1、高度脂溶性钙离子拮抗剂在高血压、动脉硬化中的应用北京大学人民医院 孙宁玲,高血压的进展,2000全球死亡率: 高血压对其他危险因素的影响,高死亡率, 发展中地区,低死亡率 发展中地区,发达地区,高血压 (BP),吸烟,高胆固醇,低体重,性别为男性,高体重指数,少动生活方式,饮酒,室内环境污染,缺铁,0,1000,2000,3000,4000,5000,6000,7000,8000,死亡率分布 (In thousands; total 55,861,000),Adapted from Ezzati et al, Lancet, 2002.,高血压患者心血管事件危险性增高,弗明翰心脏研究 - 高血
2、压与正常血压的心血管事件危险性 (患者年龄35-64岁，随 访36年),Risk Ratio 2.0 2.2 3.8 2.6 2.0 3.7 4.0 3.0 Excess Risk 22.7 11.8 9.1 3.8 4.9 5.3 10.4 4.2,冠脉疾病,中风,外周血管疾病,心衰,Biennial Age-Adjusted Rate per 1000,Kannel WB JAMA 1996;275(24):1571-1576.,高血压及动脉硬化 参与心血管事件的发生,高血压与动脉硬化是相联的,a,Hypertension,Other factors - hypercholesterola
3、emia - glucose intolerance etc.,Atherosclerosis,Coagulation factors,Clinical events of CHD - angina - infarction - sudden death,(very late stage),Relationship between hypertension, atherosclerosis and cardiovascular events,a,Hypertension,出血性卒中,Atherosclerosis,缺血性 卒中,其他致 动脉硬化因素,血栓,心绞痛/心肌梗死,a,高血压是动脉硬化
4、的启动因素,动脉粥样硬化的进展过程与高血压有关,LDL Oxidised LDL,动脉壁损伤 细胞粘附于内皮表面,内皮功能失调 使内皮渗透性增加,生长因子 eg. PDGF, FGF, TGF-b,平滑肌细胞增殖,高血压,高血压,高血压,高血压怎样导致动脉硬化： haemodynamic factors,a,Internal Carotid,External Carotid,Flow Divider,Common Carotid Artery,Main steps in the atherosclerotic process (atherogenesis),a,平滑肌细胞增殖.,迁移至内皮下,
5、高血压,高血压怎样导致动脉硬化: mechanical factors,a,内皮损伤,High BP,Lipids/free radicals,渗透性增加,内皮的收缩因子(内皮素)占优,Main steps in the atherosclerotic process (atherogenesis),a,(Per-) Oxidation,吞噬细胞增殖,Esterification,（脂化作用）,炎症与动脉粥样硬化形成及演变,正常 黏附 侵润 剥落,内皮细胞,平滑肌细胞,CAMs,基质,泡沫细胞,T淋巴细胞,激活的巨核细胞,组织因子栓塞MMPs基质降解,高血压,L-NMMA = NG monom
6、ethyl L-arginine monoacetate. John and Schmieder. J Hypertens. 2000;18:363-374.,Gene expression,G,Endothelial Cell,L-Arginine,L-NMMA,eNOS,Ca2+ calmodulin,Acetylcholine,Substance P,Bradykinin,2-agonists,pathway,L-Arginine,NO,Soluble guanylate cyclase,cGMP,Endothelium-dependent vasodilation,Smooth Mus
7、cle Cell,Endothelium-Dependent Vasodilation: L-ArginineNitric Oxide Pathway,Endothelial injury,Removal of endothelial cells,Cytokines and growth factors,Cell adhesion molecules,Endothelial repair,Incorporation of endothelial progenitor cells,Cytokines and growth factors,Cell adhesion molecules,Adapt
8、ed from Omoigui and Dzau. J Vasc Med Biol. 1991;3:382-391.,高血压是内皮功能 不良的重要原因 并导致血管组织 结构的病变,Abnormal Endothelium,Vasocon- striction,Platelet/ leukocyte adhesion,SMC migration and growth,Lipid deposition Clearance,高血压,糖尿病,Dysfunction,血脂紊乱,既往研究发现：积极降脂治疗可以改善内皮 功能，降低预后事件,Effects of Lipid-Lowering Therapy
9、on Endothelial Function in CHD Patients,Treasure et al. N Engl J Med. 1995;332:481-487.,Change in Diameter (%),30,20,10,0,-10,-20,-30,-40,-50,Initial,Follow-up,Placebo Group,Initial,Follow-up,Lovastatin Group,Dilation,Constriction,Acetylcholine Challenge,Effect of Aggressive Lipid Lowering on Caroti
10、d IMT in Heterozygous Familial Hypercholesterolemia: ASAP,Smilde et al. Lancet. 2001;357:577-581.,Change in IMT (mm),0.09,0.07,0.05,0.03,0.01,-0.01,-0.03,-0.05,-0.07,-0.09,0,1,2,Atorvastatin 80 mg (n=160),Years,Baseline LDL,8.33 mmol/L,Overview of Statin Trials,AF/TexCAPS 6605 -24%,4S 4444 -35%,LIPI
11、D 9014 -25%,CARE 4159 -28%,WOS 6595 -20%,Trial N LDL,% Reduction Major Coronary Events,Secondary,Primary,*P.001; P=.002 LaRosa et al. JAMA. 1999;282:2340-2346.,-38*,-25*,-25,-31*,-38*,结 论,积极的降脂治疗可以改善内皮功能积极的降脂治疗可以改善动脉硬化及中间终点积极降脂治疗可以改善预后终点,降压治疗是否可以改善预后？降压治疗是否有改善内皮功能的作用？什么样降压药物具有较好的抗动脉硬化效果？,问题的提出：,Redu
12、ction of events with antihypertensive therapy,a,a,20-25%,35-45%,Antihypertensive therapy,CHF,Stroke,MI,-20,-0,-40,-60,50%,2003 JNC7,钙离子在高血压及动脉硬化中的作用,a,a,Ca,+,Calciumions,1)内皮细胞(内皮素)2) 血管平滑肌细胞3) 巨噬/泡沫细胞4) LDL/胆固醇代谢,钙离子拮抗剂是否能过阻断这些过程？,降压治疗（CCB）是否可以改善预后降压治疗（CCB)是否有改善内皮功能的作用？什么样降压药物具有较好的抗动脉硬化效果？,回答提出的问题,
13、CCBs 在动脉硬化中的临床试验,Jukema J, et al. Arterioscler Thromb Vasc Biol 1996;16:42530. Lichtlen P, et al. Lancet 1990;335:110913. Pitt B, et al. Circulation 2000;102:150310.,结果已经发表在11月8日的Lancet 2003，362：1527-35.荟萃 29个随机试验162,341例患者700,000余次的病人年,降压治疗试验协作研究组（ABPL）第二轮分析,ABPL 试验（血压的差异与事件的关系）活性药物 vs plac,mmHg 差异
14、 ACEI / plac ( -5 / -2 ) CCB / plac ( - 8 / - 4 ),R R R R 总死亡率 0.80 0.89 CVD死亡 0.80 0.78CVD事件 0.72 0.82 脑卒中 0.72 0.62冠心病 0.80 0.78心力衰竭 0.82 1.21,ABPL 试验（血压的差异与事件的关系）活性药物 vs 活性药物,mmHg 差异 ACEI CCB ACEID / BB (+ / 0 ) D/BB (+1/ 0 ) CCB (+1 / +1 ),R R R R R R 总死亡率 1.00 0.99 1.04 CVD死亡 1.03 1.05 1.03CVD事
15、件 1.02 1.04 0.97脑卒中 1.09 0.93 1.12冠心病 0.98 1.01 0.96心力衰竭 1.07 1.33 0.82,卒 中 不同活性药的比较,随机治疗,ACEI vs D/BBCA vs D/BBACEI vs CA,试验数,696,病例数,474496846725767,(mmHg),0/20/01/1,0.5 1.0 2.0,RR (95% CI),1.09(1.00, 1.180.93(0.86, 1.011.12(1.01, 1.25,Relative Risk,前者更好,后者更好,第二轮分析,ABPL,降压治疗（CCB)是否可以改善预后？降压治疗（CCB）
16、能够改善内皮功能什么样降压药物具有较好的抗动脉硬化效果？,回答提出的问题,Circulating endothelial progenitor cells are derived from bone marrow,EPC: endothelial progenitor cell,EPC,Smooth muscle,Endothelium,Coronary artery,Bone marrow,EPC migration,EPC,Bone marrow,EPC incorporation,EPC: endothelial progenitor cell,心血管危险因素是与内皮原细胞数量的减少及不
17、同有关,Endothelial progenitor cells (colony-forming units),5,0,5,10,15,Framingham risk score,0,20,40,60,30,50,70,10,20,p=0.001, r= 0.47,Hill J et al. N Engl J Med 2003,内皮功能改善与内皮源性细胞数量加有关,Endothelial progenitor cells (colony-forming units),0,2,4,6,8,Change in brachial reactivity (%),0,20,40,60,30,50,70,
18、10,16,10,12,14,Hill J et al. N Engl J Med 2003,p=0.001, r= 0.59,EPC: endothelial progenitor cell,TREND: Endothelial Function and ACE Inhibition,*P.0003 for quinapril vs placebo. Mancini et al. Circulation. 1996;94:258-265.,P=.002 overall,Net Change (%) in Target Segment Response After 6 Months,Acety
19、lcholine Dose (mol/L),10-6,10-4,*,Placebo,Quinapril,*,NO Production From Human Coronary Microvessels: Amlodipine and Ramiprilat,Zhang et al. Am J Cardiol. 1999;84:27L-33L.,Change in Nitrite (pmol/mg),Concentration (log),Amlodipine,*,*,*,*,*,*,*,Ramiprilat,*P.01 vs control,Brovkovych V et al. Hyperte
20、nsion 2001,Nifedipine preserves NO concentration stimulates NO release,Electrochemical sensor,0.01 0.1 1 10 100 1,000,240,120,40,0,80,200,160,NO release (nmol/L),Nifedipine (nmol/L),Loke et al. Hypertension. 1999;34:563-567; Zhang et al. J Pharmacol Exp Ther. 1999;288:742-751; Laufs et al. Circulati
21、on. 1998;97:1129-1135.,Postulated Effects of Different Agents on Endothelial Cell NO Production,Endothelial Cell,Statins,Kinins,Inactive peptides,CCB,eNOS,NO2,ACE,BK2,eNOS mRNA,ACEI,不同药物对内皮功能不良的治疗作用,ACE-Is,ARBs,CCBs,动脉,coronary,+,+,no data,peripheral,+,+,皮下微循环,+,+,+,肌性微循环,acetylcholine, metacholine,
22、bradykinin,+,+,+,no data,ACE-I: angiotension-converting enzyme inhibitor, ARB: angiotensin II receptor blocker, CCB: calcium channel blocker,降压治疗（CCB)是否可以改善预后？降压治疗（CCB)是否有改善内皮功能的作用？CCB具有较好的抗动脉硬化效果,回答提出的问题,ESC/ESH建议 分析心血管事件终点 既要看终末终点又要分析中间终点（替代终点）,危险因素阶段,靶器官损害阶段,临床疾病阶段,终末疾病阶段,高血压 糖尿病 其它危险因素,颈动脉中内膜增厚
23、冠状动脉病变 血管内皮功能紊乱 左室肥厚 蛋白尿,心绞痛 心肌梗塞 脑卒中 肾脏损害,心力衰竭 肾功能衰竭 卒中后功能障碍 死亡,中间终点,逆转中间终点的目的是减少终末终点发生,心肌梗塞或中风与颈动脉厚度的关系,内膜-中层厚度的五分位数 (combined measure of max CCA and ICA),每1000名病人 出现心梗或中风的比率-年,13.6,18.4,22.2,40.9,New England Journal of Medicine, 1999;340:14-22,7.8,SECURE: Progression Slope of Mean Maximum IMT,Pro
24、gression Mean Max IMT Slope (mm/y),0.022,0.018,Placebo (n=227),Ramipril 2.5 mg/d (n=232),0.014,Ramipril 10 mg/d (n=234),37% Relative Reduction P=.028 vs Plac,Effect of Ramipril Was Significant After Adjustment for BP and Hx Hypertension,Lonn et al. Circulation. 2001;103:919-925.,PREVENT：氨氯地平 显著延缓 颈动
25、脉粥样硬化,内膜中层厚度变化,(mm),氨氯地平 安慰剂, 0.033, 0.013,Pitt et al. Circulation. 2000.,P=0.007,INSIGHT impact on intima-media thickness,Simon A, et al. Circulation 2001;103:294954.,Follow-up (years),Change from baseline in carotid artery IMT (mm),Nifedipine GITS,0.040.030.020.0100.01,Co-amilozide,Progression,Reg
26、ression,p=0.007,p=0.001,p=0.006,Baseline 2 3 4,Verapamil in Hypertension and Atherosclerosis Study (VHAS),Correlation of rate of change in mean maximum intima-media thickness (Mmax) and initial Mmax,Modified from Zanchetti A, et al. J Hypertens 1998;16:166776.,0.06 0.04 0.02 0 0.02 0.04 0.06 0.08 0.
27、10 0.12,Rate of Mmax change (mm/year),y = 0.037x + 0.051,y = 0.082x + 0.086,Verapamil,Chlorthalidone,0.5 1.0 1.5 2.0,Initial Mmax (mm),拉西地平与阿替洛尔比较 主要终点结果 (每年CBMmax 的进展),0.0146,0.0145,0.0057,0.0087,0,0.005,0.01,0.015,0.02,0.025,PP,PP2,人群,mm,阿替洛尔,拉西地平,-61%,-40%,p=0,0010,p=0,0073,Circulation.2002;19:24
28、22-2427,ELSA研究,拉西地平和细胞膜和钙通道的相互作用,High lipophilicity,Extracellular,LacidipineCa2+,Intracellular,slow dissociation,accumulation within lipid bilayer,long duration of action,INTERACTION OF LACIDIPINE WITH THE DIHYDROPYRIDINE RECEPTORS,Lacidipine inhibits the development of atherosclerosis,LDL Oxidised
29、LDL,动脉壁损伤后细胞粘附于内皮表面,拉西地平减少内皮功能失常和渗透性增加,拉西地平减少平滑肌细胞增殖,拉西地平减少 LDL的氧化,Growth factors eg. PDGF, FGF, TGF-b,The effect of lacidipine on endothelium-dependent vasodilatation in hypertensives,700,600,500,400,300,200,100,0,Bradykinin,Acetylcholine,*,*,NormotensivesHypertensivesLacidipine-treated hypertensiv
30、es,前壁血流 增加(%),* p 0.05 * p 0.01 compared to baseline,Ghiadoni et al, 1996,拉西地平能降低TNF-a 刺激内皮细胞粘附分子的表达,Journal of Hypertension, 1999;17:1837-1841,细胞粘附分子表达的减少 (%),氨氯地平,拉西地平,乐卡地平,0,-10,-20,-30,-40,-50,-60,-70,-80,-90,拉西地平抑制平滑肌细胞增殖和胆固醇脂化,剂型 胆固醇的 dose 增殖效果 研究脂化作用 (mm) Lacidipine 10-6 Inhibition Mason (199
31、2)Reduction ( 95%) 1-20 Inhibition Bernini (1993)Nifedipine Reduction Etingin, Hajjar (1985),and Schmitz (1988)Increase Daugherty (1987)No effect 10-50 Inhibition Bernini (1991, 1993)Verapamil Reduction Daugherty (1987)Reduction (91%) 50 Inhibition Bernini (1993)Diltiazem Reduction Daugherty (1987),
32、Reichardt, 1995,拉西地平治疗52周对高血压患者 血清超氧化物歧化酶 (SOD)活性的影响,Yamakado, 1994,Before lacidipine,0,1,2,4,5,3,Serum superoxide dismutase activity (U/ml),After lacidipine,*,* p 0.05,拉西地平治疗52周对高血压患者血清过氧化物酶的影响,Yamakado, 1994,Before lacidipine,0,1,2,4,5,3,Serum lipid peroxidase (nmol/ml),After lacidipine,* p 0.05,*
33、,6,7,短效及长效CCB对血压的影响,Optimal therapeutic range,0 4 8 12 16 20 0 4 8 12 16 20 0,mmHg,-30,-20,-10,0,Day 27 Day 28,Short-acting drug,Long-acting drug,Early morning blood pressure surge,凌晨血压增高的风险,6:00,0:00,12:00,18:00,Muller et al. N Engl J Med 1985;313:13151322 Marler et al. Stroke 1989;20:473476,0,20,4
34、0,60,80,100,120,140,160,180,脑血管事件 (per 2 h),0,5,10,15,20,25,30,35,40,45,50,心肌梗死 (per h),Stroke (n=1,167),Myocardial infarction (n=2,999),Time of day,钙离子拮抗剂的T/P值,药物 T/P 值SBP T/P值 DBP T/P 值 平均 T/P值硝苯地平控释片 101.8 88.2 95.0非洛地平 75 68 71.5氨氯地平 68 67 67.5缓释地尔硫卓 74 67 70.5,拉西地平治疗后血压峰值和谷值的变化,Peak,Systolic bl
35、ood pressure (mmHg),Diastolic blood pressure (mmHg),55% 84% 98% 78%,0 -5 -10 -15 -20 -25,Placebo 1mg 2mg 4mg 6mg,63% 79% 89% 94%,0 -5 -10 -15 -20 -25,Meredith, 1997,Lacidipine 降低了高血压患者血压变异性,SBP,DBP,Variability,mmHg,Placebo Lacidipine,15 13 11 9 7 0,15,Baseline Treatment,mmHg,Palatini et al, 1991,Bas
36、eline Treatment,13,11,9,7,0,拉西地平长期治疗后 动脉顺应性明显改善,Pancera, 1989,Baseline,Compliance (dyne-1cm410-7),3,1 month,6 months,*,* p 0.005 vs baseline,2.5,2,1.5,1,0.5,0,钙拮抗剂-二氢吡啶类 适应证 禁忌证强制性 可能的 老年人 （无） 快速心律失常 单纯收缩期高血压 充血性心力衰竭 心绞痛 周围血管病 颈动脉粥样硬化 妊娠,2003 ESC/ESH 药物的适应证/禁忌证,Investigator assessment of lacidipine
37、efficacy,Tcherdakoff, 1995,Very good,Good,Moderate,Bad,44%,2%,All patients,43%,46%,11%,1%,42%,Patients 65 years,11%,Investigator assessment of lacidipine tolerability,Tcherdakoff, 1995,37%,All patients,58%,38%,6%,56%,Patients 65 years,5%,Very good,Good,Moderate,乐卡地平治疗老年 高血压患者的耐受性,THE COHORT STUDY,Se
38、ptember 2001,研究人群,COHORT,0-8 months 6-12 months* 12-18 months* 18-24 months*,Safety/ITT population n = 828,氨氯地平 n = 200,n = 118,n = 70,n = 30,拉西地平 n = 208,n = 134,n = 84,n = 45,乐卡地平 n = 420,n = 276,n = 169,n = 78,Adjusted mean change from baseline (ITT 6 months),COHORT,Supine DBP,-35,-30,-25,-20,-15
39、,-10,-5,0,Lercanidipine,Amlodipine,Lacidipine,ANCOVA: NS,Mean SE,ADVERSE EVENTS SPONTANEOUSLY REPORTED OR DETECTED BY THE INVESTIGATOR (% of patients with AE typical of CCB),COHORT,0,5,10,15,20,水肿,头晕,眩晕,脸潮红,头痛,心悸,心动过速,Lercanidipine,Amlodipine,Lacidipine,P0.0001,%,% PTS WITH EDEMA (up to 6 months),CO
40、HORT,0,5,10,15,20,25,30,35,40,45,50,水肿,红肿,体重增加,Lercanidipine,Amlodipine,Lacidipine,X2 (P):,%,0.0001,0.0001,0.0008,症状,ESC/ESH 2003 抗高血压药物的选择,抗高血压治疗的获益并非来源于所用的降压药物，而主要是取决于血压降低本身但亦有证据表明，不同类别的抗高血压药物具有特别的临床益处钙拮抗剂颈动脉粥样硬化,Endothelial progenitor cells,Anti-inflammatory,Decreased leukocyte adhesion,Reduced permeability,Increased NO availability,Effects of Lacidipine,REDUCED RISK OF A CV EVENT,DECREASED BLOOD PRESSURE,乐息平对内皮功能不良和器官损害过程的纠正,单核细胞,损伤的内皮,巨噬细胞,泡沫 细胞,脂质,血小板,斑块,氧化应激,2,3,CCB的抗动脉粥样硬化过程 斑块形成的不同阶段,平滑肌细胞,4,Emerging Drugs 1998; 3:135-145,5,谢 谢,
