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Abstract：
Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, frequently associated with aortopathies and valvulopathies. The congenital origin of BAV is suspected to impact the development of the disease in the adult life. During the last decade, a number of studies dealing with the embryonic development of congenital heart disease have significantly improved our knowledge on BAV etiology. They describe the developmental defects, at the molecular, cellular and morphological levels, leading to congenital cardiac malformations, including BAV, in animal models. These models consist of a spontaneous hamster and several mouse models with different genetic manipulations in genes belonging to a variety of pathways. In this review paper, we aim to gather information on the developmental defects leading to BAV formation in these animal models, in order to tentatively explain the morphogenetic origin of the spectrum of valve morphologies that characterizes human BAV. BAV may be the only defect resulting from gene manipulation in mice, but usually it appears as the less severe defect of a spectrum of malformations, most frequently affecting the cardiac outflow tract. The genes whose alterations cause BAV belong to different genetic pathways, but many of them are direct or indirectly associated with the NOTCH pathway. These molecular alterations affect three basic cellular mechanisms during heart development, i.e., endocardial-to-mesenchymal transformation, cardiac neural crest (CNC) cell behavior and valve cushion mesenchymal cell differentiation. The defective cellular functions affect three possible morphogenetic mechanisms, i.e., outflow tract endocardial cushion formation, outflow tract septation and valve cushion excavation. While endocardial cushion abnormalities usually lead to latero-lateral BAVs and septation defects to antero-posterior BAVs, alterations in cushion excavation may give rise to both BAV types. The severity of the original defect most probably determines the specific aortic valve phenotype, which includes commissural fusions and raphes. Based on current knowledge on the developmental mechanisms of the cardiac outflow tract, we propose a unified hypothesis of BAV formation, based on the inductive role of CNC cells in the three mechanisms of BAV development. Alterations of CNC cell behavior in three possible alternative key valvulogenic processes may lead to the whole spectrum of BAV.
摘要：
双叶主动脉瓣(BAV)是最常见的先天性心脏畸形,常伴有主动脉病变和瓣膜病变。怀疑BAV的先天性起源会影响成年生活中疾病的发展。在过去的十年里，大量有关先天性心脏病胚胎发育的研究显著提高了我们对BAV病因学的认识.他们描述了发育缺陷，在分子上，细胞和形态学水平，导致先天性心脏畸形，包括BAV,在动物模型中。这些模型由自发仓鼠和几种小鼠模型组成，这些小鼠模型在属于多种途径的基因中具有不同的遗传操作。在这篇综述论文中，我们的目标是收集这些动物模型中导致BAV形成的发育缺陷的信息，为了初步解释表征人类BAV的瓣膜形态谱的形态发生起源。BAV可能是小鼠基因操作导致的唯一缺陷，但通常表现为一系列畸形中较不严重的缺陷，最常影响心脏流出道。导致BAV改变的基因属于不同的遗传途径，但其中许多与NOTCH途径直接或间接相关。这些分子改变影响心脏发育过程中的三种基本细胞机制，即，心内膜到间质转化，心脏神经峰（CNC）细胞行为和瓣膜垫间充质细胞分化。有缺陷的细胞功能影响三种可能的形态发生机制，即，流出道心内膜垫形成,流出道分隔和阀垫开挖。虽然心内膜垫异常通常会导致侧外侧BAV和前后BAV的间隔缺损，垫层开挖的改变可能会导致两种BAV类型。原始缺损的严重程度很可能决定了特定的主动脉瓣表型，其中包括连合融合和融合。根据目前对心脏流出道发育机制的了解，我们提出了BAV形成的统一假设，基于CNC细胞在BAV发育的三种机制中的诱导作用。在三个可能的替代关键瓣膜生成过程中，CNC细胞行为的改变可能导致BAV的整个范围。
