The R-N and R-L BAVs are different etiological entities. The R-N BAVs are the product of a morphogenetic defect that happens before the OT septation and that probably relies on an exacerbated nitric oxide-dependent epithelial-to-mesenchymal transformation. The R-L BAVs result from the anomalous septation of the proximal portion of the OT, likely caused by a distorted behavior of neural crest cells. Care should be taken in further work on BAV genetics because R-N and R-L BAVs might rely on different genotypes. Detailed screening for R-N and R-L BAVs should be performed for a better understanding of the relationships between these BAV morphologic phenotypes and other heart disease.

Background: Bicuspid aortic valve is the most frequent congenital cardiac malformation in humans. However, the morphogenesis of the defect is still unknown. Previous work showed that, in the Syrian hamster, congenital bicuspid aortic valves with the aortic sinuses arranged in ventrodorsal orientation are expressions of a trait the variation of which takes the form of a continuous phenotypic spectrum, ranging from a tricuspid aortic valve with no fusion of the ventral commissure to a bicuspid aortic valve devoid of any raphe. The present study was designed to elucidate the mechanism involved in the formation of bicuspid aortic valves in Syrian hamsters as a possible starting point for further investigation of this process in humans.Methods: The sample examined consisted of 80 embryos, aged between 10 days, 16 hours and 13 days, 1 hour postcoitum. Most (n = 59) of the embryos belonged to a laboratory-inbred family of Syrian hamsters with a high incidence of bicuspid aortic valves. The study was carried out using scanning electron microscopy and histological techniques for light microscopy.Results: Twenty-three embryos showed a still undivided conotruncus. In all of these cases there were six mesenchymal semilunar valve primordia protruding into the lumen of the conotruncus. In a further 29 embryos, the conotruncus had just divided into the aortic and pulmonary channels; the embryos were at the beginning of the valvulogenesis. In 13 of these 29 embryos there were three well-defined aortic valve cushions, right, left, and dorsal, whereas in the other 16, the right and left valve cushions were more or less fused toward the lumen of the aorta; when they were completely fused, only two aortic valve cushions, a ventral and a dorsal, could be identified. In the remaining 28 embryos, the aortic valve cushions showed a marked degree of excavation. In 23 of these cases, the valve exhibited a basically tricuspid architecture, whereas it was unequivocally bicuspid in the other five.Conclusions: All variants of the aortic valve morphologic spectrum occurring in the Syrian hamster develop from three mesenchymal valve cushions, right, left, and dorsal, after normal septation of the conotruncus. The bicuspid condition of the aortic valve is not the consequence of improper development of the conotruncal ridges, conotruncal malseptation, valve cushion agenesis, or lesions acquired after a normal valvulogenesis. Fusion of the right and left valve cushions at the beginning of the valvulogenesis appears to be a key factor in the formation of bicuspid aortic valves. Each aortic valve acquires its specific morphology prior to the end of the valvulogenetic process.

The bifoliate, or bicuspid, aortic valve (BAV) is the most frequent congenital cardiac anomaly in man. It is a heritable defect, but its mode of inheritance remains unclear. Previous studies in Syrian hamsters showed that BAVs with fusion of the right and left coronary leaflets are expressions of a trait, the variation of which takes the form of a phenotypic continuum. It ranges from a trifoliate valve with no fusion of the coronary leaflets to a bifoliate root devoid of any raphe. The intermediate stages are represented by trifoliate valves with fusion of the coronary aortic leaflets, and bifoliate valves with raphes. The aim of this study was to elucidate whether the distinct morphological variants rely on a common genotype, or on different genotypes. We examined the aortic valves from 1 849 Syrian hamsters belonging to a family subjected to systematic inbreeding by full-sib mating. The incidence of the different trifoliate aortic valve (TAV) and bifoliate aortic valve (BAV) morphological variants widely varied in the successive inbred generations. TAVs with extensive fusion of the leaflets, and BAVs, accounted for five-sixths of the patterns found in Syrian hamsters considered to be genetically alike or virtually isogenic, with the probability of homozygosity being 0.999 or higher. The remaining one-sixth hamsters had aortic valves with a tricuspid design, but in most cases the right and left coronary leaflets were slightly fused. Results of crosses between genetically alike hamsters, with the probability of homozygosity being 0.989 or higher, revealed no significant association between the valvar phenotypes in the parents and their offspring. Our findings are consistent with the notion that the BAVs of the Syrian hamster are expressions of a quantitative trait subject to polygenic inheritance. They suggest that the genotype of the virtually isogenic animals produced by systematic inbreeding greatly predisposes to the development of anomalous valves, be they bifoliate, or trifoliate with extensive fusion of the leaflets. We infer that the same underlying genotype may account for the whole range of valvar morphological variants, suggesting that factors other than genetic ones are acting during embryonic life, creating the so-called intangible variation or developmental noise, and playing an important role in the definitive anatomic configuration of the valve. The clinical implication from our study is that congenital aortic valves with a trifoliate design, but with fusion of coronary aortic leaflets, may harbour the same inherent risks as those already recognised for BAVs with fusion of right and left coronary leaflets.

It has been generally assumed that the outflow tract of the chondrichthyan heart consists of the conus arteriosus, characterized by cardiac muscle in its walls. However, classical observations, neglected for many years, indicated that the distal component of the cardiac outflow tract of several elasmobranch species was composed of tissue resembling that of the ventral aorta. The present study was outlined to test the hypothesis that this intrapericardial, non-myocardial component might be homologous to the actinopterygian bulbus arteriosus. The material consisted of Atlantic catshark adults and embryos, which were examined by means of histochemical and immunohistochemical techniques for light and fluorescence microscopy. In this species, the distal component of the outflow tract differs histomorphologically from both the ventral aorta and the conus arteriosus; it is devoid of myocardium, is covered by epicardium and is crossed by the coronary arterial trunks. In the embryonic hearts examined, this distal component showed positive reactivity for 4,5-diaminofluorescein 2-diacetate (DAF-2DA), a fluorescent nitric oxide indicator. These findings, together with other observations in holocephals and several elasmobranch species, confirm that chondrichthyans possess a bulbus arteriosus interposed between the conus arteriosus and the ventral aorta. Therefore, the primitive heart of gnathostomates consists of five intrapericardial components, sinus venosus, atrium, ventricle, conus arteriosus and bulbus arteriosus, indicating that the bulbus arteriosus can no longer be regarded as an actinopterygian apomorphy. The DAF-2DA-positive reactivity of the chondrichthyan embryonic bulbus suggests that this structure is homologous to the base of the great arterial trunks of birds and mammals, which derives from the embryonic secondary heart field.

SummaryWe studied the morphology of the aortic valves of 1,036 Syrian hamsters belonging to two families subjected to high endogamous pressure. Most (n=955) specimens were examined using a corrosion-cast technique. In the remaining 81 specimens, valvar morphology was assessed by means of a stereomicroscope, and in 18 of these cases a histologic study was also performed. In one of the families, a high proportion (30.5%) of hamsters had aortic valves with two leaflets, the aortic sinuses being oriented ventrodorsally. The percentage of such anomalous valves was found to be positively correlated with the inbreeding coefficient of specimens. In the other family, the occurrence of an aortic valve with two leaflets was a sporadic event. Stereoscopic and histologic observations demonstrated that, in 52 of 63 aortic valves with three leaflets, the ventral commissure between the right and left leaflets was partially fused, while in 10 other cases this commissure was completely fused. In addition, in nine of 18 aortic valves with two leaflets, there was a more or less well-developed raphe located in the ventral aortic sinus, approximately where the true ventral commissure would have been. Our observations suggest the existence of a continuous spectrum of aortic valvar morphology, ranging from a valve with three leaflets and no fusion of the ventral commissure to an aortic valve with two leaflets devoid of any raphe. This spectrum seems to be the result of the interaction of genetic and intrauterine environmental factors. Results of crosses between both related and unrelated hamsters suggest that the observed morphology in individuals is the result of quantitative inheritance.