Embryonic Development of the Bicuspid Aortic Valve

Abstract

Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an overall frequency of 0.5%-1.2%. BAVs result from abnormal aortic cusp formation during valvulogenesis, whereby adjacent cusps fuse into a single large cusp resulting in two, instead of the normal three, aortic cusps. Individuals with BAV are at increased risk for ascending aortic disease, aortic stenosis and coarctation of the aorta. The frequent occurrence of BAV and its anatomically discrete but frequent co-existing diseases leads us to suspect a common cellular origin. Although autosomal-dominant transmission of BAV has been observed in a few pedigrees, notably involving the gene NOTCH1, no single-gene model clearly explains BAV inheritance, implying a complex genetic model involving interacting genes. Several sequencing studies in patients with BAV have identified rare and uncommon mutations in genes of cardiac embryogenesis. But the extensive cell-cell signaling and multiple cellular origins involved in cardiac embryogenesis preclude simplistic explanations of this disease. In this review, we examine the series of events from cellular and transcriptional embryogenesis of the heart, to development of the aortic valve.

Keywords: aortic incompetence; aortic stenosis; aortic valve; bicuspid aortic valve; congenital heart disease; heart development.

Figure 1

Timeline of outflow tract and semilunar valve development post-fertilization. The colors represent contributions to cardiac development from different cell populations. These contributions are from the first heart field (red), second heart field (yellow) and cardiac neural crest (blue). Modified from [19].

Figure 2

Stages of human cardiac development with color-coding of contributing cell populations, seen from a ventral view. These contributions are from the first heart field (red), second heart field (yellow) and cardiac neural crest (blue). By day 15 post-fertilization, the cardiac crescent is specified to form specific segments of the linear heart tube, which is patterned along the anteroposterior axis to form the looped and mature heart. Cardiac neural crest cells populate the aortic arch arteries (III, IV, and VI) and aortic sac (AS) that together contribute to specific segments of the mature aortic arch. Mesenchymal cells form the cardiac valves from the conotruncal (CT) and atrioventricular valve (AVV) segments. Abbreviations: A, atrium; V, ventricle; RV, right ventricle; LV, left ventricle; RA, right atrium; LA, left atrium; PA, pulmonary artery; Ao, aorta; DA, ductus arteriosus. Modified from [24].

Figure 3

Genesis and cellular contributions to the outflow tract. Schematic shows the locations of outflow tract (OFT) colonization by the extra-cardiac cardiac neural crest (blue), vascular smooth muscle derived from the second heart field (dotted yellow) and the location of myocardium from derived from the second heart field (striped yellow). The aortic annulus or hinge region is formed where myocardial cells meet the vascular smooth muscle cells of the media of the aorta and pulmonary trunk and endothelial derived mesenchyme is the source of the fibroblastic annular tissue. The media of the aorta and pulmonary trunk is derived from secondary heart field proximally (dotted yellow) and the cardiac neural crest distally (blue). The interface between these populations is at the sinotubular junction. Abbreviations: Ao, aorta; AS, aortic sac; AVC, aorto-ventricular cushions; LV left ventricle; PT, pulmonary trunk; RV, right ventricle. Modified from [36] and [27]

Figure 4

Remodeling of the endocardial cushions. Cardiac neural crest cells (blue) provide paracrine signals to second heart field cells (yellow) to orchestrate apoptosis (depicted as dark gray cells) and changes in extracellular matrix production during semilunar valve remodeling. Modified from [25].

Figure 5

Development of the leaflets of the aortic and pulmonary valves. The semilunar valves arise from the conotruncal and intercalated cushions of the outflow tract. The conotruncal (superior and inferior septal) cushions give rise to the right and left leaflets of each of the semilunar valves. In the aorta, these are the right and left coronary leaflets, while in the pulmonary valve, these are the right and left cusps. The right-posterior and the left-anterior intercalated cushions develop respectively into the posterior aortic (non-coronary cusp of the aortic valve) and the anterior pulmonic (anterior cusp of the pulmonic valve) leaflets. Abbreviations: AL, anterior leaflet; APIC, anterior pulmonary intercalated cushion; CA, coronary artery; ISC, inferior septal cushion; LL, left leaflet; LCL, left coronary leaflet; NCL, non-coronary leaflet; PAIC, posterior aortic intercalated cushion; RCL, right coronary leaflet, RL, right leaflet

Figure 6

Transcription factors active in aortic valve development. (A) Endocardial cushions (purple) form in the cardiac outflow tract. Valve progenitor cells are generated by an endothelial-to-mesenchymal transition (EMT); (B) Endocardial cushions elongate to form valve primordia of individual valve leaflets. Extracellular matrix (ECM) remodeling and morphogenesis of the valve leaflets is dependent on Nfatc1 and Gata5; (C) ECM of the primordial semilunar valve thins, elongates and stratifies into fibrosa, spongiosa, and ventricularis layers. Modified from [45].

Figure 7

Anatomy of the bicuspid valve and potential pathways for its development. The bicuspid valve is classified as Type I: fusion of the right coronary cusp (RCC) and left coronary cusp (LCC) to create a fused left-right cusp (LRC). A Type I BAV results from persistent fusion of the left and right leaflets normally be formed by the superior and inferior septal cushions. Type II: fusion of the RCC and non-coronary cusp (NCC) to create a fused right-non-coronary cusp (RNC). Type III: fusion between the LCC and NCC to create a fused left-non-coronary cusp (LNC). Both Type II and Type III BAVs result from fusion of the posterior aortic interacted disc with either the inferior (Type II) or superior (Type III) septal cushion. These differences in anatomy imply differences in etiologic mechanisms [110].