1、脑钠肽(BNP)与心力衰竭的研究进展,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 HF,Jong P et al. Arch Intern Med. 2002;162:1689,0,25,50,75,100,20%,50%,30 days,6 mo,Hospital Readmissions,0,25,50,75,100,12%,50%,30 days,12 mo,Mortality,33%,5 yr,Median hospital LOS: 6 days,Annual mortality
2、 rate- NYHA class III HF- 12% COPERNICUS DATA NYHA class II HF- 7% SCD-HeFT DATA,在美国，因心衰入院人数=每年一百万。总费用=560亿美元 住院治疗花费中，70-75%直接用于患者护理 心衰住院治疗后再入院=6个月内达45%,心衰的治疗负担,Increased morbidity and mortality,Diuretic therapy,Impaired renal function,Decreased renalperfusion,Diuretic resistance,Diminished blood fl
3、ow,Neurohormonal activation,Potential Deleterious Effects of Diuretics and Cardiorenal Syndrome of HF,Neurohormonal activation,Vasoconstriction,Congestion,Pathologic remodeling,Hemodynamic (balanced vasodilation) veins arteries coronary arteries,B-Type Natriuretic Peptide (BNP),Neurohumoralaldostero
4、neendothelinnorepinephrine,RenaldiuresisnatriuresisGFR,Cardiac lusitropic antifibrotic anti-remodeling,Jamieson and Palade. J Cell Biol. 1964;23:151.,Natriuretic Peptides: The Heart as a Secretory Organ,Atrial stretch receptors link blood volume to renal function Distension of a balloon catheter in
5、atria of dogs resulted in diuresis Henry et al (1956) Secretory granules discovered in the atria Kisch (1956) Jamieson and Palade (1964) BNP was characterized by amino acid sequence and DNA clones Sudoh et al (1988) Seilhamer et al (1989),Natriuretic Peptides,Adapted from Burnett JC. J Hypertens. 20
6、00;17(Suppl 1):S37-S43.,ANP = Atrial Natriuretic Peptide BNP = B-type Natriuretic Peptide CNP = C-type Natriuretic Peptide,Peptide Primary Origin Stimulus of Release ANP Cardiac atria Atrial distensionBNP Ventricular myocardium Ventricular overloadCNP Endothelium Endothelial stress,Natriuretic Pepti
7、des: Origin and Stimulus of Release,H2N,H2N,COOH,COOH,COOH,pro-BNP (aa1 - aa108),Cleavage,BNP (aa77 - aa108),NT-proBNP (aa1 - aa76),P,L,G,S,P,G,S,A,S,Y,T,L,R,A,P,R,S,P,K,M,V,Q,G,S,G,C,F,C,R,K,M,D,R,I,S,S,S,S,G,L,C,C,K,V,L,R,R,H,P,L,G,S,P,G,S,A,S,Y,T,L,R,A,P,R,S,P,K,M,V,Q,G,S,G,C,F,C,R,K,M,D,R,I,S,S,
8、S,S,G,L,C,C,K,V,L,R,R,H,H2N,1,10,70,76,80,90,100,108,1,10,70,76,Myocard,Blood,pre-proBNP 1 - 134 (134 Aa),Signal peptide (26 Aa),28,17,14,6,3,kDa,Rec. A B C D E blank Rec.,Clinical BNP Results pg/,mL,:,A,B,C,D,E,Maisel,3920 3720 4010 2090 127,in,-,house Triage 1140 1440 1260,1570 584,在心衰患者中BNP主要的形式是
9、proBNP,proBNP,BNP,5 CHF patients:,Liang, Maisel et al., JACC 2007,All,55-64,65-74,75+,Age,All non-CHF,Non-CHF Male,Non-CHF Female,BNP Levels in Non-CHF Patients,BNP (pg/mL),0,50,100,(n=478),ADHF中的BNP水平和院内死亡率 BNP水平的分布,在初期评估中，77,467例患者中有 48,629 例 (63%)作了BNP评估.在ADHERE项目中仅 3.3%的患者 初始 BNP水平 100 pg/mL,Fon
10、arow et al, JACC 2007 in press,Baseline BNP and Mortality in HF: Val-HeFT Study,1.0,0.8,0.6,0.5,0,0,24,12,36,48,Survival,Month,Q1 41,Anand IS et al. Circulation. 2003;107:1276-1281.,Q2 41-97,0.9,0.7,Q3 97-238,Q4 238,P0.0001,RR 95% CI,1.0,1.47 (1.15-1.89),2.27 (1.80-2.86),3.95 3.18-4.92),BNP Levels I
11、ndependently Predict Mortality in Patients with ESRD on Hemodialysis,246 patients on hemodialysis without clinical CHF diagnosis J Am Soc Nephr. 2001;12:1508-1515.,7.14,0,1,2,3,4,5,6,7,8,Mortality OR,BNP tertile 1,BNP tertile 2,BNP tertile 3,Mortality OR 7.14 (95% CI 2.83-18.0) P0.00001,3.20,1.00,BN
12、P Predicts Sudden Death in Patients with Chronic Heart Failure,452 pts with HF, LVEF 13 0 pg/mL only multivariate predictor of SD (P=0.0006) Berger. Circulation. 2002;105:2392-2397.,连续BNP测定能指导住院治疗吗?,Courtesy of Damien Logeart.,住院期间BNP值,Logeart D, et al, JACC, 18 February 2004, Volume 43, Issue 4 Pag
13、es 635-641,BNP在急性充血性心力衰竭 住院治疗和结果评价,0,500,1000,1500,2000,2500,admission follow-up,(pg/mL),n=22 Endpoints:13 deaths9 re-admissions (30d),n=50 No Endpoints,BNP +233 pg/mL,BNP -215 pg/mL,Cheng,Maisel. JACC 2001;37:386-91,入院和出院前BNP值(pg/mL) 和住院时间(天),12,10,8,6,4,2,0,BNP on admission,BNP on discharge,Length
14、 of stay,398,123,481,127,1037,729,2.2,6.8,6.9,0,200,400,600,800,1000,1200,BNP1,BNP2,LOS,pg/ml,BNP 250 pg/ml on clinical stability,BNP 250 pg/ml after aggressive therapy,BNP 250 pg/ml,根据出院前 BNP水平作出的Kaplan-Meier曲线显示累积死亡率和再入院率,BNP 250 pg/ml after “normal” treatment,BNP 250 pg/ml,BNP 250 pg/ml after “in
15、tensive” treatment,Tarone-Wares test 0.001.,21,0,2,4,6,8,10,BNP 80 pg/mL (n=1251),BNP 80 pg/mL (n=1274),Percent of Patients (%),Death,30 days,P0.005 for each comparison,Braunwald. N Engl J Med. 2001. Vol 345, No. 14.,BNP to Risk Stratify Patients with Acute Coronary Syndromes,10 months,CHF,MI,Death,
16、CHF,MI,0,4,8,12,16,Q1,Q2,Q3,Q4,ST Elevation Non-ST Elevation Unstable Angina Myocardial Infarction Myocardial Infarction,n= 825 565 1133,10-month Mortality (%),P0.001,2525 patients with ACS in TIMI-16 (orofiban vs placebo) BNP level at average 40 hours. Braunwald. N Engl J Med. 2001;345(14).,BNP Lev
17、el (pg/mL) 5-44 44-81 82-138 139-1456,BNP to Risk Stratify Patients with Acute Coronary Syndromes,Maisel A. Rev Cardiovasc Med. 2002;3(suppl 4):S13.,Patient presenting with dyspnea,Physical examination, chest x-ray, ECG, BNP level,BNP 100 pg/mL,BNP 100-400 pg/mL,BNP 400 pg/mL,CHF very unlikely (2%),
18、Baseline LV dysfunction, underlying cor pulmonale or acute pulmonary embolism?,Yes,No,Possible exacerbation of CHF (25%),CHF likely (75%),CHF very likely (95%),Heart Failure Diagnostic Algorithm,BNP levels and NYHA class of HF,NYHA Class BNP level (pg/ml)I 244 + 286II 389 + 374III 640 + 447IV 817 +
19、435,Nesiritide,Identical to human BNP Causing vasodilation and decrease LV filling pressure Decrease pulmonary capillary wedge pressure Improves patients symptoms nesiritide resulted in improvement in hemodynamics and some self-reported symptoms more effectively and with fewer adverse effects than i
20、ntravenous nitroglycerin (VMAC trial ),Hemodynamic Effects of Nesiritide vs Placebo vs IV NTG,*, *, *, *,Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531,During 3-hr placebo period Placebo n = 62 IV NTG n = 60 Nesiritide n = 124After 3-hr period IV NTG n = 92 Nesiritide n = 154,
21、*P0.05 vs placebo P0.05 vs IV NTG,PCWP Placebo,PCWP IV NTG,PCWP Nesiritide,End of Placebo-Controlled Period,Time on Study Drug (hr),0,0.25,0.5,1,2,3,6,9,12,24,36,48,9,8,7,6,5,4,3,2,1,0, *,*,Change From Baseline in PCWP (mm Hg),24小时治疗期间 BNP 和PAW*水平的变化,Msaisel, A. et al. J Cardiac Failure, Vol. 7, No.
22、 1, 2001,*Pulmonary artery wedge.,VMAC: Dyspnea Improvement,*Added to standard care Publication Committee for the VMAC Investigators. JAMA. 2002;287:1531,Dyspnea at 3 hr,Proportion of Subjects (%),Nitroglycerin* (n = 143),Nesiritide* (n = 204),Placebo* (n = 142),40,30,20,10,0,10,20,30,40,50,60,70,80
23、,90,100,P=0.191,P=0.034,Markedly better,Moderately better,Minimally better,No change,Minimally markedly worse,THE NAPA TRIAL: Nesiritide Administered Peri-Anesthesia in Patients Undergoing Cardiac Surgery,Mark J. Russo, MD, MSDivision of Cardiothoracic Surgery & International Center for Health Outco
24、mes and Innovation Research College of Physicians and Surgeons, Columbia University, New York, NY,NAPA TRIAL DESIGN,Multi-center (54 centers)RandomizedDouble-blindPlacebo-controlled,Introduction Methods Results Summary,NAPA TRIAL DESIGN,LV dysfunction (EF40%)NYHA Class II - IVundergoing CABG MVS usi
25、ng cardiopulmonary bypass,Introduction Methods Results Summary,EXCLUSION CRITERIA,Planned AVR/r Off-pump Ongoing or chronic dialysis Hemodynamic criteria Mean PAP 15 mm Hg CVP 6 mm Hg SBP 90 mm Hg,Introduction Methods Results Summary,STUDY PROTOCOL,Introduction Methods Results Summary,NAPA FINDINGS,
26、Introduction Methods Results Summary,Improved Survival at 180 daysImproved Postop Renal Function Greater improvement in patients with renal dysfunction at baseline Decreased LOS,新活素TM的处方资料,通用名 基因重组人脑钠肽(rhBNP) 商品名 新活素TM 结构及分子式,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,起效时间 2-15min 最大药效时间 30min T1/2 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,急、慢性失代偿性心力衰竭 急性冠脉综合征（ACS） 心脏导管手术 心胸外科手术 血浆脑利钠肽浓度升高的其他疾病,谢谢,
