利用生物标志物患者急性心血管疾病.ppt

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1、CP887679-0Use of Biomarkers in Patients with Acute Cardiovascular DiseaseAllan S.Jaffe,MD.*Consultant-Cardiology&Laboratory MedicineProfessor of MedicineMayo Clinic and Medical SchoolRochester,Minnesota*Dr.Jaffe is a consultant and receives research support from Roche,Dade Behring and Beckmann Coult

2、er.He has been or presently is a consultant to Ortho Diagnostics,Sensera,Diadexus,Abbott,Hawaii Biotech and Tartagen.CP1051812-1Clinical Outcomes by Braunwald ClassClinical Outcomes by Braunwald ClassDaysDaysDaysDaysDaysDaysPrimary Unstable AnginaPrimary Unstable AnginaPrimary Unstable AnginaClass B

3、Class BClass BPostinfarction AnginaPostinfarction AnginaPostinfarction AnginaClass CClass CClass CAccelerated AnginaAccelerated AnginaAccelerated AnginaClass IClass IClass ISubacute Angina at RestSubacute Angina at RestSubacute Angina at RestClass IIClass IIClass IIAcute Angina at RestAcute Angina a

4、t RestAcute Angina at RestClass IIIClass IIIClass IIIP PPP PPSurvivalSurvivalSurvivalInfarct freeInfarct freeInfarct freeInfarct free withoutInfarct free withoutInfarct free withoutinterventioninterventionintervention0.970.970.970.910.910.910.530.530.530.960.960.960.880.880.880.720.720.720.940.940.9

5、40.860.860.860.350.350.350.970.970.970.890.890.890.550.550.550.890.890.890.800.800.800.370.370.37JACC 25:1286,1995JACC 25:1286,1995JACC 25:1286,1995CP887679-2ECG Risk Factors in Patients with ACSDeath or MIDeath or MI(%)(%)DaysDaysJACC 36(3):970-1062,2000JACC 36(3):970-1062,2000ST elevation and depr

6、essionST elevation and depressionST depression onlyST depression onlyST elevation onlyST elevation onlyT-wave inversion onlyT-wave inversion onlyNo ST or T-wave changeNo ST or T-wave changen=237n=237n=287n=287n=93n=93n=216n=216n=78n=78CP956024-12CP887679-3Relationship of ECG Changes and FPA*FPAFPA(n

7、M)(nM)*JACC 18:898-903,1991JACC 18:898-903,1991100nl 1.5nl 1.5CP887679-4Long-Term Prognostic Value of ElevatedcTnI in Unstable Angina%freefreefromfromdeathdeathand/orand/orAMIAMITime from admission(days)Time from admission(days)Normal cTnINormal cTnILog rank 6.63,P=0.01Log rank 6.63,P=0.01Elevated c

8、TnIElevated cTnICirculation.1997;95:2053-2059 CP887679-5Antman,1998Antman,19981.1(0.4-3.5)1.1(0.4-3.5)Benamer,1998Benamer,199813.7(3.9-48.3)13.7(3.9-48.3)Brisisc,1998Brisisc,19988.0(0.9-65.1)8.0(0.9-65.1)Cin,1996Cin,199617.9(5.2-61.2)17.9(5.2-61.2)Galvani,1997Galvani,19976.6(1.3-32.3)6.6(1.3-32.3)Ha

9、mm,1992Hamm,199211.7(3.2-42.6)11.7(3.2-42.6)Luscher,1997Luscher,19972.5(1.3-4.8)2.5(1.3-4.8)Ohman,1996Ohman,19964.7(1.7-12.7)4.7(1.7-12.7)Olatidoye,1998Olatidoye,1998156.1(17.4-1,402)156.1(17.4-1,402)Ottani,1997Ottani,19976.6(2.0-22.1)6.6(2.0-22.1)Rebuzzi,1998Rebuzzi,199825.3(5.2-123.2)25.3(5.2-123.

10、2)Solymoss,1997Solymoss,19972.4(0.7-8.1)2.4(0.7-8.1)Stubbs,1996Stubbs,19961.5(0.5-4.2)1.5(0.5-4.2)Wu,1995Wu,199531.5(6.7-144.9)31.5(6.7-144.9)Antman,1996Antman,19963.8(1.8-8.03)3.8(1.8-8.03)Individual Studies of Patients with“Unstable Angina”Individual Studies of Patients with“Unstable Angina”Withou

11、t Without ST Segment ElevationST Segment ElevationPeto OR&95%CI(fixed)Peto OR&95%CI(fixed)Pooled OR P0.0001Pooled OR P0.00010.20.11 51050FavorsFavorslower risklower riskFavorsFavorshigher riskhigher risk4.8(3.6-6.5)4.8(3.6-6.5)CP887679-6Antman,1996Antman,19963.82(1.03-14.18)3.82(1.03-14.18)Benamer,1

12、998Benamer,199813.68(3.87-48.33)13.68(3.87-48.33)Brisisc,1998Brisisc,19987.96(0.97-65.25)7.96(0.97-65.25)Cin,1996Cin,199617.91(5.24-61.25)17.91(5.24-61.25)Galvani,1997Galvani,19976.55(1.32-32.38)6.55(1.32-32.38)Hamm,1992Hamm,199211.71(3.22-42.57)11.71(3.22-42.57)Luscher,1997Luscher,19975.93(1.61-21.

13、79)5.93(1.61-21.79)Olatidoye,1998Olatidoye,1998156.17(17.39-1,402.09)156.17(17.39-1,402.09)Rebuzzi,1998Rebuzzi,199825.27(5.18-123.23)25.27(5.18-123.23)Solymoss,1997Solymoss,19974.93(0.72-33.19)4.93(0.72-33.19)Wu,1995Wu,199531.52(6.89-144.19)31.52(6.89-144.19)Individual Studies of Individual Studies

14、of Patients with“Unstable Angina”and Normal Patients with“Unstable Angina”and Normal CKMB ValuesCKMB ValuesPeto OR&95%CI(fixed)Peto OR&95%CI(fixed)Pooled ORPooled ORP0.0001P0.00010.20.11 51050FavorsFavorslower risklower riskFavorsFavorshigher riskhigher risk11.83(7.56-18.51)11.83(7.56-18.51)CP887679

15、-7cTnI in Patients with Unstable AnginaMortality at 42 daysMortality at 42 days(%of patients)(%of patients)CP886232-7NEJM 335:1342-1349,1996NEJM 335:1342-1349,1996Cardiac Troponin I(ng/mL)Cardiac Troponin I(ng/mL)83117414813450671.01.83.53.96.27.8Risk ratio-95%CI CP887679-8Synergism of ECG and Eleva

16、ted Troponins(PARAGON)CP1099500-8JACC 41:376,2003JACC 41:376,20036-6-momodeath/death/MI rateMI raten=262ST-depressionST-depressionP=0.20P=0.20n=125n=259n=174n=57n=82P=0.13P=0.13P=0.15P=0.15TroponinTroponinTroponin+Troponin+CP887679-9FRISC-II GUSTO IV(Death and MI)CP1142356-17James et al:Am J Med 115

17、:181,2003James et al:Am J Med 115:181,200314141212101088664422000.01 0.01 g/Lg/LFRISC-IIFRISC-IIDeath and MI at 30 days(%)Death and MI at 30 days(%)0.03 0.03 g/Lg/LP=0.04P=0.04Below cutoffBelow cutoffAbove cutoffAbove cutoff0.1 0.1 g/Lg/LP=0.01P=0.01P=0.15P=0.15CutoffCutoff0.01 0.01 g/Lg/LGUSTO-IVGU

18、STO-IV0.03 0.03 g/Lg/LP0.001P0.0010.1 0.1 g/Lg/LP0.001P0.001P0.001P0.001CutoffCutoff11118080171774743030616166665215211111114764762012013863862658093287464306441,992 5,1232,563 4,5523,446 3,679CP887679-100.010.020.030.040.050.060.0ABCDEGHTotal CV,%ACS180CentaurImmuno 1AccessAccess2VidasLiaisonRXL CS

19、OpusImmuliteAlpha DxECiAIA 21IFCC Precision Study(Clinical Chem 2004)CP887679-11Rapid Troponin I AssayRapid Troponin I AssayOutcomes in Relation to Troponin Values:The Issue of Assay SensitivityCP1148152-9Int J Cardiol 93:113,2004Int J Cardiol 93:113,2004%NegNegDeathDeathMIMIDeath or MIDeath or MI56

20、9892130132205Troponin T(0.1 Troponin T(0.1 g/L)g/L)Troponin T(0.01 Troponin T(0.01 g/L)g/L)PosPos%4115113139862513619711636221301CP887679-12Correspondence Between Commercial Assays and Correspondence Between Commercial Assays and Western BlottingWestern BlottingAssay Positive WBDSA Negative WBDSA To

21、talBeckman 10%CV+17 20 37-11 106 117Roche 10%CV+16 8 24-12 118 130Beckman 99th%+20 38 58-8 88 96Roche 99th%+21 44 65-7 82 89CP887679-13MyeloperoxidaseMyeloperoxidasePredictions of Events When cTNT“Negative”Predictions of Events When cTNT“Negative”CP1131968-3NEJM 349:1600,2003NEJM 349:1600,2003Odds r

22、atioOdds ratioOdds ratioOdds ratioRevascularizationRevascularizationMyeloperoxidase quartile 2Myeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 3Myeloperoxidase quartile 4Myeloperoxidase quartile 4Major adverse cardiac eventsMajor adverse cardiac eventsMyeloperoxidase quar

23、tile 2Myeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 3Myeloperoxidase quartile 4Myeloperoxidase quartile 430 Days30 Days6 Months6 MonthsUnadjustedUnadjustedAdjustedAdjustedCP887679-14Prognostic Effects of MPO at 72 HoursPrognostic Effects of MPO at 72 HoursCP1132618-7De

24、ath,Death,Death,MIMIMI(%)(%)(%)Circulation 108:1443,2003Circulation 108:1443,2003Before PCIBefore PCIBefore PCIAdjusted hazard ratioAdjusted hazard ratioAdjusted hazard ratio2.04(0.65-6.42)2.04(0.65-6.42)2.04(0.65-6.42)Adjusted hazard ratioAdjusted hazard ratioAdjusted hazard ratio3.07(1.21-4.26)3.0

25、7(1.21-4.26)3.07(1.21-4.26)MPO highMPO highMPO highMPO lowMPO lowMPO lowAfter PCIAfter PCIAfter PCIHoursHoursHoursCP887679-15cTnI Negative ACS?Circulation 107:533,2003Circulation 107:533,2003Circulation 107:533,2003CP1104508-19CP887679-16Sensitivity of cTnI,CK-MB,and Myoglobin with Sensitive Sensiti

26、vity of cTnI,CK-MB,and Myoglobin with Sensitive Contemporary AssaysContemporary AssaysAHJ 148:577,2004AHJ 148:577,2004TnI(0.1 g/L)TnI(0.1 g/L)CK-MB(3.5 g/L)CK-MB(3.5 g/L)Myo(98/56 g/L)Myo(98/56 g/L)CP1176222-20 min30 min60 min90 minSensitivity2 hr3 hr6 hr6 hrSpecificity TnI(0.4 g/L)TnI(0.4 g/L)TnI(0

27、.1 g/L)TnI(0.1 g/L)TnI(0.07 g/L)TnI(0.07 g/L)CP887679-17cTnT and Angiographic MeasuresCP1179389-5TnT(0.01)TnT(0.01)Prog Cardiovasc Dis 47(3),2004Prog Cardiovasc Dis 47(3),2004P0.001P0.01)TnT(0.01)P=0.02P=0.02Thrombus(%)Thrombus(%)P=0.03P=0.03TFG 0/1(%)TFG 0/1(%)P0.001P0.001TMPG 0/1(%)TMPG 0/1(%)CP88

28、7679-18JACC 36(3):970-JACC 36(3):970-1062,20001062,2000Medical and Interventional Response to GP IIb/IIIa Agents in Medical and Interventional Response to GP IIb/IIIa Agents in Troponin Positive PatientsTroponin Positive Patients+24h+24h+48h+48h +24h+24h+48h+48h +72h+72hn=1,265n=1,265OR=0.37OR=0.37P

29、=0.032P=0.032CAPTURECAPTURE2.8%2.8%1.3%1.3%n=9,461n=9,461OR=0.72OR=0.72P=0.003P=0.003PURSUITPURSUITn=1,570n=1,570OR=0.45OR=0.45P=0.016P=0.016PRISM-PLUSPRISM-PLUSn=12,296n=12,296OR=0.66OR=0.66P=0.001P=0.001AllAlln=1,239n=1,239OR=0.46OR=0.46P=0.009P=0.009n=1,228n=1,228OR=0.71OR=0.71P=0.105P=0.105n=287

30、n=287OR=0.35OR=0.35P=0.062P=0.062n=2,754n=2,754OR=0.59OR=0.59P=0.001P=0.0015.8%5.8%2.8%2.8%10.3%10.3%7.6%7.6%8.0%8.0%2.9%2.9%8.0%8.0%4.9%4.9%4.4%4.4%3.2%3.2%3.8%3.8%1.8%1.8%4.3%4.3%3.9%3.9%Death or MIDeath or MI(%)(%)Start GP IIb/IIIa inhibitor/placeboStart GP IIb/IIIa inhibitor/placeboPercutaneous

31、coronary interventionPercutaneous coronary interventionCP956024-13CP887679-19LMW Heparin vs VF Heparin in TIMI 11BLMW Heparin vs VF Heparin in TIMI 11BJ Am Coll Cardiol 36:1812,2000J Am Coll Cardiol 36:1812,2000CP1008642-5Clinical events at 14 days(%)Clinical events at 14 days(%)CKMB negative patien

32、tsCKMB negative patientsEnoxaparinEnoxaparinUFHUFH6 6P=0.006P=0.0066 60 04 46 69 9171710101111404021212828P=0.007P=0.007cTnI NegativecTnI Negativen=179n=179cTnI PositivecTnI Positiven=180n=180CP887679-20TACTICS(TIMI 18)CP1036852-9ConservativeConservativeInvasiveInvasiveNo.No.treatmenttreatmenttreatm

33、enttreatmentPrimary endpointPrimary endpoint0.1 ng/mL0.1 ng/mL734734 4.3 4.36.66.60.1-0.40.1-0.418118116.516.54.44.40.4-1.50.4-1.521321317.617.65.45.4 1.51.569369315.615.68.88.8Death or MIDeath or MI0.1 ng/mL0.1 ng/mL734734 1.9 1.93.03.00.1-0.40.1-0.418118112.112.14.44.40.4-1.50.4-65 yr old65 yr old

34、 6,208 6,20815.315.313.313.3ST-segment deviationST-segment deviation 6,275 6,27514.314.311.511.5No ST-segment deviationNo ST-segment deviation 6,287 6,287 8.6 8.6 7.0 7.0Enzymes elevated at entryEnzymes elevated at entry 3,176 3,17613.013.010.710.7Enzymes not elevated at entryEnzymes not elevated at

35、 entry 9,386 9,38610.910.9 8.8 8.8DiabetesDiabetes 2,840 2,84016.716.714.214.2No diabetesNo diabetes 9,722 9,722 9.9 9.9 7.9 7.9Low riskLow risk 4,187 4,187 6.7 6.7 5.1 5.1Intermediate riskIntermediate risk 4,185 4,185 9.4 9.4 6.5 6.5High riskHigh risk 4,184 4,18418.018.016.316.3History of revascula

36、rizationHistory of revascularization 2,246 2,24614.414.4 8.4 8.4No history of revascularizationNo history of revascularization10,31610,31610.710.7 9.5 9.5Revascularization after randomization Revascularization after randomization 4,577 4,57713.913.911.511.5No revascularization after randomization No

37、 revascularization after randomization 7,985 7,98510.010.0 8.1 8.1Relative risk(95%CI)Relative risk(95%CI)ClopidogrelClopidogrelbetterbetterPlaceboPlacebobetterbetterNEJM 345:494,2001NEJM 345:494,2001CP887679-23CP1189452-44 4 peptides related with each other regarding peptides related with each othe

38、r regarding biochemistry and physiological functionbiochemistry and physiological function Atrial Atrial natriureticnatriureticpeptide(ANP)peptide(ANP)Brain(or B type)Brain(or B type)natriureticnatriuretic peptide peptide(BNP)(BNP)C-type C-type natriureticnatriuretic peptide peptide(CNP)(CNP)Urodila

39、tinUrodilatin,a slightly extended form of ANP,a slightly extended form of ANPH H2 2N NCOOHCOOHCOOHCFCDRISGLCCNatriuretic Peptide Family CP887679-24 Common 17-amino acidCommon 17-amino acidring structurering structure Ring structure highlyRing structure highlyconservedconserved 11/17 amino acids11/17

40、 amino acidsare homologousare homologous Ring structure essentialRing structure essentialfor physiological activityfor physiological activityH H2 2N NCOOHCOOHCOOHCFCDRISGLCCCP1189452-5Natriuretic Peptide FamilyBiochemistryCP887679-25CardiomyocyteBloodBloodproBNPproBNP(108 aa)(108 aa)BNP-32(proBNP 77

41、-108)BNP-32(proBNP 77-108)BNP-32BNP-32Physiologically active formPhysiologically active formNT-proBNP 1-76NT-proBNP 1-76SecretionSecretionLV stretchLV stretchWall tensionWall tensionPre-proBNP(134 aa)Pre-proBNP(134 aa)Signal peptide(26 aa)Signal peptide(26 aa)proBNPproBNPSerin proteaseSerin protease

42、(Corin?)(Corin?)Mair:Scand J Clin Lab Invest,1999Mair:Scand J Clin Lab Invest,1999CP1189452-10CP887679-26CP1189452-2097.5%97.5%percentilepercentile(pg/mL)(pg/mL)303030-3930-3940-4940-4950-5950-59 6060Age groupsAge groupsMalesMalesFemalesFemalesAge-Specific Reference Rangefor NT-proBNPCP887679-27AHJ

43、149(4),April 2005AHJ 149(4),April 2005pg/mLpg/mLpg/mLNT-proBNPNT-proBNPNT-proBNPpg/mLpg/mLpg/mLBNPBNPBNPWeight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)Weight categories(BMI)252525 25-29.925-29.925-29.9 303030 252525 25-29.925-29.925-29.9

44、 303030 P0.001P0.001P0.001 P0.001P0.001P0.001 Values of BNP and NTproBNP by WeightCP1189452-21CP887679-2838 438 4BNPBNPconcentrationconcentration(pg/mL)(pg/mL)DiagnosisDiagnosisn=139n=1391,076 1381,076 138No CHFNo CHFCP1189452-25n=97n=97CHFCHFLV dysfunctionLV dysfunctionNo acute CHFNo acute CHFn=14n

45、=14141 31141 31BNP Levels of Patients Diagnosed Without CHF,with BNP Levels of Patients Diagnosed Without CHF,with Baseline Left Ventricular Dysfunction,and with CHFBaseline Left Ventricular Dysfunction,and with CHFCP887679-29BNP Levels in Heart FailureMedianMedianBNP BNP levellevel(pg/mL)(pg/mL)CP1

46、189452-26BNP Levels in Normal Subjects and InpatientsBNP Levels in Normal Subjects and Inpatientswith Heart Failurewith Heart FailureNormalNormalI III IIIIIIIIIVIVClassClassCP887679-30CP1189452-27ED Probability of CHF RecordedED Probability of CHF RecordedP0.0001 from clinical judgment to combinedP0

47、.0001 from clinical judgment to combinedMcCullough PA et al:Circulation 106:416,2002McCullough PA et al:Circulation 106:416,2002Diagnostic accuracy(%)Diagnostic accuracy(%)ClinicalClinicaljudgmentjudgmentBNPBNPCombinedCombined707072727474767678788080828274.081.281.5n=1,538n=1,538BNP Study Primary En

48、d PointCP887679-31n=1,586;n=1,586;50%CHF;56%male;50%CHF;56%male;6417 yo;41%COPD;6417 yo;41%COPD;30%Hx CHF30%Hx CHFCP1189452-28 BNPBNP(pg/mL)(pg/mL)SensSensSpecSpecPPVPPVNPVNPV 50 50979762627171959510010090907676797989891501508585838383838585AUC=0.91AUC=0.91Breathing Not Proper(BNP)Multicenter TrialC

49、P887679-32AJC 95,April 15,2005AJC 95,April 15,2005OptimalOptimal cut-point cut-point SensSens SpecSpec PPVPPV NPVNPV AccuracyAccuracy(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)(%)Rule-in cutpointsRule-in cutpointsAll pt(n=599)All pt(n=599)9009009090858576769494878750 yr old50 yr old45045093939595676799999595n

50、=144n=144 50 yr old50 yr old90090091918080777792928585n=455n=455Rule-out ptRule-out ptAll pt(n=599)All pt(n=599)300 30099996868626299998383CP1189452-30Optimal NT-proBNP Cutpoints for Acute Congestive Heart FailureCP887679-33McCullough PA et al for the BNP Multinational Study Investigators:McCullough