Figure 1.9 a PAS

PAF

b

m

Dorsal

Right

Left

Ventral

this time, a gap exists between the septum and the atrioventricular cushions, with which it will eventually fuse (Figures 1.9 a and b). This gap is known as the primary atrial foramen. At E l 1.5, the mesenchymal cap of the septum fuses with the superior atrioventricular cushion, closing the primary atrial foramen and dividing the atrial chambers into left and right (Figure 1.9 c). However, at around the time that the primary atrial septum fuses with the atrioventricular cushions, another foramen appears within the primary atrial septum, close to the atrial wall (Figure 1.9c). This is the secondary atrial foramen (also called the oval foramen). As the secondary atrial foramen forms, a protrusion appears in the atrial wall, which has been called the secondary atrial septum (Figure 1.9c), although it is actually an infolding of the atrial wall rather than a true septum (Webb et a l, 1998a). This infolding overlaps the primary atrial septum, covering the oval foramen and forming a flap valve. This flap valve is vital to the survival of the embryo, allowing the oxygenated blood received in the right atrium to be shunted into the left atrium. At birth, the valve shuts due to the reduction in pressure in the pulmonary circulation, and so in the right atrium, that occurs

following inflation of the lungs. The valve then fuses shut. Failure of this fusion following closure results in a probe-patent oval foramen and occurs in a third of live births. Under normal physiological circumstances, however, it is of no clinical significance.

Six in 10,000 live births have an atrial septal defect (Larsen, 1993). Frequently, these are due to the flap valve not being large enough to cover the oval foramen.

Despite its clinical significance, little is understood about the cellular and molecular controls involved in the development of the primary atrial septum. However, molecular expression data in human and mouse suggest that the septum expresses proteins and genes, such as creatine kinase B and Pitx2, associated with the left atrium, rather than the right (Wessels et a l, 2000; Kitamura et a l, 1999). This supports the clinical

observation that isomerism of the right atrial appendages (the appendages being the mature derivatives of the embryonic atria), in which the heart has two morphologically right atrial appendages, is more frequently associated with an absence of the primary atrial septum than isomerism of the left atrial appendages (Brown and Anderson, 1999).

1.2.6.2 Ventricular septation

The ventricles are separated by the upward growth of the muscular

interventricular septum. The septum originates as a ridge of muscular tissue at the junction of the two ventricles at late E9.5. The interventricular septum grows to meet

and fuse with the atrioventricular and outflow tract cushions at E l 3.5 (Figures 1.10 a-c) separating blood flow in the right and left ventricles.

Currently, there are at least two models to explain the development of the interventricular septum. One model suggests that it forms by the coalescence of

trabeculae in the ventricles (Figures 1.11 a-c). This was suggested to occur in the chick by Ben-Shachar et al. (1985), who used scanning electron microscopy to analyse interventricular septal development. Another theory is that the apposition of the ventricles during their expansion forces the medial aspects of the ventricles inwards, forming the interventricular septum (Figures 1.11 d-f). Evidence for this was provided by De la Cruz et al. (1997), who labelled cells in the interventricular sulcus of

developing chicks with India Ink, prior to development of the interventricular septum. Subsequently, as the septum grew, the label was found in the apical third of the septum, supporting the idea that some growth was due to the apposition o f the expanding

ventricles forcing up the interventricular septum (black dots, Figures 1.11 d-f). There is no reason why fusing of trabeculae and the apposition of the expanding ventricles should be mutually exclusive explanations for the development o f the interventricular septum. In the mammalian heart, however, there is no direct evidence for either of these

Figure 1.10 Development of the interventricular septum Diagrammatic overview of interventricular septal growth.

a)-c) The interventricular septum grows from between the two ventricles to completely divide them once it fuses with the atrioventricular cushions and outflow tract cushions (not shown in these diagrams).

AVC = Fused atrioventricular cushions IC = inferior atrioventricular cushion IVS = interventricular septum

LV = left ventricle RV = right ventricle

Figure 1.10

a

b

Rostral

Right

Left

Caudal

Figure 1.11 Possible mechanisms for the development of the interventricular septum

a)-c) and d)-e) Diagrams representing the two models for the development of the interventricular septum. Blue represents epicardium, red myocardium and green endocardium.

a)-c) The model for interventricular growth resulting from fusion of the trabeculae. Following such fusion, endocardial channels may form within the septum, as shown by the endocardial “islands” in b) and c). These are progressively lost as the septum grows (c).

d)-f) Expansion o f the ventricular chambers o f the heart (indicated by the arrows) may result in apposition of the medial surfaces of the left and right ventricles and so

contribute to the growth of the interventricular septum. This might result in the trapping of epicardial cells at the base o f the septum (white arrow in f)). Formation of the

interventricular septum by this mechanism obligates an increase in its length. The developing interventricular septum is indicated by the boxed area. The black circle represents a hypothetical label. According this model, it can be seen how if the label is placed in the interventricular sulcus before appearance o f the septum (d)), it will

eventually become incorporated into the more apical region of the septum (f)). LA = left atrium

LV = let ventricle RA = right atrium RV = right ventricle