干细胞移植治疗AMI临床研究进展.ppt

干细胞移植治疗AMI临床研究进展,哈尔滨医科大学第一临床医学院,李悦,Despiteadvancesinreperfusionstrategiesandmedicaltreatment,MIandsubsequentHFremainmajorcausesofmorbidityandmortality.Theuseofcelltherapytopromotemyocardialrepairhasgainedprofoundscientificandpublicinterest.,干细胞移植（stemcelltransplantation)亦称为细胞心肌成形术（cellularcardiomyoplasty,CCMP),胚胎干细胞伦理问题、来源有限、免疫排斥、发生肿瘤风险，研究受到很大限制。成体干细胞横向分化(transdifferentiation),临床角度，成体干细胞优于胚胎干细胞，自体干细胞优于同种干细胞。骨髓间质干细胞（mesenchymalstemcells，MSC）从骨髓中分离，可使用G-CSF动员或在体外扩增。内皮祖细胞（endothelialprogenitorcells，EPC）数量往往不足，特别是从外周血采集时，需要分离、纯化并在体外培养扩增EPC。成骨骼肌细胞（skeletalmyoblasts，SM）为获得足够数量SM，需要大块肌肉组织。体外培养、扩增卫星细胞周期较长。,可供移植干细胞,Experimentalstudieshaveshownthatbonemarrowcells(BMCs)arecapableofinducingmyogenesisandangiogenesis;thisleadsinturntoameliorationofcardiacfunctioninmiceandpigs.,Nature.2019;410:701705NatMed.2019;7:430436ProcNatlAcadSciUSA.2019;98:1034410349.JThoracCardiovascSurg.2019;123:11321135.,ThefirststudyonintracoronarymBMCtherapyshortlyafterAMIinhumanswasreportedin2019.,Circulation2019;15:19138.,10patientsweretransplantedwithautologousmononuclearBMCsviaaballooncatheterplacedintotheinfarct-relatedarteryduringballoondilatation。,Frombenchtobedside,Conclusions：Demonstrateforthefirsttimethatselectiveintracoronarytransplantationofautologous,mononuclearBMCsissafeandseemstobeeffectiveunderclinicalconditions.,However,theefficacyresultsvarybetweenstudies.Possibleexplanationsforthesedifferencesaresmallstudysamples,differentimagingtechniquesanddifferencesintimingoftreatment,celldose,placebotreatmentorcellprocessingprotocols.Concernshavebeenraisedaboutacceleratedatherosclerosis,intramyocardialcalcificationsandriskforarrhythmias.Long-termdataonsafetyandefficacyofthistreatmentareneeded.,20192019年，黄禹锡在科学杂志发表伪造的干细胞论文，夸张干细胞治疗绝症的可能性，并由此从农协和SK领取20亿韩元研究费、政府支援的研究费(特定经济犯罪加重处罚法的诈骗及工作上的贪污)。并且还涉嫌非法买卖卵子(违反生命伦理法)，因而于2019年5月被拘留立案。,REPAIR-AMItrial（randomized,double-blind,placebocontrolled,multicenter),NEnglJMed.2019;355:12101221,204AMIpatientsreceiveintracoronaryinfusionofprogenitorcellsderivedfrombonemarrow(BMC)orplacebomediumintotheinfarctartery3to7daysaftersuccessfulreperfusiontherapy.,RESULTS:At4months,theabsoluteimprovementintheglobalLVEFwassignificantlygreaterintheBMCgroupthanintheplacebogroup(5.5+/-7.3%vs.3.0+/-6.5%;P=0.01).BaselineLVEFatorbelowthemedianvalueof48.9%derivedthemostbenefit.At1year,intracoronaryinfusionofBMCwasassociatedwithareductioninclinicalendpointofdeath,recurrenceofMIandanyrevascularizationprocedure(P=0.01).,Extendedclinicalfollow-upintheREPAIR-AMItrial,toassesslong-termsafetyanddurabilityoftheobservedbeneficialeffectsoncardiovasculareventrateandcardiacfunctionat2years.,精读（1）,CircHeartFail.2019;3:89-96,Studyflowdiagram(17centers),EF45%byvisualestimate,OTWballoon,Therewerenosignificantdifferencesinbaselinecharacteristics.MedicationdidnotsignificantlydifferbetweenplaceboandBMCathospitaldischargeandupto2yearsfollow-up,withtheexceptionofaldosteroneantagonists,whichweresignificantlylessfrequentlyusedintheBMCgroupathospitaldischargeandat12monthsfollow-up.,EndPoints,Theprimaryendpoint：TheabsoluteimprovementinglobalLVEFfrombaselineto4months.Combinedclinicalendpoints:Death,repeatedMIoranyrevascularizationprocedurereflectingprogressionofvasculardisease.Death,MI,orrehospitalizationforheartfailure,reflectingprogressionofdiseasetowardHF.,MRI,Inasubgroupof59patients,MRIimagingat2-yearfollow-upwasavailable.preformedbyblindedinvestigators.,Only27patientshadbaselineMRI.,ClinicalEventsat2-YearFollow-Up,ClinicalEventsat2-YearFollow-Up,PredictorsofCombinedEndPoint(Death,MI,orRehospitalizationforHF),MultivariableCoxregressionanalysisrevealedthatrandomizationtotheBMCgroup(P=0.032)andage(P=0.045)remainedtheonlysignificantindependentpredictorsofanimprovedclinicaloutcomeasassessedbythecombinedendpoint.,CardiacFunctionAfter2Y(59casesBMC,26;Con,33),梗死节段室壁增厚率,梗死面积,射血分数,Conclusion,The2-yearfollow-updemonstrates：NolatehazardsassociatedwithBMCtherapy,Restenosis/atherscleroticdiseaseprogression,?,RevascularizationratesweresignificantlyreducedintheBMCgroupwithinthefirstyear,stilltendtobelowerintheBMCgroupcomparedtoplaceboat2yearsfollow-up.,Adverse:inflammatoryBeneficial:enhancedreendothelialization,vascularrepair,Malignantventriculararrhythmia,?,Noevidenceofmalignantventriculararrhythmiasorsyncopeswithin2yearsafterintracoronaryinfusionofBMC.,Neoplasms,?,Although20%oftheintracoronaryinfusedcellsactuallyretainedintheheart,withtheremainingcellsdistributingthroughoutthebodyincludinglung,liver,andspleen,Nosignalofanincreasedrateofneoplasmswithin2years.,The2-yearfollow-updemonstrates：ThebeneficialeffectsofBMCtherapyoncardiovascularoutcomearepreservedbeyondthefirstmonthsuptotheendofthepresentobservationperiod.Moreover,thebetterregionalrecoveryofLVfunctionintheBMCgroupismaintainedforatleast2years.,Neovascularization,NeovascularizationinducedbyintracoronaryinfusionofBMCmaybeakeymechanismleadingtorecoveryofcontractilefunctionandsubsequentreductionofclinicaleventrate.,心脏功能及预后改善机制,AsubstudyofREPAIR-AMIassessingtheeffectofintracoronaryBMCadministrationoncoronaryflowdynamicsusingintracoronaryDopplerflowvelocitymeasurementsatbaselineandat4monthfollow-up:Significantgreaterrecoveryofcoronarybloodflowreserve(CFR)intheBMC-treatedinfarctarterycomparedwithinfarctvesselsreceivingplaceboinfusion.,Circulation.2019;116:366374,Paracrineeffects,Variousstudiesconfirmedthatprogenitorcellsreleaseparacrinefactors(cytokinesandgrowthfactors)thatmodulateangiogenesis,cardiomyocyteapoptosis,fibrosis,andinflammation.,FibrogenesisTissueRepair.2019Oct13;1(1):4,JCardiovascTranslRes.2019Feb26.Epubaheadofprint,SwinesubjectedtoAMIbytemporaryballoonocclusionoftheLADusingpercutaneoustechniquesreceivedintracoronaryinjectionofeitherconcentratedMSC-derivedgrowthfactorsorcontrolmedium.MSC-derivedfactorssignificantlyreducedcardiactroponin-Televationandimprovedechocardiographicparameters,decreasedthefibroticarea,reducedmyocardialdamageandpreventedcardiomyocyteapoptosis.,旁分泌因子作用,StrategiesdesignedtoaugmentMSCparacrinefunctionhavebeenemployedinanattempttoimprovetheirtherapeuticefficacy.IthasbeendemonstratedthattreatingMSCswithtransforminggrowthfactor-(TGF-)canstimulateVEGFproductioninvitro.,扩大旁分泌作用,AmJPhysiolRegulIntegrCompPhysiol.2019;299(1):R371-8,Usingamodelofisolatedheartperfusion,MSCspretreatedwithTGF-wasassociatedwithdecreasedmyocardialinjuryandincreasedmyocardialfunctionafterglobalischemia/reperfusionwhencomparedtoinfusionofuntreatedMSCs.,Circulation.2019;121:2019-2019,MethodsandResults:Vectorsthatencodedinduciblesuicidegenesunderthecontrolofendothelium(endothelialnitricoxidesynthase)-,smoothmuscle(SM22)-,andcardiomyocyte(-MHC)-specificpromoters,therebyallowingselectivedepletionoftheindividualcelllineageacquiredbythetransplantedundifferentiatedbonemarrowderivedcells.,DepletionofeNOS-expressingcells(内皮细胞）wasassociatedwithareductionofcapillaryandarterioledensityandinducedadeteriorationofregionalandglobalLVEF.ThedepletionofcellsthatexpressedSM22-（平滑肌细胞）inducedadeteriorationincontractilefunction.Theeliminationofcellsthatexpressedthecardiacmyocytemarker-MHC（心肌细胞）didnotsignificantlyaffectcardiacfunction.,移植途径,Intracoronaryinjection,However,traditionalreperfusionstrategiesfailtoopenthearteryinsomepatients,makingeffectivedeliveryimpossible.Thestudydemonstratedasafeandefficientapproachtodeliveringbonemarrowstemcellsviaanoninfarctedarteryinananimalmyocardialinfarctionmodel.,CardiovascTher.2019Mar10.Epubaheadofprint,NOGAsystem,支持文献,Clinicalimplications,ThesamplesizeoftheREPAIR-AMItrialwasnotpoweredtodefinitelyanswerthequestionwhetherBMCadministrationiscapabletomodifymortalityandmorbidityafterAMI.Therefore,thisanalysisshouldbeviewedashypothesisgenerating.Assuch,thisanalysisprovidestherationaletodesignalargerclinicaloutcometrialaddressingtheclinicalend.,精读（2）,PatientsfromtheAutologousStemcellTransplantationinAcuteMyocardialInfarction(ASTAMI)studywerere-assessed3yearsafterinclusion.,Heart200995:1983-1989,Randomised,controlledtrialTwouniversityhospitalsinOslo,Norway,Theprimaryendpoint:ThechangeinLVEFfrombaselineto6monthsmeasuredbySPECT.EchocardiographyandMRIwereusedforserialassessmentofLVfunction.Secondaryendpoints:Changesinexercisecapacityandquality-of-life(QoL).,EndPoints,Results:Theratesofadverseclinicaleventsinthegroupswerelowandequal.TherewerenosignificantdifferencesbetweengroupsinchangeofglobalLVsystolicfunctionbyechocardiographyorMRIduringthefollow-up.,Onexercisetesting,themBMC-treatedpatientshadlargerimprovementinexercisetimefrom23weeksto3years(1.5minutesvs0.6minutes,p=0.05),butthechangeinpeakoxygenconsumptiondidnotdiffer(3.0ml/kg/minvs3.1ml/kg/min,p=0.75).,Conclusion:IntracoronarymBMCinjectionafterAMIdidnotimproveglobalLVfunctionorclinicaloutcomeduringthe3yearsofobservation.AmoderatelylargerincreaseinexercisetimeisobservedinmBMC-treatedpatients.Thetreatmentappearssafe,withnoadver