Folic acid prevents functional and structural heart defects induced by prenatal ethanol exposure

2021 ◽  
Author(s):  
Stephanie M Ford ◽  
Cameron J Pedersen ◽  
Matthew R Ford ◽  
Jun W Kim ◽  
Ganga H Karunamuni ◽  
...  
Keyword(s):  
Blood Flow ◽  
Folic Acid ◽  
Heart Diseases ◽  
Prenatal Alcohol Exposure ◽  
Heart Defects ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Endocardial Cushion ◽  
Prenatal Ethanol Exposure ◽  
Endocardial Cushions

Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in quail embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.

Prenatal ethanol exposure impairs the conduction delay at the atrioventricular junction in the looping heart

2021 ◽  
Author(s):  
Shan Ling ◽  
Michael W Jenkins ◽  
Michiko Watanabe ◽  
Stephanie M Ford ◽  
Andrew M Rollins
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Early Stage ◽  
Heart Defects ◽  
Ethanol Exposure ◽  
Cardiac Conduction ◽  
Conduction Delay ◽  
Prenatal Ethanol Exposure ◽  
Endocardial Cushions ◽  
Atrioventricular Junction

The etiology of ethanol-related congenital heart defects has been the focus of much study, but most research has concentrated on cellular and molecular mechanisms. We have shown with optical coherence tomography (OCT) that ethanol exposure led to increased retrograde flow and smaller atrioventricular (AV) cushions compared to controls. Since AV cushions play a role in patterning the conduction delay at the atrioventricular junction (AVJ), this study aims to investigate whether ethanol exposure alters the AVJ conduction in early looping hearts and whether this alteration is related to the decreased cushion size. Quail embryos were exposed to a single dose of ethanol at gastrulation, and Hamburger-Hamilton stage 19 - 20 hearts were dissected for imaging. Cardiac conduction was measured using an optical mapping microscope and we imaged the endocardial cushions using OCT. Our results showed that, compared with controls, ethanol-exposed embryos exhibited abnormally fast AVJ conduction and reduced cushion size. However, this increased conduction velocity (CV) did not strictly correlate with decreased cushion volume and thickness. By matching the CV map to the cushion size map, we found that the slowest conduction location was consistently at the atrial side of the AVJ, which had the thinner cushions, not at the thickest cushion location at the ventricular side as expected. Our findings reveal regional differences in the AVJ myocardium even at this early stage in heart development. These findings reveal the early steps leading to the heterogeneity and complexity of conduction at the mature AVJ, a site where arrhythmias can be initiated.

scholarly journals NGF and BDNF Alterations by Prenatal Alcohol Exposure

2019 ◽  
Vol 17 (4) ◽  
pp. 308-317 ◽  
Author(s):  
Valentina Carito ◽  
Mauro Ceccanti ◽  
Giampiero Ferraguti ◽  
Roberto Coccurello ◽  
Stefania Ciafrè ◽  
...  
Keyword(s):  
Prenatal Alcohol Exposure ◽  
Neuronal Cell Death ◽  
Antioxidant Properties ◽  
Neuronal Cell ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Signalling Pathways ◽  
Prenatal Ethanol Exposure ◽  
Developmental Defects ◽  
Prenatal Alcohol

Background: It is now widely established that the devastating effects of prenatal alcohol exposure on the embryo and fetus development cause marked cognitive and neurobiological deficits in the newborns. The negative effects of the gestational alcohol use have been well documented and known for some time. However, also the subtle role of alcohol consumption by fathers prior to mating is drawing special attention. Objective: Both paternal and maternal alcohol exposure has been shown to affect the neurotrophins' signalling pathways in the brain and in target organs of ethanol intoxication. Neurotrophins, in particular nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are molecules playing a pivotal role in the survival, development and function of the peripheral and central nervous systems but also in the pathogenesis of developmental defects caused by alcohol exposure. Methods: New researches from the available literature and experimental data from our laboratory are presented in this review to offer the most recent findings regarding the effects of maternal and paternal prenatal ethanol exposure especially on the neurotrophins' signalling pathways. Results: NGF and BDNF changes play a subtle role in short- and long-lasting effects of alcohol in ethanol target tissues, including neuronal cell death and severe cognitive and physiological deficits in the newborns. Conclusion: The review suggests a possible therapeutic intervention based on the use of specific molecules with antioxidant properties in order to induce

Abstract 14860: Echocardiographic Assessment of Shunt Fraction in Complex Cyanotic Heart Diseases Palliated With Aortopulmonary Shunts

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Joan K Lee ◽  
briana olson ◽  
Neal Jorgensen ◽  
Matthew D Files
Keyword(s):  
Blood Flow ◽  
Pulmonary Blood Flow ◽  
Heart Diseases ◽  
Heart Defects ◽  
Ductus Arteriosus ◽  
Ventricular Volume ◽  
Systemic Circulation ◽  
Repeated Measurements ◽  
Observer Agreement ◽  
Shunt Fraction

Introduction: Neonates with complex heart defects with inadequate pulmonary blood flow require aortopulmonary shunts (APS) either as surgical-placed modified Blalock-Taussig shunt or a catheter-based stent implantation into a patent ductus arteriosus. An ideal APS provides equal pulmonary blood flow (Qp) as the systemic blood flow (Qs), which is considered balanced circulation. Pulmonary over-circulation leads to complications from inadequate systemic circulation, such as organ dysfunction, shock, and death. Accurately determining Qp:Qs ratio in these patients relies on catheterization, which is invasive and may falsely lower the Qp due to anesthetic effects. To our knowledge, there has not been any studies on echocardiographic comparisons of balanced versus overcirculated APS. We aim to evaluate echocardiographic Doppler assessment of velocity-time integral (VTI) at the aortic arch isthmus distal to APS origin as a measure of shunt fraction in APS patients. We defined shunt fraction ratio (SFR) as retrograde to prograde flow by VTI. Methods: This is a retrospective pilot study of neonates with APS. We selected two cohorts of patients with appropriately balanced circulation (n=12) and those with excessive Qp (n=5) resulting in end-organ damage. We analyzed serial echocardiograms, with repeated measurements for inter-observer agreement. Results: Mean SFR is lower in balanced cohort compared to the overcirculated cohort (0.45 ± 0.07 vs. 0.55 ± 0.09, p=0.02). For both groups, SFR was positively associated with oxygen saturation (r= 0.57, p=0.01), as well as markers of ventricular volume load, such as the highest brain naturetic peptide during hospitalization (Pearson’s correlation r=0.83, p= 0.04) and as outpatient (r= 0.72, p =0.02). Inter-observer agreement was 0.74, suggesting that this is a reproducible technique. Conclusions: SFR by VTI is a simple echocardiographic technique to estimate the volume of APS flow and appears to have important implications for clinical outcomes. Prompt characterization of pulmonary overcirculation without invasive assessment could improve clinical management. Further prospective studies are needed to validate these findings.

scholarly journals Prenatal Alcohol Exposure and Congenital Heart Defects: A Meta-Analysis

PLoS ONE ◽  
2015 ◽  
Vol 10 (6) ◽  
pp. e0130681 ◽  
Author(s):  
Jiaomei Yang ◽  
Huizhen Qiu ◽  
Pengfei Qu ◽  
Ruo Zhang ◽  
Lingxia Zeng ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Prenatal Alcohol Exposure ◽  
Heart Defects ◽  
Meta Analysis ◽  
Alcohol Exposure ◽  
Prenatal Alcohol

Vascular function in alcohol-treated pregnant and nonpregnant mice

2001 ◽  
Vol 281 (5) ◽  
pp. R1449-R1455 ◽  
Author(s):  
Jocelynn L. Cook ◽  
Yunlong Zhang ◽  
Sandra T. Davidge
Keyword(s):  
Nitric Oxide ◽  
Vascular Function ◽  
Vascular System ◽  
Prenatal Alcohol Exposure ◽  
Control Diet ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Vascular Response ◽  
Oxide Component ◽  
Pregnant Mice

The effect of alcohol on maternal vascular adaptations to pregnancy is unknown. This study was designed to determine the effect of alcohol consumption on nitric oxide-mediated vascular function in mice during pregnancy. Female pregnant or nonpregnant C57BL/6J mice were fed a control diet or a liquid diet of 25% ethanol-derived calories for 13 days (from gestational days 6–18). Phenylephrine vasoconstriction was blunted in pregnancy compared with the nonpregnant state due to enhanced nitric oxide modulation, which was impaired by ethanol exposure. Although the EC50 and maximal responses to methacholine were not different in nonpregnant vs. pregnant mice, the nitric oxide component to methacholine-induced vasorelaxation was greater in the pregnant mice. Interestingly, alcohol affected only the pregnant animals in their response to methacholine. These data indicate that alcohol reduced the nitric oxide modulation of vascular response, which was more pronounced during pregnancy. These studies provide novel information regarding the effects of alcohol on the maternal vascular system during pregnancy and thereby contribute to further understanding of the adverse effects associated with prenatal alcohol exposure.

scholarly journals Acetaldehyde-Mediated Neurotoxicity: Relevance to Fetal Alcohol Spectrum Disorders

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Ming Tong ◽  
Lisa Longato ◽  
Quynh-GiaoLy Nguyen ◽  
William C. Chen ◽  
Amy Spaisman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Mitochondrial Function ◽  
Alcohol Exposure ◽  
Ethanol Exposure ◽  
Ethanol Metabolism ◽  
Toxic Metabolite ◽  
Prenatal Ethanol Exposure ◽  
Impaired Insulin ◽  
Insulin Responsiveness ◽  
Igf Signaling

Ethanol-induced neuro-developmental abnormalities are associated with impaired insulin and IGF signaling, and increased oxidative stress in CNS neurons. We examined the roles of ethanol and its principal toxic metabolite, acetaldehyde, as mediators of impaired insulin/IGF signaling and oxidative injury in immature cerebellar neurons. Cultures were exposed to 3.5 mM acetaldehyde or 50 mM ethanol ± 4-methylpyrazole (4-MP), an inhibitor of ethanol metabolism, and viability, mitochondrial function, oxidative stress, DNA damage, and insulin responsiveness were measured 48 hours later. Acetaldehyde or ethanol increased neuronal death and levels of 8-OHdG and 4-HNE, and reduced mitochondrial function. Ethanol inhibited insulin responsiveness, whereas acetaldehyde did not. 4-MP abated ethanol-induced oxidative stress and mitochondrial dysfunction, but failed to restore insulin responsiveness. Furthermore, alcohol and aldehyde metabolizing enzyme genes were inhibited by prenatal ethanol exposure; this effect was mediated by acetaldehyde and not ethanol + 4MP. These findings suggest that brain insulin resistance in prenatal alcohol exposure is caused by direct effects of ethanol, whereas oxidative stress induced neuronal injury is likely mediated by ethanol and its toxic metabolites. Moreover, the adverse effects of prenatal ethanol exposure on brain development may be exacerbated by down-regulation of genes needed for metabolism and detoxification of alcohol in the brain.

scholarly journals Prenatal exposure to alcohol alters the Golgi apparatus of newborn rat hepatocytes: a cytochemical study.

1987 ◽  
Vol 35 (2) ◽  
pp. 221-228 ◽  
Author(s):  
J Renau-Piqueras ◽  
F Miragall ◽  
C Guerri ◽  
R Baguena-Cervellera
Keyword(s):  
Golgi Apparatus ◽  
Prenatal Exposure ◽  
Prenatal Alcohol Exposure ◽  
Alcohol Exposure ◽  
Rat Hepatocytes ◽  
Ethanol Exposure ◽  
Newborn Rat ◽  
Cytochemical Study ◽  
Cerium Phosphate ◽  
Osmium Impregnation

The effect of prenatal exposure to ethanol on the Golgi apparatus of newborn rat hepatocytes has been studied cytochemically using several trans-Golgi markers (thiamine pyrophosphatase, uridine diphosphatase, inosine diphosphatase, acid phosphatase, and 5'-nucleotidase) as well as a cis-side marker (osmium impregnation). The amount of cerium phosphate formed in the cytochemical reactions was roughly quantitated by stereologic methods. The Golgi apparatus of about 40% of the hepatocytes appeared disorganized after alcohol treatment, and in the other 60%, the electron density of reaction product deposits for all phosphatases investigated was decreased. 5'-Nucleotidase was completely absent in cisternae of Golgi apparatus of treated cells. In control cells impregnated with osmium tetroxide, reduced osmium compounds were observed in most Golgi cisternae and in nearby vesicles. In contrast, only small vesicles appeared positive in treated hepatocytes. These results suggest that prenatal alcohol exposure alters some Golgi functions. Thus, the decrease in nucleoside diphosphatase and 5'-nucleotidase cytochemical activities after ethanol exposure strongly suggests that this treatment could affect glycosylation in the Golgi apparatus of newborn rat hepatocytes.

scholarly journals Association of Alcohol Use Diagnostic Codes in Pregnancy and Offspring Conotruncal and Endocardial Cushion Heart Defects

2022 ◽  
Author(s):  
Drayton C. Harvey ◽  
Rebecca J. Baer ◽  
Gretchen Bandoli ◽  
Christina D. Chambers ◽  
Laura L. Jelliffe‐Pawlowski ◽  
...  
Keyword(s):  
Heart Defects ◽  
Health Planning ◽  
Birth Certificate ◽  
Demographic Factors ◽  
Alcohol Exposure ◽  
Endocardial Cushion ◽  
Diagnostic Codes ◽  
Increased Risk ◽  
Maternal Demographic Factors ◽  
In Pregnancy

Background The pathogenesis of congenital heart disease (CHD) remains largely unknown, with only a small percentage explained solely by genetic causes. Modifiable environmental risk factors, such as alcohol, are suggested to play an important role in CHD pathogenesis. We sought to evaluate the association between prenatal alcohol exposure and CHD to gain insight into which components of cardiac development may be most vulnerable to the teratogenic effects of alcohol. Methods and Results This was a retrospective analysis of hospital discharge records from the California Office of Statewide Health Planning and Development and linked birth certificate records restricted to singleton, live‐born infants from 2005 to 2017. Of the 5 820 961 births included, 16 953 had an alcohol‐related International Classification of Diseases , Ninth and Tenth Revisions (ICD‐9; ICD‐10 ) code during pregnancy. Log linear regression was used to calculate risk ratios (RR) for CHD among individuals with an alcohol‐related ICD ‐9 and ICD10 code during pregnancy versus those without. Three models were created: (1) unadjusted, (2) adjusted for maternal demographic factors, and (3) adjusted for maternal demographic factors and comorbidities. Maternal alcohol‐related code was associated with an increased risk for CHD in all models (RR, 1.33 to 1.84); conotruncal (RR, 1.62 to 2.11) and endocardial cushion (RR, 2.71 to 3.59) defects were individually associated with elevated risk in all models. Conclusions Alcohol‐related diagnostic codes in pregnancy were associated with an increased risk of an offspring with a CHD, with a particular risk for endocardial cushion and conotruncal defects. The mechanistic basis for this phenotypic enrichment requires further investigation.

A novel role for VEGF in endocardial cushion formation and its potential contribution to congenital heart defects

Development ◽  
2001 ◽  
Vol 128 (9) ◽  
pp. 1531-1538 ◽  
Author(s):  
Y. Dor ◽  
T.D. Camenisch ◽  
A. Itin ◽  
G.I. Fishman ◽  
J.A. McDonald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Heart Development ◽  
Heart Defects ◽  
Negative Regulator ◽  
Congenital Defects ◽  
Endocardial Cushion ◽  
Potential Contribution ◽  
Vegf Receptor ◽  
Endocardial Cushions ◽  
Mesenchymal Transformation

Normal cardiovascular development is exquisitely dependent on the correct dosage of the angiogenic growth factor and vascular morphogen vascular endothelial growth factor (VEGF). However, cardiac expression of VEGF is also robustly augmented during hypoxic insults, potentially mediating the well-established teratogenic effects of hypoxia on heart development. We report that during normal heart morphogenesis VEGF is specifically upregulated in the atrioventricular (AV) field of the heart tube soon after the onset of endocardial cushion formation (i.e. the endocardium-derived structures that build the heart septa and valves). To model hypoxia-dependent induction of VEGF in vivo, we conditionally induced VEGF expression in the myocardium using a tetracycline-regulated transgenic system. Premature induction of myocardial VEGF in E9.5 embryos to levels comparable with those induced by hypoxia prevented formation of endocardial cushions. When added to explanted embryonic AV tissue, VEGF fully inhibited endocardial-to-mesenchymal transformation. Transformation was also abrogated in AV explants subjected to experimental hypoxia but fully restored in the presence of an inhibitory soluble VEGF receptor 1 chimeric protein. Together, these results suggest a novel developmental role for VEGF as a negative regulator of endocardial-to-mesenchymal transformation that underlies the formation of endocardial cushions. Moreover, ischemia-induced VEGF may be the molecular link between hypoxia and congenital defects in heart septation.

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