Abnormal neurogenesis and cortical growth in congenital heart disease.
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ABSTRACT:
SUBMITTER: Morton PD
PROVIDER: S-EPMC5467873 | biostudies-literature | 2017 Jan
REPOSITORIES: biostudies-literature
Publications
Abnormal neurogenesis and cortical growth in congenital heart disease.
Morton Paul D PD Korotcova Ludmila L Lewis Bobbi K BK Bhuvanendran Shivaprasad S Ramachandra Shruti D SD Zurakowski David D Zhang Jiangyang J Zhang Jiangyang J Mori Susumu S Frank Joseph A JA Jonas Richard A RA Gallo Vittorio V Ishibashi Nobuyuki N
Science translational medicine 20170101 374
Long-term neurological deficits due to immature cortical development are emerging as a major challenge in congenital heart disease (CHD). However, cellular mechanisms underlying dysregulation of perinatal corticogenesis in CHD remain elusive. The subventricular zone (SVZ) represents the largest postnatal niche of neural stem/progenitor cells (NSPCs). We show that the piglet SVZ resembles its human counterpart and displays robust postnatal neurogenesis. We present evidence that SVZ NSPCs migrate ...[more]
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Project description:Congenital heart disease (CHD) is among the most common birth defects. Children with CHD frequently display long-term intellectual and behavioral disability. Emerging evidence indicates that cardiac anomalies lead to a reduction in cerebral oxygenation, which appears to profoundly impact on the maturation of cerebral regions responsible for higher-order cognitive functions. In this review we focus on the potential mechanisms by which dysregulation of cortical neuronal development during early life may lead to the significant cognitive impairments that commonly occur in children with CHD. Further understanding of the mechanisms underlying cortical dysmaturation due to CHD will be necessary to identify strategies for neonatal neuroprotection and for mitigating developmental delays in this patient population.
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2008-05-11 | E-GEOD-7527 | biostudies-arrayexpress
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Project description:Lack of the conserved NK2-domain of the cardiac transcription factor Nkx2.5 causes multiple heart defects . The NK2 family of homeobox genes constitutes a family of transcription factors that play an important role in different developmental processes. Members of this group are characterized by two highly conserved protein domains: the homeodomain, conferring DNA binding activity, and the NK2-specific domain (NK2-SD) of yet unknown function. One of the best characterized members of this group is the early cardiogenic marker Nkx2.5. Loss of function of Nkx2.5 leads to embryonic lethality around E10.5 due to an arrest of heart development at the looping stage. We have further dissected the function of Nkx2.5 in vivo by creating a knockout mouse line harboring an in frame deletion of the NK2-SD by Cre/loxP mediated excision. Homozygous mutant mice die at E14.5 due to severe cardiac malformations, e.g. common AV canal, DORV, and VSD. Lack of the NK2-SD leads to downregulation of the ventricular markers MLC-2v and Irx4 specifically in the right ventricle, and is accompanied with reduced right ventricular function. This function of Nkx2.5 seems to be independent of its ability to bind target DNA, since lack of the NK2-SD does not alter the DNA binding activity of Csx/Nkx2.5 in vitro. Heterozygous mutant mice show a spectrum of cardiac defects related to cardiac septation and valve morphogenesis, but lack conduction system defects as reported for heterozygous Nkx2.5 mice. The phenotype observed in NK2-SD mutant mice shows that Nkx2.5 is not only crucial during early steps of cardiogenesis but also plays an important role at later developmental stages. Embryos were isolated at embryonic day 12.5. The entire embryo heart was taken and isolated in ice-cold PBS and immediately frozen on dry-ice. Total RNA was extracted from pooled samples of wildtype, heterozygous and mutant embryos. Keywords = congenital heart disease, Csx, Nkx2.5 Keywords: other
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Project description:Congenital heart disease (CHD) is the most frequent birth defect and affects nearly 1% of newborns. The etiology of CHD is largely unknown and only a small percentage can be assigned to environmental risk factors such as maternal diseases or exposure to mutagenic agents during pregnancy. Chromosomal imbalances have been identified in many forms of syndromic CHD, but next to nothing is known about the impact of DNA copy number changes in non-syndromic CHD. Here we present a sub-megabase resolution array CGH screen of a cohort with CHD as the sole abnormality at the time of diagnosis. Keywords: array CGH
2008-05-12 | GSE7527 | GEO
Project description:Altered brain development is a common feature of the neurological sequelae of complex congenital heart disease (CHD). These alterations include abnormalities in brain size and growth that begin prenatally and persist postnatally. However, the longitudinal trajectory of changes in brain volume from the prenatal to postnatal environment have not been investigated. We aimed to evaluate the trajectory of brain growth in a cohort of patients with complex CHD (n?=?16) and healthy controls (n?=?15) to test the hypothesis that patients with complex CHD would have smaller total brain volume (TBV) prenatally, which would become increasingly prominent by three months of age. Participants underwent fetal magnetic resonance imaging (MRI) at a mean of 32?weeks gestation, a preoperative/neonatal MRI shortly after birth, a postoperative MRI (CHD only), and a 3-month MRI to evaluate the trajectory of brain growth. Three-dimensional volumetric analysis was applied to the MRI data to measure TBV, as well as tissue-specific volumes of the cortical gray matter (CGM), white matter (WM), subcortical (deep nuclear) gray matter (SCGM), cerebellum, and cerebrospinal fluid (CSF). A random coefficients model was used to investigate longitudinal changes in TBV and demonstrated an altered trajectory of brain growth in the CHD population. The estimated slope for TBV from fetal to 3-month MRI was 11.5?cm3 per week for CHD infants compared to 16.7?cm3 per week for controls (p?=?0.0002). Brain growth followed a similar trajectory for the CGM (p?<?0.0001), SCGM (p?=?0.002), and cerebellum (p?=?0.005). There was no difference in growth of the WM (p?=?0.30) or CSF (p?=?0.085). Brain injury was associated with reduced TBV at 3-month MRI (p?=?0.02). After removing infants with brain injury from the model, an altered trajectory of brain growth persisted in CHD infants (p?=?0.006). These findings extend the existing literature by demonstrating longitudinal impairments in brain development in the CHD population and emphasize the global nature of disrupted brain growth from the prenatal environment through early infancy.
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Project description:PurposeWe aimed to describe the weight-for-age Z-score growth trajectory (WAZ-GT) of infants with complex congenital heart disease (cCHD) after neonatal cardiac surgery in the first 4 months of life and assess potential risk factors.MethodsWe utilized data from a previously reported trial of the REACH telehealth home monitoring (NCT01941667) program which evaluated 178 infants with cCHD from 2012 to 2017. Over the first 4 months of life, weekly infant weights were converted to WAZ. WAZ-GT classes were identified using latent class growth modeling. Multinomial logistic regression models were used to examine the associations between potential risk factors and WAZ-GT classes.ResultsFour distinct classes of WAZ-GT were identified: maintaining WAZ > 0, 14%; stable around WAZ = 0, 35%; partially recovered, 28%; never recovered, 23%. Compared with reference group "stable around WAZ=0," we identified clinical and sociodemographic determinants of class membership for the three remaining groups. "Maintaining WAZ > 0" had greater odds of having biventricular physiology, borderline appetite, and a parent with at least a college education. "Partially recovered" had greater odds of hospital length of stay>14 days and being a single child in the household. "Never recovered" had greater odds hospital length of stay >14 and > 30 days, tube feeding at discharge, and low appetite.ConclusionsThis study described distinct classes of WAZ-GT for infants with cCHD early in infancy and identified associated determinants.Practice implicationsFindings from this study can be used in the identification of infants at risk of poor WAZ-GT and in the design of interventions to target growth in this vulnerable patient population.
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