动脉硬化血栓病理生理学.ppt

AtherothrombosisPathophysiology,WhatIsAtherothrombosis?,TheformationofathrombusonanexistingatheroscleroticplaqueAtherothrombosisisanewtermrecognizingthatatherosclerosis(plaquedevelopment)andacutethrombosisareintegrallyrelatedtothepresentationofvasculareventsAgeneralizedprogressivediseaseoflarge-andmid-sizearteriesthataffectsmultiplevascularbeds,includingcerebral,coronary,andperipheralarteriesTheunderlyingdiseaseleadingtomyocardialinfarction(MI),peripheralarterialdisease(PAD),ischemiaandmanyformsofstroke,MI,myocardialinfarction;PAD,peripheralarterydisease.FusterV,etal.VascMed.1998;3:231-239.RauchU,etal.AnnInternMed.2001;134:122-238.,Atherothrombosis*istheLeadingCauseofDeathWorldwide1,*Atherothrombosisdefinedasischemicheartdiseaseandcerebrovasculardisease.1TheWorldHealthReport2001.Geneva.WHO.2001.,22.3,19.3,12.6,9.7,9,6.3,0,5,10,15,20,25,30,Atherothrombosis*,InfectiousDisease,Cancer,Injuries,PulmonaryDisease,AIDS,CausesofMortality(%),AtherothrombosisSignificantlyShortensLife,AnalysisofdatafromtheFraminghamHeartStudy.PeetersA,etal.EurHeartJ.2002;23:458-466.,Atherothrombosisreduceslifeexpectancybyaround8-12yearsinpatientsagedover60years1,AverageRemainingLifeExpectancyatAge60(Men),0,4,8,12,16,20,Healthy,Years,HistoryofAMI,-9.2years,HistoryofCardiovascularDisease,-7.4years,HistoryofStroke,-12years,3.2MillionHospitalAdmissions,CoronaryAtherosclerosis,AcuteMyocardialInfarction,1,153,000Admissions,829,000Admissions,HospitalizationsintheUSDuetoVascularDisease,CerebrovascularDisease,961,000Admissions,VascularDisease,OtherIschemicHeartDisease,280,000Admissions,PopovicJR,HallMJ.AdvanceData.2001;319:1-20.,PreventableDeaths,Approximately57,000deathscouldbeavoidedeachyearintheUSifpatientsweregivenappropriatecare.,NationalCommitteeforQualityAssurance.Washington,DC2003.,Cervical-cancerscreening,Prenatalcare,-blockertreatment,Breast-cancerscreening,Smokingcessation,Cholesterolmanagement,Diabetescare,High-bloodpressurecontrol,*BasedondatafromtheARICstudyoftheNationalHeart,Lung,andBloodInstitute,1987-1994.IncludesAmericanshospitalizedwithdefiniteorprobableMIorfatalCHD,notincludingsilentMIs.ACS,acutecoronarysyndrome;MI,myocardialinfarction;ARIC,AtheroscleroticRiskinCommunities,CHD,coronaryheartdisease.AmericanHeartAssociation.HeartDiseaseandStrokeStatistics2003Update.,EpidemiologyofACSintheUnitedStates,Singlelargestcauseofdeath515,204USdeathsin20001inevery5USdeathsIncidence1,100,000Americanswillhaveaneworrecurrentcoronaryattackeachyearandabout45%willdie*550,000newcasesofanginaperyearPrevalence12,900,000withahistoryofMI,angina,orboth,EpidemiologyofStrokeintheUnitedStates,Prevalence4.7millioncasesIncidence700,000neworrecurrentstrokeseachyearMorbidity/mortalityThirdleadingcauseofdeath1ofevery14deaths(168,000deaths)Stroke:aleadingcauseoflong-termdisability,AmericanHeartAssociation.HeartDiseaseandStrokeStatistics2003Update.,PeripheralArterialDisease,PADaffects12%oftheadultpopulation1,220%ofthepopulationaged70Associatedwith6-foldincreaseinCVmortality3Underrecognizedandundertreated4Measurementsimple,inexpensive,andnoninvasiveAppropriateforriskassessmentandscreeningPatientsathighriskneedaggressiverisk-factormodificationandantiplateletdrugs4,PAD,peripheralarterydisease;CV,cardiovascular.1NicolaidesAN.Symposium.Nov.1997.2HiattWR,etal.Circulation.1995;91:1472-1479.3CriquiMH,etal.NEnglJMed.1992;326:381-386.4HirschAT,etal.JAMA.2001;286:1317-1324.,Diabetes:ImpactinUnitedStates,12millionpeoplewithdiabetes1Diabetesisthe5thleadingcauseofdeath1Halfofdiabeticpatientswillexperiencekidneyfailure1Diabetesistheleadingcauseofnewadultcasesofblindness2Directandindirectdiabetescostswereestimatedat$132billion1in2002,1AmericanDiabetesAssociation.DiabetesCare.2003;26:917-932.2JuvenileDiabetesResearchFoundationInternational.DiabetesFigures,.,CerebralIschemicstrokeTransientischemicattackCardiacMyocardialinfarctionAnginapectoris(stable,unstable)PeripheralArterialDiseaseCriticallimbischemia,claudication,ClinicalManifestationsofAtherothrombosis,OverlapofVascularDiseaseinPatientsWithAtherothrombosis,PAD,peripheralarterydisease.AdaptedfromTransAtlanticInter-SocietyConsensusGroup.JVascSurg.2000;31:S16.,CoronaryDisease,PAD,12%,33%,15%,5%,14%,13%,8%,CerebralDisease,CoronaryDisease,PAD,19%,30%,25%,4%,12%,7%,3%,CerebralDisease,CAPRIE,AronowPAD,peripheralarterialdisease;CV,cardiovascular.NessJ,etal.JAmGeriatrSoc.1999;47:1255-1256.SchaferAI.AmJMed.1996;101:199-209.,AtherothromboticEvents(MI,Stroke,orCVDeath),PlaqueRupture,PlateletAdhesion,Activation,andAggregation,ThrombusFormation,MI,AtherothromboticStroke,PAD,UnstableAngina,RiskofaSecondAtherothromboticEvent,*Deathdocumentedwithin1hourofaneventattributedtoCHD.Note:Thischartisbasedonepidemiologicdataandisnotintendedtoprovideadirectbasisforcomparisonofrisksbetweeneventcategories.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.,UnstableanginaMIIschemicstroke/TIACriticallegischemiaIntermitentclaudicationCVdeath,ACS,Atherosclerosis,Stableangina/Intermittentclaudication,Atherothrombosis:AGeneralizedandProgressiveProcess,Thrombosis,AdaptedfromLibbyP.Circulation.2001;104:365-372.,Atherothrombosis:ThrombusSuperimposedonAtheroscleroticPlaque,AdaptedfromFalkE,etal.Circulation.1995;92:657-671.,CharacteristicsofUnstableandStablePlaque,Thinfibrouscap,Inflammatorycells,FewSMCs,Erodedendothelium,Activatedmacrophages,Thickfibrouscap,Lackofinflammatorycells,Foamcells,Intactendothelium,MoreSMCs,LibbyP.Circulation.1995;91:2844-2850.,Unstable,Stable,PlaqueRupture,AndrewFarb,MDbypermission.,RiskFactorsforPlaqueRupture,ImpairedFibrinolysis,Fibrinogen,DiabetesMellitus,Cholesterol,Smoking,CapFatigue,AtheromatousCore(size/consistency),CapInflammation,SystemicFactors,LocalFactors,Homocysteine,PlaqueRupture,FusterV,etal.NEnglJMed.1992;326:310-318.FalkE,etal.Circulation.1995:92:657-671.,CapThickness/Consistency,MultipleRiskFactorsforAtherothrombosis,MI,myocardialinfarction.AdaptedfromYusufS,etal.Circulation.2001;104:2746-2753.DrouetL.CerebrovascDis.2002;13(suppl1):1-6.,LifestyleSmokingDietLackofexercise,GeneticTraitsGenderPlA2,GeneralizedDisordersAgeObesity,SystemicConditionsHypertensionHyperlipidemiaDiabetesHypercoagulablestatesHomocysteinemia,AtherothromboticManifestations(MI,stroke,vasculardeath),InflammationElevatedCRPCD40Ligand,IL-6Prothromboticfactors(FIandII)Fibrinogen,LocalFactorsBloodflowpatternsShearstressVesseldiameterArterialwallstructure%arterialstenosis,RiskFactorsforIschemicStroke,ModifiableHypertensionAtrialfibrillationCigarettesmokingHyperlipidemiaAlcoholabuseCarotidstenosisPhysicalinactivityObesityDiabetes,NonmodifiableAgeSexRace/EthnicityHeredity,RCAWall,LADWall,Eccentric(“lipid-rich”),Concentric(“fibrotic”),Ectatic(“remodeled”),Black-BloodCoronaryPlaqueMR,MR,magneticresonance;LAD,leftanteriordescending;RCA,rightcoronaryartery.FayadZA,etal.Circulation.2000;102:506-510.(withpermission),LADWall,EvidenceofMultiple“Vulnerable”PlaquesinACS,ACS,acutecoronarysyndrome.AsakuraM,etal.JAmCollCardiol.2001;37:1284-1288.(withpermission),Angiographic343:915-922.(withpermission),Culpritlesion,Multipleplaquesdetected,Multipleplaquesdetected,ACS,acutecoronarysyndrome.RioufolG,etal.Circulation2002;106:804-808.(withpermission),Frequencyofmultipleactiveplaquerupturesbeyondtheculpritlesion,Patients(%),80%ofPatientsWith2Plaques,N=24,FrequencyofMultiple“Active”PlaquesinPatientsWithACS,ACS:TipoftheAtherothrombotic“Iceberg”,ACS,acutecoronarysyndrome;UA,unstableangina;NSTEMI,non-ST-segmentelevationmyocardialinfarction;STEMI,ST-segmentelevationmyocardialinfarction.AdaptedfromGoldsteinJA.JAmCollCardiol.2002;39:1464-1467.,PresenceofMultipleCoronaryPlaques,VascularInflammation,PersistentHyperreactivePlatelets,Clinical,Subclinical,AcutePlaqueRuptureACS(UA/NSTEMI/STEMI),HemostaticPlugFormation,Thrombin,AGGREGATION,Fibrin,HemostaticClot,Clotting,PlateletAggregation,0min,10min,5min,SECONDARY,PRIMARY,COAGULATION,AdaptedfromFergusonJJ,etal.AntiplateletTherapyinClinicalPractice.2000:15-35.,Adhesion,TheRoleofPlateletsinAtherothrombosis,Aggregation,1,Activation,2,3,GPIIb/IIIaInhibitors,1.PlateletAdhesion,2.PlateletActivation,Platelet,GPIb,Plaquerupture,3.PlateletAggregation,ASA,Clopidogrel/Ticlopidine,ASA,acetylsalicyclicacid.CannonandBraunwald,HeartDisease.2001.,TxA2,PlateletsRoleinThrombosis,Fibrin,Platelets,RBCs,WhiteThrombus,Fibrin,Platelets,RBCs,CoagulationThrombus,HighFlowSlowFlow,Platelets:RoleinThrombosis,RBCs,redbloodcells.,ThrombinSerotoninEpinephrineCollagen,Activation,ActivatedPlatelet,COX,Degranulation,GpIIb/IIIafibrinogenreceptor,Toneighboringplatelet,ClopidogrelTiclopidine,TXA,thromboxane;PDGF,platelet-derivedgrowthfactor.,PlateletHyperreactivityFollowingACSPredicts5-YearOutcomes,PlateletAggregabilityStatus,0,10,20,30,40,50,Death,CardiacEvents,10.3,6.4,14.9,24.1,46.2,34.6,Patients(%),*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.,PlateletsReleaseInflammatoryMediatorsandLeadtoVascularInflammationandPlaqueInstability,RANTES(RegulatedonActivation,NormalT-cellExpressedandSecreted).LibbyP,etal.Circulation.2001;103:1718-1720.,InflammatoryModulatorsCD40ligandPlateletfactor4RANTES,UnstablePlaque,ActivatedPlatelets,PlaqueRupturePDGF,platelet-derivedgrowthfactor;TGF-,transforminggrowthfactor-beta;PF4,plateletfactor4;TSP,thrombospondin.AndreP,etal.Circulation.2002:106:896-899.(withpermission),InflammatoryModulatorsProducedbyPlatelets,TGF-5Stimulatesmoothmusclecellbiosynthesis,Nitricoxide3Effectsonmonocyte,leucocyte,endothelium,andsmoothmusclecells,CD154(CD40ligand)1,4Regulatesmacrophageandsmoothmusclecellfunctions,RANTES2Influencesmacrophageadhesiontoendothelialcell,PF41Mediatesshear-resistantarrestofmonocytestoendothelium,Platelet,PDGF1Inducesprolifer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