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1、干细胞移植治疗AMI临床研究进展Stillwatersrundeep.流静水深流静水深,人静心深人静心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望Despiteadvancesinreperfusionstrategiesandmedicaltreatment,MIandsubsequentHFremainmajorcausesofmorbidityandmortality.Theuseofcelltherapytopromotemyocardialrepairhasgainedprofoundscientificandpublicinterest
2、.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（mesenchymal stem cells，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（endothelial progenitor cells，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
3、外培养扩增EPC。 成骨骼肌细胞（skeletal myoblasts，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. 2001;410:701705 Nat Med. 2001;7:430436Proc Natl A
4、cad Sci U S A. 2001;98:1034410349.J Thorac Cardiovasc Surg. 2002;123:11321135. ThefirststudyonintracoronarymBMCtherapyshortlyafterAMIinhumanswasreportedin2002.Circulation 2002;15:19138. 10patientsweretransplantedwithautologousmononuclearBMCsviaaballooncatheterplacedintotheinfarct-relatedarteryduring
5、balloondilatation。From bench to bedsideConclusions：Demonstrateforthefirsttimethatselectiveintracoronarytransplantationofautologous,mononuclearBMCsissafeandseemstobeeffectiveunderclinicalconditions.However,theefficacyresultsvarybetweenstudies.Possibleexplanationsforthesedifferencesaresmallstudysample
6、s,differentimagingtechniquesanddifferencesintimingoftreatment,celldose,placebotreatmentorcellprocessingprotocols.Concernshavebeenraisedaboutacceleratedatherosclerosis,intramyocardialcalcificationsandriskforarrhythmias.Long-termdataonsafetyandefficacyofthistreatmentareneeded.20042005年，黄禹锡在科学杂志发表伪造的干细
7、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2006年5月被拘留立案。 REPAIR-AMItrial（randomized,double-blind,placebocontrolled,multicenter)N Engl J Med.2006;355:12101221 204AMIpatientsreceiveintracoronaryinfusionofprogenitorcellsderivedfrombonemarrow(BMC)orplac
8、ebomediumintotheinfarctartery3to7daysaftersuccessfulreperfusiontherapy.RESULTS:uAt4months,theabsoluteimprovementintheglobalLVEFwassignificantlygreaterintheBMCgroupthanintheplacebogroup(5.5+/-7.3%vs.3.0+/-6.5%;P=0.01).uBaselineLVEFatorbelowthemedianvalueof48.9%derivedthemostbenefit.uAt1year,intracoro
9、naryinfusionofBMCwasassociatedwithareductioninclinicalendpointofdeath,recurrenceofMIandanyrevascularizationprocedure(P=0.01).Extendedclinicalfollow-upintheREPAIR-AMItrial,toassesslong-termsafetyanddurabilityoftheobservedbeneficialeffectsoncardiovasculareventrateandcardiacfunctionat2years.精读（1）Circ H
10、eart Fail. 2010;3:89-96Studyflowdiagram(17centers)EF45% by visual estimateOTW balloonuTherewerenosignificantdifferencesinbaselinecharacteristics.uMedicationdidnotsignificantlydifferbetweenplaceboandBMCathospitaldischargeandupto2yearsfollow-up,withtheexceptionofaldosteroneantagonists,whichweresignifi
11、cantlylessfrequentlyusedintheBMCgroupathospitaldischargeandat12monthsfollow-up.EndPointsTheprimaryendpoint：TheabsoluteimprovementinglobalLVEFfrombaselineto4months.Combinedclinicalendpoints:Death,repeatedMIoranyrevascularizationprocedurereflectingprogressionofvasculardisease.Death,MI,orrehospitalizat
12、ionforheartfailure,reflectingprogressionofdiseasetowardHF.MRIInasubgroupof59patients,MRIimagingat2-yearfollow-upwasavailable.preformedbyblindedinvestigators.Only27patientshadbaselineMRI.ClinicalEventsat2-YearFollow-UpClinicalEventsat2-YearFollow-UpPredictorsofCombinedEndPoint(Death,MI,orRehospitaliz
13、ationforHF)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ConclusionThe2-yearfollow-
14、updemonstrates：uNolatehazardsassociatedwithBMCtherapyRestenosis/atherscleroticdiseaseprogression?RevascularizationratesweresignificantlyreducedintheBMCgroupwithinthefirstyear,stilltendtobelowerintheBMCgroupcomparedtoplaceboat2yearsfollow-up.Adverse:inflammatoryBeneficial:enhancedreendothelialization
15、,vascularrepairMalignantventriculararrhythmia?Noevidenceofmalignantventriculararrhythmiasorsyncopeswithin2yearsafterintracoronaryinfusionofBMC.Neoplasms?Although20%oftheintracoronaryinfusedcellsactuallyretainedintheheart,withtheremainingcellsdistributingthroughoutthebodyincludinglung,liver,andspleen
16、,Nosignalofanincreasedrateofneoplasmswithin2years.The2-yearfollow-updemonstrates：uThebeneficialeffectsofBMCtherapyoncardiovascularoutcomearepreservedbeyondthefirstmonthsuptotheendofthepresentobservationperiod.Moreover,thebetterregionalrecoveryofLVfunctionintheBMCgroupismaintainedforatleast2years.Neo
17、vascularizationNeovascularizationinducedbyintracoronaryinfusionofBMCmaybeakeymechanismleadingtorecoveryofcontractilefunctionandsubsequentreductionofclinicaleventrate.心脏功能及预后改善机制AsubstudyofREPAIR-AMIassessingtheeffectofintracoronaryBMCadministrationoncoronaryflowdynamicsusingintracoronaryDopplerflowv
18、elocitymeasurementsatbaselineandat4monthfollow-up:Significantgreaterrecoveryofcoronarybloodflowreserve(CFR)intheBMC-treatedinfarctarterycomparedwithinfarctvesselsreceivingplaceboinfusion.Circulation. 2007; 116:366374 ParacrineeffectsVariousstudiesconfirmedthatprogenitorcellsreleaseparacrinefactors(c
19、ytokines and growth factors)thatmodulateangiogenesis,cardiomyocyteapoptosis,fibrosis,andinflammation.Fibrogenesis Tissue Repair. 2008 Oct 13;1(1):4 J Cardiovasc Transl Res. 2010 Feb 26. Epub ahead of print SwinesubjectedtoAMIbytemporaryballoonocclusionoftheLADusingpercutaneoustechniquesreceivedintra
20、coronaryinjectionofeitherconcentratedMSC-derivedgrowthfactorsorcontrolmedium.MSC-derivedfactorssignificantlyreducedcardiactroponin-Televationandimprovedechocardiographicparameters,decreasedthefibroticarea,reducedmyocardialdamageandpreventedcardiomyocyteapoptosis.旁分泌因子作用StrategiesdesignedtoaugmentMSC
21、paracrinefunctionhavebeenemployedinanattempttoimprovetheirtherapeuticefficacy.IthasbeendemonstratedthattreatingMSCswithtransforminggrowthfactor-(TGF-)canstimulateVEGFproductioninvitro.扩大旁分泌作用Am J Physiol Regul Integr Comp Physiol. 2010;299(1):R371-8 Usingamodelofisolatedheartperfusion,MSCspretreated
22、withTGF-wasassociatedwithdecreasedmyocardialinjuryandincreasedmyocardialfunctionafterglobalischemia/reperfusionwhencomparedtoinfusionofuntreatedMSCs.Circulation. 2010;121:2001-2011MethodsandResults:Vectorsthatencodedinduciblesuicidegenesunderthecontrolofendothelium(endothelialnitricoxidesynthase)-,s
23、moothmuscle(SM22)-,andcardiomyocyte(-MHC)-specificpromoters,therebyallowingselectivedepletionoftheindividualcelllineageacquiredbythetransplantedundifferentiatedbonemarrowderivedcells.DepletionofeNOS-expressingcells(内皮细胞）wasassociatedwithareductionofcapillaryandarterioledensityandinducedadeterioratio
24、nofregionalandglobalLVEF.ThedepletionofcellsthatexpressedSM22-（平滑肌细胞）inducedadeteriorationincontractilefunction.Theeliminationofcellsthatexpressedthecardiacmyocytemarker-MHC（心肌细胞）didnotsignificantlyaffectcardiacfunction.移植途径uIntracoronaryinjectionHowever,traditionalreperfusionstrategiesfailtoopenthe
25、arteryinsomepatients,makingeffectivedeliveryimpossible.Thestudydemonstratedasafeandefficientapproachtodeliveringbonemarrowstemcellsviaanoninfarctedarteryinananimalmyocardialinfarctionmodel.Cardiovasc Ther. 2010 Mar 10. Epub ahead of print uNOGAsystem支持文献ClinicalimplicationsThesamplesizeoftheREPAIR-A
26、MItrialwasnotpoweredtodefinitelyanswerthequestionwhetherBMCadministrationiscapabletomodifymortalityandmorbidityafterAMI.Therefore,thisanalysisshouldbeviewedashypothesisgenerating.Assuch,thisanalysisprovidestherationaletodesignalargerclinicaloutcometrialaddressingtheclinicalend.精读（2）PatientsfromtheAu
27、tologousStemcellTransplantationinAcuteMyocardialInfarction(ASTAMI)studywerere-assessed3yearsafterinclusion. Heart 2009 95: 1983-1989Randomised,controlledtrialTwouniversityhospitalsinOslo,NorwayTheprimaryendpoint:ThechangeinLVEFfrombaselineto6monthsmeasuredbySPECT.EchocardiographyandMRIwereusedforser
28、ialassessmentofLVfunction.Secondaryendpoints:Changesinexercisecapacityandquality-of-life(QoL).EndPointsResults:Theratesofadverseclinicaleventsinthegroupswerelowandequal.TherewerenosignificantdifferencesbetweengroupsinchangeofglobalLVsystolicfunctionbyechocardiographyorMRIduringthefollow-up.Onexercis
29、etesting,themBMC-treatedpatientshadlargerimprovementinexercisetimefrom23weeksto3years(1.5minutesvs0.6minutes,p=0.05),butthechangeinpeakoxygenconsumptiondidnotdiffer(3.0ml/kg/minvs3.1ml/kg/min,p=0.75).Conclusion:IntracoronarymBMCinjectionafterAMIdidnotimproveglobalLVfunctionorclinicaloutcomeduringthe
30、3yearsofobservation.AmoderatelylargerincreaseinexercisetimeisobservedinmBMC-treatedpatients.Thetreatmentappearssafe,withnoadverseeffectsobservedafter3years.显示无效文献FutureclinicaltrialsTotestandconfirmthemostbeneficialsubpopulationsofautologousstemcells.Toidentifytheoptimaldosageandtimingofcelltherapeu
31、tics.Toexplainandexplorethemechanismsofcelltherapyinhumans.(paracrine?myocardialregeneration?)Toproduceoptimumcelldeliveryandhomingcapacity.Am Heart J 2010;159:354-60.TrialDesignTheENACT-AMItrialisaphaseIIb,double-blind,randomizedplacebo-controlledtrial,usingtransplantationofautologousearlyendotheli
32、alprogenitorcells(EPCs)forpatientswhohavesufferedlargeMI.Thiswillbethefirstclinicaltrialtoincludeastrategydesignedtoenhancethefunctionofautologousprogenitorcellsbyoverexpressingendothelialnitricoxidesynthase,andthefirsttousecombinationgeneandcelltherapyforthetreatmentofcardiacdisease.PhaseIII,multi-centre,randomised,placebo-controlledefficacyandsafetystudy(n=100)analyzingtheeffectofcombinedapplicationofG-CSFandSitagliptin(西他列汀)afterAMI(“SITAGRAMI-Trial”;EudraCTNumber:2007-003941-34).
