肺高压生化标记物

张锐，荆志成心肺循环中心肺动脉高压生物标记物和预后BiomarkersinPulmonaryArterialHypertension生物标记物？评价临床疗效定义明确的临床终点事件临床终点事件替代指标6分钟步行距离生化标志物......*BiomarkersDefinitionsWorkingGroup.ClinPharmacolTher.2001;69:89-95.NIH*:可以被客观测量并且作为正常生物学过程、发病过程或者对于治疗干预的药理学反响指示某些疾病所致的病理状态下，血清中可测得的含量增高的化学物质。〔体液、外周静脉血……〕生物标记物？疾病诊断和严重程度疗效判定疾病进展预后评估评价重要指标肺动脉高压候选生物标记物

内皮功能障碍:

ET-1、PGI2、

NO

神经体液过度激活:Catecholamines、Renin、

Norepinephrine、Angiotensin血小板/凝血:Thromboxane、Serotonin、

vWF、D-dimer,PAI-1

ET-1andNerohormanalcorrelatewithsurvivalofPPHGalièN,etal.EurJClinInvest1996;26:141.481.00.50.00122436Survival(%)P=0.04—ET-1≥4.3pg/ml----ET-1<4.3pg/mlmonthsBaseYear1Year2Year3Year4Year50.80.60.40.21.0EstimatedSurvival(%)norepinephrine<370ng/mlnorepinephrine=370to500ng/mlnorepinephrine>5000ng/mlNootensM.JACC1995;7:1581-1585.Nerohormonalactivationoccursinpatientswithisolatedrightventricularfailure.TheelevationinendothelinlevelsisconsistentwithiterelaeaseinresponsetoPH.ESC/ERS

GUIDELINESGalièN,etal.EurHeartJ2021;30(20):2493-2537.Brainnatriureticpeptide(BNP)/NT-proBNPWaewickG.EurRespirJ2021;32(2):503-512.Brainnatriureticpeptide(BNP)/NT-proBNPCOOHHPLGGPSSSAYTLRRAPPSSSSSSRRRCRCCCGGGKKKMMDIFLLVVQHPSSSSSSRRRCRCCCGGGKKKMMDIFLLVVQHfurinHPLGGPSSSAYTLRRAPproBNPBNPCOOHNT-proBNPH2NCOOHH2NH2N7710810811107076SchematicofproBNPshowingenzymaticcleavageintobiologicallyactiveBNPandNT-proBNP.Brainnatriureticpeptide(BNP)/NT-proBNPBNPNT-proBNP成分32个氨基酸76个氨基酸生物活性有无来源proBNP裂解proBNP裂解半衰期18min60-120min清除中性内肽酶受体清除、肾脏清除肾脏清除体外室温稳定性4h（采集后马上开始降解）>72h受年龄增长影响+++++可否床旁即时检测是否完成学术论文（篇）137039CHF诊断Cut-off值100pg/ml年龄<75:125pg/ml年龄≥75:450pg/mlBNP：判断右心功能不全血浆BNP浓度与肺动脉高压患者右心室功能不全的程度成比例增加2003001000PlasmaBNPLevels(pg/ml)**†Cont.RVVORVPO210PlasmaBNP/ANPRatio*†Cont.RVVORVPOChangeinBNPinsurvivorstreatedwithprostanoidsBNP：观察药物疗效NagayaN,etal.

Circulation.2000;102:865-870.BaselineplasaminPPHaccordingtoNYNAclass.160012008004000PlasmaBNPLevel(pg/ml)Control(n=15)NYHAII(n=6)NYHAIII(n=42)NYHAIV(n=12)BNP*†‡*†*Time(months)Survivalrate(%)100806040200012243648BNP<150pg/mLBNP≥150pg/mLBaselineBNPFollow-upBNPNagayaN,etal.

Circulation.2000;102:

865-870.BNP：判断预后BNP<180pg/mLBNP≥180pg/mLTime(months)median100806040200012243648Survivalrate(%)medianFijalkowskaA.EurHeartJSupplements2007;9(SupplH):H41-H47.NT-proBNP:筛选和诊断右心衰竭10002000300040005000pg/mlHyperthyreosisRVfailureStartoftreprostinilinfectionDateDateNT-proBNPtrendin60-yearoldmanwithIPAHstartofsildenafilFijalkowskaA.EurHeartJSupplements2007;9(SupplH):H41-H47.18Nov2003pg/ml1800140010002006002200startofsildenafilPneumoniaDignosisofCTDStartofsteroids31July200328June2005DateNT-proBNPtrendin40-yearoldwomanwithIPAH27Dec2006NT-proBNP:筛选和诊断右心衰竭NT-proBNP：判断预后NT-proBNP≥1400pg/mlentirestudygroup:IPAH+CTD-PAH+CHD-PAH+CTEPHSubgroupwithIPAHFijalkowskaA.Chest2006;129:1313-1321.Cumulativesurvival0.00.20.40.60.81.0NT-proBNP<1400pg/ml061218243036P=0.0089monthsCumulativesurvival0.00.20.40.60.81.0NT-proBNP<1400pg/ml061218243036NT-proBNP≥1400pg/mlP=0.0087months010203040500.00.20.40.60.81.0CumulativeSurvivalTime[months]BNPratio>2.5BNPratio<2.5010203040500.00.20.40.60.81.0CumulativeSurvivalTime[months]NT-proBNPratio>2.5NT-proBNPratio<2.5LeuchteHH.Chest2007;131:402-409.Conclusion:ThediagnosticaccuracyofNT-proBNPasaparameterofthehemodynamicstatusisdiminishedbyrenalfunction.However,NT-proBNPcouldbesuperiortoBNPasasurvivalparameterinPHbecauseitintegrateshemodynamicimpairmentandrenalinsufficiency,whichservesasasignofincreasedmortalityperse.NT-proBNP：判断预后NT-proBNP：判断预后能够反映病情严重程度、疗效和预后。对肺动脉高压患者应常规检测BNP和NT-proBNP。BNP和NT-proBNP正常仍不能排除疾病。治疗过程中尽量维持正常或接近正常范围。NT-proBNP对于预后的判断优于BNP。干扰因素包括：左心疾病、性别、年龄、肾衰和肥胖等。基线BNP>150pg/ml、随访BNP>180pg/ml—预后差。〔Nagaya，2000〕NT-proBNP>1400pg/ml—预后差。〔Fijalkowska,2006〕BNP/NT-proBNPinPAH肌钙蛋白：Cardiactroponin〔cTn〕cTnT/I检测敏感性和特异性很高。血循环中cTn的浓度与心肌受损的程序呈正比，当检测值稍高于正常值上限时即有诊断价值。心肌细胞膜完整时，不会透出细胞膜进入血循环；心肌损伤时,细胞膜破坏时释放入血。TorbickiA.Circulation2003;108:844-848.cTnT升高：预后不良预测因子PAH

(n=51)+CTEPH(n=5)061218240.00.20.40.60.81.0P=0.003P=0.005P=0.001CumulativeSurvivalcTNT(-)cTnT(+)Time(months)252302334434488cTnT(+)cTnT(-)Subjectsatrisk,ncTnT≥0.01ng/mlconsideredabonormal

cTnT

是反映PAH严重程度和右心功能受损的血清标志物。

cTnT是PAH和CTEPH独立的预后指标。主要临床意义：发现需要优化治疗的高危PAH患者

cTnT水平可受左心疾病和肾脏损伤影响。cTnT：右心功能不全尿酸〔SerumUricAcid〕尿酸是嘌呤代谢终产物：组织缺氧ATP消耗↑—腺嘌呤核苷酸降解↑尿酸↑因为：PAH患者经常使用别嘌呤醇，血浆尿酸水平受高尿酸血症和利尿剂影响因而：消弱了临床监测价值FijalkowskaA.EurHeartJSupplements2007;9(SupplH):H41-H47.024681012*†*†‡Control(n=30)NYHAII(n=5)NYHAIII(n=72)NYHAIV(n=13)SerumUricAcidLevel(mg/dl)0246810010080604020Time(year)SurvivalRate(%)UA<6.4mg/dlUA≥6.4mg/dlFemale尿酸〔SerumUricAcid〕0246810010080604020Time(year)SurvivalRate(%)UA≥8.9mg/dlUA<8.9mg/dlMalemedianmedianbaselinevonWillebrandFactor:血管性血友病因子01230.00.250.500.751.00CumulativeSurvivalYear456789vWF≤220%vWF>220%Log-ranktestχ2=5.6P=0.01801230.00.250.500.751.00CumulativeSurvivalYear456789vWF≤220%vWF>220%Log-ranktestχ2=9.2P=0.003Follow-upRetrospective66PAHpatientsReflecttheseverityofendothelialinjuryanddysfunction生长分化因子-15(GrowthDifferentiationFactor-15)

转化生长因子超家族成员之一。作用于心肌肥厚及心肌肥厚向心力衰竭转变的过程。在正常的心肌细胞中不表达。缺氧或压力负荷过重等应激状态下，心肌细胞表达增高。GDF-15:右心功能标志物GDF-15Notacardiac-specificcytokine.Notchangein3to6monthsaftermedicaltherapyC-reactiveprotein：炎症标志物炎症参与肺动脉高压的发生和开展。PAH患者血清hsCRP、IL-6、TNF-α水平升高。既是对PAH诱发因素的应激，也对心肌功能产生有害作用并加速右心衰的进展。一种炎症急性时相的反响物，在应激状态下主要由肝脏合成分泌C-reactiveprotein：炎症标志物HDL-C:高密度脂蛋白胆固醇Time(months)1.00.80.60.40.20100200300400500HDL-c<35mg/dlHDL-c>35mg/dlP=0.001EstimatedratewithoutdeathEstimatedratewithoutclinicalworseningTime(months)1.00.80.60.40.20100200300400500HDL-c<35mg/dlHDL-c>35mg/dlP=0.002Thisassociationdoesnotappeartobeexplainedbyunderlyingcardiovascularriskfactors,insulinresistance,ortheseverityofPAH.HDL-C:高密度脂蛋白胆固醇HDL-C:高密度脂蛋白胆固醇0.006.0012.0018.000.00.20.40.81.0CumulativeSurvival24.00HDL＜

1.02mmol/LLog-ranktestp=0.0160.6HDL≥1.02mmol/LTime(months)Bilirubin:胆红素05001000150020000.00.20.40.60.81.0CumulativeSurvivalTime(days)Bilirubin>1.2mg/dlRedcelldistributionwidth:红细胞分布宽度151025Alive20DeceasedBaselineRDW(%)1.000.900.800.700.600.5001234SurvivalTertileITertileIITertileIIITime(years)UrinaryF2-isoprostane:8-异前列烷Time(years)1.00.80.60.40.20123Urinary15F2t-IsoP<median≥medianP=0.04Howtoimprove?NeurohormonesCardiacinjuryMatrix/endothelialprolif/inflamatoryOxidativestressHormonalandcachexiamarkersGenetictestsComorbidities8-Iso-PGF2αinIPAHpatientsandcontrolsubjects8-Iso-PGF2α(pg/mL)050100150200250p<0.001Control(n=95)IPAH(n=80)Thelinedrawnthroughthemiddleoftheboxesrepresentsthemedian.

Baselinecharacteristicsinrelationto8-IsoPGF2α

Baselinecharacteristicsinrelationto8-IsoPGF2α

BaselinecharacteristicsinIPAHpatientsaccordingtosurvival

BaselinecharacteristicsinIPAHpatientsaccordingtosurvival

8-Iso-PGF2α(pg/mL