FIG 3.29 Image using the same episcopic dataset as Fig 3.25, but reconstructed to show the spiraling course of the cushions extending through the proximal and intermediate parts of the outflow tract The reconstruction also shows the solitary lumen of the distal outflow tract, and the arteries arising from the aortic sac to pass through the third, fourth, and sixth pharyngeal arches The cushion that is located caudally at the intermediate part of the outflow tract turns beneath the other cushion at the bend and achieves a septal location within the outlet of the right ventricle The cushion that is positioned cranially at its distal margin spirals to attach parietally to the wall of the outlet of the right ventricle This means that, as the cushions approximate one another, fusing along their facing surfaces, the proximal outflow tract will eventually be separated into ventral and dorsal channels, with right-sided and left-sided channels formed distally Fusion of the cushions along their length, however, does not occur at the same time It commences distally, with the act of closure moving in proximal direction The outflow cushions, like the cushions within the atrioventricular canal, are initially formed by the process of epithelial-to-mesenchymal transformation An additional migration of cells takes place in the outflow tract, this time from the neural crest The cells derived from the neural crest, furthermore, not only populate the cushions, but also migrate to occupy the surface of the protrusion from the dorsal wall of the aortic sac When the two components eventually fuse to obliterate the embryonic aortopulmonary foramen, therefore, the act of fusion depends on the appropriate migration from the neural crest This fusion of the distal ends of the outflow cushions with each other, and with the aortopulmonary septum (see Fig 3.28), then connects the right-sided and caudal channel of the distal outflow tract to the extrapericardial systemic arteries This leaves the left-sided and cranial channel of the outflow tract in communication with the caudally located right and left pulmonary arteries and the artery of the left sixth arch The changes in the distal part of the outflow tract, therefore, have produced the intrapericardial parts of the aorta and pulmonary trunk, with the major outflow cushions having also fused in the intermediate part of the outflow tract Additional cushions have also developed during this period within the intermediate part of the outflow tract, with one cushion being placed much more cranially compared with the other (see Fig 3.28) These are the intercalated cushions Cavitation within the distal ends of these cushions, and also within the opposite ends of the fused major cushions, then produces the primordiums of the aortic and pulmonary valves (Fig 3.30) The arterial valves, therefore, are formed within the intermediate component of the outflow tract (see Fig 3.28), which initially retains its myocardial walls.16 As the cushions cavitate, so there is ongoing growth of the nonmyocardial tissues from the second heart field This forms the walls of the sinuses of the arterial roots, with the cavitating cushions themselves remodeling to become the valvar leaflets and their semilunar hinges Although the middle parts of the major cushions have fused to separate the aortic and pulmonary roots, the opposing edges of the cushions themselves do not fuse, thus producing the trifoliate arrangement of the aortic and pulmonary valves (see Fig 3.30) With ongoing development, the central component of the fused cushions breaks down along a line that is normal to the line of fusion In this way, the newly formed aortic root is separated from the pulmonary root This central part of the fused cushions was initially occupied by the cells derived from the neural crest, which die during this process by apoptosis.17 FIG 3.30 Short-axis section through the intermediate part of the outflow tract of a human embryo at Carnegie stage 18 showing the developing primordiums of the arterial valves Note that both valves are still surrounded by a myocardial cuff The valvar leaflets are forming by a process of cavitation of the cushions Note also the site of the initial zone of fusion between the cushions The arterial roots will eventually separate at right angles to this plane At the initial stage of formation of the arterial valves and their supporting sinuses within the intermediate part of the outflow tract, the components of the major cushions occupying the proximal part of the outflow tract remain unfused (see Fig 3.20) With further development, these cushions not only fuse with each other, but also fuse with the crest of the ventricular septum, thus walling the aortic root into the left ventricle (see Fig 3.21) As with the cushions in the intermediate part of the outflow tract, the central core of the proximal cushions is also occupied by the cells that migrated from the neural crest And, as occurred within the developing arterial roots, these cells again disappear by the process of apoptosis The surface of the fused proximal cushions, in contrast, becomes muscularized, thus forming the subpulmonary infundibulum (Fig 3.31).18 Subsequent to closure of the persisting embryonic interventricular foramen by the tubercles of the atrioventricular cushions (see Fig 3.31), the musculature of the inner heart curvature initially continues to separate the developing leaflets of the aortic and mitral valves It is only at a much later stage that this myocardium disappears, producing the aortic-to-mitral valvar continuity that is a feature of the postnatal heart Similarly, at much later stages, once more by a process of apoptosis, the entirety of the myocardial walls surrounding the developing