非ST段抬高急性冠狀動(dòng)脈綜合征患者血漿NT_ProBNP與G

1、作者單位:100029北京首都醫(yī)科大學(xué)附屬北京安貞醫(yī)院-北京市心肺血管疾病研究所心內(nèi)科通信作者:劉文嫻,E-mail :liuwenxian DOI :10.3969/j.issn.1007-5062.2011.02.005·臨床論著·非ST 段抬高急性冠狀動(dòng)脈綜合征患者血漿NT-ProBNP 與GRACE 危險(xiǎn)分層的關(guān)系趙晗劉文嫻摘要目的:探討非ST 段抬高急性冠狀動(dòng)脈綜合征(NSTE-ACS 患者血漿N-末端腦鈉肽前體(NT-proBNP 與全球急性冠狀動(dòng)脈事件注冊(cè)(GRACE 評(píng)分以及危險(xiǎn)分層的關(guān)系。方法:入選126例在我院住院的NSTE-ACS 患者,其中不穩(wěn)定性心

2、絞痛(UA 84例,非ST 段抬高心肌梗死(NSTEMI 42例。入院后測(cè)定血漿NT-proBNP 濃度,進(jìn)行常規(guī)實(shí)驗(yàn)室檢測(cè)及超聲心動(dòng)圖檢查。采用GRACE 評(píng)分標(biāo)準(zhǔn)對(duì)患者進(jìn)行風(fēng)險(xiǎn)評(píng)估,計(jì)算GRACE 積分并進(jìn)行危險(xiǎn)分層。分析NSTE-ACS 患者血漿NT-ProBNP 濃度與GRACE 積分及分層的關(guān)系。結(jié)果:NSTEMI 組LgNT-ProBNP 高于UA 組(2.870.57vs.(2.110.56,P <0.001,NSTEMI 組GRACE 分值高于UA 組(141.4533.13vs.(102.7330.44,P <0.001。將所有NSTE-ACS 患者作GRACE

3、危險(xiǎn)分層,高危組LgNT-ProBNP 顯著高于中危組、低危組(P <0.001。NT-ProBNP 按照四分位數(shù)分組后,P 75以上組GRACE 分值分別高于另外3個(gè)四分位數(shù)組(P <0.001,P 75以上組中GRACE 高危百分比高于P 75以下組(P <0.001。UA 及NSTEMI 組的LgNT-ProBNP 與其GRACE 分值均有正相關(guān)關(guān)系(r =0.40,P <0.001vs.r =0.52,P <0.001,全部NSTE-ACS 患者的LgNT-ProBNP 與GRACE 分值也呈正相關(guān)關(guān)系(r =0.59,P <0.001。結(jié)論:NST

4、E-ACS 患者NT-ProBNP 水平越高,GRACE 積分越高,NT-ProBNP 的檢測(cè)在對(duì)NSTE-ACS 患者進(jìn)行早期、快速的危險(xiǎn)度分層方面有著獨(dú)特的價(jià)值。關(guān)鍵詞腦鈉肽;急性冠狀動(dòng)脈綜合征;GRACE 評(píng)分;風(fēng)險(xiǎn)評(píng)估中圖分類(lèi)號(hào)R 541.4文獻(xiàn)標(biāo)識(shí)碼A文章編號(hào)1007-5062(201102-111-05Relationship between N-terminal pro-brain natriuretic peptide and GRACE risk stratification in non-ST-segment elevation acute coronary syndrom

5、e ZHAO Han ,LIU Wenxian Department of Cardiology ,Capital Medical University affiliated Beijing Anzhen Hospital ,Beijing Institute of Heart ,Lung and Blood VesselDiseases ,Beijing 100029,ChinaAbstract Objective :To study the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP le

6、vel and global registry of acute coronary events (GRACE risk score as well as risk stratification in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS .Methods :We enrolled 126pa-tients with non-ST-segment elevation acute coronary syndrome that admitted in our hospital ,84pati

7、ents with UA and 42patients with NSTEMI.All the patients received plasma NT-ProBNP measurement ,routine laboratory tests and echocardiography examination.The GRACE risk score were used for risk assessment.Analyze the re-lationship between NT-proBNP level and GRACE risk score as well as risk stratifi

8、cation in patients with NSTE-ACS.Results :The LgNT-proBNP of NSTEMI group was higher than UA group (2.870.57vs.2.110.56,P <0.001,as well as GRACE risk score (141.4533.13vs.102.7330.44,P <0.001.After GRACE risk stratification ,LgNT-ProBNP of high-risk group was the highest among the three group

9、s (P <0.001.Accord-ing to NT-ProBNP levels ,patients were stratified into four groups by quartile.Compared with lowest ,second ,and third quartiles ,the GRACE risk score was the highest in the fourth quartile (P <0.001.Patients with NT-ProBNP level above the 75percentile had higher ratio of hi

10、gh risk than patients with NT-ProBNP under the 75percentile (P <0.001.The LgNT-ProBNP in patients with UA and NSTEMI had positive correlation withtheir GRACE risk score(r=0.40,P<0.001vs.r=0.52,P<0.001,LgNT-ProBNP of all NSTE-ACS pa-tients had positive correlation with GRACE risk score(r=0.5

11、9,P<0.001.Conclusion:Increased GRACE risk score was associated with increased NT-ProBNP level in NSTE-ACS patients,measurement of NT-ProBNP is valuable for risk stratification in patients with NSTE-ACS.Key wordsBrain natriuretic peptide;Acute coronary syndrome;Global registry of acute coronary e-

12、vents risk score;Risk assessment非ST段抬高急性冠狀動(dòng)脈綜合征(NSTE-ACS包括非ST段抬高心肌梗死(NSTEMI和不穩(wěn)定性心絞痛(UA,其臨床表現(xiàn)類(lèi)型多樣,冠狀動(dòng)脈病變程度及血流動(dòng)力學(xué)變化不一,預(yù)后差異大1,因此對(duì)NSTE-ACS患者早期、快速的危險(xiǎn)分層,對(duì)決定治療策略有著重要的意義。全球急性冠狀動(dòng)脈事件注冊(cè)(GRACE風(fēng)險(xiǎn)評(píng)分系統(tǒng)是目前常用的對(duì)NSTE-ACS患者進(jìn)行風(fēng)險(xiǎn)評(píng)估的方法,其不足是缺少能夠反映神經(jīng)體液因素及血流動(dòng)力學(xué)變化的指標(biāo)。腦鈉鈦/N-末端腦鈉鈦前體(BNP/NT-ProBNP是一項(xiàng)可反映機(jī)體神經(jīng)體液因素及血流動(dòng)力學(xué)變化的生物標(biāo)記物,近年來(lái)

13、隨著對(duì)心肌缺血可致心肌收縮力減弱、室壁張力增加,從而促使心肌細(xì)胞大量釋放BNP的新認(rèn)識(shí)2-4,有關(guān)BNP/NT-ProBNP在冠心病尤其是急性冠狀動(dòng)脈綜合征(ACS患者中的應(yīng)用逐漸受到關(guān)注。本文探討在NSTE-ACS患者中,NT-ProBNP與GRACE風(fēng)險(xiǎn)評(píng)分系統(tǒng)的相關(guān)性。資料與方法研究對(duì)象:連續(xù)入選2009年9月至2010年5月在我院心內(nèi)科住院的NSTE-ACS患者。入選標(biāo)準(zhǔn)為:年齡在18 85歲之間的男性或非妊娠女性;臨床癥狀、心電圖、心肌標(biāo)志物檢測(cè)符合2007年美國(guó)心臟病學(xué)會(huì)(ACC/美國(guó)心臟協(xié)會(huì)(AHA發(fā)布的UA/NSTEMI診斷和治療指南1;冠狀動(dòng)脈造影明確有1支或多支血管狹窄50

14、%。排除標(biāo)準(zhǔn):ST段抬高心肌梗死;既往有心肌梗死病史;單純由于冠狀動(dòng)脈痙攣所致變異性心絞痛;慢性心力衰竭(心衰,射血分?jǐn)?shù)<45%;心臟瓣膜病,心肌炎,心肌病;未加控制的心律失常,如持續(xù)心房顫動(dòng)(房顫等,起搏器植入術(shù)后;合并嚴(yán)重肝、腎、肺疾病、感染、惡性腫瘤、嚴(yán)重貧血、甲亢及自身免疫病等情況。本研究共入選患者126例,其中UA患者84例,NSTE-MI患者42例。研究方法:NT-ProBNP的檢測(cè)及基線(xiàn)資料記錄:患者入院后采集靜脈血,用肝素管抗凝,立即送檢,使用我院檢驗(yàn)科Dimension自動(dòng)檢測(cè)系統(tǒng)測(cè)定血漿NT-proBNP濃度,可測(cè)量范圍10 30000 ng/L;同步進(jìn)行常規(guī)實(shí)驗(yàn)室檢

15、查,入院后24h內(nèi)行超聲心動(dòng)圖檢查;記錄患者基線(xiàn)資料。風(fēng)險(xiǎn)評(píng)估方法:患者入院后依據(jù)臨床資料進(jìn)行風(fēng)險(xiǎn)評(píng)估,采用GRACE評(píng)分標(biāo)準(zhǔn)中的8項(xiàng)指標(biāo)(年齡、心率、動(dòng)脈收縮壓、血肌酐、心電圖ST段變化、心功能Killip分級(jí)、心肌標(biāo)志物升高及入院時(shí)心臟驟停計(jì)算患者的積分之和。其中GRACE積分88為低危,89 118為中危,118為高危。統(tǒng)計(jì)學(xué)方法:采用SPSS13.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。連續(xù)變量作正態(tài)性檢驗(yàn),符合正態(tài)分布或經(jīng)數(shù)據(jù)轉(zhuǎn)換后符合正態(tài)分布者以均數(shù)標(biāo)準(zhǔn)差表示;非正態(tài)分布資料采用中位數(shù)(M及四分位數(shù)間距(P25,P75表示。對(duì)計(jì)量資料進(jìn)行組間比較時(shí)采用t檢驗(yàn)及單因素方差分析;分類(lèi)變量采用2檢驗(yàn);非參

16、數(shù)檢驗(yàn)使用秩和檢驗(yàn)。雙變量之間作線(xiàn)性相關(guān)分析。檢驗(yàn)水準(zhǔn)=0.05,取P<0.05為差異有統(tǒng)計(jì)學(xué)意義。結(jié)果UA組與NSTEMI組的NT-ProBNP及GRACE評(píng)分組間比較:2組患者的基線(xiàn)資料見(jiàn)表1。本研究顯示,2組患者的NT-ProBNP為非正態(tài)分布,作以10為底的對(duì)數(shù)轉(zhuǎn)換后LgNT-ProBNP符合正態(tài)分布,作兩獨(dú)立樣本的t檢驗(yàn),組間差異具有統(tǒng)計(jì)學(xué)意義(P< 0.001,NSTEMI組的LgNT-ProBNP高于UA組。2組患者的GRACE積分均符合正態(tài)分布,作兩獨(dú)立樣本的t檢驗(yàn),組間差異具有統(tǒng)計(jì)學(xué)意義(P<0.001, NSTEMI組的GRACE積分值高于UA組(表1。2

17、.NSTE-ACS患者NT-ProBNP水平與GRACE 危險(xiǎn)分層的關(guān)系:(1將所有NSTE-ACS患者根據(jù)GRACE積分進(jìn)行危險(xiǎn)分層(低危組28例,中危組38例,高危組60例,分析對(duì)比各組NT-ProBNP水平發(fā)現(xiàn)高危組LgNT-ProBNP顯著高于中危組(P< 0.001及低危組(P<0.001,而中危組和低危組的LgNT-ProBNP組間差異無(wú)統(tǒng)計(jì)學(xué)意義(P=0.116,表2。(2將所有NSTE-ACS患者按照血漿表1UA 組與NSTEMI 組資料珋x s ,M (P 25,P 75,n (%項(xiàng)目UA 組(n =84NSTEMI 組(n =42P 值年齡/(歲59.8810.

18、5961.4011.570.462男性50(59.532(76.20.064吸煙47(56.023(54.80.899高血壓64(76.230(71.40.563糖尿病27(32.116(38.10.506血脂異常64(76.226(61.90.094心率/(次/min 70.3211.5373.8113.040.128血紅蛋白/(g /L 141.4215.09140.1716.470.672血小板/(109/L 203.0951.81198.0858.830.626肌酐/(mol /L 79.7719.4393.2121.820.001尿酸/(mmol /L 365.23110.39367

19、.90126.690.903LDL-C /(mmol /L 2.780.92 2.780.760.990HDL-C /(mmol /L 1.090.27 1.130.570.640糖化血紅蛋白/(% 5.90(5.60,6.88 5.95(5.60,7.200.617CK-MB /(U /L 14.235.8568.5762.94<0.001cTnI /(ng /L 0.02(0.00,0.077.01(2.24,14.59<0.001左心室舒末內(nèi)徑/(mm 48.00(45.00,51.0048.00(45.75,53.000.514射血分?jǐn)?shù)/(%64.677.4256.9810

20、.93<0.001E /A 比值0.75(0.61,0.920.81(0.65,1.140.334NT-ProBNP /(ng /L 142.90(50.15,283.70747.05(320.15,1792.38(LgNT-ProBNP 2.110.56 2.870.57<0.001GRACE 積分102.7330.44141.4533.13<0.001注:LDL-C :低密度脂蛋白;HDL-C :高密度脂蛋白;CK-MB :肌酸激酶;cTcl :心肌鈣蛋白表2不同GRACE 分層之間比較M (Q R ,珋x s 項(xiàng)目低危組(n =28中危組(n =38高危組(n =60N

21、T-ProBNP 90.80(48.03,197.85144.10(49.55,422.83497.30(177.20,1175.08LgNT-ProBNP1.920.512.150.592.700.61表3GRACE 四分位積分比較(珋x s 項(xiàng)目P 25P 26-P 50P 51-P 75>P 75GRACE 積分91.1621.83109.2534.82114.6633.04147.7129.66NT-ProBNP 水平進(jìn)行四分位數(shù)分組,分別為P 25組(n =31、P 26 P 50組(n =32、P 51 P 75組(n =32、>P 75組(n =31,比較各組的GRA

22、CE 積分情況。研究發(fā)現(xiàn)P 25組的GRACE 積分顯著低于P 26 P 50組(P =0.019、P 51 P 75組(P =0.003、>P 75組(P <0.001;>P 75組的GRACE 積分顯著高于P 25組(P <0.001、P 26 P 50組(P <0.001、P 51 P 75組(P <0.001;但P 26 P 50組與P 51 P 75組的GRACE 積分組間差異無(wú)統(tǒng)計(jì)學(xué)意義(P =0.477,表3。進(jìn)一步將P 25組、P 26 P 50組、P 51 P 75組合并通稱(chēng)為P 75以下組,研究發(fā)現(xiàn)P 75以上組中GRACE 高危者有26

23、例,占83.9%;而P 75以下組中,GRACE 高危者34例,占35.8%,對(duì)比2組中GRACE 高?；颊叩谋壤M間差異具有統(tǒng)計(jì)學(xué)意義(P <0.001,P 75以上組的GRACE 高危百分比高于P 75以下組。(3UA 及NSTEMI 患者NT-proBNP 水平與GRACE 風(fēng)險(xiǎn)評(píng)分的相關(guān)性分析:將UA 組與NSTE-MI 組患者的LgNT-ProBNP ,與其GRACE 評(píng)分,分別作雙變量相關(guān)分析,得到UA 組及NSTEMI 組的LgNT-ProBNP 與GRACE 評(píng)分的相關(guān)系數(shù)分別為0.40(P <0.001及0.52(P <0.001,2組的LgNT-ProBN

24、P 與GRACE 評(píng)分均呈正相關(guān)關(guān)系。而所有NSTE-ACS (n =126患者的LgNT-ProBNP 與GRACE 評(píng)分亦呈正相關(guān)關(guān)系(r =0.59,P <0.001,圖1。討論目前對(duì)于NSTE-ACS 患者的常用風(fēng)險(xiǎn)評(píng)估方法主要有Braunwald 分層、ACC /AHA 分層、心肌梗死中的溶栓治療(TIMI 風(fēng)險(xiǎn)評(píng)分、PURSUIT 評(píng)分及GRACE 風(fēng)險(xiǎn)評(píng)分等。其中GRACE 風(fēng)險(xiǎn)評(píng)分在預(yù)測(cè)住院期間及出院后6個(gè)月、1年的心血管事件風(fēng) 圖1LgNT-ProBNP與GRACE評(píng)分相關(guān)性險(xiǎn)方面要優(yōu)于其他方法5-8。然而,GRACE評(píng)分與其他風(fēng)險(xiǎn)評(píng)估方法一樣未納入能夠反映機(jī)體神經(jīng)體液

25、因素及血流動(dòng)力學(xué)變化的指標(biāo),限制了其在錯(cuò)綜復(fù)雜的臨床情況中的應(yīng)用。BNP是一種神經(jīng)激素,當(dāng)心肌細(xì)胞受到牽張時(shí),BNP前體(ProBNP快速釋放入血,裂解為活性形式的BNP和無(wú)生物活性的NT-ProBNP。BNP具有增加腎小球?yàn)V過(guò)率,抑制Na+重吸收、利尿、松弛血管平滑肌、減輕心臟負(fù)荷及抑制交感系統(tǒng)等生物活性。NT-ProBNP雖無(wú)生物活性,但由于其與BNP 為等摩爾釋放9,且半衰期較長(zhǎng),體外穩(wěn)定性強(qiáng),不受晝夜變化、飲食及日?；顒?dòng)等影響,使其更易于在臨床中應(yīng)用。國(guó)內(nèi)外多項(xiàng)研究10-14發(fā)現(xiàn),BNP/NT-ProBNP既與ACS預(yù)后相關(guān),又與冠狀動(dòng)脈病變程度相關(guān),體現(xiàn)了其在評(píng)價(jià)ACS危險(xiǎn)度方面的獨(dú)

26、特意義。本研究以NSTE-ACS患者為研究對(duì)象,并且所有入選患者排除了多種影響NT-ProBNP釋放的因素,基線(xiàn)資料中,UA及NSTEMI患者的年齡、男性比例、吸煙、合并高血壓、血脂異常、糖尿病的比例、心率、血紅蛋白、血小板、尿酸、LDL-C、HDL-C、糖化血紅蛋白、左心室舒末內(nèi)徑、E/A比值的組間差異均無(wú)統(tǒng)計(jì)學(xué)意義(P>0.05,NSTEMI組的肌酐雖高于UA組,但本研究已經(jīng)排除了慢性腎功能不全對(duì)NT-ProBNP的影響,因此并無(wú)臨床意義,2組患者的基線(xiàn)情況具有可比性。UA組射血分?jǐn)?shù)高于NSTEMI 組,這與NSTEMI患者心肌存在部分壞死,對(duì)心功能有一定的影響有關(guān)。本研究結(jié)果發(fā)現(xiàn),

27、NSTEMI組的LgNT-ProBNP高于UA組(2.870.57vs.(2.110.56,P<0.001,與文獻(xiàn)15報(bào)道一致。本研究結(jié)果也顯示NSTEMI組的GRACE評(píng)分分值高于UA組(141.4533.13vs.(102.7330.44,P<0.001,這主要與NSTEMI患者心肌標(biāo)志物升高以及部分患者Killip分級(jí)在II級(jí)以上致使GRACE分值較高有關(guān)。關(guān)于BNP的釋放機(jī)制,近年來(lái)有多項(xiàng)研究2-4發(fā)現(xiàn),心肌缺血可致使心肌收縮力減弱、室壁張力增加,從而促使心肌細(xì)胞大量釋放BNP。另外,有動(dòng)物實(shí)驗(yàn)和臨床研究16-17表明,一過(guò)性的缺血缺氧可直接誘導(dǎo)BNP基因的轉(zhuǎn)錄增快和表達(dá)的

28、增加,ACS 患者心肌缺血可刺激BNP分泌。這說(shuō)明ACS患者心肌缺血越重、血流動(dòng)力學(xué)越不穩(wěn)定,BNP/NT-ProBNP升高越明顯。本研究將全部NSTE-ACS患者作GRACE危險(xiǎn)分層后發(fā)現(xiàn),高危組患者lgNT-ProBNP高于中低危組,高度的臨床風(fēng)險(xiǎn)與NT-ProBNP的明顯升高是相關(guān)的;而中危組和低危組的LgNT-ProBNP的差異無(wú)統(tǒng)計(jì)學(xué)意義,考慮可能與這2組患者病例數(shù)較少有關(guān)。將全部NSTE-ACS患者按照血漿NT-ProBNP水平進(jìn)行四分位數(shù)分組后發(fā)現(xiàn),NT-ProBNP水平在P75以上組的GRACE積分分別高于其余3個(gè)四分位數(shù)組,且P75以上組GRACE高?；颊叩谋壤哂赑75以下

29、組,提示NT-ProBNP處于較高水平者,其GRACE 分值亦較高,在危險(xiǎn)層級(jí)中級(jí)別較高,更應(yīng)引起我們的關(guān)注。以往在有關(guān)BNP/NT-ProBNP與臨床常用ACS危險(xiǎn)分層之間的相關(guān)性研究中,曹雅旻等18研究發(fā)現(xiàn),ACS患者血漿NT-ProBNP濃度與疾病嚴(yán)重程度存在良好的相關(guān)性,隨著B(niǎo)raunwald分級(jí)增高, UA患者血漿NT-ProBNP濃度逐漸增高,這與我們的研究是一致的。另外,經(jīng)過(guò)相關(guān)性分析我們發(fā)現(xiàn),無(wú)論在UA還是NSTEMI患者中,LgNT-ProBNP與其GRACE積分均有良好的正相關(guān)關(guān)系,而且對(duì)于所有未分組的NSTE-ACS患者,LgNT-ProBNP與GRACE積分也存在良好的

30、正相關(guān)關(guān)系,體現(xiàn)了NT-ProBNP與GRACE 積分的一致性,可輔助臨床醫(yī)生對(duì)疾病的嚴(yán)重程度進(jìn)行快速判斷。蘇洪亮等19報(bào)道,血漿BNP水平與TIMI危險(xiǎn)積分呈正相關(guān)(r=0.71,P<0.05,隨著TIMI危險(xiǎn)積分評(píng)分值增加,患者血漿BNP亦逐漸升高,隨訪(fǎng)期主要心血管事件發(fā)生率也增多(P <0.05,這從另一方面提示著B(niǎo)NP/NT-ProBNP與現(xiàn)有ACS風(fēng)險(xiǎn)評(píng)估方法之間有著良好的一致性。綜上所述,NT-ProBNP是一項(xiàng)能夠快速檢測(cè)、性質(zhì)穩(wěn)定、可反映神經(jīng)體液因素及血流動(dòng)力學(xué)變化的生物標(biāo)志物,在對(duì)NSTE-ACS患者的危險(xiǎn)度分層方面有著獨(dú)特的價(jià)值,可對(duì)臨床現(xiàn)有危險(xiǎn)分層方法進(jìn)行補(bǔ)充

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