动脉粥样硬化不稳定斑块的炎症机制

InflammationinAtherosclerosis——FrominflammationbiologytotheclinicFromhealthyarterytoheartattackInflammationinatherosclerosis.Nature2002OverviewHistoryofvulnerableplaqueInflammationinatherosclerosisFrominflammationbiologytotheclinicConclusionHistoryofthevulnerableplaque1884-FirstreporteddescriptionofplaqueruptureattheautopsyoftheneoclassicalDanishartistandsculptorBertelThorvaldsen1985--Daviesdescribesplaqueruptureasthecausetocoronarythrombosisin90%ofsuddencoronarydeath.1989--JamesE.Mullercategorizeshemodynamicallyinsignificant,albeitdangerous,lesionsas“vulnerableplaques”.RakeshKJainetal.Nature20072000--VirmaniandcolleaguesintroduceamodifiedclassificationschemebasedontheAHAconsensusreports.Thisreportcategorizesthevulnerableplaqueasthethin-capfibroatheroma.SeekingAlternativestoHardEndPoints:IsImagingtheBestApproach?Circulation20102003--Kolodgieandvirmaniintroducetheconceptoferythrocyte-derivedcholesterolandnecroticcoreexpansionasamechanismoflesionvulnerablity.InflammationinatherosclerosisInflammationinatherosclerosis—frominitiationtoprogressionOneofthemajorlimitationsoftheoriginalAHAclassification--alackofunderstandingthatthefibrouscapundergoesthinningbeforetheonsetofrupture.(aconceptforwardedbyDr.PeterLibby)Geneticsusceptibilitytocoronaryarterydisease:frompromisetoprogress.NatrueReviews2006InnateandAdaptiveImmunity:TwinArmsoftheImmuneResponseInvolvedinAtherosclerosisInnateimmunityinatherosclerosisRecruitmentmonocyteinatherogenesisInflammationinatherosclerosis.Nature2002HeterogeneityofmousemonocytesubsetsDifferentiationofmonocytesubsets.Monocytesinatherosclerosis:subsetsandfunctions.Nature2009MonocyterecruitmentMonocytesinatherosclerosis:subsetsandfunctions.Nature2009RecruitmentandfunctionsofmastcellsinatherogenesisInflammationinatherosclerosis.Nature2002AdaptiveimmunityinatherosclerosisCellsInvolvedinAdaptiveImmunityInflammationinAtherosclerosis:FromPathophysiologytoPractice.JACC2009Humoralimmunityinatherosclerosis•Humoralimmunitycanattenuateratherthanpromoteatherogenesis.(eg:splenectomyaggravatesatherosclerosis)•Hypercholesterolemicmicedevelopastronghumoralresponsedirectedagainstepitopescharacteristicofox-LDL.•TheantibodieselicitedinmiceinresponsetooxLDLalsorecognizeapneumococcalantigen.TherapeuticexplorationsofvaccinationagainstoxidizedLDL?FrominflammationbiologytotheclinicTargetinginflammationinatherosclerosisImagingofinflammationinatherosclerosisGeneticsofinflammationinatherosclerosisTheRoleofBiomarkersObesity,inflammation,andatherosclerosisTranslationofinflammationbiologytotheclinicManysystemicanti-inflammatorystrategiessuchasglucocorticoids,nonsteroidalanti-inflammatorydrugs,oranticytokineagentsexertunwantedactionsthatrenderthemlessthanidealcandidatesforevaluationaslong-termtherapeuticsformodulationofatherosclerosis.Ofmanypromisingmorespecificanti-inflammatoryagentsindevelopmentforatherosclerosis,noneappearsufficientlyvalidatedforclinicaluseatpresent.Targetinginflammationinatherosclerosis:beyondstatins.•Variousproteintherapeuticstrategiessuchasanti-integrinoranticytokinetherapieshavereceivedconsiderationfortherapeuticapplication.•Therapeuticvaccinationwithlipoproteinpeptidesisalsobeingconsideredforclinicalevaluation.Imagingofinflammationinatherosclerosis•Theidentificationofmolecularmediatorsofinflammationthatoperateduringatherogenesishasgeneratedconsiderableinterestinharnessingthemastargetsforimaging.RepresentativeimagesfromanApoE-/-mouseonHypercholesterolemicdiet•A,Theaorticarchby2-dimensionalultrasoundimaging(Ao).•B,Pulsed-waveDopplerimagingofthearch.•CandD,Contrast-enhancedultrasoundimagesoftheaorticarch10minutesafterintravenousinjectionofeitherVCAM-1–targeted(C)orcontrol(D)microbubbles.BeatA.etal.Circulation2007Atherosclerosisimagingwith18F-FDGPETisusefulfortrackinginflammationwithinplaqueCoronalCT(left),18F-FDGPET(middle),andfusedPET/CT(right)imagesoffemoralarteryterritoryJamesH.F.Ruddetal.THEJOURNALOFNUCLEARMEDICINE2008•Genome-wideassociationscreens(GWAS)•TheidentificationofaregiononChromosome9asassociatedwithcardiovascularhasreinforcedfuturepotentialofgeneticsinidentifyingriskpredictorsandpotentialtherapeutictargets.Geneticsofinflammationinatherosclerosis•GWASshouldidentifyparticipantsininflammatorypathwaysthatwillbroadenourunderstandingandmasteryofinflammationinatherosclerosis.TheRoleofBiomarkers•Biomarkersofinflammationinriskprediction.InflammationandAtherothrombosis:FromPopulationBiologyandBenchResearchtoClinicalPractice.JACC2006CRP--aleadingbiomarkerofinflammationforclinicalapplication•Inwellindividualswithoutacuteinfectionsorinflammatorydiseases,levelsofhsCRPremainstableoverlongperiodsoftimewithayear-to-yearanddecade-to-decadevariabilitycomparabletothatofcholesterol.•CRPhasconsiderablechemicalstability,requiresnospecialprecautionsforsampling,andhasarelativelylonghalf-lifewithoutthediurnalvariationthatplaguescertainotherbiomarkers.TargetingtherapyusinghsCRP•WellindividualswithaveragelevelsofLDL-C,currentlybelowtreatmentthresholds,mightnonethelessbenefitfromstatintherapyiftheyhadc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