Gittenberger-de Groot Adriana C, Calkoen Emmeline E, Poelmann Robert E, Bartelings Margot M, Jongbloed Monique R M
Department of Cardiology, Leiden University Medical Center , Leiden , The Netherlands.
Ann Med. 2014 Dec;46(8):640-52. doi: 10.3109/07853890.2014.959557. Epub 2014 Oct 13.
The primary unseptated heart tube undergoes extensive remodeling including septation at the atrial, atrioventricular, ventricular, and ventriculo-arterial level. Alignment and fusion of the septal components is required to ensure full septation of the heart. Deficiencies lead to septal defects at various levels. Addition of myocardium and mesenchymal tissues from the second heart field (SHF) to the primary heart tube, as well as a population of neural crest cells, provides the necessary cellular players. Surprisingly, the study of the molecular background of these defects does not show a great diversity of responsible transcription factors and downstream gene pathways. Epigenetic modulation and mutations high up in several transcription factor pathways (e.g. NODAL and GATA4) may lead to defects at all levels. Disturbance of modulating pathways, involving primarily the SHF-derived cell populations and the genes expressed therein, results at the arterial pole (e.g. TBX1) in a spectrum of ventricular septal defects located at the level of the outflow tract. At the venous pole (e.g. TBX5), it can explain a variety of atrial septal defects. The various defects can occur as isolated anomalies or within families. In this review developmental, morphological, genetic, as well as epigenetic aspects of septal defects are discussed.
原始的未分隔心脏管会经历广泛的重塑，包括在心房、房室、心室和心室 - 动脉水平的分隔。隔膜组件的对齐和融合是确保心脏完全分隔所必需的。缺陷会导致不同水平的隔膜缺损。来自第二心脏场（SHF）的心肌和间充质组织以及一群神经嵴细胞添加到原始心脏管中，提供了必要的细胞成分。令人惊讶的是，对这些缺陷分子背景的研究并未显示出负责的转录因子和下游基因途径有很大差异。几种转录因子途径（如NODAL和GATA4）上游的表观遗传调控和突变可能导致各个水平的缺陷。主要涉及SHF衍生细胞群体及其表达基因的调节途径紊乱，在动脉极（如TBX1）会导致一系列位于流出道水平的室间隔缺损。在静脉极（如TBX5），它可以解释各种房间隔缺损。各种缺陷可以作为孤立的异常出现，也可以在家族中出现。在这篇综述中，将讨论隔膜缺损的发育、形态、遗传以及表观遗传方面。
