Original ORIGINAL Article ARTICLE Korean Circulation J 2006;36:200-207 ISSN 1738-5520 c 2006, The Korean Society of Circulation 급성심부전환자에서조기추적 BNP 수치와울혈정도및예후와의관계 연세대학교원주의과대학순환기내과학교실, 1 응급의학과학교실 2 정일형 1 유병수 1 유호열 1 왕희성 1 최현민 1 김장영 1 이승환 1 황성오 2 윤정한 1 최경훈 1 The Relationship between the Early Follow-Up BNP Level and Congestive Status or Prognosis in Acute Heart Failure Il-Hyung Chung, MD 1, Byung-Su Yoo, MD 1, Ho Yoel Ryu, MD 1, Hee-Sung Wang, MD 1, Hyun-Min Choi 1, Jang-Young Kim, MD 1, Seung-Hwan Lee, MD 1, Sung-Oh Hwang, MD 2, Junghan Yoon, MD 1 and Kyung-Hoon Choe, MD 1 1 Department of Cardiology and 2 Emergency Medicine, Wonju College of Medicine, Yonsei University, Wonju, Korea ABSTRACT Background and Objectives:A correlation between the BNP reduction ratio and prognosis could be expected to be found by evaluating the BNP reduction depending on the volume status during the early period. Subjects and Methods:Between October 2002 and June 2004, 120 patients with acute heart failure (AHF)(<1 month) were included. The patients were divided into three groups according to their volume status, as follows. Group I: patients with clinical & radiological wet status, Group II: clinical dry & radiological wet status and Group III: clinical & radiological dry status. The blood BNP (Triage ) level and clinical parameters were analyzed. The bad prognostic parameters were defined as readmission due to heart failure, a major adverse cardiac event or cardiovascular death. Results:The mean patient age was 68.0±12.7 years, and 50.0% of the subjects were male. The most frequent etiology of AHF was ischemic heart disease (35.8%). There were 61.7, 24.1 and 14.2% in Groups I, III and III, respectively. The baseline BNP level was higher in group I and II than in group III patients (I: 1540.4±1202.8, II: 1482.8±1281.6, III: 666.4±827.9 pg/ml, p=0.036) as was the early BNP reduction ratio (I: 69.8±27.1, II: 67.4±32.8, III: 1.3±144.9%, p=0.007). Sixteen (13.3%) patients had a poor prognosis. From a logistical analysis, the early BNP reduction ratio (p=0.004) and creatinine level (p=0.029) were significant predictors of the clinical outcomes. Conclusion:The early change in the BNP level varied depending on the degree of congestive status, and was also correlated with the level of clinical outcomes. Therefore, in our opinion, the early monitoring of the BNP level will provide significant clinical information in AHF patients. (Korean Circulation J 2006;36:200-207) KEY WORDS:B-type natriuretic peptide;heart failure, congestive;prognosis. 서 B-type natriuretic peptide(bnp) 나 N-terminal pro-bnp 론 논문접수일 :2005 년 8 월 23 일수정논문접수일 :2005 년 12 월 28 일심사완료일 :2006 년 1 월 24 일교신저자 : 유병수, 220-956 강원도원주시일산동 162 연세대학교원주의과대학순환기내과학교실전화 :(033) 741-0917 전송 :(033) 741-1219 E-mail:yubs@wonju.yonsei.ac.kr (NT-pro-BNP) 의혈중농도는심실용적증가및심실압력과부하등의혈역학적인자극에반응하여주로심실에서생성분비되어심실기능이상을잘반영하는것으로알려져있다, 1) 특히급성호흡곤란을주소로내원한환자에있어서 BNP 수치는심부전의진단에유용하고 2-6) 예민도와특이도가높은것으로알려져있으며 7)8) 최근에는 BNP 수치를치료의목표혹은추적검사치로이용하여치료반응내지약제의용량결정에중요한생화학적지표로사용될수있을지에대한연구가진행되고있다. 9) 또한 BNP 수치의변화는 200
Il-Hyung Chung, et al:early Follow-Up BNP Level and Congestive Status 201 임상상태및예후와관련있으며대부분 BNP 수치변화는치료초기에발생하는것으로알려져있다. 10)11) 그러나 BNP 수치변화는환자의임상양상의정도, 울혈상태및약제사용에따라다양하게나타날수있으며환자의울혈상태에따른 BNP 수치의감소정도및환자의임상양상을연구한보고는드물다. 따라서저자들은급성심부전환자를대상으로치료초기에환자의울혈상태와 BNP 수치변화와의관계및 BNP 변화에따른임상예후와의연관성에대해알아보고자하였다. 대상및방법 대상환자 2002 년 10월부터 2004 년 6월까지호흡곤란을주소로본원에내원하여급성심부전또는급성으로악화된심부전으로진단된환자를후향적으로분석하였고이중내원초기 BNP 및조기에 BNP 를추적검사하고의무기록이충실했던연속적인 120 명의환자를대상으로하였다. 심부전의정의는내원시자가증상및이학적소견이 Framingham 기준에합당하고 12) 심장초음파검사상좌심실구혈율이 50% 미만인경우나 50% 이상인경우심초음파상이완기기능장애를보이는경우로정의하였다. 13) 또한, 급성심부전은증상악화가한달이내였던경우로심부전의증상악화 (NYHA 분류상 Ⅰ도이상증가 ) 및 NYHA 분류상 Ⅱ도이상인환자로정의하였다. 14) 대상환자중지난한달내에증상의악화없이내원시심부전으로진단된만성안정형심부전환자, 급성혹은만성폐질환환자, 수술적치료가필요한심장판막질환및급성판막질환환자, 급성심근염, 내원 6개월이내에급성심근경색이발병된환자및심초음파상결과가모호한경우는제외하였다. 환자의울혈정도와 BNP 수치와의연관성을알아보기위하여환자의울혈상태를임상적울혈 (clinical congestion: 부종이있거나청진상수포음이들리는경우 ) 및단순흉부방사선사진에따라방사선학적울혈 (radiological congestion: 단순흉부촬영상폐부종이나폐울혈이있는경우 ) 로나누었고이를근거로대상환자를세군으로분류하였다. Ⅰ군은부종이나수포음이있고단순흉부사진상폐울혈이있는 (clinical wet & radiological wet status) 환자군, Ⅱ군은부종, 수포음은없으나단순흉부사진상폐울혈이있는 (clinical dry & radiological wet status) 환자군, Ⅲ군은부종, 수포음이없고단순흉부사진상폐울혈이없는 (clinical dry & radiological dry status) 환자군으로정의하였다. 15)16) 대상환자의임상검사및 BNP 검사모든대상환자에서내원당시흉부방사선촬영, 심전도, 심장초음파검사를시행하였고혈액학검사, 전해질및임상화학검사, BNP 수치, 키, 몸무게를측정하였다. 혈중 BNP 농도측정은최소 EDTA 가포함되거나혹은전혈이포함된시험관에 3~5 ml 혈액을채취한후 BNP kit(triage, Biosite, San Diego, USA) 로형광면역측정법을이용하여정량적으로측정하였고측정값의하한선은 5 pg/ml 이었고상한선은 5000 pg/ml이었다. 심장초음파검사를시행하여좌심실구혈율및이완기장애정도를측정하였다. 환자의내원초기이후의추적검사는조기 1~3 개월에 ( 평균 2.2±0.8 개월 ) 재차 BNP 수치를측정하여 (early period BNP follow-up) 조기 BNP 감소율을아래와같은방법으로산출하였다. 조기 BNP 감소율 =[(baseline BNP level-early follow up BNP level)/baseline BNP level] 100 대상환자의추적관찰평균 6개월동안 ( 평균 6.1±1.9 개월 ) 환자를추적관찰하였고, 예후가불량한경우 (poor prognosis) 는임상증세의악화로인한재입원, 주요심혈관사건 ( 급성심근경색, 뇌졸중등 ) 의발생및심장사가발생한경우로정의하였다. 17) 자료분석및통계통계분석은 SPSS version 12.0(SPSS Inc. Chicago. US) 을이용하였으며, 모든자료는평균 ± 표준편차로표시하였다. 각환자군간의좌심실구혈율, 초기 BNP 수치, 조기추적 BNP 수치, 조기 BNP 감소율등의명목변수에대한비교는 one-way ANOVA 를사용하여비교분석하였고비명목변수는 chi-square test 를이용하여분석하였다. 환자의예후에미치는영향을분석하고자불량한임상결과유무와초기 BNP 수치, 조기추적 BNP 수치, 조기 BNP 감소율, 좌심실구혈율및여러임상변수등을단변량혹은다변량로지스틱회귀분석을이용하여그연관성을분석하였고, ROC (Receiver Operating Characteristic) curve 를그려조기추적 BNP 수치와조기 BNP 감소율의 cut off value 를구하였다. 모든통계자료에있어서 p<0.05 인경우에통계학적으로유의한결과로해석하였다. 결 대상환자의임상양상 120 명대상환자의평균나이 (p=0.286), 성별 (p=0.072), 체표지수 (p=0.502) 및내원시평균 NYHA 지수 (p=0.36) 는각군간에통계적으로차이가없었고환자의울혈상태에따른환자군의분포는 Ⅰ군 74예 (61.7%), Ⅱ군 29예 (24.1%), Ⅲ군 17예 (14.2%) 였고부종이나수포음은있으나단순흉부사진상폐울혈이없는경우 (radiological dry status) 의환자군은한명도없었다 (Table 1). 각환자군에서위험인자인당뇨 (p=0.433), 고혈압 (p= 0.869), 흡연 (p=0.152) 의빈도도각군간에통계적유의성 과
202 Korean Circulation J 2006;36:200-207 Table 1. Demographics Group I Group II Group III p No. 74 29 17 Age 68.7±13.2 68.9±8.8. 63.5±15.9 0.286 Male (%) 41.9 (31) 65.5 (19) 58.8 (10) 0.072 BSA (m 2 ) 1.53±0.19 1.54±0.24 1.45±0.22 0.502 EF (%) 28.2±7.60 29.6±7.60 34.5±0.70 0.453 Diabetes (%) 25.7 (19) 31.0 (09) 41.2 (07) 0.433 Hypertension (%) 54.1 (40) 48.3 (14) 52.9 (09) 0.869 Smoking (%) 40.5 (30) 62.1 (18) 52.9 (09) 0.152 Group I: patients with clinical & radiological wet status, Group II: clinical dry & radiological wet status, Group III: clinical & radiological dry status, BSA: body surface area, EF: ejection fraction Table 2. Comparisons of various parameters among three groups Underlying disease (%) Ischemic HD Hypertensive HD Valvular HD Dilated CMP Others Precipitating factor (%) Ischemia Arrhythmia Infection Hypertension Anemia Inadequate therapy Echo profile EF (%) DT (msec) Pseudonormal (%) Restrictive (%) Drug (%) ACEI ARB Beta blocker Diuretics Aldactone Digitalis Poor prognosis (%) Readmission MACE Group I (n=74) 32.4 (24) 13.5 (10) 31.1 (23) 16.2 (12) 06.8 (05) 40.5 (30) 17.6 (13) 35.1 (26) 01.4 (01) 01.4 (01) 04.1 (03) 28.2±7.6.189±71. 08.1 (06) 12.2 (09) 77.0 (57) 13.5 (10) 52.7 (39) 100 (74) 87.8 (65) 16.2 (12) 5.4 (04) 4.1 (03) 4.1 (03) Group II (n=29) 34.5 (10) 24.1 (07) 27.6 (08) 10.3 (03) 03.4 (01) 48.3 (14) 20.7 (06) 24.1 (07) 06.9 (02) 29.6±7.6.194±73. 06.9 (02) 10.3 (03) 79.3 (23) 10.3 (03) 72.4 (21) 93.1 (27) 72.4 (21) 10.3 (03) 6.9 (02) 3.4 (01) 3.4 (01) Group III (n=17) 52.9 (09) 11.8 (02) 17.6 (03) 11.8 (02) 05.9 (01) 52.9 (09) 29.4 (05) 17.6 (03) 34.5±0.7.207±44. 11.8 (02) 70.6 (12) 05.9 (01) 52.9 (09) 76.5 (13) 58.8 (10) 17.6 (03) 5.9 (01) 5.9 (01) 0.0 (00) 은없었다 (Table 1). 심부전증의원인이되는기저심질환은허혈성심질환이가장흔하였고 (35.8%, n=43) 각군별로도허혈성심질환이 Ⅰ 군에서 32.4%(n=24), Ⅱ군에서 34.5%(n=10), Ⅲ군에서는 52.9%(n=9) 였다 (Table 2). p 0.278 0.366 0.538 0.710 0.813 0.570 0.542 0.267 0.731 0.731 0.527 0.453 0.817 0.841 0.320 0.791 0.655 0.175 0.000 0.013 0.715 0.959 0.921 0.702 CV Death Group I: patients with clinical & radiological wet status, Group II: clinical dry & radiological wet status, Group III: clinical & radiological dry status, HD: heart disease, CMP: cardiomyopathy, EF: ejection fraction, DT: deceleration time, ACEI: angiotensin converting enzyme inhibitor, ARB: angiotensin receptor blocker, MACE: major adverse cardiac event, CV: cardiovascular 심부전의악화인자는심근허혈이가장흔하였는데 (44.2%, n=53) 심근허혈은급성심근경색및불안정성협심증양상의심근허혈을모두포함한다. 각군별로도 Ⅰ군에서는심근허혈이 40.5%(n=30), Ⅱ군에서는 48.3%(n=14), Ⅲ군에서는 52.9%(n=9) 였다. 그리고심부전의기저질환및악화요인모두환자군간의유의한차이는없었다 (p>0.05). 평균좌심실구혈율도 Ⅰ군에서 28.2±7.6%, Ⅱ군에서 29.6±7.6%, Ⅲ군에서 34.5±0.7% 로서각군간에유의한차이는없었으며 (p=0.453) 이완기장애에대한도플러검사결과도각군간에유의한차이가없었다 (Table 2). 대상환자는평균 6개월 ( 평균 6.1±1.9 개월 ) 동안추적관찰을시행하였다. 환자중임상증상의악화로인한재입원 7예, 주요심장사건 5예, 심질환으로인한사망 4예로모두 16예 (13.3%) 에서임상예후가불량하였다. 이들환자는 Ⅰ군 10예 (13.5%), Ⅱ군 4예 (13.8%), Ⅲ군 2예 (11.8%) 로서각군간에유의한차이는없었다 (p=0.978)(table 2). BNP 수치변화및울혈상태에따른 BNP 변화전체환자 120 명을대상으로분석하였을때평균초기 BNP 수치는 Ⅰ군에서 1517.4±1194.1 pg/ml, Ⅱ군에서 1404.3± 1226.6 pg/ml, Ⅲ군에서 607.9±793.7 pg/ml 로울혈상태가청진및흉부사진상관찰된환자군에서가장높았고울혈상태가없었던환자군에서유의하게낮았으며 (p=0.016) 평균조기추적 ( 평균 2.2±0.8 개월 ) BNP 수치는 Ⅰ군에서 681.5±1212.2 pg/ml, Ⅱ군에서 643.2±884.1 pg/ml, Ⅲ 군에서 500.5±543.1 pg/ml 로세군간의유의한차이는없었다 (p=0.870). 평균조기 BNP 감소율은예후가좋은 104 명의환자에서 59.9±61.7% 였고예후가불량한 16명의환자에서는 -504.7±852.4% 였으며 (p<0.001) 울혈상태에따른조기추적 BNP 수치의감소정도는예후가양호한 104 명의환자를대상으로비교분석하였다. 그결과초기 BNP 수치와조기추적 BNP 수치간의차이는 Ⅰ군, Ⅱ군에서통계적으로유의성이있었으나 (p<0.001, p<0.001) Ⅲ군에서는유의성이없었고 (p=0.533) 평균초기 BNP 수치는 Ⅰ군에서 1540.4±1202.8 pg/ml, Ⅱ군에서 1482.8±1281.6 pg/ml, Ⅲ군에서 666.4±827.9 pg/ml로울혈상태가청진및흉부사진상관찰된환자군에서가장높았고울혈상태가없었던환자군에서유의하게낮았다 (p=0.036)(fig. 1). 평균조기추적 BNP 수치는 Ⅰ군에서 442.6±814.3 pg/ml, Ⅱ군에서 418.2±497.7 pg/ml, Ⅲ군에서 464.7±571.2 pg/ml 였으며세군간의유의한차이는없었다 (p=0.985)(fig. 1). 평균조기 BNP 감소율은 Ⅰ군에서 69.8±27.1%, Ⅱ군에서 67.4±32.8%, Ⅲ군에서 1.3±144.9% 로 Ⅰ군과 Ⅱ군에서 Ⅲ 군보다유의한감소율을나타내었다 (p=0.007)(fig. 2). 그러나예후가불량한 16명의환자를대상으로울혈상태에따른 BNP 수치의감소정도를비교분석한결과초기 BNP 수치, 조기추적 BNP 수치및조기 BNP 감소율모두세군
Il-Hyung Chung, et al:early Follow-Up BNP Level and Congestive Status 203 BNP (pg/ml) 2000 1500 1000 0500 0000 p=0.000 1540±1202 442±814 p=0.000 1482±1281 418±497 Group I Group II Group III Initial BNP Early follow-up BNP p=0.533 666±827 464±571 Fig. 1. Initial BNP level and early follow-up BNP levels (mean±sd) in good prognosis group. There was significant difference between initial BNP and early follow-up BNP in group I, II (p<0.001, p<0.001), but, not in group III (p=0.533). There was significant difference among 3 groups in initial BNP level (p=0.036). But, there was no significant difference among 3 groups in the early follow-up BNP level (p=0.985). Group I: patients with clinical & radiological wet status, Group II: clinical dry & radiological wet status, Group III: clinical & radiological dry status, BNP: B-type natriuretic peptide. Early BNP reduction rate (%) 100 080 060 040 020 000 69.8±27.1 67.4±32.8 1.3±144.9 Group I Group II Group III Fig. 2. The early BNP reduction rates (mean±sd) in good prognosis group. There was significant difference in early BNP reduction rates among three groups (p=0.007). There was no significant difference between group I and group II (p=0.765). Group I: patients with clinical & radiological wet status, Group II: clinical dry & radiological wet status, Group III: clinical & radiological dry status, BNP: B-type natriuretic peptide. 간에통계적으로유의한차이는없었다 (p=0.338, p=0.660, p=0.605). 조기 BNP 수치변화와임상예후임상예후가양호한환자군과불량한환자군을비교시두군간의임상양상, 심초음파소견, 검사실소견등은차이가없었고울혈정도또한두군간에차이가없었으나 (p=0.837) 조기추적 BNP 수치, 조기 BNP 감소율은두군간에유의한차이가관찰되었다 (p=0.000, p=0.000). 그러나초기 BNP 수치는두군간에유의한차이가관찰되지않 Table 3. Comparisons of various parameters between good and poor prognosis group Good prognosis (n=104) Poor prognosis (n=16) Age 0067.4±13.300 0-.71.3±7.2000 0.258 Male (%) 48.1 (50) 62.5 (10) 0.283 Systolic BP (mmhg) 0139.6±27.500 -.133.6±26.200 0.411 Diastolic BP (mmhg) 0082.4±15.000 0-. 78.9±21.800. 0.422 Heart Rate (/min) 0090.2±24.400 0-.87.8±22.200 0.706 Creatinine (mg/dl) 001.05±0.2200 0.-0.94±0.2000 0.125 Creatinine clearance 0050.5±22.200 0-.56.8±25.100 0.452 (ml/min) LV dimension (cm) 0005.9±0.9000 00-.6.3±0.9000 0.174 LA dimension (cm) 0004.9±0.7000 00-.4.5±0.7000 0.083 Ejection fraction (%) 0031.3±9.9000 0-.30.7±7.4000 0.855 Initial BNP (pg/ml) 1400.5±1205.4-1106.1±1062.7 0.358 Early follow-up BNP 0439.1±697.60-1804.3±1770.2 0.000 (pg/ml) Early BNP reduction 0059.9±61.700 0-504.7±852.40 0.000 rate (%) Congestion* 85.6 (89) 87.5 (14) 0.837 BP: blood pressure, LV: left ventricle, LA: left atrium, BNP: B-type natriuretic peptide. *: clinical congestion or radiological congestion Table 4. Univariable logistic regression analysis of various parameters for prognosis Exp (B) 95% C.I. for Exp (B) Lower Upper Age 1.030 0.979 1.084 0.257 Systolic BP (mmhg) 0.992 0.972 1.012 0.408 Diastolic BP (mmhg) 0.987 0.955 1.019 0.419 Heart rate (/min) 0.996 0.973 1.019 0.704 Creatinine (mg/dl) 2.025 1.075 3.815 0.029 Congestion* 0.848 0.175 4.113 0.837 LV dimension (cm) 1.460 0.845 2.524 0.175 LA dimension (cm) 0.504 0.231 1.102 0.086 Ejection fraction (%) 0.964 0.925 1.004 0.078 Initial BNP (pg/ml) 1.000 0.999 1.000 0.364 Early follow-up BNP (pg/ml) 1.001 1.000 1.002 0.003 Early BNP reduction rate (%) 0.988 0.979 0.996 0.004 BP: blood pressure, LV: left ventricle, LA: left atrium, dummy variable, BNP: B-type natriuretic peptide. *: clinical congestion or radiological congestion 았다 (p=0.358)(table 3). 임상결과에영향을미치는변수를알아보고자임상결과와초기 BNP 수치, 조기추적 BNP 수치, 조기 BNP 감소율, 좌심실구혈율, 크레아티닌수치및여러임상변수와의관계를로지스틱회귀분석을사용하여분석하였다. 그결과단변량로지스틱회귀분석에서는조기 BNP 감소율, 크레아티닌수치가임상결과와통계적으로유의성이있었으나 (p=0.004, p=0.029) 다변량로지스틱회귀분석에서는크레아티닌수치만이통계적으로유의성이있었다 (p=0.048)(table 4, 5). 그리고불량한예후와좋은예후를결정하는데있어서조기추적 BNP 수치와조기 BNP 감 p p
204 Korean Circulation J 2006;36:200-207 소율의 cut off value 를구하기위하여 ROC curve 를분석하였다. 조기추적 BNP 수치의 AUC(area under the curve) 는 0.872(p=0.000) 이고 cut off value 는 494.5 pg/ml(sensitivity 81.8%, specificity 79.4%) 였고, 조기 BNP 감소율의 AUC(area under the curve) 는 0.905(p=0.000) 이고 cut off value 는 37.06%(sensitivity 80.6%, specificity 81.8%) 였다 (Fig. 3, 4). 고 본연구에서 BNP 수치의변화는환자의울혈상태에따 Table 5. Multivariable logistic regression analysis of various parameters for prognosis 찰 95% C.I. for Exp (B) Exp (B) Lower Upper Age 01.180 0.868 0001.603 0.291 Systolic BP (mmhg) 00.971 0.832 0001.134 0.713 Diastolic BP (mmhg) 00.943 0.713 0001.248 0.684 Heart rate (/min) 01.078 0.974 0001.194 0.145 Creatinine (mg/dl) 33.537 1.036 1085.820 0.048 Congestion* 00.000 0.000 0.998 LV dimension (cm) 02.263 0.055 0092.886 0.667 LA dimension (cm) 00.681 0.030 0015.379 0.809 Ejection fraction (%) 01.020 0.810 0001.283 0.867 Initial BNP (pg/ml) 00.997 0.989 0001.005 0.437 Early follow-up BNP (pg/ml) 01.002 0.996 0001.008 0.530 Early BNP reduction rate (%) 00.975 0.936 0001.015 0.213 BP: blood pressure, LV: left ventricle, LA: left atrium, BNP: B-type natriuretic peptide. *: clinical congestion or radiological congestion, dummy variable 1.00 ROC curve p 라다양하게나타났으며조기에추적관찰한 BNP 수치의변화 ( 조기 BNP 감소율 ) 는급성심부전환자에서크레아티닌수치와함께환자의예후와연관성이있음을입증하였다. 조기 BNP 추적검사 BNP 가기전적으로생화학적 Swan-Ganz 도자로생각되며이는당뇨환자에서의당화혈색소혹은간암환자에서의 alpha fetoprotein(afp) 과같은역할을할것으로기대된다. 16) 이는심부전의기전적인측면을고려할때병이호전되고안정화된다면 BNP 수치는감소할것으로생각된다. 16)17) 치료후 BNP 수치의감소는신경호르몬의활성화가되는심부전의기전에서 natriuretic peptide 가레닌-안지오텐신-알도스테론및교감신경계호르몬의역호르몬 (counter-hormone) 이므로이와같은신경호르몬이안정화되는시점까지분비될것이라생각된다. 16) 이와같은근거는 Kazanegra 등 18) 이실제심부전환자에서 Swan-Ganz 도자를통한폐동맥쐐기압과 BNP 수치의감소정도를관찰하였고폐동맥쐐기압은심부전치료후에감소하면서일정시간이지난후에는압력변화가없지만 BNP 는그이후에도지속적으로감소하여혈역학적지표보다도 BNP 를추적하는것이실제환자의추적에유용함을주장하였다. 또한 Lee 등 19) 은실제임상연구에서심부전환자의 BNP 수치는 NYHA class 의객관적인생화학적지표임을보고하였고심부전을치료하는동안 NYHA class 를객관적으로평가하는데있어서 BNP 의우수성을입증하였다. 본연구에서는환자의추적검사시명확한증상의정도를반영하는 NYHA class 가자료부족으로누락되어있어실제호전여부와 BNP 변화정도를객관적으로비교분석하지는못하였다. 그러나급성심 ROC curve 1.00 0.75 0.75 Sensitivity 0.50 Sensitivity 0.50 0.25 0.25 0.00 0.00.25.50.75 1.00 1-Specificity Diagonal segments are produced by ties 0.00 0.00.25.50 1-Specificity.75 1.00 Fig. 3. ROC curve of early follow-up BNP levels. AUC (area under the curve) was 0.872 and it was significant statistically (p=0.000). The cut off value of early follow-up BNP levels was 494.5 pg/ml (sensitivity 81.8%, specificity 79.4%). BNP: B-type natriuretic peptide, ROC: receiver operating characteristic. Fig. 4. ROC curve of early BNP reduction rates. AUC (area under the curve) was 0.905 and it was significant statistically (p=0.000). The cut off value of early BNP reduction rates was 37.057% (sensitivity 80.6%, specificity 81.8%). BNP: B-type natriuretic peptide, ROC: receiver operating characteristic.
Il-Hyung Chung, et al:early Follow-Up BNP Level and Congestive Status 205 부전의특성상조기에임상적변화 (clinical course) 가예후인자에반영되어임상변화에대한간접적인분석을시행하였고, 또한실제많은연구에서다양한시기에 BNP 를측정하여그유용성및이에따른다양한감소율을보고하였다. Bayes 등 20) 이호흡곤란을동반한좌심실기능부전환자를대상으로 NT-pro-BNP 수치를측정하고로지스틱회귀분석을사용하여분석한결과입원후 7일째측정한 NT-pro- BNP 수치는입원당시와비교하였을때통계적으로의미있게감소하였음을보여입원기간동안치료에따른임상결과를모니터하는지표로서 NT-pro-BNP 가유용함을입증하였다. Logeart 등 21) 은퇴원전의 BNP 수치가재입원이나사망의강력한독립적인지표임을증명하였고임상양상, 심장초음파소견, 급성치료후의 BNP 수치변화보다도중요하다고보고하였다. Gackowski 등 22) 은급성심부전의임상결과및예후판정에있어입원 2일째 BNP 수치가내원시 BNP 수치의 10% 이상감소하거나입원 7일째 BNP 수치가 300 pg/ml 이하일경우에임상결과및예후가좋다고보고하였다. 대규모임상연구인 Val-HeFT trial 에서는평균 BNP 감소가 12% 이내인 21 pg/ml 만감소되었다고보고하였다. 23)24) 또한이전의 NT-pro-BNP 연구에서도지속적인비보상성심부전상태로유지되는환자는 BNP 수치가 21% 정도감소되었으나안정형심부전으로완전회복한환자는 57% 정도회복되었음을보고한바있고 Knebel 등 25) 은심부전의급성악화환자에서혈역학적변화없이비보상성상태로유지되는환자군에서는초기 BNP 수치의 13.5% 가감소한반면혈역학적소견이호전된보상성심부전환자군에서는 57.7% 가감소하였다고보고하였다. 본연구에서도실제좋은임상결과를보인급성심부전환자에서내원시평균 BNP 가 1~3 개월 ( 평균 2.2±0.8 개월 ) 후약 70% 감소되었고예후가불량한환자군보다양호한환자군에서유의하게더감소되었다. 그러나대상환자가만성심부전혹은급성심부전으로각기다르기때문이고또한다양한시기에 BNP 를측정하여일률적인비교는어려울것으로생각된다. 그리고다양한시기에여러번 BNP 를반복측정하여그임상적의의를분석할수있으면좋겠지만실제환자의추적검사시많은비용이소요되어임상적적용에제한점이될수있다. 저자등은급성심부전의임상변화를고려할때조기에반복측정하는것이좋을것으로판단된다. 그러나이러한추적검사가실제로치료방침을결정하고약물의용량을판단하는 guideline 인지, 또한어느정도감소하는효과가실제임상양상과관계가있는지는더연구가필요할것으로생각되며실제단순한감소정도만을가지고평가하기에는무리가있으나대규모임상연구의결과에따라 BNP 수치에따른치료의 guideline 이세워질수있으리라생각되며추후좀더많은임상연구가필요할것으로생각된다. 울혈정도와조기추적 BNP 수치의변화급성심부전의치료에따른 BNP 수치의감소와치료효과판정의예측인자로서의 BNP 에대한연구는현재까지많이있었지만 26-29) 울혈정도를임상적, 방사선학적으로구분하여치료에따른 BNP 수치의변화에대한연구는아직까지없었고본연구에서저자들은심부전환자의급성악화혹은급성심부전환자에서임상적울혈정도에따른 BNP 수치의감소정도를증명하였다. 저자들은방사선학적으로울혈상태를보인환자군에서는그렇지않은군보다상대적으로초기 BNP 수치가높으며조기 BNP 감소율도높음을증명하였고이는내원당시에호흡곤란을호소하면서단순흉부촬영상폐부종및폐울혈을보인환자군은초기 BNP 수치가상대적으로더높으나치료를함에따라 BNP 수치가상대적으로많이감소함을나타내고있다. 이는환자의울혈상태에따라 BNP 감소정도가다르게나타남을시사하며환자의추적검사에따른 BNP 수치를분석할때환자의울혈상태를고려해야할것으로생각된다. 그러나본연구에서는울혈정도가환자의예후에는직접적인영향을미치지는못하였다. 급성심부전의예후인자와조기 BNP 감소율 Fonarow 등 30) 이 ADHERE registry 를기반으로하여급성심부전환자에있어신장기능의악화및수축기혈압의감소는높은원내사망률과관련있다고보고하였다. 그러나본연구결과수축기혈압은임상결과와연관성이없었고단변량분석에서는조기 BNP 감소율및크레아티닌수치가심부전의급성악화및급성심부전환자의임상결과와연관성이있는것으로나타났으며다변량분석에서는크레아티닌수치만이임상결과와연관성이있는것으로나타났다. 그러나예후가양호한군과불량한군사이의크레아티닌수치의평균값이 Table 3과같이통계적으로유의한차이가없는것으로나타나는데이는전체대상환자군의수가적어서발생한것으로본연구의제한점으로사료되지만환자가급성심부전또는심부전의급성악화로내원하였을당시에크레아티닌수치가높다면불량한임상결과를예측할수있을것으로생각되며 ADHERE registry cart analysis 30) 와일치하는결과이다. 그리고조기 BNP 감소율도단변량분석시임상결과와연관성이있는것으로나타났으며이는급성심부전시치료를함에따라조기 BNP 감소율이높다면좋은임상결과를기대할수있을것으로생각되며초기에방사선적으로울혈상태를보인환자군에서는그렇지않은환자군에비해치료를함에따라높은조기 BNP 감소율을보이고있어내원시심한울혈상태를보이더라도적절한치료를하여조기 BNP 감소율을높인다면좋은임상결과를기대할수있을것으로생각된다. 본연구는울혈상태를방사선및청진상태만으로분류하였고실제환자의울혈및관류 (perfusion) 정도로구분하거
206 Korean Circulation J 2006;36:200-207 나혈역학적지수로울혈정도를정확히평가하지않아울혈상태에따른변화가실제울혈상태와차이가있을것으로생각된다. 또한환자의임상양상이다양하고전향적연구가아니어서실제울혈상태외에다른요소가 BNP 변화에영향을미쳤을가능성을배제할수없다. 그리고심장초음파검사시점이심부전치료후상당한시간이지난후에시행되어좌심실이완기능평가가적절치못했던점은본연구가후향적인연구로진행됨으로써가질수밖에없는제한점으로사료되지만제한된환자에서비교적임상적으로판단이용이한울혈상태에따른 BNP 수치의변화정도와이에따른임상경과를규명하는것은의의가있을것으로생각되며앞으로보다많은환자군을대상으로전향적연구가필요하리라생각된다. 요약 배경및목적 : 임상양상에따른 BNP 수치의변화는다양하다. 따라서저자들은급성심부전또는급성악화된심부전환자를대상으로치료초기에울혈상태에따른 BNP 수치의감소정도및예후인자를알아보고자하였다. 방법 : 2002 년 10월부터 2004 년 6월까지급성심부전또는급성악화된심부전으로진단된 120 명의환자를대상으로하여울혈상태에따라다음세군으로분류하였다. Ⅰ군은부종, 수포음이있고흉부사진상폐울혈이있는 (clinical & radiological wet status) 환자군, Ⅱ군은부종, 수포음은없으나단순흉부사진상폐울혈이있는 (clinical dry & radiological wet status) 환자군, Ⅲ군은부종, 수포음이없고단순흉부사진상폐울혈이없는 (clinical & radiological dry status) 환자군으로정의하였다. 초기 BNP 수치, 조기추적 BNP 수치 ( 평균 2.2 개월 ) 및임상변수와의예후와연관성을분석하였고불량한예후는심부전의악화로인한재입원, 주요심장사건및심장사가발생한경우로정의하였다. 결과 : 대상환자의평균나이는 68세였고성별은남성이 50% 였다. 기저심질환은허혈성심질환이가장흔하였고 (35.8%) 심부전의악화인자는심근허혈이가장흔하였다 (44.2%). 평균 NYHA 수치는 2.79 였다. Ⅰ군은 61.7%(n=74), Ⅱ군은 24.1%(n=29), Ⅲ군은 14.2%(n=17) 였다. 내원시 BNP 수치는 Ⅰ, Ⅱ군에서유의하게증가되어있었고 (Ⅰ군 1540.4± 1202.8, Ⅱ군 1482.8±1281.6, Ⅲ군 666.4±827.9 pg/ml, p=0.036) 조기 BNP 감소율도 Ⅰ, Ⅱ군에서유의하게증가되어있었다 (Ⅰ군 69.8±27.1, Ⅱ군 67.4±32.8, Ⅲ군 1.3± 144.9%, p=0.007). 임상결과가불량한환자는 13.3%(n= 16) 였고임상결과와의연관성은단변량분석결과조기 BNP 감소율및크레아티닌수치 (p=0.004, p=0.029), 다변량분 석결과크레아티닌수치만이통계적으로유의성이있었다 (p=0.048). 결론 : 심부전환자에서조기추적 BNP 는환자의울혈상태에따라다양한변화를보이고환자의예후와연관성이있을가능성이있고크레아티닌수치는환자의예후와연관이있으며 BNP 조기추적검사는급성심부전환자에서유용한임상정보를제공할것으로생각된다. 중심단어 :B-type natriuretic peptide; 울혈성심부전 ; 예후. REFERENCES 1) Muders F, Kromer EP, Griese DP, et al. Evaluation of plasma natriuretric peptides as marker for left ventricular dysfunction. Am Heart J 1997;134:442-9. 2) Kwon SH, On YK, Han DH, et al. Usefulness of B-type natriuretic peptide in congestive heart failure. Korean Circ J 2003;33: 695-700. 3) Shin HS, Sung KC, Jung CH, et al. B-type natriuretic peptide blood concentrations in differential diagnosis of dyspnea and its association to 6 minute walk. Korean Circ J 2003;33:302-10. 4) Cowie MR, Struthers AD, Wood DA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1349-53. 5) Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161-7. 6) McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416-22. 7) Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic peptide in the diagnosis of congestive heart failure in an urgent-care setting. J Am Coll Cardiol 2001;37:379-85. 8) Choi HJ, Hwang SO, Jang YS, Kim H, Lee KH. The usability of blood BNP concentration for differentiating the patients with acute dyspnea. J Korean Soc Emerg Med 2002;2:124. Abstract. 9) Spevack DM, Schwartzbard A. B-type natriuretic peptide measurement in heart failure. Clin Cardiol 2004;27:489-94. 10) Alehagen U, Lindstedt G, Levin LA, Dahlstrom U. Risk of cardiovascular death in elderly patients with possible heart failure: B- type natriuretic peptide (BNP) and the aminoterminal fragment of ProBNP (N-terminal probnp) as prognostic indicators in a 6-year follow-up of a primary care population. Int J Cardiol 2005;100:125-33. 11) Watanabe J, Shiba N, Shinozaki T, et al. Prognostic value of plasma brain natriuretic peptide combined with left ventricular dimensions in predicting sudden death of patients with chronic heart failure. J Card Fail 2005;11:50-5. 12) McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: Framingham study. N Engl J Med 1971;285:1441-6. 13) Yu CM, Lin H, Yang H, Kong SL, Zhang Q, Lee SW. Progression of systolic abnormalities in patients with isolated diastolic heart failure and diastolic dysfunction. Circulation 2002;105: 1195-201. 14) Yoo BS, Kim WJ, Jung HS, et al. The clinical experiences of B- type natriuretic peptide blood concentrations for diagnosis in congestive heart failure: the single hospital experience based on the large clinical database. Korean Circ J 2004;34:684-92.
Il-Hyung Chung, et al:early Follow-Up BNP Level and Congestive Status 207 15) Grady KL, Dracup K, Kennedy G, et al. Team management of patients with heart failure: a statement for healthcare professionals from the Cardiovascular Nursing Council of the American Heart Association. Circulation 2000;102:2443-56. 16) Maisel AS. Use of BNP levels in monitoring hospitalized heart failure patients with heart failure. Heart Fail Rev 2003;8:339-44. 17) Yoo BS, Jung HS, Kim JY, et al. The clinical value of brain natriuretic peptide (BNP) level monitoring after acute exacerbation in congestive heart failure patients. Heart Fail Rev 2004;10: S51. Abstract. 18) Kazanegra R, Cheng V, Garcia A, et al. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail 2001;7:21-9. 19) Lee SC, Stevens TL, Sandberg SM, et al. The potential of brain natriuretic peptide as a biomarker for New York Heart Association class during the outpatient treatment of heart failure. J Card Fail 2002;8:149-54. 20) Bayes-Genis A, Santalo-Bel M, Zapico-Muniz E, et al. N-terminal probrain natriuretic peptide (NT-proBNP) in the emergency diagnosis and in-hospital monitoring of patients with dyspnea and ventricular dysfunction. Eur J Heart Fail 2004;6:301-8. 21) Logeart D, Thabut G, Jourdain P, et al. Predischarge B-type natriuretic peptide assay for identifying patients at high risk of readmission after decompensated heart failure. J Am Coll Cardiol 2004;43:635-41. 22) Gackowski A, Isnard R, Golmard JL, et al. Comparison of echocardiography and plasma B-type natriuretic peptide for monitoring the response to treatment in acute heart failure. Eur Heart J 2004;25:1788-96. 23) Latini R, Masson S, Anand I, et al. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val- HeFT). Circulation 2002;106:2454-8. 24) Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation 2003;107:1278-83. 25) Knebel F, Schimke I, Pliet K, et al. NT-ProBNP in acute heart failure: correlation with invasively measured hemodynamic parameters during recompensation. J Card Fail 2005;11(Suppl): S38-41. 26) Berger R, Huelsman M, Strecker K, et al. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392-7. 27) Bettencourt P, Ferreira A, Dias P, et al. Predictors of prognosis in patients with stable mild to moderate heart failure. J Card Fail 2000;6:306-13. 28) Selvais PL, Robert A, Ahn S, et al. Direct comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure. J Card Fail 2000;6:201-7. 29) Cheng V, Kazanerga R, Garcia A, et al. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol 2001;37:386-91. 30) Fonarow GC, Adams KF Jr, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005;293:572-80.