BACKGROUND: Pretricuspid shunts have been associated with poorer survival rates in patients with Eisenmenger syndrome compared with postricuspid shunts and complex lesions. However, the risk stratification for persistent pulmonary hypertension (PH) in this population remains uncertain.
RESULTS: We retrospectively enrolled 103 patients with pretricuspid shunts with high total pulmonary resistance >4.5 Wood units (estimated pulmonary vascular resistance ≥3 Wood units). During a mean±SD follow-up of 20.95±24.84 months, 32 patients developed postoperative persistent PH after shunt correction. We identified 3 significant predictors of postoperative persistent PH, including mean pulmonary artery pressure after inhaled oxygen ≥40.5 mm Hg (odds ratio [OR], 7.78 [95% CI, 2.02-30.03]; P<0.01), total pulmonary resistance after inhaled oxygen ≥6.5 Wood units (estimated pulmonary vascular resistance ≥5 Wood units; OR, 12.23 [95% CI, 2.12-70.46]; P<0.01), and artery oxygen saturation at rest <95% (OR, 3.34 [95% CI, 1.07-10.44]; P=0.04). We established the prediction model with the C-statistics of 0.85 (95% CI, 0.77-0.93; P<0.01), and the C-statistic was 0.83 (95% CI, 0.80-0.86) after bootstrapping 10 000 times with a good performance of the nomogram calibration curve for predicting persistent PH.
CONCLUSIONS: Our study presents a multivariable risk stratification model for persistent PH after shunt correction in adults with pretricuspid shunts. This model, based on 3 hemodynamic predictors after inhaled oxygen, may assist in identifying individuals at higher risk of persistent PH after shunt correction.

Noncompaction of the ventricular myocardium (NVM), the third most diagnosed cardiomyopathy, is characterized by prominent trabeculae and intratrabecular recesses. However, the genetic etiology of 40%-60% of NVM cases remains unknown. Here, we identify two infants with NVM, in a nonconsanguineous family, with a typical clinical presentation of persistent bradycardia since the prenatal period. A homozygous missense variant (R223L) of RCAN family member 3 (RCAN3) is detected in both infants using whole-exome sequencing. In the zebrafish model, marked cardiac dysfunction is detected in rcan3 deficiency (MO-rcan3ATG-injected) and rcan-/- embryos. Developmental dysplasia of both endocardial and myocardial layers is also detected in rcan3-deficient embryos. RCAN3 R223L variant mRNAs can not rescue heart defects caused by rcan3 knockdown or knockout; however, hRCAN3 mRNAs rescue these phenotypes. RNA-seq experiments show that several genes involved in cardiomyopathies are significantly regulated through multiple signaling pathways in the rcan3-knockdown zebrafish model. In human cardiomyocytes, RCAN3 deficiency results in reduced proliferation and increased apoptosis, together with an abnormal mitochondrial ultrastructure. Thus, we suggest that RCAN3 is a susceptibility gene for cardiomyopathies, especially NVM and that the R223L mutation is a potential loss-of-function variant.

Experimental evidence has indicated a correlation between in-utero exposure to neonicotinoid pesticides (NEOs) and adverse birth outcomes in mammals. However, the distribution of NEO exposure during human pregnancy, as well as its association with congenital heart diseases (CHDs), the most common birth defects, are unclear. Our purpose was to explore the distribution of and contributing factors to NEO exposure in pregnant women during early-mid pregnancy and to assess the associations between NEOs and CHDs. This nested case-control study was conducted within an ongoing prospective birth cohort study and enrolled 141 CHD singletons and their 282 individually matched controls. Six \"parent\" NEOs and three NEO metabolites were measured in maternal serum collected at an average gestational age of 16 weeks, using liquid chromatography-tandem mass spectrometry. Logistic regression was used to quantify the NEOs-CHDs associations and explore potential contributing factors to serum NEO levels in controls. N-desmethyl acetamiprid (N-dm-ACE) and imidacloprid (IMI) were the most frequently detected NEOs, found in 100% and 20% of maternal sera, respectively. We did not find a statistically significant association between total NEOs and overall CHDs. However, there was a trend towards a higher risk of septal defects with greater serum NEOs (ORs ranged from 1.80 to 2.36), especially nitro-containing NEOs represented by IMI. Pregnant women with lower education had elevated serum total NEOs compared to women with higher education (OR = 48.39, 95% CI: 23.48-99.72). Pregnant women were primarily exposed to N-dm-ACE and IMI during early-mid pregnancy. Gestational exposure to NEOs may be associated with an increased risk of septal defects, but the evidence is limited at present. Education is a potential contributing factor to NEO exposure in pregnant women. Larger and more precise studies with longitudinal biospecimen collection, are recommended to validate our exploratory findings.

暂无摘要。

UNASSIGNED: The study aimed to monitor fetuses with tetralogy of Fallot (TOF) after prenatal counseling and how it influenced the decision of parents to terminate the pregnancy.
UNASSIGNED: Fetuses with isolated TOF diagnosed between January 2019 and December 2021 were prospectively enrolled. The follow-up period extended until termination or 6 months after the operation.
UNASSIGNED: Of the 1,026 fetuses diagnosed with cardiac defects, 129 were identified to have isolated TOF and completed the follow-up. A total of 55 (42.6%) fetuses were terminated, with larger maternal age (odds ratio: 0.893, 95% confidence interval: 0.806-0.989, P = 0.031) as the protective factor. The maternal anxiety score, gestational weeks, and pulmonary-to-aortic-diameter ratio lost significance in multivariate analysis. Subjectively, the two most common reasons for terminating the pregnancy were worries about the prognosis (41.8%) and concerns about the possible suffering of the unborn child (18.2%). The prenatal diagnosis was accurate in 73 of the 74 (98.6%) live births. Out of the 64 live births that underwent surgical repair in our center, 57 (89.1%) received primary repair, with a median age of 104 days, and 49 (76.6%) underwent valve-sparing repair. No perioperative death occurred.
UNASSIGNED: Termination for fetuses with TOF remains common in China. Live births with TOF can be safely and effectively managed.

Folic acid (FA) supplementation is associated with a lower risk of the neural tube and heart defects and is recommended for women of childbearing age. Although there are detailed recommendations, differences in the initiation time and duration of FA supplementation remain poorly studied.
A multicentre prospective study of 17,713 women was conducted. The incidence of congenital malformations in women taking a recommended dosage (e.g. 0.4 or 0.8 mg/day) of FA was compared with that in women without supplementation. The predicted probability of malformations by the initiation time and duration of FA use was estimated to determine optimal options.
Periconceptional FA supplementation was associated with a lower and insignificant risk of congenital malformations (1.59% vs. 2.37%; odds ratio [OR] 0.69; 95% confidence interval [CI]: 0.44-1.08), heart defects (3.8 vs. 8.0 per 1000 infants; OR, 0.47; 0.21-1.02), and neural tube defects (7.0 vs. 11.5 per 10,000 infants; OR, 0.64; 0.08-5.15). FA use after pregnancy provided greater protection against total malformations. Statistically significant associations were found in women who initiated FA supplementation in the first month of gestation (OR, 0.55; 95% CI: 0.33-0.91) and in those who supplemented for 1 to 2 months (OR, 0.59; 95% CI: 0.36-0.98). Similar results were found for heart defects. The optimal initiation time was 1.5 (optimal range: 1.1 to 1.9) months before pregnancy and a duration of 4.0 (3.7 to 4.4) months was reasonable to achieve the lowest risk of congenital malformations. Heart defect prevention required an earlier initiation (2.2 vs. 1.1 months before pregnancy) and a longer duration (4.7 vs. 3.7 months) than the prevention of other malformations.
The timely initiation of FA supplementation for gestation was associated with a decreased risk of congenital malformations, which was mainly attributed to its protection against heart defects. The initiation of FA supplementation 1.5 months before conception with a duration of 4 months is the preferred option for congenital malformation prevention.
Chictr.org.cn identifier: ChiCTR-SOC-17010976.

Evidence remains limited about the association of maternal exposure to ambient fine particulate matter (airborne particles with an aerodynamic diameter ≤2.5 µm [PM2.5]) with fetal congenital heart defects (CHDs) in highly polluted regions, and few studies have focused on preconception exposure.
Using a nationwide surveillance-based case-control design in China, we examined the association between maternal exposure to PM2.5 during periconception (defined as 3 months before conception until 3 months into pregnancy) and risk of CHD in offspring. The study included 1 434 998 births involving 7335 CHDs from 2014 through 2017 on the basis of the National Population-Based Birth Defects Surveillance System, covering 30 provinces, municipalities, or municipal districts in China. We assigned maternal PM2.5 exposure during the periconception period to each participant using satellite-based PM2.5 concentrations at 1-km spatial resolution. Multilevel logistic regression models were used to calculate the multivariable-adjusted odds ratio and 95% CI for CHDs in offspring associated with maternal PM2.5 exposure, and the exposure-response association was investigated using restricted cubic spline analysis. Subgroup or sensitivity analyses were conducted to identify factors that may modify the association.
The average maternal exposure to PM2.5 levels across all participants was 56.51 μg/m3 (range, 10.95 to 182.13 μg/m3). For each 10 μg/m³ increase in maternal PM2.5 exposure, the risk of CHDs in offspring was increased by 2% (odds ratio, 1.02 [95% CI, 1.00 to 1.05]), and septal defect was the most influenced subtype (odds ratio, 1.04 [95% CI, 1.01 to 1.08]). The effect of PM2.5 on CHD risk was more pronounced during the preconception period. Mothers <35 years of age, those living in northern China, and those living in low-income areas were more susceptible to PM2.5 exposure than their counterparts (all P<0.05). PM2.5 exposure showed a linear association with total CHDs or specific CHD types.
High maternal PM2.5 exposure, especially during the preconception period, increases risk of certain types of CHD in offspring. These findings are useful for CHD prevention and highlight the public health benefits of improving air quality in China and other highly polluted regions.

The endothelial-mesenchymal transition (EndoMT) is a fundamental process for heart valve formation and defects in EndoMT cause aortic valve abnormalities. Our previous genome-wide association study identified multiple variants in a large chromosome 8 segment as significantly associated with bicuspid aortic valve (BAV). The objective of this study is to determine the biological effects of this large noncoding segment in human induced pluripotent stem cell (hiPSC)-based EndoMT.
A large genomic segment enriched for BAV-associated variants was deleted in hiPSCs using 2-step CRISPR/Cas9 editing. To address the effects of the variants on GATA4 expression, we generated CRISPR repression hiPSC lines (CRISPRi) as well as hiPSCs from BAV patients. The resulting hiPSCs were differentiated to mesenchymal/myofibroblast-like cells through cardiovascular-lineage endothelial cells for molecular and cellular analysis. Single-cell RNA sequencing was also performed at different stages of EndoMT induction.
The large deletion impaired hiPSC-based EndoMT in multiple biallelic clones compared with their isogenic control. It also reduced GATA4 transcript and protein levels during EndoMT, sparing the other genes nearby the deletion segment. Single-cell trajectory analysis revealed the molecular reprogramming during EndoMT. Putative GATA-binding protein targets during EndoMT were uncovered, including genes implicated in endocardial cushion formation and EndoMT process. Differentiation of cells derived from BAV patients carrying the rs117430032 variant as well as CRISPRi repression of the rs117430032 locus resulted in lower GATA4 expression in a stage-specific manner. TWIST1 was identified as a potential regulator of GATA4 expression, showing specificity to the locus tagged by rs117430032.
BAV-associated distal regions regulate GATA4 expression during hiPSC-based EndoMT, which in turn promotes EndoMT progression, implicating its contribution to heart valve development.

High-energy or high-protein feeding offers a promising approach to improving malnutrition in children after congenital heart surgery. However, the effect of high-energy or high-protein feeding in this population has not yet been systematically reviewed. Therefore, we aimed to assess the safety and effectiveness of high-energy or high-protein feeding in children after congenital heart surgery. Five electronic databases (PubMed, Embase, CENTRAL, CINAHL, and Scopus) were searched from inception to April 23, 2022. After screening the literature according to inclusion and exclusion criteria, a risk of bias assessment was performed using version 2 of the Cochrane risk-of-bias tool for randomized trials, and the certainty of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations system. Finally, the random effects model was used to perform a meta-analysis of all data. A total of 609 subjects from 9 studies were included for qualitative analysis, and meta-analyses were performed on data from 8 of these studies. The results showed that high-energy and/or high-protein feeding did not increase feeding intolerance (RR = 1.09, 95% CI: 0.80, 1.48) or fluid intake (MD =  - 12.50 ml/kg/d, 95% CI: - 36.10, 11.10); however, the intervention was beneficial in increasing weight (MD = 0.5 kg, 95% CI: 0.23, 0.77) and reducing the duration of mechanical ventilation (MD =  - 17.45 h, 95% CI: - 27.30, - 7.60), intensive care unit (ICU) stay (MD =  - 1.45 days, 95% CI: - 2.36, - 0.54) and hospital stay (MD =  - 2.82 days, 95% CI: - 5.22, - 0.43). However, high-energy and/or protein feeding did not reduce the infection rate (RR = 0.68, 95% CI: 0.25, 1.87) or mortality (RR = 1.50, 95% CI: 0.47, 4.82).
CONCLUSIONS: The certainty of the evidence was graded as moderate to high, which suggests that high-energy and/or high-protein feeding may be safe in children after congenital heart surgery. Furthermore, this intervention improves nutrition and reduces the duration of mechanical ventilation, length of ICU stay, and length of hospital stay. However, the overall conclusion of this meta-analysis will need to be confirmed in a cohort of patients with different cardiac physiologies.
BACKGROUND: • Malnutrition is highly prevalent in children with congenital heart disease (CHD) and can negatively affect the prognosis of these children. • High-energy and/or high-protein feeding can improve nutrition status and facilitate recovery; however, evidence on its safety and efficacy is lacking.
BACKGROUND: • Pooled data suggest that high-energy and/or high-protein feeding does not increase fluid intake or feeding intolerance in children with CHD. • High-energy and/or high-protein feeding may reduce the duration of mechanical ventilation, length of intensive care unit stay, and length of hospital stay.

Copy number variant-sequencing (CNV-seq) and exome sequencing (ES) have been used as powerful tools in understanding the role of genetic variants in congenital heart diseases (CHDs). A few previous large cohort studies have utilized CNV-seq and ES to investigate prenatally diagnosed CHD. Here, we sought to determine the value of CNV-seq and ES for genetic evaluation of foetal CHDs.
We recruited 398 pregnant women diagnosed with CHDs between 8 January 2017 and 30 November 2020. CNV-seq and ES were performed on foetal and parent samples. CHD cases were classified following the guidelines of the International Paediatric and Congenital Cardiac Code and the Tenth and Eleventh Revisions of the International Classification of Diseases. Data on aneuploids (AUP), pathogenic CNVs (pCNVs), and single nucleotide variants (SNVs) were collected and compared, following appropriate procedures. We identified genetic abnormalities in 129 (32.41%) foetuses. These abnormalities included AUP (10.80%), pCNVs (13.32%), and SNVs (8.04%). ES analysis yielded higher SNVs in cases without AUP or pCNVs. Non-isolated CHDs were associated with higher genetic abnormalities than isolated CHDs, mainly due to AUP differences between the two groups. The prevalence of genetic defects was the highest in foetuses with atrioventricular septal defects (AVSD), left ventricular outflow tract obstruction (LVOTO), and conotruncal defects (CTD). AVSD and anomalies of atrioventricular junctions and valves were associated with AUP abnormalities. CTD, anomalies of extrapericardial arterial trunks, and anomalies of the ventricular outflow tracts were the most common CHD categories diagnosed using CNVs. The most common CHDs associated with single ventricle (SV) abnormalities were heterotaxy (Hex) (14.89%), LVOTO (14.58%), and ventricular septal defect (VSD) (26.67%, 4/15). Although the ES yields were higher than CNV-seq for VSD (44.4%, 4/9), LVOTO (20%, 7/35), Hex (14.89%, 7/47), and CTD (9.1%, 11/121), its diagnostic yield did not increase for SV (6.7%, 1/15), AVSD (3.8%, 1/26), or right ventricular obstruction defects (2.6%, 1/38). The most common mutations were observed in KMT2D, CHD7, and NOTCH1.
To our knowledge, this is the largest cohort study to investigate the incidence of SNVs using ES in foetal CHD. CNV-seq and ES identified genetic abnormalities in nearly 1/3 of foetal CHD cases. Thus, CNV-seq and ES can provide clinically relevant information for pregnancy management.