利用生物标志物患者急性心血管疾病

1、CP887679- 0 *Dr. Jaffe is a consultant and receives research support from Roche, Dade Behring and Beckmann Coulter. He has been or presently is a consultant to Ortho Diagnostics, Sensera, Diadexus, Abbott, Hawaii Biotech and Tartagen.CP1051812-10.00.51.00306090 120 150 1800.00.51.00306090 120 150 18

2、00.00.51.00306090 120 150 1800.00.51.00306090 120 150 1800.00.51.00306090 120 150 180CP887679- 2CP956024-120102030060120180240300360CP887679- 3100CP887679- 4Circulation. 1997;95:2053-2059 CP887679- 50.20.11 51050CP887679- 60.20.11 51050CP887679- 7CP886232- 783117414813450671.01.83.53.96.27.8Risk rat

3、io-0.5-6.71.2-10.61.3-11.71.7-22.32.6-23.095% CI CP887679- 8CP1099500-8JACC 41:376, 20036-modeath/MI raten=262ST-depressionP=0.20n=125n=259n=174n=57n=82P=0.13P=0.15TroponinTroponin+CP887679- 9CP1142356-17James et al: Am J Med 115:181, 2003141210864200.01 g/LFRISC-IIDeath and MI at 30 days (%)0.03 g/

4、LP=0.04Below cutoffAbove cutoff0.1 g/LP=0.01P=0.15Cutoff0.01 g/LGUSTO-IV0.03 g/LP0.0010.1 g/LP0.001P0.001Cutoff118017743061665211114762013862658093287464306441,992 5,1232,563 4,5523,446 3,679CP887679- 100.010.020.030.040.050.060.0ABCDEGHTotal CV, %ACS180CentaurImmuno 1AccessAccess2VidasLiaisonRXL CS

5、OpusImmuliteAlpha DxECiAIA 21IFCC Precision Study(Clinical Chem 2004)CP887679- 11OR 4.55; 2.66-7.78Rapid Troponin I AssayCP1148152-9Int J Cardiol 93:113, 2004%NegDeathMIDeath or MI569892130132205Troponin T (0.1 g/L)Troponin T (0.01 g/L)OR 1.80; 1.30-2.541.82; 1.38-2.401.64; 1.31-2.06OR 3.20; 2.22-4.

6、592.26; 1.79-2.851.47; 1.12-1.933.42; 2.57-5.984.29; 3.02-6.09Pos%4115113139862513619711636221301CP887679- 12Assay Positive WBDSA Negative WBDSA TotalBeckman 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- 13CP1131

7、968-3NEJM 349:1600, 2003Odds ratioOdds ratioRevascularizationMyeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 4Major adverse cardiac eventsMyeloperoxidase quartile 2Myeloperoxidase quartile 3Myeloperoxidase quartile 430 Days6 MonthsUnadjustedAdjustedCP887679- 14CP1132618-

8、7CP887679- 15CP1104508-19CP887679- 16AHJ 148:577, 2004TnI (0.1 g/L)CK-MB (3.5 g/L)Myo (98/56 g/L)CP1176222-20 min30 min60 min90 minSensitivity2 hr3 hr6 hr6 hrSpecificity TnI (0.4 g/L)TnI (0.1 g/L)TnI (0.07 g/L)CP887679- 17CP1179389-5TnT (0.01)Prog Cardiovasc Dis 47(3), 2004P0.01)P=0.02Thrombus (%)P=

9、0.03TFG 0/1 (%)P0.001TMPG 0/1 (%)CP887679- 18CP956024-13CP887679- 19CP1008642-5CP887679- 20CP1036852-9Conservative InvasiveNo.treatmenttreatmentPrimary endpoint0.1 ng/mL734 4.36.60.1 - 0.418116.54.40.4 - 1.521317.65.4 1.569315.68.8Death or MI0.1 ng/mL734 1.93.00.1 - 0.418112.14.40.4 - 98.6 98.677.0-

10、98.577.0-98.558.4-76.958.4-76.94.7-58.34.7-58.3Death or MI %Death or MI %25252020151510105 50 025252020151510105 50 0CP887679- 22CP1019654-1Pt with event (%)PatientsCharacteristic(no.)Placebo ClopidogrelOverall12,56211.4 9.3Associated MI 3,28313.711.3No associated MI 9,27910.6 8.6Male 7,72611.9 9.1F

11、emale 4,83610.7 9.5 65 yr old 6,354 7.6 5.465 yr old 6,20815.313.3ST-segment deviation 6,27514.311.5No ST-segment deviation 6,287 8.6 7.0Enzymes elevated at entry 3,17613.010.7Enzymes not elevated at entry 9,38610.9 8.8Diabetes 2,84016.714.2No diabetes 9,722 9.9 7.9Low risk 4,187 6.7 5.1Intermediate

12、 risk 4,185 9.4 6.5High risk 4,18418.016.3History of revascularization 2,24614.4 8.4No history of revascularization10,31610.7 9.5Revascularization after randomization 4,57713.911.5No revascularization after randomization 7,98510.0 8.1Relative risk (95% CI)ClopidogrelbetterPlacebobetterCP887679- 23CP

13、1189452-44 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 of ANPCFCDRISGLCCCP887679- 24Common 17-amino acidring structureRing

14、 structure highlyconserved11/17 amino acidsare homologousRing structure essentialfor physiological activityCFCDRISGLCCCP1189452-5CP887679- 25proBNP (108 aa)BNP-32 (proBNP 77-108) BNP-32Physiologically active formNT-proBNP 1-76SecretionLV stretchWall tensionPre-proBNP (134 aa)Signal peptide (26 aa)pr

15、oBNPSerin protease(Corin?)Mair: Scand J Clin Lab Invest, 1999CP1189452-10CP887679- 26CP1189452-2097.5%percentile(pg/mL)3030-3940-4950-59 60Age groupsMalesFemalesCP887679- 27AHJ 149(4), April 2005CP1189452-21CP887679- 2838 4BNPconcentration(pg/mL)Diagnosisn=1391,076 138No CHFCP1189452-25n=97CHFLV dys

16、functionNo acute CHFn=14141 31CP887679- 29MedianBNP level(pg/mL)CP1189452-26BNP Levels in Normal Subjects and Inpatientswith Heart FailureNormalIIIIIIIVClassCP887679- 30CP1189452-27ED Probability of CHF RecordedP0.0001 from clinical judgment to combinedMcCullough PA et al: Circulation 106:416, 2002D

17、iagnostic accuracy (%)ClinicaljudgmentBNPCombined7072747678808274.081.281.5n=1,538CP887679- 31n=1,586; 50% CHF; 56% male;6417 yo; 41% COPD; 30% Hx CHFCP1189452-28 BNP(pg/mL)SensSpecPPVNPV 50976271951009076798915085838385AUC = 0.91CP887679- 32AJC 95, April 15, 2005Optimal cut-point Sens Spec PPV NPV

18、Accuracy(%) (%)(%)(%)(%) (%)Rule-in cutpointsAll pt (n=599)900908576948750 yr old4509395679995n=144 50 yr old9009180779285n=455Rule-out ptAll pt (n=599) 3009968629983CP1189452-30CP887679- 33McCullough PA et al for the BNP Multinational Study Investigators: J Am Coll Cardiol 41:278A, 2003Application

19、of BNP Testing in CHF“Grey Zone” BNPBNP (pg/mL)“Grey Zone” BNP100-500 pg/mL26.4% of all cases16.5%CHF7.9%No CHF0100200300400500600700800900 1,000 1,100 1,200 1,300CP1189452-31CP887679- 34CP1189452-32pg/mLCoronary pulmonale200-500Primary pulmonary300-500 hypertensionAcute pulmonary150-500 embolismCP8

20、87679- 35CP1189452-33Acute or chronic systolic or diastolic HFLV hypertrophyInflammatory cardiac diseasesSystemic arterial hypertension with LVHPulmonary hypertensionAcute or chronic renal failureAscitic liver cirrhosisEndocrine disorders (eg, hyper-aldosteronism, Cushings syndrome)CP887679- 36CP118

21、9452-34Well HF patientsAcute mitral regurgitationPulmonary edema 1 hour oldOther cases “up-stream” fromleft ventricleMitral stenosisAtrial myoxmaCP887679- 371.21.85.08.401234567891030 Days6 Months%P 0.0001P = 0.9Baseline BNP & Clinical Outcomes P 0.0001P = 0.9DeathMI3.85.24.15.301234567891030 Days6 Months%BNP 80N = 1356N = 320Morrow DA JACC 2004 CP887679- 38CP1173030-6*P250 ng/L250 n