钙通道阻断剂的应用进展

CCB & CHD-HT-AR Uptodate 2007,UpToDate (15.1) of Calcium channel blocker (CCB) December 2006 June 2007,高血压冠心病-心脏性猝死的防治与钙通道阻断剂的应用进展,西安交通大学第一附属医院 心内科崔长琮2007年4月15日 宝鸡扶风,重视心脏猝死的残酷现状,他们的猝然离世为人们敲响了警钟：小心心脏性猝死！,2003年6月27日，在联合会杯的比赛中，喀麦隆国脚 维维安福猝死赛场,54岁的爱立信（中国）有限公司总裁杨迈于 2004年4月8日晚，由于心脏病突发在京猝死,全球快餐业巨头麦当劳 公司董事长兼首席执行 官吉姆坎塔卢波在2004 年4月19日凌晨猝死于家中,在雅典采访的北京电视台资深摄像记者郑立，在拍摄奥运火炬传递时心脏病突发猝死，年仅47岁,2005年2月25日，成都社保局 局长向志雄在开会时猝死,2004年10月北京交大 学生刘红斌和老年运动员胡守礼在参加北京马拉松比赛中发生猝死,SCD-ACS & JWS Shanghai 2005-1022, 重点预防和教育 因为心脏猝死只有一个 预防方法： A,B.C,D,E, + ICD. Amiodaron ?,急救 DC / 扣击处理 CPR 药物起搏,ACS-JWS-SCD 2006-8-20 Beijing IHF 2006,Early hyperacute phase of A C S and S C D-心脏原因、骤然不可预测、1小时内的自然死亡 (占SCD的),Huikuri HV. N Engl J Med. 2001;345:1473-1482.,40% SCA发生在睡眠时或没有旁人在现 场的情况下 1 80% SCA发生在家里 1 院外SCA的存活率仅 5% 2,3 （美国）,SCA 存活率统计,即使在紧急救护系统非常完善/可早期给予除颤治疗的地区，SCA的存活率仍很低，因为大多数SCA发生时无旁人在场，或即便被发现，也很难在6-8分钟内给予有效的治疗.,1 Swagemakers V. J Am Cardiol. 1997;30:1500-1505.2 Ginsburg W. Am J Emer Med. 1998;16:315-319.3 Cobb LA. Circulation. 1992;85:I98-102.,Lipid lowering with statins UpToDate 13.3 Sep 1, 2005,调脂粑目标的目的是 AS-CHD-SCD,内皮功能和斑块的动态平衡,屏障功能：血管内与内皮下组织 之间的屏障作用；分泌功能：分泌 NO ET ，促凝抗凝等；调节功能：调节血管的收收缩和舒张，调节血压；,Pathogenesis of atherosclerosis Charles E Rackley, UpToDate (14.1) February 2006. HISTOLOGY 1-Fatty streaks 2-Fibrous plaque 3-Advanced lesions PATHOGENESIS 1-Endothelial dysfunction 2-Dyslipidemia 3-Inflammation 4-Serum CRP - 5-Cytokines 6-Leukocyte activation 7-Toll-like receptor 4 8-Plaque hemorrhage 9-Plaque rupture 10-Tissue factor 11-Angiotensin II 12-Endothelin-1 13-Adhesion molecules 14-Flow characteristics 15-Anti-oxidized LDL antibodies 16- Infection 17-C. pneumoniae infection 18 H. pylori - 19-Cytomegalovirus infection 20-Pathogen burden - 21-Effect of antimicrobial therapy - 22-Effect of vaccination,影响内皮功能动脉平衡的各种因素 （自Charles E Rackley, UpToDate (14.1), February 2006.）促进内皮功能障碍的因素 保护和修复内皮功能的因素和干预措施 增龄性因素，年龄40岁 心态平衡 性别因素，男性女性 雌性素 冠心病的家族史 MEF2A AA1 抽烟 戒烟 血胆固醇或LDL胆固醇增加 降胆固醇或LDL的药物 血HDL胆固醇减少 他汀类药物的应用 高血压 降压药物，ACEI/ARB的应用 高血糖或糖尿病 降糖治疗 肥胖 控制体重 少运动 运动 高脂饮食 合理饮食 血清半胱氨酸增加,高半胱氨酸血症,内 皮 功 能 障 碍,慢 性 炎 症,高尿酸血症,高血压,遗传因素MEF2A,吸烟,低HDLTC/HLD/H,高LDLTGTC,糖尿病,促凝与抗凝紊乱,交感副交感紊乱,其他感染,螺旋杆菌,衣原体感染,各种病毒感染,C少动,L肥胖,年龄,家族史,性别,Gibbons et al. J Am Coll Cardiol. 1999;33:2092-2197,AS-CHD-ACS-HT- Stroke-CHF-SCD,SymN+RAS+,一二级预防ABCDE,-,+,T高脂饮食,心态不平精神紧张,心脏性猝死发生机制的TDR、心电图和临床,Ito-JWS-VT/VFphase 2 reentry,Ikr/Iks TDRQTdVT/VFEAD/DAD reentry,西安交通大学医学院第一附属 医院心内科科 的研究表明：,1 -崔长琮 临床心电学杂志 2007; (1):1 2 - Wang DQ,Cui CZ,Yan GX. J Wave Syndrome. WWW.SCD- 2006,OCT3- Gan-Xin Yan,et al: The First Hospital of Xian Jiaotong Univer sity, - Xian, China. Lankenau Institute for Medical Research, Wynnewood, PA Circulation. 2004;110:1036-1041. 4- Juan Shu, Tiangang Zhu,Lin Yang,Chang-cong Cui, Ganxin Yan,. ST segments elevated in the early repolarization syndrome.Idiopathyic ventricular fibrillarization, and the Brugada syndrome:Cellular and Clinical Linkage Janoury of electrocardiology 2005; 16:1436-95-严干新 王东琦 崔长琮。J波与J波综合征.中华心律失常学杂志 2004;8:360-365,1- Ajay Joshi,Changcong Cui, Gan-Xin Yan Preclinical Strategies to Assess QT Liability and Torsadogenic Potential ofNew Drugs: The Role of Experimental Models. Journal of Electro- cardiology. 2004，37 :7-14 2 Zhongxiang Yu,Changzong Cui,Gan Xin Yan, EnhancedTransmural Dispersion of Repolariza- tion is Essential to the Genesis of the Triggering Beat Capable of Indu cing Torsade de Pointes。Heart Rhythm 2004; 1(1):S124 3-廉姜芳,崔长琮,薛小临,等. 3个先天性长QT综合征家族的 基因分型.中华医学遗传学杂志，2004,21(3): 272-273 4-Jiangfang Lian, Changcong Cui, Xiaolin Xue The clinical characteristics and phenotype-genotype correlation in 6 Chinese LQTS families. J of HuaZhong University of Tecnology Science Medical Science, 2004, 24(3): 208-21,ACS-JWS-SCD 2006-8-20 Beijing IHF 2006,J wave Syndrome,1-崔长琮, 陈新. 积极开展心血管离子通道病的基础和临床研究. 中华心律失常学杂志。2004; 8（6）:325-327 2-严干新 姚青海 王东琦 崔长琮。 J波与J波综合征。 中华心律失常学杂志。 2004； 8（6）:360-3653-王东琦 崔长琮 严干新.心电图心室复极波的细胞离子流机制与临床.中华心律失常学杂志 2005；9(6):478-4824-Wang DQ,Cui CZ,Yan GX. J Wave Syndrome. WWW.SCD- 2006,OCT,心电图在心脏性猝死防治中的应用 2007-3-22,蔡-男，54岁，2004-7-1-17：30C/O; chest uncomfortable for 30min.Fu: 32 moths is well .,超级期AMI的心电图特点 1- J 点抬高-J波形成 （o.1mV;20ms， 与ST段起始部抬高融合）;2- J 波，与抬高的ST段和T波的上升支融合；3- 但是抬高的融合为一体的J波-ST段和T波的 上升支形成弓背向下的抛物曲线（Sloop done）;4- T波高尖，QT间期正常（0.44ms）或 缩短（0.36ms ）。,LVH-OMI-HFDHM-HFHCM-HF （肥厚型心肌病） HCM是年轻人最常见的死因 SCD发生危险与左室肥厚存在直接相关性，无临床症状或症状轻微但左室肥厚严重的年轻患者长期存在SCD的危险。1,2,1 Spirito P. N Engl J Med. 1997;336:775-785. 2 Maron BJ. N Engl J Med. 2000;342:365-373.,CCB & CHD-HT-AR Uptodate 2007,Mechanism of CCB,CCB & CHD-HT-AR Uptodate 2007,CCB,心脏,血管平滑肌,CCB & CHD-HT-AR Uptodate 2007,CCB & CHD-HT-AR Uptodate 2007,CCB与钙通道 电压依赖性 钙通道钠钙交换钙内流和外流,外周动脉血管平滑肌扩展 血压下降,冠状动脉血管平滑肌扩展 心绞疼缓解,动脉平滑肌增生减少内皮功能改善 抗动脉硬化,抑制心脏自律性抑制心脏传导性 抗心律失常,CCB & CHD-HT-AR Uptodate 2007,常用钙拮抗剂 Calcium Antagonists or CCB 二氢吡啶类钙拮抗剂- Dihydropyridines, 强效扩血管但不影响心肌收缩力和转导 硝苯地平 Nifedipine，控释-拜心同Bayer/30mg qd . 5.6y 缓释-/30mg qd 短效-心痛定 10mg tid, 不用 拉西地平 Lacidipine，乐息平-GSK 4mg 5.6y/三精司乐平 4mg qd .1.3y 氨氯地平 Amlodipine，络活喜Pfizer 5mg qd /伏络清东北.6.6y 非络地平 Felodipine，波依定AstraZ 5mg qd/. 5.3y Barmidipine 10mg qd Benidipine 4-8mg qd Nicardipine 40mg qd Lercanidipine 10mg qd Isradipine Nisoldipine 非二氢吡啶类钙拮抗剂- Non-dihydropyridines ,扩血管+ 影响心肌收缩力和转导 地尔硫卓 Diltiazem, 合心爽 90-120mg qd,180-240mg qd 维拉帕米 Verapamil HCl 异搏定 40tid/240mgqd,Change in Hemodynamic Profile With Age血压/心排出量/外周血管阻力的增令性变化,Cardiac Output,Peripheral Resistance,CongestiveHeart Failure,EstablishedHypertension,BorderlineHypertension,Mild,Severe,HemodynamicsBP = CO TPR,Age (years),80,60,40,20,Normal,Messerli FH. J Clin Pharmacol. 1981;21:517-528.,TPRWithCCBOrCarvedilor,CCB & CHD-HT-AR Uptodate 2007,NHTHypertension is a Syndrome !Why focus on hypertension?,CCB & CHD-HT-AR Uptodate 2007,高血压防治的严重性和迫切性,1,Why focus on hypertension?,CCB & CHD-HT-AR Uptodate 2007,USA,中国20041.6亿,18.8%18y1.6亿,2004,2004全国健康和营养检测调研,中国高血压的现状: 患病率高-18.8%(15y) 知晓率低 44.7, 治疗率低 28.2, 达标率低 8.1,降压达标的重要性: 临床试验表明,SP10-14mmHg DP5-6mmHg脑卒中 2/5 40% 冠心病 1/6 16 主要心血管病事件 1/3 33% 2005年中国高血压防治指南,“ Even a 2 mm Hg lower usual systolic blood pressure would involve about 10% lower stroke mortality and about 7% lower mortality from ischemic heart disease or other vascular causes in middle age.” Lewington S et al. Lancet. 2002;360:1903-1913.,N-RAS & ACEI / ARB,血压评估和高血压诊断 中国2005 美国JNC7-2003欧洲2004 心血管事件 (mmHg) (mmHg) (mmHg) 危险性理想血压Optimal 110/7 115/75 1正常血压Normal 120/80 120/80 120/80 120-129 / 80-84临界血压High-normal 120-139/80-89 120-139/80-89 120-139/80-89 2高血压 Hypertension 140/或90 140/或 90 140/或 90 140-149 / 90-94 级(轻度) stage 140-159 /或 90-99 140-159 /或 90-99 140-159/或 90-99 4级(中度) stage 160-179/或 100-109 160/或 100 160/或100 级(重度) stage 180 /或110 1180 / 110收缩期高血压 140 90 140 90 140 90 10降压达标值 140/90, +DM/KF130/ 80 , +AU1g/d 125/75, 老年SBP 150 mmHg,SBP 比 DBP 对心血管事件的影响更大,Antihypertensive agents:How to choose the right drugs如何选择药物,利尿剂:Thiazides: Great efficacy, but may worsen metabolic parameters. -HF, olderACE inhibitors and ARBs: improve insulin resistance and slow progression of renal insufficiency.CCBs: Efficacious, but frequently cause fluid retention.Beta-blockers: Blunt sympathetic tone, but worsen insulin resistance.,A,B,C,D,ACEI/ARB,Beta-B,CCB,Diuretic,Therapeutic Life-staling Change- 治疗性生活方式改变饮食，体重，运动，心态，戒烟.70%,CCB & CHD-HT-AR Uptodate 2007,Antihypertensive response to different drugs in blacks,Materson, BJ et al, N Engl J Med 1993; 328:914. Am J Hypertens 1995; 8:189.,Antihypertensive response to different drugs in whites,发生任何与药物相关不良反应的病人百分比,DiUritic,BB,AEEI,CCB,ARB,ARB+HCT,安慰剂,选药原则:有效性 安全性,可乐定 哌唑嗪,TOMHS Treatment of Mild Hypertension Study轻度高血压治疗的研究,试 验 目 的确定生活方式改善在轻度高血压治疗中的作用比较五种药物治疗 与生活方式改善对于轻度高血压治疗长期疗效与安全性的差异,Neaton JD, et al. JAMA 1993; 270:713 /Uptodate2007,四年的结果: DBP SBP,20,0,1,2,3,4,5,6,7,Cumulative Event Rate (%),0,4,8,12,16,ChlorthalidoneAmlodipineLisinopril,ALLHAT (The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) participants were randomly assigned to receive chlorthalidone, 12.5 to 25 mg/d (n=15,255); amlodipine, 2.5 to 10 mg/d (n=9,048); or lisinopril, 10 to 40 mg/d (n=9,054) for planned follow-up of approximately 4 to 8 years, mean follow-up 4.9 years.ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997.,ALLHAT: Cumulative Event Rates for Fatal CHD or Nonfatal MI by Treatment Group高危病人联合用药,Years to Event,Number at Risk:,Chlorthalidone,15,255,14,477,13,820,13,102,11,362,6,340,2,956,209,Amlodipine,9,048,8,576,8,218,7,843,6,824,3,870,1,878,215,Lisinopril,9,054,8,535,8,123,7,711,6,662,3,832,1,770,195,ALLHAT: CCB卒中 vs Diuretic心衰,0.5,1.5,1,0.5,1.5,1,0.5,2,1,Total,Men,Women,Black,Nonblack,Diabetic Patients,Nondiabetic Patients,ALLHAT Collaborative Research Group. JAMA. 2002;288:29812997.,Nonfatal Ml Plus CHD Death,Stroke,HF,FavorsAmlodipine,FavorsChlorthalidone,Favors Amlodipine,FavorsChlorthalidone,Favors Amlodipine,FavorsChlorthalidone,Relative Risk,Relative Risk,Relative Risk,Chlorthalidone (n=15,255)Amlodipine (n=9,048),Cumulative Event Rates for Stroke by ALLHAT Treatment Group,ChlorthalidoneAmlodipineLisinopril,ACEIHCTCCB,ALLHAT ( JAMA 2002; 288:2981-2997),ABCD2,3 (132 mm Hg),AASK1(134 mm Hg),High-Risk Hypertensive Patients Require Multiple Agents to Achieve Goal 高危病人联合用药,1Wright JT et al. JAMA. 2002;288:2421-2431. 2Bakris GL. J Clin Hypertens. 1999;1:141-147. 3Estacio RO et al. N Engl J Med. 1998;338:645-652. 4The ALLHAT Officers and Coordinators. JAMA. 2002;288:2981-2997. 5Hansson L et al. Lancet. 1998;351:1755-1762. 6Lewis EJ et al. N Engl J Med. 2001;345:851-860. 7Bakris GL et al. Arch Intern Med. 2003;163:1555-1565. 8UK Prospective Diabetes Study Group. BMJ. 1998;317:703-713.,Number of BP Medications,ALLHAT4(135 mm Hg),RENAAL7 (140 mm Hg),IDNT6(140 mm Hg),UKPDS2,8 (144 mm Hg),HOT2,5(141 mm Hg),AchievedSystolic BP,Concomitant Use of Antihypertensive Drugs高危病人联合用药- 如何联合 ?,Adapted from Chalmers J. Clin Exp Hypertens. 1993;15:1299-1313.,AASK: Progression of Hypertensive Kidney Disease高血压肾病 ARB/ACEI BB CCB,230,125,50,0,-35,-55,Baseline,12,6,18,24,30,36,42,48,Amlodipine,Ramipril,Metoprolol,Follow-up (months),Change in Geometric Mean of Proteinuria From Baseline ( %),Percentage Changes in Proteinuria by Randomized Group,Wright JT et al. JAMA. 2002;288:2421-2431.,P.001,n=217,n=436,n=441,AASK=African American Study of Kidney Disease and Hypertension.,ACEI优选,Amlodipine,Lisinopril,ALLHAT: Risk of New Diabetes*新发糖尿CCBDES,5、平滑肌细胞迁移进入内皮下组织,形成新的粥样斑块的纤维帽。斑块增大,6、平滑肌细胞迁移进入内皮下组织和粥样斑块的纤维帽。6-7、内皮细胞迁移并且在各种保护因素的作用下形成纤维帽。,8-9、纤维帽在各种促炎症因素下破裂或损害，表面血小板聚集，形成血栓，导致急生冠脉事件。纤维帽破裂或损伤后，血栓形成，在各种保护因素的作用下，在血栓的表面形成新的纤维帽，使急性冠脉事件，得到新的平衡。,Dynamic Balance of atherosclerosis:Therapeutic implications Eric J.Topol: Textbook of Cardiovascular Medicine 2003; Atherosclerosis P.5-11,The BAsel Stent Kosten Effektivitts Trial - LAte Thrombotic Events (BASKET-LATE),Object to determine the incidence of late clinical events ( 6 months following intervention) related to stent thrombosis in patients treated with DES vs BMS after patients discontinued clopidogrel therapy Study Design patients were randomized in a 2:1 fashion to receive DES or BMS in the BASKET trial. Patients who remained event-free at 6-month follow-up were subsequently enrolled in the BASKET-LATE trial. In the BASKET-LATE trial ,dual antiplatelet therapy was administered for 6 months in all patients regardless of stent type, and clopidogrel was discontinued in all patients after 6 months .Endpoint Patients were followed for an additional 12 months to determine the incidence of cardiac death or nonfatal myocardial infarction (MI) (primary endpoint) and clinically driven restenosis-related target vessel revascularization.,Major cardiac events between 7 and 18 months,Pfisterer ME. American College of Cardiology 2006 Scientific Sessions; March 14, 2006; Atlanta, GA.,100PtsReduse5 RSIncrece3.3pts Thrombosis,Pfisterer ME. American College of Cardiology 2006 Scientific Sessions; March 14, 2006; Atlanta, GA.,USA-TCT Message,Late thrombosis a very-low-frequency event We dont know about the long-term safety of DES in some individualsWe cant predict who is going to have a late clotting riskSome patients never endothelialize the strut of the stent because the drug is so effectiveSome patients have a propensity for thrombosisTell patients that there is a small risk over extended follow-up,Topol,CCB & CHD-HT-AR Uptodate 2007,Stable Angina/ OMI,ESC 2006稳定型心绞痛治疗指南Fox K, European Heart Journal 2006；27：1341-1381,This guideline updates a previous version: Management of stable angina pectoris. Recommendationsof the Task Force of the European Society of Cardiology. ESC/Eur Heart J 1997 Mar; 18(3):394-413. ACC/AHA 1999; ACC/AHA 2002;,ESC2006稳定型心绞痛治疗指南Fox K, Alonso Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, Daly C, DeBacker G, Hjemdahl P, Lopez-Sendon J, Marco J, Morais J, Pepper J, Sechtem U, Simoons M, Thygesen K. Guidelines on the management of stable angina pectoris. Sophia Antipolis, France: European Society of Cardiology; 2006. 63 p. 683 referencesFox K, European Heart Journal 2006；27：1341-1381,2006-ESC- Guidelines on the management of stable angina pectoris,一般治疗,急性发作期吸烟饮食和酒精脂肪酸维生素和抗氧化剂高血压、糖尿病等运动精神心理驾车性活动就职,2006-ESC-Gui