体外反搏与心功能保护幻灯.pptx

体外反搏与心功能保护体外反搏与心功能保护伍贵富伍贵富中山大学附属第一医院心内科中山大学附属第一医院心内科卫生部辅助循环重点实验室卫生部辅助循环重点实验室2009.8.22 2009.8.22 大连大连Enhanced External Counterpulsation（EECPEECP）A Non-invasive Therapy for Heart Failure心力衰竭治疗存在的问题社会老龄化，心肌梗塞死亡率下降，但心力衰竭患者增加，健康保障系统不堪重负目前缺乏治疗心力衰竭的有效手段心衰死亡率居高不下（53,000人/年 2001年，USA)严格定义心力衰竭不易，因其不仅仅是一个单器官病变，而是一个全身性的临床综合征心力衰竭的治疗不仅仅局限于心功能改善，还需要强调系统性的病理生理机制的干预心力衰竭的非药物治疗起搏器（Pacemaker）植入式心脏除颤器（Implantable cardioverter defibrilator）心室辅助装置/人工心脏（Ventricular assist device/Artifical heart）超滤（Utrafiltration）心室再同步化（Cardiac Resynchronization therapy）体外反搏体外反搏（EECP）体内反搏（IABP）体外反搏（EECP）辅助衰竭的心脏：从内反搏到外反搏19621962年，年，USAUSA液压水囊式体外反搏液压水囊式体外反搏非序贯式加压非序贯式加压笨重，体积大笨重，体积大未能推广未能推广19721972年年,中国中山大学中国中山大学序贯式气囊加压体外反搏序贯式气囊加压体外反搏重量轻，体积小重量轻，体积小安全、有效、无创伤安全、有效、无创伤在中国及全球推广在中国及全球推广源自中国的体外反搏（EECP）疗法获得国际主流媒体的关注和正面报道中国体外反搏技术的国际影响推广应用20个国家和地区体外反搏装置系统工作原理D/S比值1.2执行机构电池阀（开/关）管道（气体传输）主机系统DS囊套（充气/排气）效果监测信息反馈D/S比值心电图调节气泵压力体外反搏的作用原理Diastolic augmentationImprove coronary perfusion Increase Cardiac Output三级气囊序贯充气三级气囊序贯充气舒张期充气舒张期充气 Increase Venous returnECGNormal EECPLower Thigh CuffsUpper Thigh CuffsCalf Cuffs收缩期排气收缩期排气三级气囊同时排气三级气囊同时排气 Systolic UnloadingReduce Cardiac WorkloadIncrease Cardiac OutputLower Thigh CuffsUpper Thigh CuffsCalf Cuffs血流动力学效应增加心输出量增加心输出量Duplex echocardiography Descending AortaLawson,Hui:J of Critical Illness 2000;5:629-636 ControlEECP降低收缩期阻力负荷舒张期主动脉根部血流增加增加CO增加静脉回心血流增加心室舒张期充盈收缩期舒张期降低收缩期阻力负荷增加冠脉血流Michaels AD,et al.Circulation 2002;106:1237-42.Doppler Flow Velocities obtained with FloWire in the LAD增加冠脉血流Increase 150%(N=8)Intracoronary Peak Diastolic Doppler Flow VelocityIncrease 92%(N=9)Intracoronary Diastolic PressureBaselineEECPKatz WE,et al.J Am Coll Cardiol 1998;31Suppl(2):85A(825-31)EECP 1:1 ModeIABP 1:1 ModeIMA DOPPLEREECP GroupIABP GroupDD-TVIDD-TVIBaseline18 66 420 106 6Counterpulsation98 21*19 3*95 21*15 7*D:IMA Diastolic Peak VelocityD-TVI:IMA Diastolic Time Velocity Integral*p 0.0001 vs.baselineScanning Electron MicrographsScale100 m(amplification x500)The luminal surface was covered with many adherent cells.The endothelial cells were in disarray.Less cellular adherenceEndothelial cells align parallel to direction of blood flow体外反搏治疗修复损害的血管内膜Circulation 2007;116:526-534)体外反搏改善内皮依赖的血管舒张能力体外反搏改善内皮依赖的血管舒张能力706050403020100Shear Stress(dynes/cm2)BaselineDuring EECPp0.001Circulation 2007;116(5):526-536Shear Stress Intracoronary Ultrasound Coronary Blood FlowCirculation 2002;106:1237-42Blood flow Am J Cardil 2006;98:28-30020406080100120140160180Baseline 1hr12hr24hr36hr1-moafter3-moafter%increase of NOx levels over baseline Nitric Oxide *p=0.014;p0.0001;p=0.002 vs baselineDuring EECP106.894.073.984.596.7120.9114.1020406080100120140 Baseline 1 hr12 hr 24 hr 36 hr1 Moafter3 moafter*+*p 0.05 *p 0.01 +p 0.05Plasma Endothelin1 During EECP050100150200ControlCHOLCHOL+EECPeNOS protein level(%of control)*p 0.05 vs Control *p 0.05 vs CHOLTCT 2006,Oct 22-27,Washington DCeNOs Circulation 2007;116(5):526-536*NO crosses intimal to Smooth Muscular CellsSmooth Muscle cell relaxation体外反搏改善血流介导的血管舒张能力体外反搏改善血流介导的血管舒张能力Plasma cGMP 01234567High Risk(N=25)CAD(N=30)1-Hr EECPPlasma cGMP(nmol/l)p0.001p0.001BaselineAJH 2006;19:867-872Brachial Artery Flow-Mediated Dilation(FMD)J Am Coll Cardiol 2003;42:2090-5%FMD024681012Control(N=20)EECP(N=20)Baseline2-month after Enrollmentp0.01p=NS%FMD Reactive-Hyperemia Peripheral Arterial Tonometry PAT Index2.01.51.00.501st hr17th hr35th hr 1-month follow-up*N=18 ptNormal PAT Index:1.77 0.18Pre-EECPPost-EECP*p0.05;p0.05 vs pre EECP index on 1st,17th and 35th hr J Am Col Cardiol 2003:41,10,1761-8体外反搏治疗后心肌血流灌注明显改善Am J Cardiol.1992;70:859-862.and J Crit Illness 2000;15(11):629-36 uExercise(Bruce Protocol)uPre-and Post EECP exercise to the same durationu67%showed complete resolutionu11%with partial resolution andu22%no changeuN=18 pts治疗前Post-EECPStressRest StressRest治疗后Capillary Density ControlRegionEECP GroupControl Group75 m sectionInfarctedRegionEuropean Society of Cardiol Congress 1999Angiogenesis/Collateral Circulation00.511.522.533.50.03530.01110.00360.0028p0.01Area stained with anti-VEGF antibody in infarcted regions(mm2/102)Control(N=6)EECP(N=6)Vascular Endothelial Growth Factor Am J of Physiol Heart Circ Physiol 290:H248-H254,2006ControlEECPAm J of Physiol Heart Circ Physiol 290:H248-H254,2006Experimental AMI dog modelControlEECPEndothelial Cell Growth Endothelial cells stained brownEECPControl6050403020100Area strained brown(m2/mm2)p0.055,6671,8941,7101,49701234567EECPControlArea of new capillaries(m2/mm2 sample field)6475316,5922,785p0.05Smooth Muscle Cell Growth ControlEECPX1,000Cardiology 2008;110:160-166体外反搏后冠心病心绞痛患者循环内皮祖细胞增加BaselinePost-treatmentper 105 peripheral blood mononuclear cellsNumber of CD34+/KDR+Cells 02468101214161820Control(N=10)Treated(N=15)p=0.430p=0.04902468101214Control(N=10)Treated(N=15)p=0.557p=0.010EPC Colony Forming Unit per well02468101214Control(N=10)Treated(N=15)p=0.695p0.001FMD(%)Brachial artery Flow Mediated Dilatation 改善神经体液因子改善神经体液因子26.618.815.6051015202530Increase(%)HGFbFGFVEGFCirculation 2001;104(17)Suppl II:444(2109)Change in Angiogenic FactorsEur Heart J 2001;22(16):1451-58ControlDay 11 Week1 Month0102030405060Human Plasma ANP(pg/ml)19.11412.313.90102030405060Human Plasma BNP(pg/ml)36.224.116.817.8ANP and BNPANP and BNP Eur Heart J 2001;22(16):1451-5801234567High Risk(N=25)CAD(N=30)Baseline1-Hr EECPPlasma cGMP(nmol/l)p0.001p0.001Plasma cGMPAJH 2006;19:867-872020406080100120140160 Normal Volunteers(N=17)pg/ml*European Society Cardiol Congress 2001 Normal Baseline 1 hr 12 hrs 24 hrs 36 hrs*p0.001 vs normal p0.001 vs baseline CADPlasma ANG II ActivityEECP treated pts(N=20)*Blood Pressure/Myocardial Oxygen Consumption JACC doi:10.1016/j.jacc.2006.04.094N=20 patients with refractory anginaTension-Time-Index 0510152025BaselineEECPUnits x 10223 5.119 3.9p0.0010102030405060BaselineEECP56 1636 13Dynes-sec-cm2 x 102p0.001Wasted LV Energy Wasted LV pressure energy=2.09 X tp*(Ps Pi)LV Workload=Tension Time Index=area under systolic wavePre-EECPPost-EECP020406080100120140Systolic Pressure Pulse Pressure132 18121 18p=0.00161 1554 16p=0.001Blood Pressure(mm Hg)Brachial Blood Pressure 020406080100120140Systolic Pressure Pulse Pressure120 18108 18p=0.00148 1441 16p=0.001Aortic Blood Pressure Blood Pressure(mm Hg)Pre-EECPPost-EECPNat Clin Pract Cardiovasc Med 2006;3(11):623-32国际体外反搏病人注册研究国际体外反搏病人注册研究International EECP Patient Registries(IEPR)美国 Pittsburgh大学组织完成，随访体外反搏治疗后3年IEPR-1:n=5,056 Jan 1998 to July 2001 from 119 US and 21 International sitesIEPR-2:n=2,917 consecutive patients from Jan 2002 to Oct 2004 from 95 US sites with 2-year follow-up.Entry criteria:patient gave consent and underwent at least 1 hr of EECP treatment.DemographicN=7,973Age(years)SD67.0 10.8Men(%)75Systolic Hypertension(%)75Hyperlipidemia(%)84Diabetes mellitus(%)43Non-cardiac vascular disease(%)34Prior Smoker(%)61Current Smoker(%)8Risk Factors at BaselineTime since CAD diagnosis(years)11 9Prior myocardial infarction(%)69Multivessel CAD(%)80Heart failure(%)31Average LVEF%47%14Prior PCI or CABG(%)87Baseline characteristics of Patients in the IEPRNat Clin Pract Cardiovasc Med 2006;3(11):623-32Distribution of Canadian Cardiovascular Society Class%in each CCS ClassMean#of angina episodes/week 10 14 86%in Class III/IV0102030405060IIIIIIIVCAD Patients with History of CHF0%10%20%30%40%50%60%Effects of EECP on CCS Anginal ClassWithout CHF (N=1,400)Cardiology 2001;96:78-94Data from IEPR0%10%20%30%40%50%60%With CHF(N=548)No AnginaIIIIIIIV%of Patients in Each CCS ClassPre-EECPPost-EECP6-monthWithout CHFWith CHFp value#of pts1,157444MACE8.614.40.001Death2.27.90.001CABG2.01.1NSPCI2.92.5NSMI2.53.6NSCHF2.47.20.001Cardiac hospitalization13.619.10.01Unstable angina7.49.0NSEvents occurring during the 6-month following EECP2-year follow-up for Patients with LVD(EF 35%)Am J Cardiol 2006;97(1):17-20010203040506070%of patientsNoneIIIIIIIVp 1 angina class,8%had no angina post treatment(p800Patients Enrolled228Discontinued BeforeRandomization:41Randomized:187EECP:93Control:94Discontinued:22(23.7%)Adverse event:11(11.8)Protocol violation:2(2.2)Refused assignment:2(2.2)Non-compliance:1(1.1)Subjects decision:5(5.4)Lost to follow-up:2(2.2)Other:4(4.3)Discontinued:13(13.8%)Adverse event:3(3.2)Protocol violation:2(2.1)Refused assignment:1(1.1)Non-compliance:0(0)Subjects decision:6(6.4)Lost to follow-up:1(1.1)Other:1(1.1)Completed:71(76.3%)Completed:81(86.2%)PEECHJ Am Coll Cardiol 2006;48:1198-1205A Single-Blind,Controlled,Randomized Evaluation of Efficacy and SafetyFlow Chart at entry and follow-upPEECH Trial:EndpointsPrimaryPercentage of subjects with at least a 60-second increase in exercise duration from baseline to six months ORPercentage of subjects with at least 1.25 ml/min/kg increase in Peak VO2 from baseline to six monthsSecondaryChanges in exercise duration and Peak VO2Changes in NYHA classificationChanges in quality of life Adverse experiences Feldman AM,et al.J Card Fail Apr 2005;11:240-245.N9394Male72(77.4%)71(75.5%)NSRace-Caucasian76(81.7%)75(79.8%)NSAge(mean yrs,SD)62.4(11.7)63.0(10.4)NSEtiology-Ischemic 64(68.8%)66(70.2%)NSLVEF(mean%,SD)25.9(6.1)26.7(6.5)NSNYHA-Class II-Class III60(64.5%)33(35.5%)62(66.0%)32(34.0%)NSNSHF Treatment-ACEI-ARB-Beta blocker70(75.3%)18(19.4%)79(84.9%)73(77.7%)18(19.1%)81(86.2%)AllNSEECPControlp-valuePEECH:Patient DemographicsJ Am Coll Cardiol 2006;48:1198-1205PEECH:Results of Primary End-pointsPEECH:Results of Primary End-pointsJ Am Coll Cardiol 2006;48:1198-1205EECPControlIncrease 1.25 mL/kg/min from baselinePeak VO2 10.035.4%N=9325.3%N=9422.8%N=9324.1%N=940.05.015.020.025.030.035.040.0%Subjects Who Met Thresholdp=NSp=0.016Exercise DurationIncrease 60 sec from baseline%responders at 6-month follow-upCongestive Cardiac Failure:2006,Nov-Dec,307-311Subgroup Analysis:Age 65 years0510152025303540p=0.00835.1%N=3725%N=4411.4%N=4429.7%N=37p=0.017%Subjects Who Met ThresholdPeak VO2 Exercise DurationIncrease 1.25 mL/kg/min from baselineIncrease 60 sec from baselinePEECH:Changes in Exercise Duration and Peak VOPEECH:Changes in Exercise Duration and Peak VO2 2Change from Baseline(mL/kg/min)-0.10.10.30.5Note:Error bars represent standard error;Baseline Peak VO2:EECP=14.2 vs OPT=13.8,p=NS1 Week3 Months6 Months-0.3-0.5-0.7-0.9p0.001p=0.09p=0.02-1.1-1.1-0.8-0.10.3-0.2Overall PopulationExercise DurationNote:Baseline exercise duration:EECP=611 sec vs OPT=571 sec,p=NS26.434.524.7Change from Baseline(sec)p=0.01p=0.01-9.9-7-5.50.010.020.030.040.0-10.050.0-20.01 Week3 Months6 Monthsp=0.01EECPControlPatients 65 Years2352.230Change from Baseline(sec)p=0.07p0.001p=0.004-22.3-19.13.40.010203040-1050-201 Week3 Months6 MonthsNote:Error bars represent standard errorBaseline exercise duration:EECP=581 vs OPT=552,p=NSPeak VO2Note:Error bars represent standard error;Baseline Peak VO2:EECP=14.7 vs OPT=14.1,p=NS1 Week3 Months6 MonthsChange from Baseline(mL/kg/min)p=NSp=0.07p=NS-0.10.10.30.5-0.3-0.5-0.7-0.9-0.6-0.4-0.40.10.2-0.3 EECP Control%Patients With Improvement in NYHA Class33.331.631.311.412.214.305101520253035p0.001p0.02p0.011 Week3 Months6 MonthsAfter EECP TreatmentImprovement in NYHAPEECH:Secondary EndpointsJ Am Coll Cardiol 2006;48:1198-1205Total Changes in Score From Baseline-10-9-8-7-6-5-4-3-2-101 Week6 Months3 MonthsImprovementp=0.01p=0.01p=NS-8.9-3.4-7.1-2.9-3.7-2.9Quality of Life(Minnesota Living with HF)PEECH:Subjects with Ischemic EtiologyPEECH:Subjects with Ischemic Etiology-30-25-20-15-10-505101520253035Change from Baseline(sec)1 Week3 Months6 MonthsEECPControl-16.7-17.3-25.834.220.6p=0.010p=0.007p=0.01724.6Change in Exercise DurationChange in Peak VO2Change from Baseline(mL/kg/min)-0.9-0.6-0.30.00.30.2-0.7-0.4-0.9p=NSp=0.070.0-0.3p=NS1 Week3 Months6 MonthsN=53(EECP)vs.54(Control)Feldman AM,et al.presented at ACC 2005EECPControlImprovement in NYHA ClassPEECH:Subjects with Ischemic EtiologyPEECH:Subjects with Ischemic Etiology0510152025303540%Patients with Improvement in NYHA Class 1 Week3 Months6 Months37.012.712.315.5p=0.026p=0.00434.536.4p=0.025N=54(EECP)vs.55(Control)Minnesota Living with HF-8-1.1-6.5-1.5-4-1.7-8-6-4-201 Week3 Months6 MonthsFeldman AM,et al.presented at ACC 2005Improvementp=NSp=0.094p=0.04635.840.735.224.524.621.134.629.236.033.033.341.70510152025303540451 Week3 Months6 Months%Subjects Who Met Thresholdp=0.05p=0.03p=0.04p=NSp=0.01p=NS%Responders by Etiology(increased 60 seconds from baseline)PEECH:Exercise Duration19/537/248/2413/5422/5414/5719/5412/579/2510/249/269/27Feldman AM,et al.presented at ACC 2005Control(Non-ischemic)EECP(Ischemic)Control(Ischemic)EECP(Non-ischemic)PEECH:Peak VO23429.231.529.224.119.62033.31421283542%Subjects Who Met Threshold1 Week3 Months6 Monthsp=0.03p=NSp=NSp=NSp=NSp=NS%Responders by Etiology(increased 1.25 mL/kg/min from baseline)Feldman AM,et al.presented at ACC 200518.92423.226.953(EECP)vs.54(Control)N=Control(Non-ischemic)EECP(Ischemic)Control(Ischemic)EECP(Non-ischemic)Cost effectivenessPotential Cost Savings Scenario#HF ptsTotal#Hospital VisitsAverage Cost per Hospital Visit Total Cost to Healthcare System/1,000 pts Before ECP1,0003,000*$5,456$16,368,000 After ECP1,000500*$5,456$2,728,000 Reduction in hospitalization costs after treated with ECP$13,640,000Cost to treat with ECP$3,640,000 Annual savings to healthcare$10,000,000 Saving per patient$10,000*Average#of hospital visits before ECP over 12 months is 3.6*Average#of hospital visits after ECP over 12 months is 0.5(Reduction in average cost of hospitalizations)EECP reduced ER Visits&Hospitalizations in Patients with LVDHospitalizationsCHF 2007;13:36-4000.20.40.60.811.21.486%83%6-monthsPre-EECP6-monthsPost-EECPp0.001p0.001ER Visits6-monthsPre-EECP6-monthsPost-EECP 3.53.02.52.01.51.00.50PEECHPEECH研究结论研究结论与最佳药物治疗组比较，体外反搏治疗可以改善NYHA II/III心功能且LVEF 35%患者的运动耐量、生活质量和心功能状态缺血性心脏病和高龄患者（65岁以上）获益更多PEECH研究结果与既往的 MUST-EECP和临床注册研究结论相似后续的注册研究显示，心绞痛合并心力衰竭（病情稳定者）者，上述获益在随访12年后仍然保持体外反搏作用机理体外反搏作用机理改善血流动力学改善血流动力学降低收缩压(心脏负荷)舒张期增压(冠脉血流)心输出量增加(器官灌注)改善内皮功能障碍改善内皮功能障碍Vasculat tone Vasodilation Intimal Hyperplasia 神经体液因子调节神经体液因子调节BNP and ANP Angiotensin II 降低动脉僵硬度降低动脉僵硬度血压 血管阻力 心脏工作效率 减轻致炎因子表达减轻致炎因子表达TNF-,MCP-1促进血管新生和侧枝循环促进血管新生和侧枝循环Blood flow to ischemic regionCapillary density 改善内皮功能改善内皮功能血流切应力 循环内皮祖细胞 体外反搏干预心力衰竭发生机制的诸多重要环节 CO下降下降交感神经系统激活交感神经系统激活冠心病，心肌结构冠心病，心肌结构损伤损伤内皮功能障碍内皮功能障碍交感交感RAAS激活激活,内皮素内皮素心力衰竭心肌肥厚，纤维化心肌肥厚，纤维化改善冠脉灌注增加SV、CO改善血管内皮功能增加心肌收缩力降低血浆肾素,AngII 改善运动耐量和生活质量谢谢谢谢