心力衰竭糖尿病患者急性心肌梗死后無法回避的難題

心力衰竭糖尿病患者急性心肌梗死后無法回避的難題第1頁/共38頁心力衰竭

--糖尿病患者急性心肌梗死后無法回避的難題第2頁/共38頁糖尿病患者急性心肌梗死后心力衰竭Theprevalenceofheartfailureisabout12%inpeoplewithType2diabetesascomparedtoonly3.2%innon-diabeticsubjectsAt6months,theincidenceofHFwas24%(n=10)

inthediabeticsand11%(n=30)inthenon-diabetics

(P=0.015)At5years,therateofHFincreasedto43%

(n=18)inthediabeticsandto20%(n=57)inthe

non-diabetics(P=0.001).第3頁/共38頁HeartfailureinType2diabeticpatientsfollowingACSCirculation2000;102:1014-1019CHFeventrate(%)051015202503691215182124DM+,CVD+DM-,CVD+DM+,CVD-DM-,CVD-MonthsAcuteCoronarySyndrome第4頁/共38頁OR(95%CI)PAge,y1.0513(1.0284–1.0746)0.0001PeakCK,U/L1.0002(1.0001–1.0002)0.0004Six-monthLVdilation,mL1.0104(1.0038–1.0170)0.0021Diabetes1.8026(1.0374–3.1321)0.0366PredictorsofHFatMultivariateCoxAnalysis

(6months)Circulation.2004;110:1974-1979第5頁/共38頁糖尿病急性心肌梗死后HF第6頁/共38頁糖尿病急性心肌梗死后早期HF的機制第7頁/共38頁糖尿病急性心肌梗死后早期HF的機制第8頁/共38頁DiabetesandcongestiveHFindependentofCADEndocrineReviews2004;25:543-567SmallvesseldiseaseDiabeticcardiomyopathyLeftventriculardysfunctionCardiacautonomicneuropathyCardiacinsulinresistance第9頁/共38頁糖尿病急性心肌梗死后晚期HF的機制第10頁/共38頁Diabetesmellituscanacceratetheprogressionofpost-infarctiongeneticregulatoryexpressioninuntreatedStreptozotocin-inducedDiabeticRatModel-GeneticfindingsintheremotezoneofLVfreewallpostacutemyocardialinfarctionGuang-YuanSong1,Yong-JianWu1*,Yue-JinYang1,Jian-JunLi1,RuiLi2,Ru-TaiHui3,Han-JunPei1,Zhen-YanZhao1Fromthe1CenterofCoronaryHeartDisease,3CenterofHypertension,CardiovascularInstitute&Fu-WaiHospital,PekingUnionMedicalCollegeandChineseAcademyofMedicalSciences,Beijing100037,China.Fromthe2GenminixInformaticsLtd.Co*Thecorrespondingauthor:Yong-JianWu,MD,PhD;CenterofCoronaryHeartDisease,DepartmentofCardiology,CardiovascularInstitute&Fu-WaiHospital,PekingUnionMedicalCollegeandChineseAcademyofMedicalSciences,167BeiLiShiRd,Beijing,100037,P.R.China.E-mail:fuwaihospital@第11頁/共38頁StudyDesign217Sprague-Dawley(SD)ratswererandomizedintooneofthefourfollowinggroups:(1)AMIindiabeticrats(DM+AMI);(2)AMIinnon-diabeticrats(N-DM+AMI);(3)Shamindiabeticrats(DM+Sham);(4)Shaminnon-diabeticrats(N-DM+Sham).ExperimentalprotocolisshowninFigure1Bothdiabeticandnon-diabeticratsweresubjectedtoleftanteriordescendingcoronaryartery(LADCA)ischemiafor1-56dayswithoutreperfusion.Transmissionelectronmicroscopy(TEM)wasutilized10weeksafterDMinduction.Two-dimensionalechocardiographywasutilizedtoobtainLVdimensionsandLVpercentfractionalshorteningatbaseline,DM10weeks,andat1d,7d,14d,28d,56dafterAMI;hemodynamicstudieswasperformedatbaseline,DM10weeks,andat1d,28dafterAMI;andthentheremotezonetissuesofLVfreewallweretakenassamplesatday1,7,14,28,and56postAMIforgenechipmicroarrayanalysis;inaddition,heart-to-bodyweightratioandmasson’strichromestainingwasmeasuredasanindexofcardiachypertrophyandfibrosisatbaseline,DM10weeks,andat1d,7d,14d,28d,56dafterAMI.第12頁/共38頁Aminalsweresacrificedjustafterechocardiographicassessment,andtheremotezonetissuesofLVfreewallweretakenassamplesatday1,7,14,28,and56postAMI.Accordingtopreviousstudies,weusedthesamplepoolingstrategiesformicroarrayanalysisinordertoreducethewholecostofthestudy.RNAfractionsfromthethreeratsineachgroupatthetimepointwerebalancedpooledforGeneChipanalysis.SignificantdifferentexpressiongeneswerefilteredfromAffymetrixGenechipU2302.0arraybyGCOSsoftware(P<0.01).Geneticchangespostmyocardialinfarctionwereclassifiedbyhierarchicalclustering.Andthen,the

differentialexpressionsof10selectedtranscriptsidentifiedbythemicroarraywereexaminedingreaterdetailbyRealTime-PCR.GeneChipMicroarrayAnalysisandRealTime-PCR第13頁/共38頁HierarchicalClusteringGeneclusteringwasanalyzedbyusingCluster3.0andEisensoftware-Treeview.Inthisstudy,hierarchicalclusteranalysesweredoneusingtheClusterprogram(completelinkageclustering)andresultsweredisplayedusingTreeView.Thecriterionforfilteringoutageneisbaseduponthepercentageofexpressionvaluesforthatgenewhichhaveatleastaminimumfold-changefromthemedianexpressionvalueforthatgene.(Ifthedatasetcontains250ormoreexperiments,thenthemeanwillbeusedinsteadofthemedianforcomputationalefficiency.)Iflessthan50percentageofexpressionvaluesmeettheminimumfold-changerequirement,thenthegeneisfilteredout.Then164genesexpressionwerechosenfortheclustering,inwhichwefound118genesintheforegonegeneticdatabase,suchasleucine-richPPR-motifcontaining(IL-6signalingpathway),procollagentypeI,VI,VIII,andXV,fibronectin1,RT1,andTIMP-1,thatassociatedwithpost-infarctioncardiacremodeling,etc.

第14頁/共38頁HierarchicalClusteringAccordingtohierarchicalclustering,wefindthatthemolecularregulatoryexpressionrelatedtocardiacremodelingintheremotezonetomyocardialinfarctionisquitedifferentastimeelapsesinbothdiabeticandnon-diabeticrats.Thegeneexpressionatday1and7postAMIinbothgroupsissimilar,whilethegeneticchangesatday14postAMIindiabeticratsandtheonesatday14and28innon-diabeticratsareclassifiedintothesamecluster.Andthenthegeneticchangesatday28and56postAMIindiabeticratsandtheonesatday56innon-diabeticratsareclassifiedintothesamecluster.第15頁/共38頁Eight-and20-wkechocardiographydataforthe20-wkWistar-Kyoto(WKY)andGoto-Kakizaki(GK)heartfailuregroupsexpressedasaratiooftheirrespectiveshamgroups.*P<0.05,8wkGKvs.8wkWKYgroups第16頁/共38頁ChangesinEF(A),IZWMSI(B),andLVvolumes(CandD)during6monthsafterAMIinpatientswith(solidline)andwithout(dashedline)diabetes(*P<0.01vsbaseline,byANOVAanalysis)Circulation.2004;110:1974-1979第17頁/共38頁糖尿病和急性心肌梗死早期HF的特點第18頁/共38頁糖尿病和急性心肌梗死相關(guān)發(fā)現(xiàn)第19頁/共38頁早期心衰的治療策略第20頁/共38頁Ⅱb/Ⅲa受體拮抗劑的應(yīng)用EPICEPILOGEPISTENT

早期應(yīng)用可以顯著減少DM患者1年死亡率

對于胰島素使用，死亡率減少50%第21頁/共38頁兩組室壁運動異常節(jié)段評分指數(shù)梗塞24小時內(nèi)一周二周一月三月六月一年通心絡(luò)組1.75521.69691.61251.50851.40521.37671.3254對照組1.73901.75741.74631.70831.64751.53801.4890P值0.69450.15240.00430.00010.00010.00240.0378第22頁/共38頁兩組左心室舒張末容積（ml）梗塞24小時內(nèi)一周二周一月三月六月一年通心絡(luò)組n=60138.17±23.77150.86±21.91150.36±26.24150.71±27.57143.12±29.95145.27±27.93148.91±30.67對照組n=52146.43±33.13160.48±24.54163.39±24.68164.10±27.11165.6±30.92162.38±32.65166.79±33.58P值0.210.090.040.040.0020.0090.046第23頁/共38頁TheHyperglycemia:IntensiveInsulinInfusionInInfarction(HI-5)Study第24頁/共38頁ActivationofPPARenhancesmyocardialglucoseoxidationandimproves

contractilefunctioninisolatedworkingheartsofZDFratsAmJPhysiolEndocrinolMetab289:E328–E336,2005Cardiacfunctionandratesofsubstrateoxidation.A:cardiacpowerinthepresenceof5mMglucoseand5mMglucose0.4mMoleate(shadedarea)assubstrates.B:myocardialoxygenconsumption(MV˙O2)with5mMglucoseand5mMglucose0.4mMoleatepresentassubstrates.C:glucoseoxidation(Ox)ratesintheinthepresenceof5mMglucoseand5mMglucose0.4mMoleateassubstrates.D:oleateoxidationrate.FunctionswereassessedinisolatedperfusedworkingheartsfromfedZL-V(?),ZL-A(OE),ZDF-V(),andZDF-A(■)rats(60–63daysold)during40minofaerobicperfusion.ValuesaremeansSEfor10–13independentobservationsineachtreatmentgroup第25頁/共38頁第26頁/共38頁InductionofDMDMwasinducedwithasingleintraperitonealinjectionofSTZ(65mg/kgin0.1mmol/L,pH4.5sodiumcitratebuffer)18.Ageandbodyweightmatchedratsthatusedasnon-diabeticcontrolswereinjectedwiththesamedoseofsodiumcitratebuffer(0.1mmol/L,pH4.5).AllanimalsingroupsDMwithserumglucoselevels≥300mg/dl(16.8mmol/L),polyuriaandweightlosswereincludedinthestudy.Theratswiththeserumglucoselevel<300mg/dloncewereeliminatedfromthestudy.WeightBody(A)andSerumGlucoseLevels(B)inSTZ-induceddiabeticrats.***P<0.001comparedwithnondiabeticrats.DM3d=3daysafterDMinduction,DM7d=7daysafterDMinduction,etc.第27頁/共38頁PictureA-DshowthemyocardiumofSTZ-induceddiabeticheartsfor10weeks(thearrowsshowthehistopathologicalchanges);PictureEandFshowthemyocardiumofnon-diabetichearts.mitochondrialdamage(swellinganddisruptedcristae),cardiacmusclefibers,thebasallaminaofregionalsmallvessels,glycogenparticles,lipiddroplets.TEMTheseresultsindicatethattherealreadywerehistopathologicalandultrastructuralchangesrelatedtoDMintheheart10weeksafterSTZinjection.第28頁/共38頁ExperimentalAMI

10weeksafterDMinduction,AMImodelsweremadeaspreviouslydescribed.Sham-operatedratsingroup(3)andgroup(4)weretreatedsimilarlyexceptthatthesuturearoundthecoronaryarterywasnottied.Fiftysix-dayKaplan-Meiersurvivalcurvesrepresentingpercentageofsurvivingratsin4groups.SurvivalindiabeticratsafterAMIwassignificantly(P<0.01)lessthanthatobservedinshamgroup,andsimilarly,the28-daysurvivalwassignificantlyattenuatedindiabeticratssubjectedtoAMIcomparedwithnon-diabeticoneswithAMI(P<0.05).

EarlyandProlongedSurvival第29頁/共38頁CardiachypertrophyThedataabouthearttobodyweightratiosandtheheartweighttotibiallengthratiosarepresented.TimeDM+AMIN-DM+AMIHW(mg)BW(g)TL(mm)HW/BWHW/TLHW(g)BW(g)TL(mm)HW/BWHW/TLBaseline937.4±42.7218±8.530.5±1.14.2±0.4***30.7±1.2951.5±42.6216.5±9.930.6±1.14.2±0.530.9±1.1DM70d1319.2±44.3254.8±23.639.2±1.35.1±0.433.6±1.01507.5±58.4516.3±38.645.9±1.63.0±0.332.8±1.2DM+AMI1d1311.7±46.9252.7±24.139.1±1.25.2±0.6(1.8±0.6%)33.5±1.1(-0.3±0.2%)1520.1±62.6520.5±30.745.8±1.53.0±0.3(0.3±0.2%)33.1±1.3(1.0±0.3%)AMI7d1343.2±48.1258.5±25.839.5±1.35.2±0.5(2.1±0.7%)34.1±1.1(1.7±0.5%)1582.5±70.5533.7±34.646.1±1.53.0±0.4(0.9±0.6%)34.3±1.3(4.6±0.5%)AMI14d1456.1±62.7254.2±22.339.3±1.45.7±0.4*(11.6±0.7%)37.1±1.3*(10.3±0.6%)1702.6±66.4557±38.345.6±1.73.1±0.3(3.3±0.5%)37.1±1.5*(13.1±0.8%)AMI28d1588.6±70.3262.4±25.139.5±1.36.1±0.6***(19.6±1.1%???)40.2±1.8***(19.7±0.8%??)1765.4±68.9570.3±41.246.2±1.73.1±0.3(3.9±0.5%)38.2±1.6***(16.5±0.7%)AMI56d1692.5±77.8260.5±23.839.3±1.56.5±0.7***(27.5±1.3%???)43.1±1.6***(28.2±1.3%???)1862.7±75.1594.6±44.446.1±1.83.1±0.3(3.5±1.1%)40.2±1.9***(22.4±1.1%)HW,heartweight;BW,bodyweight;TL,tibiallength.HW/BW=hearttobodyweightratio;HW/TL=heartweighttotibiallength.ThedatainbracketmeanstheincreasedproportionofHW/BWandHW/TLchangescomparedwithDM70d.*P<0.05vs.DM70dinthesamegroup;***P<0.001vs.DM70dinthesamegroup.??P<0.01vs.N-DM+AMIatthesametimepoint;???P<0.001vs.N-DM+AMIatthesametimepoint.第30頁/共38頁CONCLUSION

ThedifferentpatternsofthegeneticchangesinthisuntreatedSTZ-induceddiabeticnon-perfusionmyocardialinfarctionratmodelmightsuggestthatDMcouldacceratetheprogressionofpost-infarctioncardiacremodelinginSTZ-induceduntreateddiabeticratmodel.第31頁/共38頁糖尿病患者急性心肌梗死后死亡Survivalimprovements.Kaplan–Meiersurvivalcurvesfrom1995and2003aredisplayedforcohortswithandwithoutDM.Thehighlightedarearefersto

survivalimprovementwithineachgroupbetween1995and2003第32頁/共38頁糖尿病患者PCI術(shù)后Measurementsofepicardial