Outflow Tract Formation-Embryonic Origins of Conotruncal Congenital Heart Disease.
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ABSTRACT:
SUBMITTER: Stefanovic S
PROVIDER: S-EPMC8069607 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In congenital heart disease, the presence of structural defects affects blood flow in the heart and circulation. However, because the fetal circulation bypasses the lungs, fetuses with cyanotic heart defects can survive in utero but need prompt intervention to survive after birth. Tetralogy of Fallot and persistent truncus arteriosus are two of the most significant conotruncal heart defects. In both defects, blood access to the lungs is restricted or non-existent, and babies with these critical conditions need intervention right after birth. While there are known genetic mutations that lead to these critical heart defects, early perturbations in blood flow can independently lead to critical heart defects. In this paper, we start by comparing the fetal circulation with the neonatal and adult circulation, and reviewing how altered fetal blood flow can be used as a diagnostic tool to plan interventions. We then look at known factors that lead to tetralogy of Fallot and persistent truncus arteriosus: namely early perturbations in blood flow and mutations within VEGF-related pathways. The interplay between physical and genetic factors means that any one alteration can cause significant disruptions during development and underscore our need to better understand the effects of both blood flow and flow-responsive genes.
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Project description:Blood flow plays a critical role in regulating embryonic cardiac growth and development, with altered flow leading to congenital heart disease. Progress in the field, however, is hindered by a lack of quantification of hemodynamic conditions in the developing heart. In this study, we present a methodology to quantify blood flow dynamics in the embryonic heart using subject-specific computational fluid dynamics (CFD) models. While the methodology is general, we focused on a model of the chick embryonic heart outflow tract (OFT), which distally connects the heart to the arterial system, and is the region of origin of many congenital cardiac defects. Using structural and Doppler velocity data collected from optical coherence tomography, we generated 4D ([Formula: see text]) embryo-specific CFD models of the heart OFT. To replicate the blood flow dynamics over time during the cardiac cycle, we developed an iterative inverse-method optimization algorithm, which determines the CFD model boundary conditions such that differences between computed velocities and measured velocities at one point within the OFT lumen are minimized. Results from our developed CFD model agree with previously measured hemodynamics in the OFT. Further, computed velocities and measured velocities differ by [Formula: see text]15 % at locations that were not used in the optimization, validating the model. The presented methodology can be used in quantifications of embryonic cardiac hemodynamics under normal and altered blood flow conditions, enabling an in-depth quantitative study of how blood flow influences cardiac development.
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Project description:BackgroundRight ventricular outflow tract obstruction in patients with congenital heart disease is usually assessed using echocardiographic peak instantaneous gradient at rest. Since right ventricular outflow tract obstruction may change during exercise (dynamic right ventricular outflow tract obstruction), we present a case emphasizing the potential use of exercise cardiac magnetic resonance imaging (CMR).Case summaryWe discuss a 15-year-old patient with repaired mid-ventricular sub-pulmonary stenosis type double-chambered right ventricle causing right ventricular outflow tract obstruction and symptoms on exertion. In this case, exercise CMR imaging provided additional information, allowing adequate surgical planning.DiscussionThe additional value of exercise CMR imaging in a case of right ventricular outflow tract obstruction was described. Although exercise cardiac magnetic resonance imaging did not show a significant increase in peak gradient across the right ventricular outflow tract obstruction, shifting and D-shaping of the interventricular septum with subsequent insufficient left ventricular filling (preload) was observed in the patient with recurrent double-chambered right ventricle. This case demonstrates how exercise CMR imaging can be helpful in the clinical decision beyond standard echocardiographic evaluation by providing additional evidence of adverse haemodynamics during exercise.
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Project description:Due to the prevalence of congenital heart disease in the human population, determining the role of variants in congenital heart disease (CHD) can give a better understanding of the cause of the disorder. A homozygous missense mutation in the LDL receptor-related protein 1 (Lrp1) in mice was shown to cause congenital heart defects, including atrioventricular septal defect (AVSD) and double outlet right ventricle (DORV). Integrative analysis of publicly available single-cell RNA sequencing (scRNA-seq) datasets and spatial transcriptomics of human and mouse hearts indicated that LRP1 is predominantly expressed in mesenchymal cells and mainly located in the developing outflow tract and atrioventricular cushion. Gene burden analysis of 1922 CHD individuals versus 2602 controls with whole-exome sequencing showed a significant excess of rare damaging LRP1 mutations in CHD (odds ratio (OR) = 2.22, p = 1.92 × 10-4), especially in conotruncal defect with OR of 2.37 (p = 1.77 × 10-3) and atrioventricular septal defect with OR of 3.14 (p = 0.0194). Interestingly, there is a significant relationship between those variants that have an allele frequency below 0.01% and atrioventricular septal defect, which is the phenotype observed previously in a homozygous N-ethyl-N-nitrosourea (ENU)-induced Lrp1 mutant mouse line.
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Project description:Congenital conotruncal heart defects (CCHD) are a subset of serious congenital heart defects (CHD) of the cardiac outflow tracts or great arteries. Its frequency is estimated in 1/1000 live births, accounting for approximately 10?30% of all CHD cases. Chromosomal abnormalities and copy number variants (CNVs) contribute to the disease risk in patients with syndromic and/or non-syndromic forms. Although largely studied in several populations, their frequencies are barely reported for Latin American countries. The aim of this study was to analyze chromosomal abnormalities, 22q11 deletions, and other genomic imbalances in a group of Argentinean patients with CCHD of unknown etiology. A cohort of 219 patients with isolated CCHD or associated with other major anomalies were referred from different provinces of Argentina. Cytogenetic studies, Multiplex-Ligation-Probe-Amplification (MLPA) and fluorescent in situ hybridization (FISH) analysis were performed. No cytogenetic abnormalities were found. 22q11 deletion was found in 23.5% of the patients from our cohort, 66% only had CHD with no other major anomalies. None of the patients with transposition of the great vessels (TGV) carried the 22q11 deletion. Other 4 clinically relevant CNVs were also observed: a distal low copy repeat (LCR)D-E 22q11 duplication, and 17p13.3, 4q35 and TBX1 deletions. In summary, 25.8% of CCHD patients presented imbalances associated with the disease.
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Project description:Blood flow is inherently linked to embryonic cardiac development, as haemodynamic forces exerted by flow stimulate mechanotransduction mechanisms that modulate cardiac growth and remodelling. This study evaluated blood flow in the embryonic heart outflow tract (OFT) during normal development at each stage between HH13 and HH18 in chicken embryos, in order to characterize changes in haemodynamic conditions during critical cardiac looping transformations. Two-dimensional optical coherence tomography was used to simultaneously acquire both structural and Doppler flow images, in order to extract blood flow velocity and structural information and estimate haemodynamic measures. From HH13 to HH18, peak blood flow rate increased by 2.4-fold and stroke volume increased by 2.1-fold. Wall shear rate (WSR) and lumen diameter data suggest that changes in blood flow during HH13-HH18 may induce a shear-mediated vasodilation response in the OFT. Embryo-specific four-dimensional computational fluid dynamics modelling at HH13 and HH18 complemented experimental observations and indicated heterogeneous WSR distributions over the OFT. Characterizing changes in haemodynamics during cardiac looping will help us better understand the way normal blood flow impacts proper cardiac development.
| S-EPMC4614502 | biostudies-literature
Project description:We analyzed heart wall motion and blood flow dynamics in chicken embryos using in vivo optical coherence tomography (OCT) imaging and computational fluid dynamics (CFD) embryo-specific modeling. We focused on the heart outflow tract (OFT) region of day 3 embryos, and compared normal (control) conditions to conditions after performing an OFT banding intervention, which alters hemodynamics in the embryonic heart and vasculature. We found that hemodynamics and cardiac wall motion in the OFT are affected by banding in ways that might not be intuitive a priori. In addition to the expected increase in ventricular blood pressure, and increase blood flow velocity and, thus, wall shear stress (WSS) at the band site, the characteristic peristaltic-like motion of the OFT was altered, further affecting flow and WSS. Myocardial contractility, however, was affected only close to the band site due to the physical restriction on wall motion imposed by the band. WSS were heterogeneously distributed in both normal and banded OFTs. Our results show how banding affects cardiac mechanics and can lead, in the future, to a better understanding of mechanisms by which altered blood flow conditions affect cardiac development leading to congenital heart disease.
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Project description: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.
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Project description:BACKGROUND:Previous studies using different cardiac phenotypes, technologies and designs suggest a burden of large, rare or de novo copy number variants (CNVs) in subjects with congenital heart defects. We sought to identify disease-related CNVs, candidate genes, and functional pathways in a large number of cases with conotruncal and related defects that carried no known genetic syndrome. METHODS:Cases and control samples were divided into two cohorts and genotyped to assess each subject's CNV content. Analyses were performed to ascertain differences in overall CNV prevalence and to identify enrichment of specific genes and functional pathways in conotruncal cases relative to healthy controls. RESULTS:Only findings present in both cohorts are presented. From 973 total conotruncal cases, a burden of rare CNVs was detected in both cohorts. Candidate genes from rare CNVs found in both cohorts were identified based on their association with cardiac development or disease, and/or their reported disruption in published studies. Functional and pathway analyses revealed significant enrichment of terms involved in either heart or early embryonic development. CONCLUSION:Our study tested one of the largest cohorts specifically with cardiac conotruncal and related defects. These results confirm and extend previous findings that CNVs contribute to disease risk for congenital heart defects in general and conotruncal defects in particular. As disease heterogeneity renders identification of single recurrent genes or loci difficult, functional pathway and gene regulation network analyses appear to be more informative. Birth Defects Research 109:271-295, 2017. © 2017 Wiley Periodicals, Inc.
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Project description:The angle between the inter-ventricular septum and the ascending aorta can be measured during a sonographic fetal survey while viewing the left ventricular outflow tract (LVOT angle). Our aim was to compare the LVOT angle between fetuses with and without conotruncal cardiac anomaliesrmations. In this prospective observational study, we compared the LVOT angle between normal fetuses, at different gestational age, and fetuses with cardiac malformations. The study included 302 fetuses screened at gestational age of 12-39 weeks. The LVOT angle ranged from 127 to 163 degrees (mean 148.2), in 293 fetuses with normal hearts, and was not correlated with gestational age. The LVOT angle was significantly wider in fetuses with D-transposition of the great arteries (D-TGA, eight fetuses) and valvar aortic stenosis (AS, three fetuses), than in fetuses with normal hearts (164.8 ± 5.0 vs. 148.2 ± 5.4, respectively, p < 0.001). Conversely, the LVOT angle was significantly narrower in fetuses with complete atrioventricular canal defect (AVC, eight fetuses), than in fetuses with normal hearts (124.8 ± 2.4 vs. 148.2 ± 5.4, respectively, p < 0.001). On ROC analysis, an angle of 159.6 degrees or higher had a sensitivity of 100% and a specificity of 97.3% for the detection of TGA or AS, whereas an angle of 128.8 degrees or lower had a sensitivity of 100% and a specificity of 99.7% for the detection of AVC defect. The LVOT angle is constant during pregnancy, and differs significantly in fetuses with TGA/AS, and AVC, compared to fetuses with normal hearts (wider and narrower, respectively).
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