Applications of artificial intelligence-powered prenatal diagnosis for congenital heart disease.

Artificial intelligence (AI) has made significant progress in the medical field in the last decade. The AI-powered analysis methods of medical images and clinical records can now match the abilities of clinical physicians. Due to the challenges posed by the unique group of fetuses and the dynamic organ of the heart, research into the application of AI in the prenatal diagnosis of congenital heart disease (CHD) is particularly active. In this review, we discuss the clinical questions and research methods involved in using AI to address prenatal diagnosis of CHD, including imaging, genetic diagnosis, and risk prediction. Representative examples are provided for each method discussed. Finally, we discuss the current limitations of AI in prenatal diagnosis of CHD, namely Volatility, Insufficiency and Independence (VII), and propose possible solutions.

Study on the correlation between retrograde ductus arteriosus flow and right ventricular function evaluated by Z-score of tricuspid annular plane systolic excursion in fetuses with Ebstein anomaly.

PURPOSE: To analyze the influence of RV dysfunction evaluated by Free-angle M-mode (FAM) TAPSE Z-score on retrograde ductus arteriosus flow (RDAF) in fetuses with Ebstein anomaly (EA). METHODS: A retrospective cohort study of 30 EA and 60 normal fetuses were enrolled. The EA group was divided into two groups: with RDAF (EA-RDAF group) and without RDAF (EA-NRDAF group). FAM was used to measure TAPSE of EA and normal fetuses, and Z-scores were calculated. The differences of FAM-TAPSE Z-score, gestational week (GW), maternal age (MA), and mitral valve-tricuspid valve distance (MTD) between three groups were compared. The correlation and binary logistic regression between FAM-TAPSE Z-score, GW, MA, MTD, and RDAF were analyzed. RESULTS: FAM-TAPSE Z-score was significantly lower in EA-RDAF group compared to other groups (p < 0.05). FAM-TAPSE Z-score, GW, and MA were negatively correlated with RDAF (p < 0.05), but no correlation was found between TR, MDT, and RDAF (p > 0.05). Multivariate logistic regression showed that FAM-TAPSE Z-score was an independent influencing factor for RDAF (OR = 0.102, p < 0.05). CONCLUSION: RV dysfunction is an independent factor leading to RDAF in EA fetus, which provides a feasible theoretical basis for further study on improvement of RV function through intrauterine treatment to delay and prevent the RDAF, to avoid death cycle and improve live-birth rate.

Generation of a TSC2 knockout embryonic stem cell line by CRISPR/Cas9 editing.

Tuberous Sclerosis Complex (TSC) is a severe developmental disorder with various clinical effects, primarily caused by TSC2 gene mutations, often involving loss of function(Henske,et al., 2016).To explore role of TSC2 in human heart development, we successfully developed a TSC2 knockout (TSC2-/-) human embryonic stem cells (hESCs) line using CRISPR/Cas9 gene editing. This TSC2-/- hESC line maintained a normal karyotype, expressed pluripotency markers strongly, and could differentiate into all three germ layers in vivo. This cell line will be a valuable tool for future research on the role of TSC2 in heart development.

Maternal exposure to ambient ozone and fetal conotruncal heart defects in China: A multicenter cohort study.

BACKGROUND: The relationships between maternal genetic and environmental exposure and conotruncal heart defects (CTDs) have been extensively investigated. Nevertheless, there is limited knowledge regarding the impact of ozone (O3) on the risk of CTDs. OBJECTIVE: To explore the correlation between maternal exposure to O3 and CTDs in China. METHODS: Pregnant women who underwent fetal echocardiography at Beijing Anzhen Hospital between January 2013 and December 2021 were enrolled. Their sociodemographic characteristics and lifestyle information, along with fetal data, were systematically collected. Fetal echocardiography was used to detect CTDs. Maternal exposure to ambient O3 during the embryonic period, the first trimester, the three months preceding the last menstrual period, and the perinatal period was estimated using residential addresses or hospital addresses associated with prenatal visits. The concentration of O3 was divided by quartiles, with the first quartile serving as a reference. Adjusted logistic regression models were employed to examine the associations between every 10 µg/m3 increase or quartile increase in ambient O3 exposure and CTDs. RESULTS: Among 24,278 subjects, 1069 exhibited fetuses with CTDs. Maternal exposure to ambient O3 during three pregnancy periods was associated with increased CTD risk. The adjusted odds ratio (OR) and 95% confidence interval (CI) were 1.271 (1.189-1.360) per 10 µg/m3 increase in O3 during the perinatal period. For each quartile of O3, the risk increased with increasing exposure concentration, particularly during the perinatal period (OR = 2.206 for quartile 2, 2.367 for quartile 3, and 3.378 for quartile 4, all P<0.05). CONCLUSIONS: Elevated maternal exposure to O3 during pregnancy, particularly in the perinatal period, is linked to an increased risk of fetal CTDs. Further longitudinal analyses are needed to validate these results.

Glymphatic System Impairment Contributes to the Formation of Brain Edema After Ischemic Stroke.

BACKGROUND: Blood-brain barrier damage has traditionally been considered to determine the occurrence and development of poststroke brain edema, a devastating and life-threatening complication. However, no treatment strategy targeting blood-brain barrier damage has been proven clinically effective in ameliorating brain edema. METHODS: In mice with stroke models induced by transient middle cerebral artery occlusion (MCAO), the changes in glymphatic system (GS) function impairment were detected by ex vivo fluorescence imaging, 2-photon in vivo imaging, and magnetic resonance imaging within 1 week after MCAO, and the effects of GS impairment and recovery on the formation and resolution of brain edema were evaluated. In addition, in patients with ischemic stroke within 1 week after onset, changes in GS function and brain edema were also observed by magnetic resonance imaging. RESULTS: We found that the extravasation of protein-rich fluids into the brain was not temporally correlated with edema formation after MCAO in mice, as brain edema reabsorption preceded blood-brain barrier closure. Strikingly, the time course of edema progression matched well with the GS dysfunction after MCAO. Pharmacological enhancement of the GS function significantly alleviated brain edema developed on day 2 after MCAO, accompanied by less deposition of Aß (amyloid-ß) and better cognitive function. Conversely, functional suppression of the GS delayed the absorption of brain edema on day 7 after MCAO. Moreover, patients with ischemic stroke revealed a consistent trend of GS dysfunction after reperfusion as MCAO mice, which was correlated with the severity of brain edema and functional outcomes. CONCLUSIONS: GS is a key contributor to the formation of brain edema after ischemic stroke, and targeting the GS may be a promising strategy for treating brain edema in ischemic stroke. REGISTRATION: URL: https://www.chictr.org.cn/showproj.html?proj=162857; Unique identifier: NFEC-2019-189.

Application of neural networks in prenatal diagnosis of atrioventricular septal defect.

Background: There is no relevant study on landmarks detection, one of the Convolutional Neural Network algorithms, in the field of fetal echocardiography (FE). This study aimed to explore whether automatic landmarks detection could be used in FE correctly and whether the atrial length (AL) to ventricular length (VL) ratio (AVLR) could be used to diagnose atrioventricular septal defect (AVSD) prenatally. Methods: This was an observational study. Two hundred and seventy-eight four-chamber views in end diastole, divided into the normal, AVSD, and differential diagnosis groups, were retrospectively included in this study. Seven landmarks were labeled sequentially by the experts on these images, and all images were divided into the training and test sets for normal, AVSD, and differential diagnosis groups. U-net, MA-net, and Link-net were used as landmark prediction neural networks. The accuracy of the landmark detection, AL, and VL measurements, as well as the prenatal diagnostic effectiveness of AVLR for AVSD, was compared with the expert labeled. Results: U-net, MA-net, and Link-net could detect the landmarks precisely (within the localization error of 0.09 and 0.13 on X and Y axis) and measure AL and VL accurately (the measured pixel distance error of AL and VL were 0.12 and 0.01 separately). AVLR in AVSD was greater than in other groups (P<0.0001), but the statistical difference was not obvious in the complete, partial, and transitional subgroups (P>0.05). The diagnostic effectiveness of AVLR calculated by three models, area under receiver operating characteristic curve could reach 0.992 (0.968-1.000), was consistent with the expert labeled. Conclusions: U-net, Link-net, and MA-net could detect landmarks and make the measurements accurately. AVLR calculated by three neural networks could be used to make the prenatal diagnosis of AVSD.

Maternal Exposure to Extreme Cold Events and Risk of Congenital Heart Defects: A Large Multicenter Study in China.

Over the past decade, extreme temperature events have become more frequent and longer in duration. Previous studies on the association between extreme cold events (ECEs) and congenital heart defects (CHDs) are few and inconsistent. We conducted a national multicenter study in 1313 hospitals in 26 provinces in China and collected a total of 14 808 high CHD-risk participants from 2013 to 2021. We evaluated the ECEs experienced by each pregnant women during the embryonic period (3-8 weeks). The results indicated that ECEs experienced by pregnant women during the embryonic period were associated with the development of fetal CHD and were more strongly associated with some specific fetal CHD subtypes, such as pulmonary stenosis, pulmonary atresia, and tetralogy of Fallot. Of the CHD burden, 2.21% (95% CI: 1.43, 2.99%)-2.40% (95% CI: 1.26, 3.55%) of fetal CHD cases were attributable to ECEs during the embryonic period. Our findings emphasize the need to pay more attention to pregnant women whose embryonic period falls during the cold season to reduce cold spell detriments to newborns.

Reducing SULT2B1 promotes the interaction of LncRNAgga3-204 with SMAD4 to inhibit the macrophage inflammatory response and delay atherosclerosis progression.

Inflammation is a crucial pathophysiological mechanism in atherosclerosis (AS). This study aims to investigate the impact of sulfotransferase family 2b member 1 (SULT2B1) on the inflammatory response of macrophages and the progression of AS. Here, we reported that SULT2B1 expression increased with the progression of AS. In AS model mice, knockdown of Sult2b1 led to remission of AS and reduced inflammation levels. Further exploration of the downstream molecular mechanisms of SULT2B1 revealed that suppressing Sult2b1 in macrophages resulted in decreased levels of 25HC3S in the nucleus, elevated expression of Lxr, and increased the transcription of Lncgga3-204. In vivo, knockdown of Lncgga3-204 aggravated the inflammatory response and AS progression, while the simultaneous knockdown of both Sult2b1 and Lncgga3-204 exacerbated AS and the inflammatory response compared with knockdown of Sult2b1 alone. Increased binding of Lncgga3-204 to SMAD4 in response to oxidized-low density lipoprotein (ox-LDL) stimulation facilitated SMAD4 entry into the nucleus and regulated Smad7 transcription, which elevated SMAD7 expression, suppressed NF-κB entry into the nucleus, and ultimately attenuated the macrophage inflammatory response. Finally, we identified the presence of a single nucleotide polymorphism (SNP), rs2665580, in the SULT2B1 promoter region in monocytes from coronary artery disease (CAD) patients. The predominant GG/AG/AA genotypes were observed in the Asian population. Elevated SULT2B1 expression in monocytes with GG corresponded to elevated inflammatory factor levels and more unstable coronary plaques. To summarize, our study demonstrated that the critical role of SULT2B1/Lncgga3-204/SMAD4/NF-κB in AS progression. SULT2B1 serves as a novel biomarker indicating inflammatory status, thereby offering insights into potential therapeutic strategies for AS.

Improved Multi-Head Self-Attention Classification Network for Multi-View Fetal Echocardiography Recognition.

The accurate acquisition of multiview fetal cardiac ultrasound images is very important for the diagnosis of fetal congenital heart disease (FCHD). However, these manual clinical procedures have drawbacks, e.g., varying technical capabilities and inefficiency. Therefore, exploring automatic recognition method for multiview images of fetal heart ultrasound scans is highly desirable to improve prenatal diagnosis efficiency and accuracy. In this work, we propose an improved multi-head self-attention mechanism called IMSA combined with residual networks to stably solve the problem of multiview identification and anatomical structure localization. In details, IMSA can capture short- and long-range dependencies from different subspaces and merge them to extract more precise features, thus making use of the correlation between fetal heart structures to make view recognition more focused on anatomical structures rather than disturbing regions, such as artifacts and speckle noises. We validate our proposed method on fetal cardiac ultrasound imaging datasets from a single center and 38 multicenter studies and the results outperform other state-of-the-art networks by 3%-15% of F1 scores in fetal heart six standard view recognition.Clinical Relevance- This technology has great potential in assisting cardiologists to complete the automatic acquisition of multi-section fetal echocardiography images.

Interaction between ozone and paternal smoking on fetal congenital heart defects among pregnant women at high risk: a multicenter maternal-fetal medicine study.

BACKGROUND: Evidence remains limited on the association between maternal ozone (O3) exposure and congenital heart defects (CHDs) in offspring, and few studies have investigated the interaction and modification of paternal smoking on this association. METHODS: Using a sample including pregnant women at high risk of fetal CHD (with metabolic disease, first-trimester viral infection, family history of CHD, etc.) from a maternal-fetal medicine study covering 1313 referral hospitals in China during 2013-2021, we examined the associations between maternal O3 exposure during 3-8 weeks of gestational age and fetal CHD in offspring and investigated the interaction and modification of paternal smoking on this association. CHD was diagnosed by fetal echocardiograms, maximum daily 8-hour average O3 exposure data at a 10 km × 10 km spatial resolution came from the Tracking Air Pollution in China dataset, and paternal smoking was collected using questionnaires. Logistic regression models were used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 27,834 pregnant women at high risk of fetal CHD, 17.4% of fetuses were diagnosed with CHD. Each 10 µg/m3 increase in maternal O3 exposure was associated with a 17% increased risk of CHD in offspring (OR = 1.17, 95% CI = 1.14-1.20). Compared with paternal nonsmoking and maternal low O3 exposure, the ORs (95% CI) of CHD for smoking and low O3 exposure, nonsmoking and high O3 exposure, and smoking and high O3 exposure were 1.25 (1.08-1.45), 1.81 (1.56-2.08), and 2.23 (1.84-2.71), respectively. Paternal smoking cessation seemingly mitigated the increased risk of CHD. CONCLUSIONS: Maternal O3 exposure and paternal smoking were interactively associated with an increased risk of fetal CHD in offspring, which calls for effective measures to decrease maternal exposure to O3 pollution and secondhand smoke for CHD prevention.

Echocardiographic features and influencing factors of pulmonary hypertension of total anomalous pulmonary venous connection in adults.

Background: Patients with total anomalous pulmonary venous connection (TAPVC) generally have symptoms during the neonatal period and infancy, and the fatality rate is extremely high. Most patients do not survive to adulthood. This study analyzed the clinical and transthoracic echocardiographic (TTE) manifestations of adult patients with TAPVC, summarized the echocardiographic characteristics of TAPVC, and identified the factors influencing pulmonary hypertension. Methods: Data from adult patients with TAPVC from Beijing Anzhen Hospital, China, were retrospectively collected for analyses, including sex, age, history of gestation, clinical manifestations, echocardiographic parameters, and blood oxygen levels. Patients were grouped for comparative analyses based on their pulmonary artery systolic pressure (PASP) (≥60 vs. <60 mmHg); 32 atrial septal defect (ASD) patients were included as a control group. Results: (I) Sixteen patients were identified with TAPVC (11 women and 5 men; mean age: 32.2±9.5 years), including 8, 4, and 4 patients with supra-cardiac, mixed, and intracardiac type TAPVC, respectively. Furthermore, 10 patients had moderate or severe tricuspid regurgitation, and 6 had a PASP of ≥60 mmHg. Echocardiography misdiagnosed 2 patients with an ASD. (II) The TAPVC group patients had a smaller left atrium (LA) and a lower aorta/pulmonary artery ratio than ASD-only group patients. However, the right ventricular diameter (RVd) and right atrium were larger in patients with TAPVC than in those with only ASD. (III) The RVd was larger and the LA was smaller in patients with a PASP of ≥60 mmHg than in those with a PASP of <60 mmHg. (IV) Of those with a PASP of ≥60 mmHg, TAPVC patients had a smaller LA and a larger RVd than those with only ASD. (V) Pregnancy affected the PASP (adjusted odds ratio: 15.000, 95% confidence interval: 1.031-218.300, P=0.047). (VI) Echocardiography indicated that TAPVC patients with ASD had a right to left shunt at the atrial level and the pulmonary vein (PV) was not connected to the LA. Conclusions: Searching for the PV by TTE is necessary for patients with ASDs, which may help avoid misdiagnosis. Moreover, pregnancy affects the PASP. Patients with TAPVC may present with a larger right heart, smaller LA, and lower aorta/pulmonary artery ration than those with only ASD.

Improving the Quality of Fetal Heart Ultrasound Imaging With Multihead Enhanced Self-Attention and Contrastive Learning.

Fetal congenital heart disease (FCHD) is a common, serious birth defect affecting ∼1% of newborns annually. Fetal echocardiography is the most effective and important technique for prenatal FCHD diagnosis. The prerequisites for accurate ultrasound FCHD diagnosis are accurate view recognition and high-quality diagnostic view extraction. However, these manual clinical procedures have drawbacks such as, varying technical capabilities and inefficiency. Therefore, the automatic identification of high-quality multiview fetal heart scan images is highly desirable to improve prenatal diagnosis efficiency and accuracy of FCHD. Here, we present a framework for multiview fetal heart ultrasound image recognition and quality assessment that comprises two parts: a multiview classification and localization network (MCLN) and an improved contrastive learning network (ICLN). In the MCLN, a multihead enhanced self-attention mechanism is applied to construct the classification network and identify six accurate and interpretable views of the fetal heart. In the ICLN, anatomical structure standardization and image clarity are considered. With contrastive learning, the absolute loss, feature relative loss and predicted value relative loss are combined to achieve favorable quality assessment results. Experiments show that the MCLN outperforms other state-of-the-art networks by 1.52-13.61% when determining the F1 score in six standard view recognition tasks, and the ICLN is comparable to the performance of expert cardiologists in the quality assessment of fetal heart ultrasound images, reaching 97% on a test set within 2 points for the four-chamber view task. Thus, our architecture offers great potential in helping cardiologists improve quality control for fetal echocardiographic images in clinical practice.

[Clinical and genetic characteristics of 12 cases of Loeys-Dietz syndrome].

OBJECTIVE: To summarize the clinical features and spectrum of genetic variants in 12 patients with Loeys-Dietz syndrome (LDS), and to explore the correlation between the type of genetic variants and clinical phenotypes. METHODS: Twelve patients suspected for LDS at Beijing Anzhen Hospital Affiliated to Capital Medical University from January 2015 to January 2022 were selected as the study subjects. Clinical data of the patients were collected. Genomic DNA was extracted from peripheral blood samples and subjected to genetic testing. Pathogenicity of candidate variants was analyzed. RESULTS: The clinical phenotypes of the 12 patients have mainly included cardiovascular, musculoskeletal, craniofacial, skin, ocular and other systemic signs. Four patients (patients 5-1, 5-2, 6, 7) have carried heterozygous missense variants of the TGFBR1 gene, 5 patients (patients 1-1, 1-2, 2, 3, 4) have carried heterozygous variants of the TGFBR2 gene, and 2 patients (patients 8-1, 8-2) had carried heterozygous frameshift variants of the TGFB3 gene. One patient (patient 9) had carried a heterozygous missense variant of the SMAD3 gene. Among these, TGFBR1 c.603T>G (p.1201M) and TGFB3 c.536delA (p.H179FS35) had not been reported previously. CONCLUSION: Variants of the TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 and SMAD2 genes are mainly associated with LDS. The severity of the disease phenotype caused by the same variant may vary, whilst the clinical phenotype caused by different variant sites may be specific.

Current treatment outcomes of congenital heart disease and future perspectives.

China has the largest number of individuals with congenital heart disease (CHD) in the world and a heavy burden of CHD. Therefore, understanding current CHD treatment outcomes and patterns in China will contribute to global progress in CHD treatment and be a valuable experience. Generally, CHD treatment in China has satisfactory outcomes owing to the joint efforts by all relevant stakeholders across the country. However, efforts are needed to overcome the remaining challenges: management of mitral valve disease and paediatric end-stage heart failure needs to be improved; cohesive paediatric cardiology teams should be established and collaboration between hospitals enhanced; CHD-related medical resources need to be more accessible and equitable; and nationwide CHD databases should be enhanced. In the second paper of this Series, we aim to systematically summarise the current CHD treatment outcomes in China, discuss potential solutions, and provide future perspectives.

Improving long-term care and outcomes of congenital heart disease: fulfilling the promise of a healthy life.

Advances in the prevention, diagnosis, and treatment for congenital heart disease (CHD), the most common birth defect in China, have drastically improved survival for individuals with the disease. However, China's current health system is not well prepared to manage the growing population of people with CHD and their complex medical needs, which range from early detection of the condition and intervention for physical, neurodevelopmental, and psychosocial impairment, to long-term management of major complications and chronic health problems. Health disparities caused by long-standing regional differences in access to care pose challenges when major complications such as pulmonary hypertension arise, and when individuals with complex CHD become pregnant and give birth. Currently, no data sources track neonates, children, adolescents, and adults with CHD in China and delineate their clinical characteristics and use of health resources. This scarcity of data should warrant attention from the Chinese Government and relevant specialists in the field. In the third paper of the Series on CHD in China, we summarise key literature and current data to identify knowledge gaps and call for concerted efforts by the government, hospitals, clinicians, industries, and charitable organisations to develop an actionable, lifelong framework of congenital cardiac care that is accessible and affordable for all individuals with CHD. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

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.

Uterine hemangiopericytoma with cardiac involvement and pulmonary metastasis: A case report and literature review.

Uterine hemangiopericytoma is extremely rare. This article describes a case of uterine hemangiopericytoma. The tumor involved the parauterine vein; extended into the inferior vena cava, right cardiac cavity, and pulmonary artery; and metastasized to the lungs. It was irregular in shape and exhibited the string-of-beads sign on echocardiography, and it was tightly attached to the right ventricular surface and pulmonary artery wall. The patient underwent tumor resection without adjuvant treatment. A pelvic nodule was found 3 months postoperatively and was considered a recurrent lesion.