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The morphogenesis of the four-chambered heart is one of the most intricate processes in higher vertebrate embryology, which involves a program of gene expression, differential growth, spatial organization, and cell movement. Since diffusion of nutrients from the surrounding tissues, which nourishes the rapidly growing embryo in its earliest stages, soon becomes insufficient, the embryonic cardiovascular system is the first functioning organ to appear. Thus, a primitive but functioning circulation with a beating heart is already accomplished during the beginning of the fourth week of development. During development, the primitive single-circuited tubular heart must evolve into a four-chambered double-circuited structure, while it is already committed to its lifelong task, i.e. maintaining circulation. This requires profound and complex remodeling, which is difficult to comprehend and makes great demands on one’s spatial insight. With the advent of molecular technology a new era in cardiac embryonic research has begun and the mechanisms involved in the sequential processes of cardiac development are now starting to become unraveled.

At stage 11, the heart tube has looped completely and despite the fact that it has lost its left-right symmetry, it can still be considered a homogeneous structure from both morphological and functional points of view. The embryonic cardiomyocytes, derived from the cardiogenic plate mesoderm, form a layer, which is dubbed primary myocardium. Impulse propagation and the subsequent contraction waves, which initially have a peristaltoid form, run from the inflow to the outflow end of the heart tube, i.e. in postero-anterior direction. The presence of cardiac jelly guarantees adequate propulsion of blood. From the outset on, pacemaker activity is dominant at the inflow end of the heart tube, although coupling of excitation and contraction is first achieved in the future ventricular area [Van Mierop 1967]. Which mechanisms are responsible for the pacemaker dominance of the inflow end is as yet unknown but it may well be related to the anteroposterior differentiation of the heart tube as a whole, in which retinoic acid signaling plays a quintessential role [Xavier-Neto et al. 2001]. Moreover, many molecular factors involved in early cardiac development [reviewed by e.g. Franco et al. 1998 and Xavier-Neto et al. 2001] exhibit an antero-posterior expression gradient and thus a gradual change of electrochemical properties along the heart tube.

The posterior most part of the heart tube is commonly known as the sinus venosus which receives the venous blood from the right and left side of the embryo. It consists of two horns connected to the rest of the heart tube via the sinu-atrial foramen [Steding et al., 1990]. These horns receive blood from the vitelline, umbilical and common cardinal veins. Reconstructions of the venous pole of the heart in mouse embryos, based on molecular expression patterns in the surrounding myocardium, have shown that, at least in mice, a sinus venosus does not exist at any time in development. Instead, the systemic venous tributaries, i.c. the right and left sinus horns, drain separately and directly into the atria [Soufan et al., 2004]. Whether this situation is comparable to what occurs in human embryos remains to be proven. In this atlas we will therefore conform to the current opinion regarding development of the venous pole in man. In contrast to what is seen in most vertebrate embryos, asymmetry of the venous pole in human embryos, with the left sinus horn being deviated to the right, appears to be present from the beginning onward [Knauth et al., 2002]. When viewed from the luminal side of the heart tube, a bifurcation is seen where the two horns meet [Vernall, 1962; Steding, 1990], like the crotch in a pair of trousers [Webb, 1998]. This structure is called the sinus septum and is situated caudal to the dorsal mesocardium.

As mentioned in chapter 2, the ventricles balloon out from the greater curvature of the tubular heart at the end of the looping stage by means of expansive apical growth [Harh & Paul, 1975; Steding & Seidl, 1980; Lamers et al., 1992]. As will be discussed in the next chapter, this ballooning is accompanied by the formation of myocardial trabeculation. In between the ventricles a gradually elongating ridge is formed, which is dubbed the (muscular part of the) interventricular septum. Rather than being passively formed by expansion of the trabeculed ventricles, the interventricular septum is an initially fenestrated structure that is formed by aggregation and compaction of apically enlarging trabeculae, as has been demonstrated in chicken embryos [Harh & Paul, 1975]. It should be stressed again that the inner curvature is not involved in the ballooning process but instead retains its primordial tubular phenotype, as do the outer curvature parts of the interjacent segments, being the sinus venosus, the atrioventricular canal and the outflow tract. By now, the primitive heart is on the eve of intricate developmental events which will transform the single heart tube into a double circuited structure that selectively passes the blood from the systemic veins to the pulmonary arteries and the blood from the pulmonary veins to the aorta. To this end, two separate pathways must be formed, which demands that the atria and ventricles will be connected to the proper up- and downstream segments.

As stated before, the cardiac compartments develop as progressively enlarging balloon-shaped distensions at the outer curvature of the atrial and ventricular loops. In the ventricular region this ballooning is accompanied by the formation of myocardial trabeculae, visible from stage 12 onward, which allows the ventricles to increase in size in the absence of a coronary circulation [Van Mierop & Kutsche, 1984]. Moreover, they enhance contractility [Challice & Virágh, 1973] and play an important role in the coordination of intraventricular conduction [De Jong et al., 1992]. Growth of the ballooning ventricles is achieved by tissue proliferation in the outer (compact) myocardium, which initially is only a few cell layers thick [Rumyantsev, 1977; Thompson et al., 1995; Henderson & Copp, 1998]. It is hypothesized that, as a result, the inner myocardial and endocardial layers, that do not contribute to this expansion, “crack open”. The tissue bridges between the thus formed excavations, that become subsequently recoated with endocardium, are to become the primary trabecula. This “craking open” may be facilitated by the peristaltoid contraction patterns [Thompson et al., 2000] as well as the ballooning process itself [Sedmera et al., 2000]. This process repeats itself continuously during development, leading to a radially thickening layer of trabecula, with a proliferating outer layer that retains its compact structure [Steding & Seidl, 1980; Mikawa et al., 1992].