Atrioventricular Canal Research Articles

Abstract 4140108: A CRISPR-Activation CROP-seq Screen Identifies HMGN1 as a Dosage-Sensitive Regulator of Heart Defects in Down Syndrome

Introduction/Background: Congenital heart defects (CHD) are the most common form of developmental abnormalities, occurring in ~1% of live births, and can arise due to altered dosage of genes essential for cardiogenesis. Aneuploidy accounts for nearly 15% of CHD and the most frequent form involves trisomy of chromosome 21 (Ch21), resulting in Down Syndrome (DS). CHD is present in ~50% of DS cases, with a 1000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction of the atria and ventricles. Hypothesis: We hypothesize that the presence of a third copy of one or more genes on Ch21 underlies AVC and other cardiac defects; however, the dosage-sensitive CHD gene(s) on Ch21 causing this are not fully defined. Methods: We used human pluripotent stem cells derived from an individual mosaic for DS, allowing us to compare Ch21 trisomy cells with isogenic control cells disomic for Ch21. We performed single cell RNA-sequencing (scRNA-seq) to define the transcriptional dysregulation associated with DS in atrioventricular canal myocardial cells (AVCM). We then introduced a CRISPR-activation transgene to disomic cells and delivered small guide RNAs (sgRNAs) against 66 candidate Ch21 CHD genes. We developed a new machine learning algorithm to assign a trisomic score to CRISPR perturbed (CROP-seq) cells. Finally, we reduced the copy number of our top candidate gene in a mouse model of Down Syndrome and used microCT to assess incidence of cardiac septal defects. Results: Using human pluripotent stem cell and mouse models of DS, we identify HMGN1, a nucleosome-binding epigenetic factor on Ch21, as a dosage-sensitive regulator of cardiac defects in DS. Single cell transcriptomics revealed that human AVC cardiomyocytes shifted to a more ventricular myocardial state in trisomy 21 hiPS-derived cells. CRISPR-activation in isogenic disomic cells of 66 candidate Ch21 genes expressed in heart development, followed by single cell RNA-sequencing (CROP-seq) combined with machine learning predictions indicated that increased expression levels of HMGN1 altered the transcriptional state of atrioventricular cardiomyocytes similar to trisomy 21. Finally, reduction of Hmgn1 from three to two alleles in a mouse model of DS attenuated the incidence of cardiac septal defects. Conclusion: Our results identify HMGN1 as a dosage sensitive regulator of heart defects in DS and represent a generalizable approach for identifying candidate genes within areas of aneuploidy.

Manic Fringe promotes endothelial-to-mesenchymal transition mediated by the Notch signalling pathway during heart valve development.

A fundamental event in the formation of heart valves involves the transformation of endocardial cells within the outflow tract (OFT) and atrioventricular canal (AVC) cushions through a process known as endothelial-to-mesenchymal transition (EndMT). Aberrant EndMT is a primary cause of congenital valvular malformations. Manic Fringe (MFNG) has been previously associated with cardiovascular development, although its role in heart valve development remains underexplored. In this study, we seek to enhance our understanding of MFNG's involvement in valve formation and its association with EndMT. Staining results of histological section revealed the expression of MFNG in the AVC and OFT from embryonic day 9.5 to 10.5 (E9.5-E10.5), when EndMT takes place. Cellular data demonstrated that MFNG exerts a positive regulatory influence on the EndMT process, promoting endothelial cell (EC) migration by enhancing the activity of the Notch signalling pathway. MFNG knockdown mediated by antisense morpholino oligonucleotides (MO) injection caused abnormal development of the heart and valves in zebrafish. Furthermore, through whole-exome sequencing (WES), we identified a heterozygous MFNG mutation in patients diagnosed with tetralogy of Fallot-pulmonary valve stenosis (TOF-PS). Cellular and molecular assays confirmed that this deleterious mutation reduced MFNG expression and hindered the EndMT process. In summary, our study verifies that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway during the heart and valve development. The MFNG deleterious variant induces MFNG loss of function, potentially elucidating the underlying molecular mechanisms of MFNG's involvement in the pathogenesis of congenital heart valve defects. These observations contribute to our current genetic understanding of congenital heart valve disease and may provide a potential target for prenatal diagnosis and treatment. KEY MESSAGES: Our examination revealed, for the first time, that MFNG exhibited high expression levels during EndMT of heart valve development in mice. Our findings provide compelling evidence that MFNG plays a role in promoting EndMT mediated by the Notch signalling pathway. Our results identified, for the first time, a deleterious MFNG p. T77M variant that inhibited the EndMT process by downregulating the activity of the Notch signalling pathway, thereby preventing the normal valve formation. MFNG may serve as an early diagnostic marker and an effective therapeutic target for the clinical treatment of congenital heart valve defects.

ACUTE RESPIRATORY DISTRESS REVEALING A COMPLETE ATRIOVENTRICULAR CANAL IN A 22-MONTH INFANT

The atrioventricular canal (AVC) is a complex and rare congenital cardiac anomaly. It is potentially severe due to the complexity of its lesions and associated fixed pulmonary arterial hypertension. We report the case of a 22-month-old infant girl with Trisomy 21 syndrome, admitted for acute respiratory distress. TTE showed a complete AVC with pulmonary arterial hypertension. Prognosis depends on the promptness of diagnosis and therapeutic management.

Common Atrium Concurrent with Atrioventricular Septal Defect: A Case Report

Common atrium accounts for 0.5% to 1% of congenital heart diseases. It is characterized by the atria septum's complete absence and atrioventricular canal defect. It may occur as an isolated malformation or associated with other extracardiac anomalies. Untreated cases are at risk of developing pulmonary hypertension. We present a case of an 18-month-old female baby with a recurrent chest infection, central cyanosis, and echocardiographic features of the common atrium concurrent with atrioventricular canal defect and features of pulmonary hypertension.

Evaluation of mid-term outcomes of partial and intermediate atrioventricular canal defect surgery.

The risk factors for reoperation and mortality after partial and intermediate atrioventricular canal defect repair are unclear. This study assessed the mid-term outcomes and risk factors for reoperation and mortality after partial and intermediate atrioventricular canal defect surgery. Ninety-seven patients who underwent primary repair of intermediate (n = 45) or partial (n = 52) atrioventricular canal defect between 2005 and 2019 were included in this single-centre study. The median age was 5 years (2.7-8.9 years). The median follow-up time was 32 months (1.6-90.8 months). The estimated freedom from reoperation at 1, 5, and 10 years was 97%, 91%, and 73%, respectively.In multivariable analyses, post-operative left atrioventricular valve regurgitation of grade II or higher (odds ratio [OR]: 5.3, 95% confidence interval [CI]: 1.8-15.5, p = 0.01) and post-operative residual intracardiac shunt (OR: 11.6, 95% CI: 1.6-85.8, p = 0.02) were risk factors for reoperation.In multivariable analyses, perioperative reoperation (OR: 93.4, 95% CI: 3.9-218.7, p = 0.01) and the need for right atrioventricular valve repair (OR: 11.2, 95% CI: 1.0 - 123.3, p = 0.04) were risk factors for mortality. Mortality was higher in patients under 2.6 years of age. For patients undergoing repair of partial or intermediate atrioventricular canal defect, those with post-operative left atrioventricular valve regurgitation of grade II or higher and post-operative residual intracardiac shunt have an increased reoperation risk. Higher mortality can be expected after a perioperative reoperation, and in patients requiring right atrioventricular valve repair during the index procedure.

Zonated Wnt/β-catenin signal-activated cardiomyocytes at the atrioventricular canal promote coronary vessel formation in zebrafish.

Cells functioning at a specific zone by clustering according to gene expression are recognized as zonated cells. Here, we demonstrate anatomical and functional zones in the zebrafish heart. The cardiomyocytes (CMs) at the atrioventricular canal between the atrium and ventricle could be grouped into three zones according to the localization of signal-activated CMs: Wnt/β-catenin signal+, Bmp signal+, and Tbx2b+ zones. Endocardial endothelial cells (ECs) changed their characteristics, penetrated the Wnt/β-catenin signal+ CM zone, and became coronary ECs covering the heart. Coronary vessel length was reduced when the Wnt/β-catenin signal+ CMs were depleted. Collectively, we demonstrate the importance of anatomical and functional zonation of CMs in the zebrafish heart.

Complete atrioventricular canal in a dog—sounds like a final judgment but is it actually one? A case report

Congenital heart disease (CHD) is an important subset of all cardiovascular diseases in dogs. Among them, there are a number of other less commonly described congenital malformations. One of these is the atrioventricular canal, which involves a defect that has several phenotypes. This report details a case of a complete atrioventricular canal (cAVC) defect. Using Rastelli’s classification scheme, the diagnosis of a type-A cAVC defect was based on two-dimensional, contrast, and color Doppler echocardiography. Despite a severe defect that resulted in the atypical anatomy of the atrioventricular apparatus, as well as significant hemodynamic changes in the heart, the affected dog remained asymptomatic throughout the 48-month follow-up period. Due to its stable clinical condition, the decision was made not to begin pharmacological therapy. As this defect is rare in dogs, there are limited data in the literature on this condition. Therefore, in clinical practice, the management and monitoring of the patient may pose difficulties. Due to such limited data, it can be very difficult to provide a prognosis. For the above reasons, we hope that the following case will contribute valuable information for the monitoring of this kind of CHD.

Modeling the atrioventricular conduction axis using human pluripotent stem cell-derived cardiac assembloids

The atrioventricular (AV) conduction axis provides electrical continuity between the atrial and ventricular chambers. The "nodal" cardiomyocytes populating this region (AV canal in the embryo, AV node from fetal stages onward) propagate impulses slowly, ensuring sequential contraction of the chambers. Dysfunction of AV nodal tissue causes severe disturbances in rhythm and contraction, and human models that capture its salient features are limited. Here, we report an approach for the reproducible generation of AV canal cardiomyocytes (AVCMs) with invivo-like gene expression and electrophysiological profiles. We created the so-called "assembloids" composed of atrial, AVCM, and ventricular spheroids, which effectively recapitulated unidirectional conduction and the "fast-slow-fast" activation pattern typical for the vertebrate heart. We utilized these systems to reveal intracellular calcium mishandling as the basis of LMNA-associated AV conduction block. In sum, our study introduces novel cell differentiation and tissue construction strategies to facilitate the study of complex disorders affecting heart rhythm.

High-resolution three-dimensional atlas of congenital heart defects based on micro-CT images of human postmortem wax-infiltrated heart specimens

IntroductionPostmortem heart specimens are essential for education and research on the anatomy, morphology, and pathology of congenital heart defects. However, such specimens are rarely obtained these days, and the specimens stored in formalin are inexorably deteriorating. This study aimed to develop methods to archive three-dimensional data of rare human heart specimens and to publish the data. MethodsAll wax-infiltrated human postmortem heart specimens stored in the Cardiac Registry, Boston Children's Hospital were scanned using microfocus computed tomography (X-Tek HMXST225, Nikon Metrology, Inc.), and reproduced using a three-dimensional printer (Form 3B, Formlabs Inc.). The digital models were published as an interactive three-dimensional online atlas. The resolution of the three-dimensional data was evaluated. ResultsThe primary diagnoses in the 88 specimens included in the study include normal cardiac anatomy (11 cases), transposition of the great arteries {S,D,D} (11 cases), ventricular septal defect (10 cases), double-outlet right ventricle (9 cases), hypoplastic left heart syndrome (9 cases), and common atrioventricular canal (7 cases). Twenty-five cases (28%) underwent previous surgical or percutaneous interventions to the heart, including Mustard procedure (1 case), Senning procedure (2 cases, one was performed on a postmortem heart specimen). The median voxel size of the three-dimensional data was 40.5 um (IQR, 32.8–64.2). All intracardiac structures were precisely reproduced as digital and physical three-dimensional models. ConclusionsThe methods and resultant models were considered useful for archiving and furthering the utilization of these invaluable specimens. The atlas is available at https://www.sketchfab.com/heartmodels/collections.

Evolution of cardiac tissue and flow mechanics in developing Japanese Medaka.

The effects of pressure drop across cardiac valve cushion regions and endocardial wall strain in the early developmental stages of a teleost species heart are poorly understood. In the presented work, we utilize microscale particle image velocimetry (μPIV) flow measurements of developing medaka hearts from 3 to 14 dpf (n = 5 at each dpf) to quantify the pressure field and endocardial wall strain. Peak pressure drop at the atrioventricular canal (ΔPAVC) and outflow tract (ΔPOFT) show a steady increase with fish age progression. Pressure drops when non-dimensionalized with blood viscosity and heart rate at each dpf are comparable with measurements in zebrafish hearts. Retrograde flows captured at these regions display a negative pressure drop. A novel metric, Endocardial Work (EW), is introduced by analyzing the ΔPAVC-strain curves, which is a non-invasive measure of work required for ventricle filling. EW is a metric that can differentiate between the linear heart stage (< 100 Pa-%), cardiac looped chamber stage (< 300 Pa-%), and the fully formed chamber stage (> 300 Pa-%).

Pulmonary Artery Banding and Arch Repair vs Norwood for Unbalanced Atrioventricular Canal Defect

BackgroundThe outcomes of single-ventricle palliation in unbalanced atrioventricular canal defect with coarctation of aorta (uAVC+CoA) have not been well studied. Systemic ventricle outflow tract obstruction has a propensity to develop in these patients after aortic arch repair with pulmonary artery banding (arch-PAB), which may adversely affect survival and Fontan candidacy. MethodsA retrospective review was performed of patients who underwent single-ventricle palliation for uAVC+CoA from 2000 to 2022. Patients were divided into 2 groups based on initial palliation: (1) arch-PAB and (2) Norwood procedure. Demographic and clinical characteristics were analyzed and compared along with survival data. ResultsStage 1 palliation for uAVC+CoA was performed in 41 patients. Arch-PAB was performed in 14 infants and Norwood in 27 infants. Arch-PAB patients had more chromosomal abnormalities (28.6 vs 7.4%, P < .009) and less severe systemic ventricle outflow tract obstruction on baseline echocardiogram (0.0 vs 70.4%, P < .001). Survival to stage 3 palliation was lower for the arch-PAB group (28.6% vs 66.6%, P = .02). Arch-PAB remained a significant risk factor for mortality (hazard ratio, 2.93; 95% CI, 1.05-8.53; P = .04) after adjusting for chromosomal abnormalities and atrioventricular valve regurgitation. After arch-PAB, systemic ventricle outflow tract obstruction was diagnosed in 13 of 14 patients. Echocardiography underestimated the degree of outflow tract obstruction in 10 of 13 arch-PAB patients. ConclusionsArch-PAB has worse outcomes than Norwood for uAVC+CoA. Systemic ventricle outflow tract obstruction develops in almost all patients after arch-PAB. Outflow tract obstruction is underestimated by the echocardiogram and requires a high index of suspicion, along with advanced imaging, to ensure timely diagnosis and management.

Revisiting the anatomy of the left ventricle in the light of knowledge of its development.

Despite centuries of investigation, certain aspects of left ventricular anatomy remain either controversial or uncertain. We make no claims to have resolved these issues, but our review, based on our current knowledge of development, hopefully identifies the issues requiring further investigation. When first formed, the left ventricle had only inlet and apical components. With the expansion of the atrioventricular canal, the developing ventricle cedes part of its inlet to the right ventricle whilst retaining the larger parts of the cushions dividing the atrioventricular canal. Further remodelling of the interventricular communication provides the ventricle with its outlet, with the aortic root being transferred to the left ventricle along with the newly formed myocardium supporting its leaflets. The definitive ventricle possesses inlet, apical and outlet parts. The inlet component is guarded by the mitral valve, with its leaflets, in the normal heart, supported by papillary muscles located infero-septally and supero-laterally. There is but a solitary zone of apposition between the leaflets, which we suggest are best described as being aortic and mural. The trabeculated component extends beyond the inlet to the apex and is confluent with the outlet part, which supports the aortic root. The leaflets of the aortic valve are supported in semilunar fashion within the root, with the ventricular cavity extending to the sinutubular junction. The myocardial-arterial junction, however, stops well short of the sinutubular junction, with myocardium found only at the bases of the sinuses, giving rise to the coronary arteries. We argue that the relationships between the various components should now be described using attitudinally appropriate terms rather than describing them as if the heart is removed from the body and positioned on its apex.

Identification of a Novel SCN5A gene variant in a young female with atrioventricular canal defect in the absence of classical Brugada syndrome phenotype.

Brugada syndrome is generally considered a cardiac channelopathy disorder characterized by syncope or sudden cardiac death. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene is the most commonly mutated gene associated with Brugada syndrome. Recent discoveries of new variants of this gene, along with current guidance of family screening, have identified several asymptomatic carriers with potentially causative mutations. We present the case of a 25-year-old female patient without any family history of Brugada syndrome nor related congenital cardiovascular disorders, with an extensive atrioventricular canal defect, who tested positive for a novel heterozygous variant NM_198056.3: c.3169G>C (p. Asp1057 His) in the SCN5A gene. She had no history of syncope or aborted sudden cardiac death except for recurrent chest infections since her early childhood. Intriguingly, she did not show a type I Brugada electrocardiogram pattern. This report provides a novel heterozygous variant NM_198056.3: c.3169G>C (p. Asp1057 His) in the SCN5A gene, which may have a potential detrimental effect.

Mechanical forces remodel the cardiac extracellular matrix during zebrafish development.

The cardiac extracellular matrix (cECM) is fundamental for organ morphogenesis and maturation, during which time it undergoes remodeling, yet little is known about whether mechanical forces generated by the heartbeat regulate this remodeling process. Using zebrafish as a model and focusing on stages when cardiac valves and trabeculae form, we found that altering cardiac contraction impairs cECM remodeling. Longitudinal volumetric quantifications in wild-type animals revealed region-specific dynamics: cECM volume decreases in the atrium but not in the ventricle or atrioventricular canal. Reducing cardiac contraction resulted in opposite effects on the ventricular and atrial ECM, whereas increasing the heart rate affected the ventricular ECM but had no effect on the atrial ECM, together indicating that mechanical forces regulate the cECM in a chamber-specific manner. Among the ECM remodelers highly expressed during cardiac morphogenesis, we found one that was upregulated in non-contractile hearts, namely tissue inhibitor of matrix metalloproteinase 2 (timp2). Loss- and gain-of-function analyses of timp2 revealed its crucial role in cECM remodeling. Altogether, our results indicate that mechanical forces control cECM remodeling in part through timp2 downregulation.

Surgical Outcomes of Congenital Heart Disease in the Eastern Region of Libya

Congenital heart disease (CHD) refers to a group of structural abnormalities in the heart that are present at birth. However, due to advancements in medical and surgical care, more children with CHD in developed countries are now surviving into adulthood. This study aims to assess the outcomes of surgically repaired congenital heart disease in the eastern part of Libya. Data was obtained from the medical records of 374 patients, of which 54.2% were male and 45.7% were female, who underwent surgical correction and palliative cardiac surgery between February 2015 and February 2019. The majority of patients were from Benghazi and Al-Jabal Al-Akhdar, and the most common diagnoses were ventricular septal defects (VSD) (25.4%) and complex congenital heart disease (CCHD) (21.9%). The death rate in atrioventricular canal (AVC) defects was 7.4%, CCHD had a mortality rate of 4.8%, and the total mortality rate was 2.9%. In the eastern part of Libya, pediatric cardiac surgery and cardiac surgical intensive care for children with congenital heart disease (CHD) still heavily rely on foreign cardiac surgery missions. There is a need for a comprehensive treatment plan and the development of local capabilities to manage CHD patients independently.

Oxidative damage and cardiotoxicity induced by 2-aminobenzothiazole in zebrafish (Danio rerio)

There is limited information available on cardiovascular toxicity of 2-Aminobenzothiazole (NTH), a derivative of benzothiazole (BTH) commonly used in tire production, in aquatic organisms. In the present study, the zebrafish embryos were exposed to varying concentrations of NTH (0, 0.05, 0.5, and 5 mg/L) until adulthood and the potential cardiovascular toxicity was assessed. NTH exposure resulted in striking aberrations in cardiac development, including heart looping failure and interference with atrioventricular canal differentiation. RNA-sequencing analysis indicated that NTH causes oxidative damage to the heart via ferroptosis, leading to oxygen supply disruption, cardiac malformation, and ultimately, zebrafish death. Quantitative real-time polymerase chain reaction (qPCR) analysis demonstrated the dysregulation of genes associated with early heart development, contraction, and oxidative stress. Additionally, reactive oxygen species accumulation and glutathione/malondialdehyde levels changes suggested a potential link between cardiac developmental toxicity and oxidative stress. In adult zebrafish, NTH exposure led to ventricular enlargement, decreased heart rate, reduced blood flow, and prolonged RR, QRS, and QTc intervals. To the best of our knowledge, this study is the first to provide evidence of cardiac toxicity and the adverse effects of ontogenetic NTH exposure in zebrafish, revealing the underlying toxic mechanisms connected with oxidative stress damage. These findings may provide crucial insights into the environmental risks associated with NTH and other BTHs.

Anatomical and physiological diagnostic discrepancies in fetuses with single-ventricle congenital heart disease in a contemporary cohort.

Image quality of fetal echocardiography (FE) has improved in the recent era, but few recent studies have reported the accuracy of FE, specifically in single ventricle (SV) congenital heart disease (CHD). This study aimed to assess the ability of FE to correctly predict SV-CHD postnatal anatomy and physiology in a contemporary cohort. The contemporary clinical reports of patients with SV-CHD, in which FE was performed between July 2017 and July 2021, were compared with postnatal echocardiograms from a formal quality assurance program. SV fetuses were grouped by anatomical subtype. Diagnostic errors were designated as major if the error would have caused significant alteration in parental counseling or postnatal management. The remaining errors were classified as minor. Physiological discrepancies, including prostaglandin-E (PGE) dependency, atrioventricular valve regurgitation (AVVR), pulmonary venous obstruction, and restrictive atrial septum (RAS) were assessed by chart review of the postnatal course. A total of 119 subjects were analyzed. SV subtypes in the cohort included hypoplastic left heart syndrome (HLHS) (n = 68), tricuspid atresia (n = 16), double-inlet left ventricle (n = 12), unbalanced atrioventricular canal (UAVC) (n = 11), heterotaxy (n = 9) and other (n = 3). The rate of major anatomical and physiological errors was low (n = 6 (5.0%)). A higher proportion of minor errors was noted in HLHS and tricuspid atresia, but the differences were not statistically significant. Physiological discrepancies were uncommon, with three major discrepancies, including underestimation of the degree of venous obstruction in one non-HLHS fetus with total anomalous pulmonary venous return, overestimation of RAS in one HLHS fetus and incorrect prediction of PGE dependency in one case false-negative for pulmonary blood flow. No discrepancy in degree of AVVR or RAS affected postnatal care. Minor physiological discrepancies included two false-positive predictions of PGE dependency with one false-positive for ductal-dependent systemic flow and one false-positive for pulmonary blood flow. In this contemporary review of FE at our center, there was high accuracy in describing anatomical and physiological findings in SV-CHD. Major physiological discrepancies were uncommon but included important cases of false-negative prediction of PGE dependency and underestimation of obstruction of total anomalous pulmonary venous return. These data can inform more accurate counseling of families with SV-CHD fetuses and guide diagnostic improvement efforts. © 2024 International Society of Ultrasound in Obstetrics and Gynecology.

A rare case of polysplenia syndrome associated with atrioventricular canal defect and type four ileal atresia in a preterm neonate: A case report and literature review

Antenatal diagnosis of heterotaxy syndrome is only the tip of the iceberg. These neonates can have a myriad of multi-system anomalies, each of which requires anticipation and an individualized management plan. The spectrum of heterotaxy syndrome ranges from incidentally detected innocuous anomalies to major life-threatening congenital malformations such as atrioventricular canal defects and bowel atresia. Neonatal sepsis tends to be more fulminant and catastrophic in these neonates with complex anomalies and poor outcomes that necessitates better-informed antenatal counseling regarding the termination of such pregnancies.

Increased endothelial sclerostin caused by elevated DSCAM mediates multiple trisomy 21 phenotypes.

Trisomy 21 (T21), a recurrent aneuploidy occurring in 1:800 births, predisposes to congenital heart disease (CHD) and multiple extracardiac phenotypes. Despite a definitive genetic etiology, the mechanisms by which T21 perturbs development and homeostasis remain poorly understood. We compared the transcriptome of CHD tissues from 49 patients with T21 and 226 with euploid CHD (eCHD). We resolved cell lineages that misexpressed T21 transcripts by cardiac single-nucleus RNA sequencing and RNA in situ hybridization. Compared with eCHD samples, T21 samples had increased chr21 gene expression; 11-fold-greater levels (P = 1.2 × 10-8) of SOST (chr17), encoding the Wnt inhibitor sclerostin; and 1.4-fold-higher levels (P = 8.7 × 10-8) of the SOST transcriptional activator ZNF467 (chr7). Euploid and T21 cardiac endothelial cells coexpressed SOST and ZNF467; however, T21 endothelial cells expressed 6.9-fold more SOST than euploid endothelial cells (P = 2.7 × 10-27). Wnt pathway genes were downregulated in T21 endothelial cells. Expression of DSCAM, residing within the chr21 CHD critical region, correlated with SOST (P = 1.9 × 10-5) and ZNF467 (P = 2.9 × 10-4). Deletion of DSCAM from T21 endothelial cells derived from human induced pluripotent stem cells diminished sclerostin secretion. As Wnt signaling is critical for atrioventricular canal formation, bone health, and pulmonary vascular homeostasis, we concluded that T21-mediated increased sclerostin levels would inappropriately inhibit Wnt activities and promote Down syndrome phenotypes. These findings imply therapeutic potential for anti-sclerostin antibodies in T21.

The Use of the CardioCel 3D 60° Patch for Aortic Arch Reconstruction in Infancy—A Word of Caution

BackgroundThere are limited data on outcomes after implantation of the CardioCel 3D 60° patch in great vessel repair. After anecdotally witnessing an increase in negative outcomes, we reviewed our experience using this patch in our neonate and infant patients undergoing aortic arch repair. MethodsAortic arch repair with implantation of the CardioCel 3D 60° patch was performed in 24 patients between July 2018 and July 2021. Dominant cardiac morphologies were hypoplastic left heart syndrome (66%), atrioventricular canal defects (13%), and other (21%). Median age at implantation was 44 days (interquartile range [IQR], 6-112 days). Recurrent obstruction was defined as the need for reoperation or catheter intervention or recurrent peak pressure gradient of descending aorta ≥25 mm Hg on echocardiography. ResultsFive deaths occurred after a median of 217 days (IQR, 69-239 days). Twelve patients (50%) had recurrent obstruction. Three patients (13%) required redo aortic arch operation after a median of 148 days (IQR, 128-193 day), with extensive fibrous coating of the patch interior causing obstruction. Eleven patients (46%) required at least 1 balloon angioplasty on their aorta after a median of 102 days (IQR, 83-130 days) after repair, and 3 needed >1 catheter intervention. The estimated probability of having recurrent obstruction was 85% at 6 months and 71% at the 1-year follow (P = .06). ConclusionsRecurrent aortic obstruction occurred in half of our patients shortly after repair. The use of the CardioCel 3D 60° patch for aortic arch reconstruction in neonates and infants should be reevaluated.