Morphogenesis Almost three-quarters of a century ago, Maude Abbott commented that understanding of cardiac development should provide the basis for appreciation of the different types of congenitally malformed hearts.24 Thanks to the development of episcopic microscopy,25 we now have the evidence in hand to substantiate her prediction The findings using this technique with regard to normal development of the ventricular septum provide evidence pertinent to the concepts used previously to differentiate and describe the phenotypes Evidence from genetically perturbed mice provides additional evidence in this regard to support the notion that all defects can be categorized in terms of being muscular, perimembranous, or doubly committed and juxtaarterial As already discussed in Chapter 3, ballooning of the apical components of the developing ventricles, from the inlet and outlet components of the ventricular loop, produces the first evidence of discrete morphologically left and right ventricular chambers As the apical components balloon, the primordium of the muscular ventricular septum develops between them (Fig 32.15A) FIG 32.15 Images taken from a three-dimensional dataset prepared using episcopic microscopy from a developing mouse at embryonic day (E) 10.5 (A) Frontal section illustrating how, at this early stage, the atrioventricular (AV) canal opens to the cavity of the developing left ventricle (single-headed arrow) The interventricular communication (double-headed arrow) provides access to the developing right ventricle Note that the apical muscular ventricular septum (star) appears between the ballooning apical ventricular components (B) Section, also in the frontal plane, from a developing mouse sacrificed at E11.5 Expansion of the atrioventricular canal has permitted the cavity of the right atrium to open directly to the cavity of the developing right ventricle (single-headed arrow) By this stage, the musculature of the atrioventricular canal is becoming sequestrated to form the atrial vestibule; the short arrows mark the developing plane of atrioventricular insulation Note that the developing atrioventricular bundle can be recognized on the crest of the muscular septum Previous investigations had shown that the atrioventricular bundle is formed on the crest of the developing muscular septum.26 These studies, by charting the location of the bundle and following the relationship between the crest of the septum and the insulating plane between the atrial and ventricular septa, showed that postnatally the initial muscular septum gives rise to the entirety of the muscular ventricular septum It had been suggested that an “atrioventricular canal septum,” along with a “conal septum,” were part of the definitive muscular ventricular septum.21 Absence of the alleged “atrioventricular canal” component was used to justify description of the perimembranous inlet defects associated with either atrioventricular septal alignment or malalignment as an “atrioventricular canal” or type III defect.27,28 As shown in Chapter 3 and as discussed in Chapter 31, a septum is indeed formed to divide the atrioventricular canal It is formed subsequent to muscularization of the mesenchymal cap of the primary septum and the vestibular spine.29 This component, however, subsequent to the completion of atrial septation, is sequestrated on the atrial aspect of the insulating plane It does not form part of the muscular ventricular septum (see Fig 32.15B) The sequestration of the atrioventricular canal myocardium and the separation of the atrioventricular junctions by growth of the vestibular spine accompany the process of expansion of the canal This, in turn, involves remodeling of the initial embryonic interventricular communication such that the right atrial cavity is placed in direct communication with the developing right ventricle Subsequent to this stage of development, however, the outflow tract remains supported only by the developing right ventricle (see Fig 32.16, left), even though its proximal part is already being divided into potential aortic and pulmonary components by fusion of the outflow cushions (see Fig 32.16, right) FIG 32.16 Sections taken from the same episcopic dataset as shown in Fig 32.15B As seen at left, although the right atrium now connects directly with the right ventricle (single-headed arrow), the outflow tract remains exclusively supported above the right ventricular cavity The blood entering its dorsal component, which will become the aortic root, must pass at this stage through the embryonic interventricular communication (doubleheaded arrow) This area, with the crest of the muscular ventricular septum as its floor (star), is roofed by the inner heart curvature The panel at right shows how the endocardial cushions within the outflow tract are fusing to separate the putative aortic and pulmonary outlets It is only with ongoing development that the aortic component of the outflow tract is moved dorsally and leftward This process also brings the fused proximal outflow cushions in line with the crest of the muscular ventricular septum, thus walling the aorta into the left ventricle And only when the aortic root is committed to the left ventricle is it possible for the developing embryo to close the persisting embryonic interventricular communication This is achieved by the growth of so-called tubercles from the ventricular surfaces of the atrioventricular cushions, with the tubercles subsequently becoming the membranous part of the ventricular septum (Fig 32.17A) After the completion of septation, the core of the fused outflow cushion mass is converted into an area of fibroadipose tissue This area separates the muscularized surface of the cushions from the aortic root (see Fig 32.17B) The muscularized surface becomes the freestanding muscular infundibular sleeve, also known as the pulmonary conus Because of the attenuation of the core of the initial embryonic cushion mass, there is no “conal” or “outlet” ventricular septum to be found in the normal postnatal heart The postnatal ventricular septum, therefore, has only muscular and membranous