Development Of Congenital Heart Defects Research Articles

Atractylenolide-I Alleviates Hyperglycemia-Induced Heart Developmental Malformations through Direct and Indirect Modulation of the STAT3 Pathway

BackgroundGestational diabetes could elevate the risk of congenital heart defects (CHD) in infants, and effective preventive and therapeutic medications are currently lacking. Atractylenolide-I (AT-I) is the active ingredient of Atractylodes Macrocephala Koidz (known as Baizhu in China), which is a traditional pregnancy-supporting Chinese herb. PurposeIn this study, we investigated the protective effect of AT-I on the development of CHD in embryos exposed to high glucose (HG). Study design and MethodsFirst, systematic review search results revealed associations between gestational diabetes mellitus (GDM) and cardiovascular malformations. Subsequently, a second systematic review indicated that heart malformations were consistently associated with oxidative stress and cell apoptosis. We assessed the cytotoxic impacts of Atractylenolide compounds (AT-I, AT-II, and AT-III) on H9c2 cells and chick embryos, determining an optimal concentration of AT-I for further investigation. Second, immunofluorescence, western blot, Polymerase Chain Reaction (PCR), and flow cytometry were utilized to delve into the mechanisms through which AT-I mitigates oxidative stress and apoptosis in cardiac cells. Molecular docking was employed to investigate whether AT-I exerts cardioprotective effects via the STAT3 pathway. Then, we developed a streptozotocin-induced diabetes mellitus (PGDM) mouse model to evaluate AT-I's protective efficacy in mammals. Finally, we explored how AT-I protects hyperglycemia-induced abnormal fetal heart development through microbiota analysis and untargeted metabolomics analysis. ResultsThe study showed the protective effect of AT-I on embryonic development using a chick embryo model which rescued the increase in the reactive oxygen species (ROS) and decrease in cell survival induced by HG. We also provided evidence suggesting that AT-I might directly interact with STAT3, inhibiting its phosphorylation. Further, in the PGDM mouse model, we observed that AT-I not only partially alleviated PGDM-related blood glucose issues and complications but also mitigated hyperglycemia-induced abnormal fetal heart development in pregnant mice. This effect is hypothesized to be mediated through alterations in gut microbiota composition. We proposed that dysregulation in microbiota metabolism could influence the downstream STAT3 signaling pathway via EGFR, consequently impacting cardiac development and formation. ConclusionsThis study marks the first documented instance of AT-I's effectiveness in reducing the risk of early cardiac developmental anomalies in fetuses affected by gestational diabetes. AT-I achieves this by inhibiting the STAT3 pathway activated by ROS during gestational diabetes, significantly reducing the risk of fetal cardiac abnormalities. Notably, AT-I also indirectly safeguards normal fetal cardiac development by influencing the maternal gut microbiota and suppressing the EGFR/STAT3 pathway.

Діти з дефектами генів - група ризику щодо розвитку аномалій серцево-судинної системи

To date, the prevalence of congenital heart defects (CHD), the level of disability and mortality from them in children remains an unsolved problem in pediatrics, despite the improvement of preventive measures, diagnostics and treatment in pediatric cardiology. There are a number of genetic diseases that are manifested by congenital anomalies of the cardiovascular system. Purpose - to analyze the abnormalities of the cardiovascular system in children with gene defects for the early diagnosis of genetic diseases in patients and the detection of congenital pathology of the heart and blood vessels in them, followed by their treatment tactics. This article describes a number of genetic syndromes in children, in which congenital anomalies of the heart and blood vessels are the most common. The characteristics of each of the syndromes include its definition, clinical symptoms with an emphasis on the external signs of the patient, the study of abnormalities of the cardiovascular system in this genetic disease, the examination plan for the patient and genetic testing used for the accuracy of the diagnosis. Conclusions. Based on the results of our analysis, we can conclude that there is a certain regularity between genetic diseases in children and the development of CHD in them, according to which certain CHD are formed with certain gene defects. Knowledge of the main clinical symptoms, especially external dysmorphism, in such patients helps in faster diagnosis and treatment of a genetic disease, in particular CHD. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Modulation of cAMP/cGMP signaling as prevention of congenital heart defects in Pde2A deficient embryos: a matter of oxidative stress

Phosphodiesterase 2A (Pde2A) is a dual-specific PDE that breaks down both cAMP and cGMP cyclic nucleotides. We recently highlighted a direct relationship between Pde2A impairment, a consequent increase of cAMP, and the appearance of mouse congenital heart defects (CHDs). Here we aimed to characterize the pathways involved in the development of CHDs and in their prevention by pharmacological approaches targeting cAMP and cGMP signaling. Transcriptome analysis revealed a modulation of more than 500 genes affecting biological processes involved in the immune system, cardiomyocyte development and contractility, angiogenesis, transcription, and oxidative stress in hearts from Pde2A−/− embryos. Metoprolol and H89 pharmacological administration prevented heart dilatation and hypertabeculation in Pde2A−/− embryos. Metoprolol was also able to partially impede heart septum defect and oxidative stress at tissue and molecular levels. Amelioration of cardiac defects was also observed by using the antioxidant NAC, indicating oxidative stress as one of the molecular mechanisms underpinning the CHDs. In addition, Sildenafil treatment recovered cardiac defects suggesting the requirement of cAMP/cGMP nucleotides balance for the correct heart development.

A Pilot Study of Multiplex Ligation-Dependent Probe Amplification Evaluation of Copy Number Variations in Romanian Children with Congenital Heart Defects.

Congenital heart defects (CHDs) have had an increasing prevalence over the last decades, being one of the most common congenital defects. Their etiopathogenesis is multifactorial in origin. About 10-15% of all CHD can be attributed to copy number variations (CNVs), a type of submicroscopic structural genetic alterations. The aim of this study was to evaluate the involvement of CNVs in the development of congenital heart defects. We performed a cohort study investigating the presence of CNVs in the 22q11.2 region and GATA4, TBX5, NKX2-5, BMP4, and CRELD1 genes in patients with syndromic and isolated CHDs. A total of 56 patients were included in the study, half of them (28 subjects) being classified as syndromic. The most common heart defect in our study population was ventricular septal defect (VSD) at 39.28%. There were no statistically significant differences between the two groups in terms of CHD-type distribution, demographical, and clinical features, with the exceptions of birth length, weight, and length at the time of blood sampling, that were significantly lower in the syndromic group. Through multiplex ligation-dependent probe amplification (MLPA) analysis, we found two heterozygous deletions in the 22q11.2 region, both in patients from the syndromic group. No CNVs involving GATA4, NKX2-5, TBX5, BMP4, and CRELD1 genes were identified in our study. We conclude that the MLPA assay may be used as a first genetic test in patients with syndromic CHD and that the 22q11.2 region may be included in the panels used for screening these patients.

The use of high-resolution SNP arrays to detect congenital cardiac defects

Objective Copy number variations (CNVs) detected by high-resolution single nucleotide polymorphism microarrays (SNP arrays) have been associated with congenital heart defects (CHDs). The genetic mechanism underlying the development of CHDs remains unclear. Methods High-resolution SNP arrays were used to detect CNVs and traditional chromosomal analyses, respectively, were carried out on 60 and 249 fetuses from gestational 12–37 weeks old, having isolated or complex CHDs that were diagnosed using prenatal ultrasound. Results Twenty of the 60 fetuses (33.5%) had abnormalities, of which 23 CNVs (12 pathogenic, five probable pathogenic and six of undetermined significance) were detected by SNP arrays, and two distinct CNVs were present in three of these fetuses. In addition, in 39 patients with isolated congenital heart disease who had normal karyotypes, abnormal CNVs were present in 28.2% (11/39), and in patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. In patients with complex coronary artery disease, 19.0% (4/21) had abnormal karyotypes and 42.9% (9/21) had abnormal CNVs. Conclusions In conclusion, genome-wide high-resolution SNP array can improve the diagnostic rate and uncover additional pathogenic CNVs. The submicroscopic deletions and duplications of Online Mendelian Inheritance in Man (OMIM) genes found in this study have haploinsufficient (deletion) or triplosensitive (duplication) traits, which further clarify the etiology and inheritance of CHDs.

Abstract P1005: Parallel Identification Of Gene-Environment Interactions In Cardiac Development Using Human Induced Pluripotent Stem Cells

Most human diseases are influenced by both genetic factors and environmental factors. However, it is not easy to identify causative combinations of genes and environmental factors that interplay in disease development. Congenital heart defects (CHDs), which is the most common birth defect occurring 1% of newborns in the US, are primarily caused by genetic mutations. On the other hand, phenotypes of CHDs are typically inconsistent among individuals with the same variants and the penetrance is often incomplete, which suggests the important role of environmental factors. Environmental factors known to be involved in the development of CHDs include maternal smoking, diabetes, inflammation, and use of certain medications. Here, we investigated gene-environmental interactions in cardiac development. First, we developed a CRISPR-screen system that screens essential genes in cardiac differentiation from human induced pluripotent stem cells (iPSCs). Our custom CRISPRi library targets ~ 700 genes, which are enriched in human adult or fetal hearts. Our screen system successfully identified positive control genes such as TNNT2, TNNC1, and TBX20 as well as genes that have not been intensively investigated in human cardiac development such as BAMBI and SMAD6. Second, to identify gene-environment interactions, we used the system under the exposure to various environmental stresses such as nicotine, ethanol, inflammatory cytokines, and multiple teratogenic drugs and identified stress-specific gene-environment interactions. This approach is applicable to any other screens of gene-environment interactions.

Abstract P1169: BubR1 Regulates Cardiac Development Through CamkII In Vivo

Congenital heart defects (CHD), which represent the most common type of congenital defects, are found in 8 out of 1000 births each year in the US. Aneuploidy, defined as an abnormal number of chromosomes in a cell, is the largest contributor to CHD. Defects in mitotic regulators can promote aneuploidy. For instance, mutations in the mitotic checkpoint protein BubR1 can lead to mosaic variegated aneuploidy (MVA). MVA patients display varied phenotypes including growth deficiency and a shortened lifespan. In addition, some patients develop CHDs such as atrioventricular septal defects. To determine whether BubR1 regulates cardiac development we carried out timed matings to harvest heart tissue at various embryonic stages. We found that BubR1 expression dramatically increases in the mouse heart through embryonic development. We engineered a conditional BubR1 knockout mouse model using the Cre-lox system which allows for the generation of cardiac-specific BubR1 knockout animals when crossing this BubR1 fl/fl mice to Nkx2.5-cre mice, which mediates deletion of BubR1 beginning at E7.5. Interestingly, we did not observe any homozygous cardiac-specific BubR1 knockout mice in newborn litters, suggesting that loss of BubR1 in the developing heart is embryonic lethal (n = 120, P < 0.01). We observed that deletion of BubR1 in the embryonic heart leads to cardiac malformations including the absence of trabeculations and reduction in the size of ventricles. Immunofluorescence studies reveal that cardiac-specific BubR1 knockout embryos have an increase in cell death as measured by the apoptosis marker cleaved-caspase 3. These embryos also show an increase in the apoptosis regulator CaMKII, whose upregulation has been previously tied to an increase in cardiomyocyte apoptosis. Therefore, we conclude that BubR1 suppresses the expression of CaMKII in the developing heart to regulate apoptosis during cardiogenesis. Taken together, our data suggest that BubR1 is a critical regulator for cardiac development in vivo , and its mutation or loss may contribute to the development of CHDs.

Maternal exposure to fine particulate matter and congenital heart defects during preconception and pregnancy period: A cohort-based case-control study in the Taiwan maternal and child health database

BackgroundFew studies have explored the association between maternal exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM2.5) and congenital heart defects occurring before and during pregnancy. We aimed to investigate the association and the critical time windows between the maternal exposure to PM2.5 and congenital heart defects. MethodWe conducted a cohort-based case-control study of 507,960 participants obtained from the Taiwan Maternal and Child Health Database between 2004 and 2015. We applied satellite-based spatiotemporal models with 1-km resolution to calculate the average PM2.5 concentration during preconception and the specific periods of pregnancy. We also performed conditional logistic regression with distributed lag non-linear models (DLNMs) to assess the effects of weekly average PM2.5 on both congenital heart defects and their isolated subtypes, as well as the concentration-response relationships. ResultsIn DLNMs, exposure to PM2.5 (per 10 μg/m3) during weeks 7–12 before conception and weeks 3–9 after conception was associated with congenital heart defects. The strongest association at 12 weeks before conception (odds ratio [OR] = 1.026, 95% confidence intervals [CI]: 1.012–1.040) and 7 weeks after conception (OR = 1.024, 95% CI: 1.012–1.036) for every 10 μg/m3 increase in PM2.5 concentration. In modification analysis, strongest associations were observed for low SES. ConclusionsOur study revealed that exposure to ambient PM2.5 raises the risk of congenital heart defects, particularly among individuals with lower socioeconomic status. Moreover, our findings suggest that preconception exposure to PM2.5 may be a crucial period for the development of congenital heart defects.

Transcriptional associations between maternal pregestational diabetes, congenital heart defects, and the human placenta

A critical role has been recognized for the placenta in the development of congenital heart defects (CHD), for which infants of pregestationally diabetic (PGDM) mothers are at pronounced risk. PGDM induces stark histological and gross anatomical changes in the placenta, yet little is known about the PGDM placenta’s role in CHD. High-throughput transcriptomic processes have enabled large-scale association between the gene expression signatures of the heart, placenta, and diabetic state. However, limited integrative data exists, necessitating a comparative appraisal of existing literature to identify placental and cardiac signaling pathways that may be altered in the PGDM state.

Relationship of MTHFD1 G1958A and CBS 844ins68 polymorphism with congenital heart defects in North Indian population (Jammu and Kashmir): A case-control study

Objectives: There are many multifactorial causes for Congenital Heart Defects (CHDs) in which both genetic and non-genetic factors play role. MTHFD1 and CBS are two of the key enzymes that plays pivotal role in the metabolic pathway of homocysteine. Most of the studies revealed that genes involved in folate/homocysteine pathways are involved in the occurrence of CHDs. The present study was planned to investigate the role of common polymorphisms in MTHFD1 and CBS gene in children with CHD in Jammu region of Jammu and Kashmir UT. Material and Methods: A total of 160 (80 CHD patients and 80 controls) children were enrolled for the present case-control study. After extraction of genomic DNA genotyping of SNP MTHFD1 G1958A(rs2236225) was done by PCR-RFLP and CBS 844ins68 polymorphism was done by PCR technique. Results: Our results show that there is no significant association between MTHFD1G1958A and CBS 844ins68 polymorphism with CHD. In case of SNP MTHFD1 G1958A allele A found to be higher in both patient and control group and inCBS 844ins68 polymorphism frequency of risk allele ‘I’ found higher in cases (0.06) as compared to controls (0.04). The homozygous genotype for 844ins68 (II) was found absent in both the patients and control group. Conclusion: We conclude that both MTHFD1 G1958A and CBS 844ins68 polymorphism were not found to be genetic risk factor in the development of CHD in population of Jammu region of Jammu and Kashmir UT.

Congenital heart disease in a patient with COVID-19 infection during early pregnancy: a case report

BackgroundSince the end of 2019, the world has been afflicted by a coronavirus pandemic caused by coronavirus 2 (severe acute respiratory syndrome) (SARS-CoV-2). COVID-19 causes a wide range of signs and symptoms with varying consequences. The impact of the COVID-19 infection on pregnant women and their fetuses is still under investigation.Case presentationA case of a 34-years-old non-vaccinated pregnant woman who had a COVID-19 infection in the first month of her pregnancy and went into premature labor at 34 weeks was reported. Congenital heart disease and hydrops were present in the fetus. The infant girl was cyanotic after delivery, experienced bradycardia, and was in poor overall condition; she was admitted to the NICU and died 5 days later.ConclusionsSome theories suggest that SARS-CoV-2 may be transmitted vertically from mother to fetus. Congenital abnormalities can be caused by a variety of viruses. Although, congenital heart diseases can occur due to different causes, we suggest that COVID-19 may play a role in the development of congenital heart defects.

A Common Polymorphism in the MTHFD1 Gene Is a Modulator of Risk of Congenital Heart Disease.

Several environmental and genetic factors may influence the risk of congenital heart defects (CHDs), which can have a substantial impact on pediatric morbidity and mortality. We investigated the association of polymorphisms in the genes of the folate and methionine pathways with CHDs using different strategies: a case–control, mother–child pair design, and a family-based association study. The polymorphism rs2236225 in the MTHFD1 was confirmed as an important modulator of CHD risk in both, whereas polymorphisms in MTRR, FPGS, and SLC19A1 were identified as risk factors in only one of the models. A strong synergistic effect on the development of CHDs was detected for MTHFD1 polymorphism and a lack of maternal folate supplementation during early pregnancy. A common polymorphism in the MTHFD1 is a genetic risk factor for the development of CHD, especially in the absence of folate supplementation in early pregnancy.

Association between Maternal Drug Use and Cytochrome P450 Genetic Polymorphisms and the Risk of Congenital Heart Defects in Offspring

ObjectiveThis study aimed to assess the associations between maternal drug use, cytochrome P450 (CYP450) genetic polymorphisms, and their interactions with the risk of congenital heart defects (CHDs) in offspring. MethodsA case-control study involving 569 mothers of CHD cases and 652 controls was conducted from November 2017 to January 2020. ResultsAfter adjusting for potential confounding factors, the results show that mothers who used ovulatory drugs (adjusted odds ratio [aOR] = 2.12; 95% confidence interval [CI]: 1.08–4.16), antidepressants (aOR = 2.56; 95% CI: 1.36–4.82), antiabortifacients (aOR = 1.55; 95% CI: 1.00–2.40), or traditional Chinese drugs (aOR = 1.97; 95% CI: 1.26–3.09) during pregnancy were at a significantly higher risk of CHDs in offspring. Maternal CYP450 genetic polymorphisms at rs1065852 (A/T vs. A/A: OR = 1.53, 95% CI: 1.10–2.14; T/T vs. A/A: OR = 1.57, 95% CI: 1.07–2.31) and rs16947 (G/G vs. C/C: OR = 3.41, 95% CI: 1.82–6.39) were also significantly associated with the risk of CHDs in offspring. Additionally, significant interactions were observed between the CYP450 genetic variants and drug use on the development of CHDs. ConclusionsIn those of Chinese descent, ovulatory drugs, antidepressants, antiabortifacients, and traditional Chinese medicines may be associated with the risk of CHDs in offspring. Maternal CYP450 genes may regulate the effects of maternal drug exposure on fetal heart development.

THE ROLE OF GENETICS IN THE UNDERSTANDING OF COMPLEX CONGENITAL HEART DISEASES

One of the most dynamic organs in the human body is the heart. Cardiac development is regulated by two key factors including signaling and transcriptional pathways. Thus, during the development of the fetus, any factor that disrupts the normal functioning of these factors may lead toward congenital heart defects (CHDs). Congenital heart disease is a complex multifactorial disease that involves both environmental and genetic factors.1,2 It is defined as any defect that occurs during heart development either in the cardiac structure or its associated vessels.3 Globally, it is one of the most common reasons for infant mortality and one of the most common birth defects in paediatric patients. As a rough estimate, 8 infants in every thousand live births are born with this fatal disease.4 Every year, in Pakistan approximately 40,000 children suffered from CHDs.5 Clinically depending upon the disease severity congenital heart diseases can be divided into two major subgroups one is non-syndromic and the other is syndromic. And among all these defects cardiac septation defects are the most common accounting for approximately 50% of the cases.6 It can be further sub-grouped as isolated lesions or complex diseases in combination with other heart defects.3 The exact mechanism involved in the pathogenesis of the congenital heart remains poorly understood but the most probable mechanism is multifactorial. Recent investigations suggest the role of epigenetic factors, micro RNA and small non-coding RNAs in the development of congenital heart defects. Moreover, advancements in molecular techniques including next-generation sequencing (NGS) helps in further detecting the genetic causes of CHDs such as the novel single nucleotide polymorphisms (SNPs) and copy number variants (CNVs).7 The current approaches used for genetic diagnosis of paediatric patients suffering from CHDs include karyotype analysis, copy number variation analysis, next-generation sequencing, and whole-genome or whole-exome sequencing. The targeted NGS relies on the selected region of know gene of interest and compared to whole genome or exome sequencing it provides us deeper gene coverage with easy variant detection at a lower cost. It provides robust detection of deletions, insertion and single nucleotide polymorphisms which chromosomal microarray analysis (CMA) and karyotyping cannot detect. To date, many pathogenic variants in different genes such as CITED2, CHD7, ZFPM2, MYH6 and KMT2D have been investigated by using targeted NGS. While whole-exome or genome sequencing help in the discovery of genes involves in the pathogenesis of congenital heart defects as it gives us more resolution at a single base-pair level. Thus accurate genetic diagnosis can be done by using the appropriate diagnostic techniques that can ultimately help in better patient counseling and clinical outcome.8 Furthermore, personalized medicines or finding mutations responsible for individual congenital heart disease patients can direct to better outcomes and approaches for each cardiac malformation phenotype. Thus, ultimately combined data of patients genotypic and phenotypic following well-designed guidelines will accelerate the translation of each SNP information into better treatment and clinical insights.9 Keywords: NGS, Single nucleotide polymorphisms, CHDs.

Tendencies congenital heart diseases surgical correction. Ten years experience of Amosov National Institute of Cardiovascular Surgery.

Aim: To analyze the experience of treatment of congenital heart disease. Identify the proportions and ratios of surgical and endovascular treatments. Development of diagnostic service. To determine the impact of industry funding mechanisms on the development of endovascular surgery for congenital heart disease. Materials and methods: The tendencies of cardiac surgery development of congenital heart defects on the basis of the analysis of endovascular and surgical methods of treatment are considered. Own results of 10 years of experience in the treatment of congenital heart disease are presented. Results: An increase in the proportion of endovascular methods and a decrease in surgical treatments. The obtained data show a rapid increase in the share of medical procedures (from 48.9% to 89.4%) and a sharp decline in the share of diagnostic procedures (from 51.1% to 10.6%) in endovascular surgery. Early mortality after cardiac surgery in children is <5%, mortality after edovascular interventions - <1%. Ultrasound examination (ultrasound) of the heart - allows to detect 95% of all congenital heart defects and is shown to every citizen as a screening method. The influence of industry financing mechanisms on the development of endovascular surgery of congenital heart defects is shown. Expensive equipment began to be purchased at public expense, the number of equipment representatives on the market increased and, as a result, the number of endovascular procedures increased. Over the past 5 years, public funding for the needs of the industry has increased from 16 to 75%. Conclusions: Today, pediatric cardiology and cardiac surgery are reaping the fruits of the golden age in medical science. With the development of cardiac surgery, the number of operated patients increases every year. The successful outcome of treatment of patients with CHD depends on a comprehensive multidisciplinary team (Heart Team). New evidence-based approaches in resuscitation management allow to recover as soon as possible after the intervention. We see further development of the industry in the development of multidisciplinary teams to help patients with the CHD. Finally, we expect an increase in the regulatory burden and the cost of developing new treatments and diagnostics. Key words: congenital heart defects, endovascular methods, open heart operations, minimally invasive interventions, critical heart defects.

Numerical Investigation of the Fetal Left Heart Hemodynamics During Gestational Stages.

Flow-driven hemodynamic forces on the cardiac tissues have critical importance, and have a significant role in the proper development of the heart. These mechanobiological mechanisms govern the cellular responses for the growth and remodeling of the heart, where the altered hemodynamic environment is believed to be a major factor that is leading to congenital heart defects (CHDs). In order to investigate the mechanobiological development of the normal and diseased hearts, identification of the blood flow patterns and wall shear stresses (WSS) on these tissues are required for an accurate hemodynamic assessment. In this study, we focus on the left heart hemodynamics of the human fetuses throughout the gestational stages. Computational fetal left heart models are created for the healthy fetuses using the ultrasound images at various gestational weeks. Realistic inflow boundary conditions are implemented in the models using the Doppler ultrasound measurements for resolving the specific blood flow waveforms in the mitral valve. Obtained results indicate that WSS and vorticity levels in the fetal left heart decrease with the development of the fetus. The maximum WSS around the mitral valve is determined around 36 Pa at the gestational week of 16. This maximum WSS decreases to 11 Pa at the gestational week of 27, indicating nearly three-times reduction in the peak shear stress. These findings reveal the highly dynamic nature of the left heart hemodynamics throughout the development of the human fetus and shed light into the relevance of hemodynamic environment and development of CHDs.

Association of maternal dietary habits and ADIPOQ gene polymorphisms with the risk of congenital heart defects in offspring: a hospital-based case-control study.

To estimate the association of maternal ADIPOQ gene, dietary habits in early pregnancy, and their interactions with the risk of congenital heart defects (CHDs) in offspring. A case-control study of 464 mothers of CHDs children and 504 mothers of healthy children was included. Maternal dietary habits and genetic polymorphisms of ADIPOQ were the main exposure of interest. Their independent effects and interactions in the development of CHDs were analyzed in our study. The excessive consumption of pickled vegetables (aOR = 1.58, 95%CI: 1.17-2.12), smoked foods (aOR = 1.84, 95%CI:1.34-2.52), barbecued foods (aOR = 1.62, 95%CI: 1.09-2.39), fish and shrimp (aOR = 0.37, 95%CI: 0.27-50), and milk products (aOR = 0.64, 95%CI: 0.51-80) had a significant association with total CHDs risk. The polymorphisms of ADIPOQ gene at rs1501299 (T/T vs G/G: aOR = 0.27, 95%CI: 0.14-50; G/T vs G/G: aOR = 0.67, 95%CI: 0.46-98) and rs2241766 (G/G vs T/T: aOR = 4.35, 95%CI: 2.23-8.51; T/G vs T/T: aOR = 2.23, 95%CI: 1.51-3.28) showed a significant association with total CHDs risk. Likewise, our results found that maternal dietary habits and ADIPOQ genetic variants also were significantly related to the risk of specific CHDs phenotypes. In addition, gene-diet interaction revealed significant associations between the ADIPOQ gene and maternal dietary habits with total CHDs. Maternal dietary habits, ADIPOQ gene, and their interactions show a significant association with the risk of CHDs. However, our study has some limitations, thus our findings need to be taken with caution, which highlights that more studies are required to further corroborate our findings.

Passive Smoking and Congenital Heart Defects in Offspring among Bangladesh

Objective: Maternal active smoking is significantly associated with an increased risk of congenital heart defects (CHDs), but the association between maternal passive smoking and risk of CHDs is inconclusive. This study was conducted to evaluate the effect of passive smoking and the risk of development of CHD among Bangladeshi population. Methodology: It was a case control study, conducted from July 2018 to July 2019 in Paediatric Cardiology department of Dhaka Shishu (Children) Hospital. Parents of the children with CHD visiting the out-patient department of Dhaka Shishu Hospital was considered as cases. Controls were taken from parents of the children who don’t have congenital heart disease. Face-to-face interviews were conducted to collect information on maternal active and passive smoking. Data was collected by using a structured questionnaire containing all the variables of interest and analyzed by using SPSS version 21. Chi square test (ꭓ2), Odds ratio (OR) and 95% confidence intervals (CIs) were calculated to estimate the associations between maternal passive smoking and all CHDs. Risk factors on bivariate analysis were introduced into a logistic regression model as independent factors and dependent variable was CHDs to find out the association between CHDs and maternal passive smoking. Results: Among case group no mother was active smoker, 51.9% were passive smoker and most of the cases source was husband, 19.6% took smokeless tobacco or green tobacco, 55.8% took tea and 5.8% took coffee during pregnancy period. On logistic regression analysis passive smoking (p=0.019) was independently associated with CHDs. Mother with passive smoking exposure had 1.5 times risk of developing CHDs compared to those who were not exposed. Conclusions: Passive smoking is significantly associated with CHDs.

Discordant congenital heart defects in monochorionic twins: Risk factors and proposed pathophysiology.

A six-fold increase in congenital heart defects (CHD) exists among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share an identical genotype, discordant phenotypes related to CHD and other malformations have been described, with reported rates of concordance for various congenital anomalies at less than 20%. Our objective was to characterize the frequency and spectrum of CHD in a contemporary cohort of MC twins, coupled with genetic and clinical variables to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 -March 2020 (N = 163) yielded 23 MC twin pairs (46 neonates) with CHD (n = 5 concordant CHD, n = 18 discordant CHD). The most common lesions were septal defects (60% and 45.5% in concordant and discordant cohorts, respectively) and right heart lesions (40% and 18.2% in concordant and discordant cohorts, respectively). Diagnostic genetic testing was abnormal for 20% of the concordant and 5.6% of the discordant pairs, with no difference in rate of abnormal genetic results between the groups (p = 0.395). No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data demonstrates the possibility of environmental and epigenetic influences versus genotypic factors in the development of discordant CHD in monochorionic twins.

148 Discordant congenital heart defects in monochorionic twins: risk factors and proposed pathophysiology

There is a six-fold increase in congenital heart defects (CHD) among monochorionic (MC) twins compared to singleton or dichorionic twin pregnancies. Though MC twins share a genotype, discordant phenotypes related to CHD have been described. Our objective was to characterize the spectrum of CHD in MC twins in the context of genetic results and clinical demographics for a modern cohort to provide insight into risk factors and pathophysiology of discordant CHD in MC twins. Retrospective analysis of all twins receiving prenatal fetal echocardiography at a single institution from January 2010 – March 2020 (N=163) yielded 24 MC twin pairs (48 neonates) with CHD (n=6 concordant CHD, n=18 discordant CHD). Descriptive analysis including frequencies, means, and standard deviations were conducted for all maternal, CHD diagnoses, and neonatal variables. Continuous variables were analyzed using the Student t-test and categorical variables were analyzed using the Fisher Exact test. The most common lesions were septal defects (50% and 45% in concordant and discordant cohort) and right heart lesions (33% and 18% in concordant and discordant cohort). Diagnostic genetic testing was abnormal for 17% of the concordant and 6% of the discordant pairs, with no difference between the groups (p=0.45). Six (25%) twin pairs, 2 concordant and 4 discordant, were complicated by twin-to-twin transfusion syndrome, with all recipient twins acquiring diagnosis of CHD and no twins with abnormal genetic testing. No significant association was found between clinical risk factors and development of discordant CHD (p>0.05). This data supports environmental and epigenetic influences versus genotypic factors in the development of discordant CHD, pertinent for early diagnosis and postnatal prognosis. This is illustrated by the higher rates of discordant (75%) versus concordant (25%) CHD in MC twin pairs in this population, low incidence of family history of CHD, and the low incidence of genetic abnormalities (8.3%) in our MC cohort with CHD.