冠心病患者降脂治疗获益的机理Word文档格式.docx
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冠心病患者降脂治疗获益的机理Word文档格式.docx
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GordonMSaperia,MD,FACC
Disclosures
Alltopicsareupdatedasnewevidencebecomesavailableandour
peerreviewprocess
iscomplete.
Literaturereviewcurrentthrough:
Apr2013.
|
Thistopiclastupdated:
七月26,2012.
INTRODUCTION
—
Lipidloweringwithstatinsinpatientswithhypercholesterolemiahasaprovensurvivalbenefitforbothprimaryprevention(ie,inpatientswithoutclinicalevidenceofcoronarydisease)andsecondaryprevention(ie,inpatientswithestablishedcoronarydisease),evenwhenserumcholesterolconcentrationsare"
normal"
forthepopulationorborderlinehigh.Statinsmayalsobebeneficialinpatientswithheartfailure.(See
"
Clinicaltrialsofcholesterolloweringforprimarypreventionofcoronaryheartdisease"
and
Clinicaltrialsofcholesterolloweringinpatientswithcoronaryheartdiseaseorcoronaryriskequivalents"
Statintherapyinpatientswithheartfailure"
sectionon'
PotentialbenefitsandharmsofstatintherapyinHF'
.)
TIMINGANDMECHANISMSOFBENEFIT
Themechanismsbywhichlipid-loweringtherapy(particularlywithstatins)isbeneficialareincompletelyexplainedbytheserumlowdensitylipoprotein(LDL)concentrationatbaselineoraftertreatment[1-6].Althoughstatinsprobablycauseregressionofatherosclerosis,animprovementinoutcomecanbedemonstratedasearlyassixmonths(figure1)
[7,8],atimeconsideredtooearlyforsignificantregression.Inaddition,theamountoflesionregressionissmallcomparedwiththemagnitudeoftheobservedclinicalbenefit.
Acase-controlstudyofadultswithafirstclinicalpresentationofcoronaryheartdiseasefoundthatuseofstatinswasassociatedwithadecreasedlikelihoodofthatpresentationbeinganacutemyocardialinfarction(oddsratio0.45)andthusanincreasedlikelihoodofpresentingwithstableangina[9].Theseobservationssuggestamechanismofbenefitwithstatinsthatmightinvolveunstablecoronarylesions.
Amongthenonlipidmechanismsthatmaybeinvolvedareplaquestabilization,reducedinflammation,reversalofendothelialdysfunction,anddecreasedthrombogenicity[10,11].
Regressionofatherosclerosis
Regressionoftheatheroscleroticlesionscanoccurafterlipidlowering,withoutchangeinvesselwallthicknessorvesselwallarea,andmaybeclinicallyimportant[12].Onelimitationtoarteriographicstudiesistherelativelackofsensitivitytomorphologicchangesinatheroma,whichcanbebettercharacterizedbyintracoronaryultrasonography(ICUS)[13],ortosmallchanges,whichmightbedetectablebyothertechniquessuchasB-modeultrasonographyformeasurementofcarotidintimathickness[14],electronbeamormultidetectorrowcomputedtomographytodetectcoronaryarterycalcification[15],orhigh-resolutionmagneticresonanceimagingMRI[12].(See
Diagnosticandprognosticimplicationsofcoronaryarterycalcificationdetectedbycomputedtomography"
Clinicalutilityofcardiovascularmagneticresonanceimaging"
Thebenefitoflipidloweringisillustratedbytheobservationthatindifferentstudies,coronaryangiographyhasshownincreasesinlumendiameterattwoandfouryearsoralesserdegreeofprogressionofstenosisatthreeyearsaftertheonsetofstatintherapy[16,17].
Therearelimiteddataontheexacttimingofregressionofatherosclerosis,particularlycoronaryatherosclerosis,afterstatintherapy.Thisissuewasaddressedusinghigh-resolutionMRItoassessaorticandcarotidarteryplaques.Nochangeswereseenatsixmonths[12],butprogressiveregressionwasnotedat12and24months[18].Theearliestchange,seenat12months,wasareductioninplaquesizefollowedbyanincreaseinluminalareaduetoarterialremodeling[18].
Plaquestabilization
Coronaryarteryplaqueruptureisacentralcomponentinmostpatientswithanacutecoronarysyndrome.Furthermore,thereisincreasingevidencethatmanyofthesepatientshavemultipleunstableplaquesindifferentcoronaryarteries,suggestingwidespreadinflammationinthecoronarycirculation.Thus,interventionaimedonlyattheculpritlesionisnotlikelytobeoptimalandtheabilityofstatinstoinduceplaquestabilizationmaybeanimportantmechanismofbenefit.(See
Theroleofthevulnerableplaqueinacutecoronarysyndromes"
Animalmodelsandhumanstudieshaveshownthatstatintherapycanreducetherateofprogressionofplaquedevelopmentandstabilizeatheroscleroticplaquesthathaverupturedaswellasthosethatarevulnerabletorupture[13,19-21].Onereportof131patientsevaluatedtheeffectof12monthsof
atorvastatin
therapyusingICUS[13].Comparedtoplacebo,atorvastatinreducedtheprogressionofmeanplaquevolumeorthickness(1.2versus9.6mm3forplacebo)andincreasedthehyperechogenicityoftheplaque,indicatingachangeinplaquecomposition(fromlipid-richtofibroticandcalcified)thatcorrespondstoincreasedplaquestabilityandareducedtendencyforrupture.
Avarietyoffactorsmaycontributetothepathogenesisofplaqueruptureandtheinductionofacutecoronarysyndromes[22,23].(See
Pathologyandpathogenesisofthevulnerableplaque"
.)Oneimportanteffectofstatintherapymaybemaintenanceofintegrityofthefibrouscapoftheplaque,therebyprotectingagainstplaquerupture.Thiseffectappearstobemediatedbyinhibitionofmacrophageproliferation,reducedexpressionofmatrixmetalloproteinases(MMPs)andtissuefactor(whichpromotesthrombusformation)bymacrophages,andanincreaseintissueinhibitorofmetalloproteinase-1[20,24,25]:
▪TheinhibitoryeffectonMMP’smaybemediatedinpartbystatin-inducedinhibitionofprostaglandinsynthesis[26].Incellculturesofmouseandhumanmacrophages,lipophilicstatins(fluvastatin,simvastatin)inhibitMMP-9activityby20to40percentinadose-dependentmanner[25].Thiseffectwasfullyreversedbymevalonate.
▪Inanimalmodels,certainstatinsinducesmoothmusclecellapoptosis.Thismaydiminishcollagenbiosynthesisandthustheformationoftheprotectivefibrouscap[27].Therearedifferencesamongthestatinsintheireffectsonsmoothmusclecellapoptosisandcollagenbiosynthesis[28,29].
Theclinicalrelevanceofthedifferentialtissueeffectsofstatinsisuncertain;
acomparisonstudyofstatinsinahighriskpopulationatequivalentLDL-C-loweringdoseswouldberequiredtosortthisout.Itislikelythattheseeffectsareinpartduetolipidlowering.Inanimalmodels,reductionsinmacrophagecontent,MMP,andtissuefactorexpressioncanbeinducedbydietarymodification[30,31].Additionalsupportfortheimportanceoflipidloweringcomesfromexaminationofthecoronaryarteriesandplaquemorphologyof113menwhodiedsuddenly[32].Bymultivariateanalysis,theserumconcentrationsoftotalcholesterol,HDL-cholesterol,andtheratiooftotalcholesteroltoHDL-cholesterolwereindependentlyassociatedwithplaquerupture.
Reducedinflammation
Inflammationappearstobeanotherimportantcontributortoatherosclerosisandplaquerupture.(See
.)Elevatedserummarkersofinflammation,particularlyC-reactiveprotein(CRP),areassociatedwithprogressionofatherosclerosis,predicttheriskofafirstmyocardialinfarctionamongapparentlyhealthymen,andareassociatedwithaworseprognosisamongpatientswithstableandunstableanginaandthosewhoundergocoronarystenting.(See
ScreeningforcardiovascularriskwithC-reactiveprotein"
C-reactiveproteinincardiovasculardisease"
Statintherapy,givenasprimaryorsecondaryprevention,reducestheserumCRPconcentration,aneffectthatismostlyunrelatedtolipidlevelsatbaselineorduringtherapy[33-36].ThefallinserumCRPbeginswithin14days[36].
Additionalevidencethatstatinsmayhaveananti-inflammatoryeffectisprovidedbyarandomizedtrialthatfoundthatpatientswithrheumatoidarthritisexperiencedmodestclinicalimprovementwith
atorvastatin;
atorvastatinalsoreducedCRPlevelsandtheerythrocytesedimentationratecomparedwithplacebo[37].(See"
Miscellaneousnoveltherapiesinrheumatoidarthritis"
Statins'
Suchanantiinflammatoryeffectcouldcontributetothebenefitfromtheearlyinstitutionofstatintherapyinpatientswithanacutecoronarysyndrome[38].(See
Cholesterolloweringafteranacutecoronarysyndrome"
.)ResultsfromPROVEIT,MIRACL,andPhaseZoftheAtoZtrialraisethepossibilitythattheantiinflammatoryeffectsofstatinsmaydifferamongstatins[39].(See
.)Thefirsttwotrialsshowedearlybenefitwithatorvastatin
[40,41],whileinthelasttrial,despiteachievinganLDL-Cconcentrationof68
mg/dL
(1.76
mmol/L)afteronemonthof
simvastatin
40mgdaily,therewasnoevidenceofclinicalbenefitandnoreductioninCRP[42].
Baselineinflammatorymarkers
Inclinicaltrials,statinsappeartohavegreatereffectsinpatientswithevidenceofinflammationatbaseline.
Thepotentialimportanceofstatin-inducedreductioninserummarkersofinflammationwasillustratedbyananalysisfromthesecondarypreventionCAREtrial[43].PatientswithbaselineserumconcentrationsofCRPandserumamyloidAinthehighestquintilehadarelativeriskforarecurrentevent75percenthigherthanthosewithlevelsinthelowestquintile(figure2).However,inpatientswhoweretreatedwith
pravastatin,theassociationbetweeninflammationandriskwasattenuatedandwasnolonger
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- 关 键 词:
- 冠心病 患者 治疗 获益 机理