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Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36:526-534 ISSN 1738-5520 c 2006, The Korean Society of Circulation 급성심근경색이후 B-Type Natriuretic Peptide(BNP) 농도의조기변화와예후표지자로서의의의 연세대학교원주의과대학순환기내과학교실, 1 예방의학과학교실, 2 응급의학과학교실 3 최현민 1 유병수 1 유호열 1 고상백 2 장세진 2 황성오 3 김장영 1 이승환 1 윤정한 1 최경훈 1 The Early Changing Pattern of the B-Type Natriuretic Peptide Concentration and its Significance as a Prognostic Marker after Acute Myocardial Infarction Hyunmin Choe, MD 1, Byung-Su Yoo, MD 1, Ho-Yeol Ryu, MD 1, Sang-Baek Koh, MD 2, Sei-Jin Chang, MD 2, Sung-Oh Hwang, MD 3, Jang-Young Kim, MD 1, Seung-Whan Lee, MD 1, Junghan Yoon, MD 1 and Kyung-Hoon Choe, MD 1 1 Department of Cardiology, 2 Preventive Medicine and 3 Emergency Medicine, Wonju College of Medicine, Yonsei University, Wonju, Korea ABSTRACT Background and Objectives:The BNP concentration varies considerably after the onset of AMI, and this makes it difficult to determine the right time to measure the BNP as a valid prognostic marker. The aim of this study was to examine the early changing patterns of BNP and to decide on the suitable time for measuring the BNP as a prognostic marker after the onset of AMI. Subjects and Methods:From Feb 2002 to May 2005, we analyzed the changing patterns of BNP in 321 AMI patients. BNP (Triage ) was at the acute phase ( 24 hr), the early phase (2 to 6 day), the late phase (1 to 4 week) & the long-term phase (>4 week) after the onset of AMI. The end points were major adverse cardiac events () and cardiovascular death (CVD). Results:The mean BNP was 306.2±802.8 at the acute phase (mean: 9.5 hours), 251.9±592.8 at the early phase (mean: 5.1 days), 103.1±172.9 at the late phase (mean: 26.8 days) and 179.7±353.3 pg/ml at the long-term phase (mean: 45.9 days). There were no significant differences of the demographic factors between the and Non- group. Multivariative analysis showed that early phase BNP (p=0.007) and male gender (p=0.009) were significant risk factors for. The early phase BNP (p=0.037) and age (p=0.022) were the significant risk factors of CVD. On the ROC curve, the early phase BNP for predicting the CVD risk was 186 pg/ml (AUC=0.87, p<0.001). The Kaplan-Meier survival curve showed that the survival rate was higher for the patients with an early phase BNP<186 pg/ml than it was for those patients with a BNP 186 pg/ml (p=0.000). Conclusion:The early levels or changing patterns of the BNP concentrations following AMI showed different patterns of change depending on several prognostic factors. The early phase (2 to 6 day) BNP concentration after the onset of AMI could be used as a significant prognostic marker. (Korean Circulation J 2006;36:526-534) KEY WORDS:B-type natriuretic peptide;myocardial infarction;prognosis. 논문접수일 :2006 년 2 월 20 일수정논문접수일 :2006 년 5 월 16 일심사완료일 :2006 년 6 월 28 일교신저자 : 유병수, 220-701 강원도원주시일산동 162 연세대학교원주의과대학순환기내과학교실전화 :(033) 741-0917 전송 :(033) 741-1219 E-mail:yubs@yonsei.ac.kr 526

Hyunmin Choe, et al:bnp Change after AMI 527 서 B-type natriuretic peptide( 이하 BNP) 는급성심근경색증을포함한급성관동맥증후군환자와 1) 만성울혈성심부전환자에서분비가증가하며 2) 임상예후의지표로매우중요한인자임이확인되었다. 3-6) 혈중 BNP 농도는심근허혈범위와 7) 좌심실기능장애정도에비례하여증가한다고알려져있으며 8-10) 급성심근경색이후좌심실확장은경색부위의확장과비경색부위의용량과부하에따른장력의증가로인해발생되고 11) 임상적인심부전으로발전한다. 이에따라 BNP 농도는빠르고급격한상승을보여주며, 12) 임상양상과심부전정도에따라시간대별로다양한이분형분포를나타내는것으로보고되었다. 13)14) 최근대규모급성관동맥증후군환자들을대상으로한연구에서 72시간이내 NT pro-bnp 농도가새로상승되거나상승이지속되는경우 30 일이내주요심혈관계사건 (major adverse cardiac event 이하 ) 발생가능성이매우높다고보고하였고 14) 다른연구들에서는각각급성심근경색이후 72~120 시간사이에측정한 BNP 농도가예후와연관이있고, 6)16) 급성심근경색이후 3~4 주기간동안측정한 BNP 농도가예후와밀접한연관이있음을보고하였다. 4)13) 그러나급성심근경색이후어느시간대에측정된농도가실제예후와관련이있는가에대해서는아직논란의여지가많다. 따라서본연구는급성심근경색환자에서 BNP 농도의조기변화양상을관찰하고측정된 BNP 농도가위험및예후인자로서의미가있는지평가하고자하였다. 론 대상및방법 대상환자 2002 년 6월부터 2005 년 5월까지본원에서흉통발생시간 24 시간이내로내원하여급성심근경색진단하에입원치료를받은환자 516 명중혈중 BNP 농도를측정한연속적인 321 명의환자를대상으로후향적조사를시행하였으며비 ST 분절상승심근경색환자와신기능이상 (Cr>1.5 mg/dl) 또는신증후군환자, 간경화환자, 내원시이미심폐소생술을시행받은환자, 그리고외래추적관찰이되지않았던 195 명은제외하였다. 급성심근경색의진단은전형적인흉통, 심전도상 2개이상의연속된사지유도또는흉부유도에서의 1 mm 이상의 ST분절상승, 그리고심근 Troponin Ⅰ 혹은 creatinine kinase MB( 이하 CK-MB) 효소수치의상승이동반된경우 3가지항목중 2가지이상의항목을만족할경우에진단하였다. 급성심근경색환자의검사및치료급성심근경색의치료는흉통시작 12시간이내에내원한경우, 일차적관상동맥중재시술혹은혈전용해치료를시행 하였고, 흉통시작 12시간이후에내원한경우, 선택적관상동맥중재시술혹은중재시술이불가능한경우에는보존적치료만하였다. 심초음파도검사는최초입원시 3일이내 ( 평균 1.56 일 ) 와외래추적검사기간 ( 평균 3.8 개월 ) 에실시하였고 M-mode 상이완기말과수축기말의좌심실내경및좌심실구혈율을측정하고, 국소적심실벽운동분석은 16분절법을사용하여정상또는과운동은 1점, 저운동 2점, 무운동 3점, 역운동 4점, 심실류는 5점으로국소적심실벽운동점수를주었고각분절의점수를모두합한다음분절수로나누어 wall motion score index( 이하 WMSI) 를측정하였다. 17) 또한심실의이완기능은간헐파도플러를이용한승모판혈류속도측정을통하여 E/A 비와 deceleration time( 이하 DT) 을측정하고폐정맥혈류속도인수축기좌심방의이완기 (PVs1) 및승모판하강기 (PVs2) 속도, 확장기 (PVd) 그리고심방수축시역행 (PVa) 혈류속도를같이측정하여평가하였다. 승모판혈류 E/A 비가 1~2, DT이 160~240 msec, PVs2 PVd 시정상유입 (normal filling), E/A비가 <1, DT >240 msec, PVs2 >PVd 시이완장애 (impaired relaxation), E/A 비가 1~ 1.5, DT 160~200 msec, PVa >35 cm/sec 시가성정상 (pseudonormalization), 그리고 E/A >1.5, DT <160 msec, PVs2 < PVd 시제한성유입 (restrictive filling) 으로평가하였다. 수축기심부전 (systolic heart failure 이하 SHF) 은좌심실구혈률 40% 미만으로정의하였다. 그외에심근효소수치는 Troponin Ⅰ와 CK-MB 를최초내원당시에측정하였다. 혈중 BNP 농도측정혈중 BNP 농도측정은최초내원당시모두측정하였고이후추적관찰시간대별로 BNP 농도를재차측정하였다. 급성심근경색이후심실재형성시기에따라최초내원 24 시간이내를급성기 (acute phase), 2일에서 6일까지를초기추적기 (early phase), 1주에서 4주이내를후기추적기 (late phase), 그리고 4주이상을장기추적기 (long-term phase) 로나누어정의하였다. BNP 측정은전혈혹은최소 EDTA 가포함된시험관에 3~5 ml 혈액을채취한후 BNP kit(triage, Biosite, San Diego, USA) 를이용하여형광면역측정법으로정량적인값을산출하였으며, 측정치의하한값은 5 pg/ml 이었고, 상한값은 5,000 pg/ml 이었다. 추적관찰본연구는후향적으로대상환자의임상경과를추적관찰하여결과를분석하였다. 최소 6개월이상외래추적이가능했던환자들은문진을통해임상상태를점검하였고분석시점동안외래내원이불가능했던환자들은전화면담을통해확인하였다. 추적이되지않았던환자들은본연구대상에서제외하였다. 본연구의종점은 와심혈관사망 (cardiovascular death 이하 CVD) 으로하였고 에는심혈관및심부전합병증에의한사망, 심부전에의한재입

528 Korean Circulation J 2006;36:526-534 원, 목표혈관재개통술 (target vessel revascularization 이하 TVR), 목표병변재개통술 (target lesion revascularization 이하 TLR), 생명을위협하는부정맥 ( 심실빈맥, 심실세동 ) 그리고원인미상의 CVD 를포함하였다. 임상적추적검사상 가있었던환자군 ( 군 ) 과없었던환자군 ( 비 군 ), CVD 가있었던환자군 (CVD 군 ) 과없었던환자군 ( 비 CVD 군 ) 그리고 SHF 가있었던군 (SHF 군 ) 과없었던군 ( 비 SHF 군 ) 을각각나누어 BNP 농도변화와예후를비교하였다. Received PCI (%) 229 (71.3) AMI 321 cases M/F (%) 203 (63.2)/118 (36.8) Received Thrombolytics (%) 74 (23.1) Conservative Management (%) 18 (5.6) 자료분석및통계통계분석은통계프로그램 SPSS version 12.0(SPSS Inc, Chicago, IL, USA) 을이용하였으며, 연속변수는평균 ± 표준편차로표시하였다. 두군간의연속변수비교는 student t-test 를시행하였고비연속변수인경우 chi-square test 를시행하였다. 와 CVD 의위험인자를밝히기위해나이, 성별, 당뇨, 고혈압, 고지혈증, 흡연등의위험인자, 심근효소수치, 내원시혈압, 시간대별혈중 BNP 농도, 좌심실구혈률, 그리고 WMSI 등의변수를포함하여다변량회귀분석을시행하였고독립적사망예측인자는 Cox proportional hazard regression 모델을이용하여분석하였다., CVD 그리고좌심실 SHF 위험도에대한 BNP 의 cut-off 농도는 receiver operating characteristic( 이하 ROC) curve 상예민도와특이도가가장높은값으로정의하였다. 모든자료에있어서 p값이 0.05 미만인경우를통계학적으로유의한결과로해석하였다. 결과 대상환자의임상적특성대상환자 321 명중남자는 63.2%(n=203), 평균나이는 62.4±12 세였으며관상동맥중재시술을받은환자는 71.3% (229 명 ), 혈전용해치료를받은환자는 23.1%(74 명 ) 였으며중재시술이불가능하여보존적치료를받은환자는 5.6%(18 명 ) 였다. 관상동맥중재시술을받은환자중일차적관상동맥중재시술을받은환자는 66.7%(189 명 ), 구제관상동맥성형술을받은환자는 2.5%(8 명 ), 그리고선택적관상동맥중재시술을받은환자는 30.2%(98 명 ) 였다 (Fig. 1). 대상환자들은급성심근경색이후평균 15.6 개월동안추적관찰을하였다. 이중 6개월추적관상동맥조영술을시행받은환자는총 195 명 (86.6%) 이었으며재협착이발생한환자는 8명 (4.1%) 이었다. 추적관찰중 발생률은평균 4.1 개월에총 26.8%(86 명 ) 였고전체사망률은평균 4.8 개월에 19.3% (62 명 ) 였다. 는재발성심근경색혹은부정맥에의한급성심장사망 (sudden cardiac death 이하 SCD) 이 35.4%(22 명 ), 심부전합병증에의한사망은 27.4%(17 명 ), 원인미상의심혈관사망은 37.1%(23 명 ) 이었으며 SHF 에의한재입원이 Table 1. Demographic, therapeutic, and laboratory characteristics of patients in Non- and group Primary (%) 189 (66.7) Rescue (%) 8 (2.5) Non- (n=235) (n=86) Elective (%) 98 (30.2) Fig. 1. Therapeutic strategy and result in patients with acute myocardial infarction. PCI: percutaneous coronary intervention, AMI: acute myocardial infarction, M/F: male/female. Age (year)* 059.7±12.000 069.6±11.4000 0.253 Male (%) 155 (65.9) 48 (55.8) 0.095 Risk factor (%) Smoking 071 (30.2) 27 (31.4) 0.849 Diabetes 093 (39.6) 43 (50.0) 0.094 Hypertension 113 (48.1) 46 (53.5) 0.391 Dyslipidemia 080 (34.3) 30 (37.0) 0.661 PCI (%) Primary 143 (60.9) 46 (53.5) 0.467 Elective 076 (32.3) 20 (23.3) 0.450 Rescue 007 (02.9) 01 (01.2) 0.100 Thrombolysis (%) 057 (24.3) 17 (19.8) 0.398 Cardiac enzyme* CK-MB (ng/ml) 003.9±10.900 025.9±75.8000 0.003 Troponin I (ng/ml) 001.0±4.5700 006.8±20.6000 0.006 Initial BP (mmhg)* 128.0±34.000 120.1±45.8000 0.063 BNP conc. (pg/ml)* Acute phase ( 24 hr) 177.0±537.60 658.7±1207.80 0.001 Early phase (2-6 day) 145.3±253.30 680.5±1139.70 0.001 Late phase (1-4 wk) 105.5±181.60 085.3±89.5000 0.276 phase 156.3±359.00 308.5±316.400 0.557 (>4 wk) *: by Chi-square test for dichotomous variables, : by student t-test for continuous variables. : major adverse cardiac event, PCI: percutaneous coronary intervention, CK-MB: creatinine kinase-mb, BP: blood pressure, BNP: brain natriuretic peptide, Conc.: concentration 31.4%(27 명 ), TLR 이 8.1%(7 명 ) 그리고 TVR 은 2.3%(2 명 ) 였다. 대상환자의임상적, 관상동맥조영술, 생화학적지표, 그리고심초음파도상의특징을두군별로비교분석한결과 p

Hyunmin Choe, et al:bnp Change after AMI 529 상관상동맥위험인자는비 군, 군사이에통계학적으로유의한차이는없었다. 혈중생화학검사결과상내원당시 CK-MB(302 명 ), Troponin Ⅰ(321 명 ) 농도는 군이비 군보다 CK-MB(3.9±10.9 vs. 25.9±75.8 ng/ml, p=0.003) 농도와 Troponin Ⅰ(1.0±4.6 vs. 6.8± 20.6 ng/ml, p=0.006) 농도가유의하게높았다 (Table 1). 관상동맥조영술결과상단일혈관질환은비 군 52.9% Table 2. Angiographic and echocardiographic characteristics of patients in Non- and group CAD extent (%)* (n=293) Non- (n=225) (n=68) 1VD 119 (52.9) 24 (35.3) 0.010 2VD 061 (27.1) 23 (33.3) 0.279 3VD 037 (16.4) 21 (30.9) 0.012 IRA (%)* (n=292) LAD 102 (45.5) 33 (48.5) 0.671 LCX 025 (11.2) 09 (13.2) 0.642 RCA 095 (42.4) 26 (38.2) 0.536 LV EF (%) Initial (n=305) 52.9±12.10 45.9±14.70 0.032 FU (n=105) 53.6±14.00 47.3±16.60 0.941 LV filling (%)* (n=305) Normal 030 (12.8) 03 (04.2) 0.001 Impaired relaxation 185 (79.0) 46 (64.7) 0.001 Pseudonormalization 010 (04.3) 08 (11.3) 0.001 Restrictive 009 (03.8) 14 (19.7) 0.001 LV dimension (cm) LVEDD (n=284) 5.34±0.620 5.46±0.850 0.112 LVEDD FU (n=105) 5.48±0.680 5.91±1.070 0.044 WMSI Initial (n=288) 01.4±0.320 1.53±0.370 0.214 FU (n=101) 1.38±0.340 1.53±0.460 0.043 *: by Chi-square test for dichotomous variables, : by student t-test for continuous variables. CAD: coronary artery disease, VD: vessel disease, IRA: infarct related artery, LAD: left anterior descending artery, LCX: left circumflex artery, RCA: right coronary artery, LV EF: left ventricular ejection fraction, LVEDD: left ventricular end diastolic dimension, LVESD: left ventricular end systolic dimension, FU: follow-up, WMSI: wall motion score index p (119 명 ), 군 35.3%(24 명 ) 로비 군에서유의하게많았고 (p=0.010), 삼중혈관질환은비 군 16.4% (37 명 ), 군 30.9%(21 명 ) 로 군에서유의하게 (p=0.012) 많았다. 최초내원시심초음파도결과 (305 명 ) 는좌심실구혈률이비 군 52.9±12.1%, 군 45.9±14.7% 로 군에서유의하게낮았고 (p=0.032), 심실이완기능결과상정상유입이비 군 12.8%(30 명 ), 군 4.2%(3 명 ) 이완장애는비 군 79.0%(185 명 ), 군 64.7%(46 명 ) 으로비 군에서정상유입과이완장애가의미있게많았으며 (p=0.001) 가성정상은비 군 4.3%(10 명 ), 군 11.3%(8 명 ) 제한유입은비 군 3.8%(9 명 ), 군 19.7%(14 명 ) 으로 군에서가성정상과제한유입이의미있게많았다 (p=0.001). 추적관찰심초음파도검사를시행받은 105 명 (32.7%) 결과상이완기말심실직경은비 군이 5.48±0.68 cm, 군이 5.91±1.07 cm였고 (p=0.044), 추적관찰 WMSI 는비 군이 1.38±0.34, 군이 1.53±0.46 으로 (p=0.043) 군에서모두유의하게높았다 (Table 2). 혈중 BNP 농도와시간대별변화양상평균혈중 BNP 농도는급성기에 306.2±802.8, 초기추적기에 251.9±592.8, 후기추적기에 103.1±172.9, 그리고장기추적기에 179.7±353.3 pg/ml 로측정되었다. 전체환자는모두내원당시에 BNP 농도검사가이루어졌으며이후초기추적기에는 73.5%(236 명 ), 후기추적기에는 28.7%(92 명 ), 그리고장기추적기에는 12.1%(39 명 ) 의추적검사율을보였다 (Fig. 2). 급성기와초기추적기평균 BNP 농도는여성이남성보다급성기 ( 여성 465.3±906.4 vs. 남성 213.7±722.4 pg/ml, p=0.002) 와초기추적기 ( 여성 417.6±759.5 vs. 남성 171.6±474.8 pg/ml, p=0.000) 에높았으며전벽경색이하벽경색보다초기추적기 ( 전벽 281.3±620.5 vs. 하벽 128.7± 217.8 pg/ml, p=0.003) 에높았고, SHF 군이비 SHF 군보다급성기 (SHF 군 686.1±1237.7 vs. 비 SHF 군 178.6±498.6 pg/ml, p=0.000) 와초기추적기 (SHF군 671.8±1083.5 vs. Acute phase 321 cases Death 62 cases (72.1%) Non- 235 cases (73.2%) 86 cases (26.8%) Early phase 189 cases (80.4%) Late phase 81 cases (34.5%) phase 33 cases (14.0%) Early phase 47 cases (54.7%) Late phase 11 cases (12.8%) phase 6 cases (7.0%) Fig. 2. Follow-up rates of plasma BNP concentration at each phases. : major adverse cardiac event, BNP: brain natriuretic peptide.

530 Korean Circulation J 2006;36:526-534 비 SHF 군 179.9±442.1 pg/ml, p=0.000) 에평균 BNP 농도가유의하게높았다 (Table 3). 또한 유무로평균 BNP 농도를비교하였을때급성기 BNP 농도 ( 비 군 177± 537.6 vs. 군 658.7±1207.8 pg/ml, p=0.000) 와초기추적기 BNP 농도 ( 비 군 145.3±253.3 vs. 군 680.5±1139.7 pg/ml, p=0.000) 는 군에서유의하게높았다 (Table 3). 군의시간대별 BNP 농도는급성기 (658.7±1207.8 pg/ml) 와초기추적기 (680.5±1139.7 pg/ ml) 모두급격하게증가하며후기추적기 (85.6±89.3 pg/ ml) 에서감소하다가장기추적기 (308.3±316.8 pg/ml) 에다시증가하는이상성상승양상 (biphasic elevation pattern) 을보여주고있으며비 군에서도같은변화양상이관찰되나 BNP 농도의증가는크지않았다. 연구기간동안 BNP 농 Table 3. Acute and early phase BNP concentration according to sex, infarct area, SHF and Sex Acute phase BNP (mean) pg/ml p Early phase BNP (mean) pg/ml Male 213.7±722.40 0.002 171.6±474.80 0.000 Female 465.3±906.40 417.6±171.60 Infarct area Anterior 287.2±733.40 0.993 281.3±620.50 0.003 Inferior 250.5±744.00 128.7±217.80 SHF Yes 686.1±1237.7 0.000 671.8±1083.5 0.000 No 178.6±498.60 179.9±442.10 Yes 658.7±1207.8 0.000 680.5±1139.7 0.000 No 177.0±537.60 145.3±253.30 Boldfacing indicates variables that retained statistical significance. BNP: B-type natriuretic peptide, SHF: systolic heart failure, : major adverse cardiac event p 도는급성기, 초기그리고장기추적기에서모두 군이유의하게높았다 (Fig. 3). 또한CVD 와 SHF 유무에따른 BNP 농도변화양상도유사한결과를보여주었다 (Fig. 4, 5). 예후분석 와 CVD 의독립적위험인자를찾기위해다양한인자들에대해다변량회귀분석을실시하였으며결과상 의독립적위험인자로는초기추적기 BNP 농도 (p=0.007) 와남성 (p=0.009) 이었으며 (Table 4), CVD 의독립적위험인자로는초기추적기 BNP 농도 (p=0.037) 와연령 (p=0.022) 이었다 (Table 5). 독립적 CVD 예측인자분석을위해 Cox proportional hazard regression 모델을적용했을때나이 (p= 1200 1000 800 600 400 200 0 BNP pg/ml 834±1370* 179±521* 149±266* Acute 24 hr (Mean 9.5 hrs) 1044±1368* Early 2-6 day 163±146 101±174 Late 1-4 week Death Survival *: p<0.05 700±80 151±340 >4 week (Mean 5.1 days) (Mean 26.8 days) (Mean 45.9 days) Fig. 4. Plasma BNP concentrations at acute, early, late and long-term phase of patients in survival and death groups. Significant difference between survival and death groups at acute and early phase BNP concentrations expressed as *: p<0.05. BNP: B-type natriuretic peptide. 800 BNP pg/ml 800 BNP pg/ml 600 658±1207* 680±1139* Non- *: p<0.05 600 686±1237* 671±1083* SHF (+) SHF (-) *: p<0.05 400 308±316 400 299±317 210±201 200 105±181 200 0 177±537* Acute 24 hr 145±253* Early 2-6 day 85±89 Late 1-4 week 156±359 >4 week 0 178±498* Acute 24 hr 179±442* Early 2-6 day 89±167 108±226 Late 1-4 week >4 week (Mean 9.5 hrs) (Mean 5.1 days) (Mean 26.8 days) (Mean 45.9 days) Fig. 3. Plasma BNP concentrations at acute, early, late and long-term phase of patients in and Non-. Significant difference between and Non- groups at acute and early phase BNP concentrations expressed as *: p<0.05. BNP: B-type natriuretic peptide, : major adverse cardiac event. (Mean 9.5 hrs) (Mean 5.1 days) (Mean 26.8 days) (Mean 45.9 days) Fig. 5. Plasma BNP concentrations at acute, early, late and long-term phase of patients in SHF and Non-SHF. Significant difference between SHF and Non-SHF group at acute and early phase BNP concentration expressed as *: p<0.05. BNP: B-type natriuretic peptide, SHF: systolic heart failure.

Hyunmin Choe, et al:bnp Change after AMI 531 Table 4. Multivariative analysis of independent risk factors of Age (years) Sex Hypertension Smoking Diabetes Dyslipidemia Serum creatine (mg/dl) Serum CK-MB (ng/ml) Serum troponin I (ng/ml) Initial systolic BP (mmhg) Acute phase BNP (pg/ml) Early phase BNP (pg/ml) LV ejection fraction (%) WMSI Table 5. Multivariative analysis of independent risk factors of CVD Age (years) Sex Hypertension Smoking Diabetes Dyslipidemia Serum creatine (mg/dl) Serum CK-MB (ng/ml) Serum troponin I (ng/ml) Initial systolic BP (mmhg) Acute phase BNP (pg/ml) Early phase BNP (pg/ml) LV ejection fraction (%) WMSI Odd ratio 0.959 0.222 1.228 1.019 1.078 1.443 1.157 1.002 1.003 0.993 0.998 1.020 0.594 Odd ratio 1.126 7.243 0.151 3.445 1.552 0.813 0.805 1.004 0.934 0.998 1.001 1.002 0.946 0.558 Lower 0.919 0.071 0.519 0.402 0.444 0.603 0.684 0.997 0.979 0.980 0.999 0.997 0.961 0.079 Lower 1.107 0.922 0.023 0.429 0.328 0.159 0.280 0.997 0.860 0.974 0.855 0.015 95% CI 95% CI Upper 1.001 0.691 2.903 2.587 2.616 3.450 1.959 1.007 1.028 1.007 1.001 1.083 4.487 Upper 01.247 56.926 01.015 27.699 07.331 04.150 02.319 01.012 01.013 01.022 01.002 01.004 01.046 20.404 0.002) 가독립적 CVD 예측인자로서의미가있었다 (Table 6). 와 CVD 를예측할수있는초기추적기 BNP 농도의정확도를알아보기위하여 군과비 군, 그리고 CVD 군과비 CVD 군을대상으로각시간대별 BNP 농도를분석하였으며다변량회귀분석상의미가있었던초기추적기 BNP 농도로작성한 ROC curve 상 예측 BNP 농도는 199 pg/ml 에서예민도가 53.2%, 특이도가 83.1%, accuracy ( 이하 AUC) 가 0.715(p<0.001)(Fig. 5), CVD 예측 BNP 농도는 186 pg/ml 에서예민도 81.5%, 특이도 79.9%, AUC 가 0.855(p<0.001)(Fig. 6), 그리고좌심실 SHF 예측 BNP 농도는 151 pg/ml 에서예민도 65.6%, 특이도 72.9%, AUC 가 0.713(p<0.001) 으로나타났다 (Fig. 7). 초기추적기 BNP 농 p* 0.022 0.060 0.052 0.245 0.579 0.804 0.688 0.256 0.100 0.842 0.177 0.037 0.278 0.750 *: by multiple logistic regression model. Boldfacing indicates variables that retained independent risk factors in the multivariative model. CVD: cardiovascular death, CK-MB: creatine kinase-mb, BP: blood pressure, BNP: B-type natriuretic peptide, LV: left ventricle, WMSI: wall motion score index, CI: confidence interval p* 0.057 0.009 0.640 0.968 0.869 0.410 0.586 0.445 0.811 0.325 0.794 0.007 0.514 0.614 *: by multinominal logistic regression model. Boldfacing indicates variables that retained independent risk factors in the multivariative model. CK-MB: creatine kinase-mb, BP: blood pressure, BNP: B-type natriuretic peptide, LV: left ventricle, WMSI: wall motion score index, CI: confidence interval, : major adverse cardiac event Table 6. Multivariative analysis of independent predictors of CVD Age (years) Sex Hypertension Smoking Diabetes Dyslipidemia Serum creatine (mg/dl) Serum CK-MB (ng/ml) Serum troponin I (ng/ml) Initial systolic BP (mmhg) Acute phase BNP (pg/ml) Early phase BNP (pg/ml) LV ejection fraction (%) WMSI 도의 ROC 곡선상 CVD 예측에예민도와특이도가가장높았던 BNP 186 pg/ml 를기준으로작성한 Kaplan-Meier 생존곡선상누적생존율은 BNP 186 pg/ml 환자군이유의하게 (p=0.000) 높았다 (Fig. 8). 고 Odd ratio 1.140 3.464 0.322 1.836 2.284 0.984 0.592 1.005 0.953 0.992 0.998 0.962 0.483 본연구에서는관찰된급성심근경색이후혈중 BNP 농도의변화를관찰하였고그결과각시간대별로측정된 BNP 찰 Lower 1.048 0.784 0.086 0.350 0.567 0.257 0.268 0.998 0.892 0.973 0.999 0.999 0.890 0.034 95% CI Upper 01.240 15.310 01.204 09.632 09.201 03.769 01.309 01.011 01.019 01.012 01.001 01.002 01.041 06.792 p* 0.002 0.101 0.092 0.473 0.245 0.981 0.195 0.159 0.159 0.443 0.507 0.252 0.334 0.590 *: on Cox proportional hazard regression model. Boldfacing indicates variables that retained independent predictors of cardiovascular death in the multivariative model. CK-MB: creatine kinase-mb, BP: blood pressure, BNP: B-type natriuretic peptide, LV: left ventricle, WMSI: wall motion score index, CI: confidence interval Sensitivity 1.0 0.8 0.6 0.4 0.2 0.0 BNP 199 pg/ml AUC: 0.715 p<0.001 0.0 0.2 0.4 0.6 0.8 1.0 1-specificity Fig. 6. On the ROC curve, the AUC of early period BNP concentration for predicting in patients with AMI was 0.715 (sensitivity 53.2%, specificity 83.1%), and optimum cut-off point was 199 pg/ml (p<0.001). ROC: receiver operating characteristic, AUC: accuracy, BNP: B-type natriuretic peptide, : major adverse cardiac event, AMI: acute myocardial infarction.

532 Korean Circulation J 2006;36:526-534 1.0 1.0 Sensitivity 0.8 0.6 0.4 BNP 186 pg/ml AUC: 0.855 p<0.001 Cardiovascular death free survival 0.8 0.6 0.4 0.2 0 BNP<186 pg/ml p=0.000 BNP 186 pg/ml 0 10 20 30 40 0.2 Months 0.0 0.0 0.2 0.4 0.6 0.8 1.0 1-specificity Fig. 7. On the ROC curve, the AUC of early phase BNP concentration for predicting survival in patients with AMI was 0.855 (sensitivity 81.5%, specificity 79.9%), and optimum cut-off point was 186 pg/ml (p<0.001). ROC: receiver operating characteristic, AUC: accuracy, BNP: B-type natriuretic peptide, AMI: acute myocardial infarction. Sensitivity 1.0 0.8 0.6 0.4 0.2 BNP 151 pg/ml AUC: 0.713 p<0.001 0.0 0.0 0.2 0.4 0.6 0.8 1 1-specificity Fig. 8. On the ROC curve, the AUC of early phase BNP concentration for predicting left ventricular SHF in patients with AMI was 0.713 (sensitivity 65.6%, specificity 72.9%), and optimum cut-off point was 151 pg/ml (p<0.001). ROC: receiver operating characteristic, AUC: accuracy, BNP: B-type natriuretic peptide, AMI: acute myocardial infarction, SHF: systolic heart failure. 변화는이상성양상을보여주었으며초기추적기 BNP 농도가, CVD 등의독립위험인자로서유의한인자임이관찰되었다. 급성심근경색이후 BNP 농도의변화급성심근경색이후급성기와초기추적기혈중 BNP 농도 Fig. 9. Kaplan-Meier survival curve of cumulative survival rates in patients with acute myocardial infarction divided into 2 groups according to BNP concentration. Patients with BNP 186 pg/ml differed meaningfully from patients with BNP<186 pg/ml. The significant difference between patients with BNP 186 pg/ml and with BNP< 186 pg/ml within group was expressed as *: p=0.000. BNP: B-type natriuretic peptide. 의상승기전은시기에따라차이가있다. 급성기에는심근내저장되어있던 BNP 가심근괴사와더불어분비되며농도증가는경색발생 20 시간전후에시작하여초기추적기 120 시간전후까지나타난다. 13) 초기추적기 BNP 농도증가는압력을받는경색경계부의확장에의해나타나며이시기가심실재형성의시작을의미하므로 SHF 의신호라할수있다. 18)19) 본연구에서 BNP 농도측정시기는급성심근경색이후급성기평균 9.5 시간, 초기추적기평균 5.1 일, 후기추적기평균 26.8 일, 그리고장기추적기평균 45.9 일에측정하였다. 후기및장기추적기에서경색부위의 BNP 합성은거의없으며경색이없었던심실부분의재형성이완성되는시기라고볼수있다. 본연구에서후기와장기추적기 BNP 농도는급성기와초기추적기 BNP 농도보다비교적안정되어있는것을관찰할수있는데이는심실확장이지속적으로진행되지않는경우, 경색부위의섬유화가일어나좌심실이받는압력이완화되므로 BNP 농도가안정화되는것으로추정되며반대로심실확장이진행되는경우에는심실이받는장력과과용적에따른압박의지속으로인해 BNP 농도가상승할수있을것으로예측된다. BNP 변화와임상예후와의관계혈중 BNP 농도는심근경색과좌심실 SHF 로인해증가하며특히좌심실 SHF 로인해 와 CVD 의발생위험이증가한다고볼수있다. 또한, 허혈과관계없이경색부위와정상심근부위간의일관된탈분극과재분극이없어져발생하는부정맥이혈중 BNP 농도를상승시킬수있다는사실은 BNP 농도가심근경색이후나타나는다양한합병증의위험인자로이용될수있음을의미한다. 예전부터혈중 BNP 농도가급성심근경색환자의중요한예후인자이며 3-5) 급성기에측정된 BNP 농도가예후인자로서의미가있다는여러보

Hyunmin Choe, et al:bnp Change after AMI 533 고가있었다. 20-24) 특히, Talwar 등 16) 은초기 48 시간동안 NT pro-bnp 농도의상승이조직괴사를의미하며 72~120 시간동안 NT pro-bnp 농도의상승은경색부위의확장및좌심실 SHF 의진행을반영하므로 72~120 시간동안측정한 NT pro-bnp 농도가 CVD 와좌심실 SHF 의독립적위험인자로서의미가있음을보고하였고, Suzuki 등 13) 은 BNP 농도의일차최고점 (First peak) 이심근경색발생후 20시간이내에나타나고이후약 5일이내에이차최고점 (Second peak) 이나타나지만환자개인에따라이차최고점이나타나는시기가달라정확한농도측정시기를알수없으므로 BNP 농도가안정적인심근경색발생후 3~4 주기간동안측정한 BNP 농도가믿을만한이차최고점을반영할수있어이시기에측정한 BNP 농도가예후인자로서의미가있음을보고하였다. 하지만본연구에서는후기추적기에측정한 BNP 농도가예후를반영하지못하였으며 BNP 변화양상도, CVD, 그리고 SHF 가동반된환자군에서그렇지않은환자군보다초기추적기가후기추적기보다큰차이를보였다. 이는 Talwar 등의 NT-pro BNP 연구에서초기추적기 BNP 농도가예후를반영하는데유의한검사시기로추정한것과일치하는소견이었다. 본연구에서다변량회귀분석상남성과연령이각각 와 CVD 발생의위험예측인자로의미가있었던것은남성이여성보다수적으로적으면서 가많이발생하였고 CVD 발생군에고령이많았던것이원인이라생각된다. 반면 Troponin Ⅰ와 CK-MB, 그리고좌심실구혈율은 와 CVD 발생의위험예측인자로의미가없었는데, 이중 Troponin Ⅰ와 CK-MB 는심근경색이발생한이후여러차례측정한값중에서최대값을선택하여비교하지않고입원당시측정한값만반영하였던것에기인한다고생각된다. 결론적으로급성심근경색발생이후혈중 BNP 농도측정결과분석상 BNP 농도는시간대별로급성기와초기추적기에급격한상승이있었고임상적예후인자에따라조기 BNP 값및변화양상에차이가있었다. 또한, 초기 2일에서 6일사이에측정한 BNP 농도가 와 CVD 의독립적위험인자로의미가있었고이시점의 BNP 농도가급성심근경색환자에서예후를평가할수있는객관적위험인자라하겠다. 연구제한점본연구의제한점으로첫째, 모든환자들에게각시기별로 BNP 농도를측정하지못하여각시간대별 BNP 농도검사율에차이가있었다. 각시간대별 BNP 추적검사율은급성기가 100%, 초기추적기가 73.5% 로높았던반면후기추적기는 28.7%, 장기추적기는 12.1% 로후기와장기추적기 BNP 농도의추적검사율이낮았다. 이는초기추적기 BNP 농도가급성기 BNP 농도와비교하여임상증상호전과더불어감소하는경우또는측정된농도가높더라도정상경계농도 보다 2배이상증가되지않고심부전증상이없는경우에검사를종료했기때문이며추적관찰도중본병원이아닌다른의료기관에서외래추적을받는환자들과사망하는환자가많았던것도요인으로여겨진다. 둘째로, 본연구가전향적연구가아닌후향적임상연구로실제 BNP 농도변화에영향을주는외적인임상상태가환자군마다달라분석에있어제한점으로작용하였을것으로생각된다. 요약 배경및목적 : 급성심근경색발생이후혈중 B-type natriuretic peptide (BNP) 농도는역동적으로변화하여예후에의미있는 BNP 측정시간을결정하는것은쉽지않다. 본연구는급성심근경색환자에서 BNP 농도의조기변화양상을관찰하고측정된 BNP 농도가위험및예후인자로서의미가있는지평가하고자하였다. 방법 : 2002 년 2월부터 2005 년 5월까지본원에급성심근경색으로내원한 321 명의환자를대상으로혈중 BNP 농도를측정하였다. BNP 농도측정 (Triage ) 은심근경색발생이후 24시간이내를급성기, 2일에서 6일사이를초기추적기, 1 주에서 4주사이를후기추적기, 그리고 4주이상의기간을장기추적기로나누어측정하였으며연구종점은주요심혈관계사건 () 과심혈관사망 (CVD) 으로하였다. 결과 : 평균 BNP 농도는급성기 306.2±802.8, 초기추적기 251.9±592.8, 후기추적기 103.1±172.9, 그리고장기추적기 179.7±353.3 pg/ml 였다. 군과비 군사이에인구학적인자상유의한차이는없었다. 다변량분석결과상초기 BNP 농도 (p=0.007) 와남자 (p=0.009) 가 발생의유의한위험인자로서, 그리고초기 BNP 농도 (p= 0.037) 와연령 (p=0.022) 은 CVD 발생의유의한위험인자로서의미가있었다. 초기 BNP 농도에대한 Receiver Operating Characteristic(ROC) curve 상 CVD 발생위험에대한 BNP 농도는 186 pg/ml 에서예민도가 81.5%, 특이도가 79.9% 에서 accuracy(auc) 가 0.855 로가장높게측정되었고 (p<0.001), Kaplan Meier 생존곡선상누적생존율은초기 BNP 농도가 186 pg/ml 미만인환자군이생존율이높았다 (p=0.000). 결론 : 급성심근경색발생이후혈중 BNP 농도혹은농도변화는임상적예후인자에따라다양한차이가있었다. 또한, 심근경색발생 2일에서 6일사이에측정한초기추적기 BNP 농도는의미있는예후표지자로사용될수있을것이다. 중심단어 :B-type natriuretic peptide; 심근경색 ; 예후.

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