1、 高度脂溶性鈣離子拮抗劑 在高血壓、動脈硬化中的應用 北京大學人民醫(yī)院 孫寧玲高血壓的進展2000全球死亡率: 高血壓對其他危險因素的影響高死亡率, 發(fā)展中地區(qū)低死亡率 發(fā)展中地區(qū)發(fā)達地區(qū)高血壓 (BP)吸煙高膽固醇 低體重性別為男性高體重指數(shù)少動生活方式飲酒室內環(huán)境污染缺鐵010002000300040005000600070008000死亡率分布(In thousands; total 55,861,000)Adapted from Ezzati et al, Lancet, 2002.高血壓患者心血管事件危險性增高 弗明翰心臟研究 - 高血壓與正常血壓的心血管事件危險性(患者年齡35-6

2、4歲，隨 訪36年)Risk Ratio2.02.23.82.62.03.74.03.0Excess Risk22.711.89.13.84.95.310.44.2冠脈疾病中風外周血管疾病心衰Biennial Age-Adjusted Rate per 1000Kannel WB JAMA 1996;275(24):1571-1576. 高血壓及動脈硬化 參與 心血管事件的發(fā)生 高血壓與動脈硬化是相聯(lián)的aHypertensionOther factors- hypercholesterolaemia- glucose intolerance etc.AtherosclerosisCoagula

3、tion factorsClinical events of CHD- angina- infarction- sudden death(very late stage)Relationship between hypertension, atherosclerosis and cardiovascular eventsaHypertension出血性卒中Atherosclerosis缺血性卒中其他致動脈硬化因素血栓心絞痛/心肌梗死a高血壓是動脈硬化的啟動因素Main steps in the atherosclerotic process (atherogenesis)a平滑肌細胞增殖.遷移

4、至內皮下高血壓 高血壓怎樣導致動脈硬化: mechanical factorsa內皮損傷High BPLipids/free radicals滲透性增加內皮的收縮因子(內皮素)占優(yōu)Main steps in the atherosclerotic process (atherogenesis)a(Per-) Oxidation吞噬細胞增殖Esterification（脂化作用）Endothelial repairIncorporation of endothelial progenitor cellsCytokines and growth factorsCell adhesion molec

5、ulesAdapted from Omoigui and Dzau. J Vasc Med Biol. 1991;3:382-391.高血壓是內皮功能不良的重要原因并導致血管組織結構的病變Abnormal EndotheliumVasocon-striction Platelet/leukocyteadhesionSMCmigrationandgrowth LipiddepositionClearance高血壓糖尿病Dysfunction血脂紊亂既往研究發(fā)現(xiàn)：積極降脂治療可以改善內皮 功能，降低預后事件Effects of Lipid-Lowering Therapy on Endotheli

6、al Function in CHD PatientsTreasure et al. N Engl J Med. 1995;332:481-487.Change in Diameter (%)3020100-10-20-30-40-50InitialFollow-upPlacebo GroupInitialFollow-upLovastatin GroupDilationConstrictionAcetylcholine ChallengeOverview of Statin TrialsAF/TexCAPS 6605 -24%4S 4444 -35%LIPID 9014 -25%CARE41

7、59 -28%WOS 6595 -20%Trial N LDL% Reduction Major Coronary EventsSecondaryPrimary*P50%2003 JNC7鈣離子在高血壓及動脈硬化中的作用aaCa+Calciumions1)內皮細胞(內皮素)2)血管平滑肌細胞3)巨噬/泡沫細胞4)LDL/膽固醇代謝鈣離子拮抗劑是否能過阻斷這些過程？降壓治療（CCB）是否可以改善預后降壓治療（CCB)是否有改善內皮功能的作用？什么樣降壓藥物具有較好的抗動脈硬化效果？ 回答提出的問題 CCBs 在動脈硬化中的臨床試驗 TrialnDrugregimenPatient groupOu

8、tcomeINTACT425Nifedipine vs placeboMild CAD28% new lesionsREGRESS885Pravastatin vs placeboAtherosclerosis(males)50% new lesions with concomitant CCBPREVENT825Amlodipine vs placeboCAD0.0126mm IMT (amlodipine)0.033mm IMT (placebo)J-MIC (B)210Nifedipine vs ACE inhibitorHT and CADNifedipine significantl

9、y better for preventing lesion progressionJukema 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.結果已經(jīng)發(fā)表在11月8日的 Lancet 2003，362：1527-35. 薈萃 29個隨機試驗 162,341例患者 700,000余次的病人年降壓治療試驗協(xié)作研究組 （ABPL）第二輪分析 ABPL 試驗（血壓的差異

10、與事件的關系） 活性藥物 vs plac mmHg 差異 ACEI / plac ( -5 / -2 ) CCB / plac ( - 8 / - 4 ) R R R R 總死亡率 0.80 0.89 CVD死亡 0.80 0.78CVD事件 0.72 0.82 腦卒中 0.72 0.62冠心病 0.80 0.78心力衰竭 0.82 1.21 ABPL 試驗（血壓的差異與事件的關系） 活性藥物 vs 活性藥物 mmHg 差異 ACEI CCB ACEI D / BB (+ / 0 ) D/BB (+1/ 0 ) CCB (+1 / +1 ) R R R R R R 總死亡率 1.00 0.99

11、 1.04 CVD死亡 1.03 1.05 1.03CVD事件 1.02 1.04 0.97 腦卒中 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 中不同活性藥的比較隨機治療ACEI vs D/BBCA vs D/BBACEI vs CA試驗數(shù)696病例數(shù)474496846725767BP(mmHg)0/20/01/10.5 1.0 2.0RR (95% CI)1.09(1.00, 1.180.93(0.86, 1.011.12(1.01, 1.25Relative Risk前者更好后者更好第二輪分析 ABPL 降壓治療（CCB)是否

12、可以改善預后？降壓治療（CCB）能夠改善內皮功能什么樣降壓藥物具有較好的抗動脈硬化效果？回答提出的問題 Circulating endothelial progenitor cells are derived from bone marrowEPC: endothelial progenitor cellEPCSmooth muscleEndotheliumCoronary arteryBone marrowEPCmigrationEPCBone marrowEPCincorporationEPC: endothelial progenitor cell心血管危險因素是與內皮原細胞數(shù)量的減少及

13、不同有關Endothelial progenitor cells(colony-forming units)5051015Framingham risk score02040603050701020p=0.001, r= 0.47Hill J et al. N Engl J Med 2003內皮功能改善與內皮源性細胞數(shù)量加有關Endothelial progenitor cells(colony-forming units)02468Change in brachial reactivity (%)02040603050701016101214Hill J et al. N Engl J Me

14、d 2003p=0.001, r= 0.59EPC: endothelial progenitor cellTREND: Endothelial Function and ACE Inhibition*P.0003 for quinapril vs placebo.Mancini et al. Circulation. 1996;94:258-265.P=.002 overallNet Change (%) in Target Segment Response After 6 MonthsAcetylcholine Dose (mol/L)10-610-4*PlaceboQuinapril*N

15、O Production From Human Coronary Microvessels: Amlodipine and RamiprilatZhang et al. Am J Cardiol. 1999;84:27L-33L.Change in Nitrite (pmol/mg)Concentration (log)1007550250Amlodipine*-10 M-9 M-8 M-7 M-6 M-5 M*Ramiprilat*P.01 vs controlBrovkovych V et al. Hypertension 2001Nifedipine preserves NO conce

16、ntration stimulates NO release Electrochemical sensor0.01 0.1 1 10 100 1,00024012040080200160NO 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. Circulation. 1998;97:1129-1135.Postulated Effects of Differe

17、nt Agents on Endothelial Cell NO Production Endothelial CellStatinsKininsInactive peptidesCCBeNOSNO2ACEL-ArginineNO + L-CitrullineBK2eNOS mRNAACEI不同藥物對內皮功能不良的治療作用ACE-IsARBsCCBs動脈coronary+no dataperipheral+皮下微循環(huán)+肌性微循環(huán)acetylcholine, metacholinebradykinin+no dataACE-I: angiotension-converting enzyme in

18、hibitor, ARB: angiotensin II receptor blocker, CCB: calcium channel blocker降壓治療（CCB)是否可以改善預后？降壓治療（CCB)是否有改善內皮功能的作用？ CCB具有較好的抗動脈硬化效果回答提出的問題 ESC/ESH建議分析心血管事件終點既要看終末終點又要分析中間終點（替代終點）危險因素階段 靶器官損害階段臨床疾病階段終末疾病階段高血壓糖尿病其它危險因素頸動脈中內膜增厚冠狀動脈病變血管內皮功能紊亂左室肥厚蛋白尿心絞痛心肌梗塞腦卒中腎臟損害心力衰竭腎功能衰竭卒中后功能障礙死亡中間終點 逆轉中間終點的目的是減少終末終點發(fā)生

19、心肌梗塞或中風與頸動脈厚度的關系 05101520253035404512345內膜-中層厚度的五分位數(shù)(combined measure of max CCA and ICA)每1000名病人出現(xiàn)心?；蛑酗L的比率-年13.618.422.240.9New England Journal of Medicine, 1999;340:14-227.8SECURE: Progression Slope of Mean Maximum IMT Progression Mean Max IMT Slope (mm/y)0.0220.018Placebo (n=227)Ramipril 2.5 mg/d

20、 (n=232) 0.014Ramipril 10 mg/d (n=234)37% Relative ReductionP=.028 vs PlacEffect of Ramipril Was Significant After Adjustment for BP and Hx HypertensionLonn et al. Circulation. 2001;103:919-925.PREVENT：氨氯地平 顯著延緩頸動脈粥樣硬化內膜中層厚度變化(mm)氨氯地平 安慰劑 0.033 0.013Pitt et al. Circulation. 2000. P=0.007INSIGHT impa

21、ct on intima-media thicknessSimon A, et al. Circulation 2001;103:294954.Follow-up (years)Change from baseline in carotid artery IMT (mm)Nifedipine GITS0.040.030.020.0100.01Co-amilozideProgressionRegressionp=0.007p=0.001p=0.006Baseline 2 3 4Verapamil in Hypertension and Atherosclerosis Study (VHAS)Co

22、rrelation of rate of change in mean maximum intima-media thickness (Mmax) and initial MmaxModified from Zanchetti A, et al. J Hypertens 1998;16:166776.0.060.040.0200.020.040.060.080.100.12Rate of Mmax change (mm/year)y = 0.037x + 0.051y = 0.082x + 0.086VerapamilChlorthalidone0.5 1.0 1.5 2.0Initial M

23、max (mm)拉西地平與阿替洛爾比較主要終點結果(每年CBMmax 的進展) 0.01460.01450.00570.008700.0050.010.0150.020.025PP PP2人群mm阿替洛爾拉西地平-61%-40%p=0,0010p=0,0073Circulation.2002;19:2422-2427 ELSA研究 拉西地平和細胞膜和鈣通道的相互作用High lipophilicityExtracellularLacidipineCa2+Intracellularslow dissociationaccumulation withinlipid bilayerlong dura

24、tion of actionINTERACTION OF LACIDIPINE WITH THE DIHYDROPYRIDINE RECEPTORSLacidipine inhibits the development of atherosclerosisLDLOxidised LDL動脈壁損傷后細胞粘附于內皮表面拉西地平減少內皮功能失常和滲透性增加拉西地平減少平滑肌細胞增殖拉西地平減少 LDL的氧化Growth factorseg. PDGF, FGF, TGF-bThe effect of lacidipine on endothelium-dependent vasodilatation

25、 in hypertensives7006005004003002001000BradykininAcetylcholine*NormotensivesHypertensivesLacidipine-treated hypertensives前壁血流增加(%)* p 0.05 * p 95%) 1-20InhibitionBernini (1993)Nifedipine Reduction Etingin, Hajjar (1985), and Schmitz (1988)IncreaseDaugherty (1987)No effect10-50InhibitionBernini (1991

26、, 1993)VerapamilReductionDaugherty (1987)Reduction (91%)50InhibitionBernini (1993)DiltiazemReductionDaugherty (1987)Reichardt, 1995拉西地平治療52周對高血壓患者血清超氧化物歧化酶 (SOD)活性的影響Yamakado, 1994Before lacidipine012453Serumsuperoxide dismutase activity(U/ml)After lacidipine* p 0.05拉西地平治療52周對高血壓患者血清過氧化物酶的影響Yamakado

27、, 1994Before lacidipine012453Serum lipid peroxidase(nmol/ml)After lacidipine* p 0.05*67短效及長效CCB對血壓的影響Optimal therapeutic range04 8 12 16 20 04 812 1620 0mmHg-30-20-100Day 27Day 28Short-acting drugLong-acting drugEarly morning blood pressure surge凌晨血壓增高的風險6:000:0012:0018:00Muller et al. N Engl J Med

28、1985;313:13151322Marler et al. Stroke 1989;20:473476020406080100120140160180腦血管事件 (per 2 h)05101520253035404550心肌梗死 (per h)Stroke (n=1,167)Myocardial infarction (n=2,999)Time of day鈣離子拮抗劑的T/P值 藥物 T/P 值 SBP T/P值 DBP T/P 值 平均 T/P值硝苯地平控釋片 101.8 88.2 95.0非洛地平 75 68 71.5氨氯地平 68 67 67.5 緩釋地爾硫卓 74 67 70.5拉

29、西地平治療后血壓峰值和谷值的變化PeakTroughSystolicbloodpressure(mmHg)Diastolicblood pressure(mmHg)55% 84% 98% 78%0-5-10-15-20-25Placebo1mg2mg4mg6mg 63%79% 89% 94%0-5-10-15-20-25Meredith, 1997Lacidipine 降低了高血壓患者血壓變異性SBPDBPVariabilitymmHgPlacebo LacidipinaselineTreatmentmmHgPalatini et al, 1991BaselineTr

30、eatment1311970拉西地平長期治療后動脈順應性明顯改善Pancera, 1989BaselineCompliance(dyne-1cm410-7)31 month6 months* p 65 years11%Investigator assessment of lacidipine tolerabilityTcherdakoff, 199537%All patients58%38%6%56%Patients 65 years5%Very goodGoodModerate樂卡地平治療老年高血壓患者的耐受性THE COHORT STUDYSeptember 2001研究人群COHORT0-8 m