脑钠肽脑钠肽(BNP)与心力衰竭的与心力衰竭的研究进展研究进展北京世纪坛医院北京大学第九临床医学院 杨水祥 教授2009年8月20日Outcomes in Patients Hospitalized With HFJong P et al. Arch Intern Med. 2002;162:1689025507510020%50%30days6moHospital Readmissions025507510012%50%30days12moMortality33%5yrMedian hospital LOS: 6 daysAnnual mortality rate-NYHA class III HF-12% COPERNICUS DATANYHA class II HF-7% SCD-HeFT DATA在美国，因心衰入院人数在美国，因心衰入院人数=每年一百万。总每年一百万。总费用费用=560亿美元亿美元住院治疗花费中，住院治疗花费中，70-75%直接用于患者护直接用于患者护理理心衰住院治疗后再入院心衰住院治疗后再入院=6个月内达个月内达45% 心衰的治疗负担心衰的治疗负担Increased morbidityand mortalityDiuretic therapyImpaired renalfunctionDecreased renal perfusionDiuretic resistanceDiminishedblood flowNeurohormonalactivationPotential Deleterious Effects of Diuretics and Cardiorenal Syndrome of HFNeurohormonalactivationVasoconstrictionCongestionPathologicremodelingHemodynamicHemodynamic(balanced vasodilation)(balanced vasodilation)llveinsveinsllarteriesarteriesllcoronary arteriescoronary arteriesB-Type Natriuretic Peptide (BNP)NeurohumoralNeurohumoral aldosterone aldosterone endothelin endothelin norepinephrine norepinephrineRenalRenal diuresis diuresis natriuresis natriuresis GFR GFRDRIMKRGSSSSGLGFCCSSGSGQVMKVLRRHKPSCardiac Cardiac lllusitropiclusitropicllantifibroticantifibroticllanti-remodelinganti-remodelingJamieson and Palade. J Cell Biol. 1964;23:151.Natriuretic Peptides:The Heart as a Secretory OrganAtrial stretch receptors link blood volume to renal functionDistension of a balloon catheter in atria of dogs resulted in diuresisHenry et al (1956)Secretory granules discovered in the atriaKisch (1956)Jamieson and Palade (1964)BNP was characterized by amino acid sequence and DNA clones Sudoh et al (1988)Seilhamer et al (1989)Natriuretic PeptidesAdapted from Burnett JC. J Hypertens. 2000;17(Suppl 1):S37-S43.ANP = Atrial Natriuretic PeptideBNP = B-type Natriuretic PeptideCNP = C-type Natriuretic PeptidePeptidePrimary OriginStimulus of ReleaseANPCardiac atriaAtrial distensionBNPVentricular myocardium Ventricular overloadCNPEndothelium Endothelial stressNatriuretic Peptides:Origin and Stimulus of ReleaseH2NH2NCOOHCOOHCOOHpro-BNP (aa1 - aa108)CleavageBNP (aa77 - aa108)NT-proBNP (aa1 - aa76)HPLGSPGSASYTLRAPRSPKMVQGSGCFCRKMDRISSSSGLCCKVLRRHHPLGSPGSASYTLR APRSPKMVQGSGCFCRKMDRISSSSGLCCKVLRRHH2N110707680901001081107076MyocardMyocardBloodBloodpre-proBNP 1 - 134(134 Aa)Signal peptide(26 Aa)28171463kDa Rec. A B C D E blank Rec. Clinical BNP Results pg/mL: A BCDEMaisel3920 3720 4010 2090 127in-house Triage 1140 1440 1260 1570 584在心衰患者中在心衰患者中BNP主要的形式是主要的形式是proBNPproBNP BNP5 CHF patients:Liang, Maisel et al., JACC 2007All55-6465-7475+AgeAll non-CHFNon-CHF MaleNon-CHF FemaleBNP Levels in Non-CHF PatientsBNP (pg/mL)050100(n=478)ADHFADHF中的中的中的中的BNPBNP水平和院内死亡率水平和院内死亡率水平和院内死亡率水平和院内死亡率 BNP水平的分布水平的分布(pg/mL)在初期评估中，在初期评估中，77,467例患者中有例患者中有 48,629 例例 (63%)作了作了BNP评估评估.在在ADHERE项目中仅项目中仅 3.3%的患者的患者 初始初始 BNP水平水平 100 pg/mLFonarow et al, JACC 2007 in pressBaseline BNP and Mortality in HF:Val-HeFT Study1.00.80.60.50024123648SurvivalMonthQ1 238P0.0001RR 95% CI1.01.47 (1.15-1.89)2.27 (1.80-2.86)3.95 3.18-4.92)BNP Levels Independently Predict Mortality in Patients with ESRD on Hemodialysis246 patients on hemodialysis without clinical CHF diagnosisJ Am Soc Nephr. 2001;12:1508-1515.7.14012345678Mortality ORBNP tertile 1BNP tertile 2BNP tertile 3Mortality OR 7.14 (95% CI 2.83-18.0)P0.000013.201.00BNP Predicts Sudden Death in Patients with Chronic Heart Failure452 pts with HF, LVEF 13 0 pg/mL only multivariate predictor of SD (P=0.0006)Berger. Circulation. 2002;105:2392-2397.连续连续BNP测定能测定能指导住院治疗吗指导住院治疗吗? Courtesy of Damien Logeart.住院期间住院期间BNP值值Logeart D, et al, JACC, 18 February 2004, Volume 43, Issue 4 Pages 635-641BNP在急性充血性心力衰竭在急性充血性心力衰竭 住院治疗和结果评价住院治疗和结果评价05001000150020002500admission follow-up(pg/mL)n=22Endpoints:13 deaths 9 re-admissions (30d)n=50No EndpointsBNP+233pg/BNP+233pg/ mLBNP-215pg/BNP-215pg/ mLCheng,Maisel. JACC 2001;37:386-91入院和出院前入院和出院前BNP值值(pg/mL)和住院时间和住院时间(天天)121086420BNP onadmissionBNP ondischargeLength of stay39812348112710377292.26.86.9020040060080010001200BNP1BNP2LOSpg/mlBNP 250 pg/ml on clinical stabilityBNP 250 pg/ml根据出院前根据出院前 BNP水平作出的水平作出的Kaplan-Meier曲线显曲线显示累积死亡率和再入院率示累积死亡率和再入院率BNP 250 pg/mlBNP 250 pg/ml after“intensive” treatmentTarone-Wares test 80 pg/mL (n=1274)Percent of Patients (%) Death 30 daysP0.005 for each comparisonBraunwald. N Engl J Med. 2001. Vol 345, No. 14.BNP to Risk Stratify Patients withAcute Coronary Syndromes10 monthsCHFMI DeathCHFMI0481216Q1Q2Q3Q4 ST Elevation Non-ST Elevation Unstable AnginaMyocardial Infarction Myocardial Infarctionn= 825 565 113310-month Mortality (%) P0.0012525 patients with ACS in TIMI-16 (orofiban vs placebo) BNP level at average 40 hours.Braunwald. N Engl J Med. 2001;345(14).BNP Level (pg/mL) 5-44 44-81 82-138 139-1456 BNP to Risk Stratify Patients withAcute Coronary SyndromesMaisel A. Rev Cardiovasc Med. 2002;3(suppl 4):S13.Patient presenting with dyspneaPhysical examination,chest x-ray, ECG,BNP levelBNP 400 pg/mLCHF very unlikely(2%)Baseline LV dysfunction,underlying cor pulmonale oracute pulmonary embolism?YesNoPossibleexacerbation of CHF(25%)CHF likely(75%)CHF very likely(95%)Heart Failure Diagnostic AlgorithmBNP levels and NYHA class of HFNYHA ClassBNP level (pg/ml) I244 + 286 II389 + 374 III640 + 447 IV817 + 435NesiritideIdentical to human BNPCausing vasodilation and decrease LV filling pressureDecrease pulmonary capillary wedge pressureImproves patients symptomsnesiritide resulted in improvement in hemodynamics and some self-reported symptoms more effectively and with fewer adverse effects than intravenous nitroglycerin (VMAC trial )Hemodynamic Effects of Nesiritide vs Placebo vs IV NTG*Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531During 3-hr placebo periodPlacebon = 62 IV NTGn = 60Nesiritiden = 124After 3-hr periodIV NTGn = 92Nesiritiden = 154*P 0.05 vs placeboP 0.05 vs IV NTG PCWP Placebo PCWP IV NTG PCWP NesiritideEnd of Placebo-Controlled PeriodTime on Study Drug (hr)00.250.5 12369 12 24 36 489876543210*Change From Baseline in PCWP (mm Hg)24小时治疗期间小时治疗期间 BNP 和和PAW*水平的变化水平的变化Msaisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001N = 15 (responders)PAW (mm Hg)HoursBNP (pg/ml)15171921232527293133baseline48121620246007008009001000110012001300PAWBNP*Pulmonary artery wedge.VMAC: Dyspnea Improvement *Added to standard carePublication Committee for the VMAC Investigators. JAMA. 2002;287:1531Dyspnea at 3 hrProportion of Subjects (%)Nitroglycerin* (n = 143)Nesiritide* (n = 204)Placebo* (n = 142) 40 30 20 100102030405060708090100P=0.191P=0.034Markedly betterModerately betterMinimally betterNo changeMinimally markedly worseTHENAPATRIAL:Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery MarkJ.Russo,MD,MSDivisionofCardiothoracicSurgery&InternationalCenterforHealthOutcomesandInnovationResearchCollegeofPhysiciansandSurgeons,ColumbiaUniversity,NewYork,NYNAPA TRIAL DESIGNMulti-center (54 centers)RandomizedDouble-blindPlacebo-controlledIntroductionMethodsResultsSummaryNAPA TRIAL DESIGNLV dysfunction (EF40%)NYHA Class II - IVundergoing CABG MVS using cardiopulmonary bypassIntroductionMethodsResultsSummaryEXCLUSION CRITERIAPlanned AVR/rOff-pumpOngoing or chronic dialysis Hemodynamic criteriaMean PAP 15 mm HgCVP 6 mm HgSBP 90 mm HgIntroductionMethodsResultsSummarySTUDY PROTOCOLIntroductionMethodsResultsSummaryNAPA FINDINGSIntroductionMethodsResultsSummaryImproved Survival at 180 daysImproved Postop Renal FunctionGreater improvement in patients with renal dysfunction at baselineDecreased LOS新活素新活素TM的处方资料的处方资料通用名通用名 基因重组人脑钠肽基因重组人脑钠肽(rhBNP)商品名商品名 新活素新活素TMTM结构及分子式结构及分子式SSDRIMKRGSSSSGLGFCCGSGQVMK VLRRKPSH 脑钠肽是人体分泌的一种内源性利钠肽，它是在各种病理因素诱导下发 生心功能受损时，人体产生的一种代偿性心脏保护因子。 新活素TM与内源性人脑利钠肽具有相同的氨基酸排序和立体结构。药代动力学药代动力学起效时间 2-15min最大药效时间 30minT1/2 18min代谢/排泄途径C型受体分解失活(血管内皮细胞)中性肽链内切酶肾脏过滤清除(2%)适应症适应症急、慢性失代偿性心力衰竭急、慢性失代偿性心力衰竭急性冠脉综合征急性冠脉综合征（ACS）心脏导管手术心脏导管手术心胸外科手术心胸外科手术血浆脑利钠肽浓度升高的其他疾病血浆脑利钠肽浓度升高的其他疾病