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SlideSourceLipidsOnlineHDLasaTherapeuticTargetDanielJ.Rader,M.D.SlideSourceLipidsOnline1001602200.01.02.03.0RiskofCHDLowHDL-CisanIndepend

entPredictorofCHDRiskEvenWhenLDL-CisLowHDL-C(mg/dL)LDL-C(mg/dL)25GordonTetal.AmJMed1977;62:707-714.456585SlideSourceLip

idsOnlineATPIII:NewDefinitionofLowHDL-CExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497

.LowHDL-Cwasredefinedas<40mg/dLSlideSourceLipidsOnlineATPIII:TheMetabolicSyndromeDiagnosisisestablishedwhen3oftheseriskfactor

sarepresent.ExpertPanelonDetection,Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2

497.RiskFactorDefiningLevelAbdominalobesity(Waistcircumference)MenWomen>102cm(>40in)>88cm(>35in)TG150mg/dLHDL-CMenW

omen<40mg/dL<50mg/dLBloodpressure130/85mmHgFastingglucose110mg/dLSlideSourceLipidsOnlineIsHDL-CSimplyaMarkerofIncreasedCardiovascularRis

k?◼Smoke◼Aresedentary◼Areobese◼Areinsulinresistantordiabetic◼Havehypertriglyceridemia◼HavechronicinflammatorydisordersLowHDL-Clevelsarecommonlyfoundi

npatientswho:SlideSourceLipidsOnlineProductionofApoA-IbyLiverandIntestineA-IA-IILiverIntestineHDLA-IHDLSli

deSourceLipidsOnline◼Reducedinitiationandprogressionofatherosclerosisintransgenicmiceandrabbits◼Regressionofpre-existingatherosclerosisinanima

lsIncreasedApoA-IProductionisAntiatherogenicinAnimalsSlideSourceLipidsOnline◼IncreaseapoA-Iproduction

◼Promotereversecholesteroltransport◼DelaycatabolismofHDLHDLMetabolismasaTherapeuticTarget:PotentialStrategiesSlideSourceLipidsOnli

ne◼SmallmoleculeupregulationofapoA-Igenetranscription◼Intravenousinfusionofrecombinantprotein(wild-typeapoA-I,ap

oA-IMilano)◼AdministrationofpeptidesbasedonapoA-Isequence◼SomaticgenetransferofapoA-IDNA(liver,intestine,muscle,hematopoeticcells)Approachesto

IncreasingApoA-IProductionSlideSourceLipidsOnline◼IncreaseapoA-Iproduction◼Promotereversecholesteroltransport◼Delayca

tabolismofHDLHDLasaTherapeuticTarget:PotentialStrategiesSlideSourceLipidsOnlineA-IHDLandReverseCholesterolTransportLiverCECEFCLCATFCBi

leSR-BIABCA1MacrophageMatureHDLNascentHDLA-IFCCEFCSlideSourceLipidsOnlineRegulationofCholesterolEffluxintheMacrophageFCFCoxysterolsL

XR/RXRABCA1PPARsA-ISlideSourceLipidsOnlinePharmacologicManipulationofCholesterolEffluxLXR/RXRPPARsFibrates,TZDs,newagen

tsNewagentsA-IFCABCA1SlideSourceLipidsOnline◼IncreaseapoA-Iproduction◼Promotereversecholesteroltransport◼De

laycatabolismofHDLHDLasaTherapeuticTarget:PotentialStrategiesSlideSourceLipidsOnline◼Antioxidanteffects◼Inhibitionofa

dhesionmoleculeexpression◼Inhibitionofplateletactivation◼Prostacyclinstabilization◼PromotionofNOproductionMechanismsOtherThanReverseC

holesterolTransportbyWhichHDLMaybeAntiatherogenicSlideSourceLipidsOnlineLiverCECEFCFCLCATFCBileSR-BIA-IABCA1Macrop

hageA-ITGCEHDLMetabolism:IntravascularRemodelingofHDLKidneyPLFCPLSlideSourceLipidsOnlineLiverHLA-ITGCEHDLMetabolism:RoleofHepaticLipaseK

idneyPLHDL2A-ICEPLHDL3SlideSourceLipidsOnlineLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEHDLMetabolism:RoleofCETPFCKidne

yLDLRCETGCETPBVLDL/LDLSlideSourceLipidsOnlineHDLMetabolisminCETPDeficiencyCEFCFCLCATA-IABCA1MacrophageA-ICEFCCETGCE

TPBVLDL/LDLDelayedcatabolismXSlideSourceLipidsOnline05101520253035OkamotoHetal.Nature2000;406:203-207.InhibitionofCETPbyJTT-705inCholesterol-FedR

abbitsSignificantlyReducedAorticAtherosclerosis%AorticLesionControlSimvastatinJTT-705SlideSourceLipidsOnlineHD

LMetabolism:InfluenceofCETPInhibitionLiverCECEFCFCLCATFCBileSR-BIA-IABCA1MacrophageA-IFCCEFCLDLRCETGCETPBVLDL/LDLXSlideSourceLipidsOnline◼Weig

htreductionandincreasedphysicalactivity◼LDL-Cisprimarytargetoftherapy◼Non-HDL-Cissecondarytargetoftherapy(

iftriglycerides200mg/dL)◼ConsidernicotinicacidorfibratesManagementofLowHDL-CExpertPanelonDetection,

Evaluation,andTreatmentofHighBloodCholesterolinAdults.JAMA2001;285:2486-2497.SlideSourceLipidsOnline◼Therapeuticlifestylechanges◼

Smokingcessation◼Regularaerobicexercise◼Weightloss◼Alcoholuse?ManagementofLowHDL-CSlideSourceLipidsOnline◼Therapeuticlifestylechanges

◼Pharmacologictherapy◼StatinsManagementofLowHDL-CSlideSourceLipidsOnline05101520253035PatientswithEvents(%)Scandinavian

SimvastatinSurvivalStudyGroup.Lancet1995;345:1274-1275.4S:MajorCoronaryEventsbyHDL-CSubgroupHDL-C(mg/dL)PlaceboSimvastatin3839–

4445–5253RR=0.67RR=0.71RR=0.57RR=0.70SlideSourceLipidsOnline024681012141618PatientswithEvents(%)LIPIDStudyGro

up.NEnglJMed1998;339:1349-1357.LIPID:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPravastatin39mg/dL<39mg/dL25%24%SlideSourceLipidsOnline05101520253

0PatientswithEvents(%)SacksFMetal.NEnglJMed1996;335:1001-1009.CARE:CHDEventsbyHDL-CSubgroupsHDL-CPlaceboPrav

astatin>37mg/dL37mg/dLP=0.008P<0.001SlideSourceLipidsOnline01020304050607080Events(%)DownsJRetal.JAMA1998;279:1615-1622.AFCAPS/TexCA

PS:RiskReductionbyHDL-CTertileatBaselineHDL-CLevelsPlaceboLovastatin<34mg/dl35–39mg/dl>40mg/dl71406841443544%RR40%RR20%RRSli

deSourceLipidsOnline◼Therapeuticlifestylechanges◼Pharmacologictherapy◼Statins◼FibratesManagementofLowHDL-CSlideSou

rceLipidsOnline0510152025VA-HIT:MajorCoronaryEventsinGemfibrozilvs.PlaceboGroupsCumulativeIncidence(%)

0RubinsHBetal.NEnglJMed1999;341:410-418.Copyright©1999,MassachusettsMedicalSociety.Allrightsreserved.123456YearPlaceboGemfibrozil

–22%reductionP=0.006SlideSourceLipidsOnline050100150200050100150200303132333435VA-HIT:LipidConcentrationsAccordingtoYearofStudyandTreatmen

tGroup050100150200TC(mg/dL)012345YearLDL-C(mg/dL)Year012345HDL-C(mg/dL)YearTG(mg/dL)Year012345PlaceboGemfibrozil–4%,P<0.001NochangeGemfibrozil&Pl

aceboPlaceboGemfibrozil+6%,P<0.001012345PlaceboGemfibrozil–31%,P<0.001RubinsHBetal.NEnglJMed1999;341:410-418.Copyrig

ht©1999,MassachusettsMedicalSociety.Allrightsreserved.SlideSourceLipidsOnlineVA-HIT:ChangesinPlasmaLipidsduringTreatmentasPredictorsofCor

onaryEventsVariable(Change)RiskFactor(95%CI)PDuringtreatmentHDL-C(5.0mg/dL)0.89(0.81–0.98).02Triglycerides(50mg/dL)1.

03(0.95–1.11).48LDL-C(25mg/dL)1.09(0.98–1.21).13RobinsSJetal.JAMA2001;285:1585-1591.Copyright©2001,Am

ericanMedicalAssociation.SlideSourceLipidsOnline◼Therapeuticlifestylechanges◼Pharmacologictherapy◼Statins◼Fibrates◼NiacinManagementofLo

wHDL-CSlideSourceLipidsOnline-50-40-30-20-100102030EfficacyofExtended-ReleaseNiacinChangefromBaseline2500mg3000mgGoldber

gAetal.AmJCardiol2000;85:1100-1105.2000mg1500mg1000mg500mgHDL-CLDL-CLp(a)TG–9%–14%–22%–21%–17%29.5%30%26%22%15%10%–28%–

35%–44%–39%–11%–5%–26%–3%–12%–30%–24%–17%SlideSourceLipidsOnline◼Lifestylechangesandsecondarycauses◼Pharmacologictherapy◼IfLDL-Celevated:statin

◼IfTGelevated:fibrate◼IfisolatedlowHDL-C:niacin◼CombinationtherapyManagementofLowHDL-CSlideSourceLipidsOnline-30-20-100102030C

hange(%)WolfeMLetal.AmJCardiol2001;87:476-479.Copyright©2001,ExcerptaMedicaInc.Reprintedwithpermission.AdditionofExtended-ReleaseNiacintoa

StatinbecauseofPersistentlyLowHDL-CTCLDL-CHDL-CTGSlideSourceLipidsOnlineCVEvents0510152025EventRate(%)Bro

wnBGetal.Circulation1998;98:I-635.FamilialAtherosclerosisTreatmentStudy(FATS):10-YearFollow-upResultsUsualCare(n=101)Deaths

LDL-C188→166mg/dL;HDL-C38→40mg/dL;TG208→220mg/dLLDL-C202→106mg/dL;HDL-C43→53mg/dL;TG210→134mg/dLTripleTherapy(n=75)19.818.81.3**p<

0.055.3*SlideSourceLipidsOnline◼LDL-Cremainstheprimarytargetoflipid-alteringtherapies◼HDL-CisanimportantCHDriskfactor◼Evensmal

lincreasesinHDL-Cmayconfersubstantialbenefit◼InterventiontoraiseHDL-Clevelsshouldbeconsideredinhigh-riskpatientsSummar

ySlideSourceLipidsOnline◼48-year-oldmanwithmetabolicsyndromeandCHD◼Aftertherapeuticlifestylechangesandastartingd

oseofstatin:Cholesterol179mg/dLTriglycerides252mg/dLLDL-C97mg/dLHDL-C32mg/dLGlucose104mg/dLApproachtothePati

entwithLowHDL-CSlideSourceLipidsOnline演讲完毕，谢谢观看！Thankyouforreading!Inordertofacilitatelearninganduse,thecontentofthisdocumentca

nbemodified,adjustedandprintedatwillafterdownloading.Welcometodownload!汇报人：XXX汇报日期：20XX年10月10日