二叶式主动脉瓣畸形的发病机制及并发症的研究进展



·综述·

二叶式主动脉瓣畸形的发病机制及并发症的研究进展

宫霞吴卫华

(上海市胸科医院超声科，上海200030)

Progress in Research on the Pathogenesis and Complications of Bicuspid Aortic Valve

GONGXiaWUWeihuaDepartmentofUltrasound,ShanghaiChestHospital,Shanghai200030，China

主动脉瓣二叶式畸形(bicuspid aortic valve, BAV)是最常见的先天性心脏病，发病率为1%~2%；男性发病率高于女性，男女性发病比例为 2∶1~4∶1[1-4]。BAV患者常出现主动脉瓣反流、主动脉瓣狭窄、主动脉扩张、主动脉瘤、主动脉夹层、血栓形成和感染性心内膜炎等并发症[5-6]。目前该病的诊断和治疗方法已经明确，但其发病机制尚未完全清楚。近年来，随着对BAV研究的不断深入及分子生物学的发展，其发病机制的研究也有进展。

1BAV分类

典型的 BAV 由两个不等大的瓣叶构成，其中以右冠瓣与左冠瓣融合形成前后两个瓣叶(L-R型)最常见，称为典型融合，占70%；其次是右冠窦和无冠窦瓣尖融合形成左右两个瓣叶(R-N型)，称为非典型融合，占10%~20%；左冠窦和无冠窦瓣融合(L-N型)最少见，占5%~10%[7]；罕见瓣叶对称或无‘脊’形成，即“真二瓣化”。

2BAV的基因遗传学研究

研究[8]表明，BAV具有家族聚集性，但是决定其发病的基因有多种。Martin 等[9]发现， BAV 的发病相关基因定位于染色体5q、13q 和 18q 区域。目前发现与BAV有关的基因有以下几种。

2.1Notch1基因上皮间质细胞转化 (epithelial-mesenchymal transition，EMT) 是心脏瓣膜早期发育的重要事件。房室管形成后，一部分房室管心内膜细胞发生EMT，形成心脏瓣膜。Notch1位点突变或其表达被长寿基因SirT1抑制可致房室管心内膜细胞EMT异常，形成BAV[10]。

2.2泛素融合降解1样基因(ubiquitin fusion degradation 1-like gene，UFD1L)UFD1L定位于人类 22 号染色体，是一种酵母基因同源物，高度保守，参与泛素蛋白降解[11]。UFD1L 基因在胚胎时期的心脏流出道中高度表达。Mohamed等[12]通过对比测定BAV患者和三叶主动脉瓣患者的瓣膜标本中UFD1L的表达量，认为该基因的表达下调与BAV的产生有关。

2.3eNOS 基因内皮源性一氧化氮(eNOS)在胚胎期肢体脉管系统形成以及发育期后，在血管重建和血管发生中均起作用。Lee 等[13]报告， 12 只 eNOS 基因敲除型小鼠中有 5 只主动脉瓣为二叶瓣，而26只野生型小鼠的主动脉瓣均为三叶瓣，表明 BAV 的发生与 eNOS 基因缺失相关。研究[14]发现，BAV 患者主动脉壁 eNOS 蛋白表达量较主动脉瓣三叶者显著降低，且 BAV 患者中 eNOS 蛋白的表达量与升主动脉内径呈负相关。

2.4ACTA2 基因Guo 等[15]的研究发现，编码α肌动蛋白的ACTA2基因突变与家族性胸主动脉瘤和 BAV 发生相关。

2.5GATA5基因人类GATA5基因定位于20q13.33，编码一种由397个氨基酸组成的转录因子，在心脏发育期间调节多个靶基因的表达，包括心房利钠肽、α-肌凝蛋白重链、β-肌凝蛋白重链、心肌肌钙蛋白C和心肌肌钙蛋白I等的基因[16]。Padang等[17]对100例无血缘关系的BAV患者的GATA5基因的编码外显子和其两侧的部分内含子进行了测序分析，结果在4例患者发现了4种 GATA5 基因错义突变。Laforest等[18]研究发现，在小鼠中，GATA5基因敲除或心内膜细胞GATA5特异性失活均可导致BAV，外显率达25%。

3基质金属蛋白酶(matrix metalloproteinases, MMPs )与BAV

MMPs是一类活性依赖于锌离子和钙离子的蛋白水解酶，主要作用是降解细胞外基质(extracellular matrix, ECM)。多个研究表明[19-21]，在合并升主动脉瘤的 BAV 患者的主动脉中，MMPs 的活性及表达均较主动脉瓣叶正常的主动脉瘤患者高。根据底物及片段同源性，将 MMPs 分为 4 类，其中在升主动脉中表达最多的是 MMP-2 和MMP-9，它们参与Ⅳ胶原及部分弹力蛋白、纤维胶原的降解。多种细胞可参与合成MMP-2 和 MMP-9，包括血管平滑肌细胞(vascular smooth muscle cells,VSMCs)。正常的主动脉支撑和弹性结构由相互交替的弹力纤维层和主动脉中层VSMCs组成，而BAV 患者可能由于主动脉纤维蛋白原异常，且伴有MMPs 局部骤增，以致细胞外基质完整性被破坏和VSMCs 凋亡，进而破坏了主动脉结构的完整性和弹性。 金 属 蛋 白 酶 组 织 抑 制 因 子 ( tissue inhibitors of metalloproteinases, TIMPs)通过与 MMPs 形成复合体特异性地抑制 MMPs 的活性，其中，TIMP-1 主要抑制MMP-2 和 MMP-9；TIMP-1 主要由 VSMCs 和成纤维细胞分泌，在主动脉中表达最为常见[22]。Ikonomidis 等[21]研究发现，来源于 BAV 合并升主动脉瘤患者的主动脉壁标本中MMP-2 表达上调，MMP-2/TIMP-1 比值上升；而来源于正常主动脉瓣叶的升主动脉瘤患者的主动脉壁标本中， MMP-13 表达上调，MMP-2 表达下降。蛋白激酶 C 是 MMPs 的刺激调节因子，Jones等[23]研究发现，BAV 和主动脉瓣三叶合并升主动脉瘤患者均有不同的蛋白激酶C亚型上调。

4其他因子与BAV

Paloschi等[24]研究发现，BAV患者的转化生长因子-β(transforming growth factor-β，TGF-β)异常导致外异蛋白A(EDA)的表达减少，从而引起BAV患者并发动脉瘤等。研究[25]发现，microRNAs (miRNAs)的表达异常与BAV患者的瓣膜钙化和瓣膜狭窄有一定关系。

5BAV的常见并发症

5.1主动脉扩张BAV存在升主动脉的扩张。在不考虑体表面积的前提下，升主动脉内径超过40 mm为扩张；若考虑体表面积，身材矮小的人群超过27.5 mm/m2为扩张[26-28]。BAV患者较主动脉瓣叶正常人群更易发生主动脉扩张[29]，但其发病率不详。不同种族的BAV患者发生主动脉扩张的程度不同[30]。不同类型的BAV会引起不同部位的主动脉扩张[31]，比如右冠瓣与左冠瓣融合(L-R型)中，升主动脉扩张最常见，主动脉根部的扩张也会发生；右冠瓣与无冠瓣融合(L-N型)中，仅发生升主动脉的扩张，主动脉根部扩张少见。BAV主动脉扩张的速度平均为0.5 mm/年，类似马凡氏综合征[32]；瓣膜功能正常的BAV患者，主动脉扩张的速度约 0.77 mm/年[33]。BAV患者主动脉扩张常从幼年开始，呈进行性发展。相比主动脉瓣叶正常的同龄人群，先天性BAV儿童升主动脉管径较粗，且以更快的速度扩张[5]。据报道，管状升主动脉扩张的发病率随年龄增长而增加，<30 岁、30~39 岁、40~49 岁、50~60 岁和>60 岁5组的发病率分别为 56%、74%、85%、91% 和 88%[34]。BAV患者，即使瓣膜血流动力学正常，也较年龄和性别相匹配的瓣膜正常者更易发生主动脉根部及升主动脉的扩张[35]。而且主动脉扩张及主动脉瘤的形成过程中，BAV患者更易发生动脉夹层和破裂[5]。在无其他合并瓣膜疾病的BAV患者中，有20%需在20年内行心外科治疗[15]。BAV患者升主动脉瘤形成和主动脉缩窄的平均发生率高于三尖瓣者[35]。BAV管状升主动脉扩张的速度高于乏氏窦扩张的速度，这不同于马凡氏综合征[36]，未行主动脉扩张处理的BAV主动脉瓣置换术后患者，15年内行主动脉手术或并发症的发生率达86%。另一项随访18年的研究[37]表明，主动脉瓣狭窄单纯行瓣膜置换术后发生不良主动脉事件伴轻到中度升主动脉扩张(40~50 mm)的BAV患者中，仅3%需行近端主动脉手术。

5.2主动脉夹层(aortic dissection，AD)一项随访65个月的研究[35]表明，A型主动脉夹层与主动脉扩张在BAV患者中的总发病率为6%，早期干预性外科手术很难评估；其中，A型主动脉夹层患病率为2%~9%，B型主动脉夹层患病率为3%[38]，均高于主动脉瓣瓣叶正常人群(1%~2%)。

5.3主动脉缩窄研究[39]认为，仅为左冠瓣与无冠瓣融合的BAV患者易发生主动脉缩窄。BAV患者主动脉缩窄的较少见，一项研究的结果为7%[29]；而主动脉缩窄患者中，50%~75%为右冠瓣与左冠瓣融合型BAV。伴主动脉缩窄的BAV患者发生主动脉扩张和夹层的风险明显高于单纯BAV患者[40-41]。

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