Development of the myocardium of the atrioventricular canal and the vestibular spine in the human heart

To establish the morphogenetic mechanisms underlying formation and separation of the atrioventricular connections, we studied the remodeling of the myocardium of the atrioventricular canal and the extracardiac mesenchymal tissue of the vestibular spine in human embryonic hearts from 4.5 to 10 weeks of development. Septation of the atrioventricular junction is brought about by downgrowth of the primary atrial septum, fusion of the endocardial cushions, and forward expansion of the vestibular spine between atrial septum and cushions. The vestibular spine subsequently myocardializes to form the ventral rim of the oval fossa. The connection of the atrioventricular canal with the atria expands evenly. In contrast, the expression patterns of creatine kinase M and GlN2, markers for the atrioventricular and interventricular junctions, respectively, show that the junction of the canal with the right ventricle forms by local growth in the inner curvature of the heart. Growth of the caudal portion of the muscular ventricular septum to make contact with the inferior endocardial cushion occurs only after the canal has expanded rightward. The atrioventricular node develops from that part of the canal myocardium that retains its continuity with the ventricular myocardium.     

Electro‐vectorcardiographic demonstration of bifascicular block associated with ventricular preexcitation

Down syndrome occurs more frequently in the offsprings of older pregnant women and may be associated with atrioventricular septal defect. This refers to a broad spectrum of malformations characterized by a deficiency of the atrioventricular septum and abnormalities of the atrioventricular valves caused by an abnormal fusion of the superior and inferior endocardial cushions with the midportion of the atrial septum and the muscular portion of the ventricular septum.     

The matricellular protein CCN1 is essential for cardiac development

The matricellular protein CCN1 (formerly named CYR61) regulates cell adhesion, migration, proliferation, survival, and differentiation through binding to integrin receptors and heparan sulfate proteoglycans. Here we show that Ccn1-null mice are impaired in cardiac valvuloseptal morphogenesis, resulting in severe atrioventricular septal defects (AVSD). Remarkably, haploinsufficiency for Ccn1 also results in delayed formation of the ventricular septum in the embryo and persistent ostium primum atrial septal defects (ASD) in approximately 20% of adults. Mechanistically, Ccn1 is not required for epithelial-to-mesenchymal transformation or cell proliferation and differentiation in the endocardial cushion tissue. However, Ccn1 deficiency leads to precocious apoptosis in the atrial junction of the cushion tissue and impaired gelatinase activities in the muscular component of the interventricular septum at embryonic day 12.5, when fusion between the endocardial cushion tissue and the atrial and ventricular septa occurs, indicating that these defects may underlie the observed AVSD. Moreover, human CCN1 maps to 1p21-p31, the chromosomal location of an AVSD susceptibility gene. Together, these results provide evidence that deficiency in matrix signaling can lead to autosomal dominant AVSD, identify Ccn1(+/-) mice as a genetic model for ostium primum ASD, and implicate CCN1 as a candidate gene for AVSD in humans.     

Origin of mesenchymal tissue in the septum primum: a structural and ultrastructural study

A structural, ultrastructural and histochemical study in chick embryos indicates that the septum primum mesenchymal tissue originate between 3 and 5 days of development and that their origin may be related to an activation of endocardial cells that cover the septum primum. By day 3, endocardial cells display migratory appendages, cell hypertrophy and an increase in secretory and mitotic activity. In later stages (day 4) hypertrophic endocardial cells undergoing division seem to delaminate and translocate toward the subendocardial space to give rise to free mesenchymal-type cells. These results suggest that the endocardium makes up the bulk of the septum primum mesenchymal tissue as has been demonstrated during mesenchymal tissue formation in the atrioventricular canal and outflow tract. Before and during mesenchymal tissue formation an accumulation of extracellular matrix components like proteoglycans can be visualized using tannic acid. These extracellular components might be related to the promotion of cellular events described during endocardial activation. The fusion of the septum primum with the atrioventricular (AV) endocardial cushions which would obliterate the foramen primum, occurs between mesenchymal tissues. Therefore, any alteration in the normal development of these mesenchymal tissues could be related to pathological cases of persistent atrial communications. Light microscopy preliminary observations of embryonic mouse heart indicate that septum primum mesenchymal tissue formation occurs similarly between mouse and chick embryos.     

Normal development of the pulmonary veins in human embryos and formulation of a morphogenetic concept for sinus venosus defects

A sinus venosus defect is a form of interatrial communication associated with abnormal drainage of the right pulmonary veins. Its morphogenesis still remains unclear. We therefore studied the normal development of pulmonary veins in human embryos in relation to the sinus venosus and the dorsal mesocardium using graphic reconstructions and HNK-1 immunohistochemistry. Twenty embryos, ranging from 4 to 7 weeks' gestation, were examined. At 4 weeks, the orifice of the nonlumenized common pulmonary vein is visible as an endothelial invagination within the sinus venosus segment. Development of the muscular septum primum and the ventral proliferation of extracardiac mesenchyme from the dorsal mesocardium positions the common pulmonary vein (CPV) eventually into the left atrium. The right wall of the CPV contributes to the posterior part of the atrial septum and is continuous with the dorsal sinuatrial fold (the future left venous valve). With the use of HNK-1 antigen expression as a marker for sinus venosus myocardium, this common wall between the right-sided sinus venosus and the CPV is demonstrated, and at 7 weeks the proximal part of the right upper pulmonary vein also becomes part of this common wall. This study demonstrates that the CPV develops within the sinus venosus segment and that later a common myocardial wall is present between the sinus venosus in the right atrium and the CPV. A deficiency of this wall explains the development of sinus venosus defects.     

The role of atrioventricular endocardial cushions in the septation of the heart

The hearts of human embryos, ranging from 3.6 to 25 mM crown-rump length, have been studied in view of the problem of the possible contribution of the atrioventricular endocardial cushions to septation. Serial sections and graphic reconstructions were used. It is concluded that the cushions do not materially contribute to the mature muscular septum.     

Left ventricular outflow tract obstruction in atrioventricular septal defects: a pathologic and morphometric evaluation.

Subaortic stenosis has been described with increasing frequency as an ominous feature of atrioventricular septal defect (AVSD), especially following surgical correction of the anomaly in non-Down's syndrome patients. In order to study the surgical anatomy of the left ventricular outflow tract in this malformation, 48 hearts featuring AVSD were examined. Obstructive lesions were classified into unequivocal forms (class A, 13.5%) and potential ones (class B, 10.8%). In the remaining hearts (class C, 75.7%) no obstruction was noted. In class A, subaortic stenosis was due to exaggeration of the anticipated anomalous arrangement of atrioventricular valve tensor apparatus, to the persistence of a subaortic muscular infundibulum, and to a discrete fibrous diaphragm. A potential for subaortic stenosis is provided by the unwedged position of the aortic valve. The left ventricular outflow tract is transformed into a long, forward-displaced fibromuscular channel. Morphometric analysis showed in AVSD (with both common annulus and separate orifices) a significantly (p less than 0.01) lower inflow/outflow tract ratio, and a significantly (p less than 0.01) lower right ventricular/left ventricular outflow length ratio than normal hearts. These results suggest that AVSD is characterized not only, as commonly stated, by inflow tract shortening, but by outflow tract lengthening as well. On these anatomical grounds, nearly all cases of AVSD could harbor the potential for subaortic stenosis; however, this becomes a real hazard (class B) only when associated with forward displacement of the left anterior papillary muscle, or direct insertion on the ventricular septum of the anterior bridging leaflet, and it may be converted to an actual obstruction by the effects of surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms of deficient cardiac septation in the mouse with trisomy 16

It used to be thought that the atrioventricular septum was predominantly the product of the atrioventricular endocardial cushions. In a previous study, we have shown that multiple developmental primordia are of importance in its formation. With this in mind, we have evaluated cardiac morphogenesis in the mouse with trisomy 16, an animal model with a high incidence of atrioventricular septal defects. Normal and trisomic fetuses from an Rb(11.16)2H/Rb(16.17)7Bnr x C57BL/6J cross were collected on days 10 to 15 of gestation and examined by scanning electron microscopy and histological serial sectioning. No evidence was found to suggest that atrioventricular septal defect could be explained simply on the basis of "failure of fusion" between the atrioventricular endocardial cushions. Rather, our findings supported two other developmental elements as being important in the genesis of atrioventricular septal defect. The first is an alteration in the configuration of the heart tube, with inadequate remodeling of the inner heart curvature. This resulted in the failure of the atrioventricular junction to expand to the right, with subsequent malalignment of the atrioventricular endocardial cushions with the proximal outflow cushions. The second is a variability in the connection of the primary atrial cardiac segment to the body of the embryo, the so-called dorsal mesocardium, which influences its relationship to the extracardiac mediastinal mesoderm. There appeared little difference in the connection between normal and trisomic embryos at the stage of 20 to 25 somites, but the area subsequently showed marked changes. In most trisomic embryos, the connection with the mediastinal mesoderm of the body was over a larger area than seen in normal embryos. As this area of attachment encloses the pulmonary pit, the entry point of the pulmonary vein, this gives potential for variation in the connection of the pulmonary vein. In addition, in the majority of trisomic embryos, the right pulmonary ridge (the spina vestibuli) did not accumulate extracardiac mesoderm, nor did it undergo the pronounced forward growth seen in normal embryos of equivalent stages. Consequently, the trisomic embryos show incomplete formation of both the atrial and the atrioventricular septal structures.     

Developmental aspects of atrioventricular septal defects

Three human embryos with an atrioventricular septal defect were studied. Their morphology was compared with that of 67 autopsy specimens, in which particular attention was paid to the septal attachments of the bridging leaflets. The malformed embryos showed deficiency of the inlet component of the ventricular septum. They had distinct superior and inferior bridging leaflets, which were nearly completely muscular. Myocardial undermining had taken place at two independent sites but had not been able to lead to the formation of a valve of mitral morphology. Normal delamination of myocardium to form the leaflets could not continue directly below the aortic root because the rim of the inlet septum had a more apical position. From this, we conclude that the deficiency of the inlet septum is the cause of the typical morphology of the left valve in these hearts. The role of endocardial cushion tissue is probably restricted to glueing together myocardial structures, thus determining the variable septal attachment of the bridging leaflets in atrioventricular septal defect.     

Atypical form of atrioventricular septal defect without left axis deviation: relation between morphology and unusual QRS axis.

OBJECTIVE--To clarify the morphological features relating to an intermediate axis or a right axis deviation in atrioventricular septal defect (AVSD). SUBJECTS--135 patients with typical AVSD and with nine patients with atypical AVSD, characterised by a well formed atrial septum, a milder downward displacement of the atrioventricular valves, and a shorter length of the ostium primum defect. MAIN OUTCOME MEASURES--Relation between morphology and electrocardiographic and vectorcardiographic findings; prevalence of Down's syndrome and of other cardiac anomalies. RESULTS--All nine patients with atypical AVSD had an unusual mean frontal QRS axis compared with six of the 135 patients (4%) with typical AVSD (p < 0.01). All eight patients who underwent the vector analyses showed atypical movement of the QRS loop--that is, an initial left inferior movement in the frontal loop (eight patients) and counter-clockwise rotation in the sagittal loop (seven). The corresponding values for 119 patients with typical AVSD were 20 and 22 patients (p < 0.01). Seven patients with atypical AVSD (78%) and 55 (41%) with typical AVSD had Down's syndrome (p < 0.05). None of the twenty one patients with additional cardiac anomalies had atypical AVSD, an unusual QRS axis, or unusual movement in the QRS loop. CONCLUSIONS--The atypical morphology, supposedly related to the degree of posteroinferior displacement of the conduction system, was one of the causes of unusual movement of the QRS loop in AVSD.     

Lineage and morphogenetic analysis of the cardiac valves

We used a genetic lineage-labeling system to establish the material contributions of the progeny of 3 specific cell types to the cardiac valves. Thus, we labeled irreversibly the myocardial (alphaMHC-Cre+), endocardial (Tie2-Cre+), and neural crest (Wnt1-Cre+) cells during development and assessed their eventual contribution to the definitive valvar complexes. The leaflets and tendinous cords of the mitral and tricuspid valves, the atrioventricular fibrous continuity, and the leaflets of the outflow tract valves were all found to be generated from mesenchyme derived from the endocardium, with no substantial contribution from cells of the myocardial and neural crest lineages. Analysis of chicken-quail chimeras revealed absence of any substantial contribution from proepicardially derived cells. Molecular and morphogenetic analysis revealed several new aspects of atrioventricular valvar formation. Marked similarities are seen during the formation of the mural leaflets of the mitral and tricuspid valves. These leaflets form by protrusion and growth of a sheet of atrioventricular myocardium into the ventricular lumen, with subsequent formation of valvar mesenchyme on its surface rather than by delamination of lateral cushions from the ventricular myocardial wall. The myocardial layer is subsequently removed by the process of apoptosis. In contrast, the aortic leaflet of the mitral valve, the septal leaflet of the tricuspid valve, and the atrioventricular fibrous continuity between these valves develop from the mesenchyme of the inferior and superior atrioventricular cushions. The tricuspid septal leaflet then delaminates from the muscular ventricular septum late in development.     

Ventricular trabeculations in the chick embryo heart and their contribution to ventricular and muscular septal development

Sixty-two chick embryo hearts were studied at incremental stages of development (Hamburger-Hamilton stages 16 to 39) by scanning electron microscopy following 3% glutaraldehyde fixation and critical point drying. Early in cardiac development, the primitive ventricle becomes homogeneously trabeculated with highly organized sheets of myocytes lined by endocardial cells, with the trabeculae generally oriented in the dorsoventral direction. Coalescence of these trabecular sheets begins at stage 26, initially at the area of the bulboventricular flange, and later proceeding caudally toward the floor of the ventricle. The fusion process is finished by stage 30, resulting in a muscular ventricular septum that has now divided the primitive ventricle into right and left ventricles. Further growth of the ventricular septum is by continued fusion of the adjoining trabecular sheets. Remnants of the apposing trabecular sheets are found in the solidified muscular septum in the form of endocardial channels. We suggest that persistent patency of these channels results in muscular ventricular septal defects.     

Electrophysiologic and anatomical relationships studied in primum atrioventricular septal defect

Anatomy and pattern of electrical activation predict the function and contraction pattern of the heart. Patients with primum atrioventricular septal defect (primum AVSD) present with abnormality of both anatomical arrangements and electric activation and serve therefore as an interesting population for studying electro-anatomic relationships in the heart.Understanding the relationships between anatomic and electrophysiologic abnormality is appropriate not only for diagnosis, therapy, and prognosis in patients with primum AVSD but also for understanding the developmental relationship between the conduction system and heart structures, in general.This article presents a review of the anatomical and electrophysiologic characteristics of patients with primum AVSD and provides recent knowledge of electroanatomical relationships of the heart.     

Echocardiographic assessment of atrioventricular canal defects

AV canal defects (AVCD) are caused by maldevelopment of the endocardial cushions and typically include a primum atrial septal defect (ASD), an inlet ventricular septal defect (VSD), and a common atrioventricular valve. The variations in deformities provide the basis for the many terms used in the anatomical classifications: partial, transitional, intermediate, and complete common AVCD (balanced or unbalanced). The balanced complete common AVCDs are classified as Rastelli A, B, C depending on the anomaly of the anterior bridging leaflet division and attachments. Unbalanced complete AVCDs occur when the common AV valve leads primarily into the RV or LV. Echocardiographic apical, subcostal, and parasternal views are the best views to image AV canal defects. These views can help determine the type of repair required for the various AV canal defects.     

Morphometric Analysis of Atrioventricular Septal Defect With Common Valve Orifice

Objectives. We sought to analyze morphometric features of atrioventricular septal defect (AVSD) in autopsy specimens and to consider the developmental implications of obstruction in either ventricular outflow tract.Background. Left ventricular outlet obstruction (LVO) is more prevalent in patients with Rastelli type A morphology. When tetralogy of Fallot (ToF) complicates this malformation, there is usually a free-floating superior bridging leaflet. The reasons for these associations are uncertain.Methods. In 133 hearts with AVSD and common atrioventricular (AV) valve orifice, we measured the degrees of horizontal and anterior deviation of the great arteries from the AV valve, the diameters of the ventricular outlets and the great arteries and the degree of deficiency of the ventricular septum.Results. In Rastelli type A morphology, the great arteries were deviated more leftward than in type C morphology (p < 0.01). Type A hearts also had a relatively small aorta, with a long and narrow subaortic tract. The presence of obstruction in either ventricular outlet was associated with a more oblique arrangement of the great arteries, with the pulmonary trunk being more leftward than in hearts without LVO (p < 0.01). In combination with ToF, the aorta was dextroposed and the pulmonary trunk was located more posteriorly (p < 0.01). No heart with type A morphology showed ToF (p < 0.01).Conclusions. The geometric arrangement of the great arteries correlated significantly with obstruction in either ventricular outflow tract and with the Rastelli subtypes. Malrotation of the developing outlet septum may be an embryologic factor producing obstruction, with horizontal deviation of the outlets also influencing the morphology of the superior bridging leaflet.     

Modified percutaneous suture‐mediated patent fossa ovalis closure for prevention of cerebral ischemic events

Percutaneous suture‐mediated transcatheter patent fossa ovalis (PFO) closure has been shown to be an effective and safe technique with self‐evident advantages due to the lack of a permanent device heart implant. The success of this novel technique relies on an optimal catch of the interatrial septa, especially the septum primum which is floppier than the bulkier muscular septum secundum. We hypothesized that double suture of septum primum would further improve the efficacy of the procedure by increasing the surface contact between the septa when the septum primum is bent into the right atrium. We have provided proof of this concept by implementing a modified technique in two patients with PFO and cerebral ischemic events.     

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.