Manuel Cardo

Fusion of valve cushions as a key factor in the formation of congenital bicuspid aortic valves in Syrian hamsters

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.

Coronary artery anomalies and bicuspid aortic valves in the Syrian hamster

Summary:The condition of coronary arteries and aortic valves was studied in 552 Syrian hamsters belonging to a single family subjected to high endogamous pressure. The study was carried out using a corrosion-cast technique. In 178 hamsters the aortic valve was bicuspid. In 138 specimens, 54 of them with normal aortic valves and 84 with bicuspid aortic valves, anomalies in the origin of the coronary arteries could be classified in three morphologic types: left coronary artery from the pulmonary trunk (36 cases); single right coronary artery (84 cases); left coronary artery from the dorsal aortic sinus (18 cases). Results of a ξ2 contingency test show that the frequency of left coronary artery from the pulmonary trunk and single right coronary artery significantly increases when the aortic valve is bicuspid. The present findings suggest that there is a developmental complex consisting of bicuspid aortic valve and anomalous origin of the coronary arteries.

The coronary arteries of the Syrian hamster, Mesocricetus auratus (Waterhouse 1839)

Bearing in mind that the Syrian hamster provides an animal model for the study of congenital coronary artery anomalies, we decided to undertake a definition of its normal coronary artery pattern. The sample examined consisted of 1204 specimens. They were studied both histologically and by means of a corrosion-cast technique. The course of the coronary arteries in this species is intramyocardial. The right coronary artery has two principal branches: the right circumflex branch and the dorsal interventricular branch. The conal branch usually originates from the main trunk of the right coronary artery. The main branches of the left coronary artery are the obtuse marginal branch, the left circumflex branch, and usually a dorsal ventricular branch as well. The ventral interventricular branch is often absent. When it is present, it always originates from the left coronary artery and seldom reaches the apex of the heart. The interventricular septum is principally supplied by one, or rarely two, septal arteries arising from the right and/or left coronary arteries. According to the number and origin of these vessels, three septal coronary artery patterns were established; namely, the right, the left, and the right-left septal patterns. In the Syrian hamster, the left septal pattern is the most frequent (70.4%). The right septal pattern occurred in 28.1% of the specimens studied, whereas the right-left septal pattern was only found in 1.5% of them.

Bicuspid aortic and pulmonary valves in the Syrian hamster

We studied the conditions of the aortic and pulmonary valves of 153 Syrian hamsters belonging to a single family subjected to high endogamous pressure. Semilunar valves of 143 specimens were examined using a stereomicroscope, and in 5 of these cases a histologic study was also performed. The remaining 10 specimens were studied by means of scanning electron microscopy. In 77 specimens both semilunar valves were normal. The aortic valve was bicuspid and the pulmonary valve was normal in 46 animals, while a normal aortic valve and a bicuspid pulmonary valve occurred in 24. In the remaining 6 specimens both semilunar valves were bicuspid. All bicuspid semilunar valves detected herein showed the same morphotype, namely with the leaflets oriented ventrodorsally. The incidence of these anomalous valves did not significantly differ between sexes. Results of a chi 2-test substantiate that conditions of both outflow tract semilunar valves are independent traits. Thus, concurrence of a bicuspid aortic valve and a bicuspid pulmonary valve in an individual is a random event. The present findings support the assumption that bicuspid aortic and pulmonary valves have different morphogenetic origin, although factors producing a bicuspid aortic valve and those leading to a bicuspid pulmonary valve are not mutually exclusive.

Cartilage in the Aortic Valve and Its Relationship with the Aortic Valve Morphology in Syrian Hamsters

We conducted a light-microscopic histologic study of the aortic valves of 224 Syrian hamsters aged between 1 and 771 days. Most of the hamsters examined belonged to a single laboratory-inbred family with a high incidence of bicuspid aortic valves (BAVs). In 146 specimens the aortic valve was tricuspid, and in 107 of them the ventral commissure was more or less fused. The remaining 78 specimens showed a BAV with the aortic sinuses oriented ventrodorsally. In 33 BAVs a raphe was located in the ventral aortic sinus. Cartilaginous foci were present in the aortic valves of 86 specimens, 40-771 days old. The foci were located at two different sites, namely in the ventral wall of the valve and/or in the dorsal aortic sinus. Statistical analyses substantiate that (1) chondrogenesis begins earlier in BAVs, and especially in those having a raphe, than in tricuspid aortic valves and (2) the location of the cartilaginous foci is significantly associated with the morphology of the aortic valve. The present findings support the hypothesis that, in the Syrian hamster, cartilage forms in the aortic valve as a response to locally intense mechanical stimulation.

Anomalous origin of the left coronary artery from the dorsal aortic sinus and its relationship with aortic valve morphology in Syrian hamsters

The condition of the aortic valve and the origin of the coronary arteries were examined in 2413 Syrian hamsters aged between 1 and 823 days, belonging to nine inbred laboratory families. The specimens were studied with either a stereomicroscope, a corrosion-cast technique, or histological techniques (light microscopy). The aortic valve was tricuspid in 1823 (75.5%) cases, and bicuspid in the remaining 590 (24.5%). In all bicuspid aortic valves there were two aortic sinuses, a ventral and a dorsal, each supporting one cusp. The left coronary artery arose from the dorsal aortic sinus in 71 (2.9%) hamsters, eight of which died unexpectedly between ages 1 and 622 days. In 29 (40.8%) of the 71 cases, the aortic valve was tricuspid and the right coronary artery originated from the right aortic sinus. In the remaining 42 (59.2%) cases, the aortic valve was bicuspid and the right coronary artery arose from the right side of the ventral aortic sinus. Results of a chi 2 contingency test demonstrated that the frequency of left coronary artery arising from the dorsal aortic sinus significantly increased when the aortic valve was bicuspid. This fact, together with previously reported data on coronary artery anomalies in the Syrian hamster, suggests that the left coronary artery arising from the dorsal aortic sinus may be an expression of a single morphogenetic defect which is expressed as bicuspid aortic valve in some cases, anomalous origin of the left coronary artery in others, or in the simultaneous occurrence of these two cardiac abnormalities.

Embryological Evidence for the Formation of a Quadricuspid Aortic Valve in the Syrian Hamster

Congenital quadricuspid aortic valve is a rare anomaly, the morphogenesis of which remains unclear. In this study we report the case of a Syrian hamster embryo that presented an aortic valve with four valve cushions instead of three. The embryo, aged 12 days and 2 hours postcoitum, was at an early stage of valvulogenesis. It was examined using semithin sections of the heart. Two of the four valve cushions were located, one in the dorsal and the other in the left-ventral position, corresponding, respectively, to the dorsal and left valve cushions of a normal aortic valve. The remaining two cushions were situated in the right-ventral position. They were joined at the level of their basal portions and were less developed in size than the other cushions. This report seems to be the first embryological evidence for the formation of a quadricuspid aortic valve. The present findings strongly suggest that the anomalous valve originated from three mesenchymal anlagen and that the supernumerary valve cushion resulted from the division of the anlagen that normally gives rise to the right valve cushion.

Anomalous origin of the left coronary artery from the pulmonary trunk and its relationship with the morphology of the cardiac semilunar valves in Syrian hamsters

SummaryThe conditions of the aortic and pulmonary valves and the arrangement in the origin of the coronary arteries were studied in 247 Syrian hamsters belonging to a single family subjected to high endogamous pressure. Most specimens (n=216) were examined using a stereomicroscope. The remaining 31 were studied histologically. In 110 specimens both cardiac semilunar valves were normal. The aortic valve was bicuspid and the pulmonary valve was normal in 79 animals, while a normal aortic valve and a bicuspid pulmonary valve occured in 37. In the remaining 21 specimens both semilunar valves were bicuspid. In 34 cases, the left coronary artery originated from the pulmonary trunk. Statistical analyses indicate that there is no significant relationship between the bicuspid condition of the pulmonary valve and the fact that a coronary artery arises from the pulmonary trunk. On the other hand, they substantiate that the frequency of this coronary artery anomaly significantly increases when the aortic valve is bicuspid. The present findings agree with the hypothesis that abnormal migration of the neural crest cells may be responsible for the combined occurrence of bicuspid aortic valve and anomalous origin of the left coronary artery from the pulmonary trunk. In addition, they suggest that the neural crest cells involved in the formation of the pulmonary valve diverge from those migrating into the aortic valve and those imposing spatial order upon the development of the proximal coronary arteries.

Anomalous origin of the left coronary artery from the nonfacing aortic sinus: A study in the Syrian hamster.

A coronary artery that arises from the nonfacing (posterior or dorsal) aortic sinus is regarded as having an anomalous origin. We studied 34 Syrian hamsters in which the left coronary artery originated from the nonfacing aortic sinus. All hamsters belonged to a single family subjected to high endogamous pressure in our laboratory. Twenty-four specimens were examined using a corrosion-cast technique and scanning electron microscopy, whereas the remaining 10 were studied histologically. The aortic valve was normal in 15 cases, whereas it was bicuspid in the other 19 cases. In each specimen of our series, the left coronary artery arose with an acute angle with respect to the aortic valve. Moreover, when the coronary ostium was located in the center of the nonfacing aortic sinus, the proximal coronary artery had an intramural aortic course. These left coronary artery arrangements might underlie an unfavorable coronary circulation physiology. Our morphologic findings agree with the morphogenetic hypothesis that each aortic sinus has the potential to develop coronary artery buds, which hollow out from the aorta to become coronary artery trunks.

Mucoid dysplasia of tricuspid and congenital bicuspid aortic valves in Syrian hamsters (Mesocricetus auratus)

A histological study was made of the aortic valves of 141 Syrian hamsters aged between 35 and 657 days, belonging to an inbred laboratory colony with a high incidence of congenital bicuspid aortic valves. A tricuspid aortic valve was found in 81 specimens, whereas the remaining 60 possessed a bicuspid aortic valve. In all bicuspid valves there were two aortic sinuses, a ventral and a dorsal, each supporting one cusp. Thirty-three (23.4%) of the 141 specimens showed mucoid dysplasia of the aortic valve. The defect was characterized by thickening of the valve cusps and disruption of the fibrosa layer accompanied by an increased amount of glycosaminoglycans. Ten (12.3%) of the 81 tricuspid aortic valves and 23 (38.3%) of the 60 bicuspid aortic valves were dysplastic. This difference was statistically significant (P < 0.001). The findings indicate that, in the Syrian hamster, the simultaneous occurrence of bicuspid aortic valve and aortic valve dysplasia is not a random event. However, the fact that these valve defects also occur independently suggests that there is no primary morphogenetic dependence between them, but that some other cause predisposes to their concurrence.