Once it has canalized in the mediastinum and gained its access to the heart, the pulmonary vein opens initially as a solitary orifice adjacent to the atrioventricular junctions. This is the arrangement not only in the mouse heart (Fig. 2) but also in the developing human heart (Fig. 9). The myocardium surrounding this area stains negatively for atrial natriuretic factor but positively for connexin40, indicating that it is fast-conducting and, hence, not part of the primary heart tube (Fig. 7). This mediastinal myocardium becomes integrated into the developing atrial chambers concomitant with the remodeling of the atrioventricular canal and also with remodeling of the systemic venous tributaries (Cai et al., 2003; Soufan et al., 2004; Fig. 8). It is the overall remodeling that sets the scene for atrial septation, with the primary atrial septum also taking its origin from the mediastinal myocardium, which then forms the bodies of both the definitive right and left atrial chambers. As part of the remodeling, with growth of the embryo, the channel draining the veins from the left side of the body decreases significantly in size. It becomes incorporated into the developing left atrioventricular groove as the left superior caval vein in the mouse (Fig. 10) and eventually as the coronary sinus in man (Fig. 9). As it becomes an integral part of the left atrioventricular groove, the venous channel retains its own discrete walls (Figs. 9, 10) but comes to open within the confines of the systemic venous component of the right atrium (Knauth et al., 2002). It is only by the time that it has shifted to open exclusively within the right atrium that the junction between the systemic venous tributaries and the developing right atrium become anatomically discrete, this being heralded by the appearance of the so-called venous valves (Fig. 2). By this time, when judged relative to the extent of the secondary and mediastinal myocardium, the primary myocardium of the atrial component of the tube has decreased markedly in size (Soufan et al., 2004). It now forms a corridor of tissue in the inferior and posterior wall of the developing right atrium, running from the atrioventricular canal to the so-called septum spurium. The rightward shift of the primary myocardial corridor, along with the incorporation of the atrioventricular canal, takes place as the mediastinal myocardium expands to form the posterior walls and roofs of the newly forming right and left atrial chambers. The primary atrial septum, known to be mediastinal myocardium because it stains positively for connexin40 but negatively for atrial natriuretic peptide, then grows toward the atrioventricular cushions to divide the two atrial chambers. The primary septum, along with the strip of tissue forming the posterior wall of the right atrium to the level of the left venous valve, also stains positively for pitx2, showing that it is molecularly left (Franco et al., 2000). The primary atrial septum, having grown to the right side of the pulmonary venous orifice, places the newly developed pulmonary venous component within the morphologically left atrium (Webb et al., 1998, 2000). The mediastinal myocardium, therefore, is always distinct from the sinus venosus. When the openings of the systemic venous tributaries are first recognized as discrete structures, subsequent to formation of the venous valves, they are exclusively part of the morphologically right atrium. The myocardium of the pulmonary venous component stains positively for connexin40, showing that, unlike the mouths of the systemic venous tributaries, it has never been part of the primary heart tube.
Figure 9. a,b: Sections from a human embryo at Carnegie stage 16, sectioned in the sagittal plane (a) and transverse plane (b) before growth of the primary septum. Note that, at this stage of development in the human, the pulmonary vein is a solitary channel opening to the atrium adjacent to the atrioventricular junction. Note also that the left sinus horn (future coronary sinus) is now incorporated within the junction but retains its discrete myocardial walls. LV, left ventricle; LA, left atrium; AVC, atrioventricular canal; R/L SH, right/left sinus horn; EPV, entrance pulmonary vein; IC, inferior cushion.
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Figure 10. a,b: These cranial views are from the caudal segment of the heart of a mouse embryo, with 42 somites and approximately 10.5 days of development; the left-sided systemic venous channel (left sinus horn) is becoming incorporated into the left atrioventricular junction as the coronary sinus (a) but is retaining its own walls (b). Only at this stage do the venous valves develop to demarcate the boundaries of the systemic veins (see also the reconstruction in Fig. 8d). R/L A, right/left atrial appendage; vv. venous valves; r/l pr, right/left pulmonary ridge; LSH, left sinus horn.
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In the mouse heart, the pulmonary vein retains its position as a solitary orifice adjacent to the left atrioventricular junction (Fig. 2). In the human heart, in contrast, subsequent to the division of the primary atrial chamber into its right and left parts by growth of the primary atrial septum, the pulmonary veins remodel so as to gain separate entrances at the four corners of the roof of the body of the left atrium (Fig. 3). It is only as the right pulmonary veins gain their entrance to the atrial roof that, in the human heart, we find infolding of the wall between their mouths and the orifices of the systemic venous sinus entering the right atrium (Webb et al., 2001). This infolding produces the so-called septum secundum, in reality the superior interatrial fold (Röse, 1899; Anderson et al., 2002). In the mouse heart, this so-called septum is an insignificant structure, because the pulmonary veins open into the left atrium through a solitary orifice adjacent to the atrioventricular junction (Fig. 2). In humans, there is a specific anomaly involving the right upper pulmonary vein that is known as a sinus venosus defect. In this lesion, a hole is found joining together the atrial chambers but outside the confines of the atrial septum (Al Zaghal et al., 1997). The hole cannot exist until the right pulmonary veins have achieved their definitive position on the dome of the left atrium subsequent to the completion of atrial septation. It is spurious, therefore, to argue that evidence from the so-called sinus venosus defect lends credence to the notion that the pulmonary vein originates from the embryonic systemic venous sinus (Blom et al., 2001). Any explanation of formation of the so-called sinus venosus defect (Anderson et al., 2004) must take account of the mechanisms of incorporation of the mediastinal myocardium to form the bodies of both atrial chambers, along with the primary atrial septum and the pulmonary component of the morphologically left atrium.