体外反搏与心功能保护-课件，幻灯，PPT.ppt

体外反搏与心功能保护,伍贵富 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 2009.8.22 大连,Enhanced External Counterpulsation（EECP） 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（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,1962年，USA 液压水囊式体外反搏 非序贯式加压 笨重，体积大 未能推广,1972年, 中国中山大学 序贯式气囊加压体外反搏 重量轻，体积小 安全、有效、无创伤 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）,主机系统,体外反搏的作用原理,血流动力学效应,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 Velocity,Baseline,EECP,Katz WE, et al. J Am Coll Cardiol 1998;31Suppl(2):85A(825-31),EECP 1:1 Mode,IABP 1:1 Mode,Scanning Electron Micrographs,Scale,100 µm,(amplification x500),The luminal surface was covered with many adherent cells. The endothelial cells were in disarray.,Less cellular adherence Endothelial 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,70,60,50,40,30,20,10,0,Shear Stress (dynes/cm2),Baseline,During EECP,p0.001,Circulation 2007;116(5):526-536,Shear Stress ,Am J Cardil 2006;98:28-30,Baseline,1hr,12hr,24hr,36hr,1-mo after,3-mo after,% increase of NOx levels over baseline,Nitric Oxide ,*,* p=0.014; p0.0001; p=0.002 vs baseline,During EECP,0,50,100,150,200,Control,CHOL,CHOL +EECP,eNOS protein level (% of control),*,*,* p 0.05 vs Control *p 0.05 vs CHOL,TCT 2006, Oct 22-27, Washington DC,eNOs ,Circulation 2007;116(5):526-536,*,NO crosses intimal to Smooth Muscular Cells,Smooth Muscle cell relaxation,体外反搏改善血流介导的血管舒张能力,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,Exercise (Bruce Protocol) Pre- and Post EECP exercise to the same duration 67% showed complete resolution 11% with partial resolution and 22% no change N=18 pts,Angiogenesis / Collateral Circulation,0.0353±0.0111,0.0036±0.0028,p0.01,Area 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-H254,2006,Am J of Physiol Heart Circ Physiol 290:H248-H254,2006,Experimental AMI dog model,Control,EECP,Endothelial Cell Growth ,60 50 40 30 20 10 0,Area strained brown (m2/mm2),p0.05,5,667±1,894,1,710±1,497,EECP,Control,Area of new capillaries (m2/mm2 sample field),647±531,6,592±2,785,p0.05,Smooth Muscle Cell Growth ,X1,000,Cardiology 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,改善神经体液因子,26.6,18.8,15.6,Increase (%),HGF,bFGF,VEGF,Circulation 2001;104(17) Suppl II:444(2109),Change in Angiogenic Factors,Eur Heart J 2001;22(16):1451-58,ANP and BNP,Blood Pressure / Myocardial Oxygen Consumption,JACC doi:10.1016/j.jacc.2006.04.094,N=20 patients with refractory angina,Tension-Time-Index ,Baseline,EECP,Units x 102,23 ± 5.1,19 ± 3.9,p0.001,0,10,20,30,40,50,60,Baseline,EECP,56 ± 16,36 ± 13,Dynes-sec-cm2 x 102,p0.001,Wasted LV Energy ,Wasted LV pressure energy = 2.09 X tp * (Ps Pi) LV Workload = Tension Time Index = area under systolic wave,Nat Clin Pract Cardiovasc Med 2006;3(11):623-32,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 sites IEPR-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.,Baseline characteristics of Patients in the IEPR,Nat Clin Pract Cardiovasc Med 2006;3(11):623-32,Distribution of Canadian Cardiovascular Society Class,% in each CCS Class,Mean # of angina episodes/week 10 14,86% in Class III/IV,0,10,20,30,40,50,60,I,II,III,IV,CAD Patients with History of CHF,Effects of EECP on CCS Anginal Class,Without CHF (N=1,400),Cardiology 2001;96:78-94,Data from IEPR,% of Patients in Each CCS Class,Events occurring during the 6-month following EECP,2-year follow-up for Patients with LVD (EF 35%),Am J Cardiol 2006; 97(1):17-20,0,10,20,30,40,50,60,70,% of patients,None,I,II,III,IV,p0.001,77% of patients improved 1 angina class, 8% had no angina post treatment (p0.001 baseline vs post-EECP) 55% of patients had sustained improvement in angina class at 2-year follow-up 2-year survival rate was 83%,Canadian Cardiovascular Society Angina Class,93% in Class III/IV pre-EECP,PEECH Trial Prospective Evaluation of EECP in Congestive Heart Failure,N=187 patients randomized to: EECP therapy plus optimal medical therapy Optimal medical therapy alone 29 centers participating including Cleveland Clinic, Scripps Clinic, Thomas Jefferson and UCSD Co-Primary endpoints at six months following treatment (90% Power) Exercise Tolerance: % of patients with 60 second increase from baseline or Peak VO2: % of patients with 1.25 ml/min/kg increase from baseline Blinding: blinded central core lab evaluated exercise data; blinded investigators performed subject evaluations; patients not blinded Secondary endpoints: Change in exercise duration and peak VO2, change in NYHA class, change in Quality of Life,J Am Coll Cardiol 2006;48:1198-1205,Timeline First Subject Enrolled: March 13, 2001 Last Subject Enrolled: Feb 10, 2004 Last Subject Completed: Nov 24, 2004,Patients Screened 800,Patients Enrolled 228,Discontinued Before Randomization: 41,Randomized: 187,EECP: 93,Control: 94,Discontinued: 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%),PEECH,J Am Coll Cardiol 2006;48:1198-1205,A Single-Blind, Controlled, Randomized Evaluation of Efficacy and Safety,Flow Chart at entry and follow-up,PEECH Trial: Endpoints,Primary Percentage of subjects with at least a 60-second increase in exercise duration from baseline to six months OR Percentage of subjects with at least 1.25 ml/min/kg increase in Peak VO2 from baseline to six months Secondary Changes in exercise duration and Peak VO2 Changes in NYHA classification Changes in quality of life Adverse experiences,Feldman AM, et al. J Card Fail Apr 2005;11:240-245.,EECP,Control,p-value,PEECH: Patient Demographics,J Am Coll Cardiol 2006;48:1198-1205,PEECH: Results of Primary End-points,J Am Coll Cardiol 2006;48:1198-1205,EECP,Control,Increase 1.25 mL/kg/min from baseline,Peak VO2,10.0,35.4% N=93,25.3% N=94,22.8% N=93,24.1% N=94,0.0,5.0,15.0,20.0,25.0,30.0,35.0,40.0,% Subjects Who Met Threshold,p=NS,p=0.016,Exercise Duration,Increase 60 sec from baseline,% responders at 6-month follow-up,Congestive Cardiac Failure: 2006, Nov-Dec, 307-311,Subgroup Analysis: Age 65 years,0,5,10,15,20,25,30,35,40,p=0.008,35.1% N=37,25% N=44,11.4% N=44,29.7% N=37,p=0.017,% Subjects Who Met Threshold,Peak VO2,Exercise Duration,Increase 1.25 mL/kg/min from baseline,Increase 60 sec from baseline,PEECH: Changes in Exercise Duration and Peak VO2,Overall Population,Exercise Duration,Note: Baseline exercise duration: EECP=611 sec vs OPT=571 sec, p=NS,26.4,34.5,24.7,Change from Baseline (sec),0.0,10.0,20.0,30.0,40.0,-10.0,50.0,-20.0,Peak VO2,PEECH: Secondary Endpoints,J Am Coll Cardiol 2006;48:1198-1205,PEECH: Subjects with Ischemic Etiology,Change from Baseline (sec),1 Week,3 Months,6 Months,EECP,Control,-16.7,-17.3,-25.8,34.2,20.6,24.6,Change in Exercise Duration,Change in Peak VO2,Change from Baseline (mL/kg/min),-0.9,-0.6,-0.3,0.0,0.3,0.2,-0.7,-0.4,-0.9,p=NS,p=0.07,0.0,-0.3,p=NS,1 Week,3 Months,6 Months,N = 53 (EECP) vs. 54 (Control),Feldman AM, et al. presented at ACC 2005,EECP,Control,Improvement in NYHA Class,PEECH: Subjects with Ischemic Etiology,% Patients with Improvement in NYHA Class,1 Week,3 Months,6 Months,37.0,12.7,12.3,15.5,p=0.026,p=0.004,34.5,36.4,p=0.025,N = 54 (EECP) vs. 55 (Control),Minnesota Living with HF,-8,-1.1,-6.5,-1.5,-4,-1.7,-8,-6,-4,-2,0,1 Week,3 Months,6 Months,Feldman AM, et al. presented at ACC 2005,Improvement,p=NS,p=0.094,p=0.046,35.8,40.7,35.2,24.5,24.6,21.1,34.6,29.2,36.0,33.0,33.3,41.7,0,5,10,15,20,25,30,35,40,45,1 Week,3 Months,6 Months,% Subjects Who Met Threshold,p=0.05,p=0.03,p=0.04,p=NS,p=0.01,p=NS,% Responders by Etiology (increased 60 seconds from baseline),PEECH: Exercise Duration,19/53,7/24,8/24,13/54,22/54,14/57,19/54,12/57,9/25,10/24,9/26,9/27,Feldman AM, et al. presented at ACC 2005,PEECH: Peak VO2,34,29.2,31.5,29.2,24.1,19.6,20,33.3,14,21,28,35,42,% Subjects Who Met Threshold,1 Week,3 Months,6 Months,p=0.03,p=NS,p=NS,p=NS,p=NS,p=NS,% Responders by Etiology (increased 1.25 mL/kg/min from baseline),Feldman AM, et al. presented at ACC 2005,18.9,24,23.2,26.9,Cost effectiveness,Potential Cost Savings Scenario,*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 LVD,Hospitalizations,CHF 2007;13:36-40,0,0.2,0.4,0.6,0.8,1,1.2,1.4,86% ,83% ,6-months Pre-EECP,6-months Post-EECP,p0.001,p0.001,ER Visits,6-months Pre-EECP,6-months Post-EECP,3.5,3.0,2.5,2.0,1.5,1.0,0.5,0,PEECH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,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 Vasculat tone Vasodilation Intimal Hyperplasia ,神经体液因子调节 BNP and ANP Angiotensin II ,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 TNF- , MCP-1,促进血管新生和侧枝循环 Blood flow to ischemic region Capillary density ,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,交感神经系统激活,冠心病，心肌结构损伤,内皮功能障碍,交感RAAS激活,内皮素,心力衰竭,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,