Echocardiographic features and outcomes of fetuses with isolated restrictive foramen ovale or redundant foramen ovale flap using atrial septum excursion index.

PURPOSE: This study was designed to investigate the application value of the atrial septum excursion index (ASEI) in fetuses with isolated restrictive foramen ovale (RFO) or redundant foramen ovale flap (RFOF) and the outcomes of these fetuses. METHODS: This was a retrospective study. Healthy pregnant women who were examined by antenatal fetal echocardiography from January 1, 2019 to December 31, 2021, at Sir Run Run Shaw Hospital were enrolled. One hundred seventy-seven (177) fetuses were categorized into three groups by diagnosis: (1) RFOF (n = 33), (2) RFO (n = 21), and (3) normal (n = 123). Fetal echocardiographic features and postnatal outcomes were collected. RESULTS: The median ASEIs were 0.50 (range, 0.41-0.65) in the control group, 0.76 (range, 0.67-0.88) in the RFOF group and 0.31 (range, 0.14-0.35) in the RFO group, and the differences were significant (p < 0.001). The ratios of right atrium/left atrium, right ventricle/left ventricle, and pulmonary artery diameter to aorta diameter (PA/AO) and the pulmonary annulus Z-scores were greater in fetuses with RFOF and RFO than in the controls (p < 0.05). Twenty-seven of 33 fetuses (87.9%) with RFOF and 19 of 21 fetuses (90.5%) with RFO had good outcomes after birth. CONCLUSION: The ASEI may be a new tool for quantitatively assessing the mobility of foramen ovale flaps in fetuses with isolated RFOF or RFO.

Nr2f1a balances atrial chamber and atrioventricular canal size via BMP signaling-independent and -dependent mechanisms.

Determination of appropriate chamber size is critical for normal vertebrate heart development. Although Nr2f transcription factors promote atrial maintenance and differentiation, how they determine atrial size remains unclear. Here, we demonstrate that zebrafish Nr2f1a is expressed in differentiating atrial cardiomyocytes. Zebrafish nr2f1a mutants have smaller atria due to a specific reduction in atrial cardiomyocyte (AC) number, suggesting it has similar requirements to Nr2f2 in mammals. Furthermore, the smaller atria in nr2f1a mutants are derived from distinct mechanisms that perturb AC differentiation at the chamber poles. At the venous pole, Nr2f1a enhances the rate of AC differentiation. Nr2f1a also establishes the atrial-atrioventricular canal (AVC) border through promoting the differentiation of mature ACs. Without Nr2f1a, AVC markers are expanded into the atrium, resulting in enlarged endocardial cushions (ECs). Inhibition of Bmp signaling can restore EC development, but not AC number, suggesting that Nr2f1a concomitantly coordinates atrial and AVC size through both Bmp-dependent and independent mechanisms. These findings provide insight into conserved functions of Nr2f proteins and the etiology of atrioventricular septal defects (AVSDs) associated with NR2F2 mutations in humans.

Clarifying the morphology of the ostium primum defect.

The 'ostium primum' defect is still frequently considered to be the consequence of deficient atrial septation, although the key feature is a common atrioventricular junction. The bridging leaflets of the common atrioventricular valve, which are joined to each other, are depressed distal to the atrioventricular junction, and fused to the crest of the muscular ventricular septum, which is bowed in the concave direction towards the ventricular apex. As a result, shunting across the defect occurs between the atrial chambers. These observations suggest that the basic deficiency in the 'ostium primum' defect is best understood as a product of defective atrioventricular septation, rather than an atrial septal defect. We have now encountered four examples of 'ostium primum' defects in mouse embryos that support this view. These were identified from a large number of mouse embryo hearts collected from a normal, outbred mouse colony and analysed by episcopic microscopy as part of an ongoing study of normal mouse cardiac development. The abnormal hearts were identified from embryos collected at embryonic days 15.5, 16.5 and 18.5 (two cases). We have analysed the features of the abnormal hearts, and compared the findings with those obtained in the large number of normally developed embryos. Our data show that the key feature of normal atrioventricular septation is the ventral growth through the right pulmonary ridge of a protrusion from the dorsal pharyngeal mesenchyme, confirming previous findings. This protrusion, known as the vestibular spine, or the dorsal mesenchymal protrusion, reinforces the closure of the primary atrial foramen, and muscularises along with the mesenchymal cap of the primary atrial septum to form the ventro-caudal buttress of the oval foramen, identified by some as the 'canal septum'. Detailed analysis of the four abnormal hearts suggests that in each case there has been failure of growth of the vestibular spine, with the result that the common atrioventricular junction found earlier during normal development now persists during cardiac development. Failure of separation of the common junction also accounts for the trifoliate arrangement of the left atrioventricular valve in the abnormal hearts. Analysis of the episcopic datasets also permits recognition of the location of the atrioventricular conduction axis. Comparison of the location of this tract in the normal and abnormal hearts shows that there is no separate formation of a ventricular component of the 'canal septum' as part of normal development. We conclude that it is abnormal formation of the primary atrial septum that is the cause of so-called 'secundum' atrial septal defects, whereas it is the failure to produce a second contribution to atrial septation (via growth of the vestibular spine) that results in the 'ostium primum' defect.

Fetal critical aortic stenosis with natural improvement of hydrops fetalis due to spontaneous relief of severe restrictive atrial communication.

We describe a rare case of fetal critical aortic stenosis with spontaneous relief of severe restrictive atrial communication, resulting in complete resolution of hydrops fetalis in utero. Fetal ultrasonography showed hydrops fetalis caused by critical aortic stenosis with a severely restrictive foramen ovale and severe mitral regurgitation at 23 weeks of gestation. Hydrops fetalis, however, spontaneously resolved, showing an obvious increase of flow through the foramen ovale and pulmonary vein at 26 weeks of gestation. The neonate required balloon dilation of the aortic valve and balloon atrioseptostomy immediately after birth and also received bilateral pulmonary artery banding and arterial duct stenting 1 week later. The patient was in good condition after conversion to biventricular circulation via Ross procedure at 8 months old. The present case suggests that atrioseptostomy as a fetal intervention may improve outcome in even a hydropic condition.

Atrial and ventricular septal changes in ethanol vapour exposed chick embryos.

OBJECTIVE: To study the effects of ethanol vapour exposure on development of atrial and ventricular septa of chick embryo. METHODS: The experimental study was conducted at the College of Physicians and Surgeons, Islamabad, from 2006 to 2007. The experimental and control groups were further divided into three subgroups based on the day of sacrifice. The experimental group was exposed to ethanol vapours produced in a specially-designed vapour chamber and then compared with age-matched controls. RESULTS: There were 90 eggs in each of the two groups. The development of inter-ventricular septum completed at day 7 of development in chick embryo. Ethanol vapour exposure produced a small discontinuity at day 10 of development in a chick embryo which may be labelled as ventricular septal defect since ventricular development is completed by day 7. Interatrial septum formed till day 7 with small perforations which persisted till hatching. CONCLUSIONS: Ethanol vapour exposure may lead to ventricular septal defect.

Regulatory variation in a TBX5 enhancer leads to isolated congenital heart disease.

Recent studies have identified the genetic underpinnings of a growing number of diseases through targeted exome sequencing. However, this strategy ignores the large component of the genome that does not code for proteins, but is nonetheless biologically functional. To address the possible involvement of regulatory variation in congenital heart diseases (CHDs), we searched for regulatory mutations impacting the activity of TBX5, a dosage-dependent transcription factor with well-defined roles in the heart and limb development that has been associated with the Holt-Oram syndrome (heart-hand syndrome), a condition that affects 1/100 000 newborns. Using a combination of genomics, bioinformatics and mouse genetic engineering, we scanned ∼700 kb of the TBX5 locus in search of cis-regulatory elements. We uncovered three enhancers that collectively recapitulate the endogenous expression pattern of TBX5 in the developing heart. We re-sequenced these enhancer elements in a cohort of non-syndromic patients with isolated atrial and/or ventricular septal defects, the predominant cardiac defects of the Holt-Oram syndrome, and identified a patient with a homozygous mutation in an enhancer ∼90 kb downstream of TBX5. Notably, we demonstrate that this single-base-pair mutation abrogates the ability of the enhancer to drive expression within the heart in vivo using both mouse and zebrafish transgenic models. Given the population-wide frequency of this variant, we estimate that 1/100 000 individuals would be homozygous for this variant, highlighting that a significant number of CHD associated with TBX5 dysfunction might arise from non-coding mutations in TBX5 heart enhancers, effectively decoupling the heart and hand phenotypes of the Holt-Oram syndrome.

Technical challenges of atrial septal stent placement in fetuses with hypoplastic left heart syndrome and intact atrial septum.

OBJECTIVES: The objective of this study was to describe our single-institution experience with prenatal atrial septal stent placement for fetuses with hypoplastic left heart syndrome and an intact atrial septum (HLHS/IAS). BACKGROUND: Infants born with HLHS/IAS are at high risk for neonatal death, despite maximal postnatal therapy. Prenatal atrial septoplasty by static balloon dilation has been effective in decompressing the left atrium (LA) in utero, but several factors have limited the size of septal defects. We attempted to overcome the limitations of balloon septoplasty using transcatheter atrial septal stents. METHODS: All records from our institution of fetuses with HLHS/IAS that underwent prenatal atrial septal stent placement were reviewed, including operative notes and echocardiograms. RESULTS: Nine fetuses between 24 and 31 weeks gestation with HLHS/IAS underwent attempted fetal atrial septal stent placement. A stent was deployed across the atrial septum in five fetuses, with four fetuses demonstrating flow across the stent at the time of intervention. In four cases, stent placement failed due to malposition or embolization, but in three of the four cases, atrial balloon septoplasty at the same in-utero procedure successfully and acutely decompressed the LA. There were no maternal complications. There was one fetal demise. The remaining eight fetuses survived to delivery, but four died in the neonatal period (two of which had been stented). CONCLUSIONS: Ultrasound-guided atrial septal stent placement is feasible in some fetuses with HLHS/IAS. Visualization of the septum and catheter tip is critical to technical success. Additional experience is necessary to determine the clinical impact of this intervention. © 2013 Wiley Periodicals, Inc.

Mutation in myosin heavy chain 6 causes atrial septal defect.

Atrial septal defect is one of the most common forms of congenital heart malformation. We identified a new locus linked with atrial septal defect on chromosome 14q12 in a large family with dominantly inherited atrial septal defect. The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain. The cardiac transcription factor TBX5 strongly regulates expression of MYH6, but mutant forms of TBX5, which cause Holt-Oram syndrome, do not. Morpholino knock-down of expression of the chick MYH6 homolog eliminates the formation of the atrial septum without overtly affecting atrial chamber formation. These data provide evidence for a link between a transcription factor, a structural protein and congenital heart disease.

The pathogenesis of atrial and atrioventricular septal defects with special emphasis on the role of the dorsal mesenchymal protrusion.

Partitioning of the four-chambered heart requires the proper formation, interaction and fusion of several mesenchymal tissues derived from different precursor populations that together form the atrioventricular mesenchymal complex. This includes the major endocardial cushions and the mesenchymal cap of the septum primum, which are of endocardial origin, and the dorsal mesenchymal protrusion (DMP), which is derived from the Second Heart Field. Failure of these structures to develop and/or fully mature results in atrial septal defects (ASDs) and atrioventricular septal defects (AVSD). AVSDs are congenital malformations in which the atria are permitted to communicate due to defective septation between the inferior margin of the septum primum and the atrial surface of the common atrioventricular valve. The clinical presentation of AVSDs is variable and depends on both the size and/or type of defect; less severe defects may be asymptomatic while the most severe defect, if untreated, results in infantile heart failure. For many years, maldevelopment of the endocardial cushions was thought to be the sole etiology of AVSDs. More recent work, however, has demonstrated that perturbation of DMP development also results in AVSD. Here, we discuss in detail the formation of the DMP, its contribution to cardiac septation and describe the morphological features as well as potential etiologies of ASDs and AVSDs.

Hypoplastic left heart syndrome with restrictive atrial septum and advanced heart block documented with a novel fetal electrocardiographic monitor.

Hypoplastic left ventricle with congenital heart block has been reported previously in a fetus with concurrent left atrial isomerism and levo-transposition of the great arteries. We present the unusual case of an infant diagnosed in utero with hypoplastic left heart syndrome, a restrictive atrial septum and advanced heart block but with D-looping of the ventricles and no atrial isomerism. In addition, fetal heart rhythm was documented with the assistance of a new fetal electrocardiographic monitor.

Cor triloculare biventriculare with left superior vena cava.

Cor triloculare biventriculare is a rare congenital malformation of the heart in which there is a complete absence of the atrial septum. It is usually associated with other anomalies like complete atrioventricular canal defect, polysplenic syndrome, isolated dextrocardia, Ellis-van Creveld syndrome, or persistent left superior vena cava. We report a case of a stillborn male foetus of 35 weeks gestation with common atrium, complete atrioventricular canal defect, and persistent left superior vena cava. The possible embryological basis and clinical implication of this variation are discussed.

Pulmonary vein, dorsal atrial wall and atrial septum abnormalities in podoplanin knockout mice with disturbed posterior heart field contribution.

The developing sinus venosus myocardium, derived from the posterior heart field, contributes to the atrial septum, the posterior atrial wall, the sino-atrial node, and myocardium lining the pulmonary and cardinal veins, all expressing podoplanin, a coelomic and myocardial marker. We compared development and differentiation of the myocardium and vascular wall of the pulmonary veins (PV), left atrial dorsal wall, and atrial septum in wild type with podoplanin knockout mouse embryos (E10.5-E18.5) by 3D reconstruction and immunohistochemistry. Expression of Nkx2.5 in the pulmonary venous myocardium changes from mosaic to positive during development pointing out a high proliferative rate compared with Nkx2.5 negative myocardium of the sino-atrial node and cardinal veins. In mutants, myocardium of the PVs, dorsal atrial wall and atrial septum was hypoplastic. The atrial septum and right-sided wall of the PV almost lacked interposed mesenchyme. Extension of smooth muscle cells into the left atrial body was diminished. We conclude that myocardium of the PVs, dorsal atrial wall, and atrial septum, as well as the smooth muscle cells, are derived from the posterior heart field regulated by podoplanin.

[Atrioventricular septal defect. Anatomopathologic study and embryological correlation]. / Defecto septal atrioventricular. Estudio anatomopatológico y correlación embriológica.

Atrioventricular septal defect is a complex congenital heart disease in which cardiac septation is deficient especially at atrioventricular and ventricular levels. The anatomopathologic experience at the National Institute of Cardiology "Ignacio Chávez" is described; an anatomo-embryological correlation was made to gain an insight of the pathogenesis. Seventy hearts were analyzed morphologically with the sequential segmentary system. Atrial situs, connections of cardiac segments, cardiac septa, septal defects, ventricular geometry, fibrous skeleton and associated anomalies were determined. Histologic sections of chick embryonic hearts were analyzed and compared with stages of human heart development, serving as basis to elaborate the anatomo-embryological correlation. Seventy hearts had a common atrioventricular valve and five had two separated atrioventricular valves. The ventricular septal defect was open in the first type and closed in the second; the other features were the same in both. This cardiopathy is shown as a broad spectrum of anatomical variations. The morphological knowledge of this cardiac malformation is useful to understand the physiopathology, to make a precise clinical diagnosis, and to give the best orientation to the surgeon. Delay in the development of the atrioventricular cushions is emphasized as the pathogenetic explanation for this type of congenital heart disease.

The incidental finding of a patent foramen ovale during cardiac surgery: should it always be repaired? A core review.

With the increased use of intraoperative transesophageal echocardiography, patent foramen ovale (PFO) has become a common finding during heart surgery. This finding presents a difficult dilemma for cardiac surgeons, since the impact of intraoperatively diagnosed PFOs on postoperative outcome is unknown. Changes in the surgical plan required for closure of a PFO subject the patient to the possibility of additional risk. On the other hand, a decision to not close a PFO exposes the patient to unclear immediate and long-term consequences. Deciding whether or not to close a PFO currently depends on the clinicians' personal preferences, the probability of intraoperative and postoperative hypoxemia, and any anticipated deviation from the initial surgical plan. Most clinicians agree that an intraoperatively diagnosed PFO must be closed when surgery leads to a high risk of hypoxemia (e.g., left ventricular assist devices placement, heart transplantation); should be closed in most cases when minimal deviation from the initial surgical plan is needed for PFO closure (e.g., mitral valve or tricuspid valve surgeries); and probably, should be closed during heart surgeries performed without atriotomy and bicaval cannulation when the risk of perioperative or remote PFO-related complications is increased. The recent development of percutaneous methods of PFO closure provides a valuable backup for those cases when PFO is not closed and postoperative hypoxemia or other complications may be attributable to the uncorrected PFO.

Development of the atrial septum in relation to postnatal anatomy and interatrial communications.

The atrial septum is probe patent in some 30% of the population, and is prone to have overt defects. Atrial septation is the coming together of several myocardial structures and mesenchymal tissues of intracardiac and extracardiac origin that must change identity to myocardium. We propose that the propensity for malformation of the atrial septum reflects this complicated morphogenesis. The morphogenesis of the atrial septum initiates from a ridge of mesenchyme, only a few hundred micrometres long, in the roof of the undivided atrial cavity. By growth of the myocardial primary septum, the mesenchymal ridge will be approximated to, and ultimately fuse, with the mesenchyme of the atrioventricular cushions. This fusion also takes in the so-called vestibular spine, and serves to close the primary atrial foramen. Interatrial communication is maintained by the development of perforations in the myocardial septum that will coalesce to produce the secondary foramen. Late in gestation, an infolding of the right atrial roof, previously identified as the secondary septum, will come to form the roof of the secondary foramen. Muscularisation of the mesenchymal ridge and vestibular spine serves to reinforce the attachment of the primary muscular septum to the atrioventricular insulating plane, with the muscularised components, and the cranial infolding, then producing the rims of the oval fossa as seen in the postnatal heart. We show that other lesions that produce the potential for interatrial shunting are outside the confines of the atrial septum, and hence are best considered as interatrial communications, rather than 'atrial septal defects'.

Management of sinus venosus defects.

Sinus venosus defects are not atrial septal defects, but are intra-atrial communications outside of the boundaries of the atrial septum. The superior type is located above and separate from the fossal ovalis, usually adjacent to the superior vena cava and the right upper pulmonary vein. The inferior type is located near the orifice of the inferior vena cava and the right lower pulmonary vein. The goal of surgical repair is closure of the defect with unobstructed drainage of the pulmonary veins to the left atrium and of the vena cava to the right atrium. Numerous techniques have been described, particularly for the repair of the superior vena cava type of defect. Mortality and morbidity should be minimal. The risk of either vena cava or pulmonary vein obstruction is low. Sinus node dysfunction can occur postoperatively, particularly when an incision has been made across the superior vena cava/right atrial junction. There is little long-term data on the functional outcomes following repair of these defects.