肺高壓生化標(biāo)記物

張銳，荊志成心肺循環(huán)中心肺動(dòng)脈高壓生物標(biāo)記物和預(yù)后BiomarkersinPulmonaryArterialHypertension生物標(biāo)記物？評價(jià)臨床療效定義明確的臨床終點(diǎn)事件臨床終點(diǎn)事件替代指標(biāo)6分鐘步行距離生化標(biāo)志物......*BiomarkersDefinitionsWorkingGroup.ClinPharmacolTher.2001;69:89-95.NIH*:可以被客觀測量并且作為正常生物學(xué)過程、發(fā)病過程或者對于治療干預(yù)的藥理學(xué)反響指示某些疾病所致的病理狀態(tài)下，血清中可測得的含量增高的化學(xué)物質(zhì)?！搀w液、外周靜脈血……〕生物標(biāo)記物？疾病診斷和嚴(yán)重程度療效判定疾病進(jìn)展預(yù)后評估評價(jià)重要指標(biāo)肺動(dòng)脈高壓候選生物標(biāo)記物

內(nèi)皮功能障礙:

ET-1、PGI2、

NO

神經(jīng)體液過度激活: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個(gè)氨基酸76個(gè)氨基酸生物活性有無來源proBNP裂解proBNP裂解半衰期18min60-120min清除中性內(nèi)肽酶受體清除、腎臟清除腎臟清除體外室溫穩(wěn)定性4h（采集后馬上開始降解）>72h受年齡增長影響+++++可否床旁即時(shí)檢測是否完成學(xué)術(shù)論文（篇）137039CHF診斷Cut-off值100pg/ml年齡<75:125pg/ml年齡≥75:450pg/mlBNP：判斷右心功能不全血漿BNP濃度與肺動(dòng)脈高壓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：觀察藥物療效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：判斷預(yù)后BNP<180pg/mLBNP≥180pg/mLTime(months)median100806040200012243648Survivalrate(%)medianFijalkowskaA.EurHeartJSupplements2007;9(SupplH):H41-H47.NT-proBNP:篩選和診斷右心衰竭10002000300040005000pg/mlHyperthyreosisRVfailureStartoftreprostinilinfectionDateDateNT-proBNPtrendin60-yearoldmanwithIPAHstartofsildenafilFijalkowskaA.EurHeartJSupplements2007;9(SupplH):H41-H47.18Nov2003pg/ml1800140010002006002200startofsildenafilPneumoniaDignosisofCTDStartofsteroids31July200328June2005DateNT-proBNPtrendin40-yearoldwomanwithIPAH27Dec2006NT-proBNP:篩選和診斷右心衰竭NT-proBNP：判斷預(yù)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：判斷預(yù)后NT-proBNP：判斷預(yù)后能夠反映病情嚴(yán)重程度、療效和預(yù)后。對肺動(dòng)脈高壓患者應(yīng)常規(guī)檢測BNP和NT-proBNP。BNP和NT-proBNP正常仍不能排除疾病。治療過程中盡量維持正常或接近正常范圍。NT-proBNP對于預(yù)后的判斷優(yōu)于BNP。干擾因素包括：左心疾病、性別、年齡、腎衰和肥胖等?；€BNP>150pg/ml、隨訪BNP>180pg/ml—預(yù)后差?！睳agaya，2000〕NT-proBNP>1400pg/ml—預(yù)后差?！睩ijalkowska,2006〕BNP/NT-proBNPinPAH肌鈣蛋白：Cardiactroponin〔cTn〕cTnT/I檢測敏感性和特異性很高。血循環(huán)中cTn的濃度與心肌受損的程序呈正比，當(dāng)檢測值稍高于正常值上限時(shí)即有診斷價(jià)值。心肌細(xì)胞膜完整時(shí)，不會(huì)透出細(xì)胞膜進(jìn)入血循環(huán)；心肌損傷時(shí),細(xì)胞膜破壞時(shí)釋放入血。TorbickiA.Circulation2003;108:844-848.cTnT升高：預(yù)后不良預(yù)測因子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嚴(yán)重程度和右心功能受損的血清標(biāo)志物。

cTnT是PAH和CTEPH獨(dú)立的預(yù)后指標(biāo)。主要臨床意義：發(fā)現(xiàn)需要優(yōu)化治療的高危PAH患者

cTnT水平可受左心疾病和腎臟損傷影響。cTnT：右心功能不全尿酸〔SerumUricAcid〕尿酸是嘌呤代謝終產(chǎn)物：組織缺氧ATP消耗↑—腺嘌呤核苷酸降解↑尿酸↑因?yàn)椋篜AH患者經(jīng)常使用別嘌呤醇，血漿尿酸水平受高尿酸血癥和利尿劑影響因而：消弱了臨床監(jiān)測價(jià)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生長分化因子-15(GrowthDifferentiationFactor-15)

轉(zhuǎn)化生長因子超家族成員之一。作用于心肌肥厚及心肌肥厚向心力衰竭轉(zhuǎn)變的過程。在正常的心肌細(xì)胞中不表達(dá)。缺氧或壓力負(fù)荷過重等應(yīng)激狀態(tài)下，心肌細(xì)胞表達(dá)增高。GDF-15:右心功能標(biāo)志物GDF-15Notacardiac-specificcytokine.Notchangein3to6monthsaftermedicaltherapyC-reactiveprotein：炎癥標(biāo)志物炎癥參與肺動(dòng)脈高壓的發(fā)生和開展。PAH患者血清hsCRP、IL-6、TNF-α水平升高。既是對PAH誘發(fā)因素的應(yīng)激，也對心肌功能產(chǎn)生有害作用并加速右心衰的進(jìn)展。一種炎癥急性時(shí)相的反響物，在應(yīng)激狀態(tài)下主要由肝臟合成分泌C-reactiveprotein：炎癥標(biāo)志物HDL-C:高密度脂蛋白膽固醇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:高密度脂蛋白膽固醇HDL-C:高密度脂蛋白膽固醇0.006.0012.0018.000.00.20.40.81.0CumulativeSurvival24.00HDL＜

1.02mmol/LLog-ranktestp=0.0160.6HDL≥1.02mmol/LTime(months)Bilirubin:膽紅素05001000150020000.00.20.40.60.81.0CumulativeSurvivalTime(days)Bilirubin>1.2mg/dlRedcelldistributionwidth:紅細(xì)胞分布寬度151025Alive20DeceasedBaselineRDW(%)1.000.900.800.700.600.5001234SurvivalTertileITertileIITertileIIITime(years)UrinaryF2-isoprostane:8-異前列烷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