대한임상병리학회지 : 제 19 권제 4 호 1999 Korean J Clin Pathol 1999; 19: 375-80 진단혈액학 관상동맥질환의위험인자로서혈장섬유소원의의의 김현경 송경순 박규은 박현영 * 윤영섭 * 심원흠 * 고은나 ** 지선하 ** 연세대학교의과대학임상병리과학교실, 내과학교실 *, 보건대학원 ** Plasma Levels of Fibrinogen as a Risk Factor for Coronary Artery Disease Hyun Kyung Kim, M.D., Kyung Soon Song, M.D., Quehn Park, M.D., Hyun-Young Park, M.D.*, Young-Sup Yun, M.D.*, Won Heum Shim, M.D.*, Eunna Go, MPH.**, and Sun Ha Jee, Ph.D., MHS** Departments of Clinical Pathology and Internal Medicine*, College of Medicine, Graduate School of Health Science and Management**, Yonsei University, Seoul, Korea Background : Fibrinogen is an essential cofactor for blood coagulation. The fibrinogen level has been identified as a risk factor for coronary artery disease (CAD) and stroke, but the relationship between plasma fibrinogen levels and number of atherosclerotic vesssels has been less investigated. The aim of this study is assess the possible association between plasma fibrinogen levels and the number of coronary stenosis in patients with CAD undergoing coronary catheterization. We also investigated the usefulness of plasma fibrinogen to predict CAD in a case-control study of the middle-aged men and women. Methods : We measured plasma fibrinogen, total cholesterol, HDL-cholesterol and triglyceride in 121 patients with CAD and in 109 healthy controls. Multivariate logistic regression models were performed to assess risk factors for CAD. Results : Plasma fibrinogen levels were significantly elevated in CAD group vs control group, 413.9±119.4 vs 296.3±74.1 mg/dl (P< 0.001), respectively. The levels of plasma fibrinogen were not different according to the number of coronary stenosis. Multivariate logistic regression analysis of fibrinogen level and risk factors revealed 3 independent predictors of CAD: fibrinogen, body mass index and diabetes mellitus. Those with fibrinogen levels of 331-420 mg/dl had a 6.36-fold increased risk than fibrinogen levels of less than 270 mg/dl, while fibrinogen levels higher than 420 mg/dl had 3.53-fold increased risk. Conclusions : These results provide the evidence that plasma fibrinogen is associated with an increased risk of CAD. However, the plasma fibrinogen was not correlated with the severity of coronary stenosis. (Korean J Clin Pathol 1999; 19: 375-80) Key words : Fibrinogen, coronary artery disease, Risk factor 서 론 관상동맥질환은관상동맥의죽상경화로인해심근의혈액공급 접수 : 1999년 3월 16일접수번호 : KJCP1272 수정본접수 : 1999년 7월 14일교신저자 : 송경순우 120-752 서울시서대문구신촌동 134 신촌세브란스병원임상병리과전화 : 02-361-6470, Fax: 02-313-0956 * 이연구는 98 보건의료기술연구개발사업의연구비 (HMP-98-M-1-0004) 로이루어졌음. 이결핍되어발생한다 [1]. 죽상경화의병변은괴사조직과섬유질로둘러싸인죽종 (atheroma) 이기본을이루며이러한죽종의파열은이차적으로혈전을야기하여심근경색증을일으키는것으로알려져있다 [2]. 이러한심근경색의발생에중요한역할을하는혈전은여러위험인자들이복합적으로작용하여발생되는것으로알려져있다 [3]. 혈전형성의위험인자로서섬유소원 (fibrinogen), 제 VII 혈액응고인자, plasminogen activator inhibitor-1 (PAI-1), tissue type plasminogen activator (t-pa), angiotensin converting enzyme (ACE), apo E 등이보고되어있다 [4]. 이중섬유소원 375
376 김현경 송경순 박규은외 5 인 은제 I 혈액응고인자로서혈전형성에중요한역할을담당하는혈장단백질로서혈장내섬유소원의농도상승은허혈성심질환, 뇌졸중, 말초혈관질환, 동맥경화증, 혈전증등을유발하는위험요인으로보고되고있다 [5, 6]. 섬유소원이관상동맥질환의혈전형성을유발하는인자로널리관찰되었으나, 관상동맥협착의병변정도에따른섬유소원의농도에대해서는연구가미진한실정이다. 이에본연구에서는관상동맥협착의정도가확인된관상동맥질환자와정상인에서혈장섬유소원을측정하여, 관상동맥협착정도에따른변화를분석하고아울러관상동맥질환의위험인자로서중요성을검토하여보았다. 대상및방법 1. 대상연세의료원심장혈관센터에내원하여관상동맥조영술을시행받은환자중관상동맥협착의병변이있는환자 121명 ( 남자 83 명, 여자 38명 ; 평균연령 59.5 ± 9.2세 ; 연령범위 36-84세 ) 을대상으로하였다. 이중안정형협심증은 61명, 불안정형협심증 41명, 급성심근경색증 19명이었다. 불안정형협심증은안정시에도흉통이발생하거나, 최근 1개월내흉통이발생한경우, 또는기존의흉통이 3주전부터악화된경우로정의하였으며그외의전형적인흉통증상이있는경우는안정형협심증으로정의하였다 [7]. 급성심근경색증의진단은 30분이상지속되는허혈성흉통의병력, 심전도상 2개이상의유도에서관찰된비정상 Q파, 혈청 CK-MB의 2배이상상승중 2가지이상의기준에해당하는경우로정의하였다 [8]. 관상동맥조영술소견상 50% 이상의협착을의미있는협착으로정의하였으며, 의미있는협착의관상동맥수에따라단일혈관, 두혈관, 세혈관질환으로나누었다. 환자군에서경구용항응고제나 heparin 치료중인사람은없었다. 정상대조군은과거력상심장질환이없으며, 최근 5년동안병원에입원한병력이없는사람으로건강강좌를청취하기위해병원에내원한 109명 ( 남자 70명, 여자 39명 ; 평균연령 59.3 ± 10.1세 ; 연령범위 26-79세 ) 을대상으로하였다. 환자군과정상대조군간에연령및남녀비의통계적차이는없었다. 2. 방법 1) 섬유소원, 지질및기타지표의측정환자군과대조군모두에서혈장섬유소원및혈청지질을측정하였다. 섬유소원은 Fibri-prest (Diagnostica Stago, France) 시약으로자동응고기기인 STA (Diagnostica Stago, France) 를이용하여측정하였다. 총콜레스테롤과중성지방은 Hitachi 747 (Hitachi, Nakashi, Japan) 자동생화학분석기를이용하여효소법으로측정하였다. 고밀도지단백콜레스테롤 (HDL-cholesterol) 는직 접법으로 Hitachi 747 자동생화학분석기를이용하여측정하였다. 저밀도지단백콜레스테롤 (LDL-cholesterol) 은 Friedewald 공식을이용하여계산하였다 [9]. 환자군중 32명에서만 C-반응성단백 (CRP) 및적혈구침강속도검사 (ESR) 를시행할수있었다. CRP는면역비탁법으로 IM- MAGE (Beckmann Instruments, USA) 를이용하여측정하였고 ESR은 Westergren 시험관 (Espette, Korea) 을이용하여수기법으로측정하였다. 2) 분석방법환자군과대조군간의연령, 체밀도지수 (body mass index, BMI), 여러혈청지질농도의비교는 t 검정으로시행하였고, 두군간의흡연, 고혈압, 당뇨병의차이를알기위하여카이제곱검정을하였다. 섬유소원이관상동맥질환의위험인자로서중요한지를알기위해다변량로지스틱회귀분석을실시하여 odds ratio (OR) 를산정하였다. 섬유소원은농도의분포에따라 4개군으로나누어분석하였는데섬유소원의농도가 270 mg/dl 미만인 1군, 270-330 mg/dl인 2군, 331-420 mg/dl인 3군, 420 mg/dl을초과한 4군으로분류하였다. 로지스틱회귀분석시섬유소원에영향을미칠수있는여러인자들즉, 연령, 성별, BMI, 흡연, 당뇨, 고혈압, 총콜레스테롤, 중성지방, 고밀도및저밀도지단백콜레스테롤, 심근경색증등을혼란변수로채택하여시행하였다. 모든통계분석은 Window SAS version 6.12를이용하였으며, P 값이 0.05 미만인경우통계학적의미가있는것으로판정하였다. 결과 1. 환자군과대조군에서혈장섬유소원농도및기타지표비교혈장섬유소원의농도는관상동맥질환자군이정상대조군보다매우높았다 (P < 0.001, Table 1). 연령, 흡연, 고혈압은환자군과대조군간에차이가없었으나 BMI 와당뇨는환자군에서의미있게높았다 (P=0.015, P < 0.001). 총콜레스테롤, 중성지방, 저밀도지단백콜레스테롤은환자군과대조군간의통계학적으로의미있는차이가없었고, 고밀도지단백콜레스테롤만이환자군에서의미있게낮았다 (P < 0.001). 또한총콜레스테롤 / 고밀도지단백콜레스테롤 (TC/HDL) 의비는환자군에서의미있게높았다 (P =0.001). 2. 임상적진단및관상동맥협착정도에따른혈장섬유소원의농도혈장섬유소원의농도는안정형, 불안정형협심증및급성심근경색증세군간의통계학적으로의미있는차이가관찰되었으며
관상동맥질환의위험인자로서혈장섬유소원의의의 377 Table 1. Characteristics of the 121 patients with coronary artery disease and 109 healthy controls Parameters Age (years) 59.5±9.2 59.3±10.1 0.868 Male : Female 83 : 38 70 : 39 0.483 BMI, kg/m 2 25.3±2.6 24.4±2.8 0.015* Smokers 70 61 1.000 Hypertension 56 44 0.424 Diabetes mellitus 36 9 <0.001* Triglycerides (mg/dl) 156.5±81.1 150.9±77.8 0.597 Total cholesterol (mg/dl) 197.0±36.7 201.4±36.8 0.372 HDL-cholesterol (mg/dl) 41.6±11.5 53.6±11.4 <0.001* LDL-cholesterol (mg/dl) 122.4±36.6 117.6±34.0 0.305 Total cholesterol/ 4.2±2.8 3.1±2.1 0.001* HDL-cholesterol Fibrinogen (mg/dl) 413.9±119.4 296.3±74.1 <0.001* (P=0.001), 급성심근경색증에서혈장섬유소원이가장높았다 (Table 2). 그러나관상동맥협착의정도에따른혈장섬유소원의농도에서통계적으로의미있는차이는없었다 (P=0.941). 3. 관상동맥질환의위험인자분석 관상동맥질환의위험인자를분석하기위해다중로지스틱회귀분석을시행한결과, 혈장섬유소원, 당뇨, BMI가의미있는위험인자로나타났다 (Table 3). 섬유소원의농도가 270 mg/dl 미만인 1군에비해서섬유소원의농도가 331-420 mg/dl인 3군은관상동맥질환의위험이 6.36배높고, 1군에비해서 420 mg/dl 을초과하는 4군은 3.53배더위험한것으로분석되었다. 당뇨가있는경우관상동맥질환의위험도가 4.38배증가하였다. 4. 섬유소원, ESR 및 CRP 의상관성 Patients (n=121) Controls (n=109) P -value Values are given as mean±sd or number of subjects. * P <0.05. ESR 과 CRP 를검사할수있었던 32 명의관상동맥환자에서혈 Table 2. The plasma concentrations (mean±sd) of fibrinogen in patients with coronary artery disease according to the extent of coronary stenosis and the clinical diagnosis Clinical diagnosis* Stable angina 61 394.4±109.4 Unstable angina 41 399.1±106.2 Acute myocaridal infarction 19 503.0±140.6 Coronary stenosis 1-vessel disease 56 416.6±128.5 2-vessel diseases 41 412.0±109.5 3-vessel diseases 24 406.6±117.5 * P =0.001; P =0.941. 장섬유소원과 CRP와의상관성은통계학적으로의미있는양의상관성이관찰되었다 (r=0.643, P < 0.001). 혈장섬유소원과 ESR 간에도통계학적으로의미있는양의상관성이있었다 (r=0.647, P < 0.001). Number of patients 고 혈전은관상동맥질환의죽상경화병변에서일어나는중요한변화로서급성심근경색이나심장마비, 불안정형협심증을초래하는주요원인으로밝혀져있다 [10]. 혈전은죽상경화판의손상으로발생되지만혈중혈전형성물질의증가에의해서도혈전이발생되어진행할수있다 [11]. 섬유소원은혈액응고의마지막단계에작용하는당단백으로트롬빈에의해섬유소가되며활성형응고인자 XIII의작용으로안정된섬유소를형성하여지혈하는작용을한다. 따라서섬유소원이증가하면혈액의점도를높여서혈전이발생할위험이높아지는것으로알려져있다 [4-6, 12]. 본연구에서는관상동맥협착의병변이확인된 121명의환자에서혈장섬유소원의농도가대조군에비해유의하게높았으며, 관상동맥질환군중에서는급성심근경색증에서가장높았다. 섬유소 찰 Fibrinogen (mg/dl) Table 3. Multivariate logistic analysis in coronary artery disease Risk Factors Logistic Standard 95% Odds Ratio function coefficient error of coefficient confidence interval P -value 2nd quartile of fibrinogen levels* 0.798 0.568 2.22 0.73-6.76 0.160 3rd quartile of fibrinogen levels 1.850 0.602 6.36 1.96-20.68 0.002 4th quartile of fibrinogen levels 1.260 0.276 3.53 2.05-6.06 <0.001 Diabetes mellitus (yes vs no) 1.477 0.674 4.38 1.17-16.41 0.028 Hypertension (yes vs no) 0.357 0.461 1.43 0.58-3.53 0.439 Body mass index (kg/m 2 ) 0.173 0.080 1.19 1.02-1.39 0.030 Smoking (yes vs no) -0.130 0.502 0.88 0.33-2.35 0.796 Age (years) -0.012 0.023 0.99 0.94-1.03 0.604 Sex (male vs female) 0.015 0.562 1.02 0.34-3.05 0.979 * 2nd quartile of fibrinogen levels indicates 270 to 330 mg/dl (compared with the reference category); 3rd quartile of fibrinogen, 331 to 420 mg/dl; 4th quartile of fibrinogen, >420 mg/dl; P < 0.05.
378 김현경 송경순 박규은외 5 인 원은심근손상후에증가하여 5일후최대농도를나타내는것으로알려져있는바본연구에서도급성심근경색후섬유소원의농도가증가하는일치된소견을보였다 [13]. 관상동맥질환에서증가된섬유소원은관상동맥질환의지표로사용될수있으며죽상동맥경화의형성과진행에관여할것으로추정하고있다 [14]. 본연구에서는관상동맥의협착에따른혈장섬유소의농도는차이가없었다. ECAT (European Concerted Action on Thrombosis and Disabilities) 연구팀에서보고한바에의하면여러개의관상동맥에완전폐쇄 (total occlusion) 가있는환자를제외하고는관상동맥조영술로측정된관상동맥의협착병변의수와혈장섬유소원간에연관성이없었다고하였다 [15]. 반면초고속컴퓨터단층촬영 (ultrafast computed tomography) 을이용하여측정된관상동맥의죽상경화증정도와혈장섬유소원간에는연관이있다는보고도있다 [16]. 이러한상반된결과는관상동맥내죽상경화증의정도를측정하는방법이서로다르기때문으로생각된다. 본연구에서는섬유소의농도가 270 mg/dl 미만인 1군에비해서섬유소원의농도가 331-420 mg/dl인 3군은관상동맥질환의위험이 6.36배높고, 420 mg/dl을초과하는 4군은 3.53배더위험한것으로분석되었다. 이는섬유소원의농도가 280 mg/dl 이하인경우에비해서 360 mg/dl 이상인경우관상동맥질환의위험이 6배증가한다는 Eriksson 등 [17] 의보고와유사하였다. 혈장섬유소원은급성염증성반응양물질로서관상동맥질환자체로인해증가할수있다. Kamphuisen 등 [18] 은정맥혈전증환자에서증가된혈장섬유소원의농도는다중로지스틱회귀분석에서 CRP의농도를통제한경우에도여전히의미있는혈전증의위험인자로분석됨을보여, 혈장섬유소원의증가가급성염증성반응으로인하여증가한것이아니라고주장한바있다. 본연구에서다중로지스틱회귀분석시혈장섬유소원을상승시킬수있는심근경색증을혼란변수로통제하여분석하였으므로심근경색증으로인한혈장섬유소원의상승을배제할수있을것으로생각된다. 관상동맥질환의고전적인위험인자로고혈압, 당뇨, 흡연, 고지혈증, 비만등이널리알려져있다 [19]. 본연구에서는당뇨와비만의척도인 BMI 만이위험인자로서의미있게나타났다. 또총콜레스테롤은관상동맥질환과대조군간에의미있는차이가없었으나 TC/HDL의비는환자군에서의미있게높았다. 총콜레스테롤은급성심근경색후 7-10일후에가장낮아지고 2개월이지나야정상수준으로회복되는것으로알려져있다 [20]. 따라서급성관동맥심질환을가진환자에서는 TC/HDL의비가총콜레스테롤보다더의미있는지표로사용될수있다 [21]. 본연구에서관상동맥질환자중치료약제에대한조사가가능했던사람 80명중 12명 (15%) 에서고지혈증치료약제를사용하고있어, 고지혈증약제도환자군의총콜레스테롤의농도에영향을미쳤을것으로사료된다. 최근관상동맥질환의위험인자로서만성염증의지표인 CRP, interleukin-6, 백혈구수, ESR 등이등장하고있다 [22]. Toss 등 [14] 은 CRP가불안정형협심증의예후인자로유용함을강조하였고 Gillum 등 [23] 은 ESR이관상동맥질환의위험인자임을보고한바있다. 본연구에서는여러염증성지표들을환자군과정상대조군에서측정하지못하였지만 32명의관상동맥질환자에서 ESR과 CRP를측정하여혈장섬유소원과의상관성을본결과, 모두통계학적으로의미있는양의상관성이관찰되었다. 관상동맥질환의위험인자로서이들염증성지표의유용성에대해서는앞으로더연구가필요할것이다. 최근에는유전자수준의연구가발전함에따라섬유소원의 DNA를추출하여중합효소연쇄반응 (polymerase chain reaction, PCR) 을시행한후제한효소로처리하여유전자다형성을검사할수있게되었고, 섬유소원의유전자형과혈전증간의연관성이연구되고있다 [24-26]. 섬유소원유전자에는 11개의유전자다형성이존재하는것으로알려져있는데, 이중 HaeIII 다형성과 BclI 다형성이혈장섬유소원농도와관련있는것으로알려져있다 [27-29]. Heinrich 등 [30] 은 HaeIII 다형성의 H2H2 유전자형이섬유소원농도의상승과관련성이높다고하였고, Humphries 등 [31] 은 Bcl I 다형성의 B2B2 유전자형이섬유소원농도를상승시킨다고보고하였다. 한편섬유소원농도가혈전증과는상관성이없다는보고도있다 [32]. 앞으로관상동맥질환에서이러한섬유소원유전자다형성의빈도와섬유소원의농도를조사하여한국인에서관상동맥질환의유발인자로서섬유소원유전자다형성을밝히는것이필요하리라사료된다. 요약연구배경 : 혈장섬유소원은혈액응고에중요한인자이다. 관상동맥질환이나뇌졸중에서섬유소원은위험인자로서알려져있지만이직섬유소원과죽상동맥경화의정도간의상관성에대해서는연구가미진하다. 본연구에서는관상동맥조영술로확인된협착혈관의수에따른섬유소원의농도를살펴보고, 아울러중년남자와여자를대상으로환자-대조군연구를통해관상동맥질환의위험인자로서혈장섬유소원의농도에대해분석하고자한다. 방법 : 121명의관상동맥질환자와 109명의정상대조군에서혈장섬유소원, 중성지방, 총콜레스테롤, 고밀도지단백콜레스테롤을측정하였고, 관상동맥질환의위험인자를분석하기위해다중로지스틱회귀분석을시행하였다. 결과 : 혈장섬유소원의평균농도는환자군이 413.9±119.4 mg/dl로정상대조군 296.3±74.1 mg/dl보다의미있게높았다 (P <0.001). 관상동맥협착의정도에따른혈장섬유소원의농도변화는관찰되지않았다. 다중로지스틱회귀분석으로관상동맥질환의위험인자를분석한결과, 섬유소원, body mass index, 당뇨가의미있는위험인자로분석되었다. 혈장섬유소원의농도가 331-420 mg/dl인경우섬유소원의농도가 < 270 mg/dl인군에비해관상동맥질환위험이 6.36배증가하였고, 섬유소원의
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