2019监测在心力衰竭诊治中的应用化学.ppt

BNP/NT-BNP/NT-proBNPproBNP监测在心力衰竭诊治中的应用监测在心力衰竭诊治中的应用中国医学科学院中国医学科学院 中国协和医科大学中国协和医科大学 心血管病研究所心血管病研究所 阜外心血管病医院阜外心血管病医院心力衰竭诊治中心心力衰竭诊治中心张张 健健BNP/NT-BNP/NT-proBNPproBNP在心衰中的作用在心衰中的作用 诊断预后判定有效监测人群筛选治疗ZJ利钠肽利钠肽（NatriureticNatriuretic Peptides,Peptides,NPNPs s）ANP：心钠素心钠素(Atrial NP)(Kangawak,1984)BNP：脑钠素脑钠素(Brain NP)，又称又称B型利钠肽型利钠肽 (Sudoh T,1988)CNP：C型利钠肽型利钠肽 (C-type NP)(Sudoh T,1990)CNP-53 CNP-22ZJNP:NP:起源和应激反应起源和应激反应Adapted from Burnett JC,J Hypertens 2000;17(Suppl 1):S37-S43ANP=心房促尿钠排泄缩氨酸心房促尿钠排泄缩氨酸BNP=B-型促尿钠排泄缩氨酸型促尿钠排泄缩氨酸CNP=C-型促尿钠排泄缩氨酸型促尿钠排泄缩氨酸Peptide主要起源主要起源促使其生成的刺激促使其生成的刺激生理作用生理作用ANP心房心房心房膨心房膨胀胀 利尿、利利尿、利钠钠、扩张扩张血管、阻血管、阻断断RAAS和和SNSBNP心室肌心室肌心室膨心室膨胀胀 同同ANP、半衰期、半衰期长长、标记标记物、物、可用于治可用于治疗疗CNP内皮内皮细细胞胞 内皮内皮细细胞坏死胞坏死 不利不利钠钠、不利尿、不利尿、扩张扩张血管血管ZJ肌细胞肌细胞Pre-proBNP(134 aa)proBNP(108 aa)信号缩氨酸信号缩氨酸(26 aa)分泌物分泌物NT-proBNP(1-76)BNP(77-108)BNP/NT-BNP/NT-proBNPproBNP的分泌和释放的分泌和释放ZJZJBNP的形成和分解pre-proBNP1-134Meprin A ABNP7-32DPP-IV=dipeptidyl peptidaseIVDPP-IVBNP3-32proBNP1-108BNP1-32NT-proBNP1-76proBNP1-108Signal peptide(26 amino acids)Wilkins MR.Redondo J.Brown LA.Lancet 1997;349:1307-1310Ventricular overloadUrodilatinNPR-AIncreasedNa/H20 ExcretionANP+BNPNPR-A/NPR-BDecreasedBlood PressureNeutralEndopeptidase CytokinesClearanceNPR-CDecreasedVascular GrowthCNP+-+ZJBiology of the Natriuretic PeptidesThe natriuretic peptide system has complex genetic regulationSynthesis of an intracellular precursor,proBNP1-108,precedes release of BNP1-32 and NT-proBNP1-76BNP1-32 rapidly undergoes processing and degradation into several circulating forms,including BNP3-32 and BNP7-32proBNP1-108 and NT-proBNP1-76 have absent biologic activity,while BNP3-32 and BNP7-32 have less biologic activity than BNP1-32指征研究指征研究标记标记物物临临床床类类型型建建议议诊诊断断Maisel 等等BNP急急诊诊室急性呼室急性呼吸困吸困难难患者患者100pg/ml为诊为诊断心衰的最断心衰的最优优界界值值JanuzziNT-proBNP急急诊诊室急性呼室急性呼吸困吸困难难患者患者450pg/ml（900pg/ml（50岁岁）为诊为诊断的最断的最优优界界值值CowieBNP初初级诊级诊所所76pg/ml为诊为诊断心衰的最断心衰的最优优界界值值筛查筛查Vasan BNP观观察性人群研察性人群研究究识别识别无症状左室功能不全无症状左室功能不全的的AUC97pg/ml的患者远期病死率翻倍（相对危险度 2.1）指指导导治治疗疗Troughton NT-proBNP随机临床试验NT-proBNP水平指导治疗可以显著降低由心衰、再次入院和死亡联合终点表表1 心衰患者测定心衰患者测定BNP的主要意义的主要意义Redfield BNP观察性人群研究识别亚临床型舒张功能不全的AUC0.75，意味着BNP作为筛查指标不理想筛查筛查指征研究指征研究标记标记物物临临床床类类型型建建议议ZJLainchbury et al,J Am Coll Cardiol,2003;42:728NT-proBNP is Strongly Correlated to BNP in Acute DyspneaBiositeBiosite BNP(BNP(pmolpmol/L)/L)0 01010100100100010000 01010100100100010001000010000Roche NT-proBNP(Roche NT-proBNP(pmolLpmolL)r=0.902r=0.902p0.0001p75 years(n=519)86%66%88%84%90%Overall85%88%82%82%90%900 pg/mLAll 50-75 years(n=554)95%99%76%93%97%450 pg/mLAll 50 years(n=183)AccuracyNPVPPVSpecificitySensitivityOptimalCut-pointAge StrataFinal Diagnoses#of subjectsJanuzzi et al,Am J Cardiol 2005;95:948Acute HF(N=209)No prior HF(N=355)Prior HF(N=35)Not acute HF(N=390)Januzzi et al,Am J Cardiol 2005;95:948NT-proBNP(pg/mL)P0.001Results:NT-proBNP LevelsNYHAClass II(n=17)Class III(n=80)Class IV(n=112)159115913438343855645564NT-proBNP Levels and HF Symptom Severity0100020003000400050006000NT-proBNP(pg/ml)P P=.001=.001Januzzi et al,Am J Cardiol 2005;95:948159115913438343855645564Natriuretic Peptides and LVEFJanuzzi et al,Eur Heart Journal,2006;27:3301.82.43.03.6Log-NT-proBNPLog-NT-proBNP4.24.8153045607090r=0.289r=0.289P P.001.001Left Ventricular Ejection Fraction(%)Left Ventricular Ejection Fraction(%)NT-proBNP in Aortic StenosisWeber et al,Am J Cardiol,2004;94(6):740P P.001.001NT-proBNP(pg/NT-proBNP(pg/mLmL)Prognostic Evaluation of Patients with Acute Acutely Destabilized Heart FailureJanuzzi et al,Eur Heart J,2006;27:330 Association Between Presentation NT-proBNP Values and Short-term Mortality in Acute Destabilized Heart Failure 0.850.850.900.900.950.951.001.00Cumulative SurvivalCumulative SurvivalP P.00001.000010.700.700.750.750.800.80Days from PresentationDays from PresentationNT-proBNP NT-proBNP 5,180 NT-proBNP 5,180 ngng/L/L0 010102020303040406060505080807070Log rank Log rank P P value.001value 30%Change 30%Time(Days)0100200健康人健康人NT-NT-proBNPproBNP的参考值的参考值正常人中正常人中,妇女和老人有女和老人有较高的高的 NT-proBNP,然而然而,在急性呼吸困在急性呼吸困难的病人中的病人中,则看不到看不到这种种现象象Galasko et al,Eur Heart J,2005;26:2269AgeMenWomenMedian(ng/mL)97.5th%(ng/L)95%CI(ng/mL)Median(ng/mL)97.5th%(ng/L)95%CI(ng/mL)40-6554184162-20679268228-31445-592010078-17349164150-2816040172144-17378225180-25466-7679269223-306115391339-446BNP Levels in patients with dyspnea caused by CHF or chronic obstructive pulmonary diseaseJ.Cardiac Failure 7(2):183-9 2001ZJBNP levels in patients with diagnosis of CHF and baseline left ventricular dysfunction.Diagnosis of CHF was based on independent assessment by 2 cardiologists blinded to BNP values.Values are expressed as mean+/-SEM Dao,Q.,Maisel,A.et al.J.American College of Cardiology,No.2,2001.ZJBNP Concentration(pg/ml)186 22791 1652013 266N=27N=27N=34N=34N=36N=36BNP concentrations for the degree of CHF severityBNP concentrations for the degree of CHF severityMildModerate Severe05001000150020002500J.Cardiac Failure 7(2):183-9 2001ZJBNP levels in patients with CHF NYHA ClassHeart Failure 19:557-71 2001 80 152 332 590 960 (pg/mL)ZJLg BNP(pmol/l)LVEF(%)020406080 10001.02.03.0y=-0.7,p0.001Davis et al.Lancet 1994;343:440-444.BNP vs.EF by EchocardiographyZJBNP and LVEF-ScintigraphySource:Source:ClericoClerico et al.et al.J.EndocrinolJ.Endocrinol.Invest 1998;21:170-179.Invest 1998;21:170-179.4321 Concentrations Log BNP (ng/l)0 10 20 30 40 50 60 70%LVEF 01020304050607080901000102030405060708090100 1-Specificity(%)Sensitivity(%)82118205-BNP ED diagnosisAUC0.8840.9790-ROC Curve:BNP and ED Diagnosis Diagnosis in All 250 PatientsDao,Q.et al.Dao,Q.et al.J.American College of CardiologyJ.American College of Cardiology,Vol 37,No.2,2001,Vol 37,No.2,2001ZJCumulative survival rates in CHF patients with LVDTsutamoto T.et al.Circulation 1997;96:509-51602040608010001020304050BNP 73 pg/mlMonthsCumulative Survival(%)p 0.0001Stratification based on Median BNP values at 73 pg/mlBNP Concentration for the Prediction of Clinical EventsBNP Concentration for the Prediction of Clinical EventsMaisel A,Maisel A,Ann Emerg Med.Ann Emerg Med.February 2002;39:131-138.February 2002;39:131-138.0204060801001201401601800%5%10%15%20%25%30%35%40%45%BNP 480 pg/mlDeath or Heart Failure HospitalizationDaysZJBNP 和和 NT-proBNP 的总结的总结BNP 是一个应用更广泛的标志物是一个应用更广泛的标志物 两种分子的数值不可互换两种分子的数值不可互换都是心衰中好的诊断标志物都是心衰中好的诊断标志物都可用于筛查左心室功能障碍都可用于筛查左心室功能障碍都是心衰中较好的预测标志物都是心衰中较好的预测标志物ZJ阜外心血管病医院的一些初步研究阜外心血管病医院的一些初步研究ZJ左心衰竭组不同左心衰竭组不同NYHA分级的分级的BNP箱线图箱线图注：与对照组比较：*p0.05;*p0.001；与NYHA I级比较：#p0.05;#p0.001；与NYHA级比较：$p0.05;$p0.001；与NYHA 级比较：&p0.05;&p288 pg/mlBNP288 pg/ml组的平组的平均无心源性事件生存均无心源性事件生存时间为时间为9.949.94个月个月qBNP288 pg/mlBNP288 pg/ml组的组的无心源性事件生存时无心源性事件生存时间显著长于间显著长于BNP288 BNP288 pg/mlpg/ml组（组（P0.0001P0.0001），），约为其约为其2 2倍。倍。ZJ测测定人群定人群pro值值（fmol/ml）是正常是正常对对照的照的倍数倍数正常正常对对照照(203例例)包括冠造等正常包括冠造等正常300.4(251.7,373.6)NYHA 心功能心功能级级579.7(453.6,819.4)2 倍倍NYHA 心功能心功能级级2192.8(1380.7,3650.4)7 倍倍NYHA 心功能心功能级级3663.3(2362.7,5505.9)12 倍倍NT-proBNP与与DCM n=(203)的严重程度的严重程度中国循环杂志中国循环杂志2008年第年第5期期ZJNT-proBNP预测预测DCHF的住院病死率的住院病死率中华心血管病杂志中华心血管病杂志2009年年6期期ROCROC分析表明：分析表明：NT-NT-proBNPproBNP 3500fmol/ml 3500fmol/ml为切点预测住院死亡率为切点预测住院死亡率的敏感性、特异性和准的敏感性、特异性和准确性均确性均7070左右阴性预左右阴性预测值在测值在9696以上阳性预以上阳性预测值为测值为1717,与实际死亡与实际死亡率相同（率相同（n=840n=840）ZJBNP预测预测AMI患者患者30天内心原性死亡天内心原性死亡ZJBNP预测预测AMI患者患者6个月内心原性死亡个月内心原性死亡ZJAMI患者患者1年内心原性死亡与年内心原性死亡与BNPZJproANP、NT-proBNP、NT-proCNP测定心衰患者的proANP、NT-proBNP、NT-proCNP均较对照组明显升高proANP(nmol/ml)NT-proBNP(fmol/ml)NT-proCNP(pmol/ml)正常对照正常对照(N=44)2.320.888.988.284.92.06心衰患者心衰患者(N=130)4.953.02（p=0.000)106.13111.19(p=0.000)6.414.48(p=0.004)ZJproANP、NT-proBNP与与NT-proCNP三者间相关性三者间相关性proANPNT-proBNPNT-proCNPproANP0.764P=0.0000.246P=0.005NT-proBNP0.764P=0.0000.294P=0.001NT-proCNP0.246P=0.0050.294P=0.001三者之间均两两相关，三者之间均两两相关，其中以其中以logproANP与与logNT-proBNP之间的相关性最强之间的相关性最强ZJThank you very much!