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1、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,Despite advances in reperfusion strategies and medical treatment,MI and subsequent HF remain major causes of morbidity and mortality.The use of cell therapy to promote myocardial repair has gained profound scientific and public interest.,干细胞移植（stem cell transplant
2、ation)亦称为 细胞心肌成形术（cellular cardiomyoplasty,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、纯化并在体外培养扩增EPC。成骨骼肌细胞（skeletal
3、 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,Experimental studies have shown that bone marrow cells(BMCs)are capable of inducing myogenesis and angiogenesis;this leads in turn to amelioration of cardiac function in mice and pigs.,Nature.2001;410:701705 Nat Med.2001;7:430436Proc Natl Aca
4、d Sci U S A.2001;98:1034410349.J Thorac Cardiovasc Surg.2002;123:11321135.,The first study on intracoronary mBMC therapy shortly after AMI in humans was reported in 2002.,Circulation 2002;15:19138.,10 patients were transplanted with autologous mononuclear BMCs via a balloon catheter placed into the
5、infarct-related artery during balloon dilatation。,From bench to bedside,Conclusions：Demonstrate for the first time that selective intracoronary transplantation of autologous,mononuclear BMCs is safe and seems to be effective under clinical conditions.,However,the efficacy results vary between studie
6、s.Possible explanations for these differences are small study samples,different imaging techniques and differences in timing of treatment,cell dose,placebo treatment or cell processing protocols.Concerns have been raised about accelerated atherosclerosis,intramyocardial calcifications and risk for a
7、rrhythmias.Long-term data on safety and efficacy of this treatment are needed.,20042005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2006年5月被拘留立案。,REPAIR-AMI trial（randomized,double-blind,placebo controlled,multicenter),N Engl J Med.20
8、06;355:12101221,204 AMI patients receive intracoronary infusion of progenitor cells derived from bone marrow(BMC)or placebo medium into the infarct artery 3 to 7 days after successful reperfusion therapy.,RESULTS:At 4 months,the absolute improvement in the global LVEF was significantly greater in th
9、e BMC group than in the placebo group(5.5+/-7.3%vs.3.0+/-6.5%;P=0.01).Baseline LVEF at or below the median value of 48.9%derived the most benefit.At 1 year,intracoronary infusion of BMC was associated with a reduction in clinical end point of death,recurrence of MI and any revascularization procedur
10、e(P=0.01).,Extended clinical follow-up in the REPAIR-AMI trial,to assess long-term safety and durability of the observed beneficial effects on cardiovascular event rate and cardiac function at 2 years.,精读（1）,Circ Heart Fail.2010;3:89-96,Study flow diagram(17 centers),EF45%by visual estimate,OTW ball
11、oon,There were no significant differences in baseline characteristics.Medication did not significantly differ between placebo and BMC at hospital discharge and up to 2 years follow-up,with the exception of aldosterone antagonists,which were significantly less frequently used in the BMC group at hosp
12、ital discharge and at 12 months follow-up.,End Points,The primary end point：The absolute improvement in global LVEF from baseline to 4 months.Combined clinical end points:Death,repeated MI or any revascularization procedurereflecting progression of vascular disease.Death,MI,or rehospitalization for
13、heart failure,reflecting progression of disease toward HF.,MRI,In a subgroup of 59 patients,MRI imaging at 2-year follow-up wasavailable.preformed by blinded investigators.,Only 27 patients had baseline MRI.,Clinical Events at 2-Year Follow-Up,Clinical Events at 2-Year Follow-Up,Predictors of Combin
14、ed End Point(Death,MI,or Rehospitalization for HF),Multivariable Cox regression analysis revealed that randomization to the BMC group(P=0.032)and age(P=0.045)remained the only significant independent predictors of an improved clinical outcome as assessed by the combined end point.,Cardiac Function A
15、fter 2 Y(59 cases BMC,26;Con,33),梗死节段室壁增厚率,梗死面积,射血分数,Conclusion,The 2-year follow-up demonstrates：No late hazards associated with BMC therapy,Restenosis/athersclerotic disease progression,?,Revascularization rates were significantly reduced in the BMC group within the first year,still tend to be low
16、er in the BMC group compared to placebo at 2 years follow-up.,Adverse:inflammatoryBeneficial:enhanced reendothelialization,vascular repair,Malignant ventricular arrhythmia,?,No evidence of malignant ventricular arrhythmias or syncopes within 2 years after intracoronary infusion of BMC.,Neoplasms,?,A
17、lthough 20%of the intracoronary infused cells actually retained in the heart,with the remaining cells distributing throughout the body including lung,liver,and spleen,No signal of an increased rate of neoplasms within 2 years.,The 2-year follow-up demonstrates：The beneficial effects of BMC therapy o
18、n cardiovascular outcome are preserved beyond the first months up to the end of the present observation period.Moreover,the better regional recovery of LV function in the BMC group is maintained for at least 2 years.,Neovascularization,Neovascularization induced by intracoronary infusion of BMC may
19、be a key mechanism leading to recovery of contractile function and subsequent reduction of clinical event rate.,心脏功能及预后改善机制,A substudy of REPAIR-AMI assessing the effect of intracoronary BMC administration on coronary flow dynamics using intracoronary Doppler flow velocity measurements at baseline a
20、nd at 4 month follow-up:Significant greater recovery of coronary blood flow reserve(CFR)in the BMC-treated infarct artery compared with infarct vessels receiving placebo infusion.,Circulation.2007;116:366374,Paracrine effects,Various studies confirmed that progenitor cells release paracrine factors(
21、cytokines and growth factors)that modulate angiogenesis,cardiomyocyte apoptosis,fibrosis,and inflammation.,Fibrogenesis Tissue Repair.2008 Oct 13;1(1):4,J Cardiovasc Transl Res.2010 Feb 26.Epub ahead of print,Swine subjected to AMI by temporary balloon occlusion of the LAD using percutaneous techniq
22、ues received intracoronary injection of either concentrated MSC-derived growth factors or control medium.MSC-derived factors significantly reduced cardiac troponin-T elevation and improved echocardiographic parameters,decreased the fibrotic area,reduced myocardial damage and prevented cardiomyocyte
23、apoptosis.,旁分泌因子作用,Strategies designed to augment MSC paracrine function have been employed in an attempt to improve their therapeutic efficacy.It has been demonstrated that treating MSCs with transforming growth factor-(TGF-)can stimulate VEGF production in vitro.,扩大旁分泌作用,Am J Physiol Regul Integr
24、Comp Physiol.2010;299(1):R371-8,Using a model of isolated heart perfusion,MSCs pretreated with TGF-was associated with decreased myocardial injury and increased myocardial function after global ischemia/reperfusion when compared to infusion of untreated MSCs.,Circulation.2010;121:2001-2011,Methods a
25、nd Results:Vectors that encoded inducible suicide genes under the control of endothelium(endothelial nitric oxide synthase)-,smooth muscle(SM22)-,and cardiomyocyte(-MHC)-specific promoters,thereby allowing selective depletion of the individual cell lineage acquired by the transplanted undifferentiat
26、ed bone marrowderived cells.,Depletion of eNOS-expressing cells(内皮细胞）was associated with a reduction of capillary and arteriole density and induced a deterioration of regional and global LVEF.The depletion of cells that expressed SM22-（平滑肌细胞）induced a deterioration in contractile function.The elimin
27、ation of cells that expressed the cardiac myocyte marker-MHC（心肌细胞）did not significantly affect cardiac function.,移植途径,Intracoronary injection,However,traditional reperfusion strategies fail to open the artery in some patients,making effective delivery impossible.The study demonstrated a safe and eff
28、icient approach to delivering bone marrow stem cells via a noninfarcted artery in an animal myocardial infarction model.,Cardiovasc Ther.2010 Mar 10.Epub ahead of print,NOGA system,支持文献,Clinical implications,The sample size of the REPAIR-AMI trial was not powered to definitely answer the question wh
29、ether BMC administration is capable to modify mortality and morbidity after AMI.Therefore,this analysis should be viewed as hypothesis generating.As such,this analysis provides the rationale to design a larger clinical outcome trial addressing the clinical end.,精读（2）,Patients from the Autologous Ste
30、m cell Transplantation in Acute Myocardial Infarction(ASTAMI)study were re-assessed 3 years after inclusion.,Heart 2009 95:1983-1989,Randomised,controlled trialTwo university hospitals in Oslo,Norway,The primary endpoint:The change in LVEF from baseline to 6 months measured by SPECT.Echocardiography
31、 and MRI were used for serial assessment of LV function.Secondary endpoints:Changes in exercise capacity and quality-of-life(QoL).,End Points,Results:The rates of adverse clinical events in the groups were low and equal.There were no significant differences between groups in change of global LV syst
32、olic function by echocardiography or MRI during the follow-up.,On exercise testing,the mBMC-treated patients had larger improvement in exercise time from 23 weeks to 3 years(1.5 minutes vs 0.6 minutes,p=0.05),but the change in peak oxygen consumption did not differ(3.0 ml/kg/min vs 3.1 ml/kg/min,p=0
33、.75).,Conclusion:Intracoronary mBMC injection after AMI did not improve global LV function or clinical outcome during the 3 years of observation.A moderately larger increase in exercise time is observed in mBMC-treated patients.The treatment appears safe,with no adverse effects observed after 3 year
34、s.,显示无效文献,Future clinical trials,To test and confirm the most beneficial subpopulations of autologous stem cells.To identify the optimal dosage and timing of cell therapeutics.To explain and explore the mechanisms of cell therapy in humans.(paracrine?myocardial regeneration?)To produce optimum cell
35、delivery and homing capacity.,Am Heart J 2010;159:354-60.,Trial Design The ENACT-AMI trial is a phase IIb,double-blind,randomized placebo-controlled trial,using transplantation of autologous early endothelial progenitor cells(EPCs)for patients who have suffered large MI.,This will be the first clini
36、cal trial to include a strategy designed to enhance the function of autologous progenitor cells by overexpressing endothelial nitric oxide synthase,and the first to use combination gene and cell therapy for the treatment of cardiac disease.,Phase III,multi-centre,randomised,placebo-controlled efcacy and safety study(n=100)analyzing the effect of combined application of G-CSF and Sitagliptin(西他列汀)after AMI(“SITAGRAMI-Trial”;EudraCT Number:2007-003941-34).,Thanks!,
