Cardiac development demystified by use of the HDBR atlas

Figures

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  FIGURE 1. The upper panel shows the approximate stages of cardiac development related to the Carnegie staging as modified by O'Rahilly and Müller (2010). The lower panel shows the approximate stages of appearance of the various cardiac components, with the density of colouring showing the approximations in terms of timing. IS, interventricular septum; LV, left ventricle; RV, right ventricle. The primary ring refers to the ring of cardiomyocytes that surrounds the primary interventricular foramen.

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  FIGURE 2. Panels a and c are created from an interactive PDF prepared using a human embryo at Carnegie stage 10. The sections shown in panels b and d are from a dataset contained in the HDBR atlas. The reconstructions show the linear arrangement of the heart tube at this stage, with the sections showing the myocardial mantle that clothes the inlet and outlet components.

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  FIGURE 3. The panels, again prepared from interactive PDFs but reconstructed from human embryos at Carnegie stage 11 (a, b) and 12 (c, d), show how addition of new material from the second heart field leads initially to the production of the ventricular loop (a, b), with the development of trabeculations from the outer curvature (lower panels) producing the apical components of the developing right and left ventricles.

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  FIGURE 4. The images show serial sections taken from the human embryo 11,638, dated at Carnegie stage 12, and annotated in the Atlas. Panel a shows a cross section through the atrial component of the heart tube, with the outflow tract seen ventrally. Panel b shows the atrioventricular canal and the top of the ventricular loop. The dorsal mesocardium is also seen—connecting the atrial component to the pharyngeal mesenchyme. Panel c cuts through the outflow tract and the atrioventricular canal, with panel d showing the body of the ventricular loop, which remains filled with cardiac jelly.

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  FIGURE 5. Panel a shows a reconstruction prepared from an interactive PDF from a human embryo at Carnegie stage 13, with panel c showing a section taken from the annotated dataset of human embryo 11,559, also staged at Carnegie stage 13. The atrioventricular canal at this stage is supported exclusively above the cavity of the developing left ventricle, but as seen in panel c, the walls of the developing right atrium and ventricle are already in continuity in the right border of the atrioventricular canal. Panel b shows an interactive reconstruction revealing the connections of the cavities at Carnegie stage 14, with panel d showing a image prepared from an episcopic dataset also from a human embryo staged at Carnegie stage 14. The cavity of the right atrium is now in direct continuity with that of the right ventricle (white arrow). The reconstruction in panel b shows that the outflow tract remains supported exclusively above the cavity of the right ventricle.

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  FIGURE 6. The reconstructions from interactive PDFs, along with sections taken from the annotated datasets in the HDBR Atlas, show the changes occurring as the systemic venous tributaries remodel so as to empty exclusively to the right side of the developing atrial component of the heart tube. Panels a through c show the remodelling taking place during Carnegie stages 12 through 14 that incorporates the left sinus horn into the developing left atrioventricular junction, with the vestibular spine, shown in purple, anchoring the primary atrial septum, shown in green, to the superior atrioventricular cushion. The dotted lines show the boundary between the systemic venous sinus and the remainder of the developing right atrium. The yellow structure is the developing sinus node. Panels d and e are sections taken from the annotated dataset for Carnegie stage 13 (specimen 11,559) and stage 14 (specimen A174). They confirm that the left sinus horn retains its own walls as it extends through the left atrioventricular junction.

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  FIGURE 7. The sections, taken from the annotated datasets for Carnegie stages 15, 16, 18 and 21, show that the pulmonary vein does not canalise within the persisting dorsal mesocardium (a) until after the systemic venous sinus has remodelled so as to open exclusively to the developing right atrium (b). Initially, as seen at Carnegie stage 16 (b), the pulmonary vein opens through a solitary orifice at the level of the left atrioventricular junction (c). Not until Carnegie stage 21 (d) do the venous orifices reach the atrial roof, with this remodelling producing the superior interatrial fold. Still further remodelling in the foetal period is required before the four pulmonary veins open into the corners of the roof of the left atrium.

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  FIGURE 8. The images show the stage of atrial septation. Panel (a) is a section from an episcopic dataset prepared from an embryo at Carnegie stage 14. It shows the initial growth of the primary atrial septum to the left of the systemic venous sinus, which by this stage has remodelled such that it opens exclusively to the right side of the atrial component of the heart tube. Already at this initial stage the septum has a mesenchymal cap on its leading edge. By Carnegie stage 15 (b), the septum and its mesenchymal cap are growing s the atrioventricular cushions, which by now have separated the atrioventricular canal into the tricuspid and mitral valvar orifices. By Carnegie stage 16, the cap on the septum is fusing with the cushion mass to obliterate the primary atrial foramen (c). By Carnegie stage 18, the zone of fusion has been reinforced by growth of the rightward margin of the dorsal mesocardium, known as the vestibular spine (see Figure 6—upper right hand panel). The spine and mesenchymal cap then muscularise to form the second atrial septum (d).

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  FIGURE 9. The sections show the fate of the atrioventricular cushions, by Carnegie stage 14 positioned superiorly and inferiorly within the atrioventricular canal (a). As shown in (b), by CS17 the larger parts of the atrioventricular cushions are positioned above the cavity of the developing left ventricle, providing a base for insertion of the atrial septum. By the next stage (c), the cushions have begun to fuse, dividing the canal into the tricuspid and mitral valvar orifices. The proximal outflow cushions can also be seen, at this stage, to have divided the outflow tract into the aortic and pulmonary channels. By Carnegie stage 21, the basal parts of the atrioventricular cushions have produced a bay within the base of the ventricular mass, which is now the dorsal border of the outflow tract, with the rightward margins of the cushions having fused to close the tertiary interventricular foramen (d).

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  FIGURE 10. The images, prepared from the interactive PDFs show the remodelling that takes place in the pharyngeal mesenchyme, with the concomitant changes that occur with remodelling of the arterial channels that form within the pharyngeal arches, themselves demarcated by formation of the pharyngeal pouches. At Carnegie stage 12 (a), a manifold has developed within the ventral pharyngeal mesenchyme that is known as the aortic sac. At this initial stage, as shown in the left hand panel, the manifold gives rise to arteries that percolate in symmetrical fashion through the first two pharyngeal arches. As shown in the middle panel, by Carnegie stage 13 (b), there has been formation of the two more pharyngeal arches, but with resorption of the arteries that extended through the first arch. By Carnegie stage 14 (c), an additional and ultimate pharyngeal arch has formed, but now with resorption of the larger part of the arteries of the second arch. This means that only five pharyngeal arches are formed during human development, creating problems for those who describe formation of a sixth arch, postulating vestigial formation of the fifth arch. To circumvent these problems in nomenclature, it is…

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  FIGURE 11. The reconstructions (a–d), made from the interactive PDFs show the increasing “regression” of the distal myocardial border that occurs as the migration of non‐myocardial cells from the heart‐forming areas into the arterial pole of the heart tube produces the intrapericardial arterial trunks.

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  FIGURE 12. The sections are made using episcopic datasets prepared from different human embryos at Carnegie stage 13 (panels a and b) and stage 14 (panel c). Panels a and b show the junction between the distal outflow tract and the aortic sac as seen in frontal (panel a) and sagittal (panel b) fashion. The white star with red borders shows the dorsal wall of the aortic sac, which will protrude between the origins of the systemic and pulmonary arch arteries to become the aortopulmonary septum, as seen in panel c. The white arrows with red borders show the reflections marking the margins of the pericardial cavity. Panel c, which is another frontal section, shows the aortopulmonary foramen that exists until the aortopulmonary septum fuses with the distal margins of the major outflow cushions, which divides the part of the outflow tract that retains its myocardial walls into the aortic and pulmonary channels. The section also shows the intercalated valvar swellings, which will excavate, along with the distal margins of the major outflow cushions, to form the leaflets of the arterial valves (see Figure 13).