Developmental considerations
Towards the latter part of the twentieth century, one of us wrote an inflammatory chapter in which we suggested that knowledge of cardiac development was a hindrance rather than a help.10 At the time, there was some justification for that statement, since the alleged knowledge of the developmental events was mostly speculative, and tended to be based on comparisons made between the anatomy of the malformations and the presumed fashion of development of the normal heart. All of that has now changed. We now have detailed knowledge of the stages of anatomical development of the murine heart, and we are able to compare those changes to abnormal arrangements found in mice with deficient ventricular septation.11 Evidence is now also becoming available to show that the changes observed in the murine heart provide an accurate framework for understanding human cardiac development.12 These changes now permit us to provide an equally solid framework to underpin the categorisation of both solitary and multiple ventricular septal defects.
In terms of cardiac development, the first evidence of ventricular septation is seen subsequent to so-called “looping” of the primary heart tube. This occurs on the tenth day of development in the mouse heart (Figure 1A). This is equivalent to around 5 weeks of development in the human, representing stage 13 in the system developed by the Carnegie Institute.12 At this stage, the apical components of the developing ventricles are beginning to expand from the inlet and outlet parts of the heart tube by a process known as “ballooning”.13 As the apical components extend centrifugally, so the muscular part of the ventricular septum develops between them. Significantly, the septum first becomes evident when it is a meshwork of trabeculations. Such trabculations, at this early stage, form the greater part of the developing ventricular walls.14 Another significant feature of this early stage of development is that, initially, the developing atrioventricular canal is supported exclusively by the developing left ventricle, while the outflow tract arises entirely above the cavity of the developing right ventricle (Figure 1). The consequence of this arrangement is that, initially, all the blood entering the heart through the venous tributaries must pass through the interventricular communication so as to reach the outflow tract and the arterial pole. The channel between the ventricles as seen at this stage, therefore, can be described as the primary interventricular communication.
With ongoing development, there is significant remodelling of this initial interventricular communication.11 This can be described in terms of two phases. In the first phase, there is expansion of the atrioventricular canal such that the cavity of the right ventricle achieves its own direct communication with the cavity of the right atrium. It is this expansion that produces the right atrioventricular junction. Once the right ventricle has its own connection with the right atrium, the communication between the ventricles can be considered to represent a secondary interventricular communication (Figure 2A). Subsequent to expansion of the atrioventricular canal, however, the entirety of the outflow tract remains supported above the cavity of the right ventricle, which now possesses its own inlet. This, of course, is comparable to the situation found in the setting of double outlet right ventricle.1 The outflow tract, at this stage, is itself being divided into aortic and pulmonary channels by the formation and fusion of endothelial components described as cushions (Figure 2A). The role of these cushions is directly comparable to the steps taken by the cardiac surgeon in correcting double outlet right ventricle. The fusion of the cushions produces a shelf in the roof of the right ventricle, which tunnels the blood passing through the secondary interventricular communication into the aortic root (Figure 2B). During this process, additional endothelial cushions have been separating the atrioventricular canal into discrete tricuspid and mitral orifices. It is the formation of additional processes, known as tubercles, from the rightward margins of these cushions that eventually closes the remaining communication between the aortic root and the cavity of the right ventricle (Figure 2C).11 The channel that is eventually closed, therefore, is a tertiary interventricular communication. This is because the process of completion of ventricular septation will have converted the secondary interventricular communication into the subaortic outflow tract. This tunnelling of the aortic root to the left ventricle is the second phase of remodelling of the initial primary communication. And, if development proceeds normally, the proximal outflow cushions, which themselves have formed the shelf in the roof of the right ventricle, become muscularised and remodelled, thus forming the free-standing subpulmonary infundibulum.15 Only if development is incomplete, with the tertiary foramen persisting as a ventricular septal defect, do these myocardialised cushions persist as a muscular outlet septum.