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1 2001 년도산학협동연구비 Korean Circulation J 2004;34(2): 판막질환에서의심근섬유화 ; 심근조직을이용한형태학적연구및혈청생화학적지표의분석 울산대학교의과대학서울아산병원심장내과학교실, 1 흉부외과학교실, 2 병리과학교실 3 강수진 1 박덕우 1 송재관 1 박경민 1 송종민 1 강덕현 1 한기훈 1 송현 2 이재원 2 주석중 2 송명근 2 김정선 3 Morphometric and Serum Biochemical Analysis of Myocardial Fibrosis in Patients with Valvular Heart Disease Soo-Jin Kang, MD 1, Duk Woo Park, MD 1, Jae-Kwan Song, MD 1, Kyoung Min Park, MD 1, Jong-Min Song, MD 1, Duk-Hyun Kang, MD 1, Ki Hoon Han, MD 1, Hyun Song, MD 2, Jae Won Lee, MD 2, Suk Jung Choo, MD 2, Meong Gun Song, MD 2 and Jung-Sun Kim, MD 3 1 Divisions of Cardiology, 2 Cardiothoracic Surgery and 3 Pathology, Asan Medical Center, University of Ulsan, College of Medicine, Seoul, Korea ABSTRACT Background and Objectives:To compare the pattern of myocardial fibrosis in various valvular heart diseases (VHD), the morphometric data of the myocardial tissue and serum biochemical markers of myocardial fibrosis were analyzed in patients with aortic stenosis (AS), aortic regurgitation (AR) and mitral regurgitation (MR). Subjects and Methods:Blood samples were obtained from 21 patients with AS, 23 with AR and 29 with MR. The serum levels of aminoterminal propeptide, of type I/III procollagen (PINP/PIIINP), and fibronectin were measured to estimate the synthesis of the extracelluar matrix. The carboxy-terminal telopeptide collagen type I (CITP), matrix metalloproteinase-1 (MMP-1, collagenase) and the tissue inhibitor, metalloproteinase-1 (TIMP-1), were also measured to estimate the collagen degradation and metabolism activities. The left ventricular mass (LVM) was calculated by echocardiography. Of the patients, myocardial tissue was obtained during surgery in 11 with AS, 8 with AR and 13 with MR; the collagen volume fraction (CVF) was calculated using picrosirius red staining. Results:The LVM was significantly larger in the AS and AR groups compared to the MR group (p<0.001), and the CVF also showed significant differences (13±3% in AS, 10±3% in AR, and 6±3% in MR, p<0.001). The fibronectin level was significantly elevated in the AS and AR groups than the MR group (p<0.001), whereas the CITP and MMP-1 levels were significantly higher in the MR group (p<0.05). The PINP/PIIINP showed no significant difference between the groups (p>0.05), and the biochemical markers were no different between the AS and AR groups (p>0.05). Fibronectin was the only parameter showing a positive correlation with both the CVF (r=0.388, p=0.01) and the left ventricular mass (r=0.278, p=0.02). Conclusion:Different mechanisms for the matrix synthesis and degradation were present for the maintenance of myocardial fibrosis and hypertrophy according to the type of VHD, and fibronectin, a major non-collagenous extracelluar matrix, was proved to be an important factor associated with cardiac hypertrophy and myocardial fibrosis. (Korean Circulation J 2004;34 (2): ) KEY WORDS:Myocardial fibrosis;left ventricular mass;valvular heart disease;collagen;fibronectin. 논문접수일 :2003 년 18 월 25 일심사완료일 :2003 년 11 월 25 일교신저자 : 송재관, 서울송파구풍납동 울산대학교의과대학서울아산병원심장내과학교실전화 :(02) 전송 :(02) jksong@amc.seoul.kr 230

2 서론 좌심실의압력혹은용적과부하 (pressure or volume overload) 를초래하는여러질환에서증가된부하를보상하기위해심비대 (cardiac hypertrophy) 가발생된다고알려져있다. 1-4) 최근여러연구들을통해병적심비대 (pathologic hypertrophy) 에있어서의간질 (interstitium) 의변화, 특히간질콜라겐 (interstitial collagen) 의비정상적인증가로인하여심실의수축기및이완기기능장애가유발된다고보고되고있다. 5)6) 최근의연구보고에의하면간질은비활동적인조직이아니라콜라겐의합성과분해가끊임없이일어나며이두작용의역동적인균형에의해대사작용이결정되는활동적인조직임이밝혀졌고, 또한이미알려진콜라겐외의다른물질들도간질의형성에기여하는것으로밝혀졌다. 대부분의연구가동물실험을근거로하고있으며사람의심근조직을이용한연구는드물고특히심근조직의형태학적변화와콜라겐대사의특성사이의연관성및부하형태에따른차이점에관한연구는부족한실정이다. 저자들은압력, 용적부하의대표적질환인대동맥판막폐쇄부전 (aortic regurgitation, AR), 대동맥판막협착증 (aortic stenosis, AS) 및승모판막폐쇄부전 (mitral regurgitation, MR) 환자들에서심근조직의섬유화정도를정량적으로측정하고, 콜라겐대사에관여하는생화학적지표 (biochemical marker) 들을분석하여, 이들질환에서심실부하형태의차이에따른심근간질섬유화의양상을비교분석하고자하였다. 대상및방법 대상 2001 년 9월부터 2003년 3월사이에수술을앞둔중증의대동맥판막협착증 (AS 군 ), 대동맥폐쇄부전증 (AR 군 ) 및승모판폐쇄부전증 (MR 군 ) 환자를대상으로하였다. 관동맥조영술상심외막관동맥에의미있는협착이있거나 Thallium을이용한심근관류스캔에서관류결손이있는경우는대상에서제외하였다. AS는심초음파상측정된판구면적이 0.75 cm 2 이하이거나평균수축기압력차가 50 mmhg 이상이며칼라도플러에서 1도이하의폐쇄부전이동반되는경우로하였다. AR은칼라도플러상심한이완기역류가있으며수축 기에판막을지나는최고혈류속도가 2.5 m/s 미만인경우로하였고, 중등도이상의협착증과폐쇄부전이공존하는경우는연구대상에서제외하였다. 중증 MR군에서도승모판협착이동반된경우는제외하였다. 혈청생화학적지표들의농도측정 AS군 21명, AR군 23명, MR 군 29명에서. 수술 24 시간전 10 ml의전혈을채취하여혈청을원심분리 (2000 g, 30분, 섭씨 4도 ) 한후영하 70도에서냉동보관하였다. 콜라겐합성을반영하는 aminoterminal propeptide of type Ⅰ/Ⅲ procollagen(pinp/piiinp) 과콜라겐분해의지표인 carboxy-terminal telopeptide of collagen type Ⅰ(CITP) 의농도는 radioimmunoassay kit(orion Diagnostica, Espoo, Finland) 를이용하여측정하였다 ( 예민도 2 ng/ml). 대표적비콜라겐성세포외기질 (extracellular matrix, ECM) 인 fibronectin 농도의측정은 QuantiMatrix TM ELISA kit(chemicon, Temecula, CA, USA.) 를이용하였다 ( 예민도 10~20 ng/ml). 간질내에서생성된콜라겐을분해시키는효소인 matrix metalloproteinase(mmp-1, interstitial collagenase) 의농도측정에는 two-step sandwich immunoassay kit( 예민도 ng/ml) 를, collagenase의억제물질인 tissue inhibitor of metalloproteinase(timp-1, collagenase inhibitor) 의측정에는 one-step sandwich 면역반응에기초한 solid phase enzyme immunoassay kit( 예민도 1.2 ng/ml) 를사용하였다. 좌심실질량의측정모든환자에서술전심초음파를시행하여좌심실이완기내경과심실중격및후벽의이완기두께를측정하였다. 미국심장초음파학회에서제안한공식에따라좌심실질량 (left ventricular mass) 을구하였다 ( 좌심실질량 =1.04{( 이완기내경 + 이완기중격두께 + 이완기후벽두께 ) 3 -( 이완기내경 ) 3 }). 7)8) 심근조직에서의콜라겐용적분율측정 AS군 11명, AR군 8명, MR 군 13명에서수술중좌전하행지와좌회선지사이의좌심실전벽에서심근조직이채취되었다. Supercore biopsy needle(manan medical co. USA.) 을이용하여얻은심근을 formalin 231

$Silverspring, USA) 를이용하여콜라겐용적분율 (collagen volume fraction, CVF) 을측정하였다 (Fig. 1). 통계통계분석은 SPSS software program(spss 10.0 for windows) 을이용하였다. 관측치의대표값은평균 ± 표준편차로표시하였다.$ 연속변수인혈청생화학지표측정치의비교는 student t-test 혹은 AVOVA 분석을이용하였으며, 심근조직에서측정한 CVF 의비교는비모수적분석 (Non-parametric independent group comparison, Kruskal-Wallis test) 을이용하였 A B Fig. 1.

연속변수인혈청생화학지표측정치의비교는 student t-test 혹은 AVOVA 분석을이용하였으며, 심근조직에서측정한 CVF 의비교는비모수적분석 (Non-parametric independent group comparison, Kruskal-Wallis test) 을이용하였 A B Fig. 1.

3 에고정하여 paraffin block 을만든후콜라겐특이적염색을시행하였다 (picrosirius red staining). Sirius red F3BA를 saturated picric acid 용액에녹인후 image analysis system(imagepro plus, Media cybernetics, Inc. Silverspring, USA) 를이용하여콜라겐용적분율 (collagen volume fraction, CVF) 을측정하였다 (Fig. 1). 통계통계분석은 SPSS software program(spss 10.0 for windows) 을이용하였다. 관측치의대표값은평균 ± 표준편차로표시하였다. 연속변수인혈청생화학지표측정치의비교는 student t-test 혹은 AVOVA 분석을이용하였으며, 심근조직에서측정한 CVF 의비교는비모수적분석 (Non-parametric independent group comparison, Kruskal-Wallis test) 을이용하였 A B Fig. 1. Representative histologic section of myocardial biopsy specimen showing mild fibrosis in a patient with mitral regurgitation (A) and severe fibrosis in a patient with aortic regurgitation (B)(picrosirius red stain). A: collagen volume fraction 8.9%. B: collagen volume fraction 19.6%. Table1. Baseline echocardiographic parameters AS AR MR LV dimension (mm) Diastolic 47.2± ± ±7.7 Systolic 31.8± ± ±6.7 Diastolic wall thickness (mm) Septal wall 14.0± ± ±1.7 Posterior wall 13.1± ± ±1.3 LV ejection fraction (%) 57.7± ± ±7.6 AS: aortic stenosis, AR: aortic regurgitation, MR: mitral regurgitation Table 2. Serum biochemical markers of myocardial fibrosis, left ventricular mass and collagen volume fraction in patients with various valvular heart diseases AS (N=21) AR (N=23) MR (N=29) p PINP (ng/ml) ± ± ±020.9 <0.734 PIIINP (ng/ml) ± ± ±002.9 <0.356 CITP (ng/ml) ± ± ±019.9 <0.006 Fibronectin (ng/ml) ± ± ±195.9 <0.001 MMP-1 (ng/ml) ± ± ±019.9 <0.021 TIMP-1 (ng/ml) ± ± ±041.9 <0.712 PINP/PIIINP (ratio) ± ± ±005.7 <0.948 LV mass (g) ± ± ±073.9 <0.001 CVF (%) ± ± ±003.9 <0.001 AS: aortic stenosis, AR: aortic regurgitation, MR: mitral regurgitation, PINP: aminoterminal propeptide of type I procollagen, PIIINP: aminoterminal propeptide of type III procollagen, CITP: carboxy-terminal telopeptide of collagen type I, MMP: matrix metalloproteinase, TIMP: tissue inhibitor of metalloproteinase, LV mass: left ventricular mass, CVF: collagen volume fraction 232 Korean Circulation J 2004;34(2):

4 다. Stepwise 방법을이용한다중회귀분석 (multiple regression analysis) 을통해생화학적지표들중 CVF 및좌심실질량과가장강한상관관계를갖는변수를도출하였다. 통계학적으로유의한차이는 p값이 0.05 미만인경우로하였다 Fibronectin (FNT, ng/ml) FNT CVF AS group FNT CVF AR group FNT CVF MR group Fig. 2. Scatter plots of serum fibronectin and collagen volume fraction in patients with valvular heart disesase. Table 3. p of serum markers, left ventricular mass, and collage volume fraction between groups Fibronectin CITP MMP-1 CVF LV mass AS-AR < <0.026 <0.183 AS-MR < <0.001 <0.001 AR-MR < <0.017 <0.001 AS: aortic stenosis, AR: aortic regurgitation, MR: mitral regurgitation, CITP: carboxy-terminal telopeptide of collagen type I, MMP: matrix metalloproteinase, LV mass: left ventricular mass, CVF: collagen volume fraction Table 4. Correlations between serum biochemical markers and left ventricular mass/collagen volume fraction LV mass CVF R p R p PINP (ng/ml) PIIINP (ng/ml) CITP (ng/ml) Fibronectin (ng/ml) MMP-1 (ng/m/l) TIMP-1 (ng/ml) AS: aortic stenosis, AR: aortic regurgitation, MR: mitral regurgitation, PINP: aminoterminal propeptide of type I procollagen, PIIINP: aminoterminal propeptide of type III procollagen, CITP: carboxy-terminal telopeptide of collagen type I, MMP: matrix metalloproteinase, TIMP: tissue inhibitor of metalloproteinase, LV mass: left ventriuar mass, CVF: collagen volume fraction Collagen volume fraction (CVF, %) 결과 환자들의평균연령은 AS군 63±9세, AR군 51± 16세, MR군에서 53±13 세이었으며, 남자가차지하는비율은각각 59%, 61%, 36% 이었다. 술전심초음파상좌심실질량은 AS와 AR 환자들에서 MR군에비해유의하게증가되어있었다 (p<0.001, Table 2). 환자들의혈청에서콜라겐대사와연관된 6가지의생화학적지표가측정되었는데, 콜라겐합성을반영하는 PINP 와 PIIINP의농도는세군에서의미있는차이가없었으나 (p>0.05), 대표적인비콜라겐성 ECM인 fibronectin은 AS군과 AR군에서각각 1514±367, 1536± 399 ng/ml 로 MR군에서의 700±195 ng/ml 에비해뚜렷한증가를보였다 (p<0.001, Table 2, Fig.2). 콜라겐분해의지표인 CITP 및콜라겐파괴효소인 MMP- 1은 MR군에서유의하게높았다 (Table 2). AS군과 AR 군을비교하였을때생화학적지표들의의미있는차이는없었다 (Table 3). 심근조직에서측정한 CVF 은 AS군에서 13±3%, AR군에서 10±3%, MR군에서 6 ±3% 로대동맥판막질환군에서 MR군에비하여유의하게높았다 (p<0.001, Table 2). 콜라겐분해효소억제제인 TIMP-1 은각군들에서유사하였다 (p=0.712). 다변량적분석상생화학적지표들중 fibronectin 은 CVF (r=0.388, p=0.01) 및좌심실질량 (r=0.278, p= 0.02) 과양의상관관계를나타내는유일한지표이었다 (Table 4). 고찰 심실의기계적과부하상태를일으키는고혈압이나판막질환등에서벽부하의증가에대한보상기전으로서심비대가유발되며, 이는좌심실수축기능및이완기능의장애를초래하고사망률증가에기여함이여러연구를통해보고되고있다. 1-5) 최근에는비심근세포, 특히세포외간질분포의비정상적증가를특징으로하는병적심비대의중요성이강조되고있다. 9-12) 본연구에서심초음파상의좌심실질량및심근조직에서의 CVF 는 AS와 AR군에서 MR군에비해유의하게증가되어있음을알수있었다. 같은용적과부하상태이지만, MR보다는 AR에서의심비대및심근섬유화가심 233

5 한것은심근섬유화기전에있어보다복잡한요소들이관여하는것으로보인다. 심근콜라겐대사는제 1형혹은 3형콜라겐및콜라겐분해효소 (MMP-1) 에대한 mrna 를발현하는심장섬유모세포 (cardiac fibroblast) 에의해조절되는데, 이러한콜라겐대사를반영하는생화학적지표들의분석이여러연구를통해이루어져왔다. 일차성고혈압환자들을대상으로한기존연구에따르면 procollagen type Ⅲ amino terminal peptide 및 procollagen type Ⅰ carboxy terminal peptide의농도가환자들의혈청에서증가되어있어 collagen type Ⅰ 및 Ⅲ의합성증가를반영하는지표가되며, 이는심근섬유화에대한간접적인정보를제공한다고하였다. 13) 다른연구에서는 procollagen type I carboxy terminal peptide의혈청농도가 CVF 나좌심실질량지수 (LV mass index) 와직접적인양의상관관계를갖는다고보고하였다. 14)15) 판막질환에서의심근섬유화기전을밝히기위한노력들이최근에보고되고있다. 대동맥판막질환에서의압력및용적과부하는초기에심근에서의안지오텐신변환효소를증가시키며, 레닌-안지오텐신-알도스테론축 (renin-angiotensin-aldosterone system) 의활성화로인해 TGF-β1 mrna 의유도가촉진된다. 9) TGF-β1 은 angiotensin Ⅱ의 profibrotic mediator 로서작용하여 collagen Ⅰ, Ⅲ와 fibronectin mrna 의증가를가져와심근섬유화및병적심비대의진행을유발하는것으로알려져있다 ) 이러한심근섬유화는이완기의경직도증가와수축기능의감소를일으켜결국심부전을야기하게된다. AR 및 AS 환자들을대상으로한연구를살펴보면콜라겐과 fibronectin 의 mrna 발현은좌심실이완기말압력과양의상관관계를, 좌심실구혈율과는음의상관관계를나타내었다. 4) 최근비콜라겐성세포외기질에대한중요성이부각되고있는데, 토끼를이용하여대동맥판막폐쇄부전을유발시킨후만성용적부하에대한분자세포학적반응을분석한연구에따르면, 제 1 형및 3형콜라겐합성은정상에비해증가되지않은데에반해 fibronectin 합성과이의유전자발현은유의하게증가되어있었다. 즉, AR의경우심장섬유모세포에서의비콜라겐성 ECM, 특히 fibronectin 의비정상적생산증가가용적부하에대한일차적반응일것이라고추론할수있으며이는본연구와유사한결과이다. 5) 다른동물실험연 234 구에서도조직학적으로심한섬유화가있으면서정상적인콜라겐함유량을보이는것은섬유화된심근내에비콜라겐성 ECM 의비정상적증가를의미한다고하였다. 21)22) 본저자들의연구에서 PINP 및 PIIINP의혈청농도는세군모두에서유사하였으나, fibronectin 이 MR군보다는 AS와 AS군에서현저히증가되어있었으며, 다변량적분석상 fibronectin 이 CVF 및좌심실질량과양의상관관계를갖는유일한변수임을관찰할수있었다. 이는대동맥판막질환에서심근섬유화및병적심비대의기전에있어콜라겐합성증가자체보다는비콜라겐성 ECM 변화가보다중요한역할을한다는최근연구들을지지하는결과라하겠다. 심실과부하시활성화된 Angiotensin Ⅱ는 MMP- 1의활성을저하시켜콜라겐의분해가감소한다고알려져있다. 23)24) 본저자들의연구에서콜라겐분해의지표인 CITP 및콜라겐파괴효소인 MMP-1 이대동맥판막질환과비교했을때 MR군에서유의하게높으며좌심실질량이이군에서유의하게낮은데, 이는콜라겐생성및분해에관련되는여러동적요소들이각각의판막질환에서의심근섬유화진행에서로다르게기여하고있음을시사한다. 본연구의제한점으로는심근조직을얻은환자숫자가작으며정상인에서의생화학적지표측정및심근조직분석이이루어지지않아각질환군의상대적비교만이가능하였고약제투여에따른효과를비교, 검증할수없었다는점들을들수있다. 혈액을이용하여심근섬유화과정의비침습적인연구가가능해졌으므로, 향후더많은환자들을대상으로수술전후의추적검사가진행되어이질환군에서의심근섬유화에대한이해가더욱발전할수있으리라기대된다. 요약 배경및목적 : 각종판막질환에서간질콜라겐의비정상적인증가로인해병적심비대및심실기능장애가초래됨이알려져있다. 저자들은대동맥판막폐쇄부전 (AR), 대동맥판막협착증 (AS) 및승모판막폐쇄부전 (MR) 환자들에서심근조직섬유화정도를정량적으로측정하고, 콜라겐대사에관여하는혈청생화학적지표들을측정하여, 심실부하형태의차이에따른심근섬유화의양 Korean Circulation J 2004;34(2):

6 상을비교분석하였다. 방법 : 2001 년 9월부터 2003 년 3월사이에수술을앞둔 AS 환자 21명, AR 23명, MR 29명의혈청에서콜라겐합성을반영하는 PINP/PIIINP(aminoterminal propeptide of type Ⅰ/Ⅲ procollagen) 와대표적 non-collagenous extracellular matrix 인 fibronectin 및콜라겐분해의지표인 carboxy-terminal telopeptide of collagen type Ⅰ(CITP), 콜라겐의파괴효소인 matrix metalloproteinase-1(mmp-1, collagenase) 와이를억제하는 tissue inhibitor of metalloproteinase-1 (TIMP-1, collagenase inhibitor) 등 6가지의생화학적지표들을측정하였으며. 심초음파를통해좌심실질량 (LV mass) 이구하였다. 이들중 AS 11 명 AR 8명, MR 13명에서수술중채취된심근조직의 picrosirius red stain 을이용하여 collagen volume fraction(cvf) 이측정되었다. 결과 : CVF은 AS군에서 13±3%, AR군 10±3%, MR군 6±3% 로각군간에유의한차이를보였으며 (p<0.001), 좌심실질량도 AS와 AR 환자들에서 MR군에비해증가되어있었다 (p<0.001). Fibronectin 은 MR군에비해 AS군과 AR군에서증가되어있었으며 (p<0.001), CITP 와 MMP-1 은 MR군에서유의하게높았다 (p<0.05). 그러나, 콜라겐합성의지표인 PINP/PIIINP는세군모두에서유사하였고 (p>0.05), AS군과 AR군사이에생화학적지표들의의미있는차이는없었다. 전체환자에서다변량분석상 fibronectin 은 CVF(r=0.388, p= 0.01) 및좌심실질량 (r=0.278, p=0.02) 과모두양의상관관계를나타내는유일한지표이었다. 결론 : 판막질환의종류에따라서로상이한기전을통하여심근간질이유지되며비콜라겐성간질물질인 fibronectin 이심비대의발생에있어중요한인자임을확인할수있었다. 중심단어 : 심근섬유화 ; 좌심실질량 ; 심장판막증 ; 아교질 ; 섬유결합소. 본논문은 2001 년대한순환기학회산학협동연구비의지원을받았음. REFERENCES 1) Grossman W. Cardiac hypertrophy: useful adaptation or pathologic process? Am J Med 1980;69: ) Villari B, Campbell SE, Hess OM, Mall G, Vassalli G, Weber KT, Krayenbuehl HP. Influence of collagen network on left ventricular systolic and diastolic function in aortic valve disease. J Am Coll Cardiol 1993;22: ) Carabello BA, Zile MR, Tanaka R, Cooper G 4th. Left ventricular hypertrophy due to volume overload versus pressure overload. Am J Physiol 1992;263:H ) Orsinelli DA, Aurigemma GP, Battista S, Krendel S, Gaasch WH. Left ventricular hypertrophy and mortality after aortic valve replacement for aortic stenosis: a high risk subgroup identified by preoperative relative wall thickness. J Am Coll Cardiol 1993;22: ) Borer JS, Truter S, Herrold EM, Falcone DJ, Pena M, Carter JN, Dumlao TF, Lee JA, Supino PG. Myocardial fibrosis in chronic aortic regurgitation: molecular and cellular responses to volume overload. Circulation 2002;105: ) Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G, Turina M. Left ventricular myocardial structure in aortic valve disease before, intermediate, and late after aortic valve replacement. Circulation 1989;79: ) Park SH, Shub C, Nobrega TP, Bailey KR, Seward JB. Twodimensional echocardiographic calculation of left ventricular mass as recommended by the American Society of Echocardiography: correlation with autopsy and M-mode echocardiography. J Am Soc Echocardiogr 1996;9: ) Deague JA, Wilson CM, Grigg LE, Harrap SB. Discrepancies between echocardiographic measurements of left ventricular mass in a healthy adult population. Clin Sci 1999;97: ) Fielitz J, Hein S, Mitrovic V, Pregla R, Zurbrugg HR, Warnecke C, Schaper J, Fleck E, Regitz-Zagrosek V. Activation of the cardiac renin-angiotensin system and increased myocardial collagen expression in human aortic valve disease. J Am Coll Cardiol 2001;37: ) Weber KT, Clark WA, Janicki JS, Shroff SG. Physiologic versus pathologic hypertrophy and the pressure-overloaded myocardium. J Cardiovasc Pharmacol 1987;10(Suppl 6): S ) Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation 1991;83: ) Brilla CG, Weber KT. Reactive and reparative myocardial fibrosis in arterial hypertension in the rat. Cardiovasc Res 1992;26: ) Lopez B, Querejeta R, Varo N, Gonzalez A, Larman M, Martinez Ubago JL, Diez J. Usefulness of serum carboxyterminal propeptide of procollagen type I in assessment of the cardioreparative ability of antihypertensive treatment in hypertensive patients. Circulation 2001;104: ) Querejeta R, Varo N, Lopez B, Larman M, Artinano E, Etayo JC, Martinez Ubago JL, Gutierrez-Stampa M, Emparanza JI, Gil MJ, Monreal I, Mindan JP, Diez J. Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease. Circulation 2000;101: ) Diez J, Laviades C, Mayor G, Gil MJ, Monreal I. Increased 235

7 serum concentrations of procollagen peptides in essential hypertension: relation to cardiac alterations. Circulation 1995;91: ) Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH. Increased rat cardiac angiotensin converting enzyme activity and mrna expression in pressure overload left ventricular hypertrophy: effects on coronary resistance, contractility, and relaxation. J Clin Invest 1990;86: ) Grimm D, Kromer EP, Bocker W, Bruckschlegel G, Holmer SR, Riegger GA, Schunkert H. Regulation of extracellular matrix proteins in pressure-overload cardiac hypertrophy: effects of angiotensin converting enzyme inhibition. J Hypertens 1998;16: ) Campbell SE, Katwa LC. Angiotensin II stimulated expression of transforming growth factor-beta1 in cardiac fibroblasts and myofibroblasts. J Mol Cell Cardiol 1997;29: ) Kim S, Ohta K, Hamaguchi A, Omura T, Yukimura T, Miura K, Inada Y, Ishimura Y, Chatani F, Iwao H. Angiotensin II type I receptor antagonist inhibits the gene expression of transforming growth factor-beta 1 and extracellular matrix in cardiac and vascular tissues of hypertensive rats. J Pharmacol Exp Ther1995;273: ) Swynghedauw B, Delcayre C, Cheav SL, Callens-el Amrani F. Biological basis of diastolic dysfunction of the hypertensive heart. Eur Heart J 1992;13(Suppl D): ) Goldfine SM, Pena M, Magid NM, Liu SK, Borer JS. Myocardial collagen in cardiac hypertrophy resulting from chronic aortic regurgitation. Am J Ther 1998;5: ) Truter SL, Goldin D, Kolesar J, Dumlao TF, Borer JS. Abnormal gene expression of cardiac fibroblasts in experimental aortic regurgitation. Am J Ther 2000;7: ) Funck RC, Wilke A, Rupp H, Brilla CG. Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease. Adv Exp Med Biol 1997;432: ) Brilla CG, Maisch B, Zhou G, Weber KT. Hormonal regulation of cardiac fibroblast function. Eur Heart J 1995;16 (Suppl C): Korean Circulation J 2004;34(2):

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<4D F736F F F696E74202D20BFA1C4DA5FC0D3BBF3C3CAC0BDC6C42E BC8A3C8AF20B8F0B5E55D> 심장 (Heart) 심초음파 서울대병원내과 김용진 심장은평생몇번이나뛸까요? 1) 3 백만번 2) 3 천만번 3) 3 억번 4) 30 억번 30 억박동, 2 억리터의혈액 Cause 심장질환 6.2 12.4 11.1 16.2 뇌졸중 4.3 8.5 7.7 11.3 기타심혈관질환 2.6 5.1 6.0 8.8 심혈관질환 13.1 26.0 24.8 36.3 총사망 50.4