2019年整理糖尿病性心肌缺血再灌注損傷因素及治療進(jìn)展

糖尿病性心肌缺血再灌注損傷因素及治療進(jìn)展/r/n【關(guān)鍵詞】糖尿病/r/n關(guān)鍵詞：糖尿病；心肌病；缺血：再灌注損傷；心肌保護(hù)/r/n//r/n展進(jìn)行闡述。/r/n1/r/n糖尿病性心肌病的病理生理/r/n型糖尿病（/r/n胰島素依賴性糖尿病/r/nInsulin-dependent/r/nDiabetes/r/nMellitusJDDM）/r/n型糖尿?。?r/nNon-insulin-dependent/r/n/r/nDiabetes/r/n/r/nMellitus:NIDDM）/r/nPAS/r/n糖代謝異常/r/n高血糖及英代謝異常在糖尿病性心肌病的發(fā)展過(guò)程中起著非常重要的作用。在急性糖尿病/r/n＞25mmol/L5~7/r/n天，心臟會(huì)出現(xiàn)糖尿病性心肌病病變/r/n。另外，高血糖和晚期糖基化終末產(chǎn)物/r/n（AGEs）/r/n均可引起心肌微血管內(nèi)皮細(xì)胞粘附因子/r/n-1（VCAm-1）/r/n的表達(dá)升髙，再引起血中/r/nTNF-a/r/n損/r/n［2］/r/n。/r/n脂類代謝異常/r/nATP/r/n能量代謝紊亂，引起低密度脂蛋白/r/n（LDL）/r/n氧化增高但又不能被/r/nLDL/r/nLDL/r/n在體內(nèi)蓄積，使心肌細(xì)胞的功能受損。/r/n鈣的超載/r/n。綜上所述，糖尿病性心肌病因上述原因?qū)е滦墓δ苁軗p表現(xiàn)：/r/n（1）/r/n心肌的舒張功能受損，收縮/r/n（2/r/n（LVRT/r/n（3/r/n左心室/r/n/r/nI/R/r/n［4］/r/n。/r/nI/R/r/n對(duì)糖尿病性心臟損傷的影響因素/r/nIDDM/r/nNIDDM/r/n的心肌病發(fā)病機(jī)理有相似之處，然而苴病因?qū)W和病理生理變化并不完全/r/nNIDDM/r/nI/R/r/nSTZ/r/n或四氧嚅嚨誘導(dǎo)）/r/n的在體或離體心臟/r/nI/R/r/n的動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)：糖尿/r/nI/R/r/n（2/r/n糖尿病的心臟對(duì)/r/nI/R/r/n8w/r/n［5］/r/n。臨床資料表明：糖尿病/r/nI/R/r/n損傷的耐受性明顯降低，合并糖尿病的髙血壓心臟患者較單純髙血壓者心肌梗/r/nI/R/r/n對(duì)糖尿病性心臟會(huì)造成更大的損傷/r/n［6,7］/r/nI/R/r/n對(duì)糖尿病性心臟損傷的程度，還受多種因素的影響。/r/n胰島素和胰島素樣生長(zhǎng)因子/r/nI/R/r/n［8］/r/n［10］/r/nI/r/n型糖尿病大鼠/r/n(STZ/r/n誘導(dǎo)，/r/n2W)/r/nI/R/r/n20min,/r/n再灌注后心臟功能的損傷較對(duì)照組低，這與它在缺血期心肌細(xì)胞可以保持較高的谷胱甘肽/r/n(GSH)/r/n有關(guān)，但缺/r/n4Omin,/r/n4Omin/r/n的心功能的損害：而且，在臨床上：胰島素//r/n極化液/r/n(GIK)/r/n能明顯地抑制/r/nTNF-a/r/nIL-6/r/nNO/r/n、/r/nIL-4/r/nIL-10/r/n等的產(chǎn)生，因此，對(duì)糖尿病患者并發(fā)心肌梗死/r/nGIK/r/n心臟功能的恢復(fù)/r/n［11］/r/n。/r/np53/r/nC/r/nRAS/r/nAT-I/r/n的基因表達(dá)升高，而使心肌細(xì)胞內(nèi)血管緊張素/r/n-II(AT-II)/r/n肌細(xì)胞的凋亡/r/n［12］oIGF-I/r/nIGF-IR/r/nRAS/r/n系統(tǒng)的活性，下調(diào)/r/np53/r/n的基因表達(dá)，抑制糖尿病心肌細(xì)胞的凋亡，對(duì)心肌有保護(hù)作用/r/n［13］/r/n0/r/n中性粒細(xì)胞/r/nMcdonagh/r/n等/r/n［14］/r/n通過(guò)正常和糖尿病/r/n(STZ/r/nWistar/r/nI/R/r/n的實(shí)驗(yàn)中，在/r/n5min/r/n前，采用含同型血的灌注液(稀血液，/r/nHet:0.200)/r/nifn30min,/r/n仍/r/n60/r/nmin/r/nI/R/r/n過(guò)程中產(chǎn)生更多的氧自由基加重了心肌損傷。/r/nHO-1/r/n、/r/nCOXBIII/r/nATPS6/r/nCsonka/r/nI/R/r/nNorthern/r/nRT-PCR/r/n心肌細(xì)胞內(nèi)血紅素合成酶/r/n-1/r/n(/r/nHO-1)/r/n/r/nmRNA/r/nHO-2/r/n無(wú)關(guān)。/r/n另外，/r/nSzendrei/r/n/r/n［16］/r/nI/R/r/n實(shí)驗(yàn)發(fā)現(xiàn)：/r/n心肌細(xì)胞線粒體內(nèi)細(xì)胞色素/r/nC/r/nIII(COXBIII)/r/nATP/r/n6(ATPS6)/r/n后心室纖瀕發(fā)生的發(fā)生率，而抑制兩基因表達(dá)后，能顯著降低心室纖頤的發(fā)生率，但/r/nCOXBIII/r/nATPS6/r/n基因表達(dá)水平對(duì)心功能/r/n(HR/r/n、/r/nAF/r/n、/r/nCF/r/nLVDP/r/nATP/r/n敏感性鉀通道/r/n心肌缺血預(yù)處理/r/n(IschemiaPreconditioning:IPC)/r/nI/R/r/nIPC/r/nATP/r/nRavngerova/r/nKersten/r/n［18］/r/n等分別采用正常和糖/r/nIPC/r/n的實(shí)驗(yàn)結(jié)果：/r/nIPC/r/nI/R/r/n(BS>16.67mmol/L)/r/nATP/r/n敏感性鉀通道開(kāi)放/r/n［19,20］/r/n。/r/n然而，也有不同觀點(diǎn)：/r/nNieszner/r/n等/r/n［21］/r/n在使用降糖藥磺酰服類格列苯腮/r/n(GLIB),/r/n它已被公認(rèn)/r/nATP/r/n敏感性鉀通道阻滯作用，經(jīng)它處理正常和糖尿病的大鼠，然后進(jìn)行離體心臟的/r/nI/R/r/n實(shí)驗(yàn)，其結(jié)果：/r/nGLIB/r/nIPC/r/nGLIB/r/n等/r/n［22］/r/n利用正常和糖尿病/r/n(6w)/r/nGLIB/r/n治療組和其對(duì)照組，它們的離/r/n5/r/nmin,/r/nifil/r/n25/r/nmin/r/n后，再灌注/r/n30/r/nmin,/r/nGLIB)/r/n心肌釋放的/r/nCK/r/n的量較正常組明顯降低/r/n（P<0.05）,/r/n而未使用、使用/r/nGLIB/r/n52%/r/n、/r/n93%/r/n100%/r/n/r/n（前組與后兩組比較，/r/nP/r/n均/r/n<0.05）/r/n,而/r/nIPC/r/nATP/r/nI/R/r/n心肌保護(hù)外，是否還存在其它機(jī)制有待于進(jìn)一步的探索。/r/nMg2+/r/n和/r/nCa2+/r/n糖尿病由于糖、脂類代謝異常引起心肌細(xì)胞內(nèi)代謝性酸中毒，通過(guò)/r/nNa+-H+/r/nNa+-Ca2+/r/nI/r/nCa2+/r/nI/R/r/n損傷/r/n［23］o/r/nMg2+/r/nI/R/r/n后室性心律失常的發(fā)生率。/r/nTosaki/r/n等/r/n［24］/r/n通過(guò)正常和糖尿病大鼠/r/n（8w）/r/nI/R/r/nATP/r/n通道開(kāi)放劑克羅卡林/r/n（Cromakalim）,/r/n20min,/r/n30min/r/n92%/r/n/r/n（/r/nMg2+/r/n的濃度是：/r/n1.2/r/n/r/nmmol/L）,/r/n而灌注液中/r/nMg2+/r/n2.4/r/n、/r/n3.6/r/n、/r/n4.8mmol/L/r/n時(shí)，室性心律失常的發(fā)生率分別是/r/n67%/r/n42%/r/n25%/r/n（/r/n92%/r/nP/r/n均/r/n因此，紐/r/nI/r/n胞/r/n外液適當(dāng)濃度的鎂可以減少抗高血壓藥/r/n（ATP/r/n/r/n敏感性鉀通道開(kāi)放劑）可能引起糖尿病室性心律失常的發(fā)生率。/r/n病程/r/nI/R/r/n1/r/n2/r/n型糖尿病心肌的損傷程度及心功能的恢復(fù)的好壞與其病程有關(guān)，病程越長(zhǎng)，/r/nI/R/r/n對(duì)心肌的損傷也更大。/r/nAasum/r/n等/r/n［5］/r/n在糖尿病大鼠離體工作心臟的/r/nI/R/r/n的實(shí)驗(yàn)中發(fā)現(xiàn)：/r/n6/r/nw/r/n12w,/r/n其心功能明顯減/r/nI/R/r/n損傷的耐受性/r/n［25］/r/n。/r/nP/r/n選擇素/r/nP/r/nI/r/n胞/r/n和多核粒細(xì)胞的相互作用，介導(dǎo)心肌的/r/nI/R/r/nHoshida/r/n（ZDF）/r/n和瘦肉大鼠，進(jìn)行/r/nI/R/r/n實(shí)驗(yàn)：/r/nZDF/r/n（P<0.05）,/r/nZDF/r/nP/r/nAch/r/n依賴性血管舒張因子的產(chǎn)生：另外，/r/nJones/r/n等/r/n［27］/r/nII/r/n型糖尿病大鼠，結(jié)扎/r/n冠狀/r/nA/r/n前降支/r/n30/r/n/r/nmin/r/n2h,/r/n（56.3±2.8/r/n%/r/n（PMNs）/r/n聚集/r/n（P<0.05）,/r/n由此可見(jiàn)，/r/nP/r/nI/R/r/n損傷程度密切相關(guān)。/r/n糖尿病性心肌病的病理生理/r/nGIK/r/nGIK/r/n［9］,/r/nGIK,/r/n均有利于減輕心肌及血管內(nèi)皮細(xì)胞水腫，促進(jìn)心肌功能的恢復(fù)，有利于降低患者的死亡率/r/n［28］/r/n。/r/n抗氧化劑/r/n1/r/n2/r/n型糖尿病因高血糖、糖基化終末產(chǎn)物/r/nAGES/r/nNF-kB,/r/nP38MAPK/r/n、/r/nNH2-JuN/Akt/r/n通路、/r/nPKC/r/n生、發(fā)展，如使用抗氧化劑如：/r/nVitE/r/n、/r/na-/r/n硫辛酸、/r/nN-/r/n程，對(duì)糖尿病的心肌有保護(hù)作用/r/n［29］/r/n。/r/n醛糖還原酶抑制劑/r/nZopolrestat/r/n是一種醛糖還原酶抑制劑，可抑制糖尿病的多元醇的異常代謝，能保持糖尿病/r/nI/R/r/nNADH/NAD+,/r/nATP,/r/nK+-Na+/r/n/r/nI/R/r/n對(duì)糖尿病性心肌的損傷。/r/n基因治療/r/nI/R/r/n的損傷的程度更大與英再灌注后冠脈開(kāi)放率低或無(wú)復(fù)流現(xiàn)象有關(guān)/r/n。若采用單克隆抗體技術(shù)抑制/r/nC5a/r/n的生成，它可抑制白細(xì)胞的趨向性：或降低/r/nP-/r/n-1/r/n(VCAm-1)/r/nNF-kB/r/nI/R/r/n對(duì)心肌的損傷/r/n[30]/r/nI/R/r/n的心肌有保護(hù)作用。/r/n[3/r/np;/r/nI/R/r/n中可減/r/n[32]/r/nI/R/r/n損傷有一立的保護(hù)作用，但它對(duì)糖尿病性心肌/r/nI/R/r/n胞凋亡及其機(jī)制等，有待于進(jìn)一步的探索。/r/n4展望/r/n2/r/n型糖尿患者，他們可能經(jīng)歷體外轉(zhuǎn)流/r/n(CPB)/r/n心血管手術(shù)，但由于嚴(yán)重的糖尿病性心肌病變，/r/nI/R/r/nI/R/r/n床意義。/r/n參考文獻(xiàn)：/r/n[1]GittAK,SchieleR,WienbergenH,etal.Intensivetreatmentofcoronaryarterydiseaseindiabeticpatentsinclinicalpractice:resultsoftheMITRAstudy[J].ActaDiabetol,2003,40(suppl2)：S343-347./r/nKislingerT,TanjiN,WendtT,etal.Receptorforadvancedglycationendproductsmediatesinflammationandenhaneedexpressionoftissuefactorinvasculatureofdiabeticapollipropoteine-nullmice[J].ArteriosclerosisThrombosis&VascularBiology,2001,21(6):905-910./r/nHintzKK,RenJ.Prediabeticinsulinresistaneeisnotpremissivetothedevelopmentofcardiacressistaneetoinsulin-likegrowthfactorIinventricular/r/n/r/nmyocytes/r/n[J].DiabetesResClinPract,2002,55(2):89-98./r/nPoirierP,GarneallC,MaroisL,etal.Diabeticdypsfunctioninnormotensivemenwithwellcontrolledtype2diabetes:importaneeofmaneuversinechocardiographicscreeningforpreclinicaldaibeticcardiomyophathy[J].DiabetesCare,2001,24/r/n⑴:5-10./r/nAasumE,HafstadAD,SeversonDL,etal.Age-dependentchangesinmetabolismcontractilefunctionandischemicsensitivityinheartsfromdb/dbmice[J].Diabetes.2003,52/r/n434-441./r/nIwakuraK,ItoH,IkushimaM,etal.Associationbetweenhypergliycemiaandthe/r/nreflowphenomenoninpatientswithacutemyocardialinfarction[J]JAm/r/nCardiol,2003,41(1):1-7./r/nKurisuS,InoueI,KawagoeT,etal.Diabetesmellitusisassociationwith/r/nsufficientmicrovascularreperfusionfollowingrevascularizationforanterioracutemyocardialinfarction/r/n/r/n[J] 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