Congenital Heart Disease Subtypes Research Articles

Variants in FOXC1 and FOXC2 identified in patients with conotruncal heart defects

Conotruncal heart defects (CTD), subtypes of congenital heart disease, result from abnormal cardiac outflow tract development (OFT). FOXC1 and FOXC2 are closely related members of the forkhead transcription factor family and play essential roles in the development of OFT. We confirmed their expression pattern in mouse and human embryos, identifying four variants in FOXC1 and three in FOXC2 by screening these two genes in 605 patients with sporadic CTD. Western blot demonstrated expression levels, while Dual-luciferase reporter assay revealed affected transcriptional abilities for TBX1 enhancer in two FOXC1 variants and three FOXC2 variants. This might result from the altered DNA-binding abilities of mutant proteins. These results indicate that functionally impaired FOXC1 and FOXC2 variants may contribute to the occurrence of CTD.

Diagnostic yield after next-generation sequencing in pediatric cardiovascular disease

Genetic testing with exome sequencing and genome sequencing is increasingly offered to infants and children with cardiovascular diseases. However, the rates of positive diagnoses after genetic testing within the different categories of cardiac disease and phenotypic subtypes of congenital heart disease (CHD) has been little studied. We report the diagnostic yield after next-generation sequencing in 500 patients with CHD from diverse population subgroups that were enrolled at three different sites in the Clinical Sequencing Evidence-Generating Research consortium. Patients were ascertained due to a primary cardiovascular issue comprising arrhythmia, cardiomyopathy and/or CHD and corresponding human phenotype ontology terms were selected to describe the cardiac and extracardiac findings. We examined the diagnostic yield for patients with arrhythmia, cardiomyopathy and/or CHD and phenotypic subtypes of CHD comprising conotruncal defects, heterotaxy, left ventricular outflow tract obstruction, septal defects, and ‘Other’ heart defects. We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing and for syndromic cardiac defects compared to isolated cardiac defects. We also found significantly higher diagnostic rates for patients who presented with isolated cardiomyopathy compared to isolated CHD. For patients with syndromic presentations who underwent genome sequencing, there were significant differences in the numbers of positive diagnoses for phenotypic subcategories of CHD, ranging from 31.7% for septal defects to 60% for Other. Despite variation in the diagnostic yield at each site, our results support genetic testing in pediatric patients with syndromic and isolated cardiovascular issues and in all subtypes of CHD.

Maternal and neonatal outcomes in women with congenital heart disease: A nationwide population-based study

BackgroundWe evaluated the outcomes of pregnancy in women with congenital heart disease (CHD) and their offspring in Taiwan. We also investigated how different severity levels may influence the outcomes. MethodsWe used data (2009–2017) from the Birth Certificate Application database in Taiwan, which is linked to the National Health Insurance Research Database and Taiwan Maternal and Child Health Database. We identified 2990 women with CHD who had 4227 births. Based on the CHD subtypes, patients were further divided into “severe CHD” and “simple CHD” groups. ResultsWomen with CHD have a significant risk of stillbirth. In maternal cardiac events, they had the highest risk of heart failure, followed by arrhythmia. The severity of CHD had a significant effect on the outcomes as well. The neonatal birth event that mothers with CHD have the highest risk of is preterm birth at < 32 weeks of gestation. The prominent difference in neonatal morbidities between mothers with severe and simple CHD is recurrent CHD in the offspring. The offspring of the severe CHD group had a higher risk of severe CHD, whereas those of the simple CHD group had a higher risk of simple CHD. ConclusionsDuring pregnancy, the monitoring of heart function and cardiac rhythm could be more intensive in mothers with CHD. In addition to accurately assessing fetal growth and development during antenatal care, mothers with severe CHD should be provided with careful fetal heart structure assessment and genetic testing along with counseling.

Effects of 6-month customized home-based exercise on motor development, bone strength, and parental stress in children with simple congenital heart disease: a single-blinded randomized clinical trial

BackgroundNew “noncardiac” problems in children with congenital heart disease (CHD), such as developmental delay or long-term neurodevelopmental impairments, have attracted considerable attention in recent years. It is hypothesized that exercise might attenuate CHD-associated neurodevelopmental impairments; however, this has not been thoroughly investigated. The objective of this prospective, single-blinded, randomized controlled experiment was to evaluate the impact of customized home-based exercise for children with CHD.MethodsChildren aged 0–5 years with echocardiography-confirmed simple CHD subtypes who were scheduled to undergo cardiac catheterization were screened for enrolment. Among 420 screened CHD children, 192 were enrolled and randomly assigned at a 1:1 ratio to receive a 6-month intervention (30 min daily customized home-based exercise program with supervision for no less than 5 days per week, combined with home-based exercise education) or control treatment (home-based education). The primary outcome was motor development (gross motor quotient (GMQ), fine motor quotient (FMQ), and total motor quotient (TMQ)). The secondary outcomes were cardiac function and structure, bone quality, physical development, parental anxiety, caregiver burden, and quality of life. Children and their families were assessed before and 1, 3, and 6 months after catheterization; 183 (95.3%) children were included in the primary analysis.ResultsAfter 6-month treatment, the intervention group significantly increased their motor quotient, which was consistently higher than that of the control group (GMQ p < 0.0001, FMQ p = 0.02, TMQ p < 0.001). The physical developments in height, weight, and circumferences of the upper-arm, chest, and head were also significantly improved by exercise (all p < 0.017). No significant improvements in the bone strength or the cardiac structure and function were found among patients in the intervention group (all p > 0.017). For parents, higher quality of life level (total score p = 0.016) was observed in the intervention group; while effects of exercise on the anxiety (rude score p = 0.159, standard score p = 0.159) or the Zarit caregiver burden scale score (p = 0.404) were non-significant. No adverse events occurred during the study period.ConclusionsCustomized home-based exercise improved motor development in children with CHD. While the long-term effects of parent training in home-based exercise are unknown, the study results suggest positive outcomes.Trial registrationA home-based exercise program in congenital heart disease children with cardiac catheterization: a randomized controlled trial. (http://www.chictr.org.cn/, ChiCTR-IOR-16007762, January 14, 2016).

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.

Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

Lower Socioeconomic Status is Associated with an Increased Incidence and Spectrum of Major Congenital Heart Disease and Associated Extracardiac Pathology.

Several studies have suggested an inverse relationship between lower socioeconomic status (SES) and the incidence of congenital heart disease (CHD) among live births. We sought to examine this relationship further in a Canada-wide population study, exploring CHD subtypes, trends, and associated noncardiac abnormalities. Infants born in Canada (less Quebec) from 2008 to 2018 with CHD requiring intervention in the first year were identified using ICD-10 codes through the Canadian Institute for Health Information Discharge Abstract Database. Births of CHD patients were stratified by SES (census-based income quintiles) and compared against national birth proportions using X2 tests. Proportions with extracardiac defects (ED) and nonlethal genetic syndromes (GS) were also explored. From 2008 to 2018, 7711 infants born with CHD were included. The proportions of major CHD distributed across SES quintiles were 27.1%, 20.1%, 19.2%, 18.6%, and 15.0% from lowest to highest, with significant differences relative to national birth proportions (22.0%, 20.0%, 20.6%, 20.7%, and 16.7% from lowest (1) to highest (5)) (p < 0.0001). No temporal trends in the CHD proportions across SES categories were observed over the study period. The distribution across SES quintiles was different only for specific CHD subtypes (double-outlet right ventricle (n = 485, p = 0.03), hypoplastic left heart syndrome (n = 547, p = 0.006), heterotaxy (n = 224, p = 0.03), tetralogy of Fallot (n = 1007, p = 0.008), truncus arteriosus (n = 126, p < 0.0001), and ventricular septal defect (n = 1916, p < 0.0001)), with highest proportions observed in the lowest quintile. The proportion of the total population with ED but not GS was highest in lower SES quintiles (< 0.0001) commensurate with increased proportion of CHD. Our study suggests a negative association between SES and certain CHD lesions and ED.

Survival After Cardiac Transplantation in Adults With Single-Ventricle Congenital Heart Disease

BackgroundWithout large-scale analyses of adults with single-ventricle congenital heart disease (CHD) undergoing heart transplantation, little evidence exists to guide listing practices and patient counseling. ObjectivesThis study aims to evaluate survival after heart transplantation in adults with single and biventricular CHD and compare it to that of non-CHD transplant recipients. MethodsIn this 15-year (2005-2020) retrospective analysis, outcome-blinded investigators used probability-linkage to merge the National (Nationwide) Inpatient Sample and Organ Procurement and Transplantation Network data sets. ResultsOf 382 adult (≥18 years of age) heart transplant recipients with CHD, 185 (48%) had single-ventricle physiology. Compared to biventricular CHD, single-ventricle patients showed significantly reduced survival at 1 (80% vs 91%; HR: 2.50; 95% CI: 1.40-4.49; P = 0.002) and 10 years (54% vs 71%; HR: 2.10; 95% CI: 1.38-3.18; P < 0.001). Among patients who survived the first post-transplantation year, biventricular CHD patients exhibited similar 10-year survival as single-ventricle patients, except for those with hypoplastic left heart syndrome (79% vs 71%; HR: 1.58; 95% CI: 0.85-2.92; P = 0.15). Additionally, biventricular CHD transplant recipients showed significantly better 10-year conditional survival compared to their non-CHD counterparts (79% vs 68%; HR: 0.73; 95% CI: 0.59-0.90; P = 0.003). ConclusionsAmong adult CHD transplant recipients, single-ventricle physiology correlated with higher short-term mortality. However, 10-year conditional survival was similar for biventricular and most single-ventricle CHD patients, and notably better for biventricular CHD patients compared to non-CHD heart transplant recipients. These findings have significant implications towards patient selection and listing strategies, easing concerns related to heart transplantation in adults with CHD and destigmatizing most subtypes of single-ventricle CHD.

Current status and challenges in prenatal and neonatal screening, diagnosis, and management of congenital heart disease in China.

Congenital heart disease (CHD), a wide spectrum of diseases with varied outcomes, is the most common congenital malformation worldwide. In this Series of three papers, we describe the burden of CHD in China; the development of screening, diagnosis, treatment, and follow-up strategies; and challenges associated with the disease. We also propose solutions and recommendations for policies and actions to improve the outcomes of CHD. In the first paper in this Series, we focus on prenatal and neonatal screening, diagnosis, and management of CHD. Based on advanced international knowledge, the Chinese Government has developed a network system comprising prenatal screening, diagnosis of CHD subtypes, specialist consultation appointments, and treatment centres for CHD. A new professional discipline, fetal cardiology, has been formed and rapidly developed. Consequently, the overall coverage of prenatal and neonatal screening and the accuracy of CHD diagnoses have gradually improved, and the neonatal CHD mortality rate has decreased substantially. However, China still faces several challenges in the prevention and treatment of CHD, such as insufficient diagnostic capabilities and unqualified consultation services in some regions and rural areas. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PO-04-124 ARRHYTHMIAS INCLUDING ATRIAL FIBRILLATION IN KLEEFSTRA SYNDROME: A POSSIBLE EPIGENETIC LINK

Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder (EHMT1 gene: an important epigenetic modulator) that is characterized by hypotonia, developmental delay and distinct facial features. Although congenital heart disease (CHD) is frequently reported, there is a paucity of data on the prevalence of CHD subtypes and arrhythmias in KS; no known reports of Atrial Fibrillation (AF). To systematically assess the prevalence of CHD and arrhythmias in KS. Cross-sectional analysis of the two largest known KS registries: Radboudumc (50 patients, median/IQR age: 13.5/13 years) based on health record review at Radboud University Medical Center in Netherlands, and GenIDA (163 patients, median/IQR age: 10/12 years) based on surveys of patient families from around the world. Case series of 3 additional patients with KS and atrial tachyarrhythmias. Both registries independently report 40% (20 patients in Radboudumc and 65 in GenIDA) prevalence of a cardiovascular system abnormality and 2-8% prevalence of arrhythmias (4 in Radboudumc and 3 in GenIDA). Radboudumc registry included 14% patients with atrial septal defect (ASD), 12% with ventricular septal defect (VSD), 4% patients each with Tetralogy of Fallot and pulmonary valve stenosis, and none with left ventricular dysfunction. The 8% patients with arrhythmias in this registry did not report significant CHD and included one patient with AF, two with supraventricular tachycardias (SVTs), and one with ventricular tachycardia (VT). GenIDA registry reported 1% patients with cardiomyopathy, 10% with VSD, 13% with ASD, 16% with valvular disease, and 9% with vascular malformations. This registry also included one patient with AF and another with chronic ectopic atrial tachycardia with neither patient reporting CHD. A case series of 3 additional KS patients not included in these registries with atrial tachyarrhythmias reveals two patients with AF and one with atrial tachycardia, in the absence of CHD. One patient with symptomatic AF refractory to medications underwent successful pulmonary vein isolation (first known report) at age 23 without recurrence at 16 months. The largest database of KS patients compiled to-date reveals a high prevalence of CHD and early-onset atrial tachyarrhythmias including AF, even in the absence of structural heart disease. These findings suggest a role for regular electrocardiograms and ambulatory rhythm monitoring as well as a possible novel epigenetic mechanism for AF.

Prevalence and Clinical Features of Cardiac Murmur With Its Subtypes of Congenital Heart Disease in Rajshahi, Bangladesh

Congenital heart disease (CHD) is a congenital defect affecting the structure of the heart. Early detection can be done by auscultating the murmur and this could help to diagnosis the disease. This study was aimed to detect CHD by rapid evaluation of clinical features, findings and cardiac auscultation which will help to customize the future management plan in each CHD child and reduce the progression of complications and financial burden associated with CHD on this region over time. This descriptive cross-sectional study was conducted on children hospitalized to the paediatric department. A systematic sampling technique was implemented. Total 3978 children were taken during the study period among them 54 were detected as CHD. Total 3978 children under 10 years were examined during the study. Among them-murmur with CHD was found in 54 (1.36%) cases and it was found that 30 (55.6%) were male and most (53.7%) of them from rural area came from 42.6% middle socio-economic group. It was revealed that, among the study cases 40.70% had ventricular septal defect (VSD), 63% had rapid breathing regarding clinical presentation. Regarding clinical findings among the study cases 33 (61.10%) had chest retractions. Among 54 murmur positive cases 29 (53.70%) had pansystolic murmur which help to assess regarding CHD before completing echo. Congenital heart disease, especially in the newborn era, is a pediatric cardiology emergency due to the high morbidity and mortality rates. This research could aid in the early diagnosis of CHD and save the lives of youngsters. J Bio-Sci. 30(1): 115-121, 2022 (June)

Metabolomics: A New Tool in Our Understanding of Congenital Heart Disease.

Although the genetic origins underpinning congenital heart disease (CHD) have been extensively studied, genes, by themselves, do not entirely predict phenotypes, which result from the complex interplay between genes and the environment. Consequently, genes merely suggest the potential occurrence of a specific phenotype, but they cannot predict what will happen in reality. This task can be revealed by metabolomics, the most promising of the "omics sciences". Though metabolomics applied to CHD is still in its infant phase, it has already been applied to CHD prenatal diagnosis, as well as to predict outcomes after cardiac surgery. Particular metabolomic fingerprints have been identified for some of the specific CHD subtypes. The hallmarks of CHD-related pulmonary arterial hypertension have also been discovered. This review, which is presented in a narrative format, due to the heterogeneity of the selected papers, aims to provide the readers with a synopsis of the literature on metabolomics in the CHD setting.

Deep sequencing unveils altered cardiac miRNome in congenital heart disease.

Congenital heart disease (CHD) surges from fetal cardiac dysmorphogenesis and chiefly contributes to perinatal morbidity and cardiovascular disease mortality. A continual rise in prevalence and prerequisite postoperative disease management creates need for better understanding and new strategies to control the disease. The interaction between genetic and non-genetic factors roots the multifactorial status of this disease, which remains incompletely explored. The small non-coding microRNAs (miRs, miRNAs) regulate several biological processes via post-transcriptional regulation of gene expression. Abnormal expression of miRs in developing and adult heart is associated with anomalous cardiac cell differentiation, cardiac dysfunction, and cardiovascular diseases. Here, we attempt to discover the changes in cardiac miRNA transcriptome in CHD patients over those without CHD (non-CHD) and find its role in CHD through functional annotation. This study explores the miRNome in three most commonly occurring CHD subtypes, namely atrial septal defect (ASD), ventricular septal defect (VSD), and tetralogy of fallot (TOF). We found 295 dysregulated miRNAs through high-throughput sequencing of the cardiac tissues. The bioinformatically predicted targets of these differentially expressed miRs were functionally annotated to know they were entailed in cell signal regulatory pathways, profoundly responsible for cell proliferation, survival, angiogenesis, migration and cell cycle regulation. Selective miRs (hsa-miR-221-3p, hsa-miR-218-5p, hsa-miR-873-5p) whose expression was validated by qRT-PCR, have been reported for cardiogenesis, cardiomyocyte proliferation, cardioprotection and cardiac dysfunction. These results indicate that the altered miRNome to be responsible for the disease status in CHD patients. Our data expand the existing knowledge on the epigenetic changes in CHD. In future, characterization of these cardiac-specific miRs will add huge potential to understand cardiac development, function, and molecular pathogenesis of heart diseases with a prospect of epigenetic manipulation for cardiac repair.

Congenital Heart Disease in Children Living Close to the Former Semipalatinsk Nuclear Test Site: Frequency, Structure, and Links with Connective Tissue Dysplasia

Background: Congenital heart disease (CHD) is the most common serious congenital disorder. CHD is the leading cause of death in the first year of life. One of the factors influencing the incidence of CHD is collagen structural abnormalities such as connective tissue dysplasia (CTD).&#x0D; Aim: To study the prevalence of CHD and its subtypes, to determine the combination of CHD and CTD with minor cardiac abnormalities (MCA).&#x0D; Methods: A retrospective study on the prevalence of CHD in the Republic of Kazakhstan and Semey city and a case-control study in the pediatric clinic of the Medical University Hospital was conducted.&#x0D; With CHD, CTD, and healthy children were included in the study. Children of all groups were examined according to the methodology, which included a collection of medical and family history; clinical examination; assessment of CHD severity. The collected data were then analyzed using SPSS software.&#x0D; Results: The prevalence of CHD in Semey was 6.9 per 1,000 live births. Atrial septal defect and ventricular septal defect were the most common CHD subtypes. The phenotype was represented by the asthenic physique, joint hypermobility, ear anomalies, and scoliosis. MCAs were in children with CHD and CTD. Mitral valve prolapse and left ventricular false tendons were detected most frequently.&#x0D; Conclusion: MCAs detected in children with CTD. CTD is a factor influencing the severity of CHD.

Prevalence of Congenital Heart Disease in Chinese Children With Different Birth Weights and Its Relationship to the Neonatal Birth Weight.

ObjectiveThis study aimed to examine the prevalence and the related risk factors of congenital heart disease (CHD) in children with different birth weights in China and the relationship between the subtypes of CHD and birth weight (BW).MethodsThis study conducted a cross-sectional survey on the data collected in the children’s congenital heart disease database (CHDD) established in China. This database contained data from one Grade A, Level III Children’s Public Hospital in Zhengzhou, Henan. The study included all the children and their parents in the database from 2014 to 2020 as the study subjects, and the missing data were processed by means of imputation. Diagnoses of CHD were coded using the International Classification of Diseases version 10 (ICD-10), and subtypes were classified by the codes Q20 to Q26. We reported the prevalence of CHD based on birth weight and gestational age and analyzed the related risk factors for children with CHD in different birth weight groups and factors for children of the same birth weight groups between the CHD groups and the non-CHD groups. The generalized linear model was used to assess the association between the subtypes of CHD and BW by establishing three adjusting models, and the data were stratified for further analysis by urban-rural and infant gender.ResultsA total of 42,814 children were identified as having CHD among 5,071,799 live children; the overall prevalence of CHD was 8.44 per 1,000 live births during 2014–2020; and the three subtypes with the highest prevalence of CHD were atrial septal defect (ASD) (2.75‰), ventricular septal defect (VSD) (2.57‰), and patent foramen ovale (PFO) (1.12‰). The prevalence of CHD was 18.87‰ in the group with BW <1,500 g, 12.84‰ in the group with BW 1,500–2,500 g, 8.24‰ in the group with BW 2,500–4,000 g, and 4.80‰ in the group with BW ≥4,000 g. The prevalence of CHD was 16.62‰ in the small for gestational age (SGA) group, 6.99‰ in the appropriate for gestational age (AGA) group, and 6.40‰ in the larger for gestational age (LGA) group. Parental factors such as drinking, smoking, viral infections, peri-pregnancy exposure to radioactive substances, low family monthly expenditure, and low Apgar scores at 1 and 5 min were related to the increased risk of CHD in the offspring. Parental supplementation of folic acid and exercise during the peri-pregnancy period could reduce the risk of CHD in the offspring. The results of Model 3 adjusting for confounding variables showed that infants with ASD had a birth weight 461 g lower (95% CI: −1,085, –128), infants with VSD had a birth weight 426 g lower (95% CI: –932, –120), infants with tetralogy of Fallot (TOF) had a birth weight 532 g lower (95% CI: –987, –168), and without classification, infants with CHD had a birth weight 973 g lower (95% CI: –1,502, –204).ConclusionIn very low birth weight (VLBW) and low birth weight (LBW) infants, CHDs are more prevalent than in the general live-born population. Moreover, some peri-pregnancy factors of parents are closely related to the occurrence of CHD in offspring; different types of heart defects can lead to LBW. Therefore, if the fetus is found to have a heart defect during the prenatal examination, the mother should pay more attention to maintaining weight and ensuring that the fetus is within the normal weight range, thereby increasing the postpartum survival rate, reducing complications, and promoting children’s health.

Association between maternal exposure to indoor air pollution and offspring congenital heart disease: a case\u2013control study in East China

BackgroundPrevious research suggested an association between maternal exposure to ambient air pollutants and the risk of congenital heart disease (CHD). However, the effect of individual prenatal exposure to indoor air pollutants on CHD occurrence was not reported.MethodsWe performed a hospital-based case–control study to investigate the association between personal air pollution exposure during pregnancy and the risk of CHD in offspring. A total of 44 cases and 75 controls were included from two hospitals in East China. We investigated maternal and residential environmental characteristics using a questionnaire and obtained personal indoor air samples to assess particulate matter (PM) and volatile organic compounds (VOCs) from 22–30 gestational weeks. Formaldehyde, benzene, toluene, xylene, total volatile organic compounds (TVOCs), PM2.5, and PM10 were assessed. Logistic regression was performed to assess associations and interactions between individual indoor air pollutants and CHD after adjusting for confounders. The potential residential environmental factors affecting the risks of indoor air pollutants on CHD were also assessed.ResultsMedian TVOC (0.400 vs. 0.005 mg/m3, P < 0.001) exposure levels in cases were significantly higher than controls. A logistic regression model adjusted for confounders revealed that exposure to high levels of indoor TVOCs (AOR 7.09, 95% CI 2.10–23.88) during pregnancy was associated with risks for CHD and the occurrence of some major CHD subtype in offspring. These risk effects were enhanced in pregnant women living in a newly renovated house but were mitigated by household use of smoke ventilators when cooking. We observed a positive interaction of maternal exposure to TVOCs and PM2.5 and the risk for CHD.ConclusionsMaternal exposure to indoor VOCs and PMs may increase the risk of giving birth to foetuses with CHD.

Translational potential of hiPSCs in predictive modeling of heart development and disease.

Congenital heart disease (CHD) represents a major class of birth defects worldwide and is associated with cardiac malformations that often require surgical intervention immediately after birth. Despite the intense efforts from multicentric genome/exome sequencing studies that have identified several genetic variants, the etiology of CHD remains diverse and often unknown. Genetically modified animal models with candidate gene deficiencies continue to provide novel molecular insights that are responsible for fetal cardiac development. However, the past decade has seen remarkable advances in the field of human induced pluripotent stem cell (hiPSC)-based disease modeling approaches to better understand the development of CHD and discover novel preventative therapies. The iPSCs are derived from reprogramming of differentiated somatic cells to an embryonic-like pluripotent state via overexpression of key transcription factors. In this review, we describe how differentiation of hiPSCs to specialized cardiac cellular identities facilitates our understanding of the development and pathogenesis of CHD subtypes. We summarize the molecular and functional characterization of hiPSC-derived differentiated cells in support of normal cardiogenesis, those that go awry in CHD and other heart diseases. We illustrate how stem cell-based disease modeling enables scientists to dissect the molecular mechanisms of cell-cell interactions underlying CHD. We highlight the current state of hiPSC-based studies that are in the verge of translating into clinical trials. We also address limitations including hiPSC-model reproducibility and scalability and differentiation methods leading to cellular heterogeneity. Last, we provide future perspective on exploiting the potential of hiPSC technology as a predictive model for patient-specific CHD, screening pharmaceuticals, and provide a source for cell-based personalized medicine. In combination with existing clinical and animal model studies, data obtained from hiPSCs will yield further understanding of oligogenic, gene-environment interaction, pathophysiology, and management for CHD and other genetic cardiac disorders.

Maternal Viral Infection in Early Pregnancy and Risk of Congenital Heart Disease in Offspring: A Prospective Cohort Study in Central China.

PurposeTo examine the associations of maternal virus infection in early pregnancy with risk of offspring congenital heart disease (CHD) and its seven common subtypes including atrial septal defect, ventricular septal defect, atrioventricular septal defect, patent ductus arteriosus, Tetralogy of Tallot, pulmonary stenosis, and transposition of the great arteries.Patients and MethodsA prospective cohort study was conducted in Central China. A total of 44,048 pregnant women with singleton pregnancies at 8–14 gestational weeks were finally included and followed to 3 months postpartum. Serum was tested for virus infection including hepatitis B virus (HBV), coxsackievirus-B, human cytomegalovirus (HCMV), herpes simplex virus (HSV), and rubella virus. Multivariable modified Poisson regression models were used to estimate the relative risks (RRs) of all CHDs as well as seven common subtypes of CHD in offspring of pregnant women with different types of virus infection in early pregnancy, adjusting for confounders identified by directed acyclic graphs.ResultsAt the end of follow-up, 564 births were diagnosed with CHD. Multivariable analyses showed that the presence of maternal viral infection in early pregnancy was independently associated with increased risks of CHD in offspring, with an adjusted relative risk of 2.21 (95% CI: 1.66–2.95) for HBV infection, 2.21 (95% CI: 1.63–3.00) for coxsackievirus-B infection, 3.12 (95% CI: 2.44–3.98) for HCMV infection, and 2.62 (95% CI: 1.95–3.51) for rubella virus infection. More specifically, the offspring of pregnant women with HCMV infection had the highest increased risk of patent ductus arteriosus (RR=10.50, 95% CI: 6.24–17.66). These findings persisted in analyses that were further adjusted for the other virus of interest in this study.ConclusionOur study proposed evidence that maternal virus infection in early pregnancy, including HBV, coxsackievirus-B, HCMV, and rubella virus, was implicated in CHD, although more studies remain needed to verify the results, especially associations in specific CHD phenotypes.

MRI characterization of hemodynamic patterns of human fetuses with cyanotic congenital heart disease.

To characterize, using magnetic resonance imaging (MRI), the distribution of blood flow and oxygen transport in human fetuses with subtypes of congenital heart disease (CHD) that present with neonatal cyanosis. Blood flow was measured in the major vessels of 152 late-gestation human fetuses with CHD and 40 gestational-age-matched normal fetuses, using cine phase-contrast MRI. Oxygen saturation (SaO2 ) was measured in the major vessels of 57 fetuses with CHD and 40 controls. Compared with controls, we found lower combined ventricular output in fetuses with single-ventricle physiology, with the lowest being observed in fetuses with severe forms of Ebstein's anomaly. Obstructive lesions of the left or right heart were associated with increased flow across the contralateral side. Pulmonary blood flow was reduced in fetuses with Ebstein's anomaly, while those with Ebstein's anomaly and tricuspid atresia had reduced umbilical flow. Flow in the superior vena cava was elevated in fetuses with transposition of the great arteries, normal in fetuses with hypoplastic left heart, tetralogy of Fallot or tricuspid atresia and reduced in fetuses with Ebstein's anomaly. Umbilical vein SaO2 was reduced in fetuses with hypoplastic left heart or tetralogy of Fallot. Ascending aorta and superior vena cava SaO2 were reduced in nearly all CHD subtypes. Fetuses with cyanotic CHD exhibit profound changes in the distribution of blood flow and oxygen transport, which result in changes in cerebral, pulmonary and placental blood flow and oxygenation. These alterations of fetal circulatory physiology may influence the neonatal course and help account for abnormalities of prenatal growth and development that have been described in newborns with cyanotic CHD. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Interpregnancy interval and subsequent perinatal risk of congenital heart disease in Guangzhou, Southern China: a retrospective cohort study, 2014–2019

Background The association between maternal interpregnancy interval (IPI) and congenital heart disease (CHD) in neonates remains inconclusive. This study aimed to examine the effect of maternal IPI on birth risk of CHD. Methods Chinese women with two consecutive singleton deliveries in Guangzhou between January 2014 and December 2019 were selected as participants. Information on IPI and CHD was extracted from the Guangzhou Perinatal Health Care and Delivery Registry and the Guangzhou Birth Defects Surveillance Program. We stratified IPI into four categories: <24 months, 24–35 months, 36–59 months, and ≥60 months. A multivariate logistic regression model was used to examine the association between IPI and CHD. Subgroup analysis was also performed to assess whether the associations differed across top three CHD subtypes. Results For 119,510 women enrolled in this study, the mean ages at two consecutive deliveries were 26.2 ± 3.8 and 28.8 ± 4.0 years, which yielded a median IPI of 51.2 (interquartile range, 32.1–77.2) months. Among them, 828 delivered infants with CHD during their second pregnancy. There was a J-shaped curve relationship between IPI and CHD with the lowest birth prevalence (5.33‰) at 24–35-month interval. Compared to women with an IPI of 24–35 months, those with an IPI ≥60 had an increased risk of delivering infants with CHD (adjusted odds ratio (OR), 1.41; 95% confidence interval (CI), 1.19–1.64). However, for those with an IPI <24 months (adjusted OR, 1.24; 95% CI, 0.97–1.51), IPI was statistically insignificant associated with the risk of delivering infants with CHD (p = .12). There were different patterns of associations for different CHD subtypes. Conclusions Longer maternal IPI (≥60 months) was associated with an increased risk of delivering infants with CHD in the Chinese population.

Abstract 11616: Seizures in Infants with Congenital Heart Disease

Background: Infants with congenital heart disease (CHD) may have an increased risk to develop seizures during hospitalization. Objectives: to examine the association of CHD with non-epileptic, non-traumatic seizures in hospitalized infants up to one year of age. Methods: We conducted a retrospective analysis of the U.S. National Inpatient Sample dataset (2015-2018). We used the international classification of disease-10 th version to identify infants with different types of CHD. We included infants up to one year of age. We excluded infants &lt;35 week gestational age, infants with central nervous system or with major congenital anomalies, common trisomy or genetic disorders. We used chi square testing to examine the association of subtypes of CHD with seizures excluding post traumatic and epileptic seizures. We calculated mortality in infants with CHD who developed seizures versus those who did not have seizures. Results: There was 12,023,781 infants in the weighted sample who met our inclusion criteria. Of them, 48.7% were females, 46.7% were Caucasians, 195,685 (1.63%) were identified with a CHD and 20,565 (0.17%) suffered at least one episode of seizure during hospitalization. Seizures occurred in 4225 (2.2%) of infants with any type of CHD compared to 16,340 (0.14%) in infants with no CHD, odds ratios for seizures is 15.6 (CI: 15.2-16.5, p &lt;0.001). The association of seizures with subtypes of CHD is shown in table-1. Among infants with CHD, 2205 infants expired during hospitalization. Mortality was higher in infants with CHD who suffered seizures (8.5%) vs. those who did not have seizures (1.0%), OR 9.6 (8.5-10.8, p &lt;0.001). Conclusion: Infants with CHD have a higher chance to experience seizure episodes during their hospitalization and those who have seizures have higher chances of mortality during hospitalization. Further analysis is required to understand the pathological correlation between seizures and CHD and its impact on long term developmental outcomes.