血管成形术后再狭窄

1、血管成形术后再狭窄血管成形术后再狭窄Restenosis after Angioplasty病理生理学教研室：病理生理学教研室： 刘洁刘洁第一节第一节 概概 述述Introduction冠心病的治疗冠心病的治疗v 药物治疗药物治疗v 手术治疗手术治疗v 介入治疗介入治疗History Retrospect一、历史回顾一、历史回顾19541954年年：Percutaneous Transluminal Angioplasty (PTA)美国放射学家美国放射学家DoterDoter开创经皮血开创经皮血管腔内成形术管腔内成形术Interventional radiology19741974年：年：P

2、ercutaneous Transluminal Coronary Angioplasty (PTCA)瑞士医生瑞士医生GruentzigGruentzig成功进行了经成功进行了经皮冠状动脉腔内成形术皮冠状动脉腔内成形术19961996年：年： 美国每年约有美国每年约有5050万人接万人接受受PTCAPTCA手手术治疗。术治疗。20012001年：年： 全球每年约有全球每年约有150150万人万人接受接受PTCAPTCA手手术治疗。术治疗。19841984年：年：我国实施了首例我国实施了首例 PTCAPTCA手手术。术。截止截止19961996年：年： 我国共实施了我国共实施了52095209

3、例例 PTCAPTCA手手术。术。Mechanism of 二、二、 PTCAPTCA治疗机制治疗机制Luminal Enlargementfollowing PTCAEndotheliumBasement membranevInternal elastic lamina( (IEL) )vTunica media( (media) )vExternal elastic lamina( (EEL) )vTunica externa( (adventitia) )vTunica interna( (intima) )Structure of human coronary arteryEndoth

4、eliumBasement membraneInternal elastic laminaTunica mediaExternal elastic laminaTunica externaTunica internaMediaAdventitiaThe arrow indicates the internal elastic lamina ( (IEL) ).2.2.内皮剥脱内皮剥脱(Endothelial Denudation)3.3.内膜断裂内膜断裂(Intimal Disruption)4.4.内弹力板撕裂内弹力板撕裂5.5.中膜分离移位中膜分离移位(Dissection of Medi

5、a)1. 1.粥样斑块破裂粥样斑块破裂(Plaque Rupture)(Fracture of Internal Elastic Lamina)IntimaMediaAdventitiaIntimal and medial tearsANGIOPLASTYPTCAArtery with atherosclerotic plaqueLumen size increased三、三、 PTCAPTCA局限性局限性Limitations of PTCAv急性血管闭塞约急性血管闭塞约1%1%5%5%。v术后术后3-63-6个月内再狭窄约个月内再狭窄约25%25%50%50%。Development of

6、 PTCA四、四、 PTCAPTCA的发展的发展v冠状动脉内膜支架术冠状动脉内膜支架术( (Coronary Stenting) )v冠状动脉定向旋切术冠状动脉定向旋切术v冠状动脉内膜旋磨术冠状动脉内膜旋磨术( ( Coronary Rotablation ) )v冠状动脉内膜切吸术冠状动脉内膜切吸术( (Transluminal Extraction Catheter Atherectomy ) ) ( ( Directional Coronary Atherectomy ) )Coronary Stents1986SigwartvSTRESS trial: Stent Restenosis

7、 Study( (USA) )vBENESTENT trial: Belgium NetherlandsStent Trial ( (Europe) )1994Restenosis occurs approximately 1520% within 6 months after intervention sometimes necessitating repeat revascularization.Stenting after PTCA indeed reduces the incidence of restenosis. 五、五、 再狭窄的概念再狭窄的概念Concept of Resten

8、osisHistological RestenosisThe renarrowing can be seen histologically but not angiographically and is clinically silent.Angiographic RestenosisLoss of 50% of the initial gain in lumen size produced at angioplasty.A 50% stenosis at follow-up angiography.orClinical RestenosisRecurrence of symptoms or

9、adverse events，usually death， non-fatal myocardial infarction， or need for revascularization.第二节第二节 再狭窄发生机制再狭窄发生机制Pathogenesis of Restenosis Elastic Recoil一、弹性回缩一、弹性回缩 人类冠状动脉虽为肌性动脉，人类冠状动脉虽为肌性动脉，但含有弹性纤维：但含有弹性纤维：内弹力板内弹力板( ( Internal Elastic Lamina，IEL) )外弹力板外弹力板( ( External Elastic Lamina，EEL) ) 因冠状动脉

10、壁具有弹性，当球因冠状动脉壁具有弹性，当球囊导管使其过度牵张后，将会发生囊导管使其过度牵张后，将会发生弹性回缩。一般在弹性回缩。一般在PTCAPTCA术后数术后数秒数分秒数分发生发生。PTCAArtery with atherosclerotic plaqueElastic recoilThrombus Formation二、血栓形成二、血栓形成AngioplastyEndothelial denudationMedia dissectionExposure of subintimal componentsPlatelet aggregationErythrocyte entrapmentPl

11、atelet adherenceConformational shift of IIb/IIIa receptorFibrinogen bindingRelease of TXA2 , ADP & serotoninSubintimal components1. Collagen2. von Willebrand factor( (vWF) )3. Fibronectin4. LamininIntimaMediaAdventitiaIntimal and medial tearsANGIOPLASTYThrombus FormationErythrocyte & fibrin-

12、rich thrombusPlatelet thrombusA: Thrombus covering a lesion that developed after angioplasty performed 10 months earlier.B: At higher power, a sister lesion can be seen on the opposing vessel wall, reflecting an abnormal response.Incorporation of Mural ThrombusInflammation三、炎三、炎 症症AngioplastyInjuryM

13、onocyte & lymphocyte infiltrationPlatelet adherenceRelease of cytokines,growth factors & chemoattractantsNeointimal Formation四、新生内膜形成四、新生内膜形成AngioplastyArtery injuryVSMC ActivationProliferationMigration ECM SynthesisNeointimal FormationECM:Extracellular matrixENDOTHELIUMPLATELETSCOAGULATIONM

14、ACROPHAGES LYMPHOCYTESNO,Heparan sulfatePDGF, bFGFPDGF,TGF-ThrombinPDGF,TGF- ,IL1-IFNSMCRestenosis( (+) )( (+) )( (-) )( (-) )( (+) )( (+) )PDGF bFGF( (+) )Proliferation,Migration Matrix SynthesisContractionIntimal HyperplasiaVasoconstrictionLumenEndotheliumNeointimaElastic laminaMediaChemotaxisInte

15、rconversion of phenotypes“Contractile ”differentiated“Synthetic ”undifferentiatedFig. PDGF-BB causes actin filament reorganization and lamellipodia formation in human aortic smooth muscle cells.A: Control B:PDGF-BB 10 minC & D: PDGF-BB 30 minA to C stained with FITC-labeled phalloidinD stained w

16、ith 2-integrin antibody(focal adhesion site)1 1、中膜、中膜SMCSMC增殖增殖2 2、中膜、中膜SMCSMC向内膜迁移和增殖向内膜迁移和增殖3 3、 SMCSMC增殖凋亡相对平衡期增殖凋亡相对平衡期4 4、 SMCSMC再度增殖再度增殖最危险时期最危险时期PTCAPTCA术后术后VSMCVSMC增殖的阶段增殖的阶段(Stages of VSMC Proliferation)IntimaMediaAdventitiaIntimal and medial tearsANGIOPLASTYNeointimal FormationIntimal Thic

17、keningA:AdventitiaM:MediaNI:NeointimaArrow: Internal Elastic Lamina( (IEL) )Control28 days after ballon denudationHistological cross section of rabbit iliac artery.A: Thrombus covering a lesion that developed after angioplasty performed 10 months earlier.B: At higher power, a sister lesion can be se

18、en on the opposing vessel wall, reflecting an abnormal response.Fig. Light microscopic bilayer appearance of a restenosis specimen obtained by directional atherectomy.Remodelling五、血管重塑五、血管重塑 血管壁血管壁SMCSMC增生、迁移、增生、迁移、凋亡，细胞外基质增多与堆积，凋亡，细胞外基质增多与堆积，使血管壁细胞重排，管壁各层使血管壁细胞重排，管壁各层比例及形状发生改变即血管重比例及形状发生改变即血管重塑。塑。血

19、管重塑的概念血管重塑的概念(Definition of Remodelling)Constrictive RemodellingConstrictive RemodellingIntimaMediaAdventitiaIntimal and medial tearsANGIOPLASTYConstrictive RemodellingIntimaMediaAdventitiaNeointimal formationRemodellingIntimal & medial tearsReorganization of thrombusThrombus formationIntimal th

20、ickeningConstrictive remodellingIncorporation of mural thrombusPTCAElastic recoilArtery with atherosclerotic plaque第三节第三节 再狭窄的预防再狭窄的预防Prevention of Restenosis1.Systemic treatmentsAnti-platelet agents: Aspirin, GPIIb/IIIa inhibitorsAnticoagulants: Heparin, warfarinAntagonist of PDGF: TrapidilNitric oxide donor: MolsidomineCa2+ channel blockersACE inhibitorAntioxidants: Probucol -interferon 2. Local therapy Local irradiation ( (brachytherapy) )- or - irradiation with the correct dose makes the