Urgent neonatal balloon atrial septostomy in simple transposition of the great arteries: predictive value of fetal cardiac parameters.

OBJECTIVES: To investigate the impact of abnormal perinatal loading conditions on cardiac geometry and function in term fetuses and neonates with transposition of the great arteries with intact interventricular septum (simple TGA), and to explore the predictive value of fetal cardiac parameters for an urgent balloon atrial septostomy (BAS) after birth. METHODS: This was a prospective longitudinal follow-up study of women delivering at term, including both uncomplicated pregnancies with normal outcome and pregnancies affected by fetal simple TGA. Conventional, spectral-tissue Doppler and speckle-tracking echocardiographic parameters were obtained within 1 week before delivery and within the first few hours after delivery. Neonates with simple TGA that required urgent BAS were assessed after the procedure and before corrective arterial switch surgery. Cardiac parameters were normalized by cardiac cycle length, ventricular end-diastolic length or end-diastolic dimension, as appropriate. Fetal and neonatal cardiac parameters were compared between simple-TGA cases and controls, and perinatal changes in the simple-TGA group were assessed. Receiver-operating-characteristics (ROC)-curve analysis was used to assess the predictive value of fetal cardiac parameters for urgent BAS after birth in the simple-TGA group. RESULTS: A total of 67 pregnant women delivering at term were included in the study (54 normal pregnancies and 13 with a diagnosis of fetal simple TGA). Compared with normal term fetuses, term fetuses with simple TGA exhibited more globular hypertrophied ventricles, increased biventricular systolic function and diastolic dysfunction (right ventricular (RV) sphericity index (SI), 0.58 vs 0.54; left ventricular (LV)-SI, 0.55 vs 0.49; combined cardiac output (CCO), 483 vs 406 mL/min/kg; LV torsion, 4.3 vs 3.0 deg/cm; RV isovolumetric relaxation time (IVRT'), 127 vs 102 ms; P < 0.01 for all). Compared with normal neonates, neonates with simple TGA demonstrated biventricular hypertrophy, a more spherical right ventricle and altered systolic and diastolic functional parameters (RV-SI, 0.61 vs 0.43; RV myocardial performance index, 0.47 vs 0.34; CCO, 697 vs 486 mL/min/kg; LV-IVRT', 100 vs 79 ms; RV-IVRT', 106 vs 71 ms; P < 0.001 for all). Paired comparison of neonatal and fetal cardiac indices in the simple-TGA group showed persistence of the fetal phenotype, increased biventricular systolic myocardial contractility and CCO, and diastolic dysfunction (RV systolic myocardial velocity (S'), 0.31 vs 0.24 cm/s; LV-S', 0.23 vs 0.18 cm/s; CCO, 697 vs 483 mL/min/kg; LV torsion, 1.1 vs 4.3 deg/cm; P < 0.001 for all). Several fetal cardiac parameters in term fetuses with simple TGA demonstrated high predictive value for an urgent BAS procedure after birth. Our proposed novel fetal cardiac index, LV rotation-to-shortening ratio, as a potential marker of subendocardial dysfunction, for a cut-off value of ≥ 0.23, had an area under the ROC curve (AUC) of 0.94, sensitivity of 100% and specificity of 83%. For RV/LV end-diastolic area ratio ≥ 1.33, pulmonary-valve-to-aortic-valve-dimension ratio ≤ 0.89, RV/LV cardiac output ratio ≥ 1.38 and foramen-ovale-dimension-to-total-interatrial-septal-length ratio ≤ 0.27, AUC was 0.93-0.98, sensitivity was 86% and specificity was 83-100% for all. CONCLUSIONS: Simple-TGA fetuses exhibited cardiac remodeling at term with more profound alterations in these cardiac parameters after birth, suggestive of adaptation to abnormal loading conditions and possible adaptive responses to hypoxemia. Perinatal adaptation in simple TGA might reflect persistence of the abnormal parallel arrangement of cardiovascular circulation and the presence of widely patent fetal shunts imposing volume load on the neonatal heart. The fetal cardiac parameters that showed high predictive value for urgent BAS after birth might reflect the impact of late-gestation pathophysiology and progressive hypoxemia on fetal cardiac geometry and function in simple TGA. If these findings are validated in larger prospective studies, detailed cardiac assessment of fetuses with simple TGA near term could facilitate improvements in perinatal management and refinement of the timing of postnatal intervention strategies to prevent adverse pregnancy outcomes. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Low incidence of atrial septal defects in nonmammalian vertebrates.

The atrial septum enables efficient oxygen transport by separating the systemic and pulmonary venous blood returning to the heart. Only in placental mammals will the atrial septum form by the coming-together of the septum primum and the septum secundum. In up to one of four placental mammals, this complex morphogenesis is incomplete and yields patent foramen ovale. The incidence of incomplete atrial septum is unknown for groups with the septum primum only, such as birds and reptiles. We found a low incidence of incomplete atrial septum in 11 species of bird (0% of specimens) and 13 species of reptiles (3% of specimens). In reptiles, there was a trabecular interface between the atrial septum and the atrial epicardium which was without a clear boundary between left and right atrial cavities. In developing reptiles (four squamates and one crocodylian), the septum primum initiated as a sheet that acquired perforations and the trabecular interface developed late. We conclude that atrial septation from the septum primum only results in a low incidence of incompleteness. In reptiles, the atrial septum and atrial wall develop a trabecular interface, but previous studies on atrial hemodynamics suggest this interface has a very limited capacity for shunting.

Flap valve of the heart foramen ovale revisited: macroscopic and histologic observations of human near-term fetuses.

We assessed the flap valve of the foramen ovale (FO valve) by examining 30 hearts from human fetuses of gestational age 30-40 weeks. We dissected the hearts, examined their macroscopic morphology, and then prepared semiserial sagittal sections across the valve. Although the primary septum is expected to extend along the left atrial face, eight hearts had a superior rim of the fossa ovalis on the left atrial face that was too thick and high, so there was no smooth continuation with the valve. Moreover, three of these eight hearts each had a flap valve that was fused with a long and narrow plate arising from the caval orifice. Histological analysis indicated that 21 specimens each had a candidate primary septum that contained myocardium, although the left sinuatrial valve (LSAV) contained fibrous tissue, but little or no myocardium. In each of 17 hearts, a candidate primary septum was attached to the left atrial face of the fossa, and parts of the LSAV extended to and approached the right atrial face. However, seven of these 17 hearts each had a folded small primary septum. Another four of these 17 hearts each had an LSAV that extended widely to the fossa, and a candidate primary septum (which might be a remnant) attached to the left atrial side of the LSAV. These variations suggest that the LSAV makes a major contribution to the FO valve in some fetal hearts. Consequently, the fetal FO valve appears to have heterogeneous morphology and origin.

Evolution and Development of the Atrial Septum.

The complete division of the atrial cavity by a septum, resulting in a left and right atrium, is found in many amphibians and all amniotes (reptiles, birds, and mammals). Surprisingly, it is only in eutherian, or placental, mammals that full atrial septation necessitates addition from a second septum. The high incidence of incomplete closure of the atrial septum in human, so-called probe patency, suggests this manner of closure is inefficient. We review the evolution and development of the atrial septum to understand the peculiar means of forming the atrial septum in eutherian mammals. The most primitive atrial septum is found in lungfishes and comprises a myocardial component with a mesenchymal cap on its leading edge, reminiscent to the primary atrial septum of embryonic mammals before closure of the primary foramen. In reptiles, birds, and mammals, the primary foramen is closed by the mesenchymal tissues of the atrioventricular cushions, the dorsal mesenchymal protrusion, and the mesenchymal cap. These tissues are also found in lungfishes. The closure of the primary foramen is preceded by the development of secondary perforations in the septal myocardium. In all amniotes, with the exception of eutherian mammals, the secondary perforations do not coalesce to a secondary foramen. Instead, the secondary perforations persist and are sealed by myocardial and endocardial growth after birth or hatching. We suggest that the error-prone secondary foramen allows large volumes of oxygen-rich blood to reach the cardiac left side, needed to sustain the growth of the extraordinary large offspring that characterizes eutherian mammals. Anat Rec, 302:32-48, 2019. © 2018 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Sonographic Pulmonary Abnormalities in Fetuses With Hypoplastic Left Heart Syndrome and Intact Atrial Septum Undergoing Attempted Atrial Septostomy In Utero.

Fetuses with hypoplastic left heart syndrome (HLHS) and intact atrial septum are a particular subset of HLHS neonates with high perinatal mortality. The reported mortality in these patients is 50% to 70%, even with prenatal diagnosis. Prenatal left atrial and pulmonary venous hypertension results in abnormal pulmonary vascular and parenchymal development. The goal of this study was to compare the sonographic appearance of the lungs in fetuses with HLHS/intact atrial septum to neonatal outcome and/or pathology in cases where in utero intervention was performed to open the atrial septum. We found that lung inhomogeneity on ultrasound corresponded to peripheral lymphatic dilatation at autopsy and was associated with a dismal prognosis even when in utero intervention was successful.

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'.

Tbx5 and Osr1 interact to regulate posterior second heart field cell cycle progression for cardiac septation.

RATIONALE: Mutations of TBX5 cause Holt-Oram syndrome (HOS) in humans, a disease characterized by atrial or occasionally ventricular septal defects in the heart and skeletal abnormalities of the upper extremity. Previous studies have demonstrated that Tbx5 regulates Osr1 expression in the second heart field (SHF) of E9.5 mouse embryos. However, it is unknown whether and how Tbx5 and Osr1 interact in atrial septation. OBJECTIVE: To determine if and how Tbx5 and Osr1 interact in the posterior SHF for cardiac septation. METHODS AND RESULTS: In the present study, genetic inducible fate mapping showed that Osr1-expressing cells contribute to atrial septum progenitors between E8.0 and E11.0. Osr1 expression in the pSHF was dependent on the level of Tbx5 at E8.5 and E9.5 but not E10.5, suggesting that the embryo stage before E10.5 is critical for Tbx5 interacting with Osr1 in atrial septation. Significantly more atrioventricular septal defects (AVSDs) were observed in embryos with compound haploinsufficiency for Tbx5 and Osr1. Conditional compound haploinsufficiency for Tbx5 and Osr1 resulted in a significant cell proliferation defect in the SHF, which was associated with fewer cells in the G2 and M phases and a decreased level of Cdk6 expression. Remarkably, genetically targeted disruption of Pten expression in atrial septum progenitors rescued AVSDs caused by Tbx5 and Osr1 compound haploinsufficiency. There was a significant decrease in Smo expression, which is a Hedgehog (Hh) signaling pathway modulator, in the pSHF of Osr1 knockout embryos at E9.5, implying a role for Osr1 in regulating Hh signaling. CONCLUSIONS: Tbx5 and Osr1 interact to regulate posterior SHF cell cycle progression for cardiac septation.

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.

A detailed comparison of mouse and human cardiac development.

BACKGROUND: Mouse mutants are used to model human congenital cardiovascular disease. Few studies exist comparing normal cardiovascular development in mice vs. humans. We carried out a systematic comparative analysis of mouse and human fetal cardiovascular development. METHODS: Episcopic fluorescence image capture (EFIC) was performed on 66 wild-type mouse embryos from embryonic day (E) 9.5 to birth; 2-dimensional and 3-dimensional datasets were compared with EFIC and magnetic resonance images from a study of 52 human fetuses (Carnegie stage 13-23). RESULTS: Time course of atrial, ventricular, and outflow septation were outlined and followed a similar sequence in both species. Bilateral venae cavae and prominent atrial appendages were seen in the mouse fetus; in human fetuses, atrial appendages were small, and a single right superior vena cava was present. In contrast to humans with separate pulmonary vein orifices, a pulmonary venous confluence with one orifice enters the left atrium in mice. CONCLUSION: The cardiac developmental sequences observed in mouse and human fetuses are comparable, with minor differences in atrial and venous morphology. These comparisons of mouse and human cardiac development strongly support that mouse morphogenesis is a good model for human development.

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.

Patent foramen ovale.

Patent foramen ovale (PFO) is a common developmental anomaly that allows for the passage of blood and other substances from the venous to the arterial circulation. The study of PFO closure has been challenging due to widely available off-label closures performed outside the clinical trial setting. To date, no study has demonstrated benefit of closure using intention-to-treat analyses. Secondary and subpopulation analyses suggest that there is benefit to closure in patients with atrial septal aneurysms and/or substantial degrees of right-to-left shunting. This article reviews the history, associated technologies, and current data regarding PFO closure.

Histone H3 lysine 9 methyltransferases, G9a and GLP are essential for cardiac morphogenesis.

Lysine methylation of the histone tail is involved in a variety of biological events. G9a and GLP are known as major H3-K9 methyltransferases and contribute to transcriptional silencing. The functions of these genes in organogenesis remain largely unknown. Here, we analyzed the phenotypes of cardiomyocyte specific GLP knockout and G9a knockdown (GLP-KO/G9a-KD) mice. The H3-K9 di-methylation level decreased markedly in the nuclei of the cardiomyocytes of GLP-KO/G9a-KD mice, but not single G9a or GLP knockout mice. In addition, GLP-KO/G9a-KD mice showed neonatal lethality and severe cardiac defects (atrioventricular septal defects, AVSD). We also showed that hypoplasia in the atrioventricular cushion, which is a main part of the atrioventricular septum, caused AVSD. Expression analysis revealed downregulation of 2 AVSD related genes and upregulation of several non-cardiac specific genes in the hearts of GLP-KO/G9a-KD mice. These data indicate that G9a and GLP are required for sufficient H3-K9 di-methylation in cardiomyocytes and regulation of expression levels in multiple genes. Moreover, our findings show that G9a and GLP have an essential role in normal morphogenesis of the atrioventricular septum through regulation of the size of the atrioventricular cushion.

Expression of the BMP receptor Alk3 in the second heart field is essential for development of the dorsal mesenchymal protrusion and atrioventricular septation.

RATIONALE: The dorsal mesenchymal protrusion (DMP) is a prong of mesenchyme derived from the second heart field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular (AV) septal defect. Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated. OBJECTIVE: To determine the role of BMP signaling in DMP development. METHODS AND RESULTS: Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AV septal defects. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/transforming growth factor ß signaling were not significantly altered in the AV cushions of SHF-Alk3 mutants. CONCLUSIONS: BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.

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.

Ablation of Nkx2-5 at mid-embryonic stage results in premature lethality and cardiac malformation.

AIMS: Human congenital heart disease linked to mutations in the homeobox transcription factor, NKX2-5, is characterized by cardiac anomalies, including atrial and ventricular septal defects as well as conduction and occasional defects in contractility. In the mouse, homozygous germline deletion of Nkx2-5 gene results in death around E10.5. It is, however, not established whether Nkx2-5 is necessary for cardiac development beyond this embryonic stage. Because human NKX2-5 mutations are related to septum secundum type atrial septal defects (ASD), we hypothesized that Nkx2-5 deficiency during the processes of septum secundum formation may cause cardiac anomalies; thus, we analysed mice with tamoxifen-inducible Nkx2-5 ablation beginning at E12.5 when the septum secundum starts to develop. METHODS AND RESULTS: Using tamoxifen-inducible Nkx2-5 gene-targeted mice, this study demonstrates that Nkx2-5 ablation beginning at E12.5 results in embryonic death by E17.5. Analysis of mutant embryos at E16.5 shows arrhythmias, contraction defects, and cardiac malformations, including ASD. Quantitative measurements using serial section histology and three-dimensional reconstruction demonstrate growth retardation of the septum secundum and enlarged foramen ovale in Nkx2-5-ablated embryos. Functional cardiac defects may be attributed to abnormal expression of transcripts critical for conduction and contraction, including cardiac voltage-gated Na(+) channel pore-forming α-subunit (Na(v)1.5-α), gap junction protein connexin40, cardiac myosin light chain kinase, and sarcolipin within 4 days after tamoxifen injection. CONCLUSION: Nkx2-5 is necessary for survival after the mid-embryonic stage for cardiac function and formation by regulating the expression of its downstream target genes.

Embryology and developmental defects of the interatrial septum.

OBJECTIVE: The various types of atrial septal defects (ASDs) can be differentiated on the basis of their imaging appearance on MDCT. CONCLUSION: It is fundamental for the cardiac imager to understand the embryologic development of the interatrial septum and the morphogenic differences of ASDs.

Echocardiographic evaluation of patent foramen ovale prior to device closure.

High-quality imaging of the atrial septum has never been so relevant to the adult cardiologist. This article focuses on the role of echocardiography in the evaluation of patent foramen ovale for closure. It provides a systematic and comprehensive approach to transesophageal echocardiographic study in such a patient. The salient information required for planning the device and equipment needed for the closure procedure are discussed.