Development relative to the variable patterns of multiple ventricular septal defects
It is the changes that take place during normal development that now underscore our understanding of the phenotypic variations to be found amongst isolated ventricular septal defects. The inferences made from normal development, furthermore, have now been validated by the finding of such defects in developing mice in which the Furin enzyme had been genetically perturbed. We are unsure precisely why perturbation of the Furin enzyme should interfere with ventricular septation, but the interrogation of three-dimensional datasets from developing fetuses sacrificed at the stage when, in normal development, the ventricular septum is intact, show the phenotypic features in different fetuses of the different types of ventricular septal defect. Analysis of normal development has also shown that the muscular ventricular septum is formed by the coalescence of the components of the initial trabecular meshwork. It is often presumed that these trabeculations come together to form the compact layer of the ventricular walls. This is not the case.14 The trabeculations do coalesce, nonetheless, to form the papillary muscles of the atrioventricular valves, and also the muscular part of the ventricular septum. In the mice in which the Furin enzyme was perturbed, the process of septal coalescence was disturbed, producing the arrangement also known as the Swiss-cheese septum (Figure 3A). The inference can be made that failure of such coalescence might be less severe, leaving discrete but multiple defects with muscular borders at any site within the septum. In a proportion of the mice having undergone perturbation of the Furin enzyme, there was persistence of the tertiary embryonic interventricular communication. In these mice, there was fibrous continuity in the postero-inferior quadrants of the defects between the leaflets of the tricuspid and mitral valves. This, of course, is the phenotypic feature of the perimembranous defect.16 In a small number of the mice with perturbation of the Furin enzyme, furthermore, there was evidence that the proximal outflow cushions had fused so as to separate the aortic and pulmonary roots, but had failed to muscularise. This had left an interventricular communication between the outflow tracts that was bordered cranially by the fused proximal outflow cushions. It is this feature that is diagnostic for the ventricular septal defects that are juxta-arterial.15 The inference can also be made, on the basis of the development observed in the normal mice, and those suffering perturbation of the Furin enzyme, that either the perimembranous or juxta-arterial defects could co-exist with defects in the apical muscular part of the septum. It also follows that multiple individual defects might be anticipated to exist within the muscular septum, or that failure of coalescence could hav been sufficiently severe to produce the Swiss-cheese arrangement. All of these possibilities are borne out by examination of hearts with ventricular septal defects as found in archival collections.