대한진단검사의학회지 : 제 23 권제 2 호 23 Korean J Lab Med 23; 23: 82-7 임상화학 혈중 N-Terminal Pro-Brain Type Natriuretic Peptide 농도와심초음파검사지표와의상관관계 김신영 김정호 김동수 1 권오헌 연세대학교의과대학진단검사의학교실, 내과학교실 1 Correlation of N-Terminal Pro-Brain Type Natriuretic Peptide Level and Echocardiographic Parameters Sinyoung Kim, M.D., Jeong-Ho Kim, M.D., Dongsoo Kim, M.D. 1, and Oh Hun Kwon, M.D. Departments of Laboratory Medicine and Internal Medicine 1, Yonsei University College of Medicine, Seoul, Korea Background : N-terminal pro-brain type natriuretic peptide (NT-proBNP) has been identified as a promising biochemical marker for congestive heart failure (CHF). Recently, the NT-proBNP assay using electrochemiluminescence method has been developed. We evaluated clinical utilities of the NT-proBNP assay and its relationship with echocardiographic parameters. Methods : The NT-proBNP was measured in eighty-four patients who experienced an echocardiographic examination. We compared the NT-proBNP level with several echocardiographic parameters for the left ventricular systolic function and cardiac chamber dimensions. Results : The NT-proBNP level was significantly increased as with a decreasing left ventricular ejection fraction (LVEF). It was also positively correlated with the left ventricular mass, left ventricular mass index, left ventricular end diastolic dimension, and left ventricular end systolic dimension. In patients with left atrial and ventricular enlargement, the mean NT-proBNP level was 7418.4±9937.7 pg/ml, which was significantly elevated compared with 354.3±749.8 pg/ml in patients with normal cardiac chamber dimensions (P<.1). Conclusions : The NT-proBNP showed a significant correlation with echocardiographic parameters, especially for the systolic function and chamber enlargement. Therefore, the NT-proBNP seemed to be a new and promising alternative biochemical marker for CHF. (Korean J Lab Med 23; 23: 82-7) Key Words : N-terminal pro-brain type natriuretic peptide, Echocardiography, Echocardiographic parameter, Congestive heart failure 서 울혈성심부전의빈도는고혈압, 부정맥및허혈성심장질환의이환율이증가함에따라증가하고있으며이환된환자의 5년생존율이 5% 에미치지못하여이로인한사회 경제적인손실 접수 : 22년 9월 11일접수번호 : KJCP168 수정본접수 : 23년 1월 22일교신저자 : 권오헌우 12-752 서울시서대문구신촌동 134 연세대학교의과대학진단검사의학교실전화 : 2-361-5861, Fax: 2-393-332 E-mail : kohkoh@yumc.yonsei.ac.kr 론 이급격히증가하고있다 [1, 2]. 울혈성심부전은조기진단과적절한약물치료를통하여질병의진행을막거나늦출수있으므로울혈성심부전의조기발견은매우중요하다 [3, 4]. 현재울혈성심부전의진단은주로심초음파도 (echocardiography) 에의존하고있으며심초음파도에서측정가능한여러변수중좌심실구혈률 (left ventricular ejection fraction, LVEF) 을대표적인기준으로하고있다 [5]. 그러나심초음파도는시간, 노력, 숙련도가필요한고가의검사로대중적인선별검사로사용하기어려워이를대체할여러가지종류의생화학적지표들이개발되었다. 대표적인울혈성심부전의생화학적지표로나트륨이뇨펩타이드 82
혈중 N-Terminal Pro-Brain Type Natriuretic Peptide 농도와심초음파검사지표와의상관관계 83 (natriuretic peptides) 가있으며 atrial type natriuretic peptide (ANP), N-terminal proanp (NT-proANP), brain type natriuretic peptide (BNP), N-terminal probnp (NT-proB- NP) 등이이에속한다 [6]. 이중에서 ANP는혈중반감기가짧으며, 채혈시의자세나채혈전의약물투여에의해많은영향을받으며실온에서 2-3시간동안만안정하여정확한혈중농도측정이어려운점이있다. 이에비해 NT-proANP, BNP, NTproBNP는반감기가상대적으로길며, 분석전변수에크게영향을받지않고, 실온에서장시간안정하여측정이용이하다. 특히, NT-proBNP는생화학적활성분자인 ANP나 BNP보다분자의크기가크고, 혈중에비교적고농도로존재하여면역분석법을이용한측정에서보다우수한분석능을가진다 [6]. 나트륨이뇨펩타이드의임상적유용성은 BNP가가장활발히연구되었는데, BNP는울혈성심부전의 NYHA 분류와우수한상관관계를보이며, 울혈성심부전의예후와도연관이있고 [7-11], 또한무증상좌심실부전 (asymptomatic LV dysfunction) 과이완기기능장애 (diastolic dysfunction) 의진단에도유용한것으로보고되어있다 [12-14]. NT-proBNP의경우에는 BNP의임상적유용성과비슷하며초기의좌심실부전진단에있어서 BNP보다우수하다는보고가있다 [15, 16]. NT-proBNP는최근전기화학발광면역분석법 (electrochemiluminescence immunoassay) 을이용한자동화장비로측정할수있게되었으며정밀도, 검체종류간의상관성, 일간변동등의평가에서우수한분석능을검증받은바있다 [17]. 이는자동화장비를이용한신속한측정및보고로임상적으로유용하게사용될것으로기대된다. 본연구에서는 NTproBNP를실제로임상적으로적용하기에앞서하나의기초적인자료로써혈중 NT-proBNP 농도와여러가지심초음파도변수와의상관관계를알아보고자하였다. 대상및방법 1. 대상 22년 1월부터 3월까지세브란스병원심장혈관센터에서심초 음파도를실시한환자중좌심실구혈률값에근거하여선택한 84명을대상으로하였다. 이들의진단명으로는관상동맥질환 45 명, 관상동맥질환이없는울혈성심부전 19명, 심장판막질환 6명, 본태성고혈압 4명, 부정맥 2명, 대동맥류 2명, 확장성심근증 2명, 비후성심근증 2명, 심근염 1명, 폐성심 1명이었다. 대상군을좌심실구혈률에따라 1군 (LVEF >71%), 2군 (LVEF 61-7%), 3 군 (LVEF 51-6%), 4군 (LVEF 41-5%), 5군 (LVEF 31-4%), 6군 (LVEF <3%) 으로구분하였으며각군의일반적인특성을 Table 1에정리하였다. 2. 방법대상군에서정맥혈채혈후혈청을분리하였고검사시까지 -7 에서냉동보관하였다. NT-proBNP는 Elecsys 21 (Boehringer Mannheim, Mannheim, Germany) 장비를사용하여전기화학발광면역분석법으로측정하였다. 이방법을이용한혈중 NTproBNP의측정범위는 5-35, pg/ml이다. 이외에크레아티닌은자동생화학분석기기 (Hitachi 747, Hitachi Co., Nagashi, Japan) 를사용하여측정하였다. 심초음파도검사지표는 M형심초음파도를사용하여좌심실구혈률, 수축말기좌심실내경 (left ventricular end systolic dimension, LVESD), 이완말기좌심실내경 (left ventricular end diastolic dimension, LVEDD), 이완말기심실중격두께 (interventricular septal thickness, IVST) 와좌심실후벽두께 (left ventricular posterior wall thickness, PWT) 를측정하였으며세제곱법으로좌심실질량 (left ventricular mass, LVM) 을계산하고신장과체중을이용하여체표면적을구하고이를이용하여좌심실질량지수 (left ventricular mass index, LVMI) 를산출하였다. 위의심초음파도검사지표와혈중 NT-proBNP 농도와의상관성을조사하였으며, 또한대상군을심장비대가없는군, 좌심방비대만있는군, 좌심실비대만있는군과좌심방, 좌심실비대가함께있는군의 4군으로나누어심장비대의정도와혈중 NT-proBNP 농도와의상관성을알아보았다. SPSS (version 1., SPSS Inc., Chicago, IL, USA) 를이용하여좌심실구혈률에따른혈중 NT-proBNP 농도의차이는분 Table 1. Demographic and biochemical characteristics of study population according to left ventricular ejection fraction (LVEF) Group (LVEF) N (M/F)* Age (years) Creatinine (mg/ml) Mean (range) Mea ±SD Range Mean ±SD 1 (>71%) 19 (9 /1) 55.7 (22-81) 233.3±294.1 5.7-1129 1.±.2 2 (61-7%) 2 (11/9) 61.8 (35-77) 323.2±543.3 14.8-23662 1.±.2 3 (51-6%) 15 (7/8) 63.9 (51-76) 518.3±618.5 27.6-289.9±.2 4 (41-5%) 9 (7/2) 6.9 (46-73) 1774.5±152.9 161.-4678 1.±.2 5 (31-4%) 11 (6/5) 68.1 (59-78) 6176.6±7722.9 415.6-22374 1.7±1.1 6 (<3%) 1 (7/3) 58.3 (2-77) 899.1±9832. 1977-35 1.5±1.3 Total 84 (47/37) 61.1 (2-81) 2291.5±5286.7 5.7-35 1.2±.7 *Chi-square test, P>.5. Kruskal-Wallis test, P>.5. Kruskal-Wallis test, P<.1. Mann-Whitney test versus group 1, P<.1.
84 김신영 김정호 김동수외 1 인 Table 2. Characteristics of echocardiographic parameters of study population Group LVM (g)* LVMI (g/m 2 )* LVEDD (mm)* LVESD (mm)* IVST (mm) PWT (mm) Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD Mean ± SD 1 111.1± 28.5 66.4± 13.8 47.8± 6.1 28.8± 4.1 1.2 ± 2.3 9.6 ± 1.7 2 111.2± 2.5 65.6± 12. 48.2± 7.2 32.1± 5.2 1.2 ± 1.4 9.7 ± 1.4 3 129.5± 3.4 75.2± 17.1 52.3± 4.5 37.1± 3.5 9.9 ± 1.6 1. ± 1.4 4 138.2± 37.7 8.7± 2. 51.± 4.2 36.8± 3. 1.7 ± 2.1 1.8 ± 2.1 5 164.5± 65.5 17.1± 48.9 58.7± 6.7 48.4± 5.9 9.8 ± 1.9 1.4 ± 2.6 6 27.8± 67.9 126.7± 41. 71.4± 11.3 63.8± 11. 9. ± 1.3 9.9 ± 1.2 Total 135.8± 51.1 81.8±33. 53.3± 1.1 38.7±12.3 1. ±1.8 1. ±1.7 *Kruskal-Wallis test, P<.1. Mann-Whitney test versus group 1, P<.5. Abbreviations: LVM, left ventricular mass; LVMI, left ventricular mass index; LVEDD, left ventricular end diastolic dimension; LVESD, left ventricular end systolic dimension; IVST, interventricular septal thickness; PWT, left ventricular posterior wall thickness. Table 3. Chamber enlargement and NT-proBNP level N Mean ± SD Range P value* Normal 44 354.3 ± 749.8 5.7-4678 - LAE 12 16.4 ± 92.3 75.7-328.1 LVE 14 438.1 ± 556.4 2.6-19779. LAE & LVE 14 7418.4 ± 9937.7 392.9-35. Total 84 2291.5 ± 5286.7 5.7-35 *P value by Mann-Whitney test versus normal group. Abbreviations: LAE, left atrial enlargement; LVE, left ventricular enlargement. 산분석을시행하였으며, 혈중 NT-proBNP 농도와각심초음파검사지표와의상관분석을하였다. 또한심장비대유무에따른혈중 NT-proBNP 농도의차이를알아보기위하여분산분석을시행하였으며, 좌심실구혈률이각각 6%, 4% 미만인환자를선별하기위한혈중 NT-proBNP 농도의 ROC 분석을시행하였다. 결과좌심실구혈률에근거하여대상군을 6군으로나누었을때각군의나이및성별의분포와혈중크레아티닌농도는통계학적으로유의한차이가없었으나혈중 NT-proBNP 농도는각군간에유의한차이를보였다 (P<.1, Table 1). 각군별심초음파도검사지표중에서좌심실질량, 좌심실질량지수, 이완말기좌심실내경, 수축말기좌심실내경이통계학적으로유의한차이를보였으며 (P<.1, Table 2), 이외의검사지표인이완말기심실중격두께와좌심실후벽두께는차이가없었다 (P>.5, Table 2). 혈중 NT-proBNP 농도는심초음파도검사지표중좌심실구혈률, 좌심실질량, 좌심실질량지수, 이완말기좌심실내경과수축말기좌심실내경은유의한상관관계를보였으나 (Fig. 1) 다른심초음파도검사지표와는상관관계를보이지않았다. 좌심방과좌심실비대를동반한 14명에서의평균혈중 NTproBNP 농도는 7418.4 pg/ml로심장비대가없는 44명의 354.3 pg/ml에비하여유의하게높았을뿐만아니라좌심방비대혹은좌심실비대만을가진대상에비하여도유의하게높은값을보였다 (Table 3). 좌심실구혈률이 6% 미만인환자선별에있어서의혈중 NT-proBNP 농도의임상적유용성을평가하기위하여 ROC 분석을한결과 AUC (area under curve) 가.842이었으며, 좌심실구혈률이 4% 미만인환자를선별하기위한경우 AUC가.947이었다 (Fig. 2). 고찰노년인구의증가와함께심혈관질환을가진환자들도의학적진단및치료기술의발달로과거보다더많이생존할수있게됨에따라울혈성심부전의발생률및유병률이증가되고있는양상이다. 무증상기의울혈성심부전증환자에서의안지오텐신전환효소억제제, 베타차단제및알도스테론길항제의투여를통해질병의악화를예방하며사망률을감소시킬수있으므로울혈성심부전증의조기진단은매우중요하다 [3, 4]. 울혈성심부전증의조기진단방법으로는심초음파도가있으나이는고가의장비와숙련된검사자가필요하여실제적으로선별검사로사용되기는어려운단점이있다. 이에혈중나트륨이뇨펩타이드농도를사용하여울혈성심부전의조기진단에이용하려는시도가지속적으로있었으며최근현장검사 (point-of-care testing, POCT) 장비를이용한혈중 BNP 농도의측정방법이미국식약청 (Food and Drug Administration, FDA) 으로부터공인을받아서임상적인적용단계에이르고있다. 혈중 BNP 농도는울혈성심부전의임상적분류인 NYHA 분류와상관관계가우수하여울혈성심부전의진단에사용될수있을뿐만아니라예후판단과치료효과의판정에도사용될수있다 [7-11]. 나트륨이뇨펩타이드중에서 BNP 이외에도울혈성심부전의생화학적지표로는 ANP, NT-proANP와 NT-proBNP가있으며이에대한연구가꾸준히
혈중 N-Terminal Pro-Brain Type Natriuretic Peptide 농도와심초음파검사지표와의상관관계 85 y=156.1x+1756.8 r=.669 y=47.21x-4121.1 r=.537 2 4 6 8 LVEF 1. 2. 3. LVM (g) y=79.75x-4234.47 r=.62 y=212.75x-945.7 r=.64 5. 1. 15. 2. LVMI 4 6 8 1 LVEDD (mm) Fig. 1. Relationship between NT-proBNP level and echocardographic parameters (P value by two tailed Spearman s correlation). LVEF, left ventricular ejection fraction; LVM, left ventricular mass; LVMI, left ventricular mass index; LVEDD, left ventricular end diastolic dimension. 진행되고있다. 특히 NT-proBNP는건강인의혈중에서 BNP보다고농도로존재한다는것과분자의크기가커서 2개의서로다른항원결정기를가진항체를제작하기쉽다는점에서이론적으로측정하기가쉬운물질로알려져있다 [18]. 또한기존의나트륨이뇨펩타이드의농도측정은방사성면역측정법 (radioimmunoassay, RIA) 이나면역방사선계수측정법 (immunoradiometric assay, IRMA) 을사용하여검사소요시간이길며비용이많이드는단점이있었으나, POCT 장비를이용한 BNP의신속한측정이가능해지면서울혈성심부전의진단에많은도움을주고있다. 본연구에서는전기화학면역발광측정법을사용하여측정한혈중 NT-proBNP 농도와심초음파도검사지표간의상관관계를살펴봄으로써울혈성심부전에서의 NT-proBNP 측정의임상적유용성을알아보고자하였다. 본연구에서는이전의보고 [15, 16, 22] 와마찬가지로울혈성심부전진단의가장기초적인심초음파도검사지표인좌심실구혈률이감소함에따라서혈중 NT-proBNP 농도가증가함을알수있었으며특히좌심실구혈률이 4% 미만일경우에급격히 증가함을알수있었다. 하지만이전의보고와는다른 NT-proB- NP 측정방법을사용하였기때문에절대값을서로비교할수는없었으며신기능의장애시혈중나트륨이뇨펩타이드의농도가증가한다는많은보고 [19-21] 가있으나본연구에서는혈중크레아티닌농도가높은신기능장애환자가없어확인하지못하였다. 또한, 본연구대상에포함되지않은 2명의환자에서는혈중 NTproBNP 농도가각각 23,662, 12,214 pg/ml로증가하였으나좌심실구혈률은 68, 76% 로감소하지않은소견을보였는데, 이는 2명모두에게서심장의수축기능은유지되는반면에중증의심방세동으로인한이완기기능의장애에의하여혈중 NT-proBNP 농도가증가한것으로사료된다. 따라서심방세동을가진환자의혈중 NT-proBNP 검사결과해석시에는주의할필요가있다 [22]. 좌심방이나좌심실의비대여부에따른혈중 NT-proBNP 농도는좌심방과좌심실비대가동반되어있는경우통계학적으로유의하게증가하였으며좌심방이나좌심실비대가단독으로존재할경우에도심장비대가없는대상군에비하여증가하였다. 이는좌심실구혈률이감소함에따라서심초음파도검사지표중좌심
86 김신영 김정호 김동수외 1 인 1. 1..75.75 Sensitivity.5 AUC.842 Sensitivity.5 AUC.947.25.25...25.5.75 1....25.5.75 1. 1-Specificity A 1-Specificity B Fig. 2. Receiver-operating-characteristic (ROC) curves for NT-proBNP to (A): correctly identify patients with impaired LVEF (LVEF<6% according to M-mode echocardiography) and to (B): correctly identify patients with LVEF<4%. AUC, area under curve. 실질량, 좌심실질량지수, 이완말기좌심실내경, 수축말기좌심실내경이증가하는것과같은맥락으로해석할수있다. 또한좌심실질량, 좌심실질량지수, 이완말기좌심실내경, 수축말기좌심실내경이증가할수록혈중 NT-proBNP 농도는증가하였으며이는통계학적으로유의한상관관계를보였다. 또한좌심실구혈률 6% 를기준으로하여 ROC 분석을할경우 AUC가.842로이전의보고에서 BNP, NT-proBNP, NTproANP가각각.75,.67,.69인것에비하여본검사방법을통한혈중 NT-proBNP 농도측정은울혈성심부전에서의임상적유용성이높다고할수있다 [23]. 혈중 NT-proBNP 농도의참고범위는제조사에의하면성별, 연령별차이가존재하여 5세미만의경우남자 88 pg/ml, 여자 152 pg/ml 이하이며, 5세이상의경우남자 227 pg/ml, 여자 334 pg/ml 이하이다. Schulz 등 [24] 은연령의증가에따른 NT-proBNP의증가가관찰되며, 남녀간의차이는없다고보고한반면, BNP가 estrogen에의해여자가남자보다높다는상반된연구 [25] 도있어추후적절한정상참고군에대한논의가이루어진후참고범위의설정에관한연구가이루어져야할것이다. 혈중 NT-proBNP 농도와심초음파검사지표인좌심실구출율, 좌심실질량, 좌심실질량지수, 이완말기좌심실내경, 수축말기좌심실내경과통계학적으로유의한상관관계를보였으며이는혈중 NT-proBNP 농도가울혈성심부전의조기진단에서심초음파의역할을상당부분대체할수있는검사로평가할수있으며울혈성심부전의진단이외의예후추정과치료효과판정에관한추가적인연구가필요할것으로사료된다. 연구에서는전기화학발광면역분석법으로측정한혈중 NT-proB- NP 농도와심초음파도검사지표간의상관관계를살펴보았다. 방법 : 22년 1월부터 3월까지세브란스병원심장혈관센터에서심초음파를시행한환자중에서좌심실구혈률에따라선택한 84명을대상으로하여혈중 NT-proBNP 농도를측정하였으며심초음파검사지표중좌심실구혈률, 수축말기좌심실내경, 이완말기좌심실내경, 이완말기심실중격두께, 좌심실후벽두께, 심장비대여부를조사하였으며좌심실질량과좌심실질량지수를산출하였다. 결과 : 좌심실구혈률이감소함에따라혈중 NT-proBNP농도는통계학적으로유의하게증가하였으며특히 4% 미만일경우급격히증가하였으며, 혈중 NT-proBNP 농도는이외의심초음파검사지표중좌심실질량, 좌심실질량지수, 이완말기좌심실내경, 수축말기좌심실내경과유의한상관관계를보였다. 또한혈중 NT-proBNP 농도는좌심방과좌심실비대가동반되어있는경우심장비대가없는군에비해서통계학적으로유의하게높았다 (7418.4±9937.7 vs. 354.3±749.8 pg/ml, P<.1). 결론 : 전기화학발광면역분석법을이용한혈중 NT-proBNP의측정은심초음파검사지표, 특히좌심실구혈률, 심장비대여부와우수한상관관계를보였으며이는울혈성심부전의생화학적지표로서심초음파검사를부분대체혹은보완할수있는우수한검사로사료된다. 참고문헌 요약배경 : 울혈성심부전의진단, 예후및치료효과판정에사용되는생화학적지표로 NT-proBNP가활발히논의되고있으며, 본 1. Cowie MR, Mosterd A, Wood DA, Deckers JW, Poole-Wilson PA, Sutton GC, et al. The epidemiology of heat failure. Eur Heart J 1997; 18: 28-25. 2. Sharpe N and Doughty R. Epidemiology of heart failure and left ventricular dysfunction. Lancet 1998; 352(S): 3-7.
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