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1 원저 Korean Circulation J 2004;34(9): 관상동맥협착의진행과혈중 Adiponectin, ICAM (Intercellular Adhesion Molecule)-1 농도와의관계 계명대학교의과대학내과학교실 박형섭 김기식 박창욱 김민정 조윤경 이상원이영수 현대우 한성욱 허승호 김윤년 김권배 The Relationship between Progression of Coronary Artery Stenosis and Serum Adiponectin, ICAM(Intercellular Adhesion Molecule)-1 Level Hyoung-Seob Park, MD, Kee-Sik Kim, MD, Chang-Wook Park, MD, Min-Jung Kim, MD, Yun-Kyeong Cho, MD, Sang-Won Lee, MD, Young-Soo Lee, MD, Dae-Woo Hyun, MD, Seong-Wook Han, MD, Seung-Ho Hur, MD, Yoon-Nyun Kim, MD and Kwon-Bae Kim, MD Department of Internal Medicine, College of Medicine, Keimyung University, Daegu, Korea ABSTRACT Background and Objectives:Adiponectin is an adipocyte derived plasma protein that is known to have an anti-atherogenic effect. Low plasma adiponectin concentrations are found in obesity, diabetes and coronary artery disease. The measurement of the plasma adiponectin level is helpful in the assessment of the risk for coronary artery disease. The intercellular adhesion molecule (ICAM)-1 is associated with the atherosclerotic inflammatory response. An elevated ICAM-1 concentration is associated with increased risk of future coronary events, independent of other risk factors. The relationships between serum adiponectin and ICAM-1 levels and the progression of coronary artery stenosis with instent restenosis of previous stent sites were analyzed. Subjects and Methods:83 patients who had percutaneous transluminal coronary angioplasty and stent insertion were enrolled. The initial angiographic finding was compared with that at the 6 month follow up. The serum adiponectin and ICAM-1 level were measured with the plasma lipid profiles prior to percutaneous coronary intervention. These biochemical parameters were analyzed according to the progression of coronary artery stenosis ( 10%) and instent restenosis ( 50%). Results:In the coronary artery stenosis progression group, there were significantly lower adiponectin (3.91±1.24 μg/ml vs. 4.66±1.36 μg/ml, p=0.03) and higher ICAM-1 levels (199.16±79.13 ng/ml vs ±63.65 ng/ml, p=0.03). The instent restenosis group also showed lower adiponectin (3.99±1.22 μg/ml vs. 4.33±1.38 μg/ml) and higher ICAM-1 (195.17±68.45 ng/ml vs ±80.48 ng/ml) levels, but without statistical significance. Conclusion:The serum adiponectin and ICAM-1 levels are related to the progression of coronary artery stenosis. However, further study will be required to confirm the relationships between the serum adiponectin and ICAM-1 levels and instent restenosis. (Korean Circulation J 2004; 34(9): ) KEY WORDS:Adiponectin;Intercellular adhesion molecule-1;coronary restenosis. 논문접수일 :2004 년 6 월 02 일심사완료일 :2004 년 6 월 30 일교신저자 : 김기식, 대구광역시중구동산동 194 번지계명대학교의과대학내과학교실전화 :(053) 전송 :(053) kks7379@dsmc.or.kr 837

2 서론 Adiponectin은지방세포에서분비되는내분비인자의역할을하는단백질중의하나이다. 1) Adiponectin 은내피세포의염증반응에관여하여항동맥경화작용을나타내는것으로알려져있으며 2) 비만, 당뇨병환자와관상동맥질환환자에서그혈중농도가낮게측정된다. 3-5) 이러한 adiponectin 을이용하여동맥경화성질환특히관상동맥질환과의관계에대한연구가많이이루어졌으며지금까지의연구에서는 adiponectin 혈중농도의측정으로관상동맥질환의위험도를예측할수있다고한다. 5) 하지만관상동맥질환의진행과관련된위험인자로서의기능에대한연구는지금까지별로이루어지지않았다. ICAM(Intercellular Adhesion Molecule)-1은염증성반응에관여하는부착분자중의하나로특히동맥경화성질환에서의염증반응에중요한역할을하는것으로알려져있다. 6-8) 이는동맥경화성질환에서세포외에발현되어동맥경화를진행시키는역할을하며혈중농도가증가되어있다. 그리고증가된혈중 ICAM- 1 농도는동맥경화성질환, 특히관상동맥질환의위험인자로서의미를가지는것으로알려져있다. 9) 하지만 ICAM-1 과관상동맥질환의진행과의관계에대한연구도아직부족한실정이다. 저자들은혈중 adiponectin 과 ICAM-1 농도를측정하여이와관상동맥협착의진행여부, 철망내재협착 (Instent Restenosis) 유무와의관계를규명하기위해본연구를시행하였다. 대상및방법 정 kit(linco Research, St. Charles, MO, USA) 를사용하여측정하였으며 ICAM-1 농도는 human sicam- 1(R & D Systems, Minneapolis, MN, USA) 을사용한방사능면역측정으로시행하였다. 환자들은철망삽입술시행후 aspirin 100~200 mg, clopidogrel 75 mg의항혈소판제재를지속적으로복용하였으며당뇨병이나고지혈증에대해서도약물복용을시행하였다. 관상동맥협착의진행은추적관상동맥조영술상같은혈관부위에서이전조영술소견에비하여 10% 이상협착이진행한군으로정의하였고철망내재협착은철망삽입술을시행한부위에서추적관상동맥조영술상 50% 이상의재협착이있는것으로정의하였다. 그리고혈관내재협착도관상동맥협착이진행한군에포함하였다. 위와같은방법으로관상동맥협착이진행한군과진행하지않은군, 철망내재협착이있었던군과없었던군사이에대해대상환자의특성과위의각측정치들에대한비교, 분석을시행하였다. 각측정치에대해평균과표준편차를구하였으며평균치의비교는 Student-t 방법을사용하여시행하였다. 유의성검증은 p<0.05 를기준으로하여시행하였다. 혈중 adiponectin 과 ICAM-1 농도사이의관계에대한비교도시행하였으며이는단회귀분석을통하여 p<0.05 를기준으로하여시행하였다. 결과 총 83 명의환자들을대상으로하였다. 환자들중관상동맥협착의진행이있었던환자들은 50명 (60.2%) 이었고철망내재협착이있었던환자들은 30명 (36.1%) 이었다. 계명대학교동산의료원에서풍선확장술및철망삽입술을시행하고 6개월후추적관상동맥조영술을시행한 83 명의환자를대상으로하였다. 환자들의처음시술당시관상동맥조영술소견과 6개월추적관상동맥조영술소견을비교분석하였다. 환자들은모두금식상태에서관상동맥조영술을시행하였고풍선확장술및철망삽입술시행전에혈액을채취하여총콜레스테롤, 중성지방, 저밀도지단백, 고밀도지단백, 아포단백 -A, 아포단백 -B, 혈중 adiponectin 농도, 혈중 ICAM-1 농도를측정하였다. 혈중 adiponectin 농도는방사능면역측 838 대상환자의특성환자들의평균연령은 57.90±9.75 세였고남자가 51 명 (61.5%) 으로많이나타났다. 관상동맥협착의진행유무나철망내재협착유무에따른연령이나성별의차이는보이지않았다. 체질량계수에대한각군간의비교에도의미있는차이는보이지않았다. 위험인자에있어서도당뇨병, 고혈압흡연유무에따른각군간의차이는보이지않았으며관상동맥질환의종류도관상동맥협착의진행유무나철망내재협착유무에따른차이를보이지는않았다. 고지혈증치료제의복용유무에따른 Korean Circulation J 2004;34(9):

3 각군간의차이는없었다. 질환혈관수는단혈관질환이가장많이나타났으나각군간의차이는보이지않았다 (Table 1, 2). 분류에따른병변의형태, 참조혈관내경, 최소혈관내경, 협착의정도등에있어서철망내재협착유무에따른의미있는차이는없었다. 철망삽입부위의병변의특성과철망내재협착과의관계 (Table 3) 철망삽입부위의병변의길이, ACC/AHA(American College of Cardiology/American Heart Association) 관상동맥질환의진행유무에따른비교 (Table 4) 관상동맥질환의진행이있었던군에서총콜레스테롤농도가 ±29.99 mg/dl 로없었던군의 ± mg/dl 보다높게나타났으나통계학적유의성은 Table 1. Relation between patients clinical characteristics and coronary artery stenosis progression Progression (n=50) No progression (n=33) p Age (year) 58.52± ±9.83 Sex (M : F) 32 (64.0) : 18 (36.0%) 19 (57.6%) : 14 (42.4%) BMI (Kg/m 2 ) 24.99± ±2.70 Diabetes 16 (32.0%) 11 (33.3%) Hypertension 14 (28.0%) 10 (30.3%) Smoking 25 (50.0%) 20 (60.6%) Diagnosis AP 19 (38.0%) 12 (36.4%) UA 10 (20.0%) 05 (15.2%) AMI 21 (42.0%) 16 (48.5%) Vs number 1 Vs disease 25 (50.0%) 19 (57.6%) 2 Vs disease 23 (46.0%) 12 (36.4%) 3 Vs disease 02 (4.0%) 02 (6.1%) n: number, M: male, F: female, BMI: body mass index, AP: angina pectoris, UA: unstable angina, AMI: acute myocardial infarction, Vs: vessel, : not significant Table 2. Relation between patients clinical characteristics and instent restenosis ISR (+)(n=30) ISR (-)(n=53) p Age (year) 56.90± ±9.10 Sex (M : F) 22 (73.3%) : 8 (26.7%) 29 (54.7%) : 24 (45.3%) BMI (Kg/m 2 ) 24.89± ±3.02 Diabetes 12 (40.0%) 15 (28.3%) Hypertension 09 (30.0%) 15 (28.3%) Smoking 15 (50.0%) 30 (56.6%) Diagnosis AP 10 (33.3%) 21 (39.6%) UA 07 (23.3%) 08 (15.1%) AMI 13 (43.4%) 24 (45.3%) Vs number 1 Vs disease 17 (56.7%) 27 (50.9%) 2 Vs disease 10 (33.3%) 25 (47.2%) 3 Vs disease 03 (10.0%) 01 (01.9%) ISR: instent restenosis, n: number, M: male, F: female, BMI: body mass index, AP: angina pectoris, UA: unstable angina, AMI: acute myocardial infarction, Vs: vessel, : not significant 839

4 Table 3. Relation between angiographic characteristics and instent restenosis Pre-intervention ISR (+)(n=30) ISR (-)(n=53) p Lesion length (mm) 16.50± ±07.64 ACC/AHA lesion type A 02 (06.7%) 01 (01.9%) B1 10 (33.3%) 23 (43.4%) B2 06 (20.0%) 10 (18.9%) C 12 (40.0%) 19 (35.8%) Ref. diameter (mm) 03.20± ±00.54 MLD (mm) 00.57± ±00.32 Stenosis (%) 85.37± ±09.24 Post-intervention Stent length (mm) 19.73± ±06.14 Stent size (mm) 03.23± ±00.42 MLD (mm) 03.25± ±00.56 Stenosis (%) 07.25± ± month follow up Stenosis (%) 71.84± ± ISR: instent restenosis, n: number, ACC/AHA: American College of Cardiology/American Heart Association, Ref: reference, MLD: minimal luminal diameter, : not significant Table 4. Comparison between biochemical parameters and coronary artery stenosis progression Progression (n=50) No progression (n=33) p TC (mg/dl) ± ± TG (mg/dl) ± ± LDL-C (mg/dl) ± ± HDL-C (mg/dl) ± ± Apo-A (mg/dl) ± ± Apo-B (mg/dl) ± ± Adiponectin (μg/ml)* ± ± ICAM-1 (ng/ml)* ± ± n: number, TC: total cholesterol, TG: triglyceride, LDL-C: low density lipoprotein cholesterol, HDL-C: high density lipoprotein cholesterol, Apo: apolipoprotein, ICAM: intercellular adhesion molecule, : not significant 가지지못하였다. 이외에중성지방, 저밀도지단백, 고밀도지단백, 아포단백-A, 아포단백-B 의농도는관상동맥협착의진행에영향을미치지못하였다. 혈중 Adiponectin 농도는관상동맥협착이진행한군에서 3.91± 1.24 μg/ml 로진행하지않은군의 4.66±1.36 μg/ml 보다유의하게낮게나타났고 (p=0.03), ICAM-1 치는관상동맥협착이진행한군에서 ±79.13 ng/ml 로진행하지않은군의 ±63.65 ng/ml 보다유의하게높게나타났다 (p=0.03)(fig. 1). 철망내재협착유무에따른비교 (Table 5) 철망내재협착의유무에따르면재협착이있었던군에서중성지방의농도가 ±96.12 mg/dl 로없었던군의 ±79.25 mg/dl보다높게측정되었고, 고밀도지단백의농도는재협착이있었던군에서 36.34±9.16 mg/dl 로없었던군의 39.72±11.48 mg/dl 보다낮게측정되었다. 그러나이두측정치의차이에따른통계적유의성은없었다. 이외에각군간에총콜레스테롤, 저밀도지단백, 아포단백 -A, 아포단백- B 농도의차이도없는것으로나타났다. 840 Korean Circulation J 2004;34(9):

5 5 Adiponectin (μg/ml) 4.66± ICAM-1 (ng/ml) ± ± ± p= p= Progression No Progression 0 Progression No Progression Fig. 1. Relationship between serum adiponectin, ICAM (intercellular adhesion molecule)-1 level and coronary artery stenosis progression. There was significantly lower serum adiponectin and higher serum ICAM level in progression group. Table 5. Comparison between biochemical parameters and instent restenosis ISR(+)(n=30) ISR(-)(n=53) p TC (mg/dl) ± ±35.14 TG (mg/dl) ± ±79.25 LDL-C (mg/dl) ± ±35.48 HDL-C (mg/dl) ± ±11.48 Apo-A (mg/dl) ± ±20.94 Apo-B (mg/dl) ± ±21.80 Adiponectin (μg/ml) ± ±01.38 ICAM-1 (ng/ml) ± ±80.48 ISR: instent restenosis, n: number, TC: total cholesterol, TG: triglyceride, LDL-C: low density lipoprotein cholesterol, HDL- C: high density lipoprotein cholesterol, Apo: apolipoprotein, ICAM: intercellular adhesion molecule, : not significant 5 4 Adiponectin (μg/ml) 3.99± ± ICAM-1 (ng/ml) ± ± p= 50 p= 0 ISR (+) ISR (-) 0 ISR (+) ISR (-) Fig. 2. Relationship between serum adiponectin, ICAM (intercellular adhesion molecule)-1 level and instent restenosis (ISR). There was lower serum adiponectin and higher serum ICAM-1 level in instent restenosis group. But there was no stastistical significance. : not significant. 혈중 adiponectin 치는재협착이있었던군에서 3.99± 1.22 μg/ml 로재협착이없었던군의 4.33±1.38 μg/ml 보다낮게나타났고 ICAM-1 치는재협착이있었던군에서 ±68.45 ng/ml 로없었던군의 ± ng/ml 보다높게나타났다. 그러나 adiponectin 과 ICAM-1 의비교에서도재협착의유무에따른통계적유의성은가지지못하였다 (Fig. 2). 혈중 adiponectin 과 ICAM-1 과의상관관계혈중 adiponectin 농도와 ICAM-1 과의농도간의관 841

6 ICAM-1(ng/mL) 계에대해서도비교해보았다. 단회귀분석으로시행한이둘간의관계에대한분석에서는상관계수 (r) 는 로약한음의상관관계를보였다 (p<0.01)(fig. 3) r=-0.29 p< Adiponectin (μg/ml) Fig. 3. Relation between serum adiponectin and ICAM (intercellular adhesion moldcule)-1 level. There was weak negative relationship between serum adiponectin and ICAM-1 level. 고 Adiponectin 은지방조직의 cdna 유전자에대한연구의결과로발견된지방세포에특이적인유전자 apm1 에의해생성된내분비인자이다. 1) Adiponectin 은혈중총단백질의 0.01% 를차지하고있으며지방세포중에서가장풍부한유전자대산물이다. 3) 혈중 adiponectin 은혈관손상시에손상된혈관의내피하에침착하게되며 10) 세포배양연구에의하면 adiponectin 은내피세포에서의접착분자의발현을억제하여단핵세포의부착을감소시킨다. 11)12) 이외에 adiponectin 은대식세포의거품세포로의변형, 대식세포에서의종양괴사인자 (tumor necrosis factor-α, TNF-α) 분비, 혈관평활근육의증식을억제하는작용을가지고있다 ) 이러한작용들이동맥경화의진행에있어서중요한역할을담당하고있기때문에 adiponectin 은동맥경화가일어나는염증반응을억제하여항동맥경화작용을가질수있다. 2) Adiponectin 은비만환자 3) 와당뇨병환자, 4) 그리고관상동맥질환환자 5) 에서그농도가낮게나타난다. 특히최근에는 adiponectin 과관상동맥질환과의관계를규명하기위한연구가많이이루어졌다. 이러한연구들에의하면혈중 adiponectin 의농도가낮아져있는경우관상동맥질환이나타나는빈도가높다. 특히 4.0 μg/ml 이하의 adiponectin 농도는다른위험인자에독립적으로 찰 관상동맥질환의위험인자의역할을할수있으며이경우관상동맥질환의유병율이 2배가량증가하였다. 5) 만성신부전환자들을대상으로한연구 15) 에서는혈중 adiponectin 농도가이후의심혈관질환의예후를예측하는위험인자로서의역할을할수있다고하였다. 이외에혈중 adiponectin 농도의감소가좌심실비대및이완장애와연관이있어심혈관질환의위험인자로작용할수있다는보고도있다. 16) 본연구에서는관상동맥협착의진행유무, 철망내재협착유무와혈중 adiponectin 농도와의관계를비교분석하였다. 관상동맥질환이진행한군에서의 adiponectin 농도가유의하게낮게나타난것으로보아 adiponectin 의농도가떨어져있을경우관상동맥협착이진행할가능성이높다고추측할수있을것이다. 그러나철망내재협착유무와의관계에대해서는철망내재협착이 50% 이상있었던군에서 adiponectin 농도가재협착이없었던군에비해낮게나타났으나통계적유의성을보이지는못하였다. 최근의동맥경화증에대한연구에의하면염증반응이동맥경화의진행에중요한역할을한다고하며 17) 이러한염증반응에는여러가지부착분자들이관여하고있다. 이중 ICAM-1, VCAM (vascular cell adhesion molecule)-1 의내피세포표면에서의발현이동맥경화의염증반응과관련이있다. 6-8) ICAM-1 의혈중농도는내피세포표면의 ICAM-1 의발현정도와비례하는것으로알려져있다. 18) 이러한 ICAM-1 의측정을통해서동맥경화의유무를알수있으며몇몇의전향적연구에서는관상동맥질환의여부더나아가급성심근경색증등의관상동맥질환에대한예후를알수있다고제시하고있다. 9)19-21) 본연구에서는이러한 ICAM- 1과관상동맥협착의진행과철망내재협착유무와의관계에대하여비교분석하였다. 관상동맥협착이진행한군에서 ICAM-1 의혈중농도가진행하지않은군보다의미있게높게나타났다. 철망내재협착이있었던군에서 ICAM-1 의혈중농도는재협착이없었던군보다높게나타났으나통계학적의미를가지지는못하였다. 철망내재협착은평활근세포의과증식에의한신생내막의형성이가장중요한역할을하는것으로알려져있다. 22) 이는관상동맥질환의진행과는그기전이달라위와같은결과가나타날수있다고본다. 그러나 adiponectin 은위에서언급한바와같이평활근의증식을 Korean Circulation J 2004;34(9):

7 억제하는작용을가지고있으며철망내재협착시에일어나는염증반응에 ICAM-1 이관여하여 ICAM-1 의농도와철망내재협착이관계가있다는보고 23) 가있으므로철망내재협착과혈중 adiponectin, ICAM-1 과의관계를증명하기위한연구도더이루어져야할것으로보인다. 혈중 adiponectin 과 ICAM-1 의상관관계에대해서도비교분석하여통계적유의성을얻었으나이것이가지는의미에대해서는좀더많은연구와분석이필요하다고본다. 본연구에서는관상동맥중재술시에시행한 adiponectin 과 ICAM-1 에대한측정을통하여낮은혈중 adiponectin 농도와높은혈중 ICAM-1 농도는관상동맥협착의진행을예측할수있음을알수있었다. 반면에철망내재협착과혈중 adiponectin, ICAM-1 농도와의관계의증명을위해서는더많은연구가이루어져야할것으로보인다. 요약 배경및목적 : Adiponectin은지방세포로부터유래된단백질로혈중농도가높을수록동맥경화의진행을억제하고관상동맥질환의위험인자로서역할을할수있는것으로알려져있다. ICAM(intercellular adhesion molecule)- 1은동맥경화를일으키는염증반응에관여하여동맥경화가있을경우높은혈중농도를가지며관상동맥질환의유무또는예후를알수있는인자로알려져있다. 본연구에서는관상동맥중재술을시행한환자에서 adiponectin 과 ICAM-1 의혈중농도를측정하여관상동맥협착의진행, 철망내재협착과의관계를알아보고자하였다. 방법 : 풍선확장술및철망삽입술을시행한 83명의환자 ( 남자 51명, 평균연령 57.90±9.75 세 ) 를대상으로하여관상동맥중재술시술당시관상동맥조영술소견과 6개월추적관상동맥조영술소견을비교분석하였다. 그리고풍선확장술및철망삽입술시행전에혈중 adiponectin, ICAM-1 농도를측정하였고총콜레스테롤, 중성지방, 저밀도지단백, 고밀도지단백, 아포단백 -A, 아포단백-B 의농도도같이측정하였다. 이를관상동맥 협착의진행 (10% 이상 ) 과철망내재협착 (50% 이상 ) 유무에따라군을나누어위의측정치에대한비교를시행하였다. 결과 : 각군간의연령, 위험인자 ( 당뇨병, 고혈압, 흡연 ) 에따른차이는보이지않았으며체질량지수에대해서도차이는없었다. 관상동맥협착이진행한군은진행하지않은군에비해혈중 adiponectin 농도가의미있게낮게 (3.91±1.24 μg/ml vs 4.66±1.36 μg/ml, p=0.03) 나타났고혈중 ICAM-1 농도가높게 (199.16±79.13 ng/ml vs ±63.65 ng/ml, p=0.03) 나타났다. 철망내재협착이있었던군에서도혈중 adiponectin 농도가낮게 (3.99±1.22 μg/ml vs 4.33±1.38 μg/ml) 나타났고혈중 ICAM-1 농도가높게 (195.17±68.45 ng/ml vs ±80.48 ng/ml) 나타났으나통계적유의성은가지지못하였다. 결론 : 낮은혈중 adiponectin 과높은혈중 ICAM-1 농도는관상동맥협착의진행을예측할수있는위험인자로역할을할수있으나철망내재협착과의관계에대해서는좀더많은연구가필요할것으로보인다. 중심단어 :Adiponectin;ICAM(Intercellular Adhesion Molecule)-1; 관동맥재협착. 본연구는 1998 년도동산의료원의학유전연구소특수과제연구비로이루어졌음. REFERENCES 1) Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cdna cloning and expression of a novel adipose specific collagen-like factor, apm1(adipose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221: ) Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y. Adiponectin reduced atherosclerosis in apolipoprotein E-deficient mice. Circulation 2002;106: ) Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin in obesity. Biochem Biophys Res Commun 1999; 257: ) Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, 843

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