《生物标志物在心衰预防、评估以及管理中的作用》解读

许东旭,张海锋,李新立

(南京医科大学第一附属医院 心血管内科,南京 210029)

2017年4月,美国心脏协会(American Heart Association,AHA)发布了关于生物标志物在心衰预防,评估以及管理中的作用的科学声明,主要目的是总结现存文献为当前可用生物标志物的效用提供指导[1].

1 生物标志物的定义

1998年,美国国家健康所的工作组将生物标志物定义为:一种可以被客观测量的用来反应生理、病理或者药理过程的具有生物学意义的标志物[2].此后,生物标志物的定义不断更新,但其要点未变,即一种有效的生物标志物必须具有以下特点:能够快速精确地测定、重复性好、经济性、反应疾病的病理生理过程、指导临床决策.

2 生物标志物在心衰中的分类

根据在心衰发生的病理生理过程中发挥的作用不同,心衰的生物标志物大致可分为以下几类.

(1)神经内分泌激素.当机体内环境稳态被打破的时候,神经内分泌系统,如肾素-血管紧张素-醛固酮系统、交感神经系统,会被激活.尽管神经内分泌激素介导的血管收缩、水钠潴留在短时间内发挥了积极作用,但长时间的激活会增加心脏的负荷,引起心肌重构,最终导致心衰的发生[3].总之,血液中神经内分泌激素的水平可以反映疾病的严重程度,可以作为心衰的生物标志物.

(2)细胞外基质.当心肌遭受到损伤或者负荷增加的时候,心脏就会发生大小、形状、功能进行性改变的心肌重构过程.心肌重构在心衰的发生、发展过程中发挥了重要的作用.心肌重构过程中,除了心肌细胞,细胞外基质也发生了明显的改变.细胞外基质重构后,可以在血液中检测到相关的分子,如胶原代谢产物、促进纤维化的细胞因子和基质重构酶等[4-5].

(3)炎症调节因子.组织损伤后,激活的炎症反应可以发挥保护机体的作用,但长时间的炎症反应会破坏心脏的结构和功能.在炎症过程中大量涌入血液中的炎症调节因子可以作为有效的生物标志物来评估心衰的风险,揭示心衰的病理过程.目前,已被证实有效的生物标志物有:肿瘤坏死因子(tumor necrosis factor-α,TNF-α)、白介素1(interleukin-1,IL-1)、白介素6(interleukin-6,IL-6)、生长分化因子15(growth diあerential factor-15,GDF-15)、C反应蛋白(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)细胞损伤、应力分子.在心衰发生的过程中,神经内分泌系统的激活、炎症反应、氧化应激都会导致心肌细胞的损伤,而细胞损伤破裂后会释放出肌丝蛋白,如肌钙蛋白T(troponin T,TnT)、肌钙蛋白I(troponin I,TnI).此外,当心脏容量负荷或者压力负荷增加的时候,心脏舒张末压也会升高,从而促使心肌细胞分泌B型钠利尿肽(B-type natriuretic peptide,BNP)、N末端B型钠利尿肽(N-terminal pro-BNP,NT-proBNP)释放入血[12-14].血液中上述细胞损伤、应力分子的增加与心衰的发生、发展均具有明显的相关性.

(6)其他生物标志物.MicroRNAs(miRNAs)是一类非编码的短RNA序列,通过结合mRNA的3′端非编码区发挥调节基因表达的作用.MicroRNAs在血液中稳定存在,而且已有众多研究表明它们是冠心病、心梗、高血压、糖尿病、心肌炎和心衰等疾病潜在的生物标志物[15].

3 生物标志物在预测心衰发生中的作用

心衰的发生与年龄具有密切的相关性,年龄越大,心衰的发病率越高[16].影响心衰的因素较多,因此预测心衰的发生相对比较困难.尽管如此,通过几十年的研究,人们还是找到了一些具有潜在价值的生物标志物.

(1)钠利尿肽.美国的弗雷明汉心脏病研究中心(Framingham Heart Study,FHS)认为,BNP、尿蛋白肌酐比可以预测心衰的发生[17].另有研究表明,在初始水平较低的老年人中,NT-proBNP升高大于25%与心脏肌钙蛋白T(cardiac troponin T,cTnT)升高大于50%是发生心脏收缩功能障碍、心衰和心血管死亡的重要危险因素[18].在预防肾脏和血管终末期病变(prevention of renal and vascular end-stage disease,PREVEND)研究中,共找到了13种预测新发心衰风险的生物标志物,其中包括NT-proBNP[19-20].虽然它们都属于钠利尿肽家族,但BNP、NT-proBNP相比心钠素(atrial natriuretic peptide,ANP)和NT-proANP更具有预测价值[21],这是因为ANP是事先储存在心房肌细胞的颗粒中,而BNP是心室肌细胞在压力负荷增加时快速合成的.

(2)肌钙蛋白.50%～80%无症状的心血管疾病患者中,血液中心脏肌钙蛋白(cardiac troponin,cTn)的水平都超过了正常范围[22-23].较高水平的cTn与心衰的危险因素,如糖尿病、肥厚型心肌病、慢性肾脏病,均具有一定的相关性[22,24-25].相比于预测未来发生心肌缺血性事件的可能性,血液中cTn的增高更能反映新发心衰的风险[23].

(3)肾功能不全的指标.越来越多的证据表明,肾功能不全的指标,如血肌酐、胱抑素C尿蛋白肌酐比,都是新发心衰强有力的预测因子[17,26].但是,还需进一步的对比试验来明确哪种指标能够更好地发挥预测作用.

(4)炎症因子:Gal-3,sST2,GDF-15.在FHS研究中,Gal-3被认为是具有预测心衰发生价值的指标[27].虽然PREVEND的总体研究没有表明Gal-3的预测价值,但是在具有高危风险人群的亚组分析中得到了阳性的结果[19].此外,在平均随访11年的3 428名患者中发现,sST2,GDF-15同样具有新发心衰的预测意义[27],但也有研究得出了阴性的结果[28].总体来说,以上这些生物标志物定会在预测心衰发生的模型中发挥作用.

(5)其他生物标志物.其他一些生物标志物也被证实能够预测心衰的发生,如社区动脉硬化风险(atherosclerosis risk in communities,ARIC)研究中的铜蓝蛋白[29],Health ABC(health,aging,and body composition)研究中的IL-6,TNF-α和CRP[30].

4 生物标志物在心衰治疗决策中的作用

(1)反应血流动力学.急性心衰患者经过住院治疗后,血流动力学、临床症状体征都会发生明显的改变,且这些改变往往都能反映在生物标志物的变化上,其中最具特征的就是钠利尿肽水平的变化.决定钠利尿肽从心肌细胞释放的首要因素就是心肌应力,有效的心衰治疗会降低心肌应力,从而使钠利尿肽的水平下降[12].有文献报道,急性心衰经过有效治疗后,钠利尿肽的水平会下降25%～40%[31-33].急性心衰患者的cTn水平往往是升高的.随着有效治疗的开始,肌钙蛋白的水平也会逐步地下降[34-36].另有研究表明,急性心衰经过短期治疗后,患者血液中的sST2发生了动态的改变,sST2下降20%以上预示着患者具有良好的预后[37-38].

(2)反应肾功能.早期的观察性研究表明,在20%～40%的急性心衰患者的治疗过程中,肾功能会发生恶化,而且与预后具有相关性[39].在反应肾功能恶化的生物标志物中,研究较多的是血肌酐水平,但实验结果却不尽相同[40-43].胱抑素C是一种肾小球率过滤的指标,因为不受体重、蛋白摄入量的影响,所以能比肌酐更敏感地反映肾功能.但是,目前的研究尚未明确胱抑素C能够指导急性心衰的治疗[44-45].此外,还有许多具有潜在价值的生物标志物,如中性粒细胞明胶酶相关脂质运载蛋白、肾损伤分子1、N-乙酰-β-D-葡萄糖苷酶、IL-18[46-47].

(3)反应预后.通过监测心衰患者在住院期间的生物标志物水平变化,理论上可以帮助医生决定患者是否达到出院的指征以及出院后随访的频率.目前相关的研究主要集中在钠利尿肽.早期的研究表明,不管是出院时心衰患者的钠利尿肽水平还是住院期间钠利尿肽下降的水平,都可以用来预测心衰患者出院后的预后[31,33].此外,充血性心衰和肺动脉导管插入术的有效性评估研究(evaluation study of congestive heart failure and pulmonary artery catheterization eあectiveness,ESCAPE)、心衰住院患者有组织启动救生治疗项目(organized program to initiate lifesaving treatment in hospitalized patients with heart failure,OPTIMIZE-HF)等表明,出院时的BNP水平更有预测患者预后的价值[48-49].但是,上述结果仍需在随机对照试验中进一步加以验证,从而获得更高的证据等级.

5 结束语

流行病学资料预测全球心衰的发病率将会在接下来的几十年进一步增加,因此更为有效的诊断、治疗手段的出现迫在眉睫,其中能够预测心衰发生、指导心衰治疗决策的生物标志物正在经历较大的发展.本工作结合2017年AHA发表的科学声明归纳总结了目前在诊治心衰中发挥作用的生物标志物,包括神经内分泌激素,如肾素-血管紧张素-醛固酮系统激素、交感神经系统激素;细胞外基质,如胶原代谢产物、基质重构酶;炎症调节因子,如TNF-α,IL-1,IL-6,GDF-15,CRP,sST2,Gal-3;细胞损伤和应力分子,如TnT,TnI,BNP,NT-proBNP;其他生物标志物,如MicroRNAs等.越来越多的证据表明,上述生物标志物在预测心衰发生和指导临床工作者在心衰治疗的决策过程中发挥了重要的作用.随着对心衰发生的病理生理过程研究的更加深入,新的、更有效的生物标志物必将被发现,并在心衰的预防、评估和管理过程中发挥重要作用.

[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.