糖尿病心肌病發(fā)病機(jī)制及病理改變研究進(jìn)展 - 王靜娜-

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9、blation for hypertrophic cardiomyopathy and the timing of pace-maker implantation J J Interv Cardiol ,2007,20(1:73-76收稿日期:2016-02-17修回日期:2016-03-01糖尿病心肌病發(fā)病機(jī)制及病理改變研究進(jìn)展王靜娜1侯瑞田2史亦男1王?；?綜述金鳳表1審校(1承德醫(yī)學(xué)院附屬醫(yī)院內(nèi)分泌科,河北承德067000;2承德醫(yī)學(xué)院附屬醫(yī)院心內(nèi)科,河北承德067000 摘要長(zhǎng)期糖尿病可引起一種獨(dú)立于高血壓、冠心病等疾病的特異性心肌病變,即糖尿病心肌病。糖尿病心肌病是一種漸進(jìn)性疾病,其

10、發(fā)病機(jī)制尚未完全闡明,高血糖、高血脂、炎癥及心肌舒縮功能障礙等均影響糖尿病心肌病的進(jìn)展?，F(xiàn)對(duì)近幾年糖尿病心肌病的發(fā)病機(jī)制及病理改變最新研究進(jìn)展綜述如下 。 關(guān)鍵詞糖尿病心肌病;發(fā)病機(jī)制; 病理變化 中圖分類號(hào) 5418 文獻(xiàn)標(biāo)志碼 A DOIesearch Progress on Pathogenesis and Pathological Changesof Diabetic CardiomyopathyWANG Jingna 1,HOU uitian 2,SHI Yinan 1,WANG Fuhui 1,JIN Fengbiao 1(1Department of Endocrinology

11、,The Affiliated Hospital of Chengde Medical College ,Chengde 067000,Hebei ,China ;2Department of Cardiology ,The Affiliated Hospital of Chengde Medical College ,Chengde 067000,Hebei ,China AbstractLong-term diabetes can cause diabetic cardiomyopathy (DCM ,a specific form of cardiomyopathy ,independe

12、nt hyperten-sion ,coronary heart disease and other diseasesDCM is a progressive disease and its pathogenesis has not been fully understoodIts progres-sion is affected by high blood sugar ,high cholesterol ,inflammation and myocardial function disorders and many other factorsIn this paper ,the latest

13、 research progress of DCM is summarized as follows in recent yearsKey wordsDiabetic cardiomyopathy ;Pathogenesis ;Pathological changes作者簡(jiǎn)介:王靜娜(1990,在讀碩士,主要從事內(nèi)分泌與代謝性疾病研究。Email :940392589qqcom 通信作者:金鳳表(1965,主任醫(yī)師,教授,主要從事內(nèi)分泌與代謝性疾病研究。Email :hrt65sohucom目前糖尿病已影響超過(guò)全球371億人口,僅2012年全球因糖尿病患者的醫(yī)療保健支出費(fèi)用已超出4 710億美

14、元1。糖尿病通過(guò)3種方式影響心臟:(1冠狀動(dòng)脈疾病;(2心臟自主神經(jīng)病變;(3糖尿病心肌病。前兩種病變已引起臨床醫(yī)生的高度重視,但大多數(shù)醫(yī)生乃至糖尿病專家對(duì)糖尿病心肌病的認(rèn)識(shí)尚不足?，F(xiàn)對(duì)糖尿病心肌病發(fā)病機(jī)制及產(chǎn)生的病理變化的最新研究進(jìn)展進(jìn)行綜述,進(jìn)一步加強(qiáng)對(duì)該病的認(rèn)識(shí)及診斷治療。1糖尿病心肌病的發(fā)病機(jī)制及病理變化11高血糖高血糖在DCM的發(fā)病及病理改變過(guò)程中間起到了關(guān)鍵作用。高血糖能直接使正常心肌細(xì)胞發(fā)生病變,出現(xiàn)細(xì)胞的變性、肥大、纖維化及灶性壞死等;高血糖亦可通過(guò)影響線粒體功能促使程序性細(xì)胞死亡增加2-3。慢性高血糖可直接或間接影響心肌細(xì)胞的功能,使成纖維細(xì)胞和內(nèi)皮細(xì)胞功能受損,導(dǎo)致內(nèi)皮依賴

15、的血管舒張功能異常,細(xì)胞間的連接作用減弱,白細(xì)胞及單核細(xì)胞趨化增強(qiáng);此外,高血糖作用可促使蛋白質(zhì)非酶糖化,糖基化終末產(chǎn)物堆積形成,使毛細(xì)血管基膜增厚以及微血管瘤形成增加,引起程序性細(xì)胞死亡。慢性高血糖亦可通過(guò)腺苷二磷酸聚合酶(PAP誘導(dǎo)程序性細(xì)胞死亡的活性氧化物激活,促進(jìn)電子鏈的傳遞4。PAP通過(guò)介導(dǎo)核糖基化和阻斷磷酸甘油醛脫氫酶,將葡萄糖從糖酵解途徑轉(zhuǎn)移到生化級(jí)聯(lián)反應(yīng),參與高糖誘導(dǎo)的細(xì)胞損害。因心肌細(xì)胞有不可再生性,當(dāng)其程序性細(xì)胞死亡數(shù)量達(dá)到一定程度時(shí),就會(huì)導(dǎo)致心肌重構(gòu)和心力衰竭。12高血脂糖尿病患者存在不同程度的胰島素缺乏或抵抗,因而心肌細(xì)胞幾乎全部通過(guò)脂肪酸氧化供能。當(dāng)脂肪酸氧化增加時(shí),

16、游離脂肪酸和三酰甘油等脂肪顆粒在心肌細(xì)胞內(nèi)聚積增加,從而導(dǎo)致胞漿分布異常而使心臟舒縮功能受到影響5,此種情況反復(fù)、惡化最終導(dǎo)致糖尿病心肌病。研究表明,高脂血癥可直接或間接引起或促進(jìn)糖尿病心肌病的發(fā)生和發(fā)展6。最近調(diào)查顯示2型糖尿病常與肥胖有關(guān),高血脂可導(dǎo)致細(xì)胞脂肪化,甚至死亡,出現(xiàn)心功能不全7。高血脂引起心肌功能障礙的機(jī)制目前尚未研究透徹,但潛在機(jī)制已被證實(shí)。例如,長(zhǎng)鏈脂肪酸可以通過(guò)改變血漿中的磷脂成分和線粒體膜結(jié)構(gòu)從而改變心肌細(xì)胞結(jié)構(gòu)。飽和長(zhǎng)鏈棕櫚酸通過(guò)減少線粒體內(nèi)的陰性磷脂從而誘導(dǎo)大鼠心肌程序性細(xì)胞死亡等8。脂質(zhì)代謝紊亂增加了糖尿病心肌病心功能的改變和能量代謝,是加速糖尿病心肌病發(fā)生、發(fā)展

17、的重要因素。13蛋白激酶C的活化蛋白激酶C(PKC是一種廣泛存在于人體各種組織細(xì)胞中的磷酸化酶,可調(diào)控靶酶激活細(xì)胞質(zhì)中的生化反應(yīng),同時(shí)作用于細(xì)胞核中的轉(zhuǎn)錄因子,參與基因表達(dá)的調(diào)控及細(xì)胞因子和血管活性物質(zhì)的跨膜信號(hào)轉(zhuǎn)導(dǎo)。PKC可產(chǎn)生多方面的作用:(1調(diào)節(jié)基因的表達(dá)和細(xì)胞周期;(2增加白細(xì)胞黏附性及內(nèi)皮對(duì)白細(xì)胞的通透性;(3參與炎癥及免疫應(yīng)答反應(yīng)9-10。高血糖及高游離脂肪酸可增加二酰甘油的產(chǎn)生,從而激活PKC途徑誘導(dǎo)高血糖狀態(tài)下的氧化應(yīng)激。14腎素-血管緊張素系統(tǒng)的激活腎素-血管緊張素系統(tǒng)(AS對(duì)糖尿病患者心功能障礙的進(jìn)程起重要作用11-13。Guleria等11研究表明糖尿病患者AS激活是心臟

18、結(jié)構(gòu)和病理變化發(fā)生發(fā)展的重要機(jī)制。在經(jīng)典和旁路途徑作用下血管緊張素原轉(zhuǎn)變?yōu)檠芫o張素,后者刺激成纖維細(xì)胞及膠原增生,引起心肌重塑,促使心肌間質(zhì)纖維化。研究發(fā)現(xiàn),阿利吉侖、貝那普利和纈沙坦等可通過(guò)抑制AS的不同環(huán)節(jié)對(duì)心臟起到保護(hù)作用14。15細(xì)胞因子作用151腫瘤壞死因子-腫瘤壞死因子-(TNF-可誘導(dǎo)原癌基因c-fox 的mNA表達(dá),促使心肌細(xì)胞產(chǎn)生功能差的蛋白,引起心肌間質(zhì)膠原纖維堆積、間質(zhì)纖維化形成,出現(xiàn)心肌重構(gòu)現(xiàn)象15。TNF-也降低基質(zhì)金屬蛋白酶活性,增加膠原纖維沉積,從而抑制蛋白酶活性16。152胰島素樣生長(zhǎng)因子胰島素樣生長(zhǎng)因子通過(guò)自身受體磷酸化,激活相應(yīng)Bc-1蛋白表達(dá),發(fā)揮抗心肌

19、程序性細(xì)胞死亡的作用。糖尿病心肌病患者中,胰島素樣生長(zhǎng)因子表達(dá)下降,出現(xiàn)心功能受損。153瘦素瘦素是蛋白質(zhì)類激素,參與糖、脂質(zhì)及能量代謝的調(diào)節(jié),使機(jī)體攝食減少,能量釋放增加,并抑制脂肪細(xì)胞的合成作用,進(jìn)而達(dá)到減輕體質(zhì)量效果。瘦素通過(guò)抑制體內(nèi)神經(jīng)肽刺鼠肽基因相關(guān)蛋白的活躍程度17,從而使體內(nèi)另一種荷爾蒙黑色素細(xì)胞的活躍度增強(qiáng)。Vasselli18認(rèn)為,瘦素缺乏或抵抗導(dǎo)致的細(xì)胞營(yíng)養(yǎng)過(guò)剩,可導(dǎo)致細(xì)胞發(fā)生死亡或變性;瘦素在心肌及胰島等非脂肪細(xì)胞大量聚集亦可誘導(dǎo)使其死亡增加,導(dǎo)致糖尿病心肌病發(fā)生。16心肌細(xì)胞鈣調(diào)節(jié)異常糖尿病心肌病患者心功能受損的直接原因即為Ca2+調(diào)節(jié)異常19。造成Ca2+調(diào)節(jié)異常的原

20、因有:(1鈣泵活性降低,促使肌漿網(wǎng)上Ca2+質(zhì)量濃度升高;(2鈣通道磷酸化酶活性降低,促使通道磷酸化時(shí)間延長(zhǎng),導(dǎo)致Ca2+內(nèi)流增加;(3鈉-鈣交換受限,促使Ca2+停留在心肌細(xì)胞上。糖尿病患者血脂水平升高,其中的磷脂和膽固醇是心肌纖維膜的主要成分,當(dāng)磷脂中的溶血磷脂酰膽堿升高時(shí)能促使Ca2+進(jìn)入心肌增多而造成Ca2+超載,使心肌縮舒功能直接受到影響20-21。17自噬自噬是將自身的細(xì)胞器或細(xì)胞質(zhì)蛋白吞噬入囊泡,并在溶酶體的作用下將其降解的過(guò)程22。生理狀態(tài)下,機(jī)體低水平的自噬可將受損細(xì)胞器及異常蛋白質(zhì)吞噬,從而維持心臟的正常功能。通常所講的自噬為巨自噬,由信號(hào)通路介導(dǎo)其發(fā)生。目前已知經(jīng)典的信號(hào)

21、通路是以哺乳動(dòng)物雷帕霉素靶蛋白(mammalian target of rapamycin,mTO為中心的信號(hào)通路。mTO是自噬的負(fù)性調(diào)控因子,可經(jīng)PI3K-Akt通路將其激活,從而抑制自噬的發(fā)生23。胰島素作為信號(hào)因子激活PI3K-Akt/PKB-mTO通路,進(jìn)而抑制自噬24。因此推測(cè)在胰島素缺乏有關(guān)的1型糖尿病心肌病和胰島素抵抗有關(guān)的2型糖尿病心肌病中,心肌細(xì)胞自噬可能會(huì)被激活;但通常情況下,糖尿病心肌病伴有血糖和脂質(zhì)代謝紊亂、高胰島素血癥以及其他信號(hào)通路的改變等亦可作用于心肌細(xì)胞的自噬24。所以,糖尿病心肌病最終表現(xiàn)出的自噬狀態(tài)是多種疾病綜合作用的最終凈表現(xiàn)。18心臟微血管病變糖尿病心肌

22、病也存在微血管病變,這些變化既有毛細(xì)血管基膜增殖或增厚,又有毛細(xì)血管微血管瘤形成等25。糖尿病患者高灌注和血流量的血流動(dòng)力學(xué)狀態(tài)是最終導(dǎo)致微血管病變發(fā)展的關(guān)鍵因素。當(dāng)糖代謝紊亂時(shí),紅細(xì)胞聚集性增強(qiáng),血小板高黏附及抗凝血機(jī)制異常,使微循環(huán)功能障礙,促進(jìn)微血管病變的發(fā)生。已有證據(jù)顯示:高糖高脂毒性及血流狀態(tài)改變等都參與糖尿病心肌病微血管病變的發(fā)生發(fā)展,可引起血管功能及結(jié)構(gòu)改變,使心肌細(xì)胞受損,最終發(fā)展為糖尿病心肌病26。19心臟自主神經(jīng)病變自主神經(jīng)病變?cè)谔悄虿』颊咧蟹浅３Ｒ?受損的自主神經(jīng)系統(tǒng)包括交感神經(jīng)和副交感神經(jīng)系統(tǒng),兩者可單獨(dú)或同時(shí)受累27。當(dāng)交感神經(jīng)系統(tǒng)功能亢進(jìn)時(shí),心肌微血管發(fā)生痙攣,血管

23、普遍狹窄或閉塞,心肌間質(zhì)糖蛋白沉著及心肌纖維變粗,致使心肌發(fā)生彌漫性小灶性壞死;副交感神經(jīng)系統(tǒng)病變時(shí)亦可導(dǎo)致心功能異常27。盡管自主神經(jīng)病變不是糖尿病心肌病的特異性表現(xiàn),但可通過(guò)增加靜息心率和猝死風(fēng)險(xiǎn)而使上述異常加重,從而使病情惡化28。2結(jié)語(yǔ)糖尿病心肌病是長(zhǎng)期糖尿病患者重要但未引起醫(yī)務(wù)工作者廣泛關(guān)注的并發(fā)癥,其發(fā)病機(jī)制及病理過(guò)程尚未完全闡明,長(zhǎng)期糖脂毒性、氧化應(yīng)激、代謝異常、微血管及自主神經(jīng)病變等均可導(dǎo)致糖尿病心肌病的發(fā)生。進(jìn)一步研究糖尿病心肌病的發(fā)病機(jī)制及相應(yīng)病理過(guò)程,了解疾病的發(fā)生發(fā)展過(guò)程,為糖尿病心肌病的治療做好理論基礎(chǔ)準(zhǔn)備。參考文獻(xiàn)1Guariguata LBy the number

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