Risk Of Congenital Heart Disease Research Articles

Interdependence of placenta and fetal cardiac development.

The placenta and fetal heart undergo development concurrently during early pregnancy, and, while human studies have reported associations between placental abnormalities and congenital heart disease (CHD), the nature of this relationship remains incompletely understood. Evidence from animal studies suggests a plausible cause and effect connection between placental abnormalities and fetal CHD. Biomechanical models demonstrate the influence of mechanical forces on cardiac development, whereas genetic models highlight the role of confined placental mutations that can cause some forms of CHD. Similar definitive studies in humans are lacking; however, placental pathologies such as maternal and fetal vascular malperfusion and chronic deciduitis are frequently observed in pregnancies complicated by CHD. Moreover, maternal conditions such as diabetes and pre-eclampsia, which affect placental function, are associated with increased risk of CHD in offspring. Bridging the gap between animal models and human studies is crucial to understanding how placental abnormalities may contribute to human fetal CHD. The next steps will require new methodologies and multidisciplinary approaches combining innovative imaging modalities, comprehensive genomic testing, and histopathology. These studies may eventually lead to preventative strategies for some forms of CHD by targeting placental influences on fetal heart development.

Paternal peri-conceptional physical activity and the risk of congenital heart disease in offspring: A case-control study.

Genetic and environmental factors have been shown to contribute to the development of congenital heart disease (CHD). To date, the focus of scientific articles has primarily centered on genetics and maternal environmental factors, with comparatively less attention given to paternal risk factors. This study aims to investigate the potential association between paternal pre-conceptional physical activity levels (PA), along with paternal peri-conceptional smoking and alcohol consumption, and the risk of CHD in offspring. An observational case-control study was conducted in Lebanon, with 279 participants, aiming to investigate potential risk factors for CHD. We included children with confirmed CHD, born between 2012 and 2022. Controls born in the same timeframe were selected randomly from the general population using online questionnaire forms. Mean age of children included was 6 years old (0-10). The pre-conceptional PA was assessed using the Global Physical Activity Questionnaire validated in Arabic. In addition, paternal smoking, alcohol consumption, and maternal risk factors were collected. The study included 128 CHD cases (45.9%) and their parents, as well as 151 healthy infants (54.1%) and their parents. There were no statistically significant variations in the alcohol consumption noted between the fathers in the case and control groups (p=0.18). The paternal involvement in recreational-related PA during the peri-conception period was associated with a reduced risk of the CHD development in offspring by 46.9% (OR=0.531, 95% CI: 0.301-0.936, p=0.029). Additionally, increasing paternal total sitting time by 1 h above the average, which was approximately 260 min (4h), increased the risk of CHD in offspring by 0.4% (p=0.001). Moreover, paternal smoking exhibited an apparent association with a 56% increased risk of offspring developing CHD, notwithstanding that the confidence intervals included the null (OR=1.56, 95% CI: 0.86-2.8, p=0.136). This observational study is the first to report a potential association between paternal PA, and CHD in offspring. This study aligns with previous reports, advocating for the paternal engagement in PA and the adoption of healthy lifestyle habits, especially during the critical stages of conception. Such practices are strongly recommended to enhance fertility and promote optimal health for offspring. However, due to the subjectivity in reporting PA and lack of molecular proof, additional prospective and molecular studies are required to validate these findings.

Association of maternal weight gain in early pregnancy with congenital heart disease in offspring: a China birth cohort study

ObjectivesLittle study has reported the association of maternal weight gain in early pregnancy with fetal congenital heart disease (CHD). We aimed to explore the potential relationship based on a China...

Novel and deleterious nucleotide variations in the HAND1 gene probably affect miRNA target sites and protein function in pediatric patients with congenital heart disease.

Congenital heart disease (CHD) is the most prevalent developmental defect and principal cause of infant mortality and affects cardiac and large blood vessel structures in approximately 1% of live births worldwide. To date, numerous studies have related critical genetic dysfunctions to the pathogenesis of CHDs. However, the genetic basis underlying CHD remains largely unknown. In the present study, we investigated the association of nucleotide variations in coding and noncoding regions of the HAND1 gene with the risk of CHD. The HAND1 gene, encoding a helix-loop-helix transcription factor, is particularly relevant for mechanisms underlying CHD since it plays a significant role in heart development. The genomic DNA of 150 unrelated pediatric patients with CHD was screened by PCR-SSCP and direct sequencing. Four novel and heterozygous missense mutations were identified in the first exon, with three causing amino acid substitutions (p.Val149Met, p.Tyr142His, and p.Leu146Met). In-silico analysis also indicated their deleterious impact on protein structure and function. In addition, we identified five novel nucleotide variants in the 3'UTR region (c.*461, c.*342, c.*529, c.*448, c.*593), potentially altering the target sites of miRNAs. These changes include the loss of certain target sites and the acquisition of new ones. These findings confirm the phenotypic association between CHDs and HAND1 mutations and can pave the way for developing new preventive and therapeutic strategies.

Epidemiological Survey of Congenital Heart Disease Among Children Aged from 2 to 18 in Suo County, Nagqu, Tibet.

Lin, Tian, Huaping Jia, Yunming Li, Yongxing Xu, Bei Zhao, Dong Zheng, Hongfeng Yan, Meihui Zhao, Yanlei Li, Liping Xia, Fengxia Zhou, Cuiping Liu, Ke Ma, Ma Mi, and Jianwen Gu. Epidemiological survey of congenital heart disease among children aged from 2 to 18 in Suo County, Nagqu, Tibet. High Alt Med Biol. 00:000-000, 2024. Background: Studies have reported the prevalence of congenital heart disease (CHD) in parts of Tibet, but relative epidemiological surveys are rare. We aimed to explore the prevalence of CHD in children and its relationship with family history in Suo County, Nagqu, Tibet, an altitude of 3,980 meters. Methods: We recruited 4,002 children aged 2-18 years. Subjects underwent a family history investigation, cardiac auscultation, and clinical manifestation examination and then received echocardiographic screening. Results: The prevalence of CHD among children in Suo County was 0.97% (39 cases), much higher than the prevalence at sea level. The most common subtype was atrial septal defect, accounting for 53.9% of CHD, followed by patent ductus arteriosus (33.3%) and ventricular septal defect (12.8%). We also found that children whose mothers had previously borne children with CHD had a higher risk of CHD than those without (p = 0.002); other factors related to CHD during pregnancy, such as smoking, drinking, drug use, and viral infection, showed no statistical differences between children with and without CHD. Conclusions: The prevalence of CHD in children in Suo County is much higher than at low altitude, consisting mostly of simple forms with left-to-right shunt, with rare complex CHD. These results support implementing diagnostic and treatment plans to prevent CHD in Suo County.

Prenatal exposure to poly/perfluoroalkyl substances and risk for congenital heart disease in offspring

Congenital heart disease (CHD) is the most prevalent congenital malformation worldwide, and the association between per- and polyfluoroalkyl substances (PFASs) exposure and CHD in population has only received limited study. Therefore, we conducted a multicenter case-control study to explore the associations between prenatal exposure to individual PFASs, and also a PFAS mixture, and CHD risk, including 185 CHDs and 247 controls in China from 2016 to 2021. Thirteen PFASs in maternal plasma were quantified using liquid chromatography-tandem mass spectrometry. Logistic regression and two multipollutant models (Bayesian kernel machine regression [BKMR] and quantile g-computation [qgcomp]) were used to assess the potential associations between any individual PFAS, and also a PFAS mixture, and CHD risk. After adjusting for potential confounders, logistic regression indicated significant associations between elevated levels of perfluorononanoic acid (odds ratio [OR]= 1.30, 95% confidence intervals [CI]: 1.07–1.58), perfluorodecanoic acid (OR=2.07, 95%CI: 1.32–3.26), and perfluoroundecanoic acid (OR=2.86, 95%CI:1.45–5.65) and CHD risk. The BKMR model and qgcomp approach identified that a significant positive association between the PFAS mixture and risk for CHD. These findings provide essential evidence that there is indeed a health crisis associated with PFASs and that it is linked to 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.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study

BackgroundThe majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring.MethodsA multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene–gene and gene–phthalates exposure interactions.ResultsThere was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28–2.37; dominant: aOR = 1.86, 95% CI:1.25–2.78; recessive: aOR = 2.50, 95% CI: 1.26–4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54–121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed.ConclusionsThe polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

Association between lipid profile in early pregnancy and the risk of congenital heart disease in offspring: a prospective cohort study

This study aimed to investigate the association of lipid profile in early pregnancy and the risk of congenital heart disease (CHD) in offspring. This study was a prospective cohort design based on the Fujian Birth Cohort Study in China. We recruited pregnant women at ≤ 14 weeks of gestation between 2019 and 2022, and all participants in this study filled out the questionnaire about periconceptional exposure. Simultaneously, we collected participants’ fasting blood samples to measure their lipid profile by automatic biochemical analyzer. The outcome was defined as offspring with CHD. A multivariable logistic regression model was used to calculate adjusted odds ratio (AOR) risk estimates, which indicate the associations between maternal lipid profiles and CHD in offspring. Restricted cubic splines were used to estimate their nonlinear relationship. A total of 21,425 pregnant women with an average gestational age of 11.3 (± 1.40) weeks were included in the analysis. The higher triglyceride (AOR 1.201, 95% CI [1.036, 1.394]), low-density lipoprotein (AOR 1.216, 95% CI [1.048, 1.410]), apolipoprotein B (Apo B) (AOR 2.107, 95% CI [1.179, 3.763]) levels were correlated with increased odds of CHD in offspring, while high-density lipoprotein (OR 0.672, 95% CI [0.490, 0.920]) related with decreased odds of CHD in offspring. The restricted cubic spline suggested a nonlinear relationship between total cholesterol (TC) levels and the risk of CHD in offspring (P = 0.0048), but no significant nonlinear relationships were found in other lipid profile. Apolipoprotein A was not related to the risk of CHD in offspring as either a continuous variable or a hierarchical variable. Elevated lipid profile in early pregnancy levels are associated with an increased risk of CHD in offspring. Additionally, there is a non-linear relationship between TC levels and the risk of CHD in offspring.

Risk of major congenital heart disease in pregestational maternal diabetes is modified by hemoglobin A1c.

The association between pregestational diabetes mellitus (PDM) and risk of congenital heart disease (CHD) is well recognized; however, the importance of glycemic control and other coexisting risk factors during pregnancy is less clear. We sought to determine the relative risk (RR) of major CHD (mCHD) among offspring from pregnancies complicated by PDM and the effect of first-trimester glycemic control on mCHD risk. We determined the incidence of mCHD (requiring surgery within 1 year of birth or resulting in pregnancy termination or fetal demise) among registered births in Alberta, Canada. Linkage of diabetes status, maximum hemoglobin A1c (HbA1c) at < 16 weeks' gestation and other covariates was performed using data from the Alberta Perinatal Health Program registry. Risk of mCHD according to HbA1c was estimated as an adjusted RR (aRR), calculated using log-binomial modeling. Of 1412 cases of mCHD in 594 773 (2.37/1000) births in the study period, mCHD was present in 48/7497 with PDM (6.4/1000; RR, 2.8 (95% CI, 2.1-3.7); P < 0.0001). In the entire cohort, increased maternal age (aRR, 1.03 (95% CI, 1.02-1.04); P < 0.0001) and multiple gestation (aRR, 1.37 (95% CI, 1.1-1.8); P = 0.02) were also associated with mCHD risk, whereas maternal prepregnancy weight > 91 kg was not. The stratified risk for mCHD associated with HbA1c ≤ 6.1%, > 6.1-8.0% and > 8.0% was 4.2/1000, 6.8/1000 and 17.1/1000 PDM/gestational diabetes mellitus births, respectively; the aRR of mCHD associated with PDM and HbA1c > 8.0% was 8.5 (95% CI, 5.0-14.4) compared to those without diabetes and 5.5 (95% CI, 1.6-19.4) compared to PDM with normal HbA1c (≤ 6.1%). PDM is associated with a RR of 2.8 for mCHD, increasing to 8.5 in those with HbA1c > 8%. These data should facilitate refinement of referral indications for high-risk pregnancy screening. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Maternal Gestational Diabetes Mellitus and Congenital Heart Disease in Offspring: A Meta-Analysis.

Maternal diabetes has been related to an increased risk of congenital heart disease (CHD) in offspring. However, inconsistent results were retrieved for studies evaluating the association between gestational diabetes mellitus (GDM) and CHD in offspring. We therefore performed a systematic review and meta-analysis for comprehensive investigation. Observational studies were identified by searching PubMed, Embase, and Web of Science according to the aim of the meta-analysis. A randomized-effects model was used to pool the data by incorporating the influence of potential heterogeneity. Twenty-three observational studies, involving 46953078 mother-child pairs, were available for the meta-analysis. Among them, 2131800 mothers were diagnosed as GDM and 214379 newborns had CHD. Overall, maternal GDM was associated with a higher incidence of CHD in offspring [odds ratio (OR): 1.32, 95% confidence interval (CI): 1.21 to 1.45, p<0.001; I2=62%]. Sensitivity analysis limited to studies with adjustment of maternal age and other potential confounding factors showed similar results (OR: 1.40, 95% CI: 1.30 to 1.51, p<0.001; I2=47%). Subgroup analysis suggested that the association between maternal GDM and CHD in offspring was not significantly affected by methods for diagnosis of GDM, methods for confirmation of CHD, or study quality scores (p for subgroup difference all>0.05). Subsequent analysis according to types of CHD showed that maternal GDM was associated with higher risks of atrial septal defect, ventricular septal defect, and Tetralogy of Fallot. Maternal GDM may be associated with a higher risk of CHD in offspring.

Genetics and etiology of congenital heart disease.

Congenital heart disease (CHD) is the most common severe birth anomaly, affecting almost 1% of infants. Most CHD is genetic, but only 40% of patients have an identifiable genetic risk factor for CHD. Chromosomal variation contributes significantly to CHD but is not readily amenable to biological follow-up due to the number of affected genes and lack of evolutionary synteny. The first CHD genes were implicated in extended families with syndromic CHD based on the segregation of risk alleles in affected family members. These have been complemented by more CHD gene discoveries in large-scale cohort studies. However, fewer than half of the 440 estimated human CHD risk genes have been identified, and the molecular mechanisms underlying CHD genetics remains incompletely understood. Therefore, model organisms and cell-based models are essential tools for improving our understanding of cardiac development and CHD genetic risk. Recent advances in genome editing, cell-specific genetic manipulation of model organisms, and differentiation of human induced pluripotent stem cells have recently enabled the characterization of developmental stages. In this chapter, we will summarize the latest studies in CHD genetics and the strengths of various study methodologies. We identify opportunities for future work that will continue to further CHD knowledge and ultimately enable better diagnosis, prognosis, treatment, and prevention of CHD.

Association between abnormal uterine artery pulsatility index and the risk of fetal congenital heart defects: a hospital-based cohort study

To explore the associations between high uterine artery pulsatility index (UtA-PI) values and congenital heart disease (CHD) risk and whether they differed between singleton and multiple pregnancies. This hospital-based cohort study involving 52,047 pregnant women who underwent prenatal examinations from 2012 to 2016. Infants born to the included pregnant women were followed until 42 days after birth to identify those with CHDs. Generalized estimating equations were used to estimate the associations of high right UtA-PI (> 95th percentile) values with maternal preeclampsia and fetal CHDs. Logistic regression analyses were conducted using path analysis models to quantify the effect of high right UtA-PI values on fetal CHD risk. A total of 42,552 women and 43,470 infants (147 with CHDs) were included. Preeclampsia risk was associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 3.01; 95% CI 2.57–3.52). CHD risk was marginally associated with a high right UtA-PI in singleton-pregnant women (adjusted PR, 2.26, 95% CI 1.03–4.95). Considering only two factors, 96.0% of the fetal CHD risk was mediated by preeclampsia in singleton-pregnant women, while 93.8% of the risk was related to a high right UtA-PI in multiple-pregnant women. A high right UtA-PI was marginally associated with an increased fetal CHD risk in singleton-pregnant women and might play an important role in multiple-pregnant women. Further studies are warranted to confirm these findings given the high loss to follow-up rate.

Long-term outcomes after heart transplantation in adult patients with univentricular versus biventricular congenital heart disease.

Heart transplantation (HT) is the only life-extending therapy in adults with congenital heart disease (CHD) and end-stage heart failure. HT is considered at high risk in complex CHD given the anatomical complexity and past medical history. Little is known about long-term outcomes after HT in these patients. We aimed to evaluate early and long-term outcomes after HT in adult patients with univentricular versus biventricular CHD. This multicentre retrospective cohort study included all adult CHD patients who underwent HT between 1988 and 2021 in 3 tertiary centres. Factors associated with early (<30 days) and conditional long-term survival were assessed in the entire cohort. Over a mean follow-up of 10.1 ± 7.8 years, 149 patients were included, of whom 55 (36.9%) had univentricular CHD. Sixty-four patients died during follow-up including 47 deaths before discharge from hospital. In multivariable analysis, univentricular physiology and female recipient gender were independently associated with a higher risk of early mortality (odds ratio 2.99; 95% confidence interval [1.33-6.74] and odds ratio 2.76; 95% confidence interval [1.23-6.20], respectively). For patients who survived the early period, conditional long-term survival was excellent for both groups and was not different between 2 groups (P = 0.764). Adult CHD patients have a high incidence of overall mortality due to a high rate of early mortality. Univentricular physiology was associated with a significant increased risk of early death compared to biventricular physiology. However, late mortality was excellent and no longer different between the 2 physiologies.

Associations of elevated glucose levels at each time point during OGTT with fetal congenital heart diseases: a cohort study of 72,236 births

BackgroundIt remains unclear how the condition of glucose metabolism during pregnancy affects fetal outcomes. This study aimed to investigate the associations of gestational diabetes mellitus (GDM) and elevated glucose levels at each time point during oral glucose tolerance test (OGTT) with congenital heart disease (CHD) risk in offspring.MethodsWe conducted a retrospective cohort study of mothers with singleton pregnancies of 20 weeks or more registered at Maternal and Child Health Centers in Fujian Province, China. The OGTT results and offspring CHD occurrence were collected. We used logistic regression to analyse the association between elevated blood glucose at each time point during OGTT and CHD.ResultsA total of 71,703 normal and 533 CHD fetuses were included. Compared to the corresponding normal group, women with GDM, elevated blood glucose at different time points in OGTT (0 h ≥ 5.1 mmol/L, 1 h ≥ 10 mmol/L, and 2 h ≥ 8.5 mmol/L) showed an increased risk of CHD in offspring (adjusted OR = 1.41, 1.36, 1.37, and 1.41, all P < 0.05, respectively). Compared to group 1 (normal OGTT 0 h, 1 h and 2 h), the risk of CHD was higher in group 3 (normal OGTT 0 h and abnormal OGTT 1 h or 2 h) and group 4 (abnormal OGTT 0 h, 1 h and 2 h), OR = 1.53 and 2.21, all P < 0.05, respectively. Moreover, we divided participants by advanced maternal age, multipara, assisted reproduction, fetal sex, and others, similar associations were observed in the subgroup analyses.ConclusionElevated blood glucose at different time points during OGTT was associated with CHD in offspring. Fetuses of pregnant women with GDM should be screened for a high risk of CHD.

The risk of pediatric cardiovascular diseases in offspring born to mothers with systemic lupus erythematosus: a nationwide study.

Systemic lupus erythematosus (SLE), a common autoimmune disease predominantly affecting women, has been linked to various complications during pregnancy. The transfer of anti-Ro/SSA antibodies from SLE-affected mothers to their offspring can lead to neonatal lupus and cardiac issues. This study investigated the association between maternal SLE and the risk of pediatric cardiovascular disorders. The study utilized South Korea's National Health Insurance Service (NHIS) database, covering 3,505,737 children born between 2007 and 2017 and tracked until 2020. Maternal SLE cases were identified using the World Health Organization's International Classification of Diseases Tenth revision (ICD-10) codes and linked with delivery records. Cardiologic disorders were categorized into congenital heart disease (CHD), arrhythmic disorders, and acquired heart disease. Propensity score matching with 1:4 ratios was applied to the set control group. Among 3,505,737 children, 0.7% (n = 23,330) were born to mothers with SLE. The incidence of preterm birth was significantly higher in the maternal SLE group (5.9% vs. 3.0%). Compared with the control group, children born to mothers with SLE exhibited a significantly elevated risk of overall CHDs (5.5%, adjusted odds ratio [aOR] 1.21; 95% confidence interval [CI] 1.14-1.29), including atrial septal defect (1.18; 1.09-1.28) and patent ductus arteriosus (1.15; 1.03-1.30). In addition, a notably higher risk was observed in arrhythmic disorders (complete atrioventricular block 7.20; 2.41-21.49) and acquired cardiac disorders, including cardiomyopathy (1.40; 1.17-1.68) and mucocutaneous lymph node syndrome (MCLS) (1.27; 1.15-1.43). Maternal SLE is associated with congenital and acquired cardiac disorders in offspring, including structural, arrhythmic, and MCLS. This study highlights the need for continuous cardiovascular monitoring from the prenatal stage to preadolescence in these children due to multifactorial influences involving maternal autoantibodies, genetic predisposition, and environmental factors.

Single-Cell Reconstruction and Mutation Enrichment Analysis Identifies Dysregulated Cardiomyocyte and Endothelial Cells in Congenital Heart Disease.

Congenital heart disease (CHD) is one of the most prevalent neonatal congenital anomalies. To catalog the putative candidate CHD risk, we collected 16,349 variants (single nucleotide variants (SNVs) and Indels) impacting 8,308 genes in 3,166 CHD cases for a comprehensive meta-analysis. Using ACMG guidelines we excluded the 0.1% of benign/likely benign variants and resulting data set consisted of 83% predicted loss of function variants and 17% missense variants. Seventeen percent were de novo variants. A stepwise analysis identified 90 variant-enriched CHD genes, of which six (GPATCH1, NYNRIN, TCLD2, CEP95, MAP3K19 and TTC36) were novel candidate CHD genes. Single cell transcriptome cluster reconstruction analysis on six CHD tissues and four controls revealed upregulation of top 10 frequently mutated genes primarily in cardiomyocytes. NOTCH1 (highest number of variants) and MYH6 (highest number of recurrent variants) expression was elevated in endocardial cells and cardiomyocytes, respectively, and 60% of these gene variants were associated with tetralogy of Fallot and coarctation of the aorta, respectively. Pseudobulk analysis using single cell transcriptome, revealed significant (p<0.05) upregulation of both NOTCH1 (endocardial cells) and MYH6 (cardiomyocytes) in the control heart data. We observed nine different subpopulations of CHD heart cardiomyocytes of which only four were observed in the control heart. This is the first comprehensive meta-analysis combining genomics and CHD single cell transcriptomics, identifying the most frequently mutated CHD genes, and demonstrating CHD gene heterogeneity, suggesting that multiple genes contribute to the phenotypic heterogeneity of CHD. Cardiomyocytes and endocardial cells are identified as major CHD-related cell types.

Trends in mortality risk of patients with congenital heart disease during the COVID-19 pandemic

Cardiovascular conditions are considered risk factors for poor outcomes associated with COVID-19. However, the effect of the COVID-19 pandemic on the mortality of patients with congenital heart disease (CHD) is unclear. Our study aims to examine the trends in mortality risk of CHD patients during the COVID-19 pandemic. This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for CHD. We included patients having US residence and direct identifiers; death events were captured by matching with the National Death Index. The observation window (2017-2022) was divided into pre-COVID-19 and COVID-19 era defined around the national onset of COVID-19 disease in 2020. Stratified Cox model was used to assess all-cause mortality between the pre- and the COVID-19 era. Among 45,130 patients with CHD (median age in 2017: 23.3 years, IQR: 19.0-28.4), 503 deaths occurred during the pandemic with 44 deaths (8.7%) attributed to COVID-19 (COVID-19 mortality rate of 0.09%). The overall risk of death for patients with all types of CHD during the pandemic was significantly higher compared to the pre-COVID-19 era (aHR 1.28, 95%CI: 1.08-1.53), with a differential trend towards increased risk in patients with two-ventricle (aHR 1.44, 95% CI: 1.19-1.76) vs unchanged risk for those with single ventricle CHD (aHR=0.83, 95% CI: 0.57-1.21). Adjusted subgroup analysis revealed a higher risk of death during the pandemic for CHD patients with male and chromosomal abnormalities. The excess deaths during the pandemic were attributed to COVID-19 itself rather than CHD or cardiovascular conditions. In this large CHD cohort study, there was a higher risk of death among CHD patients with male and chromosomal abnormalities. A differential trend towards higher risk for those with two vs. unchanged risk for single ventricle CHD was presented. The excess mortality was attributed to the COVID-19 itself and not to conditions potentially related to deferral of care. These results justify targeted protective measures towards the CHD population and may provide guidance for public health and medical care response in future epidemics.

A cluster-based ensemble approach for congenital heart disease prediction

BackgroundOne of the most prevalent birth disorders is congenital heart diseases (CHD). Although CHD risk factors have been the subject of numerous studies, their propensity to cause CHD has not been tested. Particularly few research has attempted to forecast CHD risk using population-based cross-sectional data, which is inherently imbalanced. ObjectiveThe main goals of this study are to create a reliable data analysis model that can help with (i) a better understanding of congenital heart disease prediction in the presence of missing and unbalanced data and (ii) creating cohorts of expectant mothers with similar lifestyle characteristics. MethodsClusters of patient cohorts are produced using the unsupervised data mining technique density-based spatial clustering of applications with noise (DBSCAN). For more accurate CHD prediction, a random forest model was trained using these clusters and their corresponding patterns. This study uses a dataset of 33,831 expectant mothers to make its prediction. Missing data were handled using the k-NN imputation approach, while extremely unbalanced data were balanced using SMOTE. These techniques are all data-driven and need little to no user or expert involvement. Results and ConclusionUsing DBSCAN, three cohorts were found. The cluster information enhanced the random forest-based CHD prediction and revealed intricate factors that influence prediction accuracy. The proposed approach gave the highest results with 99 % accuracy and 0.91 AUC and performed better than the state-of-the-art methodologies. Hence, the suggested method using unsupervised learning can provide intricate information to the classifier and further enhance the performance of the classification.

TRENDS IN THE INCIDENCE AND CHARACTERISTICS OF CONGENITAL HEART DISEASE IN LOPBURI PROVINCE, CENTRAL THAILAND, 2017-2021

Background: Congenital heart disease (CHD) is the newborn’s most common congenital anomaly. Nevertheless, limited evidence is available of CHD incidence in Thailand. Therefore, we aimed to determine the trends in CHD incidence from 2017 to 2021.&#x0D; Methods: A descriptive epidemiology study was conducted using data from 2017-2021. We collected data from the medical records of pediatric patients with CHD at the Pediatric Cardiology Clinic at Ananda Mahidol Hospital, central Thailand. The pediatric cardiologist reviewed medical records to obtain participants’ characteristics and medical data, including CHD diagnosis, sex, child order and maternal risk factors during pregnancy.&#x0D; Results: In total, 27,882 live births were recorded between 2017 and 2021 in Lopburi Province, Thailand. The study included 584 pediatric patients with CHD born between 2017 and 2021. Of these, 312 (53.4%) were males, and 89 (15.2%) presented cyanotic CHD. Sex-adjusted CHD incidence was 22.4 per 1000 live-births (95% CI: 17.6-34.5) in 2017; then rose to 25.7 per 1000 live-births (95% CI 21.7- 30.2) in 2019 and dropped to 15.4 per 1000 live-births (95% CI 12.1-19.3) in 2021 (p for trend = 0.317). Two hundred and fourteen patients (36.6%) presented a ventricular septal defect. In 2017, the proportion of patients receiving a diagnosis of CHD before one year of age was 57.7% and continuously rose to 100% in 2021 (p-for trend &lt;0.001). The proportion of alcohol consumption during pregnancy was consistently high, ranging from 61.6 to 74.8% (p for trend = 0.189). In addition, contraindicated drug use during the first trimester of pregnancy was also constantly high (73.1%) among study participants over five years (p for trend = 0.235).&#x0D; Conclusion: CHD incidence in Lopburi Province has been persistently high from 2017 to 2021. The average age at diagnosis with CHD in this study population continuously declined over five years. Characteristics of CHD risk factors during pregnancy constituted a constantly high proportion among these study participants over one half decade.