冠心病血管内皮保护的非药物干预方法体外反搏课件

冠心病血管内皮保护的非药物干预方法 -体外反搏 伍贵富 中山大学附属第一医院心内科 心血管康复中心 卫生部辅助循环重点实验室 2011.12.4 杭州 A Novel Modality of Vascular Endothelial Protection: Enhanced External Counterpulsation 2010-2030 中国CVD事件将 发生警报性增长 （50%) WHO疾病负担项目 Circulation. 2011; 124:314-323. Circulation. 2011; 124:278-279. 中国心脑血管病防治面临挑战更为严峻！ 脑卒中死亡率 冠心病死亡率 Evolution of Cardiovascular Diseases Risk Factors Hypertension Atherogenic Dyslipidemia Diabetes Mellitus Abdominal Obesity Prothrombotic state Proinflammatory state Genetics Ethnic Predisposition Aging Hormonal imbalance Physical inactivity Smoking Common Factors Exercise capacity Arterial wall thickening Vascular Stiffness Atherosclerosis LV- contractility LV- relaxation Endothelial Dysfunction Inflammation Catabolism Atrophy Early fatigue Skeletal Muscle Dysfunction Ventilatory Abnormalities Neurohormonal activation Renal Single organ dysfunction Angina Heart Attack Stroke Silent Ischemia Multiple organs dysfunction Heart failure Renal Failure Cerebral Pulmonary Disease Progression Complex factors that determine the rate of progression from risk to organ failure Linking risk factors to cardiovascular disease is endothelial dysfunction 血流切应力与血管内皮保护 生理状态的切应力 低切应力状态 低血流切应力和湍流区域 是动脉粥样硬化斑块高发区域 血流切应力与冠心病的临床联系 体内反搏 （IABP） 体外反搏 （ECP） 辅助衰竭的心脏：从内反搏到外反搏 增强型体外反搏工作原理 Enhanced External Counterpulsation, EECP 时 间体外反搏发展的重要事件 1980年代初增强型体外反搏装置（EECP）诞生并进入临床应用 1990年代初EECP装置获美国FDA批准，进入美国并经此进入世界其他国家和地区 1995-1997年 美国第一个体外反搏RCT（MUST-EECP）：哈佛大学、耶鲁大学、哥 伦比亚大学、纽约州立大学及加州州立大学等联合攻关 1998年第一个“国际EECP病人登记中心（IEPR）”（美国匹兹堡大学） 2002年美国ACC/AHA冠心病稳定型心绞痛治疗指南（IIb） 2006年欧洲心脏病协会（ESC）冠心病心绞痛治疗指南(IIb) 中华医学会心血管病分会冠心病心绞痛治疗指南（IIb） 2009年在中国老年学会的支持下，中国体外反搏专业委员会(EAC)成立 增加心输出量 Duplex echocardiography Descending Aorta Lawson, Hui: J of Critical Illness 2000;5:629-636 Control EECP 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 体外反搏对心脏血流的影响 Bhavananda T. Reddy, Andrew D. Michaels Journal of Geriatric Cardiology 2010;7(2):67 体外反搏与IABP比较的血流动力学差异 舒张压 主动脉平均压 收缩压 冠脉平均流速 舒张期冠脉流速 Health Volunteer Atherosclerotic 10 20 30 10 20 0 Change of blood velocity (%) 收缩期流速舒张期平均流速 -6.0% -19.3%* 9.6% 13.7%* 3.2% 23.6%* *p0.05 , *p0.01 体外反搏对其它重要脏器的影响-眼底动脉血流 Werner D, et al: Graefes Arch Clin Exp Ophthalmol. 239:599-6-2 健康志愿者 动脉粥样硬化 颈动脉 (n=35) 肾动脉 (n=18) Applebaum RM, et al: Am Heart J 1997;133:611-5. 10 20 30 0 22% 19% p=0.001 (%) p=0.0001 血流速度积分变化率 20 40 60 0 56 40 (cm/sec) 舒张期平均流速 体外反搏对其它重要脏器的影响-颈动脉、肾动脉 Confidential Nat Clin Pract Cardiovasc Med 2006;3(11):623-32 Change in Angina Functional Class from IEPR-1 Baseline CCS anginal Class Distribution1-year CCS anginal Class Distribution 86% in Class III/IV25% in Class III/IV 27 19 30 19 6 0 10 20 30 40 50 60 No Angina IIIIIIIV % of patients in each CCS Class 76% maintained at least 1 CCS class improvement 0 10 20 30 40 50 60 IIIIIIIV % of patients in each CCS Class N=4,565 29.7 18.4 27.8 17.9 6.2 0 10 20 30 40 50 60 No anginaIIIIIIIV 2-year CCS anginal Class Distribution 24% in Class III/IV Am Journal of Cardiol 2004;93:461 - 464 3-year CCS anginal Class Distribution 0 10 20 30 40 50 60 No Angina I IIIIIIV 21% in Class III/IV 5% 16% 24.8% 19.3% 34.9% Clin.Cardiol 2008; 31,4:159 - 164 Confidential Changes in patients with Left Ventricular Dysfunction With diabetes mellitus (DM, n=36) versus non-diabetes (Non-DM, n=27) 6-minute WalkNYHA Classification 2.7 1.1 2.9 1.3 p0.001 p0.001 p0.001p0.001 Increase 37%Increase 30% No significant difference in the increase in both group Pre-EECP Post-EECP 747 873 1,025 1,137 (ft) AHA 2008 Confidential Changes in patients with Left Ventricular Dysfunction With diabetes mellitus (DM, n=36) versus non-diabetes (Non-DM, n=27) Cardiac Output 3.1 3.9 3.3 4.1 p0.001 p0.001 Pre-EECP Post-EECP 0 5 10 15 20 25 30 35 40 DMNon-DM Ejection Fraction p0.001 p0.001 Increase 21%Increase 20% No significant difference in the increase in both group 29.8 29.9 36.2 35.9 (%)(l/min) Increase 25%Increase 22% No significant difference in the increase in both group AHA 2008 Cost effectiveness Potential Cost Savings Scenario # HF pts Total # Hospital Visits Average Cost per Hospital Visit Total Cost to Healthcare System /1,000 pts Before ECP 1, 0003,000*$5,456$16,368,000 After ECP 1,000500*$5,456$2,728,000 Reduction in hospitalization costs after treated with ECP $13,640,000 Cost 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 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 p0.001p0.001 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 流流 速速切应力切应力 体外反搏对猪颈总动脉内的血液流速和切应力变化 0.89% 9.18% 2.17% 0 2 4 6 8 10 正常组高脂组反搏组 AS+体外反搏 AS 正常对照 体外反搏对实验动物（猪）动脉硬化的影响 Zhang Y, et al: Circulation 2007,116:526-34 体外反搏治疗对实验性动脉粥样硬化猪冠脉内膜的影响 Zhang Y, et al: Circulation 2007, 116: 526-34 Confidential x400 x40 正常组 动脉硬化组 动脉硬化组体外反搏 体外反搏保护血管内膜促进冠状动脉血管重构 HE 染色弹力纤微染色 Zhang Y, et al: Circulation 2007, 116: 526-34 体外反搏降低冠脉前降支CRP和补体C3a表达 Zhang Y, et al: ATVB 2010 Tao J, et al: International Journal of Cardiology 2006, 112:269-274 体外反搏治疗改善高胆固醇血症猪 内皮依赖的血管舒张功能（离体动脉环） Cardiology 2008;110:160-166 Circulating Endothelial Progenitor Cells (EPC) in patients with Angina Pectoris BaselinePost-treatment Assessed by flow activated cell sorter per 105 peripheral blood mononuclear cells Number of CD34+/KDR+ Cells p=0.430p=0.049 p=0.557p=0.010 EPC Colony Forming Unit per well Arterial Stiffness and Myocardial Oxygen Demand Results of a randomized sham control study Am J Cardiol 2011;107(10):1466-1472 Aortic Augmentation Index (Alx) Change in Alx (%) *p0.01 p0.05 p0.05 * * * Wasted Left Ventricular Energy Ew (dynes cm 2 sec) p0.05 p0.05 EECP (N=28)Sham Control (N=14) Pulse-Wave Velocity Carotid Femoral Carotid - Femoral (m/sec) *p0.05 p0.05 p0.05 * * Changes in Exercise Capacity Results of a randomized sham control study Am J Cardiol 2011;107(10):1466-1472 EECP (N=28)Sham Control (N=14) Exercise Time Treadmill Exercise Time (sec) *p0.05p0.001p0.01 * * * Modified Naughton protocol Peak Time to Angina Peak Time to Angina (sec) *p0.05p0.001p0.0 1 * * * Peak Oxygen Uptake Peak Oxygen Uptake (ml/kg/min) *p0.05 p0.001 p0.01 * * * EECP improves endothelial function A randomized sham-controlled study Braith: Circulation 2010;122:1612-1620 Effects on Vasomotor Flow-Mediated Dilation: Brachial Artery Percent Change (%) p0.01 Sham N= 14, EECP N=28Pre-EECP Post-EECP 2% 51% Percent Change (%) Flow-Mediated Dilation: Femoral Artery p0.01 3%30% Change in Plasma NOx p0.01 mol/L 2%36% Change in Prostaglandin 6-keto-PGF1 p0.01 pg/mL 1%71% Change in Endothelin -1 p0.01 pg/mL 5% 25% EECP improves endothelial function A randomized sham-controlled study Braith: Circulation 2010;122:1612-1620 Inflammatory Cytokines and Adhesion Molecules Tumor Necrosis Factor - Sham N= 14, EECP N=28 Pre-EECPPost-EECP Soluble Vascular Cell Adhesion Molecule p0.01 1%6% * ng/mL High-sensitivity C-reactive Protein p0.01 5% 32% * mg/L p0.01 12%16% * pg/mL Monocyte chemoattractant Protein-1 p0.01 0.2%13% pg/mL * EECP improves endothelial function A randomized sham-controlled study Pre-EECPPost-EECP Sham N= 14, EECP N=28 Braith: Circulation 2010;122:1612-1620 Functional and Exercise Capacity CCS Functional Class p0.001 * Angina Episodes per day p0.01 * Daily Nitrate Usage p0.01 * 1.01.0 0.9 0.2 Peak Time to angina p0.01* sec 406449 471645 p0.001 Peak Exercise Duration * sec Peak Oxygen Consumption p0.001 * mL/kg/minute Peripheral Pulse Wave Velocity * p 0.07 * Carotid-to-Radial Baseline35 Sessions Femoral-to-Foot * * p 0.06 Pulse Wave Velocity and Arterial Stiffness Decreased PWV Increased tp/ 2 64 66 68 70 72 74 Pre-EECPPost-EECP 68 8.0 74 6.6 p=0.001 Travel Time (msec ) Travel Time of Reflected Wave J Am Coll Cardiol 2006;48:1208-1214 0 5 10 15 20 25 30 Pre-EECPPost-EECP 27 10% 19 10% p=0.001 Augmentation Index (%) Arterial Stiffness Arterial Stiffness Augmentation Index AS进展期斑块破裂破裂斑块修复 体外反搏- 从动脉粥样硬化病变的早期开始介入 Peter Libby, Circulation 2001;104;365-372 斑块形成 体外反搏 血管