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Chapter 9: MOLECULAR DEVELOPMENT OF THE HEART MECHANISMS OF CARDIAC SEPTATION Cardiac and Extracardiac Orientation
Because of rapid growth and the progressive curvature of the longitudinal axis of the embryo during organogenesis, it is critical to define cardiac morphogenesis, including septation, with reference to extracardiac morphologic landmarks that relate to the longitudinal axis of the embryo.438 In the following discussion of cardiac septation, therefore, the diaphragm (septum transversum) is assumed to maintain an approximately horizontal position, as it does in the mature heart. The terms anterior, posterior, superior, and inferior are employed accordingly. Although the formation of the various cardiac septa occurs almost simultaneously, for clarity it is necessary to consider their development separately.
Cardiac septation involves the formation of several septal (myocardial and mesenchymal/fibrous) and valvar structures. All the original tissues of the tubular heart (myocardium, endocardium, endocardial cushion tissues) as well as the so-called extracardiac cell populations, which arrive in the heart at relatively late stages of development (neural crest, epicardium, ventral neural tube cells), appear to play a role during valvuloseptal morphogenesis.
In the 3-mm human embryo, the sinus venosus consists of a central, transverse portion of the sinus venosus and the right and left sinus horns Fig. 9-9). The sinus venosus receives three pairs of veins: the omphalomesenteric (vitelline) veins, the umbilical (allantoic) veins, and the common cardinal veins. The proximal portions of the umbilical veins soon disappear. As a result of the increased blood flow associated with the right and left systemic veins, the right sinus horn and the proximal cardinal and vitelline veins attain a vertical position, increase in size, and form the smooth-walled, intercaval part of the atrium. The transverse portion and the proximal left sinus horn become the coronary sinus. Infolding of the sinoatrial junctional tissue at the right border of the sinoatrial foramen results in the formation of the right venous valve.139,140 The left valve develops as a result of active growth, similar to that of the primary atrial septum (i.e., the left valve does not develop as a fold) (Fig. 9-10). Thus, the vertical sinoatrial orifice is flanked on each side by a valvelike structure in the 4- to 6-mm human embryo. Superiorly, the venous valves join to form the septum spurium. The venous valves, particularly the right venous valve, are relatively large in the 16-mm embryo. The superior aspect of the right venous valve eventually develops into the crista terminalis, or terminal crest. The left sinus valve fuses partly with the atrial septum. Inferiorly, the left venous valve intersects with the inferior part of the right venous valve. As a result, the right venous valve becomes divided into the relatively large inferior vena caval (or eustachian) valve and a smaller coronary sinus (or thebesian) valve.
Figure 9-10: A model for the development of the atrial septal complex in the human heart. Panels A-C of this cartoon illustrate the key events in the formation of the primary atrial septum (A-C). Panel D schematically depicts the formation of the atrial septum and venous valves. Panel A represents a heart at approximately 4% weeks of development. The AV cushions can be distinguished but have not yet fused. The leading edge of the primary septum is covered by a mesenchymal cap which is in continuity with the dorsal mesenchymal protrusion of the dorsal mesocardium. Panel B represents the situation at approximately 6 weeks of development. The leading edge of the primary atrial septum, covered with a mesenchymal cap, is now approaching the AV cushions, which are in the process of fusing. Within the myocardial portion of the primary septum, multiple fenestrations represent the developing secondary foramen. Completion of fusion of the mesenchymal tissues at 6 to 7 weeks of development (panel C) results in the closure of the primary interatrial foramen. At this time, a prominent secondary foramen can be found within the superior portion of the primary septum. The cartoon in panel D shows how the secondary atrial septum is formed as a result of infolding of the atrial roof. This occurs at the margin between the myocardium and the left and right atrial expression domain. The myocardium of the primary atrial septum is part of the left atrial expression domain; the orifice of the pulmonary vein also is surrounded by myocardium with a left atrial molecular phenotype. This panel also illustrates that based on the gene expression patterns, the left venous valve develops as a myocardial structure with a right atrial molecular phenotype, whereas the right venous valve (just like the secondary atrial septum) develops by infolding, in this case of the junctional tissue between the right atrium and the sinus venosus. iAVC = inferior atrioventricular cushion; sAVC = superior atrioventricular cushion; DM = dorsal mesocardium; DMP = dorsal mesenchymal protrusion; pf = primary foramen; PS = primary atrial septum; sf = secondary foramen; LA = left atrium; RA = right atrium; OF = oval fossa; pAS = primary atrial septum; sAS = secondary atrial septum; PuV = pulmonary vein; LVV = left venous valve; RVV = right venous valve (From Wessels et al.i39)
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