血管成形術(shù)后再狹窄課件

血管成形術(shù)后再狹窄RestenosisafterAngioplasty病理生理學(xué)教研室：劉潔血管成形術(shù)后再狹窄RestenosisafterAngi1第一節(jié)概述Introduction第一節(jié)概述Introduction2冠心病的治療

藥物治療

手術(shù)治療

介入治療冠心病的治療藥物治療手術(shù)治療介入治療3HistoryRetrospect一、歷史回顧HistoryRetrospect一、歷史回顧41954年：PercutaneousTransluminalAngioplasty(PTA)美國放射學(xué)家Doter開創(chuàng)經(jīng)皮血管腔內(nèi)成形術(shù)Interventionalradiology1954年：PercutaneousTranslumina51974年：PercutaneousTransluminalCoronaryAngioplasty(PTCA)瑞士醫(yī)生Gruentzig成功進(jìn)行了經(jīng)皮冠狀動脈腔內(nèi)成形術(shù)1974年：PercutaneousTranslumina61996年：

美國每年約有50萬人接受PTCA手術(shù)治療。1996年：72001年：全球每年約有150萬人接受PTCA手術(shù)治療。2001年：81984年：我國實(shí)施了首例PTCA手術(shù)。1984年：我國實(shí)施了首例PTCA手術(shù)。9截止1996年：

我國共實(shí)施了5209例PTCA手術(shù)。截止1996年：我國共實(shí)施了5209例PTCA手10Mechanismof

二、

PTCA治療機(jī)制LuminalEnlargementfollowingPTCAMechanismof二、PTCA治療機(jī)制Lumina11EndotheliumBasementmembraneInternalelasticlamina(IEL)Tunicamedia(media)Externalelasticlamina(EEL)Tunicaexterna(adventitia)Tunicainterna(intima)StructureofhumancoronaryarteryEndotheliumBasementmembraneIn12EndotheliumBasementmembraneInternalelasticlaminaTunicamediaExternalelasticlaminaTunicaexternaTunicainternaEndotheliumBasementmembraneIn13MediaAdventitiaThearrowindicatestheinternalelasticlamina(IEL).MediaAdventitiaThearrowindic142.內(nèi)皮剝脫(EndothelialDenudation)3.內(nèi)膜斷裂(IntimalDisruption)4.內(nèi)彈力板撕裂5.中膜分離移位(DissectionofMedia)1.粥樣斑塊破裂(PlaqueRupture)(FractureofInternalElasticLamina)2.內(nèi)皮剝脫(EndothelialDenudation)15IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYIntimaMediaAdventitiaIntimala16PTCAArterywithatheroscleroticplaqueLumensizeincreasedPTCAArterywithatheroscleroti17三、

PTCA局限性LimitationsofPTCA三、PTCA局限性LimitationsofPTCA18急性血管閉塞約1%～5%。術(shù)后3-6個(gè)月內(nèi)再狹窄約25%～50%。急性血管閉塞約1%～5%。術(shù)后3-6個(gè)月內(nèi)再狹窄約25%～519DevelopmentofPTCA四、

PTCA的發(fā)展DevelopmentofPTCA四、PTCA的發(fā)展20冠狀動脈內(nèi)膜支架術(shù)(CoronaryStenting)冠狀動脈定向旋切術(shù)冠狀動脈內(nèi)膜旋磨術(shù)(

CoronaryRotablation)冠狀動脈內(nèi)膜切吸術(shù)(TransluminalExtractionCatheterAtherectomy)(

DirectionalCoronaryAtherectomy)冠狀動脈內(nèi)膜支架術(shù)(CoronaryStenting)冠狀21CoronaryStents1986SigwartCoronaryStents1986Sigwart22STRESStrial:StentRestenosisStudy(USA)BENESTENTtrial:BelgiumNetherlandsStentTrial(Europe)1994Restenosisoccursapproximately15～20%within6monthsafterinterventionsometimesnecessitatingrepeatrevascularization.STRESStrial:StentRestenosis23StentingafterPTCAindeedreducestheincidenceofrestenosis.

StentingafterPTCAindeedred24五、

再狹窄的概念ConceptofRestenosis五、再狹窄的概念ConceptofRestenosis25HistologicalRestenosisTherenarrowingcanbeseenhistologicallybutnotangiographicallyandisclinicallysilent.HistologicalRestenosisTher26AngiographicRestenosisLossof≥50%oftheinitialgaininlumensizeproducedatangioplasty.A﹥50%stenosisatfollow-upangiography.orAngiographicRestenosisLossof27ClinicalRestenosisRecurrenceofsymptomsoradverseevents，usuallydeath，non-fatalmyocardialinfarction，orneedforrevascularization.ClinicalRestenosisRecurrence28第二節(jié)再狹窄發(fā)生機(jī)制PathogenesisofRestenosis

第二節(jié)再狹窄發(fā)生機(jī)制PathogenesisofRes29ElasticRecoil一、彈性回縮ElasticRecoil一、彈性回縮30

人類冠狀動脈雖為肌性動脈，但含有彈性纖維：內(nèi)彈力板(

InternalElasticLamina，IEL)外彈力板(

ExternalElasticLamina，EEL)人類冠狀動脈雖為肌性動脈，但含有彈性纖維：內(nèi)彈力板31

因冠狀動脈壁具有彈性，當(dāng)球囊導(dǎo)管使其過度牽張后，將會發(fā)生彈性回縮。一般在PTCA術(shù)后數(shù)秒～數(shù)分發(fā)生。因冠狀動脈壁具有彈性，當(dāng)球囊導(dǎo)管使其過度牽張后32PTCAArterywithatheroscleroticplaqueElasticrecoilPTCAArterywithatheroscleroti33ThrombusFormation二、血栓形成ThrombusFormation二、血栓形成34AngioplastyEndothelialdenudationMediadissectionExposureofsubintimalcomponentsPlateletaggregationErythrocyteentrapmentPlateletadherenceConformationalshiftofIIb/IIIareceptorFibrinogenbindingReleaseofTXA2,ADP&serotoninAngioplastyEndothelialdenudat35Subintimalcomponents1.Collagen2.vonWillebrandfactor(vWF)3.Fibronectin4.LamininSubintimalcomponents1.Collag36IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYThrombusFormationErythrocyte&fibrin-richthrombusPlateletthrombusIntimaMediaAdventitiaIntimala37A:Thrombuscoveringalesionthatdevelopedafterangioplastyperformed10monthsearlier.B:Athigherpower,asisterlesioncanbeseenontheopposingvesselwall,reflectinganabnormalresponse.A:Thrombuscoveringalesion38IncorporationofMuralThrombusIncorporationofMuralThrombu39Inflammation三、炎癥Inflammation三、炎癥40AngioplastyInjuryMonocyte&lymphocyteinfiltrationPlateletadherenceReleaseofcytokines,growthfactors&chemoattractantsAngioplastyInjuryMonocyte&ly41NeointimalFormation四、新生內(nèi)膜形成NeointimalFormation四、新生內(nèi)膜形成42AngioplastyArteryinjuryVSMCActivationProliferationMigrationECMSynthesisNeointimalFormationECM:ExtracellularmatrixAngioplastyArteryinjuryVSMCA43ENDOTHELIUMPLATELETSCOAGULATIONMACROPHAGESLYMPHOCYTESNO,HeparansulfatePDGF,bFGFPDGF,TGF-βThrombinPDGF,TGF-β,IL1βγ-IFNSMCRestenosis(+)(+)(-)(-)(+)(+)PDGFbFGF(+)Proliferation,MigrationMatrixSynthesisContractionIntimalHyperplasiaVasoconstrictionENDOTHELIUMPLATELETSCOAGULATIO44LumenEndotheliumNeointimaElasticlaminaMediaChemotaxisInterconversionofphenotypes“Contractile”differentiated“Synthetic”undifferentiatedLumenEndotheliumNeointimaElast45Fig.PDGF-BBcausesactinfilamentreorganizationandlamellipodiaformationinhumanaorticsmoothmusclecells.A:ControlB:PDGF-BB10minC&D:PDGF-BB30minAtoCstainedwithFITC-labeledphalloidinDstainedwithɑ2-integrinantibody(focaladhesionsite)Fig.PDGF-BBcausesactinfila461、中膜SMC增殖2、中膜SMC向內(nèi)膜遷移和增殖3、SMC增殖凋亡相對平衡期4、SMC再度增殖—最危險(xiǎn)時(shí)期PTCA術(shù)后VSMC增殖的階段(StagesofVSMCProliferation)1、中膜SMC增殖2、中膜SMC向內(nèi)膜遷移和增殖3、SMC47IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYNeointimalFormationIntimaMediaAdventitiaIntimala48IntimalThickeningIntimalThickening49A:AdventitiaM:MediaNI:NeointimaArrow:InternalElasticLamina(IEL)Control28daysafterballondenudationHistologicalcrosssectionofrabbitiliacartery.A:AdventitiaM:MediaNI:Neointim50A:Thrombuscoveringalesionthatdevelopedafterangioplastyperformed10monthsearlier.B:Athigherpower,asisterlesioncanbeseenontheopposingvesselwall,reflectinganabnormalresponse.A:Thrombuscoveringalesion51Fig.Lightmicroscopicbilayerappearanceofarestenosisspecimenobtainedbydirectionalatherectomy.Fig.Lightmicroscopicbilayer52Remodelling五、血管重塑Remodelling五、血管重塑53

血管壁SMC增生、遷移、凋亡，細(xì)胞外基質(zhì)增多與堆積，使血管壁細(xì)胞重排，管壁各層比例及形狀發(fā)生改變即血管重塑。血管重塑的概念(DefinitionofRemodelling)血管壁SMC增生、遷移、凋亡，細(xì)胞外基質(zhì)增多與54ConstrictiveRemodellingConstrictiveRemodelling55ConstrictiveRemodellingConstrictiveRemodelling56IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYConstrictiveRemodellingIntimaMediaAdventitiaIntimala57IntimaMediaAdventitiaNeointimalformationRemodellingIntimal&medialtearsReorganizationofthrombusThrombusformationIntimaMediaAdventitiaNeointima58IntimalthickeningConstrictiveremodellingIncorporationofmuralthrombusPTCAElasticrecoilArterywithatheroscleroticplaqueIntimalthickeningConstrictive59第三節(jié)再狹窄的預(yù)防PreventionofRestenosis第三節(jié)再狹窄的預(yù)防PreventionofResten601.Systemictreatments⑴Anti-plateletagents:Aspirin,GPIIb/IIIainhibitors⑵Anticoagulants:Heparin,warfarin⑶AntagonistofPDGF:Trapidil⑷Nitricoxidedonor:Molsidomine⑸Ca2+channelblockers⑹ACEinhibitor⑺Antioxidants:Probucol⑻γ-interferon⑼…1.Systemictreatments⑴Anti-pla612.Localtherapy⑴Localirradiation(brachytherapy)β-orγ-irradiationwiththecorrectdosemakestheVSMCsremainviablebutunabletoreplicate.2.Localtherapy⑴Localirradi62⑵CoatedstentsMuchinteresthasbeenfocusedondesigningstentscoatedwithdrug-elutingpolymers.⑵CoatedstentsMuchinteresth63⑶DeliverycathetersVariouscatheterdeviceshavebeendevelopedtoenablelocaldrugdeliveryorgenetherapy.⑶DeliverycathetersVariousca64⑷Antisenseoligodeoxynucleotides◆short-livedcell-cycleproteins◆proliferatingcellnuclearantigen◆c-myc(PCNA)⑷Antisenseoligodeoxynucleotid65⑸Localgenetherapy①TransferringvariouscytostaticgenesdirectlyintotheproliferatingSMCs.◆cell-cyclespecificinhibitoryproteins◆P53,dominant-negativeRas…⑸Localgenetherapy①Transferri66②Othertargetsofgenetherapy:

◆Tissueinhibitorofmatrixmetalloproteinases

◆Thrombininhibitor—hirudin◆Cyclooxygenase1orprostacyclinsynthase◆Nitricoxidesynthase②Othertargetsofgenetherapy67血管成形術(shù)后再狹窄RestenosisafterAngioplasty病理生理學(xué)教研室：劉潔血管成形術(shù)后再狹窄RestenosisafterAngi68第一節(jié)概述Introduction第一節(jié)概述Introduction69冠心病的治療

藥物治療

手術(shù)治療

介入治療冠心病的治療藥物治療手術(shù)治療介入治療70HistoryRetrospect一、歷史回顧HistoryRetrospect一、歷史回顧711954年：PercutaneousTransluminalAngioplasty(PTA)美國放射學(xué)家Doter開創(chuàng)經(jīng)皮血管腔內(nèi)成形術(shù)Interventionalradiology1954年：PercutaneousTranslumina721974年：PercutaneousTransluminalCoronaryAngioplasty(PTCA)瑞士醫(yī)生Gruentzig成功進(jìn)行了經(jīng)皮冠狀動脈腔內(nèi)成形術(shù)1974年：PercutaneousTranslumina731996年：

美國每年約有50萬人接受PTCA手術(shù)治療。1996年：742001年：全球每年約有150萬人接受PTCA手術(shù)治療。2001年：751984年：我國實(shí)施了首例PTCA手術(shù)。1984年：我國實(shí)施了首例PTCA手術(shù)。76截止1996年：

我國共實(shí)施了5209例PTCA手術(shù)。截止1996年：我國共實(shí)施了5209例PTCA手77Mechanismof

二、

PTCA治療機(jī)制LuminalEnlargementfollowingPTCAMechanismof二、PTCA治療機(jī)制Lumina78EndotheliumBasementmembraneInternalelasticlamina(IEL)Tunicamedia(media)Externalelasticlamina(EEL)Tunicaexterna(adventitia)Tunicainterna(intima)StructureofhumancoronaryarteryEndotheliumBasementmembraneIn79EndotheliumBasementmembraneInternalelasticlaminaTunicamediaExternalelasticlaminaTunicaexternaTunicainternaEndotheliumBasementmembraneIn80MediaAdventitiaThearrowindicatestheinternalelasticlamina(IEL).MediaAdventitiaThearrowindic812.內(nèi)皮剝脫(EndothelialDenudation)3.內(nèi)膜斷裂(IntimalDisruption)4.內(nèi)彈力板撕裂5.中膜分離移位(DissectionofMedia)1.粥樣斑塊破裂(PlaqueRupture)(FractureofInternalElasticLamina)2.內(nèi)皮剝脫(EndothelialDenudation)82IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYIntimaMediaAdventitiaIntimala83PTCAArterywithatheroscleroticplaqueLumensizeincreasedPTCAArterywithatheroscleroti84三、

PTCA局限性LimitationsofPTCA三、PTCA局限性LimitationsofPTCA85急性血管閉塞約1%～5%。術(shù)后3-6個(gè)月內(nèi)再狹窄約25%～50%。急性血管閉塞約1%～5%。術(shù)后3-6個(gè)月內(nèi)再狹窄約25%～586DevelopmentofPTCA四、

PTCA的發(fā)展DevelopmentofPTCA四、PTCA的發(fā)展87冠狀動脈內(nèi)膜支架術(shù)(CoronaryStenting)冠狀動脈定向旋切術(shù)冠狀動脈內(nèi)膜旋磨術(shù)(

CoronaryRotablation)冠狀動脈內(nèi)膜切吸術(shù)(TransluminalExtractionCatheterAtherectomy)(

DirectionalCoronaryAtherectomy)冠狀動脈內(nèi)膜支架術(shù)(CoronaryStenting)冠狀88CoronaryStents1986SigwartCoronaryStents1986Sigwart89STRESStrial:StentRestenosisStudy(USA)BENESTENTtrial:BelgiumNetherlandsStentTrial(Europe)1994Restenosisoccursapproximately15～20%within6monthsafterinterventionsometimesnecessitatingrepeatrevascularization.STRESStrial:StentRestenosis90StentingafterPTCAindeedreducestheincidenceofrestenosis.

StentingafterPTCAindeedred91五、

再狹窄的概念ConceptofRestenosis五、再狹窄的概念ConceptofRestenosis92HistologicalRestenosisTherenarrowingcanbeseenhistologicallybutnotangiographicallyandisclinicallysilent.HistologicalRestenosisTher93AngiographicRestenosisLossof≥50%oftheinitialgaininlumensizeproducedatangioplasty.A﹥50%stenosisatfollow-upangiography.orAngiographicRestenosisLossof94ClinicalRestenosisRecurrenceofsymptomsoradverseevents，usuallydeath，non-fatalmyocardialinfarction，orneedforrevascularization.ClinicalRestenosisRecurrence95第二節(jié)再狹窄發(fā)生機(jī)制PathogenesisofRestenosis

第二節(jié)再狹窄發(fā)生機(jī)制PathogenesisofRes96ElasticRecoil一、彈性回縮ElasticRecoil一、彈性回縮97

人類冠狀動脈雖為肌性動脈，但含有彈性纖維：內(nèi)彈力板(

InternalElasticLamina，IEL)外彈力板(

ExternalElasticLamina，EEL)人類冠狀動脈雖為肌性動脈，但含有彈性纖維：內(nèi)彈力板98

因冠狀動脈壁具有彈性，當(dāng)球囊導(dǎo)管使其過度牽張后，將會發(fā)生彈性回縮。一般在PTCA術(shù)后數(shù)秒～數(shù)分發(fā)生。因冠狀動脈壁具有彈性，當(dāng)球囊導(dǎo)管使其過度牽張后99PTCAArterywithatheroscleroticplaqueElasticrecoilPTCAArterywithatheroscleroti100ThrombusFormation二、血栓形成ThrombusFormation二、血栓形成101AngioplastyEndothelialdenudationMediadissectionExposureofsubintimalcomponentsPlateletaggregationErythrocyteentrapmentPlateletadherenceConformationalshiftofIIb/IIIareceptorFibrinogenbindingReleaseofTXA2,ADP&serotoninAngioplastyEndothelialdenudat102Subintimalcomponents1.Collagen2.vonWillebrandfactor(vWF)3.Fibronectin4.LamininSubintimalcomponents1.Collag103IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYThrombusFormationErythrocyte&fibrin-richthrombusPlateletthrombusIntimaMediaAdventitiaIntimala104A:Thrombuscoveringalesionthatdevelopedafterangioplastyperformed10monthsearlier.B:Athigherpower,asisterlesioncanbeseenontheopposingvesselwall,reflectinganabnormalresponse.A:Thrombuscoveringalesion105IncorporationofMuralThrombusIncorporationofMuralThrombu106Inflammation三、炎癥Inflammation三、炎癥107AngioplastyInjuryMonocyte&lymphocyteinfiltrationPlateletadherenceReleaseofcytokines,growthfactors&chemoattractantsAngioplastyInjuryMonocyte&ly108NeointimalFormation四、新生內(nèi)膜形成NeointimalFormation四、新生內(nèi)膜形成109AngioplastyArteryinjuryVSMCActivationProliferationMigrationECMSynthesisNeointimalFormationECM:ExtracellularmatrixAngioplastyArteryinjuryVSMCA110ENDOTHELIUMPLATELETSCOAGULATIONMACROPHAGESLYMPHOCYTESNO,HeparansulfatePDGF,bFGFPDGF,TGF-βThrombinPDGF,TGF-β,IL1βγ-IFNSMCRestenosis(+)(+)(-)(-)(+)(+)PDGFbFGF(+)Proliferation,MigrationMatrixSynthesisContractionIntimalHyperplasiaVasoconstrictionENDOTHELIUMPLATELETSCOAGULATIO111LumenEndotheliumNeointimaElasticlaminaMediaChemotaxisInterconversionofphenotypes“Contractile”differentiated“Synthetic”undifferentiatedLumenEndotheliumNeointimaElast112Fig.PDGF-BBcausesactinfilamentreorganizationandlamellipodiaformationinhumanaorticsmoothmusclecells.A:ControlB:PDGF-BB10minC&D:PDGF-BB30minAtoCstainedwithFITC-labeledphalloidinDstainedwithɑ2-integrinantibody(focaladhesionsite)Fig.PDGF-BBcausesactinfila1131、中膜SMC增殖2、中膜SMC向內(nèi)膜遷移和增殖3、SMC增殖凋亡相對平衡期4、SMC再度增殖—最危險(xiǎn)時(shí)期PTCA術(shù)后VSMC增殖的階段(StagesofVSMCProliferation)1、中膜SMC增殖2、中膜SMC向內(nèi)膜遷移和增殖3、SMC114IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYNeointimalFormationIntimaMediaAdventitiaIntimala115IntimalThickeningIntimalThickening116A:AdventitiaM:MediaNI:NeointimaArrow:InternalElasticLamina(IEL)Control28daysafterballondenudationHistologicalcrosssectionofrabbitiliacartery.A:AdventitiaM:MediaNI:Neointim117A:Thrombuscoveringalesionthatdevelopedafterangioplastyperformed10monthsearlier.B:Athigherpower,asisterlesioncanbeseenontheopposingvesselwall,reflectinganabnormalresponse.A:Thrombuscoveringalesion118Fig.Lightmicroscopicbilayerappearanceofarestenosisspecimenobtainedbydirectionalatherectomy.Fig.Lightmicroscopicbilayer119Remodelling五、血管重塑Remodelling五、血管重塑120

血管壁SMC增生、遷移、凋亡，細(xì)胞外基質(zhì)增多與堆積，使血管壁細(xì)胞重排，管壁各層比例及形狀發(fā)生改變即血管重塑。血管重塑的概念(DefinitionofRemodelling)血管壁SMC增生、遷移、凋亡，細(xì)胞外基質(zhì)增多與121ConstrictiveRemodellingConstrictiveRemodelling122ConstrictiveRemodellingConstrictiveRemodelling123IntimaMediaAdventitiaIntimalandmedialtearsANGIOPLASTYConstrictiveRemodellingIntimaMediaAdventitiaIntimala1