New Concepts in the Development and Malformation of the Arterial Valves

Abstract

Although in many ways the arterial and atrioventricular valves are similar, both being derived for the most part from endocardial cushions, we now know that the arterial valves and their surrounding structures are uniquely dependent on progenitors from both the second heart field (SHF) and neural crest cells (NCC). Here, we will review aspects of arterial valve development, highlighting how our appreciation of NCC and the discovery of the SHF have altered our developmental models. We will highlight areas of research that have been particularly instructive for understanding how the leaflets form and remodel, as well as those with limited or conflicting results. With this background, we will explore how this developmental knowledge can help us to understand human valve malformations, particularly those of the bicuspid aortic valve (BAV). Controversies and the current state of valve genomics will be indicated.

Excess Provisional Extracellular Matrix: A Common Factor in Bicuspid Aortic Valve Formation

“…In coordination with the fusion of the major OFT cushions, the intercalated cushions develop at right angles to the midline fusion, and give rise to the non-coronary cusp (NC) of the AoV and anterior (An) cusp of the PV (Figure 1C,D) [21]. In the developing AoV, formation of the intercalated cushion involves invagination of the endocardial lining into the RC prevalvular cushion; however, the majority of the cells that contribute to the intercalated cushions are derived from the cTnnt2-Cre myocardial lineage [21,25,26]. The intercalated cushion of the PV forms from an inward expansion of cTnnt2-Cre lineage cells and develops independently of the R and L prevalvular cushions.…”

“…It remains unclear how cell lineage patterning affects normal and abnormal cusp morphologies including the formation of BAVs. (Henderson et al describe the potential origins of malformed AoVs in a complementary and thorough developmental review [25]).…”

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

“…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.…”

“…In mammals and birds tricuspid semilunar valves are the rule, while in reptiles bicuspid valves are consistently present. Mammalian bicuspidy is considered a congenital malformation [35] that is often associated with a fragile wall of the ascending aorta later in life [56]. Therefore, we need to find an explanation for the bicuspid valve in our crocodilians associated with a healthy aortic wall.…”

“…Consequentially, the fully grown location of the FOP being enclosed in the distal part of the septal cushion, is located outside the heart, connecting the facing sinus of Valsalva between the roots of both aortae. This has implications on the way we envisage semilunar valve development from the 'massive' OFT cushion towards the 'hollow' valve leaflets containing the sinus of Valsalva (Henderson 2020). The proximal part of the cushions remains attached to the myocardial border, while the developing leaflets and commissures develop from the distal part of the cushion, that enlarges concomitantly with the expanding arterial wall.…”