Introduction
From the functional point of view, the heart is simply a specialized part of the vascular system. Nonetheless, development of the heart as a specialized pump is of great significance. We have learned a great deal over recent decades regarding the origin of the muscular parts of this pumping organ. Until recently, it was believed that the initial linear tube, which gives rise to the heart, contained the precursors of all the components as seen in the postnatal organ. We now know that this is not the case, and that tissue is continually added to the heart tube as it grows and loops. The initial straight part of the tube ( Fig. 3.1 ) eventually forms little more than the left ventricle. This knowledge now permits better interpretation of the morphogenesis of many congenital cardiac malformations. The opening sections of this chapter discuss the new evidence that has emerged concerning the appearance of the cardiac components. Thereafter, we revert to providing an account of the so-called cardiac segments. In this respect, we do not use “segment” in its biologic sense. Thus we do not imply that each purported segment is identical to the others, as is seen in invertebrates such as annelids. As explained in Chapter 1 , however, the segmental approach, in its sequential modification, is now the preferred means of describing the cascade of information acquired during clinical diagnosis. We will continue, therefore, to describe the cardiac components as segments, in this way providing the necessary background to interpret the anomalous development that leads to the congenital malformations described in the body of this book. There are discrepancies between the terms used by biologists to describe developing heart and the attitudinally appropriate terms used by clinicians when describing the formed organ. Biologists and embryologists use the term “anterior” to describe structures that are toward the head, and “posterior” for those toward the feet. We circumvent these problems by describing cranial and caudal structures. To avoid further confusion, we also avoid use of the terms “anterior” and “posterior” when describing structures located toward the spine and sternum, as is the wont of clinicians. For this purpose in this chapter, we use the adjectives “dorsal” and “ventral.” Right and left, of course, retain their time-honored usage. Throughout the chapter, we concentrate on illustrating the morphologic changes that take place during development of the heart. Huge advances have been made over the past quarter century in understanding the genetic and molecular changes that underscore the morphologic and temporal remodeling. Space does not permit us, however, to assess these features in the depth they deserve. We therefore restrict ourselves to consideration of the changing morphology.
Origin of the Heart Tube
Recent studies have now validated the notion that, after formation of the linear heart tube (see Fig. 3.1 ), cells are continuously added at both its venous and arterial poles. The source of this new material is the second heart field, with the linear tube itself derived from the first heart field. The cells forming these fields are derived from the heart-forming areas. These are located within the original embryonic disc, which is bounded by the junction of the embryo with the extraembryonic tissues formed by the amnion and yolk sac. There are three germ layers within the disc: the ectoderm, which faces the amniotic cavity; the endoderm, which faces the yolk sac; and the intermediate mesodermal layer ( Fig. 3.2 ). Folding of this disc, concomitant with extensive growth, gives the embryo its characteristic shape. The cells producing the heart-forming areas, initially found to either side of the midline, have migrated from the cranial part of the primitive streak during the process of gastrulation. With continuing development, they join across the midline to form the cardiac crescent ( Fig. 3.3 ). It remains to be determined whether the first and second fields are discrete entities. Boundaries between morphologic regions of the developing embryo are not necessarily formed at subsequent stages by the same cells as were present initially. If we accept that the material from which the heart is formed is derived from the same basic heart-forming areas, nonetheless there is an obvious temporal order in the differentiation of its first and second cardiac lineages. This order may reflect the evolutionary development of the cardiovascular system. When initially developed during evolution of the animal kingdom, the heart contained no more than the components of the systemic circulation—namely, an atrium, a ventricle, and a myocardial outflow tract. The pulmonary circulation, represented by the right ventricle, and most, but not all, of the left atrium, including the atrial septum, appears appreciably later in evolutionary development. Therefore it is unlikely to be coincidental that the atrial septum in mammals, along with the dorsal atrial wall, is formed from material that is added to the heart relatively late in its development. The evolutionary considerations suggest strongly that novel patterning, with different temporal sequences, but within the same heart-forming area, is sufficient to provide all the material needed to construct the four-chambered hearts of birds and mammals, albeit that not all precursors are present in the linear heart tube when it is first seen (see Fig. 3.1 ).
Formation of the Cardiac Loop
The initial heart tube is more or less straight (see Fig. 3.1 ). With the addition of the new material at its arterial and venous poles, it rapidly becomes S-shaped, in this way achieving its ventricular loop ( Fig. 3.4 ). Experiments have shown that the tube will continue to loop even when deprived of its normal arterial and venous attachments, and will also loop when no longer beating. Looping, therefore, is an intrinsic feature of the heart itself, although the precise cause has still to be determined. The tube usually curves to the right, with the direction of turning being independent of the overall left-right asymmetry of the developing embryo. It is often said that rightward looping is the first sign of breaking of cardiac symmetry. This is incorrect. The region of the tube that will become the atrioventricular canal is asymmetrical even before the beginning of looping (see Fig. 3.1 ).
Cardiac Segments
The process of looping of the heart tube sets the scene for the appearance of the building blocks of the ventricles, with additional ingrowth of tissues from the heart-forming areas producing the primordiums of the arterial trunks and the atrial chambers at the arterial and venous poles, respectively. It used to be thought that five segments could be recognized in the initial linear tube. We now know that this is not the case. The development of the cardiac chambers depends on the expansion, or ballooning, of their cavities from the lumen of the components of the primary tube. Subsequent to looping, the cells that made up the initial components of the linear tube are negative for both connexin40 and atrial natriuretic peptide, characterizing them as primary myocardium ( Fig. 3.5 ). As the cavity of the linear tube begins to balloon out from both its atrial and ventricular components, the myocardium forming the walls of the ballooning components changes its molecular nature, being positive for both connexin40 and atrial natriuretic peptide. This myocardium is called chamber, or secondary, myocardium. The parts ballooning from the atrial component of the primary tube do so in relatively symmetric fashion ( Fig. 3.6 ). The pouches thus formed will eventually become the atrial appendages. Examination of the atrial component of the heart at this early stage, however, reveals the presence of a third population of cells (see Fig. 3.5 ). These cells are positive for connexin40 but negative for atrial natriuretic peptide. They make up the part of the tube that retains its connection with the developing mediastinum through the dorsal mesocardium. Hence they are described as representing mediastinal myocardium. These cells form the dorsal wall of the left atrium and a small part of the dorsal wall of the right atrium. They provide the site of formation of the primary atrial septum and give rise to the pulmonary venous myocardium. Ballooning also takes place from the ventricular part of the heart tube. Unlike the situation in the atrial component, where the appendages of both definitive atriums balloon in parallel, the pouches that form the apexes of the left and right ventricles balloon in sequence from the inlet and outlet components of the ventricular loop. The ballooning of the apical components in series produces the primordium of the muscular ventricular septum (see Fig. 3.6 ). The process of cardiac septation requires appreciable remodeling of the initial lumen of the primary heart tube. This is because, subsequent to looping and after the initial phases of ballooning, the blood passing through the atrioventricular canal drains to the inlet of the ventricular loop, albeit that a direct connection already exists through its rightward margin between the developing walls of the right atrium and right ventricle (see Fig. 3.6 ). At this initial stage, furthermore, the developing outlet segment of the heart tube is supported exclusively by the outlet part of the ventricular loop, from which will develop the right ventricle. Again, a direct connection already exists through the walls of the tube between the developing left ventricle and the arterial segment ( Fig. 3.7 ). Remodeling of the lumen of the primary tube, along with the concomitant rearrangements of the junctions with the developing atrial and arterial segments, will underscore the definitive arrangement, which then permits eventual closure of the plane between the systemic and pulmonary blood streams.
Development of the Venous Components
The ongoing addition of tissues from the heart-forming areas gives rise not only to the primary atrial component of the heart tube, but also to the systemic venous tributaries at its venous pole. Subsequent to the process of looping, there is symmetry between the venous channels formed in both sides of the developing embryo. These channels, which provide return of the blood streams from the yolk sac, the placenta, and the embryo itself, come together to drain into the atrial component of the heart tube through venous confluences, which are known as the horns of the systemic venous sinus ( Fig. 3.8 ). The systemic venous sinus, or sinus venosus, is anatomically discrete in lower animals, such as fish. No such anatomically discrete structure, however, is to be found in the early stages of development of the mammalian heart. Instead, the venous tributaries on both sides of the embryo simply empty into the atrial component through the sinus horns (see Fig. 3.8 ). Only after the systemic venous tributaries have been remodeled to drain to the right side of the initial atrial component of the heart tube does it become possible to recognize structures demarcating their borders. These structures are the valves of the systemic venous sinus. A key part of normal development, therefore, is remolding of the systemic venous tributaries. This process involves the formation of anastomoses between the various venous systems such that left-sided venous return is shunted to the right side of the embryo. A major anastomosis, the venous duct, or ductus venosus, diverts the umbilical venous return from the placenta to the caudal part of the cardinal venous system. The vitelline veins, draining the yolk sac, largely disappear, although some of these structures are incorporated into the venous system of the liver. A second important anastomosis develops in the cranial part of the embryo, diverting the venous return from the left-sided to the right-sided cardinal vein. With this shift of the cranial venous return to the right-sided cardinal channel, and with the disappearance of the left-sided vitelline and umbilical veins, there is gradual diminution in size of the left sinus horn. As it diminishes in size, so its walls, which remains separated from those of the left atrium, become incorporated into the left half of the developing atrioventricular junction, eventually becoming the coronary sinus ( Fig. 3.9 ).
The remodeling of the systemic venous sinus sets the scene for development of the pulmonary venous system. The pulmonary veins, of course, cannot be formed without development of the lungs themselves. These appear as buds within the mediastinal mesenchyme on the ends of the bifurcating tracheobronchial tube. Venous structures then develop within the lung buds, concomitant with canalization of a venous channel from a midline strand initially formed within the mediastinal tissues. When canalized, the midline channel, or primary pulmonary vein, drains the developing intrapulmonary venous plexuses from both lungs. It joins the heart at the site of the persisting dorsal mesocardium. Most of the mesocardium that initially connected the length of the heart tube with the mediastinum breaks down during ventricular looping. When viewed internally, the edges of the persisting mesocardial connection are seen as two ridges, the pulmonary ridges, which bulge into the lumen of the atrial cavity (see Figs. 3.9 and 3.10 ). The canalizing primary pulmonary vein opens to the atrial cavity between these ridges, its opening being adjacent to the developing atrioventricular junction ( Fig. 3.11 ).
Controversy has long raged as to the relationship between the newly formed pulmonary venous confluence and the tributaries of the systemic venous sinus. During normal development, the primary pulmonary vein has never had any connection with the systemic venous tributaries. It forms as a new structure within the mediastinum, opening within the mediastinal myocardium to the cavity of the left atrium. As such, it is positioned to the left of the site of appearance of the primary atrial septum, which is also derived from mediastinal myocardium (see Fig. 3.5 ). The pulmonary venous structures are similarly recognizable from the outset of their development as being derived from mediastinal myocardium, whereas the systemic venous tributaries initially possess a primary myocardial lineage, and can be identified in molecular terms by their expression of the transcription factor Tbx18. When first seen, the pulmonary vein in both the murine and human heart drains to the heart directly adjacent to the atrioventricular junction (see Fig. 3.11 ). There is then significant remodeling so that, at first, separate orifices drain the blood from the right and left lungs. Eventually, in the human heart, four orifices are formed at the corners of the atrial root ( Fig. 3.12 ). Only at the late stages is it possible to see formation of the so-called secondary atrial septum, which is no more than the fold between the right-sided pulmonary veins and the systemic venous tributaries (see Fig. 3.12 ).
Septation of the Atrial Chambers
The shift rightward of the tributaries of the systemic venous sinus, so that they open exclusively to the developing right atrium, permits septation of the atrial component of the heart. By this stage, the addition of the new mediastinal myocardium has formed the larger part of the body of the developing atrial component (see Fig. 3.7 ). The atrioventricular canal, of course, was present from the outset, and is also composed of primary myocardium. The myocardium of the atrial component itself was also initially composed of primary myocardium, but as we have seen, the two appendages balloon in symmetrical fashion from this lumen tract (see Fig. 3.6 ). It is at this stage that the primary atrial septum, or “septum primum,” grows as a shelf from the atrial roof ( Fig. 3.13 ). By the time the primary atrial septum has appeared, endocardial cushions have also developed within the atrioventricular canal. The cushions, positioned superiorly and inferiorly within the canal, grow toward each other to divide it into right-sided and left-sided channels. As the cushions grow toward each other, so the primary septum also grows toward the cushions, carrying on its leading edge a further collection of endocardial tissue, the mesenchymal cap. By the time the primary septum and mesenchymal cap have approached the cushions, the cranial part of the septum, at its origin from the atrial roof, has broken down, creating the secondary interatrial foramen. The primary foramen is the diminishing space between the mesenchymal cap and the fusing atrioventricular endocardial cushions ( Fig. 3.14 ). Fusion of the mesenchymal cap with the endocardial cushions obliterates the primary atrial foramen. Since this process occurs to the right side of the pulmonary ridges, the solitary opening of the newly canalized pulmonary vein is committed to the left side of the dividing atrial component. The base of the newly formed atrial septum, formed by the mesenchymal cap, is then further reinforced by growth into the heart of mesenchymal tissues through the right pulmonary ridge. Initially illustrated by Wilhelm His the Elder, this protrusion seen in the caudal wall of the atrium was labeled the vestibular spine, or “spina vestibuli” ( Fig. 3.15 ). It is now frequently described as the dorsal mesenchymal protrusion.
