利用生物标志物患者急性心血管疾病.ppt

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1、Use of Biomarkers in Patients with Acute Cardiovascular Disease,Allan 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 Coulter.He ha

2、s been or presently is a consultant to Ortho Diagnostics,Sensera,Diadexus,Abbott,Hawaii Biotech and Tartagen.,CP1051812-1,Clinical Outcomes by Braunwald Class,Days,Days,Primary Unstable AnginaClass B,Postinfarction AnginaClass C,Accelerated AnginaClass I,Subacute Angina at RestClass II,Acute Angina

3、at RestClass III,P,P,0.97,0.91,0.53,0.96,0.88,0.72,0.94,0.86,0.35,0.97,0.89,0.55,0.89,0.80,0.37,JACC 25:1286,1995,ECG Risk Factors in Patients with ACS,Death or MI(%),Days,JACC 36(3):970-1062,2000,ST elevation and depression,ST depression only,ST elevation only,T-wave inversion only,No ST or T-wave

4、change,n=237,n=287,n=93,n=216,n=78,CP956024-12,Relationship of ECG Changes and FPA*,FPA(nM),*JACC 18:898-903,1991,nl 1.5,Long-Term Prognostic Value of ElevatedcTnI in Unstable Angina,%freefromdeathand/orAMI,Time from admission(days),Normal cTnI,Log rank 6.63,P=0.01,Elevated cTnI,Circulation.1997;95:

5、2053-2059,Antman,19981.1(0.4-3.5)Benamer,199813.7(3.9-48.3)Brisisc,19988.0(0.9-65.1)Cin,199617.9(5.2-61.2)Galvani,19976.6(1.3-32.3)Hamm,199211.7(3.2-42.6)Luscher,19972.5(1.3-4.8)Ohman,19964.7(1.7-12.7)Olatidoye,1998156.1(17.4-1,402)Ottani,19976.6(2.0-22.1)Rebuzzi,199825.3(5.2-123.2)Solymoss,19972.4(

6、0.7-8.1)Stubbs,19961.5(0.5-4.2)Wu,199531.5(6.7-144.9)Antman,19963.8(1.8-8.03),Individual Studies of Patients with“Unstable Angina”Without ST Segment Elevation,Peto OR&95%CI(fixed),Pooled OR P0.0001,0.20.11 51050,Favorslower risk,Favorshigher risk,4.8(3.6-6.5),Antman,19963.82(1.03-14.18)Benamer,19981

7、3.68(3.87-48.33)Brisisc,19987.96(0.97-65.25)Cin,199617.91(5.24-61.25)Galvani,19976.55(1.32-32.38)Hamm,199211.71(3.22-42.57)Luscher,19975.93(1.61-21.79)Olatidoye,1998156.17(17.39-1,402.09)Rebuzzi,199825.27(5.18-123.23)Solymoss,19974.93(0.72-33.19)Wu,199531.52(6.89-144.19),Individual Studies of Patien

8、ts with“Unstable Angina”and Normal CKMB Values,Peto OR&95%CI(fixed),Pooled ORP0.0001,0.20.11 51050,Favorslower risk,Favorshigher risk,11.83(7.56-18.51),cTnI in Patients with Unstable Angina,Mortality at 42 days(%of patients),CP886232-7,NEJM 335:1342-1349,1996,Cardiac Troponin I(ng/mL),831,174,148,13

9、4,50,67,1.0,1.8,3.5,3.9,6.2,7.8,Risk ratio,-,95%CI,Synergism of ECG and Elevated Troponins(PARAGON),CP1099500-8,JACC 41:376,2003,6-modeath/MI rate,n=262,ST-depression,P=0.20,n=125,n=259,n=174,n=57,n=82,P=0.13,P=0.15,FRISC-II GUSTO IV(Death and MI),CP1142356-17,James et al:Am J Med 115:181,2003,14121

10、086420,0.01 g/L,FRISC-II,Death and MI at 30 days(%),0.03 g/L,P=0.04,0.1 g/L,P=0.01,P=0.15,Cutoff,0.01 g/L,GUSTO-IV,0.03 g/L,P0.001,0.1 g/L,P0.001,P0.001,Cutoff,11,80,17,74,30,61,66,521,111,476,201,386,265,809,328,746,430,644,1,992,5,123,2,563,4,552,3,446,3,679,0.0,10.0,20.0,30.0,40.0,50.0,60.0,A,B,C

11、,D,E,G,H,Total CV,%,ACS180,Centaur,Immuno 1,Access,Access2,Vidas,Liaison,RXL,CS,Opus,Immulite,Alpha Dx,ECi,AIA 21,IFCC Precision Study(Clinical Chem 2004),Rapid Troponin I Assay,Outcomes in Relation to Troponin Values:The Issue of Assay Sensitivity,CP1148152-9,Int J Cardiol 93:113,2004,%,Neg,Death,M

12、I,Death or MI,56,98,92,130,132,205,Troponin T(0.1 g/L),Troponin T(0.01 g/L),Pos,%,%,41,15,113,139,86,25,136,197,116,36,221,301,Correspondence Between Commercial Assays and Western Blotting,Assay Positive WBDSA Negative WBDSA Total,Beckman 10%CV+17 20 37-11 106 117Roche 10%CV+16 8 24-12 118 130Beckma

13、n 99th%+20 38 58-8 88 96Roche 99th%+21 44 65-7 82 89,MyeloperoxidasePredictions of Events When cTNT“Negative”,CP1131968-3,NEJM 349:1600,2003,Odds ratio,Odds ratio,RevascularizationMyeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 4Major adverse cardiac eventsMyeloperoxidas

14、e quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 4,30 Days,6 Months,Prognostic Effects of MPO at 72 Hours,CP1132618-7,Death,MI(%),Circulation 108:1443,2003,Before PCI,Adjusted hazard ratio2.04(0.65-6.42),Adjusted hazard ratio3.07(1.21-4.26),MPO high,MPO low,After PCI,Hours,cTnI Negativ

15、e ACS?,Circulation 107:533,2003,CP1104508-19,Sensitivity of cTnI,CK-MB,and Myoglobin with Sensitive Contemporary Assays,AHJ 148:577,2004,TnI(0.1 g/L)CK-MB(3.5 g/L)Myo(98/56 g/L),CP1176222-2,0 min,30 min,60 min,90 minSensitivity,2 hr,3 hr,6 hr,6 hrSpecificity,TnI(0.4 g/L)TnI(0.1 g/L)TnI(0.07 g/L),cTn

16、T and Angiographic Measures,CP1179389-5,TnT(0.01),Prog Cardiovasc Dis 47(3),2004,P0.001,Stenosis(%),TnT(0.01),P=0.02,Thrombus(%),P=0.03,TFG 0/1(%),P0.001,TMPG 0/1(%),JACC 36(3):970-1062,2000,Medical and Interventional Response to GP IIb/IIIa Agents in Troponin Positive Patients,+24h,+48h,+24h,+48h,+

17、72h,n=1,265,OR=0.37,P=0.032,CAPTURE,2.8%,1.3%,n=9,461,OR=0.72,P=0.003,PURSUIT,n=1,570,OR=0.45,P=0.016,PRISM-PLUS,n=12,296,OR=0.66,P=0.001,All,n=1,239,OR=0.46,P=0.009,n=1,228,OR=0.71,P=0.105,n=287,OR=0.35,P=0.062,n=2,754,OR=0.59,P=0.001,5.8%,2.8%,10.3%,7.6%,8.0%,2.9%,8.0%,4.9%,4.4%,3.2%,3.8%,1.8%,4.3

18、%,3.9%,Death or MI(%),Start GP IIb/IIIa inhibitor/placebo,Percutaneous coronary intervention,CP956024-13,LMW Heparin vs VF Heparin in TIMI 11B,J Am Coll Cardiol 36:1812,2000,CP1008642-5,TACTICS(TIMI 18),CP1036852-9,ConservativeInvasiveNo.treatmenttreatmentPrimary endpoint0.1 ng/mL734 4.36.60.1-0.418

19、116.54.40.4-1.521317.65.41.569315.68.8Death or MI0.1 ng/mL734 1.93.00.1-0.418112.14.40.4-1.521311.82.71.569310.05.9,Cardiac troponin I,JAMA 286:2405,2001,Favors invasive treatment,Favors Conservative treatment,Odds ratio,Relation Between Creatinine Clearance,Troponin T,and Outcomes,CURERates and Rel

20、ative Risks of First Primary Outcome,CP1019654-1,NEJM 345:494,2001,CP1189452-4,4 peptides related with each other regarding biochemistry and physiological functionAtrial natriureticpeptide(ANP)Brain(or B type)natriuretic peptide(BNP)C-type natriuretic peptide(CNP)Urodilatin,a slightly extended form

21、of ANP,Natriuretic Peptide Family,Common 17-amino acidring structureRing structure highlyconserved11/17 amino acidsare homologousRing structure essentialfor physiological activity,CP1189452-5,Natriuretic Peptide FamilyBiochemistry,Cardiomyocyte,Blood,proBNP(108 aa)BNP-32(proBNP 77-108),BNP-32Physiol

22、ogically active form,NT-proBNP 1-76,SecretionLV stretchWall tension,Pre-proBNP(134 aa),Signal peptide(26 aa),proBNP,Serin protease(Corin?),Mair:Scand J Clin Lab Invest,1999,CP1189452-10,CP1189452-20,97.5%percentile(pg/mL),3030-3940-4950-5960,Age groups,Age-Specific Reference Rangefor NT-proBNP,AHJ 1

23、49(4),April 2005,pg/mL,NT-proBNP,pg/mL,BNP,Weight categories(BMI),Weight categories(BMI),25,25-29.9,30,25,25-29.9,30,P0.001,P0.001,Values of BNP and NTproBNP by Weight,CP1189452-21,38 4,BNPconcentration(pg/mL),Diagnosis,n=139,1,076 138,No CHF,CP1189452-25,n=97,CHF,LV dysfunctionNo acute CHF,n=14,141

24、 31,BNP Levels of Patients Diagnosed Without CHF,with Baseline Left Ventricular Dysfunction,and with CHF,BNP Levels in Heart Failure,MedianBNP level(pg/mL),CP1189452-26,BNP Levels in Normal Subjects and Inpatientswith Heart Failure,Normal,I,II,III,IV,Class,CP1189452-27,ED Probability of CHF Recorded

25、,P0.0001 from clinical judgment to combined,McCullough PA et al:Circulation 106:416,2002,Diagnostic accuracy(%),Clinicaljudgment,BNP,Combined,70727476788082,74.0,81.2,81.5,n=1,538,BNP Study Primary End Point,n=1,586;50%CHF;56%male;6417 yo;41%COPD;30%Hx CHF,CP1189452-28,BNP(pg/mL)SensSpecPPVNPV 50976

26、271951009076798915085838385,AUC=0.91,Breathing Not Proper(BNP)Multicenter Trial,AJC 95,April 15,2005,Optimal cut-point SensSpecPPVNPVAccuracy(%)(%)(%)(%)(%)(%)Rule-in cutpointsAll pt(n=599)900908576948750 yr old4509395679995n=14450 yr old9009180779285n=455Rule-out ptAll pt(n=599)3009968629983,CP1189

27、452-30,Optimal NT-proBNP Cutpoints for Acute Congestive Heart Failure,McCullough PA et al for the BNP Multinational Study Investigators:J Am Coll Cardiol 41:278A,2003,Application of BNP Testing in CHF,“Grey Zone”BNP,BNP(pg/mL),“Grey Zone”BNP100-500 pg/mL,26.4%of all cases,16.5%CHF,7.9%No CHF,0,100,2

28、00,300,400,500,600,700,800,900,1,000,1,100,1,200,1,300,CP1189452-31,CP1189452-32,pg/mLCoronary pulmonale200-500Primary pulmonary300-500 hypertensionAcute pulmonary150-500 embolism,BNP ElevationsRight-Sided Coronary Heart Failure,CP1189452-33,Acute or chronic systolic or diastolic HFLV hypertrophyInf

29、lammatory cardiac diseasesSystemic arterial hypertension with LVHPulmonary hypertensionAcute or chronic renal failureAscitic liver cirrhosisEndocrine disorders(eg,hyper-aldosteronism,Cushings syndrome),When Can Non-CHF Patients Present with BNP Elevations?,CP1189452-34,Well HF patientsAcute mitral r

30、egurgitationPulmonary edema 1 hour oldOther cases“up-stream”fromleft ventricleMitral stenosisAtrial myoxma,When Will CHF PresentWithout BNP Elevations?,P 0.0001,P=0.9,Baseline BNP&Clinical Outcomes,P 0.0001,P=0.9,Death,MI,N=1356,N=320,Morrow DA JACC 2004,CP1173030-6,Relationship of NT-proBNP and cTn

31、T,*P0.01 vs NT-proBNP 250 ng/LCirculation 110:3206,2004,*,*,Death/MI at 6 months,Test for interaction:P=NS,%,BNP negBNP cut point=80 pg/mL,CP1189452-45,CONS,INV,BNP pos(19%BNP pos),n=681685156164,Morrow DA:JACC,2004,Baseline BNP:CONS vs INV Strategy,Beta-Blocker Therapy and BNP Levels,Luchner A et a

32、l:JACC 32:1839,1998,pg/mL,pmol/mL,ANP 32%,BNP 89%,cGMP 18%,n=592,n=80,P0.01,P0.01,P0.01,No b-blocker(n=592)b-blocker(n=80),CP1189452-59,Outcomes by Number of Positive OutcomesTACTICS-TIMI 18,CP1143360-10,Circ 109:584,2004,Deathor MI(%),P=NS,Positive markers(no.),P=NS,P=NS,2.9,4.4,6.2,6.5,12.1,13.3,Death or MI by Multimarker Approach,Odds of Positive MarkerTACTICS-TIMI 18,CP1143360-7,Circ 109:583,2004,T18 TnlT11 TnlCombinedT18 TnTT11 TnTCombinedT18 BNPT16 BNPCombinedT18 CRPT11 CRPCombined,Male more likely,Female more likely,00.511.52,