動脈硬化血栓病理生理學(xué)課件

2022/11/5動脈硬化血栓病理生理學(xué)2022/11/1動脈硬化血栓病理生理學(xué)1Atherothrombosis*isthe

LeadingCauseofDeathWorldwide1* Atherothrombosisdefinedasischemicheartdiseaseandcerebrovasculardisease.1 TheWorldHealthReport2001.Geneva.WHO.2001.22.319.312.69.796.3051015202530Atherothrombosis*InfectiousDiseaseCancerInjuriesPulmonaryDiseaseAIDSCausesofMortality(%)Atherothrombosis*isthe

Leadi2AtherothrombosisSignificantly

ShortensLifeAnalysisofdatafromtheFraminghamHeartStudy.PeetersA,etal.EurHeartJ.2002;23:458-466.Atherothrombosisreduceslifeexpectancybyaround

8-12yearsinpatientsagedover60years1AverageRemainingLifeExpectancyatAge60(Men)048121620HealthyYearsHistoryofAMI-9.2yearsHistoryofCardiovascularDisease-7.4yearsHistoryofStroke-12yearsAtherothrombosisSignificantly33.2MillionHospitalAdmissionsCoronaryAtherosclerosisAcuteMyocardialInfarction

1,153,000Admissions829,000

AdmissionsHospitalizationsintheUS

DuetoVascularDiseaseCerebrovascularDisease961,000AdmissionsVascularDiseaseOtherIschemic

HeartDisease280,000AdmissionsPopovicJR,HallMJ.AdvanceData.2001;319:1-20.3.2MillionHospitalAdmission4PreventableDeathsApproximately57,000deathscouldbeavoidedeachyear

intheUSifpatientsweregivenappropriatecare.NationalCommitteeforQualityAssurance.Washington,DC2003.700Cervical-cancerscreeningPrenatalcare-blockertreatmentBreast-cancerscreeningSmokingcessationCholesterolmanagementDiabetescareHigh-bloodpressurecontrol1500170025002700650013,60028,300PreventableDeathsApproximatel5* BasedondatafromtheARICstudyoftheNationalHeart,Lung,andBloodInstitute,1987-1994.Includes AmericanshospitalizedwithdefiniteorprobableMIorfatalCHD,notincludingsilentMIs.

ACS,acutecoronarysyndrome;MI,myocardialinfarction;ARIC,AtheroscleroticRiskinCommunities,CHD, coronaryheartdisease.AmericanHeartAssociation.HeartDiseaseandStrokeStatistics—2003Update.EpidemiologyofACSintheUnitedStatesSinglelargestcauseofdeath515,204USdeathsin20001inevery5USdeathsIncidence1,100,000Americanswillhaveaneworrecurrentcoronaryattackeachyearandabout45%willdie*550,000newcasesofanginaperyearPrevalence12,900,000withahistoryofMI,angina,orboth* BasedondatafromtheARIC6EpidemiologyofStrokeintheUnitedStatesPrevalence4.7millioncasesIncidence700,000neworrecurrentstrokeseachyearMorbidity/mortalityThirdleadingcauseofdeath1ofevery14deaths(168,000deaths)Stroke:aleadingcauseoflong-termdisabilityAmericanHeartAssociation.HeartDiseaseandStrokeStatistics—2003Update.EpidemiologyofStrokeinthe7PeripheralArterialDiseasePADaffects12%oftheadultpopulation1,220%ofthepopulationaged>70Associatedwith6-foldincreaseinCVmortality3Underrecognizedandundertreated4Measurementsimple,inexpensive,andnoninvasiveAppropriateforriskassessmentandscreeningPatientsathighriskneedaggressiverisk-factormodificationandantiplateletdrugs4 PAD,peripheralarterydisease;CV,cardiovascular.1 NicolaidesAN.Symposium.Nov.1997.

2 HiattWR,etal.Circulation.1995;91:1472-1479.3 CriquiMH,etal.NEnglJMed.1992;326:381-386.

4 HirschAT,etal.JAMA.2001;286:1317-1324.PeripheralArterialDiseasePA8Diabetes:ImpactinUnitedStates12millionpeoplewithdiabetes1Diabetesisthe5thleadingcauseofdeath1Halfofdiabeticpatientswillexperiencekidneyfailure1Diabetesistheleadingcauseofnewadultcases

ofblindness2Directandindirectdiabetescostswereestimatedat$132billion1in20021 AmericanDiabetesAssociation.DiabetesCare.2003;26:917-932.2 JuvenileDiabetesResearchFoundationInternational.DiabetesFigures,.Diabetes:ImpactinUnitedSta9CerebralIschemicstrokeTransientischemicattackCardiacMyocardialinfarctionAnginapectoris(stable,unstable)PeripheralArterialDisease

Criticallimbischemia,claudicationClinicalManifestationsofAtherothrombosisCerebralClinicalManifestation10OverlapofVascularDiseaseinPatients

WithAtherothrombosisPAD,peripheralarterydisease.AdaptedfromTransAtlanticInter-SocietyConsensusGroup.JVascSurg.2000;31:S16.Coronary

DiseasePAD12%33%15%5%14%13%8%Cerebral

DiseaseCoronary

DiseasePAD19%30%25%4%12%7%3%Cerebral

DiseaseCAPRIEAronow&AhnOverlapofVascularDiseasein11CommonUnderlyingAtherothromboticDiseaseProcessMI,myocardialinfarction;PAD,peripheralarterialdisease;CV,cardiovascular.NessJ,etal.JAmGeriatrSoc.1999;47:1255-1256.SchaferAI.AmJMed.1996;101:199-209.AtherothromboticEvents(MI,Stroke,orCVDeath)PlaqueRupturePlateletAdhesion,Activation,andAggregationThrombusFormationMIAtherothromboticStrokePADUnstableAnginaCommonUnderlyingAtherothromb12RiskofaSecondAtherothromboticEvent* Deathdocumentedwithin1hourofaneventattributedtoCHD. Note:Thischartisbasedonepidemiologicdataandisnotintendedtoprovideadirectbasisfor comparisonofrisksbetweeneventcategories. MI,myocardialinfarction;TIA,transientaschemicattack,PAD,peripheralarterydisease. AdultTreatmentPanelII.Circulation.1994;89:1333-1363. Kannel,WB.JCardiovascRisk.1994;1:333-339. Wilterdink,JI,etal.ArchNeurol.1992;49:857-863.

Crique,MH,etal.NEnglJMed.1992;326:381-386.RiskofaSecondAtherothrombo13Unstable

angina

MIIschemicstroke/TIACriticalleg

ischemiaIntermitent

claudicationCVdeathACSAtherosclerosisStableangina/IntermittentclaudicationAtherothrombosis:AGeneralizedandProgressiveProcessThrombosisAdaptedfromLibbyP.Circulation.2001;104:365-372.Unstable

angina

MIACSAtherosc14Atherothrombosis:ThrombusSuperimposedonAtheroscleroticPlaqueAdapted

fromFalkE,etal.Circulation.1995;92:657-671.Atherothrombosis:ThrombusSup15CharacteristicsofUnstableand

StablePlaqueThin

fibrouscapInflammatory

cellsFew

SMCsEroded

endotheliumActivated

macrophagesThick

fibrouscapLackof

inflammatory

cellsFoamcellsIntact

endotheliumMore

SMCsLibbyP.Circulation.1995;91:2844-2850.UnstableStableCharacteristicsofUnstablean16PlaqueRuptureAndrewFarb,MDbypermission.PlaqueRuptureAndrewFarb,MD17RiskFactorsforPlaqueRuptureImpaired

FibrinolysisFibrinogenDiabetes

MellitusCholesterolSmokingCapFatigueAtheromatousCore

(size/consistency)CapInflammationSystemicFactorsLocalFactorsHomocysteinePlaque

RuptureFusterV,etal.NEnglJMed.1992;326:310-318. FalkE,etal.Circulation.1995:92:657-671.CapThickness/ConsistencyRiskFactorsforPlaqueRuptur18MultipleRiskFactorsforAtherothrombosisMI,myocardialinfarction.AdaptedfromYusufS,etal.Circulation.2001;104:2746-2753.DrouetL.CerebrovascDis.2002;13(suppl1):1-6.LifestyleSmokingDietLackofexerciseGeneticTraitsGenderPlA2GeneralizedDisordersAgeObesitySystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulablestatesHomocysteinemiaAtherothromboticManifestations(MI,stroke,

vasculardeath)InflammationElevatedCRPCD40Ligand,IL-6Prothromboticfactors(FIandII)FibrinogenLocalFactorsBloodflowpatternsShearstressVesseldiameterArterialwallstructure%arterialstenosisMultipleRiskFactorsforAthe19RiskFactorsforIschemicStrokeModifiableHypertensionAtrialfibrillationCigarettesmokingHyperlipidemiaAlcoholabuseCarotidstenosisPhysicalinactivityObesityDiabetesNonmodifiableAgeSexRace/EthnicityHeredityRiskFactorsforIschemicStro20RCAWallLADWallEccentric(“l(fā)ipid-rich”)Concentric(“fibrotic”)Ectatic(“remodeled”)Black-BloodCoronaryPlaqueMRMR,magneticresonance;LAD,leftanteriordescending;RCA,rightcoronaryartery.FayadZA,etal.Circulation.2000;102:506-510.(withpermission)LADWallRCAWallLADWallEccentric(“l(fā)i21EvidenceofMultiple“Vulnerable”Plaques

inACSACS,acutecoronarysyndrome.AsakuraM,etal.JAmCollCardiol.2001;37:1284-1288.(withpermission)Angiographic&angioscopicimagesin58-year-oldman

withanteriormyocardialinfarctionMultiple“vulnerable”plaques

detectedinnon-culpritsegments10-12Culpritlesion(#8)detectedwiththrombus(red)Multiple“vulnerable”plaquesdetectedinnon-culpritsegments1-7EvidenceofMultiple“Vulnerab22MultipleComplexCoronaryPlaquesinPatientsWithAcuteMIMI,myocardialinfarction.GoldsteinJA,etal.NEngJMed.2000;343:915-922.(withpermission)CulpritlesionMultipleplaquesdetectedMultipleplaquesdetectedMultipleComplexCoronaryPlaq23ACS,acutecoronarysyndrome.RioufolG,etal.Circulation2002;106:804-808.(withpermission)FrequencyofmultipleactiveplaquerupturesbeyondtheculpritlesionPatients(%)80%ofPatientsWith2Plaques

N=24FrequencyofMultiple“Active”PlaquesinPatientsWithACSACS,acutecoronarysyndrome.F24ACS:TipoftheAtherothrombotic“Iceberg”ACS,acutecoronarysyndrome;UA,unstableangina;NSTEMI,non-ST-segmentelevationmyocardial

infarction;STEMI,ST-segmentelevationmyocardialinfarction.AdaptedfromGoldsteinJA.JAmCollCardiol.2002;39:1464-1467.PresenceofMultipleCoronaryPlaquesVascularInflammationPersistentHyperreactivePlateletsClinicalSubclinicalAcutePlaqueRuptureACS(UA/NSTEMI/STEMI)ACS:TipoftheAtherothrombot25HemostaticPlugFormationThrombinAGGREGATIONFibrinHemostaticClotClottingPlateletAggregation0min10min5minSECONDARYPRIMARYCOAGULATION

Adaptedfrom

FergusonJJ,etal.AntiplateletTherapyinClinicalPractice.2000:15-35.HemostaticPlugFormationThrom26AdhesionTheRoleofPlateletsinAtherothrombosisAggregation1Activation23AdhesionTheRoleofPlatelets27GPIIb/IIIaInhibitors1.PlateletAdhesion2.PlateletActivationPlateletGPIbPlaqueruptureActivatedPlateletGPIIb/IIIa

3.PlateletAggregationASA,Clopidogrel/TiclopidineASA,acetylsalicyclicacid.CannonandBraunwald,HeartDisease.2001.TxA2FibrinogenPlateletsRoleinThrombosisGPIIb/IIIaInhibitors1.Plat28FibrinPlateletsRBCsWhiteThrombusFibrinPlateletsRBCsCoagulationThrombus HighFlow SlowFlowPlatelets:RoleinThrombosisRBCs,redbloodcells.FibrinPlateletsRBCsWhiteThrom29ThrombinSerotoninEpinephrineCollagenADPActivationTXA2ActivatedPlateletCOXDegranulationAspirinGpIIb/IIIa

fibrinogenreceptorToneighboringplateletClopidogrelTiclopidinePlateletagonistsADPATPserotonincalciummagnesiumAdhesiveproteinsthrombospondinfibrinogenp-selectinvWFCoagulationfactorsfactorVfactorXIPAI-1Inflammatoryfactorsplateletfactor4CD154(CD40ligand)PDGFIVGpIIb/IIIaInhibitorsTXA,thromboxane;PDGF,platelet-derivedgrowthfactor.ThrombinADPActivationTXA2Activ30PlateletHyperreactivityFollowingACSPredicts5-YearOutcomesPlateletAggregabilityStatus01020304050DeathCardiacEvents10.36.414.9Patients(%)*RR=1.6(CI0.5-5.5)Negative(n=94)*RR=1.6(CI0.7-3.5)*RR=5.4(CI2.2-13.4)*RR=3.1(CI1.6-5.8)Intermediate(n=29)Positive(n=26) ACS,acutecoronarysyndrome.*Relativeriskcomparedtogroupwithnegativeaggregation.

AdaptedfromTripMD,etal.NEnglJMed.1990;322:1549-1554.PlateletHyperreactivityFollo31PlateletsReleaseInflammatoryMediators

andLeadtoVascularInflammationand

PlaqueInstabilityRANTES(RegulatedonActivation,NormalT-cellExpressedandSecreted).LibbyP,etal.Circulation.2001;103:1718-1720.InflammatoryModulatorsCD40ligandPlateletfactor4RANTESUnstablePlaqueActivated

PlateletsPlaque

Rupture&ThrombosisThrombospondinPlatelet-derivedgrowthfactorNitricoxidePlateletsReleaseInflammatory32CD40LisactivatedbyagonistssuchasADP,thrombin,orcollagen.Thetranslocation

ofCD40Lseemstocoincidewiththepresenceofrelease-granulecontents,includingplatelet-derivedgrowthfactor(PDGF),transforminggrowthfactorbeta,plateletfactor4,andthrombospondin.GPIIb/IIIaantagonistsblockthehydrolysisandsubsequent

releaseofSCD40Lfromplatelets.TheSheddingofSolubleSCD40LDuringPlateletStimulationSCD40L,SCD40ligand;PDGF,platelet-derivedgrowthfactor;TGF-,transforminggrowthfactor-beta;PF4,plateletfactor4;TSP,thrombospondin.AndreP,etal.Circulation.2002:106:896-899.(withpermission)ADPThrombinCollagenCD4OLsCD4OLGPIIb-IIIaAntagonistsPDGFTGFPF4TSPCD40Lisactivatedbyagonists33InflammatoryModulators

ProducedbyPlateletsTGF-?5StimulatesmoothmusclecellbiosynthesisNitricoxide3Effectsonmonocyte,leucocyte,endothelium,andsmoothmusclecellsCD154(CD40ligand)1,4RegulatesmacrophageandsmoothmusclecellfunctionsRANTES2InfluencesmacrophageadhesiontoendothelialcellPF41Mediatesshear-resistantarrestofmonocytestoendotheliumPlateletPDGF1

InducesproliferationofsmoothmusclecellsThrombospondin1Interactswithcellsurfacereceptors1 LibbyP,etal.Circulation.2001;103:1718-1720.2vonHundelshausenP,et

al.Circulation.2001;103:

1772-1777.3WeverRMF,etal.Circulation.1998;97:108-112.4HermannA,etal.Platelets.2001;12:74-82.

5RobbieL,etal.AnnNYAcadSci.2001;947:167-79.InflammatoryModulators

Produ34TheDetrimentalRoleofPlatelet-DerivedsCD40LigandinCardiovascularDiseaseAdaptedfromAndreP,etal.Circulation.2002:106:896-899.

Inflammation – inducesproduction/release

ofpro-inflammatory

cytokinesfromvascular

andatheromacells

Thrombosis

–stabilizesplatelet-rich

thrombi

Restenosis

–preventsreendothelialization

oftheinjuredvessel

–contributestoactivation

andproliferationof

smoothmusclecellsTheDetrimentalRoleofPlatel35HeeschenC,etal.NEnglJMed.2003;348:1104-1111.(withpermission)AssociationBetweenSolubleCD40LigandLevelsandtheRateofCardiacEventsTimeDeathorNonfatal

MyocardialInfarction(%)P=.13P=.003P=.004P<.001HeeschenC,etal.NEnglJMe36015304560750246810Monocyte–PlateletAggregates(%)SolubleCD40Ligand(g/Liter)r

=0.75P<.001LevelOfSolubleCD40Ligandand

Monocyte—PlateletActivationin161PatientsWithChestPain

HeeschenC,etal.NEnglJMed.2003:348:1104-1111.(withpermission)015304560750246810Monocyte–Pla372022/11/5動脈硬化血栓病理生理學(xué)2022/11/1動脈硬化血栓病理生理學(xué)38Atherothrombosis*isthe

LeadingCauseofDeathWorldwide1* Atherothrombosisdefinedasischemicheartdiseaseandcerebrovasculardisease.1 TheWorldHealthReport2001.Geneva.WHO.2001.22.319.312.69.796.3051015202530Atherothrombosis*InfectiousDiseaseCancerInjuriesPulmonaryDiseaseAIDSCausesofMortality(%)Atherothrombosis*isthe

Leadi39AtherothrombosisSignificantly

ShortensLifeAnalysisofdatafromtheFraminghamHeartStudy.PeetersA,etal.EurHeartJ.2002;23:458-466.Atherothrombosisreduceslifeexpectancybyaround

8-12yearsinpatientsagedover60years1AverageRemainingLifeExpectancyatAge60(Men)048121620HealthyYearsHistoryofAMI-9.2yearsHistoryofCardiovascularDisease-7.4yearsHistoryofStroke-12yearsAtherothrombosisSignificantly403.2MillionHospitalAdmissionsCoronaryAtherosclerosisAcuteMyocardialInfarction

1,153,000Admissions829,000

AdmissionsHospitalizationsintheUS

DuetoVascularDiseaseCerebrovascularDisease961,000AdmissionsVascularDiseaseOtherIschemic

HeartDisease280,000AdmissionsPopovicJR,HallMJ.AdvanceData.2001;319:1-20.3.2MillionHospitalAdmission41PreventableDeathsApproximately57,000deathscouldbeavoidedeachyear

intheUSifpatientsweregivenappropriatecare.NationalCommitteeforQualityAssurance.Washington,DC2003.700Cervical-cancerscreeningPrenatalcare-blockertreatmentBreast-cancerscreeningSmokingcessationCholesterolmanagementDiabetescareHigh-bloodpressurecontrol1500170025002700650013,60028,300PreventableDeathsApproximatel42* BasedondatafromtheARICstudyoftheNationalHeart,Lung,andBloodInstitute,1987-1994.Includes AmericanshospitalizedwithdefiniteorprobableMIorfatalCHD,notincludingsilentMIs.

ACS,acutecoronarysyndrome;MI,myocardialinfarction;ARIC,AtheroscleroticRiskinCommunities,CHD, coronaryheartdisease.AmericanHeartAssociation.HeartDiseaseandStrokeStatistics—2003Update.EpidemiologyofACSintheUnitedStatesSinglelargestcauseofdeath515,204USdeathsin20001inevery5USdeathsIncidence1,100,000Americanswillhaveaneworrecurrentcoronaryattackeachyearandabout45%willdie*550,000newcasesofanginaperyearPrevalence12,900,000withahistoryofMI,angina,orboth* BasedondatafromtheARIC43EpidemiologyofStrokeintheUnitedStatesPrevalence4.7millioncasesIncidence700,000neworrecurrentstrokeseachyearMorbidity/mortalityThirdleadingcauseofdeath1ofevery14deaths(168,000deaths)Stroke:aleadingcauseoflong-termdisabilityAmericanHeartAssociation.HeartDiseaseandStrokeStatistics—2003Update.EpidemiologyofStrokeinthe44PeripheralArterialDiseasePADaffects12%oftheadultpopulation1,220%ofthepopulationaged>70Associatedwith6-foldincreaseinCVmortality3Underrecognizedandundertreated4Measurementsimple,inexpensive,andnoninvasiveAppropriateforriskassessmentandscreeningPatientsathighriskneedaggressiverisk-factormodificationandantiplateletdrugs4 PAD,peripheralarterydisease;CV,cardiovascular.1 NicolaidesAN.Symposium.Nov.1997.

2 HiattWR,etal.Circulation.1995;91:1472-1479.3 CriquiMH,etal.NEnglJMed.1992;326:381-386.

4 HirschAT,etal.JAMA.2001;286:1317-1324.PeripheralArterialDiseasePA45Diabetes:ImpactinUnitedStates12millionpeoplewithdiabetes1Diabetesisthe5thleadingcauseofdeath1Halfofdiabeticpatientswillexperiencekidneyfailure1Diabetesistheleadingcauseofnewadultcases

ofblindness2Directandindirectdiabetescostswereestimatedat$132billion1in20021 AmericanDiabetesAssociation.DiabetesCare.2003;26:917-932.2 JuvenileDiabetesResearchFoundationInternational.DiabetesFigures,.Diabetes:ImpactinUnitedSta46CerebralIschemicstrokeTransientischemicattackCardiacMyocardialinfarctionAnginapectoris(stable,unstable)PeripheralArterialDisease

Criticallimbischemia,claudicationClinicalManifestationsofAtherothrombosisCerebralClinicalManifestation47OverlapofVascularDiseaseinPatients

WithAtherothrombosisPAD,peripheralarterydisease.AdaptedfromTransAtlanticInter-SocietyConsensusGroup.JVascSurg.2000;31:S16.Coronary

DiseasePAD12%33%15%5%14%13%8%Cerebral

DiseaseCoronary

DiseasePAD19%30%25%4%12%7%3%Cerebral

DiseaseCAPRIEAronow&AhnOverlapofVascularDiseasein48CommonUnderlyingAtherothromboticDiseaseProcessMI,myocardialinfarction;PAD,peripheralarterialdisease;CV,cardiovascular.NessJ,etal.JAmGeriatrSoc.1999;47:1255-1256.SchaferAI.AmJMed.1996;101:199-209.AtherothromboticEvents(MI,Stroke,orCVDeath)PlaqueRupturePlateletAdhesion,Activation,andAggregationThrombusFormationMIAtherothromboticStrokePADUnstableAnginaCommonUnderlyingAtherothromb49RiskofaSecondAtherothromboticEvent* Deathdocumentedwithin1hourofaneventattributedtoCHD. Note:Thischartisbasedonepidemiologicdataandisnotintendedtoprovideadirectbasisfor comparisonofrisksbetweeneventcategories. MI,myocardialinfarction;TIA,transientaschemicattack,PAD,peripheralarterydisease. AdultTreatmentPanelII.Circulation.1994;89:1333-1363. Kannel,WB.JCardiovascRisk.1994;1:333-339. Wilterdink,JI,etal.ArchNeurol.1992;49:857-863.

Crique,MH,etal.NEnglJMed.1992;326:381-386.RiskofaSecondAtherothrombo50Unstable

angina

MIIschemicstroke/TIACriticalleg

ischemiaIntermitent

claudicationCVdeathACSAtherosclerosisStableangina/IntermittentclaudicationAtherothrombosis:AGeneralizedandProgressiveProcessThrombosisAdaptedfromLibbyP.Circulation.2001;104:365-372.Unstable

angina

MIACSAtherosc51Atherothrombosis:ThrombusSuperimposedonAtheroscleroticPlaqueAdapted

fromFalkE,etal.Circulation.1995;92:657-671.Atherothrombosis:ThrombusSup52CharacteristicsofUnstableand

StablePlaqueThin

fibrouscapInflammatory

cellsFew

SMCsEroded

endotheliumActivated

macrophagesThick

fibrouscapLackof

inflammatory

cellsFoamcellsIntact

endotheliumMore

SMCsLibbyP.Circulation.1995;91:2844-2850.UnstableStableCharacteristicsofUnstablean53PlaqueRuptureAndrewFarb,MDbypermission.PlaqueRuptureAndrewFarb,MD54RiskFactorsforPlaqueRuptureImpaired

FibrinolysisFibrinogenDiabetes

MellitusCholesterolSmokingCapFatigueAtheromatousCore

(size/consistency)CapInflammationSystemicFactorsLocalFactorsHomocysteinePlaque

RuptureFusterV,etal.NEnglJMed.1992;326:310-318. FalkE,etal.Circulation.1995:92:657-671.CapThickness/ConsistencyRiskFactorsforPlaqueRuptur55MultipleRiskFactorsforAtherothrombosisMI,myocardialinfarction.AdaptedfromYusufS,etal.Circulation.2001;104:2746-2753.DrouetL.CerebrovascDis.2002;13(suppl1):1-6.LifestyleSmokingDietLackofexerciseGeneticTraitsGenderPlA2GeneralizedDisordersAgeObesitySystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulablestatesHomocysteinemiaAtherothromboticManifestations(MI,stroke,

vasculardeath)InflammationElevatedCRPCD40Ligand,IL-6Prothromboticfactors(FIandII)FibrinogenLocalFactorsBloodflowpatternsShearstressVesseldiameterArterialwallstructure%arterialstenosisMultipleRiskFactorsforAthe56RiskFactorsforIschemicStrokeModifiableHypertensionAtrialfibrillationCigarettesmokingHyperlipidemiaAlcoholabuseCarotidstenosisPhysicalinactivityObesityDiabetesNonmodifiableAgeSexRace/EthnicityHeredityRiskFactorsforIschemicStro57RCAWallLADWallEccentric(“l(fā)ipid-rich”)Concentric(“fibrotic”)Ectatic(“remodeled”)Black-BloodCoronaryPlaqueMRMR,magneticresonance;LAD,leftanteriordescending;RCA,rightcoronaryartery.FayadZA,etal.Circulation.2000;102:506-510.(withpermission)LADWallRCAWallLADWallEccentric(“l(fā)i58EvidenceofMultiple“Vulnerable”Plaques

inACSACS,acutecoronarysyndrome.AsakuraM,etal.JAmCollCardiol.2001;37:1284-1288.(withpermission)Angiographic&angioscopicimagesin58-year-oldman

withanteriormyocardialinfarctionMultiple“vulnerable”plaques

detectedinnon-culpritsegments10-12Culpritlesion(#8)detectedwiththrombus(red)Multiple“vulnerable”plaquesdetectedinnon-culpritsegments1-7EvidenceofMultiple“Vulnerab59MultipleComplexCoronaryPlaquesinPatientsWithAcuteMIMI,myocardialinfarction.GoldsteinJA,etal.NEngJMed.2000;343:915-922.(withpermission)CulpritlesionMultipleplaquesdetectedMultipleplaquesdetectedMultipleComplexCoronaryPlaq60ACS,acutecoronarysyndrome.RioufolG,etal.Circulation2002;106:804-808.(withpermission)FrequencyofmultipleactiveplaquerupturesbeyondtheculpritlesionPatients(%)80%ofPatientsWith2Plaques

N=24FrequencyofMultiple“Active”PlaquesinPatientsWithACSACS,acutecoronarysyndrome.F61ACS:TipoftheAtherothrombotic“Iceberg”ACS,acutecoronarysyndrome;UA,unstableangina;NSTEMI,non-ST-segmentelevationmyocardial

infarction;STEMI,ST-segmentelevationmyocardialinfarction.AdaptedfromGoldsteinJA.JAmCollCardiol.2002;39:1464-1467.PresenceofMultipleCoronaryPlaquesVascularInflammationPersistentHyperreactivePlateletsClinicalSubclinicalAcutePlaqueRuptureACS(UA/NSTEMI/STEMI)ACS:TipoftheAtherothrombot62HemostaticPlugFormationThrombinAGGREGATIONFibrinHemostaticClotClottingPlateletAggregation0min10min5minSECONDARYPRIMARYCOAGULATION

Adaptedfrom

FergusonJJ,etal.AntiplateletTherapyinClinicalPractice.2000:15-35.HemostaticPlugFormationThrom63AdhesionTheRoleofPlateletsinAtherothrombosisAggregation1Activation23AdhesionTheRoleofPlatelets64GPIIb/IIIaInhibitors1.PlateletAdhesion2.PlateletActivationPlateletGPIbPlaqueruptureActivatedPlateletGPIIb/IIIa

3.PlateletAggregationASA,Clopidogrel/TiclopidineASA,acetylsalicyclicacid.CannonandBraunwald,HeartDisease.2001.TxA2FibrinogenPlateletsRoleinThrombosisGPIIb/IIIaInhibitors1.Plat65FibrinPlateletsRBCsWhiteThrombusFibrinPlateletsRBCsCoagulationThrombus HighFlow SlowFlowPlatelets:RoleinThrombosisRBCs,redbloodcells.FibrinPlateletsRBCsWhiteThrom66ThrombinSerotoninEpinephrineCollagenADPActivationTXA2ActivatedPlateletCOXDegranulationAspirinGpIIb/IIIa

fibrinogenreceptorToneighboringplateletClopidogrelTiclopidinePlateletagonistsADPATPserotonincalciummagnesiumAdhesiveproteinsthrombospondinfibrinogenp-selectinvWFCoagulationfactorsfactorVfactorXIPAI-1Inflammatoryfactorsplateletfactor4CD154(CD40ligand)PDGFIVGpIIb/IIIaInhibitorsTXA,thromboxane;PDGF,platelet-derivedgrowthfactor.ThrombinADPActivationTXA2Activ67PlateletHyperreactivityFollowingACSPredicts5-YearOutcomesPlateletAggregabilityStatus01020304050DeathCardiacEvents10.36.414.9Patients(%)*RR=1.6(CI0.5-5.5)Negative(n=94)*RR=1.6(CI0.7-3.5)*RR=5.4(CI2.2-13.4)*RR=3.1(CI1.6-5.8)Intermediate(n=29)Positive(n=26) ACS,acutecoronarysyndrome.*Relativeriskcomparedtogroupwithnegativeaggregation.

AdaptedfromTripMD,etal.NEnglJMed.1990;322:1549-1554.PlateletHyperreactivityFollo68PlateletsReleaseInflammatoryMediators

andLeadtoVascularInflammationand

PlaqueInstabilityRANTES(RegulatedonActivation,NormalT-cellExpressedandSecre