scholarly journals Epigenomic and Transcriptomic Dynamics During Human Heart Organogenesis

2020 ◽  
Vol 127 (9) ◽  
Author(s):  
Jennifer VanOudenhove ◽  
Tara N. Yankee ◽  
Andrea Wilderman ◽  
Justin Cotney
Keyword(s):  
Gene Expression ◽  
Congenital Heart Defects ◽  
Human Heart ◽  
Congenital Heart ◽  
Heart Defects ◽  
Regulatory Control ◽  
Whole Genome Sequencing Data ◽  
Regulatory Sequences ◽  
Sequencing Data ◽  
Number Of Patients

Rationale: There is growing evidence that common variants and rare sequence alterations in regulatory sequences can result in birth defects or predisposition to disease. Congenital heart defects are the most common birth defect and have a clear genetic component, yet only a third of cases can be attributed to structural variation in the genome or a mutation in a gene. The remaining unknown cases could be caused by alterations in regulatory sequences. Objective: Identify regulatory sequences and gene expression networks that are active during organogenesis of the human heart. Determine whether these sites and networks are enriched for disease-relevant genes and associated genetic variation. Methods and Results: We characterized ChromHMM (chromatin state) and gene expression dynamics during human heart organogenesis. We profiled 7 histone modifications in embryonic hearts from each of 9 distinct Carnegie stages (13–14, 16–21, and 23), annotated chromatin states, and compared these maps to over 100 human tissues and cell types. We also generated RNA-sequencing data, performed differential expression, and constructed weighted gene coexpression networks. We identified 177 412 heart enhancers; 12 395 had not been previously annotated as strong enhancers. We identified 92% of all functionally validated heart-positive enhancers (n=281; 7.5× enrichment; P <2.2×10 −16 ). Integration of these data demonstrated novel heart enhancers are enriched near genes expressed more strongly in cardiac tissue and are enriched for variants associated with ECG measures and atrial fibrillation. Our gene expression network analysis identified gene modules strongly enriched for heart-related functions, regulatory control by heart-specific enhancers, and putative disease genes. Conclusions: Well-connected hub genes with heart-specific expression targeted by embryonic heart-specific enhancers are likely disease candidates. Our functional annotations will allow for better interpretation of whole genome sequencing data in the large number of patients affected by congenital heart defects.

scholarly journals Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yonatan R. Lewis-Israeli ◽  
Aaron H. Wasserman ◽  
Mitchell A. Gabalski ◽  
Brett D. Volmert ◽  
Yixuan Ming ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Self Assembly ◽  
Human Heart ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Defects ◽  
Cell Types ◽  
Cellular Level ◽  
Cardiac Tissues

AbstractCongenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects.

scholarly journals SERCA2a, Phospholamban, Sarcolipin, and Ryanodine Receptors Gene Expression in Children with Congenital Heart Defects

2007 ◽  
Vol 13 (1-2) ◽  
pp. 105-111 ◽  
Author(s):  
Simona Vittorini ◽  
Simona Storti ◽  
Maria Serena Parri ◽  
Alfredo Giuseppe Cerillo ◽  
Aldo Clerico
Keyword(s):  
Gene Expression ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Ryanodine Receptors

scholarly journals Pulmonary hypertension in infants with congenital heart defects: are leukotrienes involved?

1997 ◽  
Vol 6 (5-6) ◽  
pp. 323-326 ◽  
Author(s):  
A. Serraf ◽  
J-P. Gascard ◽  
J. Bruniaux ◽  
C. Labat ◽  
C. Planche ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Congenital Heart Defects ◽  
Pulmonary Blood Flow ◽  
Congenital Heart ◽  
Heart Defects ◽  
Blood Levels ◽  
Blood Samples ◽  
Number Of Patients ◽  
Pulmonary Arterial

The circulating levels of leukotriene E4in infants with congenital heart defects, increased pulmonary blood flow and pulmonary arterial hypertension, were determined and compared with infants with decreased pulmonary blood flow (Tetralogy of Fallot). There was no correlation (r=0.38) between the pulmonary arterial pressure (56 ± 4 mmHg) and the leukotriene E4levels (1.37 ± 0.67 ng/ml blood) measured in peripheral blood samples from the hypertensive group prior to surgery. There was considerable variation in the detectable leukotriene E4levels in blood samples from different patients. The levels detected in the blood samples between the two groups of patients was similar. These data suggest that neither the surgical repair during cardiopulmonary bypass nor the pulmonary hypertension appeared to modify the leukotriene E4blood levels in the small number of patients studied.

Abstract 3408: Folate Suppresses Wnt/Beta-Catenin Inhibition of Cardiogenesis to Protect Against Induction of Congenital Heart Defects

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Maria Serrano ◽  
Mingda Han ◽  
James C Huhta ◽  
Rosana Lastra-Vicente ◽  
Barbara Garita ◽  
...  
Keyword(s):  
Gene Expression ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Glycogen Synthase ◽  
Heart Defects ◽  
Ebstein’S Anomaly ◽  
Beta Catenin ◽  
Ebstein's Anomaly ◽  
Islet 1 ◽  
Heart Fields

Lithium (Li), a mood stabilizing drug, and elevated homocysteine (HCy), a metabolite in the folic acid (FA) cycle, are linked to induction of human congenital heart defects. We determined noninvasively by echocardiography, that exposure of the mouse embryo by an i.p. injection to the dam of Li or HCy during gastrulation on embryonic day E6.75 induces cardiac and valve defects. A single dose of 125 μl Li (25 mM) or HCy (75 μM) on E5.5 to 6.5 results in mouse embryonic lethality; on E6.75 to 7.0, both induce tricuspid and semilunar valve defects (Li: n=131 ; HCy: n=78). The tricuspid valve septal leaflet fails to delaminate, a characteristic of Ebstein’s Anomaly. Use of Li during human pregnancy has been associated with Ebstein’s Anomaly. Li mimics the Wnt/β-catenin (β-cat) signaling pathway by inactivating glycogen synthase kinase-3β. During chick cardiac specification, Li, Wnt 3A, or HCy exposure adversely affects chick cardiogenesis with severity of anomalies based on timing of early exposure. To initiate cardiogenesis, the secreted Wnt antagonist Dickkopf-1 acts extracellularly on the endoderm to upregulate Hex , an inducer of cardiomyogenesis. Exposure of stages 3+/4− chick embryos to Li/Wnt3A/ HCys inhibits Hex and Islet-1 gene expression in the cardiogenic crescent via an intracellular mechanism, thus augmenting inhibitory Wnt/β-cat signaling. FA deficiency leads to elevated HCys levels. We hypothesize that HCys/FA metabolism intersects with Wnt/β-cat signaling and that mechanistically FA supplementation acts by overriding Wnt/β-cat inhibition of gene expression in the embryonic heart fields that leads to cardiac defects. FA, known to protect against HCys-mediated neural tube defects, was tested for protective effects against Li/Wnt3A/HCy during cardiogenesis. With all three experimental exposures, FA addition results in reexpression of the cardiac inducers Hex and Islet-1 at high levels in the chick heart fields. In the mouse, no valve defects were detected in HCys/FA exposed embryos (n=27). Regimen and concentration of FA supplementation necessary to fully rescue Li effects are being tested. In conclusion, folate supplementation potentiates the repression of Wnt/β-cat signaling and protects formation of heart and valve defects. This research has received full or partial funding support from the American Heart Association, AHA Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).

scholarly journals Congenitalis vitiumok genetikai heterogenitása és komplexitása

2018 ◽  
Vol 159 (17) ◽  
pp. 661-670
Author(s):  
Dóra Nagy ◽  
Márta Széll
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Developmental Disorders ◽  
Isolated Heart ◽  
Heart Defects ◽  
Molecular Genetic ◽  
Genetic Alterations ◽  
Reproductive Age ◽  
Number Of Patients ◽  
Monogenic Diseases

Abstract: Congenital heart defects are the most common birth defects, they account for approximately one third of all cases. They are clinically heterogeneous, vary widely in severity, treatability and prognosis and may occur as part of multiple developmental disorders, such as chromosome aberrations, microdeletion syndromes and monogenic diseases, or as isolated defects. Syndromic forms account for 25–40%, isolated forms for 60–75% of all cases. With conventional cytogenetic and next-generation molecular genetic methods, numerous genetic alterations have been identified in evolutionarily highly conserved genes of transcriptional regulators, signaling molecules and structural proteins, which are critical to normal cardiogenesis, mostly in cases with syndromic congenital heart defects. On the other hand, the genetic cause can be detected only in around 11% of isolated heart defects. The survival rate and life quality of patients with congenital heart defects have improved significantly in the last decades thanks to the remarkable development of prenatal, postnatal diagnostics as well as of heart and thoracic surgery of cardiovascular diseases. Since the number of patients, living into adulthood and reproductive age, is constantly increasing, the better understanding of the genetics of congenital heart defects may be crucial for the diagnosis, prognosis and positive family planning of patients. Orv Hetil. 2018; 159(17): 661–670.

scholarly journals Congenital Anomalies of the Kidney and Urinary Tract in Children with Congenital Heart Defects

2020 ◽  
Vol 45 (2) ◽  
pp. 307-313
Author(s):  
Dapeng Jiang ◽  
Qi Wang ◽  
Zhengzhou Shi ◽  
Jie Sun
Keyword(s):  
Urinary Tract ◽  
Congenital Heart Defects ◽  
Congenital Anomalies ◽  
Congenital Heart ◽  
Medical Center ◽  
Heart Defects ◽  
Clinical Manifestations ◽  
Number Of Patients ◽  
Significant Difference ◽  
History Of

Background/Aims: To investigate the incidence and clinical characteristics of congenital anomalies of the kidney and urinary tract (CAKUT) in children with congenital heart defects (CHD). Methods: We retrospectively analyzed the clinical data of children with CHD with CAKUT admitted to the Shanghai Children’s Medical Center affiliated with the Shanghai Jiao Tong University School of Medicine between September 2018 and March 2019. Patients underwent routine examinations for liver, kidney, and coagulation function, and urinary tract ultrasonography, and we summarized patients’ clinical manifestations and imaging abnormalities. Results: A total of 1,410 children with CHD were diagnosed and treated in our hospital. The total number of patients with abnormal urogenital systems was 104, and hydronephrosis was the most common abnormality, followed by vesicoureteral reflux and duplication of the kidney and ureter. The overall prevalence of CAKUT was 7.4%. There was no statistically significant difference for maternal age, sex, parity, gestational age, and history of medication during pregnancy between the patients with CAKUT and those without CAKUT. Conclusion: The incidence of CAKUT in our patients with CHD was significantly higher than that in the general population. We recommend urinary ultrasonography as a routine examination for children with CHD for early detection of CAKUT, to avoid missed diagnoses, and to initiate appropriate treatment.

scholarly journals Perspectives in the management of congenital heart defects in adult patients

2015 ◽  
Vol 156 (3) ◽  
pp. 92-97
Author(s):  
István Hartyánszky ◽  
Sándor Varga ◽  
Kálmán Havasi ◽  
Barna Babik ◽  
Márta Katona ◽  
...  
Keyword(s):  
Heart Transplantation ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Diseases ◽  
Heart Defects ◽  
Adult Patients ◽  
Univentricular Heart ◽  
Transposition Of Great Arteries ◽  
Number Of Patients

Due to improving results in congenital heart surgery, the number of adult patients with congenital heart defect is increasing. The question is: what kind of problems can be managed in this patient-group? The authors review the different problems of management of congenital heart defects in adults based on national and international literature data. Simple defects recognised in adults, postoperative residual problems, changing of small grafts and valves, correction of primary or operated coarctation aortae can be usually managed without problems. A very close follow-up is necessary to establish the correct period for heart transplantation in patients with transposition of great arteries with Senning/Mustard operation, and univentricular heart corrected with “Fontan-circulation” type surgical procedure. The authors conclude that although the number of patients increases, only a few congenital heart diseases may cause problems. It seems important (1) to monitor asymptomatic patient who underwent operation (Fallot-IV, Ross procedure, etc.), (2) follow up regularly patients who underwent Senning/Mustard procedure (magnetic resonance imaging, echocardiography, brain natriuretic peptide measurement), (3) define the proper period of preparation for heart transplantation of patients with a univentricular heart, with special attention to the possibility of multiorgan (lung, liver, etc.) failure. Due to the improvement of foetal diagnosis of congenital heart defects, the number of patients with complex congenital heart defects is decreasing. The standard management of these patients could be primary heart transplantation in infancy. Orv. Hetil., 2015, 156(3), 92–97.

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