钙离子调节异常对心房颤动影响的研究进展



钙离子调节异常对心房颤动影响的研究进展

作者单位:646000 四川 泸州，泸州医学院附属医院心内科

吴鹏，刘星，范忠才

[关键词]钙离子；异常调节；心房颤动；异位激动；折返；综述

房颤(atrial fibrillation，AF)是临床上最常见的心律失常之一。据初步估计，全世界AF患者已超过3300万人[1]。随着人口老龄化的到来，它将成为一个更加普遍性的医学和社会问题[2]。AF是中风和心力衰竭的重要危险因素，其发病率与致死率密切相关[3]。目前，用于恢复AF患者窦性心律的药物主要包括Ⅰ类和Ⅲ类抗心律失常药物，但是其疗效差强人意。在>1年的随访中，窦性心律的维持率仅为30%~70%[4]。而且，这些药物同时也存在致心律失常和心外毒副作用等不良反应[5-6]，其安全性也限制了其使用。因此，更好地认识AF的病理生理机制，寻找新的治疗靶向，对提高抗心律失常治疗效果非常重要[7]。越来越多的证据显示：异常的钙离子(Ca2+)调节是AF发病机制的中心环节[8-10]。本文主要总结近年来有关Ca2+异常调节在AF发病机制中的研究进展，为进一步深入探讨AF的发病机制和寻找更为有效的治疗提供新的思路。

1正常心房肌细胞的结构特性

包括人在内的哺乳动物的心室肌细胞拥有为数众多的发达的T管系统。但是，与心室肌细胞相比，心房肌细胞的T管系统明显减少。这种心房和心室心肌细胞间结构的差异，可能是心房肌细胞Ca2+调节独特的原因[11-13]。虽然人类心房心肌细胞的T管结构较少，但是也存在分布差异，而且在心脏疾病(包括房颤)中存在重构的现象[12,14]。

2正常心房肌细胞的电生理特点

心房肌细胞的动作电位(AP)是由去极化和复极化离子电流决定。其中，超快激活延迟整流K+电流(IKur)和乙酰胆碱敏感K+电流(IK,ACh)在心房肌细胞表达显著[15]。心肌细胞膜去极化引起电压依赖性L型Ca2+通道开放，少量Ca2+内流进入胞浆，激发肌浆网(sarcoplasmic reticulum,SR)2型Ryanodine受体通道(RyR2)开放，引起Ca2+的大量释放，该过程称为钙诱导的钙释放(CICR)，从而促进心房肌细胞的收缩[16-17]。近年来的研究发现，三磷酸肌醇(IP3)受体不但可直接激活钠-钙交换体1(NCX1)，而且可以激活邻近RyR2，诱导Ca2+的释放[8,18]。

3心房颤动与RyR2的异常Ca2+释放

AF的发生是电冲动形成或者传导异常的结果[19-20]。在窦房结以外的电冲动的产生被称为异位电活动，它可以驱动AF发生，也可以在有效不应期缩短、缓慢和不均一传导的不稳定基质中形成折返激动。而这种不稳定基质的形成可能与遗传背景以及老化有关，也可能与心力衰竭、高血压等疾病相关[20]。折返激动可以在解剖或者功能异常的情况下发生，它也被认为是AF维持的主要机制。一旦AF持续，心房心动过速相关的电重构和结构重构可进一步促进AF的持续和稳定，最终可导致更加难以治疗的持续性AF的形成。

细胞水平的异位激动机制主要包括早后去极化(EADs)和迟后去极化(DADs)。当APD过度延长，失活的Ca2+通道可重新恢复开放，导致Ca2+内流产生EADs；当EADs足够大，便可产生新的动作电位，触发心律失常[21]。在房性心律失常的形成过程中，DADs起着重要的作用，这与舒张期Ca2+在肌浆网RyR2的异常释放密切相关[22]。当舒张期产生过量的Ca2+，就可以激活细胞膜上的钠钙交换体(NCX)，这将促进Ca2+-3Na+的交换，从而产生瞬时内向电流(Iti)，导致DADs；如果这个产生的DADs足够大，达到阈值便可产生异位激动，而反复出现的DADs则会导致房性心动过速。

SR的钙超载或者RyR2功能紊乱均可导致肌浆网内Ca2+的释放。RyR2的功能是通过通道磷酸化来调节的，RyR2的过度磷酸化可致Ca2+异常释放和心律失常[23]。RyR2磷酸化后可以增加它的Ca2+敏感性，增强通道开放的概率[24]。FK506结合蛋白12.6是RyR2的抑制物，当其缺失时可明显增加大鼠心房肌细胞SR Ca2+释放和触发激动，进而易发展为AF；在获得性RyR2基因突变的大鼠，也有相同的发现[24-25]。系列研究发现，蛋白激酶A(PKA)磷酸化RyR2第2808位点的丝氨酸后，以及Ca2+/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)或β1肾上腺受体激动剂cAMP2(Epac2)磷酸化RyR2第2814位点的丝氨酸后，均可以促进肌浆网内Ca2+的释放，从而增加AF的发生率[24,26-28]。

CaMKⅡ参与的RyR2过度磷酸化和相关的Ca2+异常调节是促发AF的最重要因素之一[22]。以往研究发现，CaMKⅡ的活性是通过Ca2+和钙调蛋白复合物激活[26]。但是，近年来的研究证实，钙调蛋白也可以直接调节RyR2，稳定SR Ca2+释放[29]。有研究发现，在AF发生后，不但总的钙调蛋白水平增加[30]，而且CaMKⅡ氧化也随之增加[31]。血管紧张素除可以促进结构的重构与AF的发生相关外，研究还发现其也可氧化CaMKⅡ，并增强CaMKⅡ对RyR2磷酸化作用促进AF的形成[32]。

有研究发现，RyR2表达与RyR2单通道开放概率在阵发性AF(pAF)患者中是增加的，同时伴随SR Ca2+的负荷增加，可能与PKA依赖的肌浆网受磷蛋白(PLB)过度磷酸化有关[33]，因为PLB过度磷酸化可以导致Ca2+超载，诱导RyR2的功能障碍。移除肌浆网Ca2+-ATP酶(SERCA)的PLB抑制物，可以增强SR对Ca2+的摄取。增强PKA和/或CaMKⅡ的活性，或增加碱性磷酸酶抑制蛋白的活性，都能减少碱性磷酸酶的作用，促进肌浆网PLB的过度磷酸化[22,34]。

在许多AF相关的研究中，可以很普遍地观察到存在NCX表达增强，舒张期SR Ca2+释放增多，导致Iti的产生[12,26,34]，增加了DADs和触发激动的风险[22]。有证据显示，使用β肾上腺受体激动剂后，CaMKⅡ可以使NCX1的转录上调[35]，使NCX1表达增加，可能与AF的发生相关。IP3受体(IP3R2)也参与了Ca2+的转运，促进了心律失常SR Ca2+的释放[36]，可能导致AF相关的触发激动[37]。

4房颤治疗新靶点的研究进展

大量研究表明，Ca2+异常调节在AF发病机制中起着重要的作用，提示其将是一个有价值的治疗心律失常的新靶点。RyR2的稳定化治疗，可以作为抑制Ca2+异常释放，有效控制心律失常的新方法。目前几种有效的抗心律失常药物，包括Ic类Na+通道阻滞剂(氟卡尼)[38]、β肾上腺受体阻滞剂(卡维地洛)[39]和抗心绞痛治疗药物(雷诺嗪)[40]，都可以结合或者抑制RyR2通道，可能是其治疗AF有效性的原因之一。已有研究证实，氟卡尼成功用于与Ca2+异常释放有关的儿茶酚胺敏感性多形性室速(CPVT)的治疗[41]。而且，氟卡尼也可以抑制心房细胞IK,ACh[42]，可能对AF治疗有效。CaMKⅡ抑制剂或者抑制RyR2依赖CaMKⅡ的磷酸化，已经被证实在AF老鼠模型具有抗心律失常作用，并且在慢性AF患者心房肌细胞实验中显示了有利的影响[9,24,43]。但是，CaMKⅡ在许多生理过程中均有重要的作用，广泛的CaMKⅡ抑制可能出现各种各样的副作用，包括生育能力下降和记忆障碍等[44-45]。近年来还有研究显示，145微小RNA和30b-5p微小RNA可以抑制CaMKⅡδ的表达[46-47]。因此，增加这些微小RNA在心脏的水平，或许能选择性抑制CaMKⅡ，从而可能是AF治疗的新策略。

总之，Ca2+的调节异常不但促进异位激动产生导致AF，而且促成折返形成导致AF维持。目前抗心律失常药物治疗AF仅有有限的疗效和安全性。更好地了解这些AF调节的机制对改进治疗策略，提高疗效，减少副作用至关重要。Ca2+的调节异常为治疗AF提供了一个潜在的新颖的治疗靶点。然而，临床AF的发生和发展是多种病因和复杂机制调控的结果，不同发病机制和调控机制导致的AF，必须采用针对性的个体化治疗。抑制心脏舒张期Ca2+异常释放的特异性药物，有可能成为特定AF患者的治疗策略。

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(收稿日期:2014-08-30)

文章编号1004-0188(2015)01-0107-04

doi:10.3969/j.issn.1004-0188.2015.01.046

中图分类号R 541.75

文献标识码A

通讯作者:范忠才，E-mail：wpflying@163.com