10郑州-急性心肌炎的诊断与治疗现状

ICUHInstituteofCardiologyUnionHospital急性心肌炎的诊断与治疗现状华中科技大学协和医院心血管病研究所生物靶向治疗教育部重点实验室廖玉华ICUHInstituteofCardiologyUnionHospitalICUHInstituteofCardiologyUnionHospital概述病毒性心肌炎是指嗜心肌性病毒感染引起的，以心肌非特异性间质性炎症为主要病变的心肌炎临床谱包括心肌局灶性炎症引起的无症状心肌炎到心肌弥漫性炎症所致的重症心肌炎41％～88％病人有前驱病毒感染史临床观察1～2月，异常体征消失者属轻症；重症心肌炎病程约需半年，大多数患者可完全恢复健康临床上大约12.5％急性病毒性心肌炎可以演变为扩张型心肌病ICUHInstituteofCardiologyUnionHospital病因和发病机理主要病原是柯萨奇B组2～5型和A组9型病毒，其次是艾柯病毒和腺病毒，还有流感病毒、脑心肌病毒、风疹病毒、合胞病毒等20余种国内七省市调查表明，儿童以柯萨奇病毒为主占43.6％，腺病毒占21.2％，艾柯病毒占10.9％，其他病毒共占14.3％ICUHInstituteofCardiologyUnionHospitalPathogenesisofMyocarditisLeslieT.Cooper,Jr.Myocarditis.NEnglJMed,2009,360:1526-38.心律失常ICUHInstituteofCardiologyUnionHospitalPathogenesisofMyocarditisLeslieT.Cooper,Jr.Myocarditis.NEnglJMed,2009,360:1526-38.心力衰竭ICUHInstituteofCardiologyUnionHospitalPathogenesisofMyocarditisLeslieT.Cooper,Jr.Myocarditis.NEnglJMed,2009,360:1526-38.心律失常后遗症扩张型心肌病慢性心力衰竭ICUHInstituteofCardiologyUnionHospital宿主防御和免疫反应中T细胞亚型KingstonHGMills.Eur.J.Immunol.,2008,38:2636-2649ShengXuandXuetaoCao.Cellular&MolecularImmunology,2010,7:164-174Tcell针对细胞内病原体/肿瘤免疫反应针对细胞外病原体免疫反应和过敏反应免疫调节炎症/自身免疫反应ICUHInstituteofCardiologyUnionHospital急性病毒性心肌炎患者Th17细胞促进体液免疫应答YuanJing,LiaoYu-Hua.JClinImmunol.2010,30:226–234ICUHInstituteofCardiologyUnionHospital通过线性回归和相关分析发现血液循环细胞因子和B细胞活性存在相关性(n=16AVMC,R=0.66,P0.01)(n=18DCM,R=0.47,P0.05)检测AVMC组患者和DCM组患者四种抗心肌抗体（包括MHC,ANT,β1-AR和M2-CR），发现在AVMC组有15例(93.8%)患者四种抗体中至少一种阳性，而在DCM组有10例(55.6%),抗体均是IgG型YuanJing,LiaoYu-Hua.JClinImmunol.2010,30:226–234ICUHInstituteofCardiologyUnionHospital研究结论急性病毒性心肌炎Th17细胞而不是Th2细胞辅助B细胞产生抗心肌抗体在病毒性心肌炎后期阶段（DCM阶段）Th2细胞介导体液免疫反应应答发挥主导作用YuanJing,LiaoYu-Hua.JClinImmunol.2010,30:226–234ICUHInstituteofCardiologyUnionHospitalCVB3诱导急性病毒性心肌炎Th17细胞促进病毒复制ICUHInstituteofCardiologyUnionHospitalCVB3病毒感染第五天心脏IL-17mRNA与CVB3-RNA水平正相关心脏IFN-γmRNA与CVB3-RNA水平负相关YuanJetal.JImmunol.2010;185(7):4004-10.IL-17通过抑制INF-γ功能促进病毒复制ICUHInstituteofCardiologyUnionHospital研究结论我们的研究提示在急性病毒性心肌炎小鼠模型，Th17细胞促进CVB3病毒复制，IL-17可能是抗病毒免疫平衡调节的重要靶点YuanJetal.JImmunol.2010;185(7):4004-10.ICUHInstituteofCardiologyUnionHospitalCVB3诱导急性病毒性心肌炎小鼠中和IL-17能够抑制抗ANT抗体产生YuanJ,etal.InternationalImmunopharmacology10(2010)272–27ICUHInstituteofCardiologyUnionHospitalCVB3小鼠急性病毒性心肌炎IL-17mAb抑制CD-19B细胞增殖和抗ANT抗体产生YuanJ,etal.InternationalImmunopharmacology10(2010)272–27CD19+B淋巴细胞增殖抗ANT抗体分泌*p0.05vsLPSorLPS+isotypecontrolICUHInstituteofCardiologyUnionHospital研究结论我们的研究结果提示IL-17通过调节自身抗心肌抗体的产生与急性病毒性心肌炎进展有关，阻滞IL-17可能代表了一个新颖有希望的治疗途径YuanJ,etal.InternationalImmunopharmacology10(2010)272–27ICUHInstituteofCardiologyUnionHospital扩张型心肌病患者应答T细胞(Tresp)对调节T细胞(Treg)抑制功能的敏感性降低ICUHInstituteofCardiologyUnionHospitalHongxiaTang,etal.Heart2010;96:765-772.ICUHInstituteofCardiologyUnionHospital增殖抑制试验比较扩张型心肌病患者和正常人群CD4+CD25highCD127lowTreg细胞调节活性ICUHInstituteofCardiologyUnionHospital细胞分离出来后加入抗CD3(1.5mg/ml)和抗CD28(2mg/ml)预先包被的平板中，孵育三天后，加入3H标记胸腺嘧啶核苷检测细胞增殖活性HongxiaTang,etal.Heart2010;96:765-772.ICUHInstituteofCardiologyUnionHospital研究结论扩张型心肌病患者Treg细胞抑制自身T应答细胞的缺陷归因于应答T细胞对Treg细胞调节的敏感性降低因此，改善T应答细胞对Treg细胞介导抑制效应的敏感性策略可能在扩张型心肌病是有益的治疗靶点ICUHInstituteofCardiologyUnionHospitalHongxiaTang,etal.Heart2010;96:765-772.ICUHInstituteofCardiologyUnionHospital心肌炎-扩张型心肌病的免疫调节InflammatoryreactionAcuteMyocardialdamageImmunesystemactivatedfunctionalimbalanceofTh1/Th2DCMHFTh0Th1Th2Th17Treg-IL-4,IL-5,DCMCHFⅹ↓TGF-β,IL-10DCMCHF＋＋IL-17A,IL-17F,IL-22AVCMTCLBcell＋＋IFN-γ,TNF-αAVCM＋＋病毒ICUHInstituteofCardiologyUnionHospital诊断手段1、心肌损伤生物标记：血沉、CRP、CK-MB、心肌肌钙蛋白T/I2、心电图（ECG）3、心脏超声（UCG）4、心脏磁共振（CMR）5、心内膜心肌活检（EMB）①心肌炎组织学诊断标准的差异②局灶性心肌炎的取材误差③组织学评价特异性的差异1984年Dallas会议制定了心肌炎组织学诊断标准：心肌炎性细胞浸润伴有心肌细胞坏死和(或)附近心肌细胞变性病毒基因探针原位杂交法和原位RT-PCR：心内膜心肌活检标本中查到病毒RNA６、外周血病原学检查：ELISA检测血清柯萨奇病毒IgM抗体，RT-PCR技术检测外周血白细胞或血清肠病毒RNA，抗心肌抗体检测ICUHInstituteofCardiologyUnionHospitalContrast-EnhancedMagneticResonanceImaging(MRI)oftheHeartofa24-Year-OldManwithAcuteMyocarditisLeslieT.Cooper,Jr.Myocarditis.NEnglJMed,2009,360:1526-38.CardiacMRIisbeingincreasinglyusedtoevaluatesuspectedacutemyocarditisandtolocalizesitesforendomyocardialbiopsy,withadditionaldetailshownwithdelayedgadoliniumenhancement(PanelA,arrows),inafourchamberview(PanelB,arrows),andinT2-weightedthree-chamberviews(PanelsCandD,arrows).ICUHInstituteofCardiologyUnionHospitalLymphocyticandHistiocyticInfiltrateandTLymphocytesinHeart-TissueSectionsfromPatientswithAcuteMyocarditisLeslieT.Cooper,Jr.Myocarditis.NEnglJMed,2009,360:1526-38.PanelAshowsacutemyocarditiswithwidespreadlymphocyticandhistiocyticinfiltrate(arrow)andassociatedmyocytedamage(arrowhead)PanelBshowsCD3immunostainingofTlymphocytesinapatientwithacutemyocarditis.ICUHInstituteofCardiologyUnionHospital急性心肌炎患者心内膜心肌活检JaredW.MagnaniandG.WilliamDec.Circulation,2006,113:876-890.Thepathologicaldiagnosisoflymphocytic(viral)myocarditisrequiresthepresenceofalymphocyte-richinflammatoryinfiltrateassociatedwithmyocytedegenerationornecrosis.Thepresenceofalymphocyticinfiltratewithoutassociatedmyocytedegenerationornecrosisisnotdiagnosticoflymphocyticmyocarditisandistypicallydescribedas“borderlinemyocarditis.”ICUHInstituteofCardiologyUnio