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PubMed2005

Morphological differences in cardiovascular anomalies induced by bis-diamine between Sprague-Dawley and Wistar rats.

It is known that animals show different responses to the same teratogen between different strains. We examined cardiac malformations in Sprague-Dawley (SD) and Wistar rats induced by bis-diamine, which produced conotruncal anomalies and aortic arch malformations in embryos when administered to the dams, to elucidate the morphological differences and pathogenesis in the two strains. Two hundred milligrams of bis-diamine dissolved in 1% gum-tragacanth was administered to pregnant rats on embryonic day (ED) 9.5, 10.5 and 11.5 in each strain. The embryos were removed on ED 20.5. External appearances, cardiovascular morphology and associated anomalies were examined under a dissecting microscope. An immunohistological study with an anti-N-CAM antibody, an excellent marker for neural crest cells, was performed on ED 12.5 embryos. Isolated aortic arch anomalies were common features of malformations induced by bis-diamine in SD rats and intracardiac defects were found in a small number of the embryos. Wistar rats showed more serious cardiovascular anomalies, such as persistent truncus arteriosus and tetralogy of Fallot, especially when dams were treated on ED 10.5 and isolated arch anomalies were significantly less prevalent than in SD rats. Immunohistology demonstrated that there were fewer N-CAM positive cells in the conotruncal region in Wistar rats than in SD rats. Bis-diamine induced more critical cardiovascular malformations in Wistar rats because neural crest cells, which play an important role in conotruncal septation, were more extensively damaged. Different susceptibility to bis-diamine and/or different time of neural crest cell emigration from the hindbrain might explain those morphological differences.

Abnormalities, Drug-Induced↗

PubMed1992

Extended fetal echocardiographic examination for detecting cardiac malformations in low risk pregnancies.

OBJECTIVE: To improve the rate of prenatal detection of cardiac malformations in a low risk population. DESIGN: Comparison of extended fetal echocardiography with the standard four chamber view in detecting abnormalities. Extended echocardiography comprised the four chamber view and visualisation of the left ventricular outflow tract, the right ventricular outflow tract, and the main pulmonary artery and its branches. In cases with abnormal results complete echocardiographic studies were performed by a paediatric cardiologist using M mode, Doppler, and colour flow mapping techniques. SETTING: Obstetric ultrasonographic unit at Shaare-Zedek Medical Centre, Jerusalem. SUBJECTS: 5400 fetuses in low risk pregnancies between 18 and 24 weeks' gestation (mean 21 weeks); 53 were lost to follow up. MAIN OUTCOME MEASURES: Detection of abnormality before and after birth. RESULTS: During the study 23 infants (0.4%) were born with cardiac abnormalities, 21 of whom had major structural and functional heart disease. 18 fetuses had heart disease diagnosed prenatally, 11 by the four chamber view alone (sensitivity 48%) and a further seven by extended echocardiography (sensitivity 78%). Five fetal cardiac defects were missed prenatally (false negative rate 22%). These included coarctation of aorta, persistent truncus arteriosus, tetralogy of Fallot, ventricular septal defect, and pulmonic stenosis. Only one false positive diagnosis (coarctation of aorta) was made (specificity 99.9%, false positive rate 0.1%). The abnormality was correctly identified in 17 out of 18 cases. CONCLUSIONS: The extended fetal heart examination detected 86% (18/21) of major abnormalities in a low risk population. The examination should be incorporated into routine prenatal ultrasonographic investigations.

Adolescent↗

PubMed1970

Ventricular inversion without transposition of the great vessels in situs inversus.

A classification of one type of congenital malformation previously reported (de la Cruz et al., 1967) is based on the integration of an embryological theory for ventricular inversions with the embryological concepts of trunco-conal malformations (de la Cruz and da Rocha, 1956). In that classification we consider that in each situs, either solitus or inversus ventricular inversions may be associated with: (a) normally arranged great vessels (not transposed); (b) transposition of the great vessels; (c) persistent truncus arteriosus. The patients had ventricular inversion without transposition of the great vessels in situs inversus.THE CORRECT ANATOMICAL DIAGNOSIS WAS NOT FORESEEN BUT THE PHYSIOPATHOLOGICAL DIAGNOSIS WAS CORRECT: pulmonary ischaemia associated with septal defects. In one case these facts were substantiated by catheterization and by angiocardiographic findings which led us to advise surgery. Haemodynamically isolated inversion of the ventricles is as severe a malformation as complete (not corrected) transposition of the great vessels. However, an operation of the anastomotic type between a systemic vessel and the narrow pulmonary artery seemed justified in these cases, as a means to convey more blood to the lungs and improve the saturation of the arterial blood. It was unsuccessfully carried out in one patient.The anatomical, radiological, and electrocardiographic features which might aid in the diagnosis are analysed.

Adult↗

PubMed1977

Atresia of the right atrioventricular orifice.

The results are reported of a study of 83 necropsied hearts with atresia of the right atrioventricular orifice. It is emphasised that right atrial or atrioventricular orificial atresia is a better term to describe this anomaly than "tricuspid atresia". Use of the latter term can be confusing when the morphologically tricuspid valve is located beneath the left atrium. It is accepted that the definition employed may include cases in which the mitral valve may be atretic, blocking normal exit from the right atrium, but it is argued that such cases would present clinically as "tricuspid atresia" and therefore are correctly designated as right atrial orificial atresia. The results show that the majority of hearts with right atrial orificial atresia have the ventricular morphology of primitive ventricle, most with, but a few without an outlet chamber. However, in a minority of hearts an imperforate membrane interposes between the right atrium and a formed but hypoplastic right ventricle. In two of the hearts, the imperforate membrane showed features of Ebstein's malformation. The hearts could be further subdivided according to the ventriculoarterial connection. Most had normally connected arteries (66 of 83), and all but 2 also had normal relations between the arteries; in these 2 hearts there was "anatomically corrected malposition". Twelve hearts showed transposition, one had double-outlet outlet chamber, and another persistent truncus arteriosus. The remaining 3 hearts, all without outlet chamber, had by definition a double outlet connection. A segmental approach provides the best way of classifying this anomaly, and an embryological explanation is offered for the variations in anatomy observed.

Aortic Valve Stenosis↗

PubMed2004

L-type Ca2+ channel function in the avian embryonic heart after cardiac neural crest ablation.

In avian and mammalian embryos, surgical ablation or severely reduced migration of the cardiac neural crest leads to a failure of outflow tract septation known as persistent truncus arteriosus (PTA) and leads to embryo lethality due partly to impaired excitation-contraction coupling stemming primarily from a reduction in the L-type Ca(2+) current (I(Ca),(L)). Decreased I(Ca,L) occurs without a corresponding reduction in the alpha(1)-subunit of the Ca(2+) channel. We hypothesize that decreased I(Ca),(L) is due to reduced function at the single channel level. The cell-attached patch clamp with Na(+) as the charge carrier was used to examine single Ca(2+) channel activity in myocytes from normal hearts from sham-operated embryos and from hearts diagnosed with PTA at embryonic days (ED) 11 and 15 after laser ablation of the cardiac neural crest. In normal hearts, the number of single channel events per 200-ms depolarization and the mean open channel probability (P(o)) was 1.89 +/- 0.17 and 0.067 +/- 0.008 for ED11 and 1.14 +/- 0.17 and 0.044 +/- 0.005 for ED15, respectively. These values represent a normal reduction in channel function and I(Ca),(L) observed with development. However, the number of single channel events was significantly reduced in hearts with PTA at both ED11 and ED15 (71% and 47%, respectively) with a corresponding reduction in P(o) (75% and 43%). The open time frequency histograms were best fitted by single exponentials with similar decay constants (tau approximately or equal 4.5 ms) except for the sham operated at ED15 (tau = 3.4 ms). These results indicate that the cardiac neural crest influences the development of myocardial Ca(2+) channels.

Animals↗

PubMed2005

Cardiovascular phenotyping of fetal mice by noninvasive high-frequency ultrasound facilitates recovery of ENU-induced mutations causing congenital cardiac and extracardiac defects.

As part of a large-scale noninvasive fetal ultrasound screen to recover ethylnitrosourea (ENU)-induced mutations causing congenital heart defects in mice, we established a high-throughput ultrasound scanning strategy for interrogating fetal mice in utero utilizing three orthogonal imaging planes defined by the fetus' vertebral column and body axes, structures readily seen by ultrasound. This contrasts with the difficulty of acquiring clinical ultrasound imaging planes which are defined by the fetal heart. By use of the three orthogonal imaging planes for two-dimensional (2D) imaging together with color flow, spectral Doppler, and M-mode imaging, all of the major elements of the heart can be evaluated. In this manner, 10,091 ENU-mutagenized mouse fetuses were ultrasound scanned between embryonic days 12.5 and 19.5, with 324 fetuses found to die prenatally and 425 exhibiting cardiovascular defects. Further analysis by necropsy and histology showed heart defects that included conotruncal anomalies, obstructive lesions, and shunt lesions as well as other complex heart diseases. Ultrasound imaging also identified craniofacial/head defects and body wall closure defects, which necropsy revealed as encephalocele, holoprosencephaly, omphalocele, or gastroschisis. Genome scanning mapped one ENU-induced mutation associated with persistence truncus arteriosus and holoprosencephaly to mouse chromosome 2, while another mutation associated with cardiac defects and omphalocele was mapped to mouse chromosome 17. These studies show the efficacy of this novel ultrasound scanning strategy for noninvasive ultrasound phenotyping to facilitate the recovery of ENU-induced mutations causing congenital heart defects and other extracardiac anomalies.

Abnormalities, Multiple↗

PubMed1986

Effects of the size of lesions of the cardiac neural crest at various embryonic ages on incidence and type of cardiac defects.

Removal of premigratory neural crest over somites 1 through 3 in chick embryos has been shown previously to result in a significant incidence of persistent truncus arteriosus. In the present study, single somite-length pieces of premigratory neural crest were removed unilaterally at slightly different embryonic ages. These lesions resulted in a number of different heart defects. Two defects, ventricular septal defect and double outlet right ventricle, were significantly correlated with the location of neural crest removed. The stage at which the ablation was performed was important in determining the incidence but not the type of defects.

Animals↗

PubMed2006

Rotation of the myocardial wall of the outflow tract is implicated in the normal positioning of the great arteries.

Congenital heart defects frequently involve a failure of outflow tract (OFT) formation during development. We analyzed the remodeling of the OFT, using the y96-Myf5-nlacZ-16 transgene, which marks a subpopulation of myocardial cells of the pulmonary trunk. Expression analyses of reporter transcript and protein suggest that the myocardial wall of the OFT rotates before and during the formation of the great arteries. Rotational movement was confirmed by Di-I injection experiments with cultured embryos. We subsequently examined the expression of the transgene in mouse models for OFT defects. In hearts with persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), or transposition of the great arteries, rotation of the myocardial wall of the OFT is arrested or fails to initiate. This is observed in Splotch (Pax3) mutants with PTA or DORV and may be a result of defects in neural crest migration, known to affect OFT septation. However, in Pitx2deltac mutant embryos, where cardiac neural crest cells are present in the heart, PTA and DORV are again associated with a rotation defect. This is also seen in Pitx2deltac mutants, which have transposition of the great arteries. Because Pitx2c is involved in left-right signaling, these results suggest that embryonic laterality affects rotation of the myocardial wall during OFT maturation. We propose that failure of normal rotation of OFT myocardium may underlie major forms of congenital heart disease.

Animals↗

PubMed1986

Hemodynamic changes in chick embryos precede heart defects after cardiac neural crest ablation.

Neural crest cells are known to contribute to the normal architecture of the heart and aortic arch arteries. Ablation of neural crest cells over somites 1 to 3 in the chick embryo prevents conotruncal septation and results in persistent truncus arteriosus. To determine whether a deficiency of cardiac neural crest cells produces hemodynamic changes prior to the development of identifiable structural defects in the heart, we measured dorsal aortic blood velocity and vitelline artery blood pressure in lesioned and control embryos at a period of cardiac morphogenesis prior to septal formation. The internal diameter of the dorsal aorta at the level of the sinus venosus and the internal diameter of the aortic arch arteries at their midpoints were measured in embryos at Stage 18 of development using a filar micrometer eyepiece and a dissecting microscope. Embryos with neural crest lesions had significantly greater dorsal aortic blood flow velocity than control embryos. In addition, embryos lacking cardiac neural crest had significantly lower systolic and diastolic blood pressures than control embryos. There was no difference in heart rate, dorsal aortic diameter or internal diameter of the aortic arch arteries between lesioned and control embryos. Scanning electron micrographs revealed no gross morphological differences in cardiac looping or conotruncal wall development between lesioned and control embryos; however, embryos with cardiac neural crest ablations developed markedly hypoplastic 4th pharyngeal arches. This data suggests that hemodynamic changes precede the onset of structural heart defects in embryos with cardiac neural crest ablations.

Animals↗

PubMed1997

Compartment-selective sensitivity of cardiovascular morphogenesis to combinations of retinoic acid receptor gene mutations.

Several aspects of normal cardiovascular development require signaling by the vitamin A metabolite retinoic acid. We have previously established germ-line mutations in mice in the genes that encode the RAR alpha 1, RAR beta, and RXR alpha retinoic acid receptors as a means of studying the function of these receptors in vivo. Although mutation of RXR alpha results in fetal ventricular defects, the RAR alpha 1 and RAR beta mutations are apparently nonphenotypic in the heart and elsewhere. In this study, we have established and analyzed combinations of these receptor gene mutations. Malformations of the ventricular chamber (chamber hypoplasia and muscular ventricular septal defects), conotruncus (double-outlet right ventricle, transposition, and membranous ventricular septal defects), aortic sac (persistent truncus arteriosus and aorticopulmonary window), and aortic arch-derived arteries were recovered in various combinations of the RAR alpha 1, RAR beta, and RXR alpha gene mutations. Depending on the combination of receptor mutations, selective defects were obtained in specific cardiovascular compartments, suggestive of differential expression or function of each receptor within domains of the developing heart.

Animals↗

PubMed2006

GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis.

GATA transcription factors play critical roles in restricting cell lineage differentiation during development. Here, we show that conditional inactivation of GATA-6 in VSMCs results in perinatal mortality from a spectrum of cardiovascular defects, including interrupted aortic arch and persistent truncus arteriosus. Inactivation of GATA-6 in neural crest recapitulates these abnormalities, demonstrating a cell-autonomous requirement for GATA-6 in neural crest-derived SMCs. Surprisingly, the observed defects do not result from impaired SMC differentiation but rather are associated with severely attenuated expression of semaphorin 3C, a signaling molecule critical for both neuronal and vascular patterning. Thus, the primary function of GATA-6 during cardiovascular development is to regulate morphogenetic patterning of the cardiac outflow tract and aortic arch. These findings provide new insights into the conserved functions of the GATA-4, -5, and -6 subfamily members and identify GATA-6 and GATA-6-regulated genes as candidates involved in the pathogenesis of congenital heart disease.

Animals↗

PubMed1982

congenital heart diseases in swine.

One hundred twenty-two congenital cardiac anomalies were diagnosed in 83 pigs (4.35%) during necropsies of 1906 pigs from one day to four years of age during an 11-month period. The incidence of cardiac malformation was higher at 29 to 56 days of age. Of the 83 pigs with cardiac anomalies, 47 (56%) were male and 36 (44%) were female, and of these, 15 (18%) were purebred and 68 (82%) were crossbred pigs. Of the 15 purebred pigs with cardiac malformation, there were seven Landrace pigs, four Large White pigs, three Duroc Jersey pigs, and one Yorkshire pig; whereas 94% of the 68 crossbred pigs were crossbred among Landrace, Duroc Jersey, and Large White. The 122 cardiac anomalies found in the 83 pigs were: dysplasia of the tricuspid valve in 42 pigs, atrial septal defect in 31 pigs, subaortic stenosis in 22 pigs, ventricular septal defect in nine pigs, persistent common atrioventricular canal in eight pigs, malformation of the moderator band in seven pigs, persistent vena cava in one pig, persistent truncus arteriosus in one pig, and pulmonary stenosis in one pig. The pathological features of the anomalies in swine were similar to those described in small animals and in man. The findings indicate that spontaneous porcine cardiac anomalies might provide models for cardiovascular investigators to study the etiology and pathogenesis of congenital heart diseases in man and other animals.

Animals↗

PubMed2006

Defective ALK5 signaling in the neural crest leads to increased postmigratory neural crest cell apoptosis and severe outflow tract defects.

BACKGROUND: Congenital cardiovascular diseases are the most common form of birth defects in humans. A substantial portion of these defects has been associated with inappropriate induction, migration, differentiation and patterning of pluripotent cardiac neural crest stem cells. While TGF-beta-superfamily signaling has been strongly implicated in neural crest cell development, the detailed molecular signaling mechanisms in vivo are still poorly understood. RESULTS: We deleted the TGF-beta type I receptor Alk5 specifically in the mouse neural crest cell lineage. Failure in signaling via ALK5 leads to severe cardiovascular and pharyngeal defects, including inappropriate remodeling of pharyngeal arch arteries, abnormal aortic sac development, failure in pharyngeal organ migration and persistent truncus arteriosus. While ALK5 is not required for neural crest cell migration, our results demonstrate that it plays an important role in the survival of post-migratory cardiac neural crest cells. CONCLUSION: Our results demonstrate that ALK5-mediated signaling in neural crest cells plays an essential cell-autonomous role in the pharyngeal and cardiac outflow tract development.

Activin Receptors, Type I↗

PubMed1987

Cardiac morphogenesis--recent research advances.

It has been demonstrated recently that a specific region of neural crest contributes cells to the septa of the outflow tract of the heart. Removal of this region of cardiac neural crest prior to migration from the neural fold results in persistent truncus arteriosus in chick embryos. Removal of other regions of cranial neural crest results in double outlet right ventricle. Since double outlet right ventricle is produced by manipulation of noncardiac neural crest, this malformation is thought to be an indirect rather than direct effect of neural crest ablation. The cranial neural crest forms the walls of all of the aortic arch arteries and it is proposed herein that flow abnormalities are produced in the pharyngeal region by injury to the neural crest. These abnormal hemodynamic characteristics influence heart development. Cardiac neural crest seeds the heart with parasympathetic postganglionic neurons as well as ectomesenchyme. Removal of the cardiac neural crest results in cardiac malformations because of the decreased ectomesenchymal cells. However, the neural population undergoes regeneration and so the innervation of malformed hearts is morphologically normal. The mechanism for this regeneration is not understood.

Animals↗

PubMed1991

Hemodynamic changes and compensatory mechanisms during early cardiogenesis after neural crest ablation in chick embryos.

Microcinephotography was used to study early heart development in chick embryos with ablations of the neural crest known to result in persistent truncus arteriosus with associated aortic arch anomalies. The premigratory neural crest destined for the 3rd and 4th pharyngeal arches and the aorticopulmonary septum were ablated. When the embryos reached the looped cardiac tube stage (stage 18), 15 experimental and 15 control embryos were filmed at 100 frames/s under controlled environmental conditions. End-diastolic and end-systolic dimensions were determined for the conotruncus and presumptive right ventricle that together compose the bulbus cordis. The results showed that the shortening fractions and ejection fractions were significantly depressed in the experimental embryos. The experimental embryos exhibited dilation and decreased emptying of the ventricle. There was no difference in heart rate or stroke volume between the control and experimental embryos. Thus, the calculated cardiac output was the same in the control and experimental groups. It appeared that the experimental embryos compensated for decreased contractility by ventricular dilation. These functional compensations in very early cardiac development may play an etiologic role in the subsequent development of structural heart defects.

Animals↗

PubMed1993

Neural crest ablation versus sham surgical effects in a chick embryo model of defective cardiovascular development.

In chick embryos, ablation of premigratory neural crest destined for the third, fourth, and sixth pharyngeal arches results in persistent truncus arteriosus and interrupted aortic arch. Studies of cardiogenesis in these embryos have shown decreased ejection fraction and ventricular dilation with normal cardiac output. The experimental embryos that survive to d 11 of incubation have a higher cardiac output than nonsurvivors at the same earlier stage of development. We hypothesize that this survival is due to a surgically induced decrease in vascular resistance of the embryonic and vitelline vessels. Embryos from 15 opened eggs, eight sham-operated embryos, and 13 neural crest-ablated embryos were examined at stage 18. The sham-operated embryos were treated identically with the experimental embryos except that neural crest was not ablated. Ejection fraction and cardiac output were determined by cinephotography. Mean dorsal aortic and diastolic ventricular (approximates mean atrial) pressures were determined by a servo-null pressure technique and used to calculate vascular resistance. The experimental embryos had a significantly decreased ejection fraction in comparison with either sham-operated embryos or embryos from eggs that remained unopened until just before cinephotography. The experimental and sham-operated embryos had a higher cardiac output than embryos from unopened eggs. The calculated vascular resistance was also significantly lower in both the experimental and sham-operated embryos than in the embryos from unopened eggs. Neural crest ablation appears to cause a decreased ejection fraction. Sham surgery is associated with a higher cardiac output and lower vascular resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Cardiac outflow tract defects in mice lacking ALK2 in neural crest cells.

Cardiac neural crest cells are multipotent migratory cells that contribute to the formation of the cardiac outflow tract and pharyngeal arch arteries. Neural crest-related developmental defects account for a large proportion of congenital heart disorders. Recently, the genetic bases for some of these disorders have been elucidated, and signaling pathways required for induction, migration and differentiation of cardiac neural crest have emerged. Bone morphogenetic proteins comprise a family of secreted ligands implicated in numerous aspects of organogenesis, including heart and neural crest development. However, it has remained generally unclear whether BMP ligands act directly on neural crest or cardiac myocytes during cardiac morphogenesis, or function indirectly by activating other cell types. Studies on BMP receptor signaling during organogenesis have been hampered by the fact that receptor knockouts often lead to early embryonic lethality. We have used a Cre/loxP system for neural crest-specific deletion of the type I receptor, ALK2, in mouse embryos. Mutant mice display cardiovascular defects, including persistent truncus arteriosus, and abnormal maturation of the aortic arch reminiscent of common forms of human congenital heart disease. Migration of mutant neural crest cells to the outflow tract is impaired, and differentiation to smooth muscle around aortic arch arteries is deficient. Moreover, in Alk2 mutants, the distal outflow tract fails to express Msx1, one of the major effectors of BMP signaling. Thus, the type I BMP receptor ALK2 plays an essential cell-autonomous role in the development of the cardiac outflow tract and aortic arch derivatives.

Activin Receptors, Type I↗

PubMed2005

Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development.

To elucidate the function of the T-box transcription factor Tbx20 in mammalian development, we generated a graded loss-of-function series by transgenic RNA interference in entirely embryonic stem cell-derived mouse embryos. Complete Tbx20 knockdown resulted in defects in heart formation, including hypoplasia of the outflow tract and right ventricle, which derive from the anterior heart field (AHF), and decreased expression of Nkx2-5 and Mef2c, transcription factors required for AHF formation. A mild knockdown led to persistent truncus arteriosus (unseptated outflow tract) and hypoplastic right ventricle, entities similar to human congenital heart defects, and demonstrated a critical requirement for Tbx20 in valve formation. Finally, an intermediate knockdown revealed a role for Tbx20 in motoneuron development, specifically in the regulation of the transcription factors Isl2 and Hb9, which are important for terminal differentiation of motoneurons. Tbx20 could activate promoters/enhancers of several genes in cultured cells, including the Mef2c AHF enhancer and the Nkx2-5 cardiac enhancer. The Mef2c AHF enhancer relies on Isl1- and Gata-binding sites. We identified a similar Isl1 binding site in the Nkx2-5 AHF enhancer, which in transgenic mouse embryos was essential for activity in a large part of the heart, including the outflow tract. Tbx20 synergized with Isl1 and Gata4 to activate both the Mef2c and Nkx2-5 enhancers, thus providing a unifying mechanism for gene activation by Tbx20 in the AHF. We conclude that Tbx20 is positioned at a critical node in transcription factor networks required for heart and motoneuron development where it dose-dependently regulates gene expression.

Animals↗