Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus

Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.     

Positional abnormalities of atrioventricular valves in transposition of the great arteries including double outlet right ventricle, atrioventricular valve straddling and malattachment.

Positional abnormalities (straddling or overriding) of the atrioventricular (A-V) valves were studied using angiographic, sector scan echocardiographic and postmortem anatomic data in 10 patients with transposition of the great arteries including double outlet right ventricle. Group I included six patients with tricuspid valve abnormalities. This group was further classified into: (a) patients with anular straddling and abnormal attachment of portions of the tricuspid leaflets in the left ventricle (malattachment) or on the ventricular septum, or both (four patients with d-transposition of the great arteries and hypoplastic right ventricle); and (2) patients with malattachment of portions of the tricuspid valve leaflet to the crest or left ventricular surface of the septum (septal malattachment) without significant anular straddling (two patients with d-transposition of the great arteries).Group II included four patients with mitral valve abnormalities without significant anular straddling, further classified into: (1) patients with septal malattachment of the portions of the mitral valve to the crest and right ventricular surface of the ventricular septum (two patients with double outlet right ventricle); and (2) patients with ventricular malattachment of portions of the mitral valve leaflets to the papillary muscles in the right ventricle (two patients with ventricular septal defect and discordant criss-cross atrioventricular connections).On the basis of these observations and reported experience, two main types of positional abnormalities of the A-V valves were recognized: (1) anular straddling in which the A-V anulus straddled the ventricular septum above the contralateral ventricle, together with ventricular leaflet malattachments, and (2) leaflet malattachment of either the septal or ventricular type without significant straddling of the valve anulus. Angiocardiography and sector scan echocardiography helped to identify these abnormalities of the A-V valves.     

Morphology and classification of atrioventricular defects

Anatomical studies were made on 114 necropsy specimens of atrioventricular defects with atrioventricular concordance. The malformation is characterised by disproportion between the ventricular inlet and outlet dimensions and a malorientation of the aortic valve relative to the atrioventricular valve or valves. Associated with this there is a characteristic 'scopped-out' appearance of the muscular ventricular septum, gross abnormalities of the membranous components of the septum as compared with the normal heart, and narrowing of the aortic outflow tract. Hearts with these anatomical features can be divided into partial and complete forms depending on the morphology of the atrioventricular annuli. In the partial form the septal leaflets are conjoined to give separate mitral and tricuspid orifices, the conjoined leaflets being displaced into the ventricles and usually attached to the crest of the septum. In the complete form, anterior and posterior components of the 'septal' leaflets are separate, so that a single valve orifice connects the atrial to the ventricular chambers. Further subdivision of the complete form, apart from the morphology of the anterior leaflet, is dependent upon the presence or absence of an ostium primum atrial septal defect.     

Mitral and tricuspid lesions associated with polypoid atrial tumors, including myxoma

The related atrioventricular valves in 11 instances of polypoid atrial tumors were examined grossly and histologically. Nine of the tumors involved the left atrium and, of these, seven were myxomas. The two right atrial tumors were myxomas.

Histologically evident lesions of the mitral valve were present in seven of the nine left atrial tumors. The most common change consisted of fibrous thickening of the endocardium in the angle between the left atrium and posterior mitral leaflet and fibrous thickening of the atrial surfaces of the leaflet. Less common changes were a fibrous thickening of the chordae and of the left ventricular mural endocardium in relation to chordae inserting into the posterior leaflet. The changes described were also evident at gross examination in two of the nine cases with left atrial tumors.

In the two cases of right atrial myxoma, both showed fibrous thickening of the atrial surfaces of the tricuspid leaflets; one also exhibited fibrous thickening of the right ventricular endocardium beneath the septal leaflet of the tricuspid valve.

The lesions described are considered responses to the effects of friction by the tumor upon the surfaces involved. It is significant that grossly evident lesions may evolve from this rubbing action.     

Dysplasia of the atrioventricular valves associated with conduction system anomalies.

Clinical, vectorcardiographic, and echocardiographic data from two siblings with atrial septal defects and dysplasia of the mitral and tricuspid valves are reported. Vectorcardiograms showed that both siblings had abnormal ventricular activation with initial electrical forces directed posteriorly. One sibling died after surgery, and necropsy showed incomplete differentiation of the leaflets and tensor apparatus producing anomalies resembling "mitral arcade." Serial histological examination of the conducting tissue showed that the atrioventricular node was located on the left side of the atrial septum, that the central fibrous body and the membranous septum were hypoplastic, and that an accessory nodoventricular pathway originating in the compact node joined the left side of the ventricular septum. This accessory pathway was probably the cause of the unusual ventricular activation. Dysplasia of the mitral and tricuspid valves together with hypoplasia of the central fibrous body and the presence of accessory pathways are probably part of a malformative complex caused by incomplete differentiation of both the cardiac atrioventricular valves and the junctional area.     

Morphology and classification of atrioventricular defects.

Anatomical studies were made on 114 necropsy specimens of atrioventricular defects with atrioventricular concordance. The malformation is characterised by disproportion between the ventricular inlet and outlet dimensions and a malorientation of the aortic valve relative to the atrioventricular valve or valves. Associated with this there is a characteristic ''scopped-out'' appearance of the muscular ventricular septum, gross abnormalities of the membranous components of the septum as compared with the normal heart, and narrowing of the aortic outflow tract. Hearts with these anatomical features can be divided into partial and complete forms depending on the morphology of the atrioventricular annuli. In the partial form the septal leaflets are conjoined to give separate mitral and tricuspid orifices, the conjoined leaflets being displaced into the ventricles and usually attached to the crest of the septum. In the complete form, anterior and posterior components of the ''septal'' leaflets are separate, so that a single valve orifice connects the atrial to the ventricular chambers. Further subdivision of the complete form, apart from the morphology of the anterior leaflet, is dependent upon the presence or absence of an ostium primum atrial septal defect.     

Reversed offsetting of the septal attachments of the atrioventricular valves and Ebstein''s malformation of the morphologically mitral valve.

Ebstein's anomaly of the tricuspid valve is characterised by downstream displacement of the tricuspid leaflets. In the case of the septal leaflet, the result is exaggerated offsetting of the atrioventricular valves. Thus it might be supposed that in Ebstein's anomaly of the mitral valve, downstream displacement of the aortic (septal) leaflet of the mitral valve could move its attachment beyond that of the tricuspid valve, resulting in reversed offsetting. To examine this hypothesis three patients each with a concordant atrioventricular connection were studied. The first, with Marfan's syndrome and without an abnormal mitral valve, had reversed offsetting shown by echocardiography. The second, without Marfan's syndrome and with Ebstein's anomaly of the mitral valve, showed echocardiographically normal offsetting but a displaced mural leaflet. The third, in whom Ebstein's anomaly of the mitral valve was confirmed at necropsy, showed all the features of the second case, with normal offsetting of the atrioventricular valves. Thus reversed offsetting is not a feature of Ebstein's anomaly of the mitral valve and in the first case this feature was caused by upward displacement of the tricuspid valve secondary to dilation of the aortic root.     

Morphology of perimembranous ventricular septal defects: implications for transcatheter device closure

Several clinical series have reported successful closure of perimembranous ventricular septal defects using trancatether devices. This review presents the morphological aspects of ventricular septal defects focusing on perimembranous septal defects. By definition, a part of the margin of perimembranous septal defects is the area of fibrous continuity abutting the central fibrous body that bears the atrioventricular conduction bundle. Depending on the excursion of the remaining margin, these defects are in proximity to the aortic, tricuspid, or mitral valves. Defects that extend to be doubly committed and juxtaarterial are roofed by contiguity between pulmonary and aortic valves. Recognition of the proximity or distance of important structures is relevant in considering perimembranous defects for device closure.     

Prolapse of atrioventricular valve leaflets in the setting of double orifice

Prolapse of the valve leaflets is reported in 2 cases in the setting of double orifice atrioventricular valve. Diagnosis in the first case, an asymptomatic 8-year-old female, was achieved by echocardiography and consisted in prolapsing leaflets of a double orifice ("bridge type") mitral valve. The second patient, a 24-year-old male, died suddenly. Postmortem examination revealed prolapsing atrioventricular valves, with double orifice ("holy type") of the septal leaflet of the tricuspid valve. There was disruption of the penetrating atrioventricular bundle into multiple fragments with fasciculo-ventricular by-pass fibers.     

Pathologic elucidation of the echocardiographic features of Ebstein''s malformation of the morphologically tricuspid valve in discordant atrioventricular connections

We defined the morphology of the left atrioventricular valve in Ebstein's malformation associated with congenitally corrected transposition to elucidate the approach to diagnosis by echocardiography. We found 14 unequivocal cases out of a total of 3,720 specimens. We noted the atrial arrangement, displacement, and nature of the tricuspid leaflets, and axis of the plane of the tricuspid orifice. We constructed ratios of volume of the atrialized to the functional right ventricle, and of the right to left ventricle, as well as distances of the septal attachments of the atrioventricular junctions to the respective ventricular apices. Three specimens had abnormalities of cardiac position, and 8 had ventricular septal defect. The tricuspid valve plane was rotated 47 ± 21 ° from its usual position into the ventricle. The tricuspid valvar tissue was variably attached to the underlying myocardium, with the most severely affected lesion being the mural leaflet followed by the septal leaflet, and the anterior leaflet attachment the least affected. Abnormalities of the tendinous cords and the effective valvar orifice occurred in 3 specimens. The ratio of the atrialized to the functional right ventricular volume was 0.74 ± 0.49; the ratio of the fetal right to left ventricular volume was 1.18:1 ± 0.70:1. These data suggest that plastic repairs of the right ventricle would leave a small functional right ventricle, but that valve replacement could restore the volume of the ventricle. Thus, the plane of displacement of the valve in corrected transposition appears less amenable to 4-chamber echocardiography than other forms of Ebstein's malformation. Changes in the echocardiographic planes should display the morphology and also provide some hemodynamic information.     

Severe Left Atrioventricular Valve Regurgitation Due to Discontinuity between the Leaflets of the Aortic and Left Atrioventricular Valves in a Patient with Endocardial Cushion Defect: A Rare Case Report

Discontinuities between the leaflets of the aortic and left atrioventricular valves are uncommon congenital malformations. The anomaly may be discovered during surgery without preoperative diagnosis. It represents a spectrum of anomalies that result from interruption of the normal development of the endocardial cushions during the fetal life. We describe a rare case of Down syndrome with transient complete atrioventricular block and discontinuity between the leaflets of the aortic and left atrioventricular valves without intervening fibrous band, leading to separation and detachment between them. It caused severe eccentric jet of regurgitation originated from left ventricular outflow tract and base of anterior leaflet of left atrioventricular valve into the left atrium. He underwent cardiopulmonary bypass, and the defect between left atrioventricular valve and aortic annuli was sewn. Permanent epicardial pacing was inserted during cardiac surgery. To the best of our knowledge, such a case has not been previously reported in the literature.     

Echocardiographic differentiation of partial and complete atrioventricular canal

Retrospective examination of echocardiograms was performed in 34 patients with persistent atrioventricular (A-V) canal who had undergone cardiac catheterization. Characteristic findings in 16 patients with partial A-V canal were lack of continuity of mitral and tricuspid valves, paradoxical interventricular septal motion, definite E and A waves of the mitral valve anterior leaflet (MVAL) echoes and late systolic anterior motion of the mitral valve. Eighteen patients with persistent A-V canal had an interventricular communication and were classified as having the complete form. They characteristically had continuous mitral and tricuspid valves, normal interventricular septal motion, disorganized MVAL echoes, and normal systolic mitral valve motion. Combining these findings allowed differentiation of 31 of the 34 patients (91%) as having partial or complete A-V canal. Determining the presence of a VSD from loss of interventricular septal echoes was unsatisfactory. The severity of mitral insufficiency could not be estimated from echocardiograms of our patients with partial A-V canal.     

Echocardiography in endocardial cushion defects: a preoperative and postoperative study.

Echocardiographic studies were performed on 14 patients with endocardial cushion defects of different anatomic varieties. Four patients were studied again after operation. Patients with partial atrioventricular canal (PAVC) showed multiple systolic echoes on mitral valve echogram, with significant mitral-septal apposition in diastole. The left ventricular outflow (LVO) appeared significantly narrowed. The septal motions were paradoxic. After corrective operation, an increase in the width of the LVO was noted and mitral-septal apposition appeared to be less pronounced. Multiple systolic echoes, however, reappeared and persisted. The echocardiograms in patients with complete atrioventricular canal (CAVC) were characterized by wide excursion of an apparent single atrioventricular valve. The echoes of the mitral component of the common anterior leaflet moved anteriorly into the right ventricular cavity and overshadowed the tricuspid component in diastole. In addition, patients with CAVC and divided and medially attached common anterior leaflets had solitary mitral and tricuspid echograms. This feature differentiates this group of patients from those patients with CAVC with undivided freefloating common anterior leaflet.     

A very unusual combination of straddling and overriding of the tricuspid valve associated with clefting of the mitral valve

We describe a patient in whom we found dual orifices in a straddling and overriding tricuspid valve, with two normally sized ventricles and a cleft in the mitral valve. The patient underwent successful surgical repair. We discuss the concept of "double-orifice right atrium", as well as the need to differentiate the isolated cleft of the morphologically mitral valve from the zone of apposition between the left ventricular components of the bridging leaflets seen in the setting of atrioventricular septal defect with common atrioventricular junction. We emphasise the unusual association of these abnormalities of the right and left atrioventricular valves in patients with separate atrioventricular junctions.     

Lipomatous hamartoma of the tricuspid valve: echocardiographic-pathologic correlations

We report the eighth example of a cardiac valvular hamartoma (five mitral, three tricuspid). An intracavitary right atrial mass was present in a 76-year-old man and was characterized echocardiographically by a mobile cystic structure involving the septal tricuspid leaflet. Microscopically, the affected leaflet was comprised predominantly of mature adipose tissue. Formation of a valvular windsock in this case was attributed to the chronic effect of right ventricular pressure on tissue that was weaker than a normal leaflet. Valvular hamartomas should be included in the differential diagnosis of lesions that produce prolapsing, cystic, or windsock malformations of atrioventricular valves.     

Overriding atrioventricular valves. An angiographic-anatomical correlate

An analysis of 6 patients with overriding atrioventricular valve was performed in order to correlate the anatomic and angiographic features of this malformation. The atrial arrangement was usual (situs solitus) in each patient. The ventricular chambers were normally related in 4 and the mirror image of normal in 2. The atrioventricular connexion was concordant in parallel fashion in 4, discordant in 1 and double inlet left ventricle in 1 heart. In 2 of 4 hearts with concordant atrioventricular connexion, the right atrioventricular valve (tricuspid) overrode the septum and connected partially to the left ventricle. In 2, the left atrioventricular valve (mitral) overrode the septum and partially connected with the right ventricle. One heart with discordant atrioventricular connexion had its right atrioventricular valve (mitral) overriding the septum. The remaining heart with double inlet left ventricle had an overriding left atrioventricular valve. Each overriding atrioventricular valve had its "septal" leaflet (the one committed to the contralateral ventricle) divided into 2 segments by a large cleft. Ventricular septal defects at different locations were present in all cases. The ventriculoarterial connexion was double outlet right ventricle in 5 patients and was discordant in 1. Malalignment of the atrial and ventricular septa was present to some degree in all cases. This was well depicted on ventriculograms in four chamber view in those with an overriding tricuspid valve. It was not detected in those with an overriding mitral valve. The displaced leaflets of the overriding and/or stradding valve had a vertical motion on cineangiograms similar to those observed in atrioventricular septal defects. Abnormal morphology and motion of the septal leaflet of the overriding atrioventricular valve and malalignment of the atrial and ventricular septal structures were the most important angiographic findings in this series.     

Isolated tricuspid prolapse in young child

The geometric and hemodynamic determinants of functional tricuspid regurgitation severity are mainly determined by septal leaflet tethering, septal-lateral annular dilatation, and the severity of pulmonary hypertension. Isolated significant tricuspid regurgitation can occur from isolated prolapse of valvar leaflets. Tricuspid prolapse has been found more frequently to be associated with mitral valve prolapse or with other cardiac and lung diseases and it has been rarely found as an isolated finding. Isolated primitive tricuspid prolapse appears in fact a relatively unknown anatomo-clinical entity and is of clinical importance, since this condition may be associated with significant tricuspid incompetence, a high incidence of cardiac arrhythmias, and possibly with bacterial endocarditis. We present a case of isolated prolapse of the tricuspid septal leaflet in an 11-year-old Italian boy. Also this case is illustrative of an isolated tricuspid prolapse.     

Asymmetrically short tendinous cords causing congenital tricuspid regurgitation: improved understanding of tricuspid valvar dysplasia in the era of color flow echocardiography.

BACKGROUND: Tricuspid regurgitation as a manifestation of an isolated congenital anomaly of the tricuspid valve is rare. Cross-sectional and color Doppler echocardiography allow improved evaluation of tricuspid valvar function. As a result, the heterogeneous category of congenital tricuspid valvar dysplasia may be better understood from a functional point of view. We are reporting a distinct entity in which tricuspid valvar regurgitation results from failure of coaptation due to short tendinous cords tethering the septal leaflet. PATIENTS AND RESULTS: Three children with significant primary tricuspid regurgitation were evaluated, treated, and followed. On echocardiographic evaluation, a central regurgitant jet of moderate or severe degree was directed toward the atrial septum through poorly coapting tricuspid valvar leaflets, which did not approximate due to tethering of the septal leaflet by abnormally short cords. In one patient, the tricuspid valve was otherwise normal; in the other two the leaflets and cords were also thickened. Two patients underwent surgery at 9 and 11 years of age. The cords tethering the septal leaflet were augmented by interposing appropriate lengths of expanded polytetrafluoroethylene suture and performing commissural annuloplasty. Both patients are asymptomatic 33 and 42 months postoperatively, with mild residual tricuspid regurgitation that has not changed since surgery. The other patient, an 8 month-old infant, has not yet undergone surgery. CONCLUSIONS: Asymmetric tendinous cords of the tricuspid valve causing tethering of the septal leaflet is a distinct cause of tricuspid regurgitation that can be recognized with echocardiography. Although rare, the importance of recognizing this lesion lies in its being readily amenable to surgical repair.     

Morphological aspects of Ebstein's anomaly in adults

The essence of the Ebstein's malformation is that the tricuspid valve leaflets do not attach normally to the valve annulus, and the effective orifice is displaced downward into the right ventricular cavity at the junction of the inlet and trabecular components of the right ventricle. Only the septal and posterior leaflets are displaced and divide the right ventricle into two portions. The inlet portion is usually integrated functionally with the right atrium ("atrialized portion"), while the other, including the trabecular and outlet portions, constitutes the functional right ventricle. The proximal atrialized right ventricle often has a wall thinner than the distal functional right ventricle, due to partial congenital absence of myocardium. An atrial septal defect is present in more than one-third of hearts, and the majority of the remainder has a patent foramen ovale resulting in a right-to-left shunt. The downward displacement of the septal tricuspid valve leaflet is associated with discontinuity of the central fibrous body and septal atrioventricular ring, thus creating a potential substrate for accessory atrioventricular connections and ventricular pre-excitation making the patient at risk of sudden death. Angiography has demonstrated that a significant number of patients with Ebstein's anomaly also have morphofunctional abnormalities of the left ventricle, which may be explained by increased fibrosis in the left ventricular wall and ventricular septum as demonstrated by histological studies. Regarding embryology, the leaflets and tensile apparatus of the tricuspid valve are believed to be formed mostly by a process of delamination of the inner layers of the inlet zone of the right ventricle. The downward displacement of the leaflets in Ebstein's anomaly suggests that delamination from the inlet portion failed to occur.     

Repair of a dysplastic tricuspid valve using artificial chordae: case report

Atrioventricular valve repair with artificial chordal replacement has been widely used for congenital and acquired mitral valve abnormalities, but not for tricuspid valve abnormalities. A case is presented of dysplastic tricuspid valve that was successfully repaired using artificial chordae. A 2-year-old female presented with poor weight gain. Echocardiography revealed severe tricuspid regurgitation due to dysplastic tricuspid valve, poor coaptation by prolapse of the anterior leaflet, and tethering of the septal leaflet by short chordae. The prolapsed anterior leaflet was repaired with three pairs of 6-0 expanded polytetrafluoroethylene sutures. The short chordae of the septal leaflet were detached, and the septal and posterior leaflets were sutured together. Trivial tricuspid regurgitation was noted postoperatively. There was no tricuspid regurgitation during the follow up period of three years. The present case provides further evidence that artificial chordal replacement is a useful technique even for small children with congenitally abnormal tricuspid valves.