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Congenital heart defects constitute the most common human birth defect, however understanding of how these disorders originate is limited by our ability to model the human heart accurately in vitro. Here we report a method to generate developmentally relevant human heart organoids by self-assembly using human pluripotent stem cells. Our procedure is fully defined, efficient, reproducible, and compatible with high-content approaches. Organoids are generated through a three-step Wnt signaling modulation strategy using chemical inhibitors and growth factors. Heart organoids are comparable to age-matched human fetal cardiac tissues at the transcriptomic, structural, and cellular level. They develop sophisticated internal chambers with well-organized multi-lineage cardiac cell types, recapitulate heart field formation and atrioventricular specification, develop a complex vasculature, and exhibit robust functional activity. We also show that our organoid platform can recreate complex metabolic disorders associated with congenital heart defects, as demonstrated by an in vitro model of pregestational diabetes-induced congenital heart defects. There is a pressing need to develop representative organ-like platforms recapitulating complex in vivo phenotypes to study human development and disease in vitro. Here the authors present a method to generate human heart organoids by self-assembly using pluripotent stem cells, compare these to age-matched fetal cardiac tissues and recreate a model of pregestational diabetes.

Background Congenital heart disease (CHD) is the most common human birth defect, and clinicians need to understand the anatomy to effectively care for patients with CHD. However, standard two-dimensional (2D) display methods do not adequately carry the critical spatial information to reflect CHD anatomy. Three-dimensional (3D) models may be useful in improving the understanding of CHD, without requiring a mastery of cardiac imaging. The study aimed to evaluate the impact of 3D models on how pediatric residents understand and learn about tetralogy of Fallot following a teaching session. Methods Pediatric residents rotating through an inpatient Cardiology rotation were recruited. The sessions were randomized into using either conventional 2D drawings of tetralogy of Fallot or physical 3D models printed from 3D cardiac imaging data sets (cardiac MR, CT, and 3D echocardiogram). Knowledge acquisition was measured by comparing pre-session and post-session knowledge test scores. Learner satisfaction and self-efficacy ratings were measured with questionnaires filled out by the residents after the teaching sessions. Comparisons between the test scores, learner satisfaction and self-efficacy questionnaires for the two groups were assessed with paired t -test. Results Thirty-five pediatric residents enrolled into the study, with no significant differences in background characteristics, including previous clinical exposure to tetralogy of Fallot. The 2D image group ( n  = 17) and 3D model group ( n  = 18) demonstrated similar knowledge acquisition in post-test scores. Residents who were taught with 3D models gave a higher composite learner satisfaction scores ( P  = 0.03). The 3D model group also had higher self-efficacy aggregate scores, but the difference was not statistically significant ( P  = 0.39). Conclusion Physical 3D models enhance resident education around the topic of tetralogy of Fallot by improving learner satisfaction. Future studies should examine the impact of models on teaching CHD that are more complex and elaborate.

Background. Antiretroviral (ARV) regimens during pregnancy are highly effective in preventing mother-to-child transmission of human immunodeficiency virus (HIV). Congenital heart defects (CHDs) and anomalies in cardiac function have been reported in zidovudine (ZDV)–exposed uninfected children. We explored these associations in a large observational cohort and a randomized clinical trial. Methods. Since 1986, the French Perinatal Cohort prospectively enrolled all HIV-infected women in 90 centers and collected follow-up on their children through 2 years of age. All CHDs were reviewed by a specialist blinded to exposures. Additionally, in a randomized trial (PRIMEVA ANRS 135) of 2 ARV regimens during pregnancy, 1 of which was without nucleoside reverse transcriptase inhibitors, infants had a specific follow-up including echocardiography at 1 month and 12 months. Results. Among 12 888 children included, ZDV exposure in the first trimester was significantly associated with CHD (1.5% vs 0.7%; adjusted odds ratio, 2.2 [95% confidence interval, 1.3–3.7]; P < .001). This association was significant for ventricular septal defects (1.1% vs 0.6%; P = .001) and other CHDs (0.31% vs 0.11%; P = .02). In the randomized trial, among 50 infants, girls (but not boys) exposed in utero to ZDV/lamivudine/ritonavir-boosted lopinavir (LPV/r) had a higher left ventricular shortening fraction at 1 month (40% vs 36%; P = .008), and an increased posterior wall thickness at 1 year (5.4 mm vs 4.4 mm; P = .01) than the LPV/r group. Conclusions. This study confirms a specific association between in utero exposure to ZDV and CHDs, and a longlasting postnatal myocardial remodeling in girls. A potential common mechanism, including the involvement of mitochondrial dysfunction, must be explored, and long-term consequences on cardiac function warrant specific attention. Clinical Trials Registration. NCT00424814.

Exome sequencing of 2,871 probands with congenital heart disease (CHD) provides new insights into the genetic architecture of these disorders. The results implicate new genes in CHD pathogenesis and highlight striking overlap between genes with damaging de novo mutations in individuals with CHD and autism. Congenital heart disease (CHD) is the leading cause of mortality from birth defects. Here, exome sequencing of a single cohort of 2,871 CHD probands, including 2,645 parent–offspring trios, implicated rare inherited mutations in 1.8%, including a recessive founder mutation in GDF1 accounting for ∼5% of severe CHD in Ashkenazim, recessive genotypes in MYH6 accounting for ∼11% of Shone complex, and dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot. De novo mutations (DNMs) accounted for 8% of cases, including ∼3% of isolated CHD patients and ∼28% with both neurodevelopmental and extra-cardiac congenital anomalies. Seven genes surpassed thresholds for genome-wide significance, and 12 genes not previously implicated in CHD had >70% probability of being disease related. DNMs in ∼440 genes were inferred to contribute to CHD. Striking overlap between genes with damaging DNMs in probands with CHD and autism was also found.

Background Total cavopulmonary connection (TCPC) is a definitive palliative procedure for functionally univentricular congenital heart disease. The study aims to compare the impact of on-pump cardioplegic arrest and on-pump beating heart cardiopulmonary bypass (CPB) on the prognosis of pediatric patients undergoing extracardiac TCPC. Methods The medical data of patients (< 18 years) who underwent extracardiac TCPC with CPB between January 2008 and December 2020 in the cardiac surgery center were retrospectively analyzed. Depending on CPB strategies, the patients were assigned to the beating-heart (BH) and cardioplegic arrest (CA) groups. Data including baseline characteristics, intra/postoperative variables, and clinical outcomes were collected for analysis with 1:1 propensity score matching and multivariable stepwise logistic regressions. Results Fifty-seven matched patient pairs were obtained. No significant difference existed between the two groups in the in-hospital mortality (3.5% vs. 1.8%, P  = 1) and one-year survival rate (100% vs. 96.4%, P  = 0.484). The BH group had significantly less intraoperative platelet transfusion (10 mL vs. 150 mL, P  = 0.019) and blood loss (100 mL vs. 150 mL, P  = 0.033) than the CA group. The CA group had significantly higher vasoactive-inotropic scores ( P  < 0.05) and longer postoperative ICU stays (2.0 d vs. 3.7 d, P  = 0.017). No significant difference existed between the two groups in the incidence of postoperative adverse events. Conclusion Although both CPB strategies are safe and feasible for extracardiac TCPC, the BH technique would cause less intraoperative platelet transfusion and blood loss, and achieve faster early-term postoperative recovery.

The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes 1 . Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1 . Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer 2 . Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD. Single-nuclear transcriptomic and proteomic analyses identify molecular characteristics shared by multiple classes of congenital heart disease, including phenotypes associated with insulin resistance.

Children with single-ventricle disease experience high mortality and complex care. In other life-limiting childhood illnesses, paediatric palliative care may mitigate maternal stress. We hypothesised that early palliative care in the single-ventricle population may have the same benefit for mothers. In this pilot randomised trial of early palliative care, mothers of infants with prenatal single-ventricle diagnoses completed surveys measuring depression, anxiety, coping, and quality of life at a prenatal visit and neonatal discharge. Infants were randomised to receive early palliative care – structured evaluation, psychosocial/spiritual, and communication support before surgery – or standard care. Among 56 eligible mothers, 40 enrolled and completed baseline surveys; 38 neonates were randomised, 18 early palliative care and 20 standard care; and 34 postnatal surveys were completed. Baseline Beck Depression Inventory-II and State-Trait Anxiety Index scores exceeded normal pregnant sample scores (mean 13.76±8.46 versus 7.0±5.0 and 46.34±12.59 versus 29.8±6.35, respectively; p=0.0001); there were no significant differences between study groups. The early palliative care group had a decrease in prenatal to postnatal State-Trait Anxiety Index scores (−7.6 versus 0.3 in standard care, p=0.02), higher postnatal Brief Cope Inventory positive reframing scores (p=0.03), and a positive change in PedsQL Family Impact Module communication and family relationships scores (effect size 0.46 and 0.41, respectively). In conclusion, these data show that mothers of infants with single-ventricle disease experience significant depression and anxiety prenatally. Early palliative care resulted in decreased maternal anxiety, improved maternal positive reframing, and improved communication and family relationships.

Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells 1 , but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors 2 , 3 identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2 -null mice 4 . Temporal single-cell-transcriptome analysis of Hand2 -null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior–posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects. Single-cell RNA-sequencing analysis reveals functions of lineage-specifying transcription factors underlying congenital defects in heart development.

Congenital heart disease is the most frequent of congenital disorders in newborns. Reliable epidemiological data for congenital heart disease, however, have been difficult to obtain owing to divergences in definitions, classifications, and methodologies of different studies. The authors of this Review discuss the latest changes in the epidemiology of congenital heart disease and its complications. Congenital heart disease is the most common congenital disorder in newborns. Advances in cardiovascular medicine and surgery have enabled most patients to reach adulthood. Unfortunately, prolonged survival has been achieved at a cost, as many patients suffer late complications, of which heart failure and arrhythmias are the most prominent. Accordingly, these patients need frequent follow-up by physicians with specific knowledge in the field of congenital heart disease. However, planning of care for this population is difficult, because the number of patients currently living with congenital heart disease is difficult to measure. Birth prevalence estimates vary widely according to different studies, and survival rates have not been well recorded. Consequently, the prevalence of congenital heart disease is unclear, with estimates exceeding the number of patients currently seen in cardiology clinics. New developments continue to influence the size of the population of patients with congenital heart disease. Prenatal screening has led to increased rates of termination of pregnancy. Improved management of complications has changed the time and mode of death caused by congenital heart disease. Several genetic and environmental factors have been shown to be involved in the etiology of congenital heart disease, although this knowledge has not yet led to the implementation of preventative measures. In this Review, we give an overview of the etiology, birth prevalence, current prevalence, mortality, and complications of congenital heart disease. Key Points The etiology of most forms of congenital heart disease is incompletely understood Genetic and environmental factors probably interact in the etiology of most nonsyndromal forms of congenital heart disease Epidemiological studies in congenital heart disease are hampered by diverging definitions, classifications, and methodology Birth prevalence estimates vary widely according to different studies, but this measure seems to be declining overall The prevalence of congenital heart disease is increasing The reported prevalence does not reflect the number of patients currently receiving care for congenital heart disease

•Poor exercise capacity and endothelial dysfunction accelerate Fontan disease.•We report baseline data for pediatric Fontan patients in an exercise intervention.•Single ventricle systolic function (3D-EF and strain) was reduced in this cohort.•Diminished systolic function correlated with decreased endothelial function.•Single ventricle systolic function and strain correlate with decreased exercise capacity. By age 40, roughly half of the individuals with Fontan circulation will have died or undergone heart transplantation. Poor exercise capacity and endothelial dysfunction accelerate disease progression. This study aims to assess the systolic function of the single ventricle (SV) in pediatric Fontan patients entering an exercise intervention (RE-ENERGIZE FONTAN) and how it is associated with exercise capacity and endothelial function. This cohort comes from an ongoing randomized trial in Fontan patients, using live video conferencing for supervised exercise. Participants (ages 8-19) cleared for exercise underwent 2D/3D echocardiograms, cardiopulmonary testing, and endothelial function (RHI). 2D longitudinal strain (LS, right ventricle), 2D global longitudinal strain (GLS, left ventricle), and circumferential strain were measured with TomTec, and 3D ejection fraction (3D-EF) and 3D-GLS were calculated. We have enrolled 114 Fontan patients. Median age was 12.7 years (IQR 10.2, 15.6). The median time from Fontan operation was 8.8 years (IQR 6.2, 12.0). Fifty-seven patients (50%) had a single right ventricle. SV systolic performance measures were: 2D-LS/GLS −15.6% ± 4.19%, circumferential strain was −18.7% ± 6.83%, 3D-EF 49.9% ± 7.26%, and 3D-GLS −16.8% ± 4.37%. Peak VO2 was 1,290 ± 502 mL/min, and percent predicted peak VO2 was 67.8% ± 15.6%. RHI was 1.44 ± 0.576. 2D-LS/GLS and 3D EF correlated with percent predicted peak VO2 (R = −0.28, P = .007 and R = 0.24, P = .019). 3D-EF correlated positively with RHI (R = 0.29, P = .0071). In this cohort of pediatric Fontan patients, SV systolic function was diminished at baseline, and there was a direct correlation between 2D strain and 3D-EF with percent predicted peak VO2, and additionally, 3D-EF with endothelial function. NCT04195451. [Display omitted]