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.