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Circulation Research Sep 2008Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine...
Congenital heart diseases are traditionally considered to be multifactorial in pathogenesis resulting from environmental and genetic interactions that determine penetrance and expressivity within a genetically predisposed family. Recent evidence suggests that genetic contributions have been significantly underestimated. However, single gene defects occur only in a minority of cases, and multigenetic causes of congenital heart diseases have not been fully demonstrated. Here, we show that interactions between alleles of 3 Pbx genes, which encode homeodomain transcription factors, are sufficient to determine the phenotypic presentation of congenital heart diseases in mice. A major role is served by Pbx1, whose inactivation results in persistent truncus arteriosus. Reduction or absence of Pbx2 or Pbx3 leads to Pbx1 haploinsufficiency and specific malformations that resemble tetralogy of Fallot, overriding aorta with ventricular septal defect, and bicuspid aortic valves. Disruption of Meis1, which encodes a Pbx DNA-binding partner, results in cardiac anomalies that resemble those caused by Pbx mutations. Each of the observed cardiac defects represents developmental abnormalities affecting distinct stages of cardiac outflow tract development and corresponds to specific types of human congenital heart disease. Thus, varied deficiencies in the Pbx gene family produce a full spectrum of cardiac defects involving the outflow tract, providing a framework for determining multigenetic causes of congenital heart anomalies.
Topics: Alleles; Animals; Heart Defects, Congenital; Homeodomain Proteins; Humans; Mice; Mice, Knockout; Myeloid Ecotropic Viral Integration Site 1 Protein; Neoplasm Proteins; Pre-B-Cell Leukemia Transcription Factor 1; Proto-Oncogene Proteins; Transcription Factors
PubMed: 18723445
DOI: 10.1161/CIRCRESAHA.108.175489 -
Cilia Dec 2012The primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the...
BACKGROUND
The primary cilium is a microtubule-based, plasma membrane-ensheathed protrusion projecting from the basal bodies of almost all cell types in the mammalian body. In the past several years a plethora of papers has indicated a crucial role for primary cilia in the development of a wide variety of organs. We have investigated heart development in cobblestone, a hypomorphic allele of the gene encoding the intraflagellar transport protein Ift88, and uncovered a number of the most common congenital heart defects seen in newborn humans.
METHODS
We generated serial sections of mutant cobblestone and wild type embryos in the region encompassing the heart and the cardiac outflow tract. The sections were further processed to generate three-dimensional reconstructions of these structures, and immunofluorescence confocal microscopy, transmission electron microscopy, and in situ hybridization were used to examine signal transduction pathways in the relevant areas. Whole mount in situ hybridization was also employed for certain developmental markers.
RESULTS
In addition to an enlarged pericardium and failure of both ventricular and atrial septum formation, the cobblestone mutants displayed manifold defects in outflow tract formation, including persistent truncus arteriosus, an overriding aorta, and abnormal transformation of the aortic arches. To discern the basis of these anomalies we examined both the maintenance of primary cilia as well as endogenous and migratory embryonic cell populations that contribute to the outflow tract and atrioventricular septa. The colonization of the embryonic heart by cardiac neural crest occurred normally in the cobblestone mutant, as did the expression of Sonic hedgehog. However, with the loss of primary cilia in the mutant hearts, there was a loss of both downstream Sonic hedgehog signaling and of Islet 1 expression in the second heart field, a derivative of the pharyngeal mesoderm. In addition, defects were recorded in development of atrial laterality and ventricular myocardiogenesis. Finally, we observed a reduction in expression of Bmp4 in the outflow tract, and complete loss of expression of both Bmp2 and Bmp4 in the atrioventricular endocardial cushions. Loss of BMP2/4 signaling may result in the observed proliferative defect in the endocardial cushions, which give rise to both the atrioventricular septa as well as to the septation of the outflow tract.
CONCLUSIONS
Taken together, our results potentially identify a novel link between Sonic hedgehog signaling at the primary cilium and BMP-dependent effects upon cardiogenesis. Our data further point to a potential linkage of atrioventricular septal defects, the most common congenital heart defects, to genes of the transport machinery or basal body of the cilia.
PubMed: 23351706
DOI: 10.1186/2046-2530-1-23 -
PloS One 2016To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global...
OBJECTIVE
To compare multi-detector computed tomography (MDCT) with cardiac catheterization and transthoracic echocardiography (TTE) in comprehensive evaluation of the global cardiovascular anatomy in patients with pulmonary atresia with ventricular septal defect (PA-VSD).
METHODS
The clinical and imaging data of 116 patients with PA-VSD confirmed by surgery were reviewed. Using findings at surgery as the reference standard, data from MDCT, TTE and catheterization were reviewed for assessment of native pulmonary vasculature and intracardiac defects.
RESULTS
MDCT was more accurate than catheterization and TTE in identification of native pulmonary arteries. MDCT is also the most accurate test for delineation of the major aortopulmonary collateral arteries. The inter-modality agreement for evaluation of overriding aorta and VSD were both excellent. In the subgroup with surgical correlation, excellent agreement was found between TTE and surgery, and substantial agreement was also found at MDCT.
CONCLUSION
MDCT can correctly delineate the native pulmonary vasculatures and intracardiac defects and may be a reliable method for noninvasive assessment of global cardiovascular abnormalities in patients with PA-VSD.
Topics: Adolescent; Cardiac Catheterization; Child; Child, Preschool; Collateral Circulation; Echocardiography; Female; Heart Septal Defects; Heart Ventricles; Humans; Infant; Male; Multidetector Computed Tomography; Preoperative Care; Pulmonary Artery; Pulmonary Atresia; Retrospective Studies; Ventricular Septum
PubMed: 26741649
DOI: 10.1371/journal.pone.0146380 -
Development (Cambridge, England) Mar 2016Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles...
Congenital heart defects are the most common birth defects in humans, and those that affect the proper alignment of the outflow tracts and septation of the ventricles are a highly significant cause of morbidity and mortality in infants. A late differentiating population of cardiac progenitors, referred to as the anterior second heart field (AHF), gives rise to the outflow tract and the majority of the right ventricle and provides an embryological context for understanding cardiac outflow tract alignment and membranous ventricular septal defects. However, the transcriptional pathways controlling AHF development and their roles in congenital heart defects remain incompletely elucidated. Here, we inactivated the gene encoding the transcription factor MEF2C in the AHF in mice. Loss of Mef2c function in the AHF results in a spectrum of outflow tract alignment defects ranging from overriding aorta to double-outlet right ventricle and dextro-transposition of the great arteries. We identify Tdgf1, which encodes a Nodal co-receptor (also known as Cripto), as a direct transcriptional target of MEF2C in the outflow tract via an AHF-restricted Tdgf1 enhancer. Importantly, both the MEF2C and TDGF1 genes are associated with congenital heart defects in humans. Thus, these studies establish a direct transcriptional pathway between the core cardiac transcription factor MEF2C and the human congenital heart disease gene TDGF1. Moreover, we found a range of outflow tract alignment defects resulting from a single genetic lesion, supporting the idea that AHF-derived outflow tract alignment defects may constitute an embryological spectrum rather than distinct anomalies.
Topics: Animals; Animals, Newborn; Disease Models, Animal; Epidermal Growth Factor; Female; Gene Deletion; Gene Expression Regulation, Developmental; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Heart Ventricles; Humans; In Situ Hybridization; MEF2 Transcription Factors; Male; Membrane Glycoproteins; Mice; Morphogenesis; Neoplasm Proteins; Organogenesis; Sequence Analysis, RNA; Tissue Distribution; Transcription, Genetic; Transposition of Great Vessels
PubMed: 26811383
DOI: 10.1242/dev.126383 -
Annals of Biomedical Engineering Dec 2021Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general...
Mechanical forces are essential for proper growth and remodeling of the primitive pharyngeal arch arteries (PAAs) into the great vessels of the heart. Despite general acknowledgement of a hemodynamic-malformation link, the direct correlation between hemodynamics and PAA morphogenesis remains poorly understood. The elusiveness is largely due to difficulty in performing isolated hemodynamic perturbations and quantifying changes in-vivo. Previous in-vivo arch artery occlusion/ablation experiments either did not isolate the effects of hemodynamics, did not analyze the results in a 3D context or did not consider the effects of varying degrees of occlusion. Here, we overcome these limitations by combining minimally invasive occlusion experiments in the avian embryo with 3D anatomical models of development and in-silico testing of experimental phenomenon. We detail morphological and hemodynamic changes 24 hours post vessel occlusion. 3D anatomical models showed that occlusion geometries had more circular cross-sectional areas and more elongated arches than their control counterparts. Computational fluid dynamics revealed a marked change in wall shear stress-morphology trends. Instantaneous (in-silico) occlusion models provided mechanistic insights into the dynamic vessel adaptation process, predicting pressure-area trends for a number of experimental occlusion arches. We follow the propagation of small defects in a single embryo Hamburger Hamilton (HH) Stage 18 embryo to a more serious defect in an HH29 embryo. Results demonstrate that hemodynamic perturbation of the presumptive aortic arch, through varying degrees of vessel occlusion, overrides natural growth mechanisms and prevents it from becoming the dominant arch of the aorta.
Topics: Animals; Aorta, Thoracic; Blood Flow Velocity; Chick Embryo; Hemodynamics; Imaging, Three-Dimensional; Models, Cardiovascular; Morphogenesis; Pharynx; Pulsatile Flow; Tomography, X-Ray Computed; Ultrasonography, Doppler
PubMed: 34117583
DOI: 10.1007/s10439-021-02802-2 -
Taiwanese Journal of Obstetrics &... Sep 2021We present rapid diagnosis of trisomy 13 of maternal origin by quantitative fluorescent polymerase chain reaction (QF-PCR) in a pregnancy with multiple fetal...
Rapid diagnosis of trisomy 13 of maternal origin by quantitative fluorescent polymerase chain reaction analysis in a pregnancy with fetal holoprosencephaly, premaxillary agenesis, postaxial polydactyly of left hand and overriding aorta.
OBJECTIVE
We present rapid diagnosis of trisomy 13 of maternal origin by quantitative fluorescent polymerase chain reaction (QF-PCR) in a pregnancy with multiple fetal abnormalities.
CASE REPORT
A 35-year-old, primigravid woman was referred for amniocentesis at 24 weeks of gestation because of multiple congenital anomalies in the fetus. Prenatal ultrasound at 23 weeks of gestation revealed holoprosencephaly, premaxillary agenesis, postaxial polydactyly of the left hand and overriding aorta. Amniocentesis was performed subsequently, and QF-PCR analysis using the polymorphic DNA markers of D13S789 (13q22.3), D13S790 (13q31.1) and D13S767 (13q31.3) on the DNA extracted from uncultured amniocytes and parental bloods showed trisomy 13 of maternal origin. Conventional cytogenetic analysis on the cultured amniocytes confirmed trisomy 13. The pregnancy was subsequently terminated, and a malformed fetus was delivered with multiple anomalies consistent with the prenatal diagnosis.
CONCLUSION
QF-PCR analysis is useful for rapid confirmation of trisomy 13 and the parental origin when prenatal ultrasound findings are suspicious of fetal trisomy 13.
Topics: Abnormalities, Multiple; Adult; Amniocentesis; Comparative Genomic Hybridization; Female; Fetus; Fingers; Heart Defects, Congenital; Holoprosencephaly; Humans; In Situ Hybridization, Fluorescence; Polydactyly; Polymerase Chain Reaction; Pregnancy; Quantitative Light-Induced Fluorescence; Toes; Trisomy 13 Syndrome
PubMed: 34507670
DOI: 10.1016/j.tjog.2021.07.020 -
European Journal of Cardio-thoracic... Jul 2019Tetralogy of Fallot is characterized by anterocephalad deviation of the outlet septum, along with abnormal septoparietal trabeculations, which lead to subpulmonary...
OBJECTIVES
Tetralogy of Fallot is characterized by anterocephalad deviation of the outlet septum, along with abnormal septoparietal trabeculations, which lead to subpulmonary infundibular stenosis. Archives of retained hearts are an important resource for improving our understanding of congenital heart defects and their morphological variability. This study aims to define variations in aortic override, coronary arterial patterns and ventricular septal defects in tetralogy of Fallot as observed in a morphological archive, highlighting implications for surgical management.
METHODS
The Birmingham Children's Hospital archive contains 211 hearts with tetralogy of Fallot, of which 164 were analysed [69 (42.1%) unrepaired and 95 (57.9%) operated specimens]. A detailed morphological and geometric analysis was performed using a rigorous 5-layer review process.
RESULTS
Anomalies were observed in the orifices, origins and course of the coronary arteries: 20 hearts (13.0%) had more than 2 orifices and 3 hearts (1.9%) had a single orifice. In 7 hearts (4.3%), a coronary artery crossed the right ventricular outflow tract. The extent of aortic override ranged from 31.0% to 100% (median of 59.5%). The ventricular septal defect was most often perimembranous (139, 84.8%), but we also found muscular (14, 8.5%), atrioventricular (7, 4.3%) and doubly committed juxta-arterial (2, 1.2%) variants.
CONCLUSIONS
Anatomical variations are common and can impact surgical management. Anomalous coronary arteries may require a conduit rather than a transannular patch. Variability in aortic override determines the size of patch used to baffle blood to the aorta. The type of ventricular septal defect affects patch closure and the risk of postoperative conduction defects.
Topics: Adolescent; Child; Child, Preschool; Cohort Studies; Coronary Vessel Anomalies; Coronary Vessels; Female; Humans; Infant; Infant, Newborn; Male; Tetralogy of Fallot
PubMed: 30657877
DOI: 10.1093/ejcts/ezy474 -
California Medicine Jun 1949Patients with congenital heart disease of the cyanotic type may be presumed to be candidates for surgical treatment if the examination of the heart reveals compatible...
Patients with congenital heart disease of the cyanotic type may be presumed to be candidates for surgical treatment if the examination of the heart reveals compatible findings, particularly murmurs characteristic of an interventricular septal defect, overriding aorta, and pulmonary stenosis; if the electrocardiogram shows right axis deviation; if the x-ray or fluoroscopic study demonstrates decreased pulmonary markings; if Diodrast injection shows right ventricular enlargement, a septal defect, overriding of the aorta, and small pulmonary arteries. In some cases some of these criteria may be missing. If there are not definite contraindications, exploratory thoracotomy is indicated for patients with congenital heart disease causing cyanosis.
Topics: Aorta; Cyanosis; Electrocardiography; Fluoroscopy; Heart; Heart Defects, Congenital; Heart Septal Defects, Ventricular; Humans; Hypertrophy, Right Ventricular; Lung; Male; Pulmonary Artery; Pulmonary Valve Stenosis; Thoracotomy
PubMed: 18131680
DOI: No ID Found -
Journal of Cardiovascular Development... Mar 2021Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac...
BACKGROUND
Left ventricular noncompaction (LVNC) is a cardiomyopathy that can lead to arrhythmias, embolic events and heart failure. Despite our current knowledge of cardiac development, the mechanisms underlying noncompaction of the ventricular myocardium are still poorly understood. The small GTPase acts as a crucial regulator of numerous developmental events. The present study aimed to investigate the cardiomyocyte specific role of in embryonic heart development.
METHODS AND RESULTS
The transgenic mice were crossed with mice to generate mice with a cardiomyocyte specific deletion of () during heart development. Embryonic hearts at E12.5-E18.5 were collected for histological analysis. Overall, hearts displayed a bifid apex, along with hypertrabeculation and a thin compact myocardium. hearts also exhibited ventricular septal defects (VSDs) and double outlet right ventricle (DORV) or overriding aorta. Cardiomyocytes had a rounded morphology and were highly disorganized, and the myocardial expression of Scrib, a planar cell polarity protein, was reduced in hearts. In addition, cell proliferation rate was significantly decreased in the ventricular myocardium at E9.5.
CONCLUSIONS
deficiency in the myocardium impairs cardiomyocyte elongation and organization, and proliferative growth of the heart. A spectrum of CHDs arises in hearts, implicating signaling in the ventricular myocardium as a crucial regulator of OFT alignment, along with compact myocardium growth and development.
PubMed: 33804107
DOI: 10.3390/jcdd8030029 -
PloS One Jul 2009Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation...
BACKGROUND
Rapid growth of the embryonic heart occurs by addition of progenitor cells of the second heart field to the poles of the elongating heart tube. Failure or perturbation of this process leads to congenital heart defects. In order to provide further insight into second heart field development we characterized the insertion site of a transgene expressed in the second heart field and outflow tract as the result of an integration site position effect.
RESULTS
Here we show that the integration site of the A17-Myf5-nlacZ-T55 transgene lies upstream of Hes1, encoding a basic helix-loop-helix containing transcriptional repressor required for the maintenance of diverse progenitor cell populations during embryonic development. Transgene expression in a subset of Hes1 expression sites, including the CNS, pharyngeal epithelia, pericardium, limb bud and lung endoderm suggests that Hes1 is the endogenous target of regulatory elements trapped by the transgene. Hes1 is expressed in pharyngeal endoderm and mesoderm including the second heart field. Analysis of Hes1 mutant hearts at embryonic day 15.5 reveals outflow tract alignment defects including ventricular septal defects and overriding aorta. At earlier developmental stages, Hes1 mutant embryos display defects in second heart field proliferation, a reduction in cardiac neural crest cells and failure to completely extend the outflow tract.
CONCLUSIONS
Hes1 is expressed in cardiac progenitor cells in the early embryo and is required for development of the arterial pole of the heart.
Topics: Animals; Base Sequence; Basic Helix-Loop-Helix Transcription Factors; Blotting, Western; Cell Proliferation; DNA Primers; Heart; Homeodomain Proteins; In Situ Hybridization; Mice; Mice, Transgenic; Morphogenesis; Myocardium; Transcription Factor HES-1; Transgenes
PubMed: 19609448
DOI: 10.1371/journal.pone.0006267