沈华宴
BACKGROUND:Cardiac myxoma (CM) is the most common (58%-80%) type of primary cardiac tumours. Currently, there is a need to develop medical therapies, especially for patients not physically suitable for surgeries. However, the mechanisms that shape the tumour microenvironment (TME) in CM remain largely unknown, which impedes the development of targeted therapies. Here, we aimed to dissect the TME in CM at single-cell and spatial resolution.METHODS:We performed single-cell transcriptomic sequencing and Visium CytAssist spatial transcriptomic (ST) assays on tumour samples from patients with CM. A comprehensive analysis was performed, including unsupervised clustering, RNA velocity, clonal substructure inference of tumour cells and cell-cell communication.RESULTS:Unsupervised clustering of 34 759 cells identified 12 clusters, which were assigned to endothelial cells (ECs), mesenchymal stroma cells (MSCs), and tumour-infiltrating immune cells. Myxoma tumour cells were found to encompass two closely related phenotypic states, namely, EC-like tumour cells (ETCs) and MSC-like tumour cells (MTCs). According to RNA velocity, our findings suggest that ETCs may be directly differentiated from MTCs. The immune microenvironment of CM was found to contain multiple factors that promote immune suppression and evasion, underscoring the potential of using immunotherapies as a treatment option. Hyperactive signals sent primarily by tumour cells were identified, such as MDK, HGF, chemerin, and GDF15 signalling. Finally, the ST assay uncovered spatial features of the subclusters, proximal cell-cell communication, and clonal evolution of myxoma tumour cells.CONCLUSIONS:Our study presents the first comprehensive characterisation of the TME in CM at both single-cell and spatial resolution. Our study provides novel insight into the differentiation of myxoma tumour cells and advance our understanding of the TME in CM. Given the rarity of cardiac tumours, our study provides invaluable datasets and promotes the development of medical therapies for CM.
Clinical and translational medicine 2024
Background:The prevalence and risk factors for failure to thrive (FTT) in pediatric patients with congenital heart disease (CHD) remain ambiguous. We aimed to investigate the prevalence, growth profiles, risk factors, and vulnerable subtypes of CHD associated with FTT in pediatric patients with CHD.Methods:This was a cross-sectional study based on Chinese Database for Congenital Heart Surgery. FTT was defined as either stunting or underweight (height or weight standard deviation score <-2), and they were standardized by references of normal Chinese population. Risk factors was determined with logistic regression model, and growth profiles were delineated in each subgroup.Findings:A total of 13,256 CHD patients were included in this study, with 3994 patients of mild CHD, 7195 patients of moderate CHD and 2067 patients of complex CHD. The prevalence of stunting, underweight and FTT was 24%, 29.3% and 36.9%, respectively. Preoperative anaemia, left ventricle systolic dysfunction, younger age, more complex CHD types, lower birth weight and genetic syndrome were found to be the risk factors for FTT in CHD patients. Interrupted aortic arch was revealed to be the most severe group associated with FTT.Interpretation:FTT is ubiquitous in patients with CHD and exacerbated in high-risk subgroups. Our findings hinted the necessity of early identification and intervention for FTT in patients with CHD during daily practice of pediatrics, as it has the potential to improve outcomes and enhance their quality of life. Furthermore, we advocate for the initiation of prospective research with longitudinal data to comprehensively investigate the association between FTT and CHD across the lifespan.Funding:This study was supported by National High Level Hospital Research Funding (2022-GSP-GG-19), Capital Health Research and Development of Special Fund (2022-1-4032) and National Key R&D Program of China (2022YFC3600202 and 2022YFC3600203).
The Lancet regional health. Western Pacific 2024
OBJECTIVES:Thoracic aortic aneurysm and dissection has a genetic predisposition and a variety of clinical manifestations. This study aimed to investigate the clinical and molecular characterizations of patients with thoracic aortic aneurysm and dissection and further explore the relationship between the genotype and phenotype, as well as their postoperative outcomes.METHODS:A total of 1095 individuals with thoracic aortic aneurysm and dissection admitted to our hospital between 2013 and 2022 were included. Next-generation sequencing and multiplex ligation-dependent probe amplification were performed, and mosaicism analysis was additionally implemented to identify the genetic causes.RESULTS:A total of 376 causative variants were identified in 83.5% of patients with syndromic thoracic aortic aneurysm and dissection and 18.7% of patients with nonsyndromic thoracic aortic aneurysm and dissection, including 8 copy number variations and 2 mosaic variants. Patients in the "pathogenic" and "variant of uncertain significance" groups had younger ages of aortic events and higher aortic reintervention risks compared with genetically negative cases. In addition, patients with FBN1 haploinsufficiency variants had shorter reintervention-free survival than those with FBN1 dominant negative variants.CONCLUSIONS:Our data expanded the genetic spectrum of heritable thoracic aortic aneurysm and dissection and indicated that copy number variations and mosaic variants contributed to a small proportion of the disease-causing alterations. Moreover, positive genetic results might have a possible predictive value for aortic event severity and postoperative risk stratification.
The Journal of thoracic and cardiovascular surgery 2023
[This corrects the article DOI: 10.1016/j.lanwpc.2022.100623.].
The Lancet regional health. Western Pacific 2023
Background:Economic data on congenital heart disease (CHD) in China are scarce. Therefore, this study aimed to explore the inpatient costs of congenital heart surgery and related healthcare policies from a hospital perspective.Method:We used data from the Chinese Database for Congenital Heart Surgery (CDCHS) to prospectively analyse the inpatient costs of congenital heart surgery from May 2018 to December 2020. The total expenditure was divided into 11 columns (medications, imaging, consumable items, surgery, medical cares, laboratory tests, therapy, examinations, medical services, accommodations, and others), and explored according to the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery (STAT) category, year, different age group, and CHD complexity. Authority economic data (index for gross domestic product [GDP], GDP per capita, per capita disposable income and average annual exchange rate of 2020 Chinese Yuan against US dollar) were accessed via the National Bureau of Statistics of China to better describe the burden. In addition, potential factors contributing to the costs were also investigated by using generalised linear model.Findings:All values are presented in 2020 Chinese Yuan (¥). A total of 6568 hospitalisations were enrolled. The median of overall total expenditure was ¥64,900 (≈9409 US Dollar [USD], interquartile range [IQR]: ¥35,819), with the lowest in STAT 1 (¥57,014 ≈ 8266 USD, [IQR]: ¥16,774) and the highest in STAT 5 (¥194,862 ≈ 28,251 USD, [IQR]: ¥130,010). The median costs during the 2018 to 2020 period were ¥62,014 (≈8991 USD, [IQR]: ¥32,628), ¥64,846 (≈9401 USD, [IQR]: ¥34,469) and ¥67,867 (≈9839 USD, [IQR]: ¥41,496). Regarding to age, the median costs were highest in the ≤1 month group (¥144,380 ≈ 20,932 USD, [IQR]: ¥92,584). Age, STAT category, emergency, genetic syndrome, delay sternal closure, mechanical ventilation time, and complications were significantly contributed to the inpatient costs.Interpretation:For the first time, the inpatient costs of congenital heart surgery in China are delineated in detail. According to the results, CHD treatment has achieved significant progress in China, but it still causes substantial economic burden to both families and society. In addition, ascending trend of the inpatient costs was observed during the period of 2018-2020, and the neonatal was revealed to be the most challenging group.Funding:This study was supported by the CAMS Innovation Fund for Medical Sciences (CIFMS,2020-I2M-C&T-A-009), Capital Health Research and Development of Special Fund (2022-1-4032), and The City University of Hong Kong New Research Initiatives/Infrastructure Support from Central (APRC, 9610589).
The Lancet regional health. Western Pacific 2023
Congenital heart disease (CHD) is one of themost common causes of major birth defects, with a prevalence of 1%. Although an increasing number of studies have reported the etiology of CHD, the findings scattered throughout the literature are difficult to retrieve and utilize in research and clinical practice. We therefore developed CHDbase, an evidence-based knowledgebase of CHD-related genes and clinical manifestations manually curated from 1114 publications, linking 1124susceptibility genes and 3591 variations to more than 300 CHD types and related syndromes. Metadata such as the information of each publication and the selected population and samples, the strategy of studies, and the major findings of studies were integrated with each item of the research record. We also integrated functional annotations through parsing ∼ 50 databases/tools to facilitate the interpretation of these genes and variations in disease pathogenicity. We further prioritized the significance of these CHD-related genes with a gene interaction network approach and extracted a core CHD sub-network with 163 genes. The clear genetic landscape of CHD enables the phenotype classification based on the shared genetic origin. Overall, CHDbase provides a comprehensive and freely available resource to study CHD susceptibilities, supporting a wide range of users in the scientific and medical communities. CHDbase is accessible at http://chddb.fwgenetics.org.
Genomics, proteomics & bioinformatics 2023
Background:Pulmonary atresia (PA) is a heterogeneous congenital heart defect and ventricular septal defect (VSD) is the most vital factor for the conventional classification of PA patients. The simple dichotomy could not fully describe the cardiac morphologies and pathophysiology in such a complex disease. We utilized the Human Phenotype Ontology (HPO) database to explore the phenotypic patterns of PA and the phenotypic influence on prognosis.Methods:We recruited 786 patients with diagnoses of PA between 2008 and 2016 at Fuwai Hospital. According to cardiovascular phenotypes of patients, we retrieved 52 HPO terms for further analyses. The patients were classified into three clusters based on unsupervised hierarchical clustering. We used Kaplan-Meier curves to estimate survival, the log-rank test to compare survival between clusters, and univariate and multivariate Cox proportional hazards regression modeling to investigate potential risk factors.Results:According to HPO term distribution, we observed significant differences of morphological abnormalities in 3 clusters. We defined cluster 1 as being associated with Tetralogy of Fallot (TOF), VSD, right ventricular hypertrophy (RVH), and aortopulmonary collateral arteries (ACA). ACA was not included in the cluster classification because it was not an HPO term. Cluster 2 was associated with hypoplastic right heart (HRH), atrial septal defect (ASD) and tricuspid disease as the main morphological abnormalities. Cluster 3 presented higher frequency of single ventricle (SV), dextrocardia, and common atrium (CA). The mortality rate in cluster 1 was significantly lower than the rates in cluster 2 and 3 (p = 0.04). Multivariable analysis revealed that abnormal atrioventricular connection (AAC, p = 0.011) and persistent left superior vena cava (LSVC, p = 0.003) were associated with an increased risk of mortality.Conclusions:Our study reported a large cohort with clinical phenotypic, surgical strategy and long time follow-up. In addition, we provided a precise classification and successfully risk stratification for patients with PA.
Frontiers in cardiovascular medicine 2022
Anomalous pulmonary venous return (APVR) is a potentially lethal congenital heart disease. Elucidating the genetic etiology is crucial for understanding its pathogenesis and improving clinical practice, whereas its genetic basis remains largely unknown because of complex genetic etiology. We thus performed whole-exome sequencing for 144 APVR patients and 1636 healthy controls and report a comprehensive atlas of APVR-related rare genetic variants. Novel singleton, loss-of-function and deleterious missense variants (DVars) were enriched in patients, particularly for genes highly expressed in the developing human heart at the critical time point for pulmonary veins draining into the left atrium. Notably, PLXND1, encoding a receptor for semaphorins, represents a strong candidate gene of APVR (adjusted P = 1.1e-03, odds ratio: 10.9-69.3), accounting for 4.17% of APVR. We further validated this finding in an independent cohort consisting of 82 case-control pairs. In these two cohorts, eight DVars were identified in different patients, which convergently disrupt the GTPase-activating protein-related domain of PLXND1. All variant carriers displayed strikingly similar clinical features, in that all anomalous drainage of pulmonary vein(s) occurred on the right side and incorrectly connected to the right atrium, which may represent a novel subtype of APVR for molecular diagnosis. Studies in Plxnd1 knockout mice further revealed the effects of PLXND1 deficiency on severe heart and lung defects and cellular abnormalities related to APVR such as abnormal migration and vascular formation of vascular endothelial cells. These findings indicate the important role of PLXND1 in APVR pathogenesis, providing novel insights into the genetic etiology and molecular subtyping for APVR.
Human molecular genetics 2022
Background Transposition of the great arteries (TGA) consists of about 3% of all congenital heart diseases and 20% of cyanotic congenital heart diseases. It is always accompanied by a series of other cardiac malformations that affect the surgical intervention strategy as well as prognosis. In this study, we comprehensively analyzed the phenotypes of the patients who had TGA with concordant atrioventricular and discordant ventriculoarterial connections and explored their association with prognosis. Methods and Results We retrospectively reviewed 666 patients with a diagnosis of TGA with concordant atrioventricular and discordant ventriculoarterial connections in Fuwai Hospital from 1997 to 2019. Under the guidance of the Human Phenotype Ontology database, patients were classified into 3 clusters. The Kaplan-Meier method was used to analyze the prognosis, and the Cox proportional regression model was used to investigate the risk factors. In this 666-patient TGA cohort, the overall 5-year survival rate was 94.70% (92.95%-96.49%). Three clusters with distinct phenotypes were obtained by the Human Phenotype Ontology database. Kaplan-Meier analysis revealed a significant difference in freedom from reintervention among 3 clusters (P<0.001). To eliminate the effect of surgeries, we analyzed patients who only received an arterial switch operation and still found a significant difference in reintervention (P=0.019). Conclusions We delineated a big cardiovascular phenotypic profile of an unprecedentedly large TGA cohort and successfully risk stratified them to reveal prognostic significance. Also, we reported the outcomes of a large TGA population in China.
Journal of the American Heart Association 2022
PURPOSE:Early detection and pathogenicity interpretation of disease-associated variants are crucial but challenging in molecular diagnosis, especially for insidious and life-threatening diseases, such as heritable thoracic aortic aneurysm and dissection (HTAAD). In this study, we developed HTAADVar, an unbiased and fully automated system for the molecular diagnosis of HTAAD.METHODS:We developed HTAADVar (http://htaadvar.fwgenetics.org) under the American College of Medical Genetics and Genomics/Association for Molecular Pathology framework, with optimizations based on disease- and gene-specific knowledge, expert panel recommendations, and variant observations. HTAADVar provides variant interpretation with a self-built database through the web server and the stand-alone programs.RESULTS:We constructed an expert-reviewed database by integrating 4373 variants in HTAAD genes, with comprehensive metadata curated from 697 publications and an in-house study of 790 patients. We further developed an interpretation system to assess variants automatically. Notably, HTAADVar showed a multifold increase in performance compared with public tools, reaching a sensitivity of 92.64% and specificity of 70.83%. The molecular diagnostic yield of HTAADVar among 790 patients (42.03%) also matched the clinical data, independently demonstrating its good performance in clinical application.CONCLUSION:HTAADVar represents the first fully automated system for accurate variant interpretation for HTAAD. The framework of HTAADVar could also be generalized for the molecular diagnosis of other genetic diseases.
Genetics in medicine : official journal of the American College of Medical Genetics 2022
