《生物標志物在心衰預防、評估以及管理中的作用》解讀

許東旭,張海鋒,李新立

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

2017年4月,美國心臟協(xié)會(American Heart Association,AHA)發(fā)布了關于生物標志物在心衰預防,評估以及管理中的作用的科學聲明,主要目的是總結現(xiàn)存文獻為當前可用生物標志物的效用提供指導[1].

1 生物標志物的定義

1998年,美國國家健康所的工作組將生物標志物定義為:一種可以被客觀測量的用來反應生理、病理或者藥理過程的具有生物學意義的標志物[2].此后,生物標志物的定義不斷更新,但其要點未變,即一種有效的生物標志物必須具有以下特點:能夠快速精確地測定、重復性好、經(jīng)濟性、反應疾病的病理生理過程、指導臨床決策.

2 生物標志物在心衰中的分類

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

(1)神經(jīng)內(nèi)分泌激素.當機體內(nèi)環(huán)境穩(wěn)態(tài)被打破的時候,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),會被激活.盡管神經(jīng)內(nèi)分泌激素介導的血管收縮、水鈉潴留在短時間內(nèi)發(fā)揮了積極作用,但長時間的激活會增加心臟的負荷,引起心肌重構,最終導致心衰的發(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重程度,可以作為心衰的生物標志物.

(2)細胞外基質(zhì).當心肌遭受到損傷或者負荷增加的時候,心臟就會發(fā)生大小、形狀、功能進行性改變的心肌重構過程.心肌重構在心衰的發(fā)生、發(fā)展過程中發(fā)揮了重要的作用.心肌重構過程中,除了心肌細胞,細胞外基質(zhì)也發(fā)生了明顯的改變.細胞外基質(zhì)重構后,可以在血液中檢測到相關的分子,如膠原代謝產(chǎn)物、促進纖維化的細胞因子和基質(zhì)重構酶等[4-5].

(3)炎癥調(diào)節(jié)因子.組織損傷后,激活的炎癥反應可以發(fā)揮保護機體的作用,但長時間的炎癥反應會破壞心臟的結構和功能.在炎癥過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志物來評估心衰的風險,揭示心衰的病理過程.目前,已被證實有效的生物標志物有: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)、生長分化因子15(growth diあerential factor-15,GDF-15)、C反應蛋白(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)細胞損傷、應力分子.在心衰發(fā)生的過程中,神經(jīng)內(nèi)分泌系統(tǒng)的激活、炎癥反應、氧化應激都會導致心肌細胞的損傷,而細胞損傷破裂后會釋放出肌絲蛋白,如肌鈣蛋白T(troponin T,TnT)、肌鈣蛋白I(troponin I,TnI).此外,當心臟容量負荷或者壓力負荷增加的時候,心臟舒張末壓也會升高,從而促使心肌細胞分泌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].血液中上述細胞損傷、應力分子的增加與心衰的發(fā)生、發(fā)展均具有明顯的相關性.

(6)其他生物標志物.MicroRNAs(miRNAs)是一類非編碼的短RNA序列,通過結合mRNA的3′端非編碼區(qū)發(fā)揮調(diào)節(jié)基因表達的作用.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志物[15].

3 生物標志物在預測心衰發(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,因此預測心衰的發(fā)生相對比較困難.盡管如此,通過幾十年的研究,人們還是找到了一些具有潛在價值的生物標志物.

(1)鈉利尿肽.美國的弗雷明漢心臟病研究中心(Framingham Heart Study,FHS)認為,BNP、尿蛋白肌酐比可以預測心衰的發(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因素[18].在預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種預測新發(fā)心衰風險的生物標志物,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更具有預測價值[21],這是因為ANP是事先儲存在心房肌細胞的顆粒中,而BNP是心室肌細胞在壓力負荷增加時快速合成的.

(2)肌鈣蛋白.50%～80%無癥狀的心血管疾病患者中,血液中心臟肌鈣蛋白(cardiac troponin,cTn)的水平都超過了正常范圍[22-23].較高水平的cTn與心衰的危險因素,如糖尿病、肥厚型心肌病、慢性腎臟病,均具有一定的相關性[22,24-25].相比于預測未來發(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)心衰的風險[23].

(3)腎功能不全的指標.越來越多的證據(jù)表明,腎功能不全的指標,如血肌酐、胱抑素C尿蛋白肌酐比,都是新發(fā)心衰強有力的預測因子[17,26].但是,還需進一步的對比試驗來明確哪種指標能夠更好地發(fā)揮預測作用.

(4)炎癥因子:Gal-3,sST2,GDF-15.在FHS研究中,Gal-3被認為是具有預測心衰發(fā)生價值的指標[27].雖然PREVEND的總體研究沒有表明Gal-3的預測價值,但是在具有高危風險人群的亞組分析中得到了陽性的結果[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)心衰的預測意義[27],但也有研究得出了陰性的結果[28].總體來說,以上這些生物標志物定會在預測心衰發(fā)生的模型中發(fā)揮作用.

(5)其他生物標志物.其他一些生物標志物也被證實能夠預測心衰的發(fā)生,如社區(qū)動脈硬化風險(atherosclerosis risk in communities,ARIC)研究中的銅藍蛋白[29],Health ABC(health,aging,and body composition)研究中的IL-6,TNF-α和CRP[30].

4 生物標志物在心衰治療決策中的作用

(1)反應血流動力學.急性心衰患者經(jīng)過住院治療后,血流動力學、臨床癥狀體征都會發(fā)生明顯的改變,且這些改變往往都能反映在生物標志物的變化上,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胞釋放的首要因素就是心肌應力,有效的心衰治療會降低心肌應力,從而使鈉利尿肽的水平下降[12].有文獻報道,急性心衰經(jīng)過有效治療后,鈉利尿肽的水平會下降25%～40%[31-33].急性心衰患者的cTn水平往往是升高的.隨著有效治療的開始,肌鈣蛋白的水平也會逐步地下降[34-36].另有研究表明,急性心衰經(jīng)過短期治療后,患者血液中的sST2發(fā)生了動態(tài)的改變,sST2下降20%以上預示著患者具有良好的預后[37-38].

(2)反應腎功能.早期的觀察性研究表明,在20%～40%的急性心衰患者的治療過程中,腎功能會發(fā)生惡化,而且與預后具有相關性[39].在反應腎功能惡化的生物標志物中,研究較多的是血肌酐水平,但實驗結果卻不盡相同[40-43].胱抑素C是一種腎小球率過濾的指標,因為不受體重、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能夠指導急性心衰的治療[44-45].此外,還有許多具有潛在價值的生物標志物,如中性粒細胞明膠酶相關脂質(zhì)運載蛋白、腎損傷分子1、N-乙酰-β-D-葡萄糖苷酶、IL-18[46-47].

(3)反應預后.通過監(jiān)測心衰患者在住院期間的生物標志物水平變化,理論上可以幫助醫(yī)生決定患者是否達到出院的指征以及出院后隨訪的頻率.目前相關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,都可以用來預測心衰患者出院后的預后[31,33].此外,充血性心衰和肺動脈導管插入術的有效性評估研究(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救生治療項目(organized program to initiate lifesaving treatment in hospitalized patients with heart failure,OPTIMIZE-HF)等表明,出院時的BNP水平更有預測患者預后的價值[48-49].但是,上述結果仍需在隨機對照試驗中進一步加以驗證,從而獲得更高的證據(jù)等級.

5 結束語

流行病學資料預測全球心衰的發(fā)病率將會在接下來的幾十年進一步增加,因此更為有效的診斷、治療手段的出現(xiàn)迫在眉睫,其中能夠預測心衰發(fā)生、指導心衰治療決策的生物標志物正在經(jīng)歷較大的發(fā)展.本工作結合2017年AHA發(fā)表的科學聲明歸納總結了目前在診治心衰中發(fā)揮作用的生物標志物,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;細胞外基質(zhì),如膠原代謝產(chǎn)物、基質(zhì)重構酶;炎癥調(diào)節(jié)因子,如TNF-α,IL-1,IL-6,GDF-15,CRP,sST2,Gal-3;細胞損傷和應力分子,如TnT,TnI,BNP,NT-proBNP;其他生物標志物,如MicroRNAs等.越來越多的證據(jù)表明,上述生物標志物在預測心衰發(fā)生和指導臨床工作者在心衰治療的決策過程中發(fā)揮了重要的作用.隨著對心衰發(fā)生的病理生理過程研究的更加深入,新的、更有效的生物標志物必將被發(fā)現(xiàn),并在心衰的預防、評估和管理過程中發(fā)揮重要作用.

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