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.

[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.

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.

Common arterial trunk with atrioventricular septal defect: new observations pertinent to repair.

BACKGROUND: The coexistence of abnormalities in both atrioventricular and ventriculoarterial junctions occasionally represents a formidable challenge to the surgeon. The association of common arterial trunk with atrioventricular septal defect is such an example. To date, only two reports have described successful operative outcome. This paucity of success might reflect the anatomical complexity that could prevent favorable results. METHODS: We reviewed six specimens with common arterial trunk and atrioventricular septal defect, focusing on how to establish a nonobstructed connection between the left ventricle and the truncal valve. RESULTS: In all cases, the common trunk arose exclusively from the right ventricle, and the only exit from the left ventricle was the ventricular component of the septal deficiency. In particular, the preferential route was limited to a space below the superior bridging leaflet that did not have any tendinous cords inserting onto the ventricular crest, in contrast to the inferior bridging leaflets that were always tethered to the crest with many short cords. Accordingly, the size of potential left ventricular outflow depended on the shape of the anterosuperior margin of the ventricular crest below the superior bridging leaflet. The potential outflow was narrower than the truncal valvar area in all hearts but one having extensive anterosuperior excavation of the ventricular crest, suggesting the necessity of septal enlargement had anatomical repair been attempted during life. CONCLUSIONS: Owing to the unique ventriculoarterial connection, the surgeon, considering anatomical repair, needs to pay attention to the anterosuperior margin of the ventricular scoop, which determines the adequacy of left ventricular outflow size.

Ventricular scoop in atrioventricular septal defect: relevance to simplified single-patch method.

BACKGROUND: The simplified single-patch repair for atrioventricular septal defect seems an attractive alternative to conventional methods despite controversies on its suitability in hearts with a large ventricular scoop. Inasmuch as previous anatomic studies were conducted before the advent of this technique, we revisited this malformation with the aim to identify morphologic markers that may aid patient selection. METHODS: We examined 43 heart specimens: 31 with the complete form and 12 with the partial form of the malformation. RESULTS: In 16 hearts with the complete form, the scoop extended antero-superiorly beyond the atrioventricular junction, resulting in a skewed shape of the scoop. By contrast, none of the other hearts had such an extension and the scoop was nearly symmetric. Hearts with the extension had significantly narrower diameters of the left ventricular outflow tract (median [interquartile range]: 22% [17% to 33%]) than the complete form without the extension (38% [29% to 50%]; p = 0.01) and partial form (43% [25% to 50%]; p = 0.01). However, when the diameters were stratified with scoop depth, no obvious difference was found between the complete form with a deep scoop (defined as the depth of 60% or greater) and those with a shallower scoop (36% [24% to 49%] versus 28% [21% to 36%], respectively; p = 0.146), indicating that antero-superior extension had more impact on the tract size than scoop depth. CONCLUSIONS: The antero-superiorly extended and skewed scoop could lead to asymmetric configuration of the valvar leaflets and outflow tract obstruction if the simplified technique is applied. Therefore, not only scoop depth but also the antero-superior extension should be recognized when repairing this lesion.

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.

Endothelial expression of bone morphogenetic protein receptor type 1a is required for atrioventricular valve formation.

BACKGROUND: Atrioventricular canal defects account for 4% of all congenital heart anomalies. They arise from failure of endocardial cushion formation, a process dependent on transition of endothelial cells into clustered mesenchymal cells in the mid-atrioventricular septum. To date, the genetic signals necessary for atrioventricular canal defects are poorly understood. We hypothesized that bone morphogenetic protein signaling in cardiac endothelial cells may be crucial to this process. METHODS: To study the role of bone morphogenetic protein receptors (Bmpr) in the developing heart, we created knockout mice with inactivation of Bmpr1a selectively in endocardium. Two strains of null mice were created: one with constitutive endothelial-specific knockout of Bmpr1a and one with time-inducible, endothelial-specific knockout of Bmpr1a. Embryos and animals were analyzed by microscopy, RNA in situ hybridization, and microangiography. RESULTS: Animals with null mutation of Bmpr1a in endothelium were embryonic lethal at E11.5 to 12.0 and demonstrated absence of endocardial cushion formation. Embryos failed to form atrioventricular valves and adjacent septa. Endocardial knockout of Bmpr1a did not affect development of the outflow tract or aortic arches. Using time-inducible, cell-specific knockout mice, we show that Bmpr1a has two functions in the developing atrioventricular canal: to induce endocardial endothelial-mesenchymal transition, and to pattern the septal mesenchyme into endocardial cushions. We demonstrate that these processes are temporally linked to expression of the transcription factors Id1 and Id3. CONCLUSIONS: Endocardial cushion formation is dependent on cell-specific expression of Bmpr1a. Our results suggest that Bmpr1a-mediated signaling is a crucial pathway involved in pathogenesis of atrioventricular septal and valve malformations, which are among the most common congenital heart defects in humans.

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.

A critical role for the EphA3 receptor tyrosine kinase in heart development.

Eph proteins are receptor tyrosine kinases that control changes in cell shape and migration during development. We now describe a critical role for EphA3 receptor signaling in heart development as revealed by the phenotype of EphA3 null mice. During heart development mesenchymal outgrowths, the atrioventricular endocardial cushions, form in the atrioventricular canal. This morphogenetic event requires endocardial cushion cells to undergo an epithelial to mesenchymal transformation (EMT), and results in the formation of the atrioventricular valves and membranous portions of the atrial and ventricular septa. We show that EphA3 knockouts have significant defects in the development of their atrial septa and atrioventricular endocardial cushions, and that these cardiac abnormalities lead to the death of approximately 75% of homozygous EphA3(-/-) mutants. We demonstrate that EphA3 and its ligand, ephrin-A1, are expressed in adjacent cells in the developing endocardial cushions. We further demonstrate that EphA3(-/-) atrioventricular endocardial cushions are hypoplastic compared to wildtype and that EphA3(-/-) endocardial cushion explants give rise to fewer migrating mesenchymal cells than wildtype explants. Thus our results indicate that EphA3 plays a crucial role in the development and morphogenesis of the cells that give rise to the atrioventricular valves and septa.

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.

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.

Evaluation of intracardiac shunts with cardiac magnetic resonance.

Intracardiac shunts including atrial septal defect, ventricular septal defect, endocardial cushion defects, and surgical baffles may be identified, localized, and quantified using cardiac MRI methods. Both dark-blood and bright-blood techniques are helpful to identify anatomy. Contrast enhancement is especially useful for identifying associated vascular anomalies. Dynamic first-pass contrast agent signal-time studies may demonstrate rapid recirculation and shunting. Volumetric and phase contrast cine methods are useful to quantify flow. Pulmonary to systemic (Qp/Qs) flow ratios may be calculated noninvasively by comparing the pulmonary artery flow to the aortic flow measurement.

Sudden unexpected death in an adult patient with endocardial cushion defect.

A 50-year-old male died following a road traffic accident. Postmortem examination revealed that the injuries caused by the accident did not seem to have caused his death. A large ostium primum defect was found, with bridging leaflets attached to the interventricular septum. In this article, we present a case of sudden death with partial endocardial cushion defect and discuss the mechanism of death. We believe that this is the first report of sudden death caused by endocardial cushion defect.

Foxp1 regulates cardiac outflow tract, endocardial cushion morphogenesis and myocyte proliferation and maturation.

We have recently described a new subfamily of Fox genes, Foxp1/2/4, which are transcriptional repressors and are thought to regulate important aspects of development in several tissues, including the lung, brain, thymus and heart. Here, we show that Foxp1 is expressed in the myocardium as well as the endocardium of the developing heart. To further explore the role of Foxp1 in cardiac development, we inactivated Foxp1 through gene targeting in embryonic stem cells. Foxp1 mutant embryos have severe defects in cardiac morphogenesis, including outflow tract septation and cushion defects, a thin ventricular myocardial compact zone caused by defects in myocyte maturation and proliferation, and lack of proper ventricular septation. These defects lead to embryonic death at E14.5 and are similar to those observed in other mouse models of congenital heart disease, including Sox4 and Nfatc1 null embryos. Interestingly, expression of Sox4 in the outflow tract and cushions of Foxp1 null embryos is significantly reduced, while remodeling of the cushions is disrupted, as demonstrated by reduced apoptosis and persistent Nfatc1 expression in the cushion mesenchyme. Our results reveal a crucial role for Foxp1 in three aspects of cardiac development: (1) outflow tract development and septation, (2) tissue remodeling events required for cardiac cushion development, and (3) myocardial maturation and proliferation.

Control of endocardial cushion and cardiac valve maturation by BMP signaling pathways.

Congenital heart defects, the leading cause of deaths from birth defects, are estimated to occur in close to 1% of live newborns. Among these, abnormal septation of the heart and valve anomalies are the most frequent forms. Despite progress defining several genes involved in normal heart development, we still have a limited understanding of the signaling pathways involved in morphogenesis of the outflow tract (OFT) and, to date, very few genes have been identified that are responsible for defects in humans. Bone Morphogenetic Protein (BMP) signaling pathways are emerging as vital regulators of multiple aspects of cardiogenesis, including the septation of the OFT and valve maturation. Genetic and other in vivo evidence is now supporting the role for BMPs as inducers of endocardial cushion epithelial-to-mesenchymal transformation that was suggested by in vitro explant studies as well as by their patterns of expression in the developing heart. Here, we review briefly the in vitro data, and detail the novel mouse models where perturbed BMP signaling pathways result in impaired OFT septation and semilunar valvulogenesis. We propose that growth of the OFT valve cushions is regulated by the level of BMP signaling, under the control of other signaling pathways.