Outflow Tract Formation—Embryonic Origins of Conotruncal Congenital Heart Disease

Abstract

Anomalies in the cardiac outflow tract (OFT) are among the most frequent congenital heart defects (CHDs). During embryogenesis, the cardiac OFT is a dynamic structure at the arterial pole of the heart. Heart tube elongation occurs by addition of cells from pharyngeal, splanchnic mesoderm to both ends. These progenitor cells, termed the second heart field (SHF), were first identified twenty years ago as essential to the growth of the forming heart tube and major contributors to the OFT. Perturbation of SHF development results in common forms of CHDs, including anomalies of the great arteries. OFT development also depends on paracrine interactions between multiple cell types, including myocardial, endocardial and neural crest lineages. In this publication, dedicated to Professor Andriana Gittenberger-De Groot and her contributions to the field of cardiac development and CHDs, we review some of her pioneering studies of OFT development with particular interest in the diverse origins of the many cell types that contribute to the OFT. We also discuss the clinical implications of selected key findings for our understanding of the etiology of CHDs and particularly OFT malformations.

Ventricular Septation and Outflow Tract Development in Crocodilians Result in Two Aortas With Bicuspid Semilunar Valves

“…In view of the human fragile aortic wall it is probably this third/noncoronary valve leaflet's etiology that associates with the differentiation of the outer media of the aortic wall, and that becomes prone to aneurysm formation. The inner media of the wall of the ascending aorta is NC derived [41,57], whereas the outer media/adventita is SHF derived [5,36]. We postulate that anomalous SHF differentiation may affect both this semilunar valve leaflet and the integrity of the ascending aorta.…”

“…development of the right side of the heart including the pulmonary trunk [32,33] participates in the development of the third, so-called non-facing semilunar valve leaflet as shown by the expression of Cardiac Troponin T2 [34,35] or NKx2.5 [31]. Furthermore, a part of the septation complex does not derive from the cardiac crest [36] This is demonstrated in quail-chicken chimeras [25] in which a narrow zone of compact chick mesenchyme remains present in an otherwise quail-dominated septation complex. This narrow strip is also recognized between the two advancing myocardial components in the conal septum of our caiman AP-septum (depicted by * in Figs 1i, 2h, 3f etc..).…”

“…The opposite side of the visceral aorta, however, is shared with the pulmonary trunk with the joining AP-septum in between. In mice [33,36,42,43] it is known that the root of the pulmonary trunk is of mixed (NCC and SHF) origin. The OFT septal complex in mouse ) and chicken [25,27,29,44], that we consider here as a fusion product of the crocodilian IA plus AP septum, derives mainly from the cardiac NC.…”

Ventricular Septation and Outflow Tract Development in Crocodilians Result in Two Aortas with Bicuspid Semilunar Valves

“…The mesenchyme of the two main semilunar valve leaflets derives likewise from the cardiac neural crest, while the second heart field, important for development of the right side of the heart including the pulmonary trunk [29,30], participates in the development of the third so-called non-facing semilunar valve leaflet, as shown by the expression of Cardiac Troponin T2 [31,32] or NKx2.5 [33]. Furthermore, a part of the septation complex does not derive from the cardiac crest [34]. This is demonstrated in quail-chicken chimeras [26] in which a narrow zone of compact chick mesenchyme remains present in an otherwise quail-dominated septation complex.…”

“…The opposite side of the visceral aorta, however, is shared with the pulmonary trunk with the joining AP septum in between. In mice [30,34,41,42], it is known that the root of the pulmonary trunk is of mixed (NCC and SHF) origin. The OFT septal complex in mouse (Peterson 2018) and chicken [26,28,35,43], which we consider here as a fusion product of the crocodilian IA and AP septa, derives mainly from the cardiac NC.…”