Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.

The problems that exist when considering the anatomic variability between the channels that permit interventricular shunting.

Although steps are being taken to produce a universally acceptable coding system for categorisation of the congenitally malformed hearts, obstacles remain in the search for consensus. One of the groups of lesions continuing to produce the greatest problems is those that permit interventricular shunting. The difficulties relate partly to the words used to describe the group itself, as those using Germanic languages describe the holes as ventricular septal defects, whereas those using Romance languages consider them to represent interventricular communications. The two terms, however, are not necessarily synonymous. Further disagreements relate to whether the lesions placed within the group should be sub-categorised on the basis of their geographical location within the ventricular mass, as opposed to the anatomic nature of their borders. In reality, attention to both the features is necessary if we are to recognise the full extent of phenotypic variability. In this review, we first review the evolution and theories of analysis naming the channels that permit interventricular shunting. We then demonstrate that embryologic techniques provide evidence that the changing morphology of the developing murine heart parallels the anatomy of the different lesions encountered in the congenitally malformed human heart. We suggest that, with attention paid to the temporal development of the normal murine heart, combined with a strict definition of the plane of separation between the right and left ventricular cavities, it will be feasible to produce a categorisation that is acceptable to all.

The FGF-BMP signaling axis regulates outflow tract valve primordium formation by promoting cushion neural crest cell differentiation.

RATIONALE: Heart valves develop from precursor structures called cardiac cushions, an endothelial-lined cardiac jelly that resides in the inner side of the heart tube. The cushions are then invaded by cells from different sources, undergo a series of complicated and poorly understood remodeling processes, and give rise to valves. Disruption of the fibroblast growth factor (FGF) signaling axis impairs morphogenesis of the outflow tract (OFT). Yet, whether FGF signaling regulates OFT valve formation is unknown. OBJECTIVE: To study how OFT valve formation is regulated and how aberrant cell signaling causes valve defects. METHODS AND RESULTS: By using mouse genetic manipulation, cell lineage tracing, ex vivo heart culture, and molecular biology approaches, we demonstrated that FGF signaling in the OFT myocardium upregulated Bmp4 expression, which then enhanced smooth muscle differentiation of neural crest cells (NCCs) in the cushion. FGF signaling also promoted OFT myocardial cell invasion to the cushion. Disrupting FGF signaling interrupted cushion remodeling with reduced NCCs differentiation into smooth muscle and less cardiomyocyte invasion and resulted in malformed OFT valves. CONCLUSIONS: The results demonstrate a novel mechanism by which the FGF-BMP signaling axis regulates formation of OFT valve primordia by controlling smooth muscle differentiation of cushion NCCs.

[Congenital heart defects of the septa, endocardial cushions and the conotruncus]. / Angeborene Herzfehlbildungen von Septen, Endokardkissen und Konotrunkus.

During embryological development the heart develops from a simple tube into a complex fully developed heart with four chambers. Hence all congenital heart defects develop before the ninth week of gestation. Currently a steadily increasing number of genetic mutations have been found to be responsible for congenital heart defects. Nevertheless, up to now it has been impossible to diagnose a heart defect just on the basis of molecular pathology. Despite the current excellent prenatal and postnatal ultrasound diagnostics, the post-mortem examination is still the gold standard for the diagnosis of complex heart malformations. However, this requires knowledge of the pathomorphology of the heart malformation in question. Therefore, characteristic and distinguishing features of septal defects including atrioventricular septal defects are presented, especially as the latter are part of complex heart defects, such as conotruncal heart malformations.

Understanding atrioventricular septal defect: anatomoechocardiographic correlation.

OBJECTIVE: Correlate the anatomic features of atrioventricular septal defect with echocardiographic images. MATERIALS AND METHODS: Sixty specimen hearts were studied by sequential segmental analysis. Echocardiograms were performed on 34 patients. Specimen hearts with findings equivalent to those of echocardiographic images were selected in order to establish an anatomo-echocardiographic correlation. RESULTS: Thirty-three specimen hearts were in situs solitus, 19 showed dextroisomerism, 6 were in situs inversus and 2 levoisomerism. Fifty-eight had a common atrioventricular valve and 2 had two atrioventricular valves. Rastelli types were determined in 21 hearts. Nine were type A, 2 intermediate between A and B, 1 mixed between A and B, 4 type B and 5 type C. Associated anomalies included pulmonary stenosis, pulmonary atresia atrial septal defect, patent ductus arteriosus and anomalous connection of pulmonary veins. Echocardiograms revealed dextroisomerism in 12 patients, situs solitus in 11, levoisomerism in 7 and situs inversus in 4. Thirty-one patients had common atrioventricular valves and three two atrioventricular valves. Rastelli types were established in all cases with common atrioventricular valves; 17 had type A canal defects, 10 type B, 3 intermediate between A and B, 1 mixed between A and B and 3 type C. Associated anomalies included regurgitation of the atrioventricular valve, pulmonary stenosis, anomalous connection of pulmonary veins, pulmonary hypertension and pulmonary atresia. CONCLUSION: Anatomo-echocardiographic correlation demonstrated a high degree of diagnostic precision with echocardiography.

Common atrioventricular canal in a newborn foal--case report and review of the literature.

This paper presents the embryological and pathological features as well as the terminology and classification of common atrioventricular canal, a type of endocardial cushion defect. The authors give a complete description of an extremely rare congenital cardiac malformation in an equine neonate. The diagnosis of a complete, balanced common atrioventricular canal of type C in Rastelli's classification scheme was based on two-dimensional, contrast and colour Doppler echocardiography and subsequent postmortem gross pathology. To support our diagnosis and study the pathophysiological effect of the alteration, physical examination, blood gas analysis and other laboratory tests, electrocardiography and thoracic radiography were also performed. Our search of the literature suggests that this type of developmental anomaly might account for a higher percentage of equine congenital cardiac defects than was thought earlier. We suppose that some previously described congenital heart abnormalities were misinterpreted: these anomalies could have actually represented some type of atrioventricular canal defect, resulting from the failure of the endocardial cushions to undergo complete and proper fusion.

Cell biology of cardiac cushion development.

The valves of the heart develop in the embryo from precursor structures called endocardial cushions. After cardiac looping, endocardial cushion swellings form and become populated by valve precursor cells formed by an epithelial-mesenchymal transition (EMT). Endocardial cushions subsequently undergo directed growth and remodeling to form the valvular structures and the membranous septa of the mature heart. The developmental processes that mediate cushion formation include many prototypic cellular actions including adhesion, signaling, migration, secretion, replication, differentiation, and apoptosis. Cushion morphogenesis is unique in that these cellular possesses occur in a functioning organ where the cushions act as valves even while developing into definitive valvular structures. Cardiovascular defects are the most common congenital defects, and one of the most common causes of death during infancy. Thus, there is significant interest in understanding the mechanisms that underlie this complex developmental process. In this regard, substantial progress has been made by incorporating an understanding of cardiac morphology and cell biology with the rapidly expanding repertoire of molecular mechanisms gained through human genetics and research using animal models. This article reviews cardiac morphogenesis as it relates to heart valve formation and highlights selected growth factors, intracellular signaling mediators, and extracellular matrix components involved in the creation and remodeling of endocardial cushions into mature cardiac structures.

Hyperplastic conotruncal endocardial cushions and transposition of great arteries in perlecan-null mice.

Perlecan is a heparan-sulfate proteoglycan abundantly expressed in pericellular matrices and basement membranes during development. Inactivation of the perlecan gene in mice is lethal at two developmental stages: around E10 and around birth. We report a high incidence of malformations of the cardiac outflow tract in perlecan-deficient embryos. Complete transposition of great arteries was diagnosed in 11 out of 15 late embryos studied (73%). Three of these 11 embryos also showed malformations of semilunar valves. Mesenchymal cells in the outflow tract were abnormally abundant in mutant embryos by E9.5, when the endocardial-mesenchymal transformation starts in wild-type embryos. At E10.5, mutant embryos lacked well-defined spiral endocardial ridges, and the excess of mesenchymal cells obstructed sometimes the outflow tract lumen. Most of this anomalous mesenchyme expressed the smooth muscle cell-specific alpha-actin isoform, a marker of the neural crest in the outflow tract of the mouse. In wild-type embryos, perlecan is present in the basal surface of myocardium and endocardium, as well as surrounding presumptive neural crest cells. We suggest that the excess of mesenchyme at the earlier stages of conotruncal development precludes the formation of the spiral ridges and the rotation of the septation complex in order to achieve a concordant ventriculoarterial connection. The observed mesenchymal overpopulation might be due to an uncontrolled migration of neural crest cells, which would arrive prematurely to the heart. Thus, perlecan is involved in the control of the outflow tract mesenchymal population size, underscoring the importance of the extracellular matrix in cardiac morphogenesis.

Tricuspid atresia or severe stenosis with partial common atrioventricular canal: anatomic data, clinical profile and surgical considerations.

The anatomic findings in 11 cases of tricuspid atresia and in two cases of severe tricuspid stenosis, both combined with partial common atrioventricular (AV) canal, are presented in detail. Twelve cases were documented by postmortem examination and the diagnosis was confirmed by echocardiography and surgical observation in the one living patient. Clinical data available in nine cases and cardiac catheterization data obtained in eight are included in this report. In three cases (23%)--two with tricuspid atresia and one with extreme tricuspid stenosis--the tricuspid valve and right ventricle exhibited characteristics seen in Ebstein's anomaly. In all 13 cases, the great arteries were normally related. The ventricular septal defect(s) in 10 (83%) of the 12 postmortem cases rapidly became smaller and this resulted in marked diminution of the pulmonary blood flow and severe hypoxia. Only three of the eight patients with available cardiac catheterization and angiocardiographic data showed the scooped-out appearance of the left ventricular septal surface characteristic of AV canal defects. By contrast, two-dimensional echocardiography, available in the three most recent cases, accurately demonstrated all the defects present and represents the diagnostic method of choice. Early surgical intervention to establish a systemic to pulmonary artery anastomosis is essential for survival. More definitive surgical treatment can be achieved later by an atriopulmonary or cavopulmonary anastomosis with or without replacement of the cleft and often regurgitant mitral valve. The one living patient exemplifies this approach. This is the largest series of this unusual type of tricuspid atresia reported to date.

Solitary coronary ostium in the aorta in Syrian hamsters. A morphological study of 130 cases.

BACKGROUND: Solitary coronary ostium in the aorta (SCOA) is a rare anomaly, the pathogenesis of which remains uncertain. The lack of an animal model is one of the reasons why little understanding of this question has been gained. The aim was to examine the coronary distribution patterns associated with SCOA in laboratory inbred Syrian hamsters. METHODS: The study concerns 130 cases detected in a database consisting of 1,202 internal casts of the heart, great arterial trunks, and coronary arteries. RESULTS: In 21 (16.2%) cases, the solitary ostium was located in the left aortic sinus. In a further 58 (44.6%) cases, it was in the right aortic sinus. In the remaining 51 (39.2%) cases, the ostium was in the right side of the ventral aortic sinus of a bicuspid aortic valve. The distribution patterns were classified according to the location of the solitary ostium and the presence, or absence, and course of the main coronary arterial vessels. Overall, 14 categories were established, 10 of which had their counterpart in man. CONCLUSIONS: The findings reported substantiate the use of the present inbred Syrian hamsters for further studying the morphogenesis of the SCOA. The results of a statistical analysis indicate that when a sole coronary ostium becomes established in the aortic root, the development of the resultant anomalous coronary arterial tree tends to happen through preferential pathways. In addition, they indicate that the branching mode of the coronary tree and the condition of the aortic valve are independent traits.

Anatomic and functional "obstruction" of the outflow tract in atrioventricular septal defects with separate valve orifices ("ostium primum atrial septal defect"): an echocardiographic study.

Left ventricular (LV) outflow tract (OT) obstruction can be treacherous in any form of atrioventricular (AV) septal defect. The properties of the LVOT were investigated echocardiographically in 64 patients with separate valve orifices ("ostium primum atrial septal defect") who had survived corrective surgery. M-mode and cross-sectional echocardiographic (echo) images were made of the LVOT. The degree of malalignment of the aorta with the ventricular septum, the left atrium-aortic ratio, the fractional LV shortening and the diameter of the LVOT were recorded. Fixed anatomical obstruction was found in 3 patients, consisting of muscular bands or abnormal attachment of tension apparatus. Malalignment of the aorta with the ventricular septum was found in 62% of the patients. The diameter of the LVOT was smaller than that of the aortic root in 71% of the cases. The mean diameter of the LVOT was 92 +/- 27% (range 35 to 143%) of the aortic root diameter. Because its walls are mainly muscular, the LVOT constricts during systole. The mean end-systolic diameter of the LVOT was 77 +/- 22% (range 23 to 129%) of the aortic root diameter. Sequential measurements showed that the LVOT constricted gradually, but the velocity of constriction in patients with the most severe narrowing showed a distinct maximum in the first fifth of systole. In conclusion, a series of elements contribute to a potentially perilous arrangement of the LVOT in patients with AV septal defect. This intrinsically narrow tunnel was constricted during systole by its muscular walls.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased adhesiveness of trisomy 21 cells and atrioventricular canal malformations in Down syndrome: a stochastic model.

Based on the finding that fetal trisomy 21 fibroblasts explanted from lungs and endocardial-cushion-derived structures appear more adhesive in vitro than those from normal control individuals, we present a stochastic model for atrioventricular (AV) canal malformations in Down syndrome (DS). Computer simulations were performed to model the normal anatomic sequences of cushion-to-cushion and cushion-to-septum fusion in AV canal development. In these simulations, random-walking endocardial cells were allowed to migrate, divide, and adhere with programmable probabilities. Low values of intercellular adhesiveness engendered simulations resembling normal AV canal development; higher values of adhesiveness yielded deficiencies of AV canal development as seen in DS. Moderately high levels of adhesiveness resulted in abnormalities in only a proportion of multiple, independently performed simulations. The model successfully predicts the temporospatial sequence of anatomic events in cushion-to-septum fusion, clinical variability among individuals with the same genotype based on chance alone, and amplified developmental instability as observed in individuals with DS.

Surgical anatomy of left ventricular outflow tract obstruction in complete atrioventricular septal defect. A concept for operative repair.

An integral part of the heart with an atrioventricular septal defect and a Rastelli type A valve configuration is left ventricular outflow tract obstruction. Current surgical techniques do not cater to this particular anatomic facet, and left ventricular outflow tract obstruction has been reported as a postoperative problem. The present study has focused on the surgical anatomy of the mode of attachment of the left superior atrioventricular valve and its relationship to the left ventricular outflow tract. It appeared that the anchoring of the superior leaflet was a major factor in limiting the excursions of the superior leaflet, contributing also to the tightness of the subaortic left ventricular outflow channel. On that basis a surgical repair is proposed in which the greater part of the tightly bound superior leaflet is detached from the septal crest, so that the left ventricular outflow tract is widened.

Double-inlet ventricle: morphologic analysis and surgical implications in 32 cases.

We analyzed, using a sequential segmental approach, 32 cases of double-inlet ventricle to assess the feasibility of surgical "correction" by either ventricular septation or a modified Fontan procedure. Twenty-two hearts had two atrioventricular valves, connected to a left ventricle in 19, a right ventricle in two, and a solitary indeterminate ventricle in one. Septation was possible in only 13. In contrast, the Fontan procedure seemed feasible in 20. The remaining 10 specimens had double inlet via a common valve to the left ventricle in two, the right ventricle in six, and an indeterminate ventricle in two. Seven of these had right atrial isomerism. Ventricular septation was not considered a possibility in these hearts. The Fontan procedure combined with atrial septation was a possibility in seven cases. From the morphologic stance, although the modified Fontan procedure seemed suitable in most cases, a significant number of hearts with two atrioventricular valves were suitable for ventricular septation.

Complete atrioventricular canal associated with tetralogy of Fallot. Morphologic and surgical considerations.

Between 1962 and 1979, 14 patients with complete atrioventricular canal and tetralogy of Fallot underwent repair of both anomalies. The ages of the patients ranged from 1 to 12 years. Six patients had Down's syndrome. Five of the 14 had one or more previous systemic-pulmonary artery shunts. The correct diagnosis was established preoperatively in 11 of the patients. The ventricular septal defect, with its large anterior subaortic extension, was repaired by a combined atrial and right ventricular approach in five patients and by an atrial approach alone in nine. Outflow tract reconstruction (transannular patch) was performed in seven patients, without affecting the surgical mortality. Mortality was higher with associated Down's syndrome, but not significantly so (p = 0.1), and was related to age less than 4 years (p = 0.04). The presence of complete atrioventricular canal should be considered in patients with tetralogy of Fallot, especially those having Down's syndrome, electrocardiographic superior-axis deviation, and vectorcardiographic counterclockwise frontal QRS loop. This diagnosis can be confirmed preoperatively by right and left ventricular angiocardiography and two-dimensional echocardiography. The overall risk of repair has been high (29% early, 14% late mortality), but the mortality has been reduced to 17% during the last 10 years. No deaths have occurred in five recent patients who underwent closure of the ventricular septal defect by a combined atrial and ventricular approach.

Unusual mitral valve abnormalities complicating surgical repair of endocardial cushion defects.

A review of 155 cases of surgically repaired endocardial cushion defects revealed 16 patients (10%) with additional unusual mitral valve abnormalities that complicated the surgical procedure. Eight patients had accessory mitral valve tissue that connected the anterior and posterior leaflets to form a double-orifice valve (Group I). In four (50%), the lesion was associated with intermediate atrioventricular canal and small left ventricle; all four died following repair. In the other four, it was associated with ostium primum defect; all survived and are well. A single papillary muscle in the left ventricle was present in six patients (Group II). Two had intermediate atrioventricular canal and both died postoperatively. The other four had complete endocardial cushion defect and three are well following the operation. Perforation of the valve leaflets was present in two patients with ostium primum (Group III). Both patients are well postoperatively. Modification of the surgical technique is required to effect satisfactory repair. The bridge connecting the posterior and anterior leaflets of the mitral valve should be left undisturbed. Otherwise, severe regurgitation may result. In patients with single papillary muscle and complete atrioventricular canal, repair may be accomplished by borrowing from the tricuspid portion of the anterior leaflet, rotating that part posteriorly, and partially closing the cleft. Small perforations of the mitral leaflet do not require closure and do not result in regurgitation. Echocardiographic and angiographic delineation of these abnormalities and thorough intraoperative exploration are important in avoiding pitfalls at the time of repair.

Situs inversus totalis and single coronary ostium: A coincidence or a pattern?

Situs inversus totalis and single coronary ostium are rare congenital anomalies, and no ontogenic connection has been described between them. Only three cases of association of single coronary ostium and situs inversus have been reported in the literature, all found on angiography. Here we present the first case of this association discovered at autopsy. Based on the apparently higher than expected frequency of this finding, an underlying pathologic connection between these conditions is proposed.

Morphology of the posterior junctional area in atrioventricular septal defects.

The location and size of the coronary sinus in hearts with atrioventricular septal defect were investigated in relation to the known disposition of the atrioventricular conduction axis. We examined the morphology in 40 hearts and supplemented this series with two other hearts that had been serially sectioned previously. The coronary sinus received drainage from a persistent left superior caval vein in 5 hearts. Six cases of 40 had malalignment of the septal structures relative to the crux of the heart. In these, the conduction axis was anticipated to course in the position where the inlet ventricular septum met the atrioventricular junction. The coronary sinus terminated in the left atrium in 4 hearts: 2 in the morphological series and 2 that were sectioned for histological studies. The sectioned hearts showed the atrioventricular conduction axis in the usual position for the defect, unrelated to the coronary sinus. The principle that the node and penetrating bundle are located at the intersection of the ventricular septum with the atrioventricular junction holds good despite the variability of the coronary sinus.

Surgical repair of complete atrioventricular septal canal defects with absent posterior leaflet.

We report 2 cases of absence of the posterior (left mural) leaflet in complete atrioventricular septal defect. Closure of the atrioventricular septal defect was successfully accomplished in both cases. We describe the technique of left atrioventricular valve repair that led to a competent reconstructed valve.

Ostium primum atrioventricular septal defect: an anatomical and surgical review.

The results of surgical repair of ostium primum atrioventricular septal defect show continued improvement. This improvement reflects the advances in open-heart surgery in general and, in particular, the better understanding of the anatomy of the conduction tissue and the morphology and function of the left atrioventricular valve. We have corrected this defect in 84 patients over a ten-year period. There were 2 early deaths (2.4%) and 2 late deaths (2.4%). Two patients had problems related to conduction. Our surgical approach has been to place the interatrial baffle in such a way as to avoid the displaced atrioventricular node and thereby leave the coronary sinus in the left atrium. Our approach to repair of the so-called cleft in the left atrioventricular valve (in reality the space between the ventricular components of the bridging leaflets), is based on the unequivocal triple-leaflet morphology of this valve.