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Biomedical subjects

A C Gittenberger-de Groot

Publications and source records attributed to A C Gittenberger-de Groot.

At least 19 recordsLinked to original sources
PubMed2006

Maternal hyperhomocysteinaemia is a risk factor for congenital heart disease.

OBJECTIVE: To investigate the inter-relation between mother and infant homocysteine, folate and vitamin B12 status and the risk of a child with congenital heart disease (CHD). DESIGN: Case-control study. SETTING: Erasmus MC, University Medical Centre, Rotterdam, the Netherlands. POPULATION: Participants were 149 case-mothers and their children with CHD (n = 151) and 183 control-mothers with their children (n = 175). METHODS: Approximately 17 months after the index-pregnancy maternal fasting, children's random venous blood samples were drawn to measure plasma total homocysteine, serum and red blood cell (RBC) folate, and serum vitamin B12 concentrations. Data were compared between cases and controls using the Mann-Whitney U test. The biochemical parameters were dichotomised according to the cutoff value of the 10th percentile of vitamin concentrations and the 90th percentile of homocysteine concentrations based on control data. Risk estimates for the association between CHD and the biochemical parameters were estimated in a logistic regression model. MAIN OUTCOME MEASURES: Medians (minimum-maximum) and odds ratios (OR) (95% confidence intervals [CI]). RESULTS: The OR (95% CI) of having a child with CHD was 2.9 (1.4-6.0) for maternal hyperhomocysteinaemia (>14.3 micromol/l). This finding is substantiated by a significant concentration-dependent risk (Ptrend = 0.004). Hyperhomocysteinaemic case-mothers showed significantly lower serum folate and vitamin B12 concentrations than normohomocysteinaemic case-mothers. Serum and RBC folate concentrations were significantly higher in case-children than that in control-children. CONCLUSIONS: Maternal hyperhomocysteinaemia is associated with an increased risk of CHD, partially due to low folate and vitamin B12 status. The folate status of children warrants further investigation.

Adult↗
PubMed2005

Development of the right ventricular inflow tract and moderator band: a possible morphological and functional explanation for Mahaim tachycardia.

Atriofascicular accessory bundles with AV-node like conduction properties can sustain atrioventricular (AV) re-entrant tachycardia (Mahaim tachycardia). During early embryogenesis, the AV canal is situated above the primitive left ventricle (LV), and a right AV connection has not been achieved yet. We studied the formation of the right ventricular (RV) inflow tract in relation to the developing cardiac conduction system and hypothesized a morphological explanation for functional atriofascicular bypass tracts. Analysis of lacZ-expression during sequential stages of cardiogenesis was performed in CCS-lacZ transgenic mice (E9.5 to 15.5). Embryos were stained for beta-galactosidase activity and the myocardial marker HHF35. At early stages CCS-lacZ expression was observed in a ring surrounding the AV canal, which connected at the inner curvature to the primary fold. The first sign of formation of the (CCS-lacZ negative) RV inlet component was a groove in the CCS-lacZ positive tissue of the primary fold. Outgrowth of the RV inlet tract resulted in division of the primary fold in a septal part, the trabecula septomarginalis and a lateral part, the moderator band, which extended laterally up to the right AV ring. Electrophysiological measurements in embryonic hearts (E15.5) in which the right atrium (RA) and RV were isolated from the left atrium (LA) and LV supported the functionality of this AV-connection via the moderator band, by demonstrating sequential atrial and ventricular activation in both RA/RV and LA/LV preparations. In conclusion, our observations may provide a possible morphological and functional explanation for atriofascicular accessory pathways via the moderator band, underlying Mahaim tachycardia.

Animals↗
PubMed2005

First-trimester fetuses with increased nuchal translucency do not show altered intracardiac flow velocities.

OBJECTIVE: To study intracardiac flow velocities in first-trimester fetuses with normal nuchal translucency thickness (NT) and those with increased NT. METHODS: Ultrasound examinations were performed in 85 normal fetuses and 45 fetuses with NT > 95(th) percentile. Follow-up was complete and postmortem examination was performed on terminated pregnancies. Flow velocities during the early (e-wave) and late (a-wave) peaks across the tricuspid and mitral valves were measured and compared, using multilevel analysis, between the fetuses with normal and those with increased NT. In the group with increased NT, fetuses with and without a heart defect irrespective of the karyotype were compared, and in this group, euploid and aneuploid fetuses were compared, irrespective of the presence of a heart defect. RESULTS: No difference in intracardiac flow velocities was found between fetuses with normal and those with increased NT. Within the group of fetuses with increased NT, there was no difference between the fetuses with and without a cardiac defect. However, comparison of aneuploid with euploid fetuses within the group with increased NT showed that both the e-wave and a-wave peaks were decreased significantly by 3.03 cm/s and 5.95 cm/s, respectively, across the tricuspid valve, and by 3.47 cm/s and 5.92 cm/s, respectively, across the mitral valve (P < 0.05). The most common cardiac malformations were septal defects. CONCLUSION: There is no difference in intracardiac blood flow velocities between normal fetuses and those with increased NT. This contradicts the theory that NT is caused by impaired atrial contraction or cardiac failure. In fetuses with increased NT, those with aneuploidy show a decreased e-wave and a-wave compared with euploid fetuses. This cannot, however, be explained by the presence of cardiac defects, because there is no difference between fetuses with and without a cardiac defect. Therefore, we hypothesize that the relationship between enlarged NT and cardiac defects can only be explained by a developmental process that coexists at this period of gestation and is linked to cardiovascular development.

Blood Flow Velocity↗
PubMed2005

Potential involvement of vascular endothelial growth factor in pathophysiology of Turner syndrome.

Vascular endothelial growth factor (VEGF) is a specific growth factor for endothelium but plays also a role in the signaling involved in embryonic endocardial-to-mesenchymal transformation of the endocardial cushions. Furthermore, VEGF is the major vascular permeability factor in both fetal and postnatal life. Overexpression of VEGF during fetal life is associated with fetal hydrops and abnormal endocardial cushion development and therefore with congenital heart defects. Cases of prenatal cervical hygroma like in Turner syndrome show both hydrops and cardiac defects. We hypothesize that excess VEGF formed in the wall of the distended jugular sacs (cervical hygroma's) results in other abnormal features characteristic for Turner syndrome such as short stature and gonadal dysgenesis. This implicates that if excess VEGF could be limited prenatally, the phenotypical expression of Turner syndrome can possibly be reduced.

Endocardium↗
PubMed2004

Development of the coronary vasculature and its implications for coronary abnormalities in general and specifically in pulmonary atresia without ventricular septal defect.

AIM: Coronary vascular anomalies are an important factor in congenital heart disease in the neonate. However, our knowledge of the pathomorphogenesis is still defective. MATERIAL AND METHODS: (1) Study of coronary anomaly variations in congenital heart disease using specimens and (2) study of the role of epicardium-derived cells (EPDC) and neural crest cells in coronary vascular formation using quail-chicken chimeras. RESULTS: The clinical and pathological data revealed the existence of ventriculo-coronary arterial communications during fetal life before pulmonary atresia was established. This supported a primary coronary developmental anomaly as the origin of some cases of pulmonary atresia as opposed to other cases in which the pulmonary orifice atresia was the primary anomaly. Our experimental work showed the high relevance of the development of the epicardium and epicardium-derived cells for the formation of the coronary vasculature, and showed the coronary vascular ingrowth into the myocardium and subsequently into the aorta and the right atrium. The absence of epicardium-derived cells leads to embryonic death, while delayed outgrowth could result in the absence of the main coronary arteries to pinpoint orifice formation. In these cases, the circulation was maintained through ventriculo-coronary arterial communications. Neural crest cells were important for the patterning of the coronary vasculature. We have extended this knowledge to a number of other heart malformations. CONCLUSIONS: Coronary vascular anomalies are highly linked to the development of extracardiac contributors like the epicardium and the neural crest. A proper interaction between these cell types and the myocardium and aortic arterial wall are important for normal vascular development.

Animals↗
PubMed2003

Decellularization of rat aortic valve allografts reduces leaflet destruction and extracellular matrix remodeling.

OBJECTIVES: Decellularization of aortic valve allografts in advance of transplantation is a promising approach to overcome immune-induced early graft failure. In this study the effects of in vitro cell extraction on extracellular matrix molecules and in vivo remodeling of decellularized aortic valves were investigated in a heterotopic aortic valve rat implantation model. METHODS: Rat aortic valve conduits were decellularized by a 2-step detergent-enzymatic extraction method involving sodium dodecyl sulfate in combination with RNase and DNase. Cellular and acellular allogeneic (2x, n = 4) and syngeneic valve grafts (2x, n = 3) were grafted infrarenally into the descending aorta for 21 days. Immunohistochemical techniques were used to study extracellular matrix constitution (elastin, collagen, fibronectin, and chondroitin sulfate) and cellular infiltration. RESULTS: The decellularization procedure resulted in a complete loss of all cellular structures from the entire valve conduit with minimal damage to the extracellular matrix. All transplanted cellular allografts became deformed, swollen, and acellular with major changes in extracellular matrix structure. The transplanted decellularized allografts, however, retained normal preserved valve leaflets comparable to transplanted cellular and acellular syngeneic grafts. With the exception of cellular syngeneic grafts, all other grafts showed retrovalvular thrombi. CONCLUSIONS: Damage to the valves caused by decellularization technique is much less than the damage caused by the recipient's immune response. In vitro removal of viable cells in (cryopreserved) homografts may decrease graft failure. Seeding with autologous or major histocompatibility complex-matched donor endothelial cells will be necessary to diminish damage induced by an absent blood-tissue barrier.

Animals↗
PubMed2001

Double-outlet right ventricle and overriding tricuspid valve reflect disturbances of looping, myocardialization, endocardial cushion differentiation, and apoptosis in TGF-beta(2)-knockout mice.

BACKGROUND: Transforming growth factor-beta(2) (TGF-beta(2)) is a member of a family of growth factors with the potential to modify multiple processes. Mice deficient in the TGF-beta(2) gene die around birth and show a variety of defects of different organs, including the heart. METHODS AND RESULTS: We studied the hearts of TGF-beta(2)-null mouse embryos from 11.5 to 18.5 days of gestation to analyze the types of defects and determine which processes of cardiac morphogenesis are affected by the absence of TGF-beta(2). Analysis of serial sections revealed malformations of the outflow tract (typically a double-outlet right ventricle) in 87.5%. There was 1 case of common arterial trunk. Abnormal thickening of the semilunar valves was seen in 4.2%. Associated malformations of the atrioventricular (AV) canal were found in 62.5% and were composed of perimembranous inlet ventricular septal defects (37.5%), AV valve thickening (33.3%), overriding tricuspid valve (25.0%), and complete AV septal defects (4.2%). Anomalies of the aorta and its branches were seen in 33.3%. Immunohistochemical staining showed failure of myocardialization of the mesenchyme of the atrial septum and the ventricular outflow tract as well as deficient valve differentiation. Morphometry documented this to be associated with absence of the normal decrease of total endocardial cushion volume in the older stages. Apoptosis in TGF-beta(2)-knockout mice was increased, although regional distribution was normal. CONCLUSIONS: TGF-beta(2)-knockout mice exhibited characteristic cardiovascular anomalies comparable to malformations seen in the human population.

Animals↗
PubMed2001

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.

CD57 Antigens↗
PubMed2001

Magnetic resonance microscopy at 17.6-Tesla on chicken embryos in vitro.

The non-destructive nature and the rapid acquisition of a three-dimensional image makes magnetic resonance microscopy (MRM) very attractive and suitable for functional imaging investigations. We explored the use of an ultra high magnetic field for MRM to increase image quality per image acquisition time. Improved image quality was characterized by a better signal-to-noise ratio (SNR), better image contrast, and higher resolution compared to images obtained at lower magnetic field strengths. Fixed chicken embryos at several stages of development were imaged at 7.0-T (300 MHz) and at 17.6-T (750 MHz). Maximum intensity projection resulted in three-dimensional vascular images with ample detail of the embryonic vasculature. We showed that at 750 MHz frequency, an image with approximately three times better SNR can be obtained by T1-weighting using a standard gadolinium contrast agent, compared to the same measurement at 300 MHz. The image contrast improved by around 20 percent and the contrast-to-noise ratio improved by almost a factor of 3.5. Smaller blood vessels of the vascular system were identified at the high field, which indicates a better image resolution. Thus, ultra high field is beneficial for MRM and opens new areas for functional imaging research, in particular when SNR, resolution, and contrast are limited by acquisition time.

Animals↗
PubMed2001

Frizzled 2 is transiently expressed in neural crest-containing areas during development of the heart and great arteries in the mouse.

Frizzled 2 acts as a 7-transmembrane receptor in the Wnt-Dishevelled signal transduction cascade. Among others, this cascade has been associated with neural crest cell proliferation and early migration during development in mammals. The genes for some components of this cascade are located in chromosomal regions that are deleted in human syndromes associated with neural crest cell defects, like DiGeorge and Velo-Cardio-Facial Syndrome. These syndromes are often accompanied by abnormalities in cardiac morphology. Furthermore, we have reported in previous studies the upregulation of the tissue polarity gene frizzled 2 in myofibroblasts during their migration into the necrotic area after myocardial infarction in the adult heart. It is known that genes that are upregulated during cardiac remodeling due to pathology often play a role during development. To investigate whether frizzled 2 can be associated with the process of cardiac morphogenesis we studied its expression in the thoracic arterial system and heart of mouse embryo's of 10, 12, 14, 16 and 18 days after conception by means of in situ hybridization. At day 10 after conception signal could be found in the pharyngeal arches and arch arteries. The outflow tract, the ascending aorta and the pulmonary trunk were positive for frizzled 2 from day 12 on. This expression decreased with time and at day 18 only some signal could be detected in the aorta and pulmonary trunk. In contrast, in coronary and pulmonary arteries no expression was observed at any time point. Minor myocardial expression was observed in the ventricular septum at days 12 and 14. Atrial expression, although considerably lower than ventricular expression, could be detected somewhat later at days 14 and 16. Our results indicate that there is transient expression of frizzled 2 in areas that are invested by neural crest cells. This expression is downregulated upon neural crest cell differentiation. The frizzled 2 expression supports a role for the Wnt-frizzled pathway in neural crest-related disorders.

Actins↗
PubMed2001

Dorsal aortic flow velocity in chick embryos of stage 16 to 28.

The objective of this study was to evaluate two Doppler frequency-detection methods to measure blood flow velocity in the developing chick embryo. We compared the commonly used directional zero-crossing counter and a customized digital bidirectional spectrum analyzer. At development stages 16 up to 28 (2.5 to 6 days incubation), a reversed flow component in the dorsal aorta was demonstrated using the bidirectional spectrum analyzer. Dorsal aortic velocities obtained with the directional zero-crossing counter were significantly lower than with the bidirectional spectrum analyzer in stages 16, 20 and 28. In addition to the differences in the absolute velocity values, there was also a remarkable discrepancy in the velocity waveform shape using the two Doppler frequency processors. The calculated heart rate using the two Doppler frequency processors was identical. It is concluded that a Doppler velocity detector based on spectral analysis is superior to the hitherto used zero-crossing counter in the chick embryo. With the customized digital bidirectional spectrum analyzer, we can accurately measure the hemodynamics of the developing chick embryo.

Animals↗
PubMed2000

Epicardial outgrowth inhibition leads to compensatory mesothelial outflow tract collar and abnormal cardiac septation and coronary formation.

In the present study, we investigated the modulatory role of the epicardium in myocardial and coronary development. Epicardial cell tracing experiments have shown that epicardium-derived cells are the source of interstitial myocardial fibroblasts, cushion mesenchyme, and smooth muscle cells. Epicardial outgrowth inhibition studies show abnormalities of the compact myocardial layer, myocardialization of cushion tissue, looping, septation, and coronary vascular formation. Lack of epicardial spreading is partly compensated by mesothelial outgrowth over the conotruncal region. Heterospecific epicardial transplant is able to partially rescue the myocardial development, as well as septation and coronary formation.

Animals↗
PubMed2000

Distribution of different regions of cardiac neural crest in the extrinsic and the intrinsic cardiac nervous system.

In this study we focused upon whether different levels of postotic neural crest as well as the right and left cardiac neural crest show a segmented or mixed distribution in the extrinsic and intrinsic cardiac nervous system. Different parts of the postotic neural crest were labeled by heterospecific replacement of chick neural tube by its quail counterpart. Quail-chick chimeras (n = 21) were immunohistochemically evaluated at stage HH28+, HH29+, and between HH34-37. In another set of embryos, different regions of cardiac neural crest were tagged with a retrovirus containing the LacZ reporter gene and evaluated between HH35-37 (n = 13). The results show a difference in distribution between the right- and left-sided cardiac neural crest cells at the arterial pole and ventral cardiac plexus. In the dorsal cardiac plexus, the right and left cardiac neural crest cells mix. In general, the extrinsic and intrinsic cardiac nerves receive a lower contribution from the right cardiac neural crest compared with the left cardiac neural crest. The right-sided neural crest from the level of somite 1 seeds only the cranial part of the vagal nerve and the ventral cardiac plexus. Furthermore, the results show a nonsegmented overlapping contribution of neural crest originating from S1 to S3 to the Schwann cells of the cranial and recurrent nerves and the intrinsic cardiac plexus. Also the Schwann cells along the distal intestinal part of the vagal nerve are derived exclusively from the cardiac neural crest region. These findings and the smaller contribution of the more cranially emanating cardiac neural crest to the dorsal cardiac plexus compared with more caudal cardiac neural crest levels, suggests an initial segmented distribution of cardiac neural crest cells in the circumpharyngeal region, followed by longitudinal migration along the vagal nerve during later stages.

Animals↗
PubMed2000

Loss of function of the Prx1 and Prx2 homeobox genes alters architecture of the great elastic arteries and ductus arteriosus.

Prx1 (MHox) and Prx2 (S8) are non-clustered homeobox genes that are expressed in a complex, mostly mesenchyme-specific pattern throughout embryogenesis. The expression pattern and gene-targeted mice previously revealed a major role for Prx1 in skeletogenesis. In addition, specific and high expression of both Prx genes was reported in the developing cardiovascular system, predominantly in prospective connective tissues of the heart and in the great arteries and veins. We examined embryos of previously generated gene-targeted mice. Prx2-/- mutants were viable and did not show cardiovascular malformations. Intracardiac morphology of Prxl-/- and Prx1/Prx2-combined null mutants also appeared normal throughout development. However, the Prx1-/- and Prx1/Prx2 double-null mutants showed a vascular abnormality with an abnormal positioning and awkward curvature of the aortic arch in addition to a misdirected and elongated ductus arteriosus, and in two of seven combined mutants, an anomalous retro-oesophageal right subclavian artery. Generally, all great arteries appeared to run somewhat tortuously through the surrounding mesenchyme. The vascular histology and vessel wall thickness were normal in all mutants. Prx1-/- and Prx double-gene-targeted mice revealed similar spectra of vascular anomalies, but double mutants appeared to be more seriously affected. The current findings suggest that other genes may compensate for the loss of Prx in the heart, but, in contrast, our data support a role for Prx in the development of vascular and perivascular matrix.

Animals↗
PubMed2000

HNK-1 expression patterns in the embryonic rat heart distinguish between sinuatrial tissues and atrial myocardium.

HNK-1 expression was studied by immunohistochemistry in serial sections of embryonic and fetal rat hearts from 11.5 to 16.5 embryonic days. Graphic reconstructions were made to obtain detailed 3D information on the localization of immunoreactive tissues. The antibody used appeared to stain most parts of the venous sinus and the sinuatrial transitional zone as well as the atrioventricular transitional zone, but the patterns varied through the different developmental stages. At 11.5 days, positive myocardium was found in the right atrium and on top of the ventricular septal primordium. At 13.5 days, the left venous valve and the posterior atrial wall containing the orifice of the pulmonary vein were immunoreactive, and so were the right venous valve, the septum spurium and the superior, right-lateral and inferior parts of the atrioventricular canal. From the latter, immunoreactivity continued onto the crest of the ventricular septum. At 15.5 days, HNK-1 positivity in the two venous valves had become continuous, whereas the right-lateral part of the atrioventricular canal had lost its positivity, thus making the positive areas in the superior and inferior parts of this canal discontinuous. From the venous valves immunoreaction continued into the venous sinus septum but this area remained discontinuous with the inferior part of the atrioventricular canal. It is concluded that the entirety of venous sinus and sinuatrial transitional zone expresses the HNK-1 antigen and that the orifice of the pulmonary vein belongs to this complex, rather than to the embryonic atrium proper, which is HNK-1 negative. Extrapolation of these data to the adult human atrium leads to the conclusion hat most "atrial septal structures" are of sinuatrial origin, leaving the flap valve of the oval fossa (atrial septum primum) as the only really atrial structure. It is suggested that the atrioventricular node is derived from the inferior portion of the atrioventricular canal, and that two expansions of sinuatrial tissue form the substrate for anterior and posterior atrionodal inputs which in the literature have been described as internodal tracts.

Animals↗
PubMed2000

Apoptosis in cardiac development.

Cell degeneration, as a phenomenon accompanying developmental processes, was originally described over a century ago. Apoptosis, a term introduced approximately three decades ago, has occupied investigators particularly with respect to cell and tissue kinetics, emphasizing its role in the disposal of supernumerary, malinstructed or damaged cells. Although apoptosis is mostly related to developmental processes, evidence has been gathered indicating that it may also perform other roles. In this review, which concentrates on cardiac development, we examine focal apoptosis and subsequent signal cascades in combination with timed morphogenetic events. Apoptosis mainly occurs in the non-myocardial compartment of the embryonic heart, a compartment that consists of cells derived from the endocardium, the epicardium and the neural crest. The last-mentioned population invades the outflow tract and the atrioventricular endocardial cushions. The signalling cascade seems to involve the activation of latent transforming growth factor beta, resulting in cardiomyocyte migration and subsequent myocardialization of the endocardial cushions. Aberrant apoptosis accompanies cardiac anomalies. Furthermore, an apoptotic population is found surrounding the developing conduction system. A possible role for differentiation is suggested.

Animals↗
PubMed1999

A subpopulation of apoptosis-prone cardiac neural crest cells targets to the venous pole: multiple functions in heart development?

A well-described population of cardiac neural crest (NC) cells migrates toward the arterial pole of the embryonic heart and differentiates into various cell types, including smooth muscle cells of the pharyngeal arch arteries (but not the coronary arteries), cardiac ganglionic cells, and mesenchymal cells of the aortopulmonary septum. Using a replication-incompetent retrovirus containing the reporter gene LacZ, administered to the migratory neural crest of chicken embryos, we demonstrated another population of cardiac neural crest cells that employs the venous pole as entrance to the heart. On the basis of our present data we cannot exclude the possibility that precursors of these cells might not only originate from the dorsal part of the posterior rhombencephalon, but also from the ventral part. These NC cells migrate to locations surrounding the prospective conduction system as well as to the atrioventricular (AV) cushions. Concerning the prospective conduction system, the tagged neural crest cells can be found in regions where the atrioventricular node area, the retroaortic root bundle, the bundle of His, the left and right bundle branches, and the right atrioventricular ring bundle are positioned. The last area connects the posteriorly located AV node area with the retroaortic root bundle, which receives its neural crest cells through the arterial pole in concert with the cells giving rise to the aortopulmonary septum. The NC cells most probably do not form the conduction system proper, as they enter an apoptotic pathway as determined by concomitant TUNEL detection. It is possible that the NC cells in the heart become anoikic and, as a consequence, fail to differentiate further and merely die. However, because of the perfect timing of the arrival of crest cells, their apoptosis, and a change in electrophysiological behavior of the heart, we postulate that neural crest cells play a role in the last phase of differentiation of the cardiac conduction system. Alternatively, the separation of the central conduction system from the surrounding working myocardium is mediated by apoptotic neural crest cells. As for the presence of NC cells in both the outflow tract and the AV cushions, followed by apoptosis, a function is assigned in the muscularization of both areas, resulting in proper septation of the outflow tract and of the AV region. Failure of normal neural crest development may not only play a role in cardiac outflow tract anomalies but also in inflow tract abnormalities, such as atrioventricular septal defects.

Animals↗