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Open in new tab Download slide Open in new tab Download slide OBJECTIVES The modified extracardiac Fontan of direct total cavopulmonary connection (dTCPC) with entirely autologous vessels is a better solution in selected patients with functionally univentricular hearts because it combines the advantages of a tubular connection and of full growth potential. We investigated the mid-term to long-term outcomes of the physical condition of patients who had the dTCPC and assessed the growth potential of the autologous dTCPC pathway. METHODS From July 2005 to June 2014, 31 patients, aged 1.8–14.0 years, underwent a modified extracardiac Fontan with dTCPC at our institution. Twenty-two patients underwent a 1-stage dTCPC and 9 patients underwent a 2-stage dTCPC. The preoperative and postoperative data were reviewed retrospectively. RESULTS There were 17 (54.8%) boys and 14 (45.2%) girls, with a median age of 6.4 years (range 1.8–14.0 years) and a mean weight of 17.8 kg (range 9–41 kg). The mean follow-up period was 6.0 years (range 2.1–10.2 years). There was 1 early death and 2 late deaths. The event-free survival rate for the 31 patients was 88.9% at 10 years during the follow-up period. Late protein-losing enteropathy, thromboembolism, arrhythmia or heart failure were not observed. There was a significant difference between the preoperative and postoperative data for body mass index and the diameters of the autologous dTCPC pathway and pulmonary artery branches, confirming that the growth potential of the autologous dTCPC pathway was realized. CONCLUSIONS The dTCPC procedure could be performed with satisfactory midterm to long-term outcomes in selected patients. It has the potential of retaining the advantage of the extracardiac Fontan operation together with the potential for growth and the avoidance of prosthetic materials. [ABSTRACT FROM AUTHOR]

Perfluorooctane sulfonate (PFOS), an endocrine-disrupting chemical pollutant, affects embryonic heart development; however, the mechanisms underlying its toxicity have not been fully elucidated. Here, Single-cell RNA sequencing (scRNA-seq) was used to investigate the overall effects of PFOS on myocardial differentiation from human embryonic stem cells (hESCs). Additionally, apoptosis, mitochondrial membrane potential, and ATP assays were performed. Downregulated cardiogenesis-related genes and inhibited cardiac differentiation were observed after PFOS exposure in vitro. The percentages of cardiomyocyte and cardiac progenitor cell clusters decreased significantly following exposure to PFOS, while the proportion of primitive endoderm cell was increased in PFOS group. Moreover, PFOS inhibited myocardial differentiation and blocked cellular development at the early- and middle-stage. A Gene Ontology analysis and pseudo-time trajectory illustrated that PFOS disturbed multiple processes related to cardiogenesis and oxidative phosphorylation in the mitochondria. Furthermore, PFOS decreased mitochondrial membrane potential and induced apoptosis. These results offer meaningful insights into the cardiogenic toxicity of PFOS exposure during heart formation as well as the adverse effects of PFOS on mitochondria. [Display omitted] • Sc-RNA sequencing displayed the transcriptional dynamics of cardiomyocytes differentiation during PFOS exposure. • PFOS produced the decrease of hESC differentiation into cardiac progenitor cell but increase of primitive endoderm cell. • PFOS interfered myocardial differentiation by blocking cells at earlier stage. • PFOS decreased mitochondria membrane potential and induced cells apoptosis. [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) are a major cause of death in infancy and childhood. Major risk factors for most CHDs, particularly those resulting from the combination of environmental exposures with social determinants and behaviors, are still unknown. This study evaluated the main effect of maternal environmental tobacco smoke (ETS), and its interaction with social-demographics and environmental factors on CHDs in China. A population-based, matched case-control study of 9452 live-born infants and stillborn fetuses was conducted using the Guangdong Registry of Congenital Heart Disease data (2004–2014). The CHDs were evaluated by obstetrician, pediatrician, or cardiologist, and confirmed by cardia tomography/catheterization. Controls were randomly chosen from singleton newborns without any malformation, born in the same hospital as the cases and 1:1 matched by infant sex, time of conception, and parental residence (same city and town to ensure sufficient geographical distribution for analyses). Face-to-face interviews were conducted to collect information on demographics, behavior patterns, maternal disease/medication, and environmental exposures. Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals of ETS exposure on CHDs while controlling for all risk factors. Interactive effects were evaluated using a multivariate delta method for maternal demographics, behavior, and environmental exposures on the ETS-CHD relationship. Mothers exposed to ETS during the first trimester of pregnancy were more likely to have infants with CHD than mothers who did not (aOR = 1.44, 95% CI 1.25–1.66). We also observed a significant dose-response relationship when mothers were exposed to ETS and an increasing number of risk factors and CHDs. There were greater than additive interactions for maternal ETS and migrant status, low household income and paternal alcohol consumption on CHDs. Maternal low education also modified the ETS-CHD association on the multiplicative scale. These findings may help to identify high-risk populations for CHD, providing an opportunity for targeted preventive interventions. [ABSTRACT FROM AUTHOR]

There are 16.5 million newborns in China annually. However, the incidence of congenital heart disease (CHD) has not been evaluated. In 2004, we launched an active province-wide hospital-based CHD registry in the Guangdong Province of southern China. In this study, we examined the incidence of CHD and its subtypes from 2004 to 2012 and compared our findings to the literature. Our results indicate there is an increasing trend of CHD incidence. The increase in incidence occurred mainly for single lesion and the most common subtypes (e.g., ventricular or atrial septal defect, patent ductus arteriosus). There were no increases found for multiple lesions or more complex subtypes. The proportion of CHD cases that were detected early (e.g., 1 week) increased over time. The incidence of CHD stabilized in 2010–2012 with the average cumulative incidences of 9.7, 9.9, and 11.1 per 1,000 live births at 1 week, 1 month, and 1 year, respectively. The incidences of CHD subtypes were comparable with recent international results. The data did not support previous reports that Asian children have a higher incidence of pulmonary outflow obstructions and lower incidence of transposition of the great arteries. However, there was a lower incidence of left ventricular outflow tract obstructions observed in our series. The increase in CHD incidence observed over time was due to improved detection and diagnosis. The true incidence of CHD in China was approximately 11.1 per 1,000 live births, which is higher than previously reported. [ABSTRACT FROM AUTHOR]

This study aimed to examine effect modification of maternal risk factor exposures and congenital heart disease (CHD) by maternal folic acid supplementation (FAS)/non-FAS. We included 8379 CHD cases and 6918 CHD-free controls from 40 clinical centers in Guangdong Province, Southern China, 2004–2016. Controls were randomly chosen from malformation-free fetuses and infants and frequency matched to the echocardiogram-confirmed cases by enrollment hospital and year of birth. We used multiple regression models to evaluate interactions between FAS/non-FAS and risk factors on CHDs and major CHD categories, adjusted for confounding variables. We detected statistically significant additive and multiplicative interactions between maternal FAS/non-FAS and first-trimester fever, viral infection, and threatened abortion on CHDs. An additive interaction on CHDs was also identified between non-FAS and living in a newly renovated home. We observed a statistically significant dose-response relationship between non-FAS and a greater number of maternal risk factors on CHDs. Non-FAS and maternal risk factors interacted additively on multiple critical CHDs, conotruncal defects, and right ventricular outflow tract obstruction. Maternal risk factor exposures may have differential associations with CHD risk in offspring, according to FAS. These findings may inform the design of targeted interventions to prevent CHDs in highly susceptible population groups. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is associated with adverse short- and long-term health outcomes among mothers and their offspring. GDM affects 0.6%–15% of pregnancies worldwide and its incidence is increasing. However, intervention strategies are lacking for GDM. Previous studies indicated a protective association between greenspace and type 2 diabetes mellitus (T2DM), while few studies have explored the association between greenness and GDM. This study aimed to investigate the association between residential greenness and GDM among women from 40 clinical centers in Guangdong province, south China. The study population comprised 5237 pregnant mothers of fetuses and infants without birth defects, from 2004 to 2016. There were n = 157 diagnosed with GDM according to World Health Organization criteria. We estimated residential greenness using the Normalized Difference Vegetation Index (NDVI), derived from satellite imagery using a spatial-statistical model. Associations between greenness during pregnancy and GDM were assessed by confounder-adjusted random effects log-binomial regression models, with participating centers as the random effect. One interquartile increments of NDVI 250m , NDVI 500m and NDVI 1000m were associated with 13% (RR = 0.87, 95%CI: 0.87–0.87), 8% (RR = 0.92, 95%CI: 0.91–0.92) and 3% (RR = 0.97, 95%CI: 0.97–0.97) lower risks for GDM, respectively. However, NDVI 3000m was not significantly associated with GDM (RR = 0.96, 95%CI: 0.78–1.19). The risk for GDM decreased monotonically with greater NDVI. The protective effect of greenness on GDM was stronger among women with lower socioeconomic status and in environments with a lower level air pollutants. Our results suggest that greenness might provide an effective intervention to decrease GDM. Greenness and residential proximity to greenspace should be considered in community planning to improve maternal health outcomes. Image 1 • Association of greenness with incident gestational diabetes mellitus (GDM) was assessed in south China. • A total of 157 GDM patients were identified among 5237 mothers of congenital malformation-free fetuses and infants. • Higher greenness levels were associated with lower GDM risk. • The probability of developing GDM decreased monotonically with higher greenness. • The protective effect of greenness was stronger in mothers with lower socioeconomic status and exposed to less air pollution. [ABSTRACT FROM AUTHOR]

• This is the first study of congenital heart defect (CHD) association with greenness. • A total of 8042 cases and 6887 controls were included. • Higher levels of maternal greenness exposure were associated with lower odds of CHD. • We identified a protective threshold of over 0.21 satellite-derived normalized difference vegetation index on CHD. Proximity to greenness has shown protective effects on coronary heart diseases by limiting exposure to environmental hazards, encouraging physical activity, and reducing mental stress. However, no studies have previously evaluated the impacts of greenness on congenital heart defects (CHDs). We examined the association between maternal residential greenness and the risks of CHDs. We conducted a case-control study (8042 children with major CHDs and 6887 controls without malformations) in 21 cities in Southern China, 2004 – 2016. CHDs cases were diagnosed and verified by obstetrician, pediatrician, or pediatric cardiologists, within one year. We estimated maternal residential greenness using satellite-derived normalized difference vegetation index (NDVI) in zones of 500 meters (m) and 1000 m surrounding participants' residences. Logistic regression models were used to assess NDVI-CHD relationships adjusting for confounders. Interquartile range NDVI increases within 500 m or 1000 m were associated with odds ratios (OR) of 0.95 (95% confidence interval (CI): 0.92, 0.98) and 0.94 (95%CI: 0.91, 0.97) for total CHDs respectively. Air pollutants mediated 52.1% of the association. We also identified a protective threshold at 0.21 NDVI on CHD. Similar protective effects from greenness were found in most CHDs subtypes. The protective associations were stronger for fall, urban or permanent residents, higher household income maternal age ≤35 years of age, and high maternal education (ORs: ranged from 0.85 to 0.96). Our findings suggest a beneficial effect of maternal residential greenness on CHDs. Further studies are needed to confirm our findings, which will help to refine preventive health and urban design strategies. [ABSTRACT FROM AUTHOR]

Prenatal exposure to toxic trace elements, including heavy metals, is an important public health concern. Few studies have assessed if individual and multiple trace elements simultaneously affect cardiac development. The current study evaluated the association between maternal blood lead (Pb), cadmium (Cd), chromium (Cr), copper (Cu), mercury (Hg), and selenium (Se) levels and congenital heart defects (CHDs) in offspring. This hospital-based case-control study included 112 case and 107 control infants. Maternal peripheral blood draw was made during gestational weeks 17–40 and used to determine trace element levels by inductively coupled plasma mass spectrometry. Multivariable logistic regression was used to assess associations and interactions between individual and multiple trace elements and fetal CHDs, adjusted for maternal age, parity, education, newborn gender, migrant, folic acid or multivitamin intake, cigarette smoking, maternal prepregnancy body mass index, and time of sample collection. Control participants had medians of 2.61 μg/dL Pb, 1.76 μg/L Cd, 3.57 μg/L Cr, 896.56 μg/L Cu, 4.17 μg/L Hg, and 186.47 μg/L Se in blood. In a model including all measured trace elements and adjusted for confounders, high levels of maternal Pb (OR = 12.09, 95% CI: 2.81, 51.97) and Se (OR = 0.25, 95% CI: 0.08, 0.77) were harmful and protective predictors of CHDs, respectively, with positive and negative interactions suggested for Cd with Pb and Se with Pb, respectively. Similar associations were detected for subgroups of CHDs, including conotruncal defects, septal defects, and right ventricle outflow tract obstruction. Our results suggest that even under the current standard for protecting human health (10 μg/dL), Pb exposure poses an important health threat. These data can be used for developing interventions and identifying high-risk pregnancies. [ABSTRACT FROM AUTHOR]

• First study of congenital heart defects (CHDs) association with PFAS in maternal and cord blood. • Higher levels of maternal PFAS exposure were associated with higher odds of CHDs. • The association is specifically significant in septal and conotuncal defects. Accumulating evidence suggests that environmental pollutants may contribute to the occurrence of congenital heart defects (CHDs). However, no previous studies have evaluated the impact of perfluoroalkyl substances (PFAS), persistent environmental pollutants, on CHDs. This exploratory study aimed to generate testable hypotheses of the association between gestational PFAS and the risk of CHDs. A nested case-control study was conducted in a cohort of 11,578 newborns. Exposure odds ratios were compared between 158 CHD cases and 158 non-malformed controls delivered at the same hospital, individually matched by maternal age (±5 years) and parity. Concentrations of 27 PFAS, including linear and branched isomers, were determined in maternal peripheral blood and cord blood plasma collected before and during delivery using a ultra-performance liquid chromatography coupled to mass spectrometry. Conditional logistic regression was utilized to evaluate associations between individual PFAS and the risk of CHDs, adjusted for confounding variables. Maternal gestational exposure to the highly branched perfluorooctanesulfonate (PFOS) isomer potassium 6-trifluoromethyperfluoroheptanesulfonate [6 m-PFOS, adjusted odds ratio (aOR) (95% CI) = 2.47(1.05,5.83)] and perfluorodecanoic acid [PFDA, aOR (95% CI) = 2.33(1.00,5.45)] were associated with increased odds of septal defects with statistical significance, while linear PFOS [aOR (95% CI) = 3.65(1.09,12.16)] and perfluoro-n-dodecanoic acid [PFDoA, aOR (95% CI) = 6.82(1.75, 26.61)] were associated with conotruncal defects. Effect estimates also suggested associations for higher maternal 6 m-PFOS and PFDA concentrations with ventricular septal defect. However, we did not observe these associations in cord blood. These exploratory findings suggested that gestational exposure to most PFAS, especially linear PFOS, 6 m-PFOS, PFDA, and PFDoA, was associated with greater risks for septal and conotruncal defects. However, a larger, adequately powered study is needed to confirm our findings, and to more comprehensively investigate the potential teratogenic effects of other more recently introduced PFAS, and on associations with individual CHD subtypes. [ABSTRACT FROM AUTHOR]

Low maternal socioeconomic status (SES) is considered as a risk factor of congenital heart diseases (CHDs) in offspring. However, the pathways underpinning the SES-CHDs associations are unclear. We assessed if first trimester maternal folic acid supplementation (FAS) is a mediator of the SES-CHDs associations. This case-control study included 8379 CHD cases and 6918 CHD-free controls from 40 participating centers in Guangdong, Southern China, 2004-2016. All fetuses were screened for CHDs using ultrasound and cases were confirmed by echocardiogram. We collected SES and FAS information during face-to-face interview by obstetricians using a structured questionnaire. Low SES was defined as education attainment <12 years, household individual income <3000 Chinese Yuan/person/month or unemployment. FAS referred to at least 0.4 mg of daily folic acid intake over 5 days/week continuously. We used causal mediation analysis to estimate the direct, indirect and proportion mediated by FAS on the SES-CHDs associations adjusted for confounders. Both low maternal income and education were significantly associated with increased risks of CHDs and lower prevalence of FAS. Low maternal FAS prevalence mediated 10% [95%CI:5%,13%] and 3% [95%CI:1%,5%] of the maternal low income-CHDs and the maternal low education-CHDs associations, respectively. In addition, FAS mediated the highest proportion of the associations between income and multiple critical CHDs [46.9%, 95%CI:24.7%,77%] and conotruncal defects [31.5%, 95%CI:17.1%,52.0%], respectively. Maternal FAS partially mediated the SES-CHDs associations, especially among the most critical and common CHDs. Promoting FAS in low SES women of childbearing age may be a feasible intervention to help prevent CHDs. [ABSTRACT FROM AUTHOR]