二甲雙胍降低心房顫動(dòng)發(fā)生風(fēng)險(xiǎn)的研究進(jìn)展

任瑞鳳，孫玉芹，王華亭

二甲雙胍降低心房顫動(dòng)發(fā)生風(fēng)險(xiǎn)的研究進(jìn)展

任瑞鳳1,2，孫玉芹3，王華亭1,2

1.山東大學(xué)齊魯醫(yī)學(xué)院，山東濟(jì)南 250012；2.濟(jì)南市中心醫(yī)院心血管內(nèi)科，山東濟(jì)南 250013；3.濰坊醫(yī)學(xué)院臨床醫(yī)學(xué)院，山東濰坊 261053

二甲雙胍的價(jià)格低廉且安全性高，是目前臨床上應(yīng)用較為廣泛的經(jīng)典降糖藥物。研究發(fā)現(xiàn)，二甲雙胍與降低心房顫動(dòng)的發(fā)生率有關(guān)，其可能是通過減少糖原和脂質(zhì)沉積、激活單磷酸腺苷活化蛋白激酶、改善鈣穩(wěn)態(tài)、減輕炎癥、促進(jìn)縫隙連接蛋白43的表達(dá)、恢復(fù)小電導(dǎo)鈣激活鉀通道電流等，改善左心房的結(jié)構(gòu)重構(gòu)和電學(xué)重構(gòu)，從而降低心房顫動(dòng)的發(fā)生風(fēng)險(xiǎn)。本文對(duì)二甲雙胍降低心房顫動(dòng)發(fā)生風(fēng)險(xiǎn)的研究進(jìn)展進(jìn)行綜述。

二甲雙胍；心房顫動(dòng)；單磷酸腺苷活化蛋白激酶；鈣穩(wěn)態(tài)

1998年，英國(guó)前瞻性糖尿病研究小組證實(shí)，二甲雙胍不僅可降低血糖，其對(duì)心血管系統(tǒng)也有明確的保護(hù)作用[1]。一項(xiàng)Meta分析研究結(jié)果顯示，二甲雙胍可降低心肌梗死和心力衰竭患者的全因病死率[2]。在一項(xiàng)應(yīng)用二甲雙胍治療糖尿病的隨訪研究中發(fā)現(xiàn)，二甲雙胍組患者發(fā)生腦卒中的風(fēng)險(xiǎn)比為0.468，明顯低于對(duì)照組[3]。既往研究認(rèn)為，二甲雙胍通過激活單磷酸腺苷活化蛋白激酶（adenosine monophosphate- activated protein kinase，AMPK）、增加一氧化氮利用度，降低促炎因子表達(dá)水平、減少氧化應(yīng)激和炎癥反應(yīng)、促進(jìn)脂肪酸氧化和葡萄糖轉(zhuǎn)運(yùn)、通過糖酵解途徑提高腺苷三磷酸（adenosine triphosphate，ATP）水平、維持細(xì)胞鈣穩(wěn)態(tài)等，發(fā)揮保護(hù)心臟的作用[4-7]。盡管二甲雙胍對(duì)心血管系統(tǒng)有益，但其對(duì)心律失常的作用機(jī)制尚不明確。心房顫動(dòng)（atrial fibrillation，AF）是臨床上最常見的心律失常疾病，研究二甲雙胍與AF的關(guān)系對(duì)其臨床診治具有重要意義。本文綜述二甲雙胍降低AF發(fā)生風(fēng)險(xiǎn)作用機(jī)制的研究進(jìn)展，為二甲雙胍的臨床應(yīng)用提供理論依據(jù)。

1 二甲雙胍降低AF的發(fā)生風(fēng)險(xiǎn)

AF是臨床上最常見的心律失常疾病，其與腦卒中、外周血管栓塞等發(fā)生風(fēng)險(xiǎn)的增加有關(guān)。據(jù)統(tǒng)計(jì)數(shù)據(jù)估算，全球AF患者總?cè)藬?shù)為3350萬[8]。近年來多項(xiàng)研究結(jié)果提示，二甲雙胍可降低AF的發(fā)生風(fēng)險(xiǎn)。在一項(xiàng)觀察性研究中，利用傾向評(píng)分匹配法評(píng)估服用不同糖尿病藥物的患者發(fā)生心律失常的風(fēng)險(xiǎn)；結(jié)果發(fā)現(xiàn)，與未使用二甲雙胍的患者相比，二甲雙胍單一治療患者發(fā)生心律失常的風(fēng)險(xiǎn)顯著降低；與磺脲類藥物相比，二甲雙胍組患者室性心動(dòng)過速/心室顫動(dòng)的發(fā)生率減少了34%；與二肽基肽酶4抑制劑單一治療相比，二甲雙胍與AF、心房撲動(dòng)或其他室上性心律失常和心動(dòng)過緩的風(fēng)險(xiǎn)顯著降低相關(guān)，發(fā)生率降低約10%；與噻唑烷二酮相比，二甲雙胍可顯著降低AF、心房撲動(dòng)或其他室上性心律失常的發(fā)生風(fēng)險(xiǎn)，其發(fā)生率分別降低14%和9%[9]。在一項(xiàng)隊(duì)列研究中，將645710例新確診為2型糖尿病且未使用過降糖藥物的患者納入研究中，平均隨訪時(shí)間為5.4年；結(jié)果顯示，與安慰劑組相比，二甲雙胍組患者的AF發(fā)生率顯著低于對(duì)照組[10]。Ozcan等[11]利用心臟特異性肝激酶B1基因敲除小鼠模型研究二甲雙胍和阿司匹林一級(jí)預(yù)防AF的效果，結(jié)果顯示，與未處理組小鼠相比，二甲雙胍和阿司匹林治療小鼠的自發(fā)性AF發(fā)生率顯著降低[11]。在2型糖尿病患者的相關(guān)研究中發(fā)現(xiàn)，二甲雙胍與AF的住院風(fēng)險(xiǎn)降低有關(guān)，且具有劑量-反應(yīng)效應(yīng)[12]。二甲雙胍與射頻導(dǎo)管消融術(shù)后再發(fā)房性心律失常風(fēng)險(xiǎn)顯著降低獨(dú)立相關(guān)[13]。Lal等[14]通過篩選確定二甲雙胍是治療AF的潛在藥物。目前，二甲雙胍降低AF發(fā)生風(fēng)險(xiǎn)的機(jī)制尚不明確。

2 二甲雙胍預(yù)防AF的潛在有效機(jī)制

2.1 減少糖原和脂質(zhì)沉積

糖尿病是AF的危險(xiǎn)因素。胰島素抵抗和血糖升高可引起心房結(jié)構(gòu)重構(gòu)和電學(xué)重構(gòu)，進(jìn)一步引起心房擴(kuò)張、間質(zhì)纖維化及心房有效不應(yīng)期（atrium effective refractory period，AERP）縮短，最終導(dǎo)致AF的發(fā)生[15-16]。AF發(fā)生時(shí)能量需求增加，葡萄糖代謝上調(diào)失敗，更依賴于脂肪酸代謝，糖原沉積導(dǎo)致心肌細(xì)胞明顯肥大，使AF持續(xù)存在。二甲雙胍是臨床上治療糖尿病的經(jīng)典用藥；其在不降低正常血糖的基礎(chǔ)上，通過促進(jìn)肌肉等外周組織攝取葡萄糖、促進(jìn)糖酵解、抑制糖異生及改善胰島素抵抗等發(fā)揮作用[17-18]對(duì)非糖尿病犬進(jìn)行快速心房起搏后發(fā)現(xiàn)，左心耳脂質(zhì)沉積的增加與AERP的縮短和分散有關(guān)[19]。研究發(fā)現(xiàn)，二甲雙胍可通過AMPK/過氧化物酶體增殖物激活受體（peroxisome proliferator-activated receptor，PPAR）-α/極長(zhǎng)鏈脂酰輔酶A脫氫酶信號(hào)傳導(dǎo)途徑，促進(jìn)脂肪酸-β氧化，減少脂質(zhì)沉積，改善心房重構(gòu)[20]。另有研究表明，二甲雙胍可通過縮小心外膜脂肪組織體積，降低患者的術(shù)后復(fù)發(fā)率[21]。綜上，二甲雙胍減少糖原和脂質(zhì)沉積，可在一定程度上減緩AF進(jìn)程。

2.2 改善鈣穩(wěn)態(tài)

研究發(fā)現(xiàn)，細(xì)胞內(nèi)鈣穩(wěn)態(tài)異常可導(dǎo)致AF的易感性增加[22-23]。Harada等[24]在AF犬模型的左心房樣本和AF術(shù)后患者的右心房組織樣本中測(cè)定Ca2+的瞬變幅度和細(xì)胞收縮能力，評(píng)估AMPK的磷酸化水平及AMPK與鈣離子轉(zhuǎn)運(yùn)蛋白的關(guān)系；研究發(fā)現(xiàn)，AMPK的激活有助于維持L型鈣通道電流、Ca2+瞬變幅度、肌質(zhì)網(wǎng)Ca2+含量和細(xì)胞收縮能力。二甲雙胍可增加AMPK的表達(dá)水平，推測(cè)其可能通過AMPK途徑維持鈣穩(wěn)態(tài)，從而減少AF的發(fā)生[19]。

2.3 促進(jìn)縫隙連接蛋白43（connexin 43，Cx43）的表達(dá)

Cx43是心臟連接蛋白的重要成員之一，可介導(dǎo)心肌細(xì)胞間的電偶合，參與相鄰細(xì)胞間的離子交換，從而調(diào)控細(xì)胞間通訊[25]。研究發(fā)現(xiàn)，Cx43在改善細(xì)胞內(nèi)電傳導(dǎo)、抑制心律失常中起關(guān)鍵作用，可預(yù)防AF的發(fā)生[26-27]。研究證實(shí)，二甲雙胍可激活A(yù)MPK[28]。研究表明，在新生大鼠的心肌細(xì)胞中，二甲雙胍通過激活A(yù)MPK，促進(jìn)Cx43和緊密連接蛋白-1的表達(dá)，抑制AERP的縮短，改善AERP的離散度[20]。同時(shí)，AMPK磷酸化可通過促進(jìn)大鼠心肌細(xì)胞中ATP敏感鉀離子通道（KATP）的開放，抑制細(xì)胞間隙通透性，增加Cx43的表達(dá)，從而減少房性心律失常的發(fā)生[29-30]。

2.4 減少氧化應(yīng)激和炎癥反應(yīng)

AF的發(fā)生與氧化應(yīng)激和炎癥反應(yīng)密切相關(guān)[31]。非糖尿病小鼠AF模型研究發(fā)現(xiàn)，二甲雙胍可通過抑制還原型煙酰胺腺嘌呤二核苷酸磷酸氧化酶，減少細(xì)胞內(nèi)活性氧的表達(dá)，抑制心房中成纖維細(xì)胞分化，從而改善心房重構(gòu)[10,32]。AF涉及炎癥過程，心外膜脂肪組織分泌的脂肪因子可誘導(dǎo)炎癥反應(yīng)，促進(jìn)AF的發(fā)生[21]。二甲雙胍可影響心外膜脂肪組織的積累、脂肪的生成和脂肪細(xì)胞的功能，包括脂肪因子的產(chǎn)生和釋放[33]。研究表明，快速心房起搏可促進(jìn)細(xì)胞內(nèi)活性氧和核因子κB的磷酸化，上調(diào)心房和心外膜脂肪組織中白細(xì)胞介素-6、腫瘤壞死因子-α和轉(zhuǎn)化生長(zhǎng)因子-β1的水平，抑制PPARγ和脂聯(lián)素的表達(dá)，并伴有心房纖維化和脂肪浸潤(rùn)；上述因子的表達(dá)在給予二甲雙胍后出現(xiàn)逆轉(zhuǎn)，氧化應(yīng)激和炎癥反應(yīng)減少，從而降低心房纖維化和AF的發(fā)生[34]。

2.5 恢復(fù)小電導(dǎo)鈣激活鉀通道（small conductance calcium-activatedpotassium channels，SK通道）電流

SK通道是一類對(duì)膜電位變化不敏感，而對(duì)細(xì)胞內(nèi)Ca2+濃度變化較為敏感的鉀離子通道蛋白，其在心臟中廣泛存在，可影響動(dòng)作電位時(shí)程。SK通道在心房肌細(xì)胞和起搏細(xì)胞中高度表達(dá)[35]。SK通道包括SK1（KCNN1基因編碼的KCa2.1）、SK2（KCNN2基因編碼的KCa2.2）和SK3（KCNN3基因編碼的KCa2.3）；KCNN2和KCNN3基因與孤立性AF存在關(guān)聯(lián)[36-37]。研究證實(shí)，SK2基因敲除小鼠的心房動(dòng)作電位時(shí)程顯著延長(zhǎng)，SK2、SK3過表達(dá)小鼠動(dòng)作電位時(shí)程縮短、放電頻率增加，SK通道的過表達(dá)可增加AF的易感性，易誘發(fā)房性心律失常[38-39]。二甲雙胍的長(zhǎng)期使用可通過蛋白激酶C/胞外信號(hào)調(diào)節(jié)激酶途徑，抑制SK2的下調(diào)和SK3的上調(diào)[40]。Fu等[41]研究證實(shí)，糖尿病大鼠SK2的表達(dá)減少，SK3的表達(dá)增加，SK總體電流減少，電流-電壓關(guān)系扭曲，導(dǎo)致動(dòng)作電位時(shí)程延長(zhǎng)并出現(xiàn)隨后的房性心律失常；經(jīng)二甲雙胍治療3個(gè)月后，SK2的表達(dá)增加，SK3的表達(dá)減少，SK的總體電流增加，正常的電流-電壓關(guān)系得以恢復(fù)，動(dòng)作電位時(shí)程正常化，從而減少房性心律失常的發(fā)生。SK通道參與糖尿病條件下心律失常的進(jìn)展過程，二甲雙胍對(duì)心房電生理有潛在益處，其可能成為房性心律失常治療的新靶點(diǎn)。

2.6 激活A(yù)MPK

二甲雙胍是已知的AMPK激活劑，可通過酪氨酸蛋白激酶/磷脂酰肌醇3激酶途徑激活A(yù)MPK，或通過抑制線粒體復(fù)合體激活A(yù)MPK[7,18]；也可通過維持胰島素/葡萄糖穩(wěn)態(tài)，調(diào)控AMPK信號(hào)通路。Harada等[24]研究發(fā)現(xiàn)，AF相關(guān)的代謝應(yīng)激使心房的收縮功能和Ca2+的處理能力下降；同時(shí)，AF能量需求增加可激活A(yù)MPK；AMPK磷酸化比例在陣發(fā)性AF患者中較高，在持續(xù)性AF患者中較低，且AMPK磷酸化活性的降低使AF患者心律失常狀態(tài)持續(xù)存在并出現(xiàn)治療抵抗。推測(cè)AMPK激活可能有助于延緩AF進(jìn)程，幫助將陣發(fā)性AF和持續(xù)性AF轉(zhuǎn)復(fù)為竇性心律。代謝正常的豬缺血再灌注損傷模型研究發(fā)現(xiàn)，酸中毒、腺苷二磷酸的積累和ATP的消耗會(huì)引起心臟KATP開放，導(dǎo)致動(dòng)作電位縮短；二甲雙胍可通過激活A(yù)MPK，增加ATP濃度，進(jìn)而抑制KATP的開放[42]。AMPK的磷酸化可增加Cx43的表達(dá)，進(jìn)而減少房性心律失常的發(fā)生[30]。綜上，無論患者是否存在代謝異常，二甲雙胍的臨床治療均可獲得明顯的心血管益處，AMPK可能是治療AF的新靶點(diǎn)。

此外，二甲雙胍不會(huì)增加低血糖風(fēng)險(xiǎn)，可減少因低血糖導(dǎo)致的AF；也可通過調(diào)節(jié)微RNA-1，改善心臟傳導(dǎo)延遲[43-44]。然而，二甲雙胍在抗心律失常的同時(shí)，可導(dǎo)致心律失常。二甲雙胍的使用和維生素B12的缺乏具有顯著相關(guān)性[45]。二甲雙胍可能通過干擾內(nèi)在因子維生素B12復(fù)合物與回腸末端相應(yīng)受體的結(jié)合，阻礙維生素B12的吸收。維生素B12的缺乏可引起或加速心臟去神經(jīng)等自主神經(jīng)病變，這與心律失常有關(guān)。

3 小結(jié)與展望

二甲雙胍被列為一線降糖藥物，其可控制血糖，亦具有降低AF和其他心律失常疾病發(fā)生的作用，但作用機(jī)制尚未完全明確。二甲雙胍預(yù)防AF的有效性值得在糖尿病患者和非糖尿病患者中進(jìn)行更深入的研究。AMPK是干預(yù)AF病程進(jìn)展的新靶點(diǎn)。未來可著眼于二甲雙胍激活A(yù)MPK、減少AF發(fā)生的具體機(jī)制及相關(guān)影響因素，并通過進(jìn)一步的動(dòng)物和臨床研究進(jìn)行不斷探索。

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（2022–12–21）

（2022–12–28）

R541

A

10.3969/j.issn.1673-9701.2023.29.033

王華亭，電子信箱：wanghuating65@163.com