Interruption Of The Aortic Arch Type Research Articles

Improved Outcomes in Patients with 22q11.2 Deletion Syndrome and Diagnosis of Interrupted Aortic Arch Prior to Birth Hospital Discharge, a Retrospective Study.

Interruption of the aortic arch (IAA) is a rare but life-threatening congenital heart defect if not corrected in the neonatal period. IAA type B is highly correlated with 22q11.2 deletion syndrome (22q11.2DS); approximately 50% of patients with IAA type B also have 22q11.2DS (Peyvandi et al.; Goldmuntz et al.). Early identification and repair of IAA can prevent severe morbidity and death. However, IAA is challenging to identify prenatally, or even in the neonatal period. In this study, we examined infants with IAA, diagnosed during pregnancy and prior to discharge (PPTD) from the birth hospital vs. those diagnosed following discharge (FD) from the newborn nursery. Our goals were to determine: (1) if early diagnosis improved outcomes; and (2) if patients with IAA and without 22q11.2DS had similar outcomes. In total, 135 patients with a diagnosis of 22q11.2DS and IAA were ascertained through the 22q and You Center at the Children's Hospital of Philadelphia (CHOP). The examined outcomes included: timing of diagnosis; age at diagnosis (days); hospital length of stay (LOS); duration of intensive care unit (ICU) stay; mechanical ventilation (days); duration of inotrope administration (days); year of surgical intervention; birth hospital trauma level; and overall morbidity. These outcomes were then compared with 40 CHOP patients with IAA but without 22q11.2DS. The results revealed that the PPTD neonates had fewer days of intubation, inotrope administration, and hospital LOS when compared to the FD group. The outcomes between deleted and non-deleted individuals with IAA differed significantly, in terms of the LOS (40 vs. 39 days) and time in ICU (28 vs. 24 days), respectively. These results support the early detection of 22q11.2DS via prenatal screening/diagnostics/newborn screening, as IAA can evade routine prenatal ultrasound and postnatal pulse oximetry. However, as previously reported in patients with 22q11.2DS and congenital heart disease (CHD), patients with 22q11.2DS tend to fare poorer compared to non-deleted neonates with IAA.

A new anatomic approach of the ventricular septal defect in the interruption of the aortic arch.

The aim of this study was to analyse the anatomy of the ventricular septal defect (VSD) in heart specimens with interruption of the aortic arch (IAA) in order to explore the hypothesis of different embryologic mechanisms for the different anatomic types of IAA. We examined 42 human heart specimens, 25 with IAA as the main disease with concordant atrioventricular and ventriculo-arterial connections and two distinct great arteries, and 17 hearts with IAA associated with other malformations [six common arterial trunk (CAT), five double-outlet right ventricle (DORV), three transposition of the great arteries (TGA), three atrioventricular septal defect (AVSD)]. The interruption was classified according to Celoria and Patton. We focused on the anatomy of the VSD viewed from the right ventricular side. There were 15 IAA type A, 27 type B, no type C. The VSD in IAA type B was always an outlet VSD, located between the two limbs of the septal band, with posterior malalignment of the outlet septum in hearts with concordant ventriculo-arterial connections, without any fibrous tricuspid-aortic continuity. In addition, the aortic arch was always completely absent. Conversely, the VSD in IAA type A could be of any type (outlet in six, muscular in four, central perimembranous in two, inlet in three) and the aortic arch was either atretic or absent. In addition, IAA type B, when found in the setting of another anomaly, was always associated with neural crest-related anomalies (CAT and DORV), whereas IAA type A was found in association with anomalies not related to the neural crest (TGA and AVSD). These results reinforce the hypothesis that different pathogenic mechanisms are responsible for the two types of IAA, and the inclusion of IAA type B in the group of neural crest defects. Conversely, IAA type A could be due to overlapping mechanisms: flow-related defect (coarctation-like) and neural crest contribution.

Loss of CXCL12/CXCR4 signalling impacts several aspects of cardiovascular development but does not exacerbate Tbx1 haploinsufficiency

The CXCL12-CXCR4 pathway has crucial roles in stem cell homing and maintenance, neuronal guidance, cancer progression, inflammation, remote-conditioning, cell migration and development. Recently, work in chick suggested that signalling via CXCR4 in neural crest cells (NCCs) has a role in the 22q11.2 deletion syndrome (22q11.2DS), a disorder where haploinsufficiency of the transcription factor TBX1 is responsible for the major structural defects. We tested this idea in mouse models. Our analysis of genes with altered expression in Tbx1 mutant mouse models showed down-regulation of Cxcl12 in pharyngeal surface ectoderm and rostral mesoderm, both tissues with the potential to signal to migrating NCCs. Conditional mutagenesis of Tbx1 in the pharyngeal surface ectoderm is associated with hypo/aplasia of the 4th pharyngeal arch artery (PAA) and interruption of the aortic arch type B (IAA-B), the cardiovascular defect most typical of 22q11.2DS. We therefore analysed constitutive mouse mutants of the ligand (CXCL12) and receptor (CXCR4) components of the pathway, in addition to ectodermal conditionals of Cxcl12 and NCC conditionals of Cxcr4. However, none of these typical 22q11.2DS features were detected in constitutively or conditionally mutant embryos. Instead, duplicated carotid arteries were observed, a phenotype recapitulated in Tie-2Cre (endothelial) conditional knock outs of Cxcr4. Previous studies have demonstrated genetic interaction between signalling pathways and Tbx1 haploinsufficiency e.g. FGF, WNT, SMAD-dependent. We therefore tested for possible epistasis between Tbx1 and the CXCL12 signalling axis by examining Tbx1 and Cxcl12 double heterozygotes as well as Tbx1/Cxcl12/Cxcr4 triple heterozygotes, but failed to identify any exacerbation of the Tbx1 haploinsufficient arch artery phenotype. We conclude that CXCL12 signalling via NCC/CXCR4 has no major role in the genesis of the Tbx1 loss of function phenotype. Instead, the pathway has a distinct effect on remodelling of head vessels and interventricular septation mediated via CXCL12 signalling from the pharyngeal surface ectoderm and second heart field to endothelial cells.

Two patients with the heterozygous R189H mutation in ACTA2 and Complex congenital heart defects expands the cardiac phenotype of multisystemic smooth muscle dysfunction syndrome.

De novo heterozygous mutations changing R179 to histidine, leucine, or cysteine in the ACTA2 gene are associated with Multisystemic Smooth Muscle Dysfunction Syndrome (MSMDS). Characteristic hallmarks of this condition, caused only by these specific ACTA2 mutations, are congenital mydriasis (mid-dilated, non-reactive pupils), a large persistent ductus arteriosus (PDA), aortic aneurysms evolving during childhood, and cerebrovascular anomalies. We describe two patients, a 3-day-old newborn and a 26-year-old woman, with this unique mutation in association with a huge PDA and an aorto-pulmonary window. In addition, one showed a coarctation of the aortic arch and the other a complete interruption of the aortic arch type A; thereby expanding the spectrum of cardiac congenital heart defect of this syndrome. Each patient displayed a huge PDA and an extra-cardiovascular phenotype consistent with MSMDS. These observations exemplify that a functional alpha 2 smooth muscle actin is necessary for proper cardiovascular organ development, and demonstrate that a very exceptional congenital heart defect (aortopulmonary window) can be caused by a mutation in a gene encoding a contractile protein of vascular smooth muscle cells. © 2017 Wiley Periodicals, Inc.

Fetal interrupted aortik ark tip B’nin antenatal değerlendirilmesi

Interruption of the aortic arch (IAA) is a rare, severe form of congenital heart defect characterized by complete anatomical discontinuity between two adjacent segments of the aortic arch. The data on the features and outcomes of fetal IAA are limited. Three anatomical types have been described according to the site of interruption. The current recommendations for screening on the obstetric fetal anomaly scan include identification of a 4-chamber view, all 4 valves, and the outflow tracts, all of which can appear to be normal to the ultrasonographer in fetuses with conotruncal anomalies. Although the identification of IAA on a prenatal echocardiogram can be challenging, a number of anatomic features can facilitate the diagnosis. We aim to present the features and outcome of a case of IAA type B referred to our centre in the light of literatures

283: A new anatomic approach to the ventricular septal defect in interruption of the aortic arch

To analyze the anatomy of the ventricular septal defect (VSD) in heart specimens with interruption of the aortic arch (IAA), in order to confirm the hypothesis of different embryologic mechanisms for the different anatomic types of IAA. We examined 27 hearts from the anatomic collection of the French Reference Center for Complex Congenital Heart Defects with IAA, concordant atrioventricular and ventriculoarterial connections, and 2 distinct great arteries. Hearts were classified according to Celoria and Patton: type A, interruption distal to the distal subclavian artery (A), type B, between the distal subclavian and the carotid artery (B), type C, between the 2 carotid arteries (C). We focused on the anatomy of the VSD viewed from the right ventricular side. There were 10 A, 17 B, no C. One A (with aortopulmonary window) and 1 B had no VSD. The VSD was conoventricular, located between the 2 limbs of the septal band (LSB), in 4/9 A and 16/16 B (p=0.005), with posterior deviation of the outlet septum. In A, the VSD was conoventricular in 4 with muscular rims in 2 and fibrous extension of the posterior LSB in 2, muscular in 3, membranous in 2. In B, the VSD had entirely muscular rims in 4, fibrous extension of the posterior LSB in 9, and was juxta-arterial in 3; there was no fibrous continuity between the tricuspid and aortic valve. The VSD in IAA type B is always conoventricular, with posterior deviation of the outlet septum, but without any fibrous tricuspid-aortic continuity. The VSD in IAA type A can be of any type. This reinforces the hypothesis of different pathogenic mechanisms responsible for the 2 types of IAA, and the inclusion of IAA type B in the group of conotruncal defects. The absence of fibrous tricuspid-aortic continuity indicates that the fibrous extension of the posterior LSB in some hearts may be due to the deviation of the outlet septum, due to an excessive rotation of the outflow tract.

Tbx1 Genetically Interacts With the Transforming Growth Factor-β/Bone Morphogenetic Protein Inhibitor Smad7 During Great Vessel Remodeling

Growth and remodeling of the pharyngeal arch arteries are vital for the development of a mature great vessel system. Dysmorphogenesis of the fourth arch arteries can result in interruption of the aortic arch type B, typically found in DiGeorge syndrome. Tbx1 haploinsufficient embryos, which model DiGeorge syndrome, display fourth arch artery defects during formation of the vessels. Recovery from such defects is a documented yet unexplained phenotype in Tbx1 haploinsufficiency. To understand the nature of fourth arch artery growth recovery in Tbx1 haploinsufficiency and its underlying genetic control. We categorized vessel phenotypes of Tbx1 heterozygotes as hypoplastic or aplastic at the conclusion of pharyngeal artery formation and compared these against the frequency of vessel defects scored at the end of great vessel development. The frequency of hypoplastic vessels decreased during embryogenesis, whereas no reduction of vessel aplasia was seen, implying recovery is attributable to remodeling of hypoplastic vessels. We showed that Smad7, an inhibitory Smad within the transforming growth factor-β pathway, is regulated by Tbx1, is required for arch artery remodeling, and genetically interacts with Tbx1 in this process. Tbx1 and Tbx1;Smad7 haploinsufficiency affected several remodeling processes; however, concurrent haploinsufficiency particularly impacted on the earliest stage of vascular smooth muscle cell vessel coverage and subsequent fibronectin deposition. Conditional reconstitution of Smad7 with a Tbx1Cre driver indicated that the interaction between the 2 genes is cell autonomous. Tbx1 acts upstream of Smad7 controlling vascular smooth muscle and extracellular matrix investment of the fourth arch artery.

The Three-Vessel View in the Fetal Mediastinum in the Diagnosis of Interrupted Aortic Arch

Interruption of the aortic arch (IAA) is difficult to detect and diagnose in utero. However, prenatal diagnosis may be beneficial because IAA is rapidly fatal (median age, 10 d) if left uncorrected. Our objective was to review the direct and indirect echocardiographic markers associated with IAA, focusing on the importance of the three-vessel view (3VV), which is obtained during routine ultrasound examination to rule out malformations. We analyzed the fetal echocardiograms of nine fetuses and compared them with 56 normal controls. In each fetus, there was a large discrepancy between the diameter of the larger, dilated pulmonary artery (PA) and smaller, narrow aortic arch (Ao). The calculated ratio of PA/Ao in fetuses with IAA was 2.6 ± 0.4 compared with 1.1 ± 0.09 in normal controls ( p < 0.0001). The calculated ratio of PA/Ao in fetuses with IAA type A was 2.1 ± 0.09 and IAA type B 2.9 ± 0.2 ( p = 0.0007). Discrepancy between PA/Ao diameters should raise the suspicion of aortic arch anomalies and a large discrepancy is a nearly pathognomonic sign of IAA type B.

Interruption of the aortic arch: diagnosis with multidetector computed tomography

We investigated retrospectively the usefulness of multidetector computed tomography (MDCT) in the preoperative diagnosis of interruption of the aortic arch (IAA). Seven neonates with IAA underwent enhanced MDCT before a surgical repair operation between April 2006 and March 2010. The MDCT procedures were performed using either a 16- or 64-MDCT scanner without electrocardiographic gating or respiratory arrest. High-quality CT images were obtained in all cases. One patient was diagnosed to be IAA type A, and 6 were diagnosed to be IAA type B (Celoria and Patton classification). The Celoria and Patton classification of IAA types and subtype classification by MDCT were confirmed by surgery. Our results show that the information from MDCT was sufficient for a preoperative diagnosis of IAA and allowed omission of a cardiac catheter examination before surgery.

Prenatal diagnosis of interruption of the aortic arch and its association with deletion of chromosome 22q11

Differentiation of interruption of the aortic arch (IAA) type A from type B by prenatal echocardiography is possible but difficult. We report nine consecutive cases of the prenatal detection of IAA and evaluate the feasibility of making a correct prenatal diagnosis with fetal echocardiography. The incidence of 22q11 microdeletion in our series, detected using fluorescent in situ hybridization (FISH) analysis, was determined. Echocardiography and FISH for the DiGeorge critical region (22q11) were performed in all cases. The findings were confirmed by autopsy (three cases) or at postnatal surgery (six cases). On fetal echocardiography we identified six type B cases and three type A. FISH detected microdeletions in 22q11 in five of nine fetuses (four type B cases and an unusual association with type A in one case). Our report confirms the feasibility of making a correct prenatal diagnosis of IAA and its different types, based on echocardiographic examination. Furthermore our data are consistent with previous reports indicating that type A and type B are distinct entities. In more than 50% of fetuses with IAA type B, 22q11 microdeletion and DiGeorge or velo-cardio-facial syndromes may be expected. IAA type A is not commonly associated with 22q11 hemizygosity.

Interrupted aortic arch: an epidemiologic study.

Interruption of the aortic arch (IAA) is a rare but severe anomaly associated with major intracardiac defects and with multisystem noncardiac malformations, recently linked to chromosome deletion of 22q11.2. The Baltimore-Washington Infant Study (1981-1989), a population-based epidemiologic study of cardiovascular malformations, evaluated 53 infants with IAA in comparison with 3,572 controls. Risk factors for the anatomic subtypes were evaluated in 14 cases of IAA type A and 32 cases of IAA type B, but no molecular genetic tests were available. The distribution of associated cardiac defects was similar for both types. DiGeorge syndrome (DGS) occurred more frequently in IAA type B. Case-control comparisons demonstrated that infants in both groups were growth retarded at birth. A family history of noncardiac defects occurred only in IAA type B cases and included relatives with cleft lip and/or cleft palate. Candidate risk factors were associated only in type B cases and differed for those with (n = 10) and for those without (n = 19) DGS: a family history of noncardiac defects (odds ratio [OR] = 7.2, 95% confidence interval [CI] = 1.5-39.2) and maternal use of aspirin during the critical period (OR = 4.8, 95% CI = 1.3-25.4) occurred with DGS, while previous stillbirth (OR = 9.4, 95% CI = 1.3-53.1), bleeding during pregnancy (OR = 3.7, 95% CI = 1.4-11.4), and maternal exposure to arts/crafts paints (OR = 4.8, 95% CI = 1.3-17.4) were associated in those without DGS. These findings confirm the heterogeneity of IAA and of the type B subtype. Risk factors specific for cases with DGS may open a window to further investigations of the etiology of IAA and of the associated molecular genetic abnormalities.

Interrupción del arco aórtico con ventana aortopulmonar. Corrección total primaria sin circulación extracorpórea en el neonato

This report describes the unusual association between the interruption of the aortic arch type B and aortopulmonary window type II in a neonate. When the patient was 20 days old, a one-stage surgical repair was done through left side thoracotomy without circulatory by-pass, making a left carotid artery to descending aorta anastomosis, closing the window with a hemaclip, respectively. A routine 2-D Doppler color echocardiography performed in the immediate postoperative period showed the absence of blood flow in the right pulmonary artery. The patient required a new intervention, changing the position of the clip in order to restore the normal pulmonary blood flow. Eight months after surgery, the "neoaortic arch" grows in harmony with the body surface area, without signs of cerebral circulatory deficiency or significant gradient at any level.

Deletion 22q11 in patients with interrupted aortic arch

In our series of 27 children with various types of interruption of the aortic arch (IAA), deletion 22q11 is prevalent in patients with simple IAA type B, and is absent in patients with IAA type A and in those with associated additional major cardiac defects. Anomalies of the infundibular septum should be considered a characteristic aspect of children with IAA and deletion 22q11.

Incidence and significance of 22q11.2 hemizygosity in patients with interrupted aortic arch

Interruption of the aortic arch (IAA) is a severe malformation of the heart with known association to DiGeorge syndrome (DGS) and 22q11.2 hemizygosity. The aim of this study was to establish incidence and significance of 22q11.2 hemizygosity in an unbiased sample of patients with IAA. All 15 children with IAA who were referred to our hospital in a 3-year period were tested by chromosome and fluorescence in situ hybridization (FISH) analysis with the probes D22S75, Tuplel, and cHKAD26 and by a set of 10 simple tandem repeat polymorphic (STRP) markers. In nine of 11 children with IAA type B, 22q11.2 hemizygosity was demonstrated by FISH and STRP analysis, but in none of the four children with type A. In all but one child, deletion size was approximately 3 Mb. The girl with the smaller deletion of approximately 1.5 Mb differed because of an Ullrich-Turner syndrome-like phenotype and severe T-cell defect. Additionally, in one patient with phenotypic signs of DGS, a small deletion distal to the known DGS region containing the marker D22S308 was suspected by STRP analysis. One deletion was shown to be inherited from a healthy father and one IAA type A recurred in a sib. T-cell anomalies were evident in eight of the nine children with classical deletion, five of whom suffered also from hypoparathyroidism. With respect to cause and clinical course, IAA type A and B were shown to represent different entities. This study showed that variable symptoms of 22q11.2 hemizygosity may cluster.

A Genetic Etiology for Interruption of the Aortic Arch Type B

Interrupted aortic arch (IAA) type B is a congenital heart defect believed to be caused by an anomaly of branchial arch mesenchymal development. IAA type B has been associated with DiGeorge syndrome (DGS), which includes conotruncal heart defects, T-cell immunodeficiency, hypocalcemia, and facial abnormalities. The great majority of DGS cases are associated with hemizygous deletions at the chromosome 22q11 locus. The present study was designed to establish the involvement of the 22q11 locus in the etiology of IAA type B, independently from the typical DGS phenotype. An evaluation was performed on 73 patients with conotruncal heart defects using fluorescence in situ hybridization (FISH) analysis with probes from the 22q11 DGS locus. From this group, 7 patients were deleted (including 4 of the 11 patients with IAA type B). FISH analysis was extended to a total of 22 patients with IAA type B and 11 of these (50%) were deleted. FISH and Southern blot analyses using additional markers within the DiGeorge chromosomal region were performed on patients found not to be deleted in the initial FISH screening. No small deletions or rearrangements were detected. In our patient population, a single, specific genetic defect is the basis for one half of the IAA type B cases. These data suggest that IAA type B is one of the most etiologically homogeneous congenital heart defects. A 22q11 deletion in IAA type B may or may not be associated with the typical DGS phenotype. Therefore, IAA type B, per se, should be an indication for 22q11 deletion testing.

Cardiac malformations in relatives of children with truncus arteriosus or interruption of the aortic arch

Familial recurrence risks for congenital cardiac malformations have been estimated at 1 to 4%, but little is known of recurrence risks for uncommon congenital cardiac malformations. This study determined the incidence of congenital cardiac malformations in relatives of patients with either truncus arteriosus (TA) or interruption of the aortic arch (IAA) seen between 1955 and 1985. Prior to this study, only 2 cases of IAA in siblings had been reported and the recurrence risk of TA had been estimated at 1.2%. In the families of 36 index cases of IAA, there were 98 siblings, 2 with congenital cardiac malformations (2.1%). All recurrences were in IAA type B families. Single cases of congenital cardiac malformations were found in second- and third-degree relatives and 2 cases in more distant relatives. In the families of 49 index cases of TA, there were 106 siblings, 7 with congenital cardiac malformations (6.6%). Two had TA, 3 had other conotruncal anomalies and 2 had other congenital cardiac malformations. Two parents had congenital cardiac malformations, 1 with TA and 1 with conotruncal malformation. Among second- and third-degree relatives, 7 had congenital cardiac malformations (5 were conotruncal, including 1 half sibling). Among greater than third-degree relatives, 3 had congenital cardiac malformations. Thus, in IAA, the recurrence rate of congenital cardiac malformations (2.1%) was higher than expected and could be related to the etiology of IAA type B as a conotruncal malformation. In TA, the recurrence rate of congenital cardiac malformations was 6.6%, higher than previously reported. When TA was complex the recurrence risk was higher (13.6%). These findings must be taken into consideration for satisfactory genetic counseling.

Anatomy and pathogenesis of aorticopulmonary septal defect

The pathologic anatomic features and associated cardiac anomalies of 13 patients with aorticopulmonary Septal defect (APSD) and of 236 previously reported cases were analyzed. Morphologically, 3 types of APSD were distinguished: (1) a defect with a more or less circular border located about halfway between the arterial valves and the bifurcation of the pulmonary trunk; (2) a similarly located defect in which the border represents a helix; and (3) a usually large defect in which there is no posterior (distal) border. The appearance of these 3 types of defects suggests a different developmental mechanism for each. Approximately half of the cases of APSD are not associated with other cardiovascular anomalies. Of the anomalies that do occur, anoma lous origin of a coronary artery from the pulmonary trunk and Interruption of the aortic arch (IAA) type A or severe pred uctal coarctation are seen far more often than expected. An association with DIGeorge syndrome, frequently noted with persistent truncus arteriosus (TA) and IAA type 13, was not seen. Certain cardiac anomalies often seen with TA are rarely seen with APSD, and defects often seen with APSD are rarely seen with TA. These observations indicate that APSD and TA are pathogenetically unrelated even though located in the same region of the heart and, unlike TA and IAA type 13, APSD Is probably not due to a developmental error involving the neural crest.

Interruption of the aortic arch and coarctation of the aorta: Pathogenetic relations

The pathologic anatomic features and associated cardiac anomalies of 63 cases of interruption of the aortic arch (IAA) type A (54 reported and 9 observed) and 145 cases of type B (124 reported and 21 observed) were analyzed and compared with those seen in 57 autopsy cases of infant coarctation of the aorta (CA). There was no significant sex predominance within the 3 groups and the prognosis without surgery was uniformly poor. Ventricular septal defect was much more common in IAA type B than in type A or CA. Anomalous origin of the subclavian artery and DiGeorge syndrome were commonly associated with IAA type B but were rare in type A and CA. Transposition of the great arteries and double-inlet left ventricle are less common in IAA type B than in types A and CA. On the basis of these findings and the observation by Le Lièvre and Le Douarin that neural crest cells contribute significantly to the formation of the visceral arch system and associated organs, we postulate that IAA type B may be a manifestation of a developmental error involving the neural crest, as is the DiGeorge syndrome. We believe IAA type A and CA to be closely related anomalies that may be prenatally acquired and pathogenetically distinct from IAA type B.