Etiology Of Heart Defects Research Articles

A neural crest origin for cohesinopathy heart defects.

Mutations in subunits or regulators of cohesin cause a spectrum of disorders in humans known as the 'cohesinopathies'. Cohesinopathies, including the best known example Cornelia de Lange syndrome (CdLS), are characterized by broad spectrum, multifactorial developmental anomalies. Heart defects occur at high frequency and can reach up to 30% in CdLS. The mechanisms by which heart defects occur are enigmatic, but assumed to be developmental in origin. In this study, we depleted cohesin subunit Rad21 by 70-80% in a zebrafish cohesinopathy model. The hearts of Rad21-depleted animals were smaller, often failed to loop, and functioned less efficiently than size-matched controls. Functional deficiency was accompanied by valve defects and reduced ejection fraction. Interestingly, neural crest cells failed to populate the heart and instead exhibited a wandering behavior. Consequently, these cells also failed to condense correctly into pharyngeal arches. Transcriptome analysis revealed that Wnt pathway, chemokine and cadherin genes are dysregulated at the time of cardiac neural crest development. Our results give insight into the etiology of heart defects in the cohesinopathies, and raise the possibility that mild mutations in cohesin genes may be causative of a fraction of congenital heart disease in human populations.

O6. Association between fetal congenital heart defects and maternal risk of hypertensive disorders of pregnancy in concurrent and subsequent pregnancies

Introduction Pregnant women carrying fetuses with heart defects and women with hypertensive disorders of pregnancy (HDP) both often exhibit angiogenic imbalances, suggesting that the same underlying processes may play a role in the etiology of heart defects and the pathology associated with HDP. Objectives To determine whether fetal heart defects are associated with an increased risk of maternal HDP, and whether the mechanisms driving the association are primarily maternal or fetal. Methods Using Danish national registers, we constructed a cohort comprising all singleton pregnancies without chromosomal abnormalities continuing to at least 20 completed weeks gestation in Denmark, 1977–2011. We then identified both pregnancies complicated by offspring congenital heart defects and those complicated by HDP (severe preeclampsia [PE]/eclampsia, moderate PE, gestational hypertension [GH]). Using polytomous logistic regression, we estimated odds ratios (ORs) for the association between carrying a fetus with a congenital heart defect and maternal risk of an HDP in the second half of pregnancy, overall and for specific heart defects. We also estimated ORs for the association between (1) an HDP in a previous pregnancy and the risk of carrying a child with a heart defect in subsequent pregnancies, and (2) fetal congenital heart defects in a previous pregnancy and the risk of HDP in subsequent pregnancies. Results Carrying a child with a heart defect was associated with a 3-fold increase in the risk of severe PE later in pregnancy (OR 3.02, 95% confidence interval [CI] 2.71–3.37) and a modest increase in the risk of moderate PE (OR 1.29, 95% CI 1.18–1.41), but not with the risk of GH (OR 1.08, 95% CI 0.93–1.25). These associations did not appear to depend on the type of offspring heart defect. Having a child with a heart defect in a previous pregnancy was also associated with PE (severe PE: OR 1.57, 95% CI 1.24–1.97; moderate PE: OR 1.32, 95% CI 1.16–1.51) but not with GH (OR 1.00, 95% CI 0.82–1.22) in subsequent pregnancies. Similarly, a history of PE in a previous pregnancy, but not of GH alone, was associated with an increased risk of offspring heart defects in later pregnancies (severe PE: OR 1.46, 95% CI 1.21–1.77; moderate PE: OR 1.13, 95% CI 1.01–1.27; GH: OR 1.12, 95% CI 0.91–1.37). Conclusion Our findings suggest that the same pathophysiological mechanisms may be involved in both congenital heart defects and severe PE (but are less important in less severe forms of HDP), and that these processes are most likely maternal, rather than fetal.

Exposure to low-dose trichloroethylene alters shear stress gene expression and function in the developing chick heart.

Trichloroethylene is an organic solvent used as an industrial degreasing agent. Due to its widespread use and volatile nature, TCE is a common environmental contaminant. Trichloroethylene exposure has been implicated in the etiology of heart defects in human populations and animal models. Recent data suggest misregulation of Ca2+ homeostasis in H9c2 cardiomyocyte cell line after TCE exposure. We hypothesized that misregulation of Ca2+ homeostasis alters myocyte function and leads to changes in embryonic blood flow. In turn, changes in cardiac flow are known to cause cardiac malformations. To investigate this hypothesis, we dosed developing chick embryos in ovo with environmentally relevant doses of TCE (8 and 800 ppb). RNA was isolated from control and treated embryos at specific times in development for real-time PCR analysis of blood flow markers. Effects were observed on Endothelin-1 (ET-1), Nitric Oxide Synthase-3 (NOS-3) and Krüppel-like Factor 2 (KLF2) expression relative to TCE exposure and consistent with reduced flow. Further, we measured function in the developing heart after TCE exposure by isolating cardiomyocytes and measuring half-width of contraction and sarcomere lengths. These functional data showed a significant increase in half-width of contraction after TCE exposure. These data suggest that perturbation of cardiac function contributes to the etiology of congenital heart defects in TCE-exposed embryos.