Teratogenic Effect of Tedral (Theophylline, Ephedrine, and Phenobarbital) on Cardiac Development in Chick Embryos

Abstract We employed the chick embryo in a comparative study of the effect of Tedral and theophylline on anatomical development. Tedral, which contains theophylline in combination with ephedrine and phenobarbital in the relative dose ratio of theophylline 33: ephedrine 6: phenobarbital 2, or saline for control was dropped onto the surface of the chorioallantoic membrane of 2, 3, 4 and 5-day-old chick embryos. In groups A (theophylline 0.015 M, ephedrine 0.0027 M, phenobarbital 0.0009 M) and B (theophylline 0.011 M, ephedrine 0.0020 M, phenobarbital 0.0007 M), 100% of embryos treated on the 5th day of incubation developed aortic aneurysms with associated cardiovascular malformations. In group C (theophylline 0.005 M, ephedrine 0.0009 M, phenobarbital 0.0003 M), 36.8% of embryos treated on the 5th day of incubation developed aortic aneurysms, and 73.7% of embryos had cardiovascular malformations. These data were compared with those obtained by using theophylline, ephedrine or phenobarbital alone. The commonest cardiovascular anomalies induced by Tedral were double-outlet right ventricle with ventricular septal defect. Aneurysms were larger in size and cardiovascular malformations were more complex in embryos exposed to Tedral than in those treated with theophylline alone. Complex cardiac defects produced by Tedral included transposition of the great arteries, double-outlet right ventricle with double-inlet left ventricle, and truncus arteriosus communis. A slit-like small ventricular septal defect was found in 9.5% of the ephedrine-treated (0.51 mg) chick embryo group and 9.1% in the control embryos. These data show: (1) theophylline, a major component of Tedral, produces cardiovascular anomalies in embryonic chick hearts; (2) there is synergy of all three drugs in Tedral; (3) the specific type of conotruncal defect depends on the timing of administration, e.g., truncus arteriosus communis was produced on day 4 of Tedral administration in chick embryos.     

Aortic Arch Complex Anomalies: 20-Year Experience with Symptoms,Diagnosis, Associated Cardiac Defects,and Surgical Repair

To better understand the clinical presentation and surgical management of children with aortic arch complex anomalies (``vascular rings'), a retrospective study was performed on patients who presented to Children's National Medical Center between the years 1969 and 1989. A total of 59 patients were identified ranging in age at admission from birth to 14 years, of whom 35 (59%) were male and 24 (41%) female. Patients were classified into four major subtypes based on their surgical anatomy, with 29 (49%) patients having right aortic arch and left ductus/ligamentum arteriosus, 21 (36%) double aortic arch, 6 (10%) anomalous left pulmonary artery, and 3 (5%) arch artery anomaly (no ring); 19 patients (32%) had associated cardiac defects. The mean (±SD) age at onset of symptoms was 4.6 ± 14.0 months, and the age at surgical repair was 18 ± 34 months. There were no intraoperative mortalities, but two late deaths occurred. Three (5%) patients had a surgical complication. In contrast to previous studies, the incidence of nonring lesions was lower and associated cardiac defects higher. Forty-nine percent of patients had symptoms present at birth, and patients with associated cardiac disease did not present earlier than those without. In patients with right aortic arch and left ductus/ligamentum arteriosus, few had an anomalous left subclavian artery. Finally, equal dominance of the arches was most frequent in patients with double aortic arch. Aortic arch complex anomalies present symptomatically in a variety of ways, and noninvasive methods are used to identify the specific lesion and associated cardiac defects. Surgical repair is associated with low or no mortality in patients with uncomplicated aortic arch complex anomalies.     

Tetralogy of Fallot with Right Aortic Arch and Isolation of the Left Innominate Artery from a Left-Sided Patent Ductus Arteriosus

Isolation of the left innominate artery arising from the ductus arteriosus is a rare clinical entity with only nine cases being reported in the literature [5, 7, 8]. We describe a case consisting of tetralogy of Fallot, right aortic arch, and isolation of the left innominate artery arising from a left-sided ductus arteriosus which, to the best of our knowledge, has not been previously reported. The embryology of the aortic arch anomaly is reviewed.     

圆锥动脉干畸形与染色体22q11.2微缺失之间的关系

染色体22q11.2微缺失综合征患儿中约80％合并有先天性心血管畸形.研究发现,染色体22q11.2区内基因(TBX1、CRKL、ERK2)参与染色体22q11.2微缺失的发生.合并染色体22q11.2微缺失最常见的心血管畸形是圆锥动脉干畸形,包括法洛四联症、室间隔缺损型肺动脉闭锁、永存动脉干以及主动脉弓中断.主要表型...     

Aberrant right subclavian artery with left aortic arch: Associated cardiac anomalies

Summary Anomalous origin of the right subclavian artery (ARSA) from the aorta distal to the normally positioned left subclavian artery is a relatively frequent congenital anomaly in subjects with left aortic arch. The purpose of this study was to determine the relative frequency of associated cardiovascular anomalies in individuals with this anomaly. From the records of approximately 11,000 pathologic specimens in the Registry of Cardiovascular Disease of United Hospital (St. Paul, MN, USA), we found 128 (1.2%) with ARSA.Of the 128 ARSA, 117 (2.9%) occurred among 4102 instances of congenital heart disease.The 117 cases with congenital heart disease and ARSA were conotruncal anomalies in 38%, septal defects in 28%, obstructive anomalies of the left side of the heart in 21%, right heart anomalies in 5%, and miscellaneous conditions in the other 8%. Down syndrome existed in 14 (12%) of the 117 specimens with ARSA and some congenital cardiac anomaly; nine of the latter had an atrioventricular canal (AVC) malformation.     

Hypoparathyroidism in conotruncal heart defects

This retrospective study was designed to evaluate serum levels of intact parathyroid hormone and calcium in patients with conotruncal heart defects with or without microdeletion 22q11.2 in order to investigate a correlation between various types of conotruncal heart defect and hypoparathyroidism. A total of 67 patients with truncus arteriosus, tetralogy of Fallot, pulmonary atresia and ventricular septal defect, interrupted aortic arch or vascular ring were included of whom 28 had a 22q11.2 deletion (Group I) and 39 did not (Group II). In two patients of Group I and in one patient of Group II, parathyroid hormone level was decreased with normal serum calcium levels. No patient of Group II showed hypocalcaemia. In Group I, complete hypoparathyroidism with low parathyroid hormone and hypocalcaemia occurred in seven patients; 5 patients had bilateral anomalies of the right and the left 4th aortic arch derivates. In addition to an interrupted aortic arch type B or a high aortic arch, the contralateral subclavian artery arose cervically, high thoracically or anomalously from the descending aorta. Two patients had unilateral anomalies of the 4th aortic arch system: The origin of the right subclavian artery was cervical or from the descending aorta. CONCLUSION: Hypoparathyroidism occurred in 7 of our 28 patients with conotruncal heart defect and monosomy 22q11.2 and was associated with an extended regression of the 4th aortic arch development on both sides of the aortic arch system.     

MDCT angiography of isolated right subclavian artery

Isolation of a subclavian artery is an uncommon congenital anomaly of the aortic arch in which one subclavian artery loses its connection with the aorta and originates from the homolateral pulmonary artery by way of a ductus arteriosus. Isolation of the left subclavian artery in patients with a right aortic arch is well known. However, isolated right subclavian artery with a left-sided aortic arch is an extremely rare condition. In this report, we present multidetector computed tomographic (MDCT) angiography findings of an isolated right subclavian artery associated with a common carotid trunk and an anomalous origin and proximal interruption of the left pulmonary artery.     

MR imaging of isolated right subclavian artery

We report the MRI findings in a 3-week-old boy with D-transposition of the great arteries and an abnormal origin of the right subclavian artery from the pulmonary artery. This anomaly of the subclavian arteries is called isolation. It is infrequent in patients with a right aortic arch, but exceedingly rare in those with a left aortic arch. This is a unique report of the MRI findings in this congenital abnormality of the aortic arch.     

Vascular ring formed by right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum: a rare cause of respiratory distress in newborn infants

Vascular ring, in which the trachea and esophagus are completely surrounded by vascular structures, is one of the causes of respiratory distress in children. Right aortic arch with aberrant left subclavian artery is a common aortic arch anomaly; however, respiratory distress due to vascular ring is seldom associated with this anomaly. We report herein a newborn infant treated surgically because of severe respiratory distress caused by vascular ring formed by right aortic arch with aberrant left subclavian artery and left ligamentum arteriosum. As laryngomalacia was first thought to be the reason for respiratory distress, we suggest that patients with respiratory distress diagnosed with laryngomalacia be evaluated for possible vascular ring.     

Right circumflex retro-oesophageal aortic arch with coarctation of a high-positioned right arch

We present a rare case of right circumflex retro-oesophageal aortic arch with coarctation of a high-positioned right arch. A 7-month-old boy presented with a cardiac murmur. Cardiac situs was normal and there was no evidence of an intracardiac shunt or patent ductus arteriosus. MR aortography revealed a right aortic arch that was high-positioned, tortuous and narrowed. This right aortic arch crossed the midline behind the oesophagus and continued as a left-sided descending aorta. The left common carotid and subclavian arteries arose from a large branching vascular structure that derived from the top of the left-sided descending aorta. The right common carotid artery arose from the ascending aorta. The proximal portion of the right common carotid artery showed very severe stenosis and poststenotic dilatation. The right subclavian artery originated distal to the narrowed and tortuous segment of the aortic arch.     

Crossed Pulmonary Arteries: A Report on 20 Cases With an Emphasis on the Clinical Features and the Genetic and Cardiac Abnormalities

Crossed pulmonary arteries (CPAs) are a rare abnormality in which the ostium of the left pulmonary artery originates superior to the right pulmonary artery and to its right. Recognition of this rare pathology is important because it generally is accompanied by other congenital heart defects, extracardiac anomalies, and certain genetic problems. To date, only a few cases have been reported, and most of these cases have been associated with complex cardiac abnormalities. The authors detected 20 cases of CPA between June 2009 and November 2012 through their increasing awareness of this anomaly. Approximately 9,250 echocardiograms were performed during this period, and all of them also were checked for this anomaly. This report describes 20 cases of this CPA, with an emphasis on the clinical features and the genetic and cardiac abnormalities. The patients ranged in age from 1 day to 13 years at the time of the initial diagnosis. Four patients had complex cardiac pathologies such as tetralogy of Fallot, truncus arteriosus, transposition of the great arteries, and complete atrioventricular septal defect. Of the 20 patients, 11 had ventricular septal defects, and 12 had atrial septal defects. Pulmonary artery stenosis was detected in 12 (55 %) of the 20 patients. Aortic arch abnormalities such as interrupted aortic arch, right aortic arch, and coarctation of the aorta were detected in six patients. One patient had a left persistent superior vena cava. In 45 % of the cases, an associated genetic syndrome (DiGeorge-, Noonan-, Holt–Oram syndromes, vertebral, anal, cardiac, tracheal, esophageal, renal, limb anomalies [VACTERL] anomalies) was present. These syndromes were diagnosed based on their clinical features. Karyotype and fluorescent in situ hybridization (FISH) analyses for a 22q11 deletion were performed for 11 patients, with 10 patients found to have normal karyotype and FISH results. Only one patient had a 22q11 deletion. Six patients underwent successful operations. During the follow-up period, 3 of the 20 patients died. At this writing, the remaining patients are clinically stable and being followed without surgery. The authors believe that CPA is not a rare anomaly. If careful echocardiographic examination is performed, CPA will be diagnosed more frequently. Although this pathology usually is associated with genetic syndromes and other cardiac abnormalities, patients with CPA generally are asymptomatic.     

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.     

Laterality of the aortic arch and anomalies of the subclavian artery—reliable indicators for 22q11.2 deletion syndromes?

A variety of cardiac defects, encompassing truncus arteriosus, tetralogy of Fallot, pulmonary atresia with ventricular septal defect and interrupted aortic arch, are generally summarised as conotruncal malformations. Patients with these cardiac defects were frequently found to have a common microdeletion on chromosome 22, the so-called monosomy 22q11.2. The aim of our study was to determine whether the laterality of the aortic arch or the presence of subclavian artery anomalies (SAA) represent markers for monosomy 22q11.2 in these patients. 170 patients with these cardiac anomalies were recruited at presentation in the paediatric cardiology units of two tertiary referral centres from 1994 until 2003. Of the 170 children and young adults, 33 had interrupted aortic arch, 35 tetralogy of Fallot, 31 truncus arteriosus communis and 71 pulmonary atresia with ventricular septal defect. All were screened for monosomy 22q11.2 and the results were correlated with the laterality of the aortic arch and the presence of SAA contralateral to the aortic arch (aberrant origin from the descending aorta, isolation, distal ductal origin from the pulmonary artery and cervical origin of the right subclavian artery). Monosomy 22q11.2 was present in 59/170 patients (35%). A left aortic arch (LAA) was found in 118 (69%), a right aortic arch (RAA) in 52 (31%) patients. Almost 50% of the patients with RAA (46%), but only 30% of the patients with LAA had monosomy 22q11.2 (P=0.054). A total of 47 patients (28%) had an anomaly of the subclavian artery, 81% of whom had monosomy 22q11.2. This deletion was found in decreasing percentage in patients with LAA+SAA (85%) >RAA+SAA (75%) >RAA without SAA (28%) >LAA without SAA (13%). Conclusion:In patients with conotruncal malformations, anomalies of the subclavian arteries are the most important anatomical marker for the presence of monosomy 22q11.2, independent of the laterality of the aortic arch. Therefore, we recommend cytogenetic testing for this microdeletion in all patients with subclavian artery anomalies and conotruncal malformations.     

An Isolated Left Common Carotid Artery from the Main Pulmonary Artery: Possible Malseptation of the Truncoaortic Sac

An isolated left common carotid artery (LCA) is an extremely rare condition with only four reported cases. In each case, the isolated carotid artery connects to the right or left pulmonary artery via the ductus arteriosus and the embryologic basis for the abnormalities is believed to reflect an error in the development of the branchial arches. We present a case of an isolated LCA connecting to the main pulmonary artery in association with a right aortic arch and an anomalous origin of the left subclavian artery from the descending aorta. The left ligamentus arteriosus was identified separately. This may represent a disturbance in the septation of the truncoaortic sac secondary to abnormal migration of neural crest cells rather than a pure developmental anomaly of the branchial arches.     

Aortic Arch Anomalies Associated with Chromosome 22q11 Deletion (CATCH 22)

Chromosome 22q11 deletion or CATCH 22 is associated with DiGeorge syndrome, conotruncal anomaly face syndrome, and velocardiofacial syndrome. Associated congenital heart diseases include tetralogy of Fallot, truncus arteriosus, and ventricular septal defect. Associated anomalies of the aortic arch, aortic branches, ductus arteriosus, and pulmonary arteries are more frequent in patients with the deletion than in those without the deletion. Associated anomalies include right aortic arch, cervical aorta, aberrant origin or isolation of the subclavian artery, the absence of the ductus arteriosus, major aortopulmonary collateral arteries, isolation of the left pulmonary artery, and vascular ring formed by the right aortic arch, retroesophageal aortic arch, and left descending aorta.     

Increased NCAM expression and vascular development in trisomy 16 mouse embryos: relationship with nuchal translucency

Increased nuchal translucency in the human fetus is associated with chromosomal abnormalities, enlarged jugular lymphatic sacs, cardiac defects and changed flow through the ductus venosus. The developmental background of this nuchal edema in relation to the associated anomalies remains elusive. We studied the morphologic correlation between neurogenesis and vasculogenesis in neck, heart, and ductus venosus region of wild type and trisomy 16 mice embryos (E10- E18), using an antibody against Neural Cell Adhesion Molecule (NCAM). Trisomy 16 mice are a model for the above described human phenotype. From E12 trisomy 16 mice showed an altered arrangement of cranial nerves IX, X and XI, which are positioned between the carotid artery, jugular vein and enlarged lymphatic sac. The vagal nerve was significantly smaller, compared with wild type embryos. NCAM was over expressed in both neuronal and cardiovascular structures in trisomy 16 mice, being particularly prominent in the 4th and 6th pharyngeal arch arteries, and the ductus venosus. In the 4th and 6th pharyngeal arch arteries, NCAM over expression was located to the part of the vessel wall that is closely related to the vagal and recurrent nerve. In case of 4th pharyngeal arch artery abnormalities NCAM expression, on the other hand, was reduced. In conclusion, the interaction between neurogenesis and vasculogenesis is disturbed in the trisomy 16 mouse model, and might be a common denominator in the spectrum of anomalies associated with increased nuchal translucency.     

Right aortic arch with coarctation in Chinese children

Background Because of the rarity of right aortic arch coarctation there are few reports of large groups of patients. Objective To characterize the frequency and type of right aortic arch coarctation in a large group of pediatric patients. Materials and methods From June 1997 through May 2007, 11,276 consecutive children with congenital heart disease underwent multidetector CT (MDCT), MRI or angiocardiography examination. All children with a right aortic arch or coarctation were reviewed. Results Right aortic arch coarctation was found in 11 children representing 0.1% of the total group of 11,276 children, 1.7% of 658 children with native coarctations and 2.3% of 473 children with a right aortic arch. Among the 11 patients, 6 had long-segment narrowing and 7 had an aberrant left subclavian artery. Conclusion MDCT, MRI and angiocardiography are reliable imaging techniques for the diagnosis of right aortic arch and coarctation. Our findings showed that the pattern of right aortic arch coarctation was different from that of left aortic arch coarctation, suggesting that they are different etiological entities. The pivotal role possibly played by flow dynamics in the development of right aortic arch coarctation is discussed.     

Aortic valvular atresia

Summary The pathological anatomy of 109 specimens of aortic valvular atresia was reviewed for the purpose of identifying the cardiovascular anomalies associated with that condition. We found the most commonly associated anomaly to be coarctation of the aorta, which was present in 71 percent of our cases and judged to be of hemodynamic significance in one-third of the involved cases. Other associated anomalies, in order of decreasing frequency, were mitral atresia, anomalous systemic and pulmonary venous connections, abnormalities of branching of the aortic arch, and ventricular septal defect. The study demonstrated that aortic atresia is associated with a significant incidence of other cardiovascular anomalies. Additional anomalies, when present, may complicate emerging attempts at surgical correction of this condition. Supported by Public Health Service Research Grant 5 RO1 HL05694 from the National Heart, Lung and Blood Institute.     

Immunohistochemical Distribution of HNK-1 and N-CAM in Rat Embryos Treated with Bis-Diamine

Bis-diamine is known to induce congenital anomalies including cardiac defects, thymic hypoplasia and snout defects in rat embryos. Cardiovascular lesions consist of persistent truncus arteriosus, tetralogy of Fallot and aortic arch anomalies, which are often found in DiGeorge syndrome. In the the present study, we investigated effects of bisdiamine on cardiac neural crest cells, which may be important to the teratogenecity. A single dose of 200 mg bis-diamine was administered to pregnant rats at 10.5 embryonic day (ED). Immunohistochemical studies were performed on embryos at 11.5, 12.5 and 13.5 ED using anti-HNK-1 and anti-N-CAM antibodies. The embryos at 11.5 and 12.5 ED showed the similar distributional patterns of either HNK-1 or N-CAM positive cells in control and bis-diamine treated embryos. N-CAM immunoreactivities in the splanchnic mesoderm were quite weakly detectable in the bis-diamine treated embryos at 12.5 ED. Closure of the neural tube was delayed in the treated embryos at this period. Immunohistochemistry of the control embryos at 13.5 ED demonstrated a continuous chain of N-CAM expression between the neural plexus near the foregut and the fourth aortic arch, while no apparent continuity of N-CAM positive tissue was observed in the bis-diamine treated embryos. These findings suggested that bis-diamine reduced the amount of neural crest cells which appeared to participate in the aortic arch formation or conotruncal septation. The primary effect of bis-diamine in the induction of various congenital anomalies including cardiovascular malformations may be an inhibition of the normal development of the neural tube and neural crest.     

Persistent truncus arteriosus: Pathologic anatomy in 54 cases

Summary Fifty-four specimens of heart with persistent truncus arteriosus (PTA) were reviewed anatomically. According to the Collett-Edwards classification [11] there were 28 examples of type I and 26 type II. The sex distribution was equal. The number of the truncal cusps ranged from one to four (42% tricuspid, 30% bicuspid, 24% quadricuspid, and 4% unicommissural). A unicommissural truncal valve has not been previously reported. In 72% of cases, the truncal valve leaflets were thickened or dysplastic. Two valves were stenotic. The truncus arteriosus originated from both ventricles equally in 42% of the cases, predominantly from the right ventricle in 42%, and predominantly from the left ventricle in 16% of the cases. In unoperated cases of PTA originating predominantly from the right ventricle, it appeared to us that usual operative correction might result in left ventricular outflow obstruction. Variations in coronary arterial origins and patterns were present in nearly half of the cases. A single coronary artery was observed in ten cases (18.5%). Stenosis of the ostium of one coronary artery was seen in each of four cases (7%). High posterior origin of the left coronary artery was observed in ten cases (18.5%). Among the associated cardiovascular anomalies, the most common were right aortic arch (36%) and interruption of the aortic arch (11%). Three cases with the latter condition exhibited crossed pulmonary arteries. Isolated cases with tricuspid atresia, vascular sling (left pulmonary artery arising from right pulmonary artery), and persistent common atrioventricular canal were encountered.