum thioredoxin (TRX) levels in patients with heart failure. Jpn Circ J 21;65: ) Shioji K, Matsuura Y, Iwase T, et al. Successful immunoglobulin treatment for fulminant myocarditis and serial analysis of serum thioredoxin: a case report. Circ J 22;66: ) Hokamaki J, Kawano H, Soejima H, et al. Plasma thioredoxin levels in patients with unstable angina. Int J Cardiol 25;99: ) Soejima H, Suefuji H, Miyamoto S, et al. Increased plasma thioredoxin in patients with acute myocardial infarction. Clin Cardiol 23;26: ) Jun JE, Chun BY, Choi YS, et al. Effects of antioxidant supplementation on the lipid peroxidation and antioxidative enzyme activities in patients with coronary heart disease. Korean Circ J 21;31: ) Cho YS, Choi JH, Zhang SY, et al. Relationship of polymorphisms in the oxidative stress related genes: paraoxonase and p22phox- to variant angina and coronary artery stenosis in Korean. Korean Circ J 23;33: ) Kakisaka Y, Nakashima T, Sumida Y, et al. Elevation of serum thioredoxin levels in patients with type 2 diabetes. Horm Metab Res 22;34: ) Miwa K, Kishimoto C, Nakamura H, et al. Serum thioredoxin and alpha-tocopherol concentrations in patients with major risk factors. Circ J 25;69: ) Yamawaki H, Haendeler J, Berk BC. Thioredoxin: a key regulator of cardiovascular homeostasis. Circ Res 23;93: ) Martindale JL, Holbrook NJ. Cellular response to oxidative stress: signaling for suicide and survival. J Cell Physiol 22;192: ) Jekell A, Hossain A, Alehagen U, Dahlstrom U, Rosen A. Elevated circulating levels of thioredoxin and stress in chronic heart failure. Eur J Heart Fail 24;6: ) Guan W, Osanai T, Kamada T, Ishizaka H, Hanada H, Okumura K. Time course of free radical production after primary coronary angioplasty for acute myocardial infarction and the effect of vitamin C. Jpn Circ J 1999;63: ) Ide T, Tsutsui H, Kinugawa S, et al. Direct evidence for increased hydroxyl radicals originating from superoxide in the failing myocardium. Circ Res 2;86: ) Tsutsui H, Ide T, Hayashidani S, et al. Enhanced generation of reactive oxygen species in the limb skeletal muscles from a murine infarct model of heart failure. Circulation 21;14: ) Madjid M, Awan I, Willerson JT, Casscells SW. Leukocyte count and coronary heart disease: implications for risk assessment. J Am Coll Cardiol 24;44: ) Han J, Hong ES, Yoon SI, et al. The relationship between initial leukocyte count and the extent of myocardial injury in patients with acute myocardial infarction who received reperfusion therapy. Korean Circ J 24;34: ) Barron HV, Cannon CP, Murphy SA, Braunwald E, Gibson CM. Association between white blood cell count, epicardial blood flow, myocardial perfusion, and clinical outcomes in the setting of acute myocardial infarction: a thrombolysis in myocardial infarction 1 substudy. Circulation 2;12: ) Becker LB. New concepts in reactive oxygen species and cardiovascular reperfusion physiology. Cardiovasc Res 24;61: ) Turoczi T, Chang VW, Engelman RM, Maulik N, Ho YS, Das DK. Thioredoxin redox signaling in the ischemic heart: an insight with transgenic mice overexpressing Trx1. J Mol Cell Cardiol 23;35: ) Das DK, Maulik N. Preconditioning potentiates redox signaling and converts death signal into survival signal. Arch Biochem Biophys 23;42: ) Marczin N, el-habashi N, Hoare GS, Bundy RE, Yacoub M. Antioxidants in myocardial ischemia-reperfusion injury: therapeutic potential and basic mechanisms. Arch Biochem Biophys 23; 42:

Jksvs019(8-15).hwp

Jksvs019(8-15).hwp Grade I Grade II Grade III 12 대한혈관외과학회지 : 제 20 권 제 1 호 2004 Control Group A Group B Fig. 4. Microscopic findings of vein wall in control, group A and group B on the day of 7 after venous occlusion. The