鈣離子調節(jié)異常對心房顫動影響的研究進展

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鈣離子調節(jié)異常對心房顫動影響的研究進展

作者單位:646000 四川 瀘州，瀘州醫(yī)學院附屬醫(yī)院心內科

吳鵬，劉星，范忠才

[關鍵詞]鈣離子；異常調節(jié)；心房顫動；異位激動；折返；綜述

房顫(atrial fibrillation，AF)是臨床上最常見的心律失常之一。據(jù)初步估計，全世界AF患者已超過3300萬人[1]。隨著人口老齡化的到來，它將成為一個更加普遍性的醫(yī)學和社會問題[2]。AF是中風和心力衰竭的重要危險因素，其發(fā)病率與致死率密切相關[3]。目前，用于恢復AF患者竇性心律的藥物主要包括Ⅰ類和Ⅲ類抗心律失常藥物，但是其療效差強人意。在>1年的隨訪中，竇性心律的維持率僅為30%~70%[4]。而且，這些藥物同時也存在致心律失常和心外毒副作用等不良反應[5-6]，其安全性也限制了其使用。因此，更好地認識AF的病理生理機制，尋找新的治療靶向，對提高抗心律失常治療效果非常重要[7]。越來越多的證據(jù)顯示：異常的鈣離子(Ca2+)調節(jié)是AF發(fā)病機制的中心環(huán)節(jié)[8-10]。本文主要總結近年來有關Ca2+異常調節(jié)在AF發(fā)病機制中的研究進展，為進一步深入探討AF的發(fā)病機制和尋找更為有效的治療提供新的思路。

1正常心房肌細胞的結構特性

包括人在內的哺乳動物的心室肌細胞擁有為數(shù)眾多的發(fā)達的T管系統(tǒng)。但是，與心室肌細胞相比，心房肌細胞的T管系統(tǒng)明顯減少。這種心房和心室心肌細胞間結構的差異，可能是心房肌細胞Ca2+調節(jié)獨特的原因[11-13]。雖然人類心房心肌細胞的T管結構較少，但是也存在分布差異，而且在心臟疾病(包括房顫)中存在重構的現(xiàn)象[12,14]。

2正常心房肌細胞的電生理特點

心房肌細胞的動作電位(AP)是由去極化和復極化離子電流決定。其中，超快激活延遲整流K+電流(IKur)和乙酰膽堿敏感K+電流(IK,ACh)在心房肌細胞表達顯著[15]。心肌細胞膜去極化引起電壓依賴性L型Ca2+通道開放，少量Ca2+內流進入胞漿，激發(fā)肌漿網(sarcoplasmic reticulum,SR)2型Ryanodine受體通道(RyR2)開放，引起Ca2+的大量釋放，該過程稱為鈣誘導的鈣釋放(CICR)，從而促進心房肌細胞的收縮[16-17]。近年來的研究發(fā)現(xiàn)，三磷酸肌醇(IP3)受體不但可直接激活鈉-鈣交換體1(NCX1)，而且可以激活鄰近RyR2，誘導Ca2+的釋放[8,18]。

3心房顫動與RyR2的異常Ca2+釋放

AF的發(fā)生是電沖動形成或者傳導異常的結果[19-20]。在竇房結以外的電沖動的產生被稱為異位電活動，它可以驅動AF發(fā)生，也可以在有效不應期縮短、緩慢和不均一傳導的不穩(wěn)定基質中形成折返激動。而這種不穩(wěn)定基質的形成可能與遺傳背景以及老化有關，也可能與心力衰竭、高血壓等疾病相關[20]。折返激動可以在解剖或者功能異常的情況下發(fā)生，它也被認為是AF維持的主要機制。一旦AF持續(xù)，心房心動過速相關的電重構和結構重構可進一步促進AF的持續(xù)和穩(wěn)定，最終可導致更加難以治療的持續(xù)性AF的形成。

細胞水平的異位激動機制主要包括早后去極化(EADs)和遲后去極化(DADs)。當APD過度延長，失活的Ca2+通道可重新恢復開放，導致Ca2+內流產生EADs；當EADs足夠大，便可產生新的動作電位，觸發(fā)心律失常[21]。在房性心律失常的形成過程中，DADs起著重要的作用，這與舒張期Ca2+在肌漿網RyR2的異常釋放密切相關[22]。當舒張期產生過量的Ca2+，就可以激活細胞膜上的鈉鈣交換體(NCX)，這將促進Ca2+-3Na+的交換，從而產生瞬時內向電流(Iti)，導致DADs；如果這個產生的DADs足夠大，達到閾值便可產生異位激動，而反復出現(xiàn)的DADs則會導致房性心動過速。

SR的鈣超載或者RyR2功能紊亂均可導致肌漿網內Ca2+的釋放。RyR2的功能是通過通道磷酸化來調節(jié)的，RyR2的過度磷酸化可致Ca2+異常釋放和心律失常[23]。RyR2磷酸化后可以增加它的Ca2+敏感性，增強通道開放的概率[24]。FK506結合蛋白12.6是RyR2的抑制物，當其缺失時可明顯增加大鼠心房肌細胞SR Ca2+釋放和觸發(fā)激動，進而易發(fā)展為AF；在獲得性RyR2基因突變的大鼠，也有相同的發(fā)現(xiàn)[24-25]。系列研究發(fā)現(xiàn)，蛋白激酶A(PKA)磷酸化RyR2第2808位點的絲氨酸后，以及Ca2+/鈣調蛋白依賴性蛋白激酶Ⅱ(CaMKⅡ)或β1腎上腺受體激動劑cAMP2(Epac2)磷酸化RyR2第2814位點的絲氨酸后，均可以促進肌漿網內Ca2+的釋放，從而增加AF的發(fā)生率[24,26-28]。

CaMKⅡ參與的RyR2過度磷酸化和相關的Ca2+異常調節(jié)是促發(fā)AF的最重要因素之一[22]。以往研究發(fā)現(xiàn)，CaMKⅡ的活性是通過Ca2+和鈣調蛋白復合物激活[26]。但是，近年來的研究證實，鈣調蛋白也可以直接調節(jié)RyR2，穩(wěn)定SR Ca2+釋放[29]。有研究發(fā)現(xiàn)，在AF發(fā)生后，不但總的鈣調蛋白水平增加[30]，而且CaMKⅡ氧化也隨之增加[31]。血管緊張素除可以促進結構的重構與AF的發(fā)生相關外，研究還發(fā)現(xiàn)其也可氧化CaMKⅡ，并增強CaMKⅡ對RyR2磷酸化作用促進AF的形成[32]。

有研究發(fā)現(xiàn)，RyR2表達與RyR2單通道開放概率在陣發(fā)性AF(pAF)患者中是增加的，同時伴隨SR Ca2+的負荷增加，可能與PKA依賴的肌漿網受磷蛋白(PLB)過度磷酸化有關[33]，因為PLB過度磷酸化可以導致Ca2+超載，誘導RyR2的功能障礙。移除肌漿網Ca2+-ATP酶(SERCA)的PLB抑制物，可以增強SR對Ca2+的攝取。增強PKA和/或CaMKⅡ的活性，或增加堿性磷酸酶抑制蛋白的活性，都能減少堿性磷酸酶的作用，促進肌漿網PLB的過度磷酸化[22,34]。

在許多AF相關的研究中，可以很普遍地觀察到存在NCX表達增強，舒張期SR Ca2+釋放增多，導致Iti的產生[12,26,34]，增加了DADs和觸發(fā)激動的風險[22]。有證據(jù)顯示，使用β腎上腺受體激動劑后，CaMKⅡ可以使NCX1的轉錄上調[35]，使NCX1表達增加，可能與AF的發(fā)生相關。IP3受體(IP3R2)也參與了Ca2+的轉運，促進了心律失常SR Ca2+的釋放[36]，可能導致AF相關的觸發(fā)激動[37]。

4房顫治療新靶點的研究進展

大量研究表明，Ca2+異常調節(jié)在AF發(fā)病機制中起著重要的作用，提示其將是一個有價值的治療心律失常的新靶點。RyR2的穩(wěn)定化治療，可以作為抑制Ca2+異常釋放，有效控制心律失常的新方法。目前幾種有效的抗心律失常藥物，包括Ic類Na+通道阻滯劑(氟卡尼)[38]、β腎上腺受體阻滯劑(卡維地洛)[39]和抗心絞痛治療藥物(雷諾嗪)[40]，都可以結合或者抑制RyR2通道，可能是其治療AF有效性的原因之一。已有研究證實，氟卡尼成功用于與Ca2+異常釋放有關的兒茶酚胺敏感性多形性室速(CPVT)的治療[41]。而且，氟卡尼也可以抑制心房細胞IK,ACh[42]，可能對AF治療有效。CaMKⅡ抑制劑或者抑制RyR2依賴CaMKⅡ的磷酸化，已經被證實在AF老鼠模型具有抗心律失常作用，并且在慢性AF患者心房肌細胞實驗中顯示了有利的影響[9,24,43]。但是，CaMKⅡ在許多生理過程中均有重要的作用，廣泛的CaMKⅡ抑制可能出現(xiàn)各種各樣的副作用，包括生育能力下降和記憶障礙等[44-45]。近年來還有研究顯示，145微小RNA和30b-5p微小RNA可以抑制CaMKⅡδ的表達[46-47]。因此，增加這些微小RNA在心臟的水平，或許能選擇性抑制CaMKⅡ，從而可能是AF治療的新策略。

總之，Ca2+的調節(jié)異常不但促進異位激動產生導致AF，而且促成折返形成導致AF維持。目前抗心律失常藥物治療AF僅有有限的療效和安全性。更好地了解這些AF調節(jié)的機制對改進治療策略，提高療效，減少副作用至關重要。Ca2+的調節(jié)異常為治療AF提供了一個潛在的新穎的治療靶點。然而，臨床AF的發(fā)生和發(fā)展是多種病因和復雜機制調控的結果，不同發(fā)病機制和調控機制導致的AF，必須采用針對性的個體化治療。抑制心臟舒張期Ca2+異常釋放的特異性藥物，有可能成為特定AF患者的治療策略。

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(收稿日期:2014-08-30)

文章編號1004-0188(2015)01-0107-04

doi:10.3969/j.issn.1004-0188.2015.01.046

中圖分類號R 541.75

文獻標識碼A

通訊作者:范忠才，E-mail：wpflying@163.com