許東旭,張海鋒,李新立

(南京醫(yī)科大學(xué)第一附屬醫(yī)院 心血管內(nèi)科,南京 210029)

2017年4月,美國(guó)心臟協(xié)會(huì)(American Heart Association,AHA)發(fā)布了關(guān)于生物標(biāo)志物在心衰預(yù)防,評(píng)估以及管理中的作用的科學(xué)聲明,主要目的是總結(jié)現(xiàn)存文獻(xiàn)為當(dāng)前可用生物標(biāo)志物的效用提供指導(dǎo)[1].

1 生物標(biāo)志物的定義

1998年,美國(guó)國(guó)家健康所的工作組將生物標(biāo)志物定義為:一種可以被客觀測(cè)量的用來(lái)反應(yīng)生理、病理或者藥理過(guò)程的具有生物學(xué)意義的標(biāo)志物[2].此后,生物標(biāo)志物的定義不斷更新,但其要點(diǎn)未變,即一種有效的生物標(biāo)志物必須具有以下特點(diǎn):能夠快速精確地測(cè)定、重復(fù)性好、經(jīng)濟(jì)性、反應(yīng)疾病的病理生理過(guò)程、指導(dǎo)臨床決策.

2 生物標(biāo)志物在心衰中的分類

根據(jù)在心衰發(fā)生的病理生理過(guò)程中發(fā)揮的作用不同,心衰的生物標(biāo)志物大致可分為以下幾類.

(1)神經(jīng)內(nèi)分泌激素.當(dāng)機(jī)體內(nèi)環(huán)境穩(wěn)態(tài)被打破的時(shí)候,神經(jīng)內(nèi)分泌系統(tǒng),如腎素-血管緊張素-醛固酮系統(tǒng)、交感神經(jīng)系統(tǒng),會(huì)被激活.盡管神經(jīng)內(nèi)分泌激素介導(dǎo)的血管收縮、水鈉潴留在短時(shí)間內(nèi)發(fā)揮了積極作用,但長(zhǎng)時(shí)間的激活會(huì)增加心臟的負(fù)荷,引起心肌重構(gòu),最終導(dǎo)致心衰的發(fā)生[3].總之,血液中神經(jīng)內(nèi)分泌激素的水平可以反映疾病的嚴(yán)重程度,可以作為心衰的生物標(biāo)志物.

(2)細(xì)胞外基質(zhì).當(dāng)心肌遭受到損傷或者負(fù)荷增加的時(shí)候,心臟就會(huì)發(fā)生大小、形狀、功能進(jìn)行性改變的心肌重構(gòu)過(guò)程.心肌重構(gòu)在心衰的發(fā)生、發(fā)展過(guò)程中發(fā)揮了重要的作用.心肌重構(gòu)過(guò)程中,除了心肌細(xì)胞,細(xì)胞外基質(zhì)也發(fā)生了明顯的改變.細(xì)胞外基質(zhì)重構(gòu)后,可以在血液中檢測(cè)到相關(guān)的分子,如膠原代謝產(chǎn)物、促進(jìn)纖維化的細(xì)胞因子和基質(zhì)重構(gòu)酶等[4-5].

(3)炎癥調(diào)節(jié)因子.組織損傷后,激活的炎癥反應(yīng)可以發(fā)揮保護(hù)機(jī)體的作用,但長(zhǎng)時(shí)間的炎癥反應(yīng)會(huì)破壞心臟的結(jié)構(gòu)和功能.在炎癥過(guò)程中大量涌入血液中的炎癥調(diào)節(jié)因子可以作為有效的生物標(biāo)志物來(lái)評(píng)估心衰的風(fēng)險(xiǎn),揭示心衰的病理過(guò)程.目前,已被證實(shí)有效的生物標(biāo)志物有:腫瘤壞死因子(tumor necrosis factor-α,TNF-α)、白介素1(interleukin-1,IL-1)、白介素6(interleukin-6,IL-6)、生長(zhǎng)分化因子15(growth diあerential factor-15,GDF-15)、C反應(yīng)蛋白(C-reaction protein,CRP)、可溶性致癌抑制因子2(soluble suppression of tumorigenicity 2,sST2)和半乳糖凝集素3(galectin-3,Gal-3)[6-11].

(4)細(xì)胞損傷、應(yīng)力分子.在心衰發(fā)生的過(guò)程中,神經(jīng)內(nèi)分泌系統(tǒng)的激活、炎癥反應(yīng)、氧化應(yīng)激都會(huì)導(dǎo)致心肌細(xì)胞的損傷,而細(xì)胞損傷破裂后會(huì)釋放出肌絲蛋白,如肌鈣蛋白T(troponin T,TnT)、肌鈣蛋白I(troponin I,TnI).此外,當(dāng)心臟容量負(fù)荷或者壓力負(fù)荷增加的時(shí)候,心臟舒張末壓也會(huì)升高,從而促使心肌細(xì)胞分泌B型鈉利尿肽(B-type natriuretic peptide,BNP)、N末端B型鈉利尿肽(N-terminal pro-BNP,NT-proBNP)釋放入血[12-14].血液中上述細(xì)胞損傷、應(yīng)力分子的增加與心衰的發(fā)生、發(fā)展均具有明顯的相關(guān)性.

(6)其他生物標(biāo)志物.MicroRNAs(miRNAs)是一類非編碼的短RNA序列,通過(guò)結(jié)合mRNA的3′端非編碼區(qū)發(fā)揮調(diào)節(jié)基因表達(dá)的作用.MicroRNAs在血液中穩(wěn)定存在,而且已有眾多研究表明它們是冠心病、心梗、高血壓、糖尿病、心肌炎和心衰等疾病潛在的生物標(biāo)志物[15].

3 生物標(biāo)志物在預(yù)測(cè)心衰發(fā)生中的作用

心衰的發(fā)生與年齡具有密切的相關(guān)性,年齡越大,心衰的發(fā)病率越高[16].影響心衰的因素較多,因此預(yù)測(cè)心衰的發(fā)生相對(duì)比較困難.盡管如此,通過(guò)幾十年的研究,人們還是找到了一些具有潛在價(jià)值的生物標(biāo)志物.

(1)鈉利尿肽.美國(guó)的弗雷明漢心臟病研究中心(Framingham Heart Study,FHS)認(rèn)為,BNP、尿蛋白肌酐比可以預(yù)測(cè)心衰的發(fā)生[17].另有研究表明,在初始水平較低的老年人中,NT-proBNP升高大于25%與心臟肌鈣蛋白T(cardiac troponin T,cTnT)升高大于50%是發(fā)生心臟收縮功能障礙、心衰和心血管死亡的重要危險(xiǎn)因素[18].在預(yù)防腎臟和血管終末期病變(prevention of renal and vascular end-stage disease,PREVEND)研究中,共找到了13種預(yù)測(cè)新發(fā)心衰風(fēng)險(xiǎn)的生物標(biāo)志物,其中包括NT-proBNP[19-20].雖然它們都屬于鈉利尿肽家族,但BNP、NT-proBNP相比心鈉素(atrial natriuretic peptide,ANP)和NT-proANP更具有預(yù)測(cè)價(jià)值[21],這是因?yàn)锳NP是事先儲(chǔ)存在心房肌細(xì)胞的顆粒中,而BNP是心室肌細(xì)胞在壓力負(fù)荷增加時(shí)快速合成的.

(2)肌鈣蛋白.50%～80%無(wú)癥狀的心血管疾病患者中,血液中心臟肌鈣蛋白(cardiac troponin,cTn)的水平都超過(guò)了正常范圍[22-23].較高水平的cTn與心衰的危險(xiǎn)因素,如糖尿病、肥厚型心肌病、慢性腎臟病,均具有一定的相關(guān)性[22,24-25].相比于預(yù)測(cè)未來(lái)發(fā)生心肌缺血性事件的可能性,血液中cTn的增高更能反映新發(fā)心衰的風(fēng)險(xiǎn)[23].

(3)腎功能不全的指標(biāo).越來(lái)越多的證據(jù)表明,腎功能不全的指標(biāo),如血肌酐、胱抑素C尿蛋白肌酐比,都是新發(fā)心衰強(qiáng)有力的預(yù)測(cè)因子[17,26].但是,還需進(jìn)一步的對(duì)比試驗(yàn)來(lái)明確哪種指標(biāo)能夠更好地發(fā)揮預(yù)測(cè)作用.

(4)炎癥因子:Gal-3,sST2,GDF-15.在FHS研究中,Gal-3被認(rèn)為是具有預(yù)測(cè)心衰發(fā)生價(jià)值的指標(biāo)[27].雖然PREVEND的總體研究沒(méi)有表明Gal-3的預(yù)測(cè)價(jià)值,但是在具有高危風(fēng)險(xiǎn)人群的亞組分析中得到了陽(yáng)性的結(jié)果[19].此外,在平均隨訪11年的3 428名患者中發(fā)現(xiàn),sST2,GDF-15同樣具有新發(fā)心衰的預(yù)測(cè)意義[27],但也有研究得出了陰性的結(jié)果[28].總體來(lái)說(shuō),以上這些生物標(biāo)志物定會(huì)在預(yù)測(cè)心衰發(fā)生的模型中發(fā)揮作用.

(5)其他生物標(biāo)志物.其他一些生物標(biāo)志物也被證實(shí)能夠預(yù)測(cè)心衰的發(fā)生,如社區(qū)動(dòng)脈硬化風(fēng)險(xiǎn)(atherosclerosis risk in communities,ARIC)研究中的銅藍(lán)蛋白[29],Health ABC(health,aging,and body composition)研究中的IL-6,TNF-α和CRP[30].

4 生物標(biāo)志物在心衰治療決策中的作用

(1)反應(yīng)血流動(dòng)力學(xué).急性心衰患者經(jīng)過(guò)住院治療后,血流動(dòng)力學(xué)、臨床癥狀體征都會(huì)發(fā)生明顯的改變,且這些改變往往都能反映在生物標(biāo)志物的變化上,其中最具特征的就是鈉利尿肽水平的變化.決定鈉利尿肽從心肌細(xì)胞釋放的首要因素就是心肌應(yīng)力,有效的心衰治療會(huì)降低心肌應(yīng)力,從而使鈉利尿肽的水平下降[12].有文獻(xiàn)報(bào)道,急性心衰經(jīng)過(guò)有效治療后,鈉利尿肽的水平會(huì)下降25%～40%[31-33].急性心衰患者的cTn水平往往是升高的.隨著有效治療的開(kāi)始,肌鈣蛋白的水平也會(huì)逐步地下降[34-36].另有研究表明,急性心衰經(jīng)過(guò)短期治療后,患者血液中的sST2發(fā)生了動(dòng)態(tài)的改變,sST2下降20%以上預(yù)示著患者具有良好的預(yù)后[37-38].

(2)反應(yīng)腎功能.早期的觀察性研究表明,在20%～40%的急性心衰患者的治療過(guò)程中,腎功能會(huì)發(fā)生惡化,而且與預(yù)后具有相關(guān)性[39].在反應(yīng)腎功能惡化的生物標(biāo)志物中,研究較多的是血肌酐水平,但實(shí)驗(yàn)結(jié)果卻不盡相同[40-43].胱抑素C是一種腎小球率過(guò)濾的指標(biāo),因?yàn)椴皇荏w重、蛋白攝入量的影響,所以能比肌酐更敏感地反映腎功能.但是,目前的研究尚未明確胱抑素C能夠指導(dǎo)急性心衰的治療[44-45].此外,還有許多具有潛在價(jià)值的生物標(biāo)志物,如中性粒細(xì)胞明膠酶相關(guān)脂質(zhì)運(yùn)載蛋白、腎損傷分子1、N-乙酰-β-D-葡萄糖苷酶、IL-18[46-47].

(3)反應(yīng)預(yù)后.通過(guò)監(jiān)測(cè)心衰患者在住院期間的生物標(biāo)志物水平變化,理論上可以幫助醫(yī)生決定患者是否達(dá)到出院的指征以及出院后隨訪的頻率.目前相關(guān)的研究主要集中在鈉利尿肽.早期的研究表明,不管是出院時(shí)心衰患者的鈉利尿肽水平還是住院期間鈉利尿肽下降的水平,都可以用來(lái)預(yù)測(cè)心衰患者出院后的預(yù)后[31,33].此外,充血性心衰和肺動(dòng)脈導(dǎo)管插入術(shù)的有效性評(píng)估研究(evaluation study of congestive heart failure and pulmonary artery catheterization eあectiveness,ESCAPE)、心衰住院患者有組織啟動(dòng)救生治療項(xiàng)目(organized program to initiate lifesaving treatment in hospitalized patients with heart failure,OPTIMIZE-HF)等表明,出院時(shí)的BNP水平更有預(yù)測(cè)患者預(yù)后的價(jià)值[48-49].但是,上述結(jié)果仍需在隨機(jī)對(duì)照試驗(yàn)中進(jìn)一步加以驗(yàn)證,從而獲得更高的證據(jù)等級(jí).

5 結(jié)束語(yǔ)

流行病學(xué)資料預(yù)測(cè)全球心衰的發(fā)病率將會(huì)在接下來(lái)的幾十年進(jìn)一步增加,因此更為有效的診斷、治療手段的出現(xiàn)迫在眉睫,其中能夠預(yù)測(cè)心衰發(fā)生、指導(dǎo)心衰治療決策的生物標(biāo)志物正在經(jīng)歷較大的發(fā)展.本工作結(jié)合2017年AHA發(fā)表的科學(xué)聲明歸納總結(jié)了目前在診治心衰中發(fā)揮作用的生物標(biāo)志物,包括神經(jīng)內(nèi)分泌激素,如腎素-血管緊張素-醛固酮系統(tǒng)激素、交感神經(jīng)系統(tǒng)激素;細(xì)胞外基質(zhì),如膠原代謝產(chǎn)物、基質(zhì)重構(gòu)酶;炎癥調(diào)節(jié)因子,如TNF-α,IL-1,IL-6,GDF-15,CRP,sST2,Gal-3;細(xì)胞損傷和應(yīng)力分子,如TnT,TnI,BNP,NT-proBNP;其他生物標(biāo)志物,如MicroRNAs等.越來(lái)越多的證據(jù)表明,上述生物標(biāo)志物在預(yù)測(cè)心衰發(fā)生和指導(dǎo)臨床工作者在心衰治療的決策過(guò)程中發(fā)揮了重要的作用.隨著對(duì)心衰發(fā)生的病理生理過(guò)程研究的更加深入,新的、更有效的生物標(biāo)志物必將被發(fā)現(xiàn),并在心衰的預(yù)防、評(píng)估和管理過(guò)程中發(fā)揮重要作用.

[1]CHOW S L,MAISEL A S,ANAND I,et al.Role of biomarkers for the prevention,assessment,and management of heart failure:a scientif i c statement from the American heart association[J].Circulation,2017,135:1054-1091.

[2]BIOMARKERS DEFINITIONS WORKING GROUP.Biomarkers and surrogate endpoints:preferred def i nitions and conceptual framework[J].Clinical Pharmacology&Therapeutics,2001,69(3):89-95.

[3]FRANCIS G S,BENEDICT C,JOHNSTONE D E,et al.Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure.a substudy of the Studies of Left Ventricular Dysfunction(SOLVD)[J].Circulation,1990,82(5):1724-1729.

[4]LOPEZ B,GONZALEZ A,QUEREjETA R,et al.The use of collagen-derived serum peptides for the clinical assessment of hypertensive heart disease[J].Journal of Hypertension,2005,23(8):1445-1451.

[5]SPINALE F G,ZILE M R.Integrating the myocardial matrix into heart failure recognition and management[J].Circulation Research,2013,113(6):725-738.

[6]HARTUPEE J,MANN D L.Positioning of inf l ammatory biomarkers in the heart failure landscape[J].Journal of Cardiovascular Translational Research,2013,6(4):485-492.

[7]KAkkAR R,LEE R T.The IL-33/ST2 pathway:therapeutic target and novel biomarker[J].Nature Reviews Drug Discovery,2008,7(10):827-840.

[8]LIU Y H,D’AMBROSIO M,LIAO T D,et al.N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3,a mammalian adhesion/growthregulatory lectin[J].American Journal of Physiology Heart&Circulatory Physiology,2008,296(2):404-412.

[9]SHARMA U C,POkHAREL S,VAN BRAkEL T J,et al.Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction[J].Circulation,2004,110(19):3121-3128.

[10]DE BOER R A,VOORS A A,MUNTENDAM P,et al.Galectin-3:a novel mediator of heart failure development and progression[J].European Journal of Heart Failure,2009,11(9):811-817.

[11]YU L,RUIFROk W P,MEISSNER M,et al.Genetic and pharmacological inhibition of galectin-3 prevents cardiac remodeling by interfering with myocardial f i brogenesis[J].Circulation:Heart Failure,2013,6(1):107-117.

[12]IWANAGA Y,NISHI I,FURUICHI S,et al.B-type natriuretic peptide strongly ref l ects diastolic wall stress in patients with chronic heart failure:comparison between systolic and diastolic heart failure[J].Journal of American College of Cardiology,2006,47(4):742-748.

[13]NAkAGAWA O,OGAWA Y,ITOH H,et al.Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy.Evidence for brain natriuretic peptide as an“emergency”cardiac hormone against ventricular overload[J].the Journal Clinical Investigation,1995,96(3):1280-1287.

[14]YASUE H,YOSHIMURA M,SUMIDA H,et al.Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure[J].Circulation,1994,90(1):195-203.

[15]TIjSEN A J,PINTO Y M,CREEMERS E E.Circulating microRNAs as diagnostic biomarkers for cardiovascular diseases[J].American Journal of Physiology Heart&Circulatory Physiology,2012,303(9):1085-1095.

[16]YANCY C W,JESSUP M,BOZkURT B,et al.2013 ACCF/AHA guideline for the management of heart failure:a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines[J].Journal of the American College of Cardiology,2013,62(16):147-239.

[17]VELAGALETI R S,GONA P,LARSON M G,et al.A multimarker approach for the prediction of heart failure incidence in the community[J].Circulation,2010,122(17):1700-1706.

[18]GLICk D,DE FILIPPI C R,CHRISTENSON R,et al.Long-term trajectory of two unique cardiac biomarkers and subsequent left ventricular structural pathology and risk of incident heart failure in community-dwelling older adults at low baseline risk[J].JACC:Heart Failure,2013,1(4):353-360.

[19]BROUWERS F P,VAN GILST W H,DAMMAN K,et al.Clinical risk stratif i cation optimizes value of biomarkers to predict new-onset heart failure in a community-based cohort[J].Circulation Heart Failure,2014,7(5):723-731.

[20]BROUWERS F P,DE BOER R A,VAN DER HARST P,et al.Incidence and epidemiology of new onset heart failure with preserved vs.reduced ejection fraction in a community-based cohort:11-year follow-up of PREVEND[J].European Heart Journal,2013,34(19):1424-1431.

[21]MCkIE P M,CATALIOTTI A,SANGARALINGHAM S J,et al.Predictive utility of atrial,N-terminal pro-atrial,and N-terminal pro-B-type natriuretic peptides for mortality and cardiovascular events in the general community:a 9-year follow-up study[J].Mayo Clinic Proceedings,2011,86(12):1154-1160.

[22]DE FILIPPI C R,DE LEMOS J A,CHRISTENSON R H,et al.Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults[J].JAMA,2010,304(22):2494-2502.

[23]SAUNDERS J T,NAMBI V,DE LEMOS J A,et al.Cardiac troponin T measured by a highly sensitive assay predicts coronary heart disease,heart failure,and mortality in the Atherosclerosis Risk in Communities Study[J].Circulation,2011,123(13):1367-1376.

[24]DANIELS L B,LAUGHLIN G A,CLOPTON P,et al.Minimally elevated cardiac troponin T and elevated N-terminal pro-B-type natriuretic peptide predict mortality in older adults:results from the Rancho Bernardo Study[J].Journal of American College of Cardiology,2008,52(6):450-459.

[25]WALLACE T W,ABDULLAH S M,DRAZNER M H,et al.Prevalence and determinants of troponin T elevation in the general population[J].Circulation,2006,113(16):1958-1965.

[26]LAM C S,LYASS A,KRAIGHER-KRAINER E,et al.Cardiac dysfunction and noncardiac dysfunction as precursors of heart failure with reduced and preserved ejection fraction in the community[J].Circulation,2011,124(1):24-30.

[27]WANG T J,WOLLERT K C,LARSON M G,et al.Prognostic utility of novel biomarkers of cardiovascular stress:the Framingham Heart Study[J].Circulation,2012,126(13):1596-1604.

[28]HUGHES M F,APPELBAUM S,HAVULINNA A S,et al.ST2 may not be a useful predictor for incident cardiovascular events,heart failure and mortality[J].Heart,2014,100(21):1715-1721.

[29]DADU R T,DODGE R,NAMBI V,et al.Ceruloplasmin and heart failure in the atherosclerosis risk in communities study[J].Circulation Heart Failure,2013,6(5):936-943.

[30]KALOGEROPOULOS A,GEORGIOPOULOU V,PSATY B M,et al.Inf l ammatory markers and incident heart failure risk in older adults:the health ABC(health,aging,and body composition)study[J].Journal of the American College of Cardiology,2010,55(19):2129-2137.

[31]BETTENCOURT P,AZEVEDO A,PIMENTA J,et al.N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients[J].Circulation,2004,110(15):2168-2174.

[32]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].Journal of Cardiac Failure,2001,7(1):21-29.

[33]LOGEART D,THABUT G,JOURDAIN P,et al.Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure[J].Journal of American College of Cardiology,2004,43(4):635-641.

[34]DEL CARLO C H,PEREIRA-BARRETTO A C,CASSARO-STRUNZ C,et al.Serial measure of cardiac troponin T levels for prediction of clinical events in decompensated heart failure[J].Journal of Cardiac Failure,2004,10(1):43-48.

[35]METRA M,NODARI S,PARRINELLO G,et al.The role of plasma biomarkers in acute heart failure.Serial changes and independent prognostic value of NT-proBNP and cardiac troponin-T[J].European Journal of Heart Failure,2007,9(8):776-786.

[36]METRA M,COTTER G,DAVISON B A,et al.Eあect of serelaxin on cardiac,renal,and hepatic biomarkers in the Relaxin in Acute Heart Failure(RELAX-AHF)development program:correlation with outcomes[J].Journal of the American College of Cardiology,2013,61(2):196-206.

[37]BOISOT S,BEEDE J,ISAkSON S,et al.Serial sampling of ST2 predicts 90-day mortality following destabilized heart failure[J].Journal of Cardiac Failure,2008,14(9):732-738.

[38]BREIDTHARDT T,BALMELLI C,TWERENBOLD R,et al.Heart failure therapy-induced early ST2 changes may oあer long-term therapy guidance[J].Journal of Cardiac Failure,2013,19(12):821-828.

[39]BUTLER J,FORMAN D E,ABRAHAM W T,et al.Relationship between heart failure treatment and development of worsening renal function among hospitalized patients[J].American Heart Journal,2004,147(2):331-338.

[40]METRA M,DAVISON B,BETTARI L,et al.Is worsening renal function an ominous prognostic sign in patients with acute heart failure?The role of congestion and its interaction with renal function[J].Circulation:Heart Failure,2012,5(1):54-62.

[41]GREENE S J,GHEORGHIADE M,VADUGANATHAN M,et al.Haemoconcentration,renal function,and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction:insights from the EVEREST trial[J].European Journal of Heart Failure,2013,15(12):1401-1411.

[42]TESTANI J M,CHEN J,MC CAULEY B D,et al.Potential eあects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival[J].Circulation,2010,122(3):265-272.

[43]FELkER G M,LEE K L,BULL D A,et al.Diuretic strategies in patients with acute decompensated heart failure[J].New England Journal of Medicine,2011,364(9):797-805.

[44]TANG W H,DUPONT M,HERNANDEZ A F,et al.Comparative assessment of short-term adverse events in acute heart failure with cystatin C and other estimates of renal function:results from the ASCEND-HF trial[J].JACC:Heart Failure,2015,3(1):40-49.

[45]CHOW S L,O’BARR S A,PENG J,et al.Renal function and neurohormonal changes following intravenous infusions of nitroglycerin versus nesiritide in patients with acute decompensated heart failure[J].Journal of Cardiac Failure,2011,17(3):181-187.

[46]BELLOMO R,KELLUM J A,RONCO C.Acute kidney injury[J].Lancet,2012,380(9843):756-766.

[47]CRUZ D N,SONI S,SLAVIN L,et al.Biomarkers of cardiac and kidney dysfunction in cardiorenal syndromes[J].Contributions to Nephrology,2010,165:83-92.

[48]KOCIOL R D,HORTON J R,FONAROW G C,et al.Admission,discharge,or change in B-type natriuretic peptide and long-term outcomes:data from organized program to initiate lifesaving treatment in hospitalized patients with heart failure(OPTIMIZE-HF)linked to medicare claims[J].Circulation Heart Failure,2011,4(5):628-636.

[49]O’CONNOR C M,HASSELBLAD V,MEHTA R H,et al.Triage after hospitalization with advanced heart failure:the ESCAPE(evaluation study of congestive heart failure and pulmonary artery catheterization eあectiveness)risk model and discharge score[J].Journal of the American College of Cardiology,2010,55(9):872-878.