BACKGROUND:Studies on cardiovascular changes after fetal growth restriction (FGR) are limited by their design in which growth-restricted neonates are compared to appropriately-grown neonates. We aim to investigate early structural cardiovascular remodeling after FGR in identical twins, controlling for confounding of genetic and maternal factors. METHODS:This study is part of a prospective cohort study including monochorionic twins from January 2019. Transthoracic echocardiography was performed within one week after birth. Z-scores for cardiac valve annuli diameters and left ventricle dimensions based on gestational age at birth were compared between smaller and larger twins. Z-score differences between birth weight and cardiac structure per twin were tested against the intercept. RESULTS:Median gestational age at birth of the 100 included twin pairs was 33.8 (interquartile range (IQR) 30.8-36.1) weeks, with birth weights of 1729 (IQR 1200-2115) grams for smaller twins and 2058 (IQR 1643-2500) grams for larger twins. Smaller twins had a lower z-score for all structures. Z-score differences in birth weight and cardiac structure were higher than the intercept. CONCLUSION:While cardiac structures are generally smaller for the twin with the lower birth weight, the deviation in birth weight tends to be more pronounced than the deviation in cardiac structure. IMPACT:Our study shows that in identical twins, the smaller twin at birth has a structurally smaller heart on neonatal echocardiography when compared to the larger twin. Yet, cardiac structures per individual twin are less affected than body size for their given gestational age at birth. We have used a unique natural experiment by studying a population of identical twins with varying degrees of birth weight discordance, eliminating any confounding of genetic, maternal and obstetrical factors. Our results are suggestive of early cardiovascular remodeling after adverse intrauterine circumstances. This provides insight into the fetal programming of cardiovascular disease.

BACKGROUND:Abnormal birth weight and infant weight gain are recognized as risk factors for cardiovascular diseases. Underlying mechanisms remain unclear. Exercise testing can detect subtle differences in cardiovascular function not present at rest. We examined associations of fetal and infant growth with the cardiovascular stress response in adolescence. METHODS:We examined a subsample of 207 children from a population-based prospective cohort from fetal life onwards. Fetal and infant growth were assessed from the second trimester to 2 years. At 16 years, participants performed an isometric handgrip exercise with continuous heart rate and blood pressure monitoring and cardiovascular magnetic resonance imaging. RESULTS:Children showed a clear peak in heart rate and systolic and diastolic blood pressure during exercise, followed by a decrease below baseline after exercise cessation, before stabilizing. Higher gestational age was associated with lower systolic blood pressure throughout the exercise (differences per SD score increase in gestational age: rest, -2.24 mm Hg [95% CI, -4.23 to -0.25 mm Hg], peak exercise (-2.37 mm Hg [95% CI, -4.70 to -0.04 mm Hg]), recovery (-2.57 mm Hg [95% CI, -4.72 to -0.42 mm Hg])) but not with heart rate or CMR outcomes. No consistent associations were present for birth weight or infant growth with the cardiovascular stress response. CONCLUSIONS:A lower gestational age at birth is associated with an altered response to exercise in systolic blood pressure. Fetal or infant growth is not associated with differences in cardiovascular response to exercise-induced stress in adolescence in a relatively healthy population. Follow-up of children born preterm is important to enable early identification and prevention of cardiovascular disease development.

The complex and variable anatomy of complex double outlet right ventricle makes it imperative to understand the spatial anatomic structures to determine whether it is feasible to repair the anomaly in a biventricular or univentricular fashion. Biventricular repair should be aimed for but is not always feasible. Choosing the correct surgical technique is of great importance in surgical planning of biventricular repair. Conventional imaging is typically insufficient to predict feasibility and technique of biventricular repair. The gap between virtual images and spatial reality can be filled using 3D prints. Retrospective observational study of all available imaging including 3D prints and operative reports in 13 patients. 3D-prints enabled accurate prediction of biventricular repair in 8 cases and of univentricular repair in 2 cases. In 2 patients, no precise prediction was possible. One 3D-print was created post repair. 3D-prints accurately predicted the optimal technique for achieving biventricular repair in 8 cases. Conventional imaging could not accurately predict biventricular repair of optimal surgical technique in any patient. In complex double outlet right ventricle, 3D-printing can predict feasibility of biventricular repair better than conventional imaging. Additionally, 3D-prints can predict the type of surgical technique better. 3D-printing is also helpful in preoperative discussion with parents, caretakers, and pediatric cardiologists. 3D-prints are strongly recommended in patients with complex double outlet right ventricle.

Neuromuscular disorders (NMD) require complex multidisciplinary care. There is an urgent need to understand the natural history, factors that influence its variability, and to develop biomarkers. Standardizing assessments in outpatient clinics provides an opportunity to combine care and research while minimizing patients’ efforts and optimizing the use of data. We present the organization of the Leiden University Medical Center NMD pediatric and adult clinics in which yearly functional assessments, cardiological, pulmonological and bone health evaluations according to the standards of care are combined with the possibility to conduct quantitative muscle MRI for specific natural history studies, and the collection of biomaterials in the morning. This is followed by a multidisciplinary team meeting and individual consultations with medical specialists in the afternoon. Data are stored in a standardized form in the electronic medical records, and transcribed into a clinical letter containing treatment recommendations that is sent to the family and local healthcare professionals. With consent from patients and families, the same data are used for Dutch Dystrophinopathy Database, a national disease registry open to all Dutch patients and female carriers combining clinician and patient reported data, and the Duchenne and Becker national biobank, a collaboration between the Dutch University Medical Centers. To facilitate interoperability the Framework for Information Specification, Modelling, and Architecture (FISMA) governs the design of our electronic health record system and these databases. The integration of clinical care and research minimizes redundant data entry and enhances data accessibility for both clinical and research purposes. As a result, relevant information can also be seamlessly incorporated into patient communications, while at the same time allowing long term natural history assessment and biomarker development.

Background Kidney disease is the most important predictor of death in patients with a Fontan circulation, yet its clinical and hemodynamic correlates have not been well established. Methods and Results A total of 53 ambulatory patients with a Fontan circulation (median age, 16.2 years, 52.8% male patients) underwent advanced cardiovascular magnetic resonance assessment, including 4‐dimensional flow imaging and computational fluid dynamics. Estimated glomerular filtration rate (eGFR) <90 mL/min per 1.73 m2 was observed in 20.8% and albumin‐to‐creatinine ratio >3 mg/mmol in 39.6%. The average eGFR decline rate was −1.83 mL/min per 1.73 m2 per year (95% CI, −2.67 to −0.99; P<0.001). Lower eGFR was associated with older age, larger body surface area at examination, longer time since Fontan procedure, and lower systemic ventricular ejection fraction. Higher albumin‐to‐creatinine ratio was associated with absence of fenestration at the Fontan operation, and older age and lower systemic ventricular ejection fraction at the assessment. Lower cross‐sectional area of the Fontan conduit indexed to flow (r=0.32, P=0.038), higher inferior vena cava–conduit velocity mismatch factor (r=−0.35, P=0.022), higher kinetic energy indexed to flow in the total cavopulmonary connection (r=−0.59, P=0.005), and higher total cavopulmonary connection resistance (r=−0.42, P=0.005 at rest; r=−0.43, P=0.004 during exercise) were all associated with lower eGFR but not with albuminuria. Conclusions Kidney dysfunction and albuminuria are common among clinically well adolescents and young adults with a Fontan circulation. Advanced cardiovascular magnetic resonance–derived metrics indicative of declining Fontan hemodynamics are associated with eGFR and might serve as targets to improve kidney health. Albuminuria might be driven by other factors that need further investigation.

Background: Overweight and obesity are among the main causes of cardiovascular diseases. Exercise testing can aid in the early detection of subtle cardiac dysfunction not present in rest. We hypothesized that the cardiovascular response to exercise is impaired among children with overweight or obesity, characterized by the inability of the cardiovascular system to adapt to exercise by increasing cardiac volumes and blood pressure. We performed a cardiovascular stress test to investigate whether the cardiovascular exercise response is altered in children with overweight and obesity, as compared to children with a normal weight. Subjects: A subgroup of the Generation R population-based prospective cohort study, consisting of 41 children with overweight or obesity and 166 children with a normal weight with a mean age of 16 years, performed an isometric exercise. Methods: Continuous heart rate and blood pressure were measured during rest, exercise and recovery. Cardiovascular magnetic resonance (CMR) measurements were performed during rest and exercise. Results: Higher BMI was associated with a higher resting systolic and diastolic blood pressure (difference: 0.24 SDS (95% CI 0.10, 0.37) and 0.20 SDS (95% CI 0.06, 0.33)) and lower systolic and diastolic blood pressure increases from rest to peak exercise (-0.11 SDS (95% CI -0.20, -0.03) and -0.07 SDS (95% CI -0.07, -0.01)). BMI was also associated with a slower decrease in systolic and diastolic blood pressure during recovery (p values < 0.05). Higher childhood BMI was associated with lower BSA corrected left ventricular mass, end-diastolic volume and stroke volume (p values < 0.05). There were no associations of childhood BMI with the cardiac response to exercise measured by heart rate and CMR measurements. Conclusion: Childhood BMI is, across the full range, associated with a blunted blood pressure response to static exercise but there were no differences in cardiac response to exercise. Our findings suggest that adiposity may especially affect the vascular exercise reaction without affecting cardiac response.

Background Lymphatic disorders such as protein‐losing enteropathy, plastic bronchitis, and chylothorax are important complications of the Fontan circulation and ultimately result in an increased risk of early death. Several European centers are now performing lymphatic procedures. The aim of this study is to map the extent of these lymphatic disorders and treatments provided across European pediatric cardiology centers. Methods and Results A survey was circulated to 49 European pediatric cardiology centers consisting of 37 questions including a mix of binary, categorical, and continuous variables. Thirty‐one centers (63%) participated in the study, performing a median of 250 (interquartile range, 178 ‐ 313) cardiopulmonary bypass procedures per year. Chylothorax emerged as the most prevalent lymphatic disorder followed by protein‐losing enteropathy and plastic bronchitis. The most common diagnostic investigation method was noncontrast magnetic resonance lymphangiography (52%). Eleven centers (35%) conducted lymphatic interventions with a median of 3 (interquartile range, 1 ‐ 4) procedures per year and 12 (interquartile range, 5 ‐ 15) interventions in total per center. Conclusions This study confirms the rarity of and variation in treatment approaches for lymphatic disorders across Europe. With at least 11 centers offering lymphatic interventions, the adoption of these procedures is on the rise in Europe. To improve the quality of care and treatment outcomes for these complex patients, it is crucial to consider evidence‐based lymphatic diagnostics, interventional lymphatic procedures, and the centralization of services in Europe.

The human umbilical cord (hUC) is the lifeline that connects the fetus to the mother. Hypercoiling of the hUC is associated with pre- and perinatal morbidity and mortality. We investigated the origin of hUC hypercoiling using state-of-the-art imaging and omics approaches. Macroscopic inspection of the hUC revealed the helices to originate from the arteries rather than other components of the hUC. Digital reconstruction of the hUC arteries showed the dynamic alignment of two layers of muscle fibers in the tunica media aligning in opposing directions. We observed that genetically identical twins can be discordant for hUC coiling, excluding genetic, many environmental, and parental origins of hUC coiling. Comparing the transcriptomic and DNA methylation profile of the hUC arteries of four twin pairs with discordant cord coiling, we detected 28 differentially expressed genes, but no differentially methylated CpGs. These genes play a role in vascular development, cell-cell interaction, and axis formation and may account for the increased number of hUC helices. When combined, our results provide a novel framework to understand the origin of hUC helices in fetal development.

BACKGROUND:There is limited data on the organisation of paediatric echocardiography laboratories in Europe. METHODS:A structured and approved questionnaire was circulated across all 95 Association for European Paediatric and Congenital Cardiology affiliated centres. The aims were to evaluate: (1) facilities in paediatric echocardiography laboratories across Europe, (2) accredited laboratories, (3) medical/paramedical staff employed, (4) time for echocardiographic studies and reporting, and (5) training, teaching, quality improvement, and research programs. RESULTS:Respondents from forty-three centres (45%) in 22 countries completed the survey. Thirty-six centres (84%) have a dedicated paediatric echocardiography laboratory, only five (12%) of which reported they were European Association of Cardiovascular Imaging accredited. The median number of echocardiography rooms was three (range 1-12), and echocardiography machines was four (range 1-12). Only half of all the centres have dedicated imaging physiologists and/or nursing staff, while the majority (79%) have specialist imaging cardiologist(s). The median (range) duration of time for a new examination was 45 (20-60) minutes, and for repeat examination was 20 (5-30) minutes. More than half of respondents (58%) have dedicated time for reporting. An organised training program was present in most centres (78%), 44% undertake quality assurance, and 79% perform research. Guidelines for performing echocardiography were available in 32 centres (74%). CONCLUSION:Facilities, staffing levels, study times, standards in teaching/training, and quality assurance vary widely across paediatric echocardiography laboratories in Europe. Greater support and investment to facilitate improvements in staffing levels, equipment, and governance would potentially improve European paediatric echocardiography laboratories.

BackgroundAutomated 4D flow MRI valvular flow quantification without time‐consuming manual segmentation might improve workflow.PurposeCompare automated valve segmentation (AS) to manual (MS), and manually corrected automated segmentation (AMS), in corrected atrioventricular septum defect (c‐AVSD) patients and healthy volunteers, for assessing net forward volume (NFV) and regurgitation fraction (RF).Study TypeRetrospective.Population27 c‐AVSD patients (median, 23 years; interquartile range, 16–31 years) and 24 healthy volunteers (25 years; 12.5–36.5 years).Field strength/SequenceWhole‐heart 4D flow MRI and cine steady‐state free precession at 3T.AssessmentAfter automatic valve tracking, valve annuli were segmented on time‐resolved reformatted trans‐valvular velocity images by AS, MS, and AMS. NFV was calculated for all valves, and RF for right and left atrioventricular valves (RAVV and LAVV). NFV variation (standard deviation divided by mean NFV) and NFV differences (NFV difference of a valve vs. mean NFV of other valves) expressed internal NFV consistency.Statistical TestsComparisons between methods were assessed by Wilcoxon signed‐rank tests, and intra/interobserver variability by intraclass correlation coefficients (ICCs). P < 0.05 was considered statistically significant, with multiple testing correction.ResultsAMS mean analysis time was significantly shorter compared with MS (5.3 ± 1.6 minutes vs. 9.1 ± 2.5 minutes). MS NFV variation (6.0%) was significantly smaller compared with AMS (6.3%), and AS (8.2%). Median NFV difference of RAVV, LAVV, PV, and AoV between segmentation methods ranged from −0.7–1.0 mL, −0.5–2.8 mL, −1.1–3.6 mL, and − 3.1–‐2.1 mL, respectively. Median RAVV and LAVV RF, between 7.1%–7.5% and 3.8%–4.3%, respectively, were not significantly different between methods. Intraobserver/interobserver agreement for AMS and MS was strong‐to‐excellent for NFV and RF (ICC ≥0.88).Data ConclusionMS demonstrates strongest internal consistency, followed closely by AMS, and AS. Automated segmentation, with or without manual correction, can be considered for 4D flow MRI valvular flow quantification.Level of Evidence3Technical EfficacyStage 3

OBJECTIVE:To determine whether it is the magnitude of early postnatal catch-up growth (CUG) in response to fetal growth restriction (FGR) or the FGR itself that negatively impacts cognitive outcome in a model of monochorionic twins discordant for fetal growth. STUDY DESIGN:This analysis is part of the LEMON study, a cohort study including all monochorionic twins with selective FGR aged 3 through 17 years. Growth measurements as documented by our primary care system were collected retrospectively. An age-appropriate neurodevelopmental test was performed generating a full-scale IQ (FSIQ). CUG at 2 years was calculated as (weight [kg] at 2 years-birth weight [kg]). We used a multivariable regression model investigating the association between FSIQ (outcome) and birth weight zscore, gestational age at birth and CUG at 2 years (predictors). Generalized estimating equations accounted for the fact that observations between cotwins are not independent. RESULTS:Median age at follow-up of the 46 included twin pairs was 11 (IQR 8-13) years. Birth weight z score and gestational age at birth were significantly associated with FSIQ, with β-coefficients of 5.897 (95% CI 3.382-8.411), and 2.589 (95% CI 1.227-3.951), respectively (P < .0001). Adjusted for birth weight z score and gestational age, CUG in the first 2 years after birth was not significantly associated with FSIQ (β-coefficient 0.108 [95% CI -1.373 to 1.590], P = .886). CONCLUSIONS:Our results, combining detailed growth measurements and neurodevelopmental follow-up in a discordant identical twin model, demonstrate that FGR itself rather than early postnatal CUG has negative consequences for cognitive development.

Introduction: Patients after surgical correction of Tetralogy of Fallot (ToF) often show adverse cardiac remodeling. To better understand the underlying biological processes, we studied the relation between changes in blood biomarkers and changes in biventricular size and function as assessed by cardiac magnetic resonance imaging (CMR). Methods: This study included 50 ToF patients, who underwent blood biomarker and CMR analysis at least twice between 2002 and 2018.34 (68 %) of these patients were male. Patients had an average age of 16.1 at first visit. Biomarkers were chosen based on earlier research by our group and included: NT-proBNP, ST2, GDF-15, DLK-1, IGFBP-1/7, and FABP-4. Pearson correlations coefficients (rpearson) were determined to quantify the relationship between changes in biomarkers and CMR measurements. Results: For changes in parameters of right ventricular (RV) size significant correlations were observed with changes in NT-proBNP, ST -2, GDF-15, IGFBP7 and FABP4 (rpearson between 0.28 and 0.51). Correlations with NT-proBNP were driven by changes in RV size induced by pulmonary valve replacement (n = 9). For LV serial size changes, significant correlations were noted with changes in NT-pro-BNP, ST -2, GDF-15 and FABP-4 (rpearson between 0.32 and 0.52). Conclusion: In clinically stable ToF patients changes in right and left ventricular size and function correlated with alterations in blood biomarkers of inflammation and immune response to stress.

ImportanceThe ability to predict sudden cardiac death (SCD) in children and adolescents with hypertrophic cardiomyopathy (HCM) is currently inadequate. Late gadolinium enhancement (LGE) by cardiovascular magnetic resonance (CMR) imaging is associated with SCD events in adults with HCM.ObjectiveTo examine the prognostic significance of LGE in patients with HCM who are younger than 21 years.Design, Setting, and ParticipantsThis multicenter, retrospective cohort study was conducted from April 8, 2015, to September 12, 2022, in patients with HCM who were younger than 21 years and had undergone CMR imaging across multiple sites in the US, Europe, and South America. Observers of CMR studies were masked toward outcomes and demographic characteristics.ExposureNatural history of HCM.Main Outcome and MeasuresThe primary outcome was SCD and surrogate events, including resuscitated cardiac arrest and appropriate discharges from an implantable defibrillator. Continuous and categorical data are expressed as mean (SD), median (IQR), or number (percentage), respectively. Survivor curves comparing patients with and without LGE were constructed by the Kaplan-Meier method, and likelihood of subsequent clinical events was further evaluated using univariate and multivariable Cox proportional hazards models.ResultsAmong 700 patients from 37 international centers, median (IQR) age was 14.8 (11.9-17.4) years, and 518 participants (74.0%) were male. During a median (IQR) [range] follow-up period of 1.9 (0.5-4.1) [0.1-14.8] years, 35 patients (5.0%) experienced SCD or equivalent events. LGE was present in 230 patients (32.9%), which constituted an mean (SD) burden of 5.9% (7.3%) of left ventricular myocardium. The LGE amount was higher in older patients and those with greater left ventricular mass and maximal wall thickness; patients with LGE had lower left ventricular ejection fractions and larger left atrial diameters. The presence and burden of LGE was associated with SCD, even after correcting for existing risk stratification tools. Patients with 10% or more LGE, relative to total myocardium, had a higher risk of SCD (unadjusted hazard ratio [HR], 2.19; 95% CI, 1.59-3.02; P < .001). Furthermore, the addition of LGE burden improved the performance of the HCM Risk-Kids score (before LGE addition: 0.66; 95% CI, 0.58-0.75; after LGE addition: 0.73; 95% CI, 0.66-0.81) and Precision Medicine in Cardiomyopathy score (before LGE addition: 0.68; 95% CI, 0.49-0.77; after LGE addition: 0.73; 95% CI, 0.64-0.82) SCD predictive models.Conclusions and RelevanceIn this retrospective cohort study, quantitative LGE was a risk factor for SCD in patients younger than 21 years with HCM and improved risk stratification.

OBJECTIVES In complex double outlet right ventricle (DORV) patients, the optimal surgical approach may be difficult to assess based on conventional 2-dimensional (2D) ultrasound (US) and computed tomography (CT) imaging. The aim of this study is to assess the added value of 3-dimensional (3D) printed and 3D virtual reality (3D-VR) models of the heart used for surgical planning in DORV patients, supplementary to the gold standard 2D imaging modalities. METHODS Five patients with different DORV subtypes and high-quality CT scans were selected retrospectively. 3D prints and 3D-VR models were created. Twelve congenital cardiac surgeons and paediatric cardiologists, from 3 different hospitals, were shown 2D-CT first, after which they assessed the 3D print and 3D-VR models in random order. After each imaging method, a questionnaire was filled in on the visibility of essential structures and the surgical plan. RESULTS Spatial relationships were generally better visualized using 3D methods (3D printing/3D-VR) than in 2D. The feasibility of ventricular septum defect patch closure could be determined best using 3D-VR reconstructions (3D-VR 92%, 3D print 66% and US/CT 46%, P < 0.01). The percentage of proposed surgical plans corresponding to the performed surgical approach was 66% for plans based on US/CT, 78% for plans based on 3D printing and 80% for plans based on 3D-VR visualization. CONCLUSIONS This study shows that both 3D printing and 3D-VR have additional value for cardiac surgeons and cardiologists over 2D imaging, because of better visualization of spatial relationships. As a result, the proposed surgical plans based on the 3D visualizations matched the actual performed surgery to a greater extent.

To examine feasibility and reproducibility and to evaluate the cardiovascular response to an isometric handgrip exercise in low-risk pediatric population using Cardiovascular Magnetic Resonance measurements. In a subgroup of 207 children with a mean age of 16 years participating in a population-based prospective cohort study, children performed an isometric handgrip exercise. During rest and exercise, continuous heart rate and blood pressure were measured. Cardiovascular magnetic resonance (CMR) measurements included left ventricular mass, aortic distensibility and pulse wave velocity at rest and left ventricular end-diastolic and end-systolic volumes, ejection fraction, stroke volume and cardiac output during rest and exercise. 207 children had successful CMR measurements in rest and 184 during exercise. We observed good reproducibility for all cardiac measurements. Heart rate increased with a mean ± standard deviation of 42.6

Pulmonary artery (PA) stenosis is a common complication after the arterial switch operation (ASO) for transposition of the great arteries (TGA). Four-dimensional flow (4D flow) CMR provides the ability to quantify flow within an entire volume instead of a single plane. The aim of this study was to compare PA maximum velocities and stroke volumes between 4D flow CMR, two-dimensional phase-contrast (2D PCMR) and echocardiography. A prospective study including TGA patients after ASO was performed between December 2018 and October 2020. All patients underwent echocardiography and CMR, including 2D PCMR and 4D flow CMR. Maximum velocities and stroke volumes were measured in the main, right, and left PA (MPA, LPA, and RPA, respectively). A total of 39 patients aged 20 ± 8 years were included. Maximum velocities in the MPA, LPA, and RPA measured by 4D flow CMR were significantly higher compared to 2D PCMR (p < 0.001 for all). PA assessment by echocardiography was not possible in the majority of patients. 4D flow CMR maximum velocity measurements were consistently higher than those by 2D PCMR with a mean difference of 65 cm/s for the MPA, and 77 cm/s for both the RPA and LPA. Stroke volumes showed good agreement between 4D flow CMR and 2D PCMR. Maximum velocities in the PAs after ASO for TGA are consistently lower by 2D PCMR, while echocardiography only allows for PA assessment in a minority of cases. Stroke volumes showed good agreement between 4D flow CMR and 2D PCMR.

Background: The Fontan operation resulted in improved survival of patients with congenital heart defects not equipped to sustain biventricular circulation. Long-term complications are common, such as veno-venous collaterals (VVC). The aim of this study was to evaluate patient characteristics, percutaneous treatment strategy and (short-term) outcomes in adult Fontan patients with VVC, and review literature to date. Methods: In this single-centre retrospective observational cohort study, patients who underwent percutaneous VVC closure between 2017 and 2023 were identified. Results: Thirteen patients underwent percutaneous VVC closure (77 % female, age at intervention 24 +/- 4 years, 77 % systemic left ventricle, 77 % extracardiac tunnel, median conduit size 16 [16-20]mm). Indications for closure were symptoms and/or significant exercise-related hypoxia. Mean Fontan pressure was 10 +/- 4 mmHg. The VVC originated from tributaries of the vena cava superior (VCS) and connected to pulmonary veins (8 VVC, 32 %), VCS to systemic atrium (3 VVC, 12 %), VCS to coronary sinus (3 VVC, 12 %) and tributaries of vena cava inferior to pulmonary veins (11 VVC, 44 %). Twenty-three VVC were occluded using coils and/or plugs. No periprocedural complications occurred. At first follow-up at least 6 months after closure (n = 11), 9 patients (82 %) reported symptom reduction. Saturation at rest and peak exercise increased significantly (96 +/- 3 to 98 +/- 1 %, p = 0.040; 89 +/- 3 to 93 +/- 5 %, p = 0.024, respectively). Exercise capacity remained unchanged. Conclusions: VVC typically connect the tributaries of the vena cava inferior and/or superior with the pulmonary veins. Low Fontan pressures do not exclude the presence of VVC. Percutaneous closure of VVC is technically feasible, safe, and associated with symptom reduction and a significant rise in resting and exercise oxygen saturation.

Background aims: Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) are increasingly used in research and therapy. To obtain hUC-MSCs, a diversity of isolation and expansion methods are applied. Here, we report on a robust and standardized method for hUC-MSC isolation and expansion. Methods: Using 90 hUC donors, we compared and optimized critical variables during each phase of the multi-step procedure involving UC collection, processing, MSC isolation, expansion and characterization. Further-more, we assessed the effect of donor-to-donor variability regarding UC morphology and donor attributes on hUC-MSC characteristics. Results: We demonstrated robustness of our method across 90 UC donors at each step of the procedure. With our method, UCs can be collected up to 6 h after birth, and UC-processing can be initiated up to 48 h after col-lection without impacting on hUC-MSC characteristics. The removal of blood vessels before explant cultures improved hUC-MSC purity. Expansion in Minimum essential medium a supplemented with human platelet lysate increased reproducibility of the expansion rate and MSC characteristics as compared with Dulbecco's Modified Eagle's Medium supplemented with fetal bovine serum. The isolated hUC-MSCs showed a purity of >> 98.9%, a viability of >97% and a high proliferative capacity. Trilineage differentiation capacity of hUC-MSCs was reduced as compared with bone marrow-derived MSCs. Functional assays indicated that the hUC-MSCs were able to inhibit T-cell proliferation demonstrating their immune-modulatory capacity. Conclusions: We present a robust and standardized method to isolate and expand hUC-MSCs, minimizing technical variability and thereby lay a foundation to advance reliability and comparability of results obtained from different donors and different studies. (c) 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Background: Fetal growth restriction (FGR) can negatively affect lung development, leading to increased respiratory morbidity and reduced lung function later in life. Studies regarding the impact of FGR on lung function in singletons are influenced by genetic, obstetric, and maternal factors. To overcome these confounding factors, we aim to investigate lung function in identical twins with selective FGR (sFGR). Methods: Lung function assessments were performed in identical twins with sFGR born in our centre between March 1, 2002, and December 31, 2017, aged between 5 and 17 years. sFGR was defined as birthweight discordance >= 20%. Outcome measures consisted of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and transfer factor for carbon monoxide (DLCO) and were compared between the smaller and larger twin. Findings: Thirty-nine twin pairs performed spirometry of sufficient quality. Median gestational age at birth was 34.3 (interquartile range (IQR) 32.1-36.0) weeks with median birthweights of 1500 (IQR 1160-1880) grams and 2178 (IQR 1675-2720) grams for the smaller and larger twin, respectively. Smaller twins had significantly lower z-scores for FEV1 (-0.94 versus -0.41, p = 0.0015), FVC (-0.56 versus -0.06, p < 0.0001) and DLCO (-0.50 versus 0.00, p < 0.0001) compared to larger co-twins. Interpretation: Although being genetically identical, sFGR in identical twins is associated with a reduction in static and dynamic lung volume and a reduction in lung diffusion, even when taking the reduced lung volume into account. This indicates that adverse growth conditions in utero negatively affect lung development and function, potentially contributing to an increase in respiratory morbidities later in life.