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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 patent ductus arteriosus is a very common condition in preterm infants, and a hemodynamically significant patent ductus arteriosus increases morbidity and mortality in these vulnerable patients. However, despite numerous randomized controlled trials, there is no consensus regarding management. Medical therapy is typically offered as first-line treatment, although it yields limited success and carries the potential for severe adverse events. In recent years, there has been rapid development in transcatheter patent ductus arteriosus closure primary with the use of the Amplatzer Piccolo Occluder, and this has gained widespread acceptance as a safe and effective alternative to surgical ligation in extremely low-birth-weight infants weighing over 700 g. This article aims to provide an appraisal of the patient selection process, a step-by-step procedural guide, and a comprehensive review of the outcomes associated with this approach.

Background The primary genetic risk factor for heritable pulmonary arterial hypertension is the presence of monoallelic mutations in the BMPR2 gene. The incomplete penetrance of BMPR2 mutations implies that additional triggers are necessary for pulmonary arterial hypertension occurrence. Pulmonary artery stenosis directly raises pulmonary artery pressure, and the redirection of blood flow to unobstructed arteries leads to endothelial dysfunction and vascular remodeling. We hypothesized that right pulmonary artery occlusion (RPAO) triggers pulmonary hypertension (PH) in rats with Bmpr2 mutations. Methods and Results Male and female rats with a 71 bp monoallelic deletion in exon 1 of Bmpr2 and their wild‐type siblings underwent acute and chronic RPAO. They were subjected to full high‐fidelity hemodynamic characterization. We also examined how chronic RPAO can mimic the pulmonary gene expression pattern associated with installed PH in unobstructed territories. RPAO induced precapillary PH in male and female rats, both acutely and chronically. Bmpr2 mutant and male rats manifested more severe PH compared with their counterparts. Although wild‐type rats adapted to RPAO, Bmpr2 mutant rats experienced heightened mortality. RPAO induced a decline in cardiac contractility index, particularly pronounced in male Bmpr2 rats. Chronic RPAO resulted in elevated pulmonary IL‐6 (interleukin‐6) expression and decreased Gdf2 expression (corrected P value1). In this context, male rats expressed higher pulmonary levels of endothelin‐1 and IL‐6 than females. Conclusions Our novel 2‐hit rat model presents a promising avenue to explore the adaptation of the right ventricle and pulmonary vasculature to PH, shedding light on pertinent sex‐ and gene‐related effects.

Dans les sociétés occidentales savantes, s’il est un modèle de communauté musicale, c’est bien celui de l’orchestre symphonique. Tel qu’il se développe à partir du xviiie siècle, l’orchestre symphonique s’offre comme un corps social à part entière. Au xixe siècle, porté par l’audace républicaine, il est érigé comme exemple modèle de la « nation » : les musiciens y travaillent en commun pour la bonne exécution de l’œuvre. Toutefois, ce corps social musicien semble répondre à l’organisation même des signes de la partition. L’existence du chef d’orchestre peut d’ailleurs apparaître comme l’allégorie de cette manière centralisatrice de penser le collectif qui se joue déjà dans la mise en place des signes musicaux. Partant d’une analyse de la verticalité et de l’autorité, cette contribution vise à conscientiser les implicites d’une musique qui suit une organisation très disciplinée et tente de penser une autre manière, pour la musique, de susciter l’organisation d’une communauté. C’est à travers l’opposition entre une organisation verticale et horizontale que peut se penser un nouveau type de « vivre-ensemble ».

Background: Stent implantation has become the preferred method of treatment for treating vessel stenosis in congenital heart diseases. The availability of covered stents may decrease complications and have an important role in the management of patients with complex anatomy. Aim: This study aims to evaluate the feasibility and safety of the pre-mounted cobalt–chromium stent-graft-covered ePTFE Aortic BeGraft in a broad spectrum of vascular lesions. Methods: This is a multicenter retrospective results analysis of 107 implanted BeGraft stents between 2016 and 2022 in six different European centers. Results: One hundred and four patients with a mean age of thirteen years (range 1–70 years) and with the body weight of 56.5 kg (range 11–115 kg) underwent the BeGraft stent implantation. Stents were implanted in the following conditions: aortic coarctation (74 patients), RVOT dysfunction (12 patients), Fontan circulation (7 patients), and miscellaneous (11 subjects with complex CHD). All the stents were implanted successfully. The median stent diameter was 16 mm (range 7–24 mm), and the median length was 39 mm (range 19–49 mm). Major complications occurred in five subjects (4.7%). During a median follow-up of fourteen (1–70) months, stents’ re-dilatation was performed in five patients. Conclusions: The BeGraft stent can be used safely and effectively in a wide spectrum of congenital heart diseases. Whether these good results will be stable in the longer term still needs to be investigated in a follow-up given its recent introduction into clinical practice, in particular regarding stent fracture or neointimal proliferation.

AimsA proportion of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) do not fit in the current classification. We aimed to analyse the applicability of an adapted clinical classification of PAH-CHD to pediatric patients using the TOPP-1 registry (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) and focus on atrial septal defects (ASD) and transposition of the great arteries (TGA).Methods and resultsHemodynamic and clinical data of all patients with PAH-CHD in the TOPP cohort were reviewed. Patients were classified according to predefined ABCDE categories (A: Eisenmenger syndrome, B: left-to-right shunt, C: coincidental defects, including all ASDs, D: corrected CHD, E: TGA), or as complex CHD (group 5), by 2 independent investigators. In case of disagreement, a third reviewer could either settle a final decision, or the patient was deemed not classifiable. Survival curves were calculated for each group and compared to idiopathic PAH patients of the registry. A total of 223 out of 531 patients in the registry had PAH-CHD, and 193 were categorized to the following groups: A 39(20%), B 27(14%), C 62(32%) including 43 ASDs, D 58(30%), E 7(4%), whereas 6 patients were categorized as group 5, and 10 patients were unable to be classified. No survival difference could be demonstrated between the groups.ConclusionsThis modified classification seems to be more applicable to pediatric PAH-CHD patients than the previous classification, but some patients with PAH-CHD who never had a shunt remain unclassifiable. The role of ASD in pediatric PH should be reconsidered.

Summary: Background: Few studies have assessed the prevalence and mortality of simple or complex congenital heart diseases (CHD) in newborns. In Latin America and Caribbean (LAC), CHD epidemiology seems highly variable, with few population-based assessments and different methodologies between studies. To date, the situation in French Guiana, a French overseas territory located in South America between Brazil and Suriname, has never been described. Methods: We analysed CHD prevalence, characteristics and related infant mortality in French Guiana, with a population-based registry analysis of all fetal and live birth CHD cases in infants under 1 year (January 2012–December 2016). Findings: Overall, 33,796 births (32,975 live births) were registered, with 231 CHD (56 fetuses), including 215 live births. Most frequent CHD categories were anomalies of the ventricular outflow tract and extra-pericardial trunks, and ventricular septal defects. 18.6% (43/231) chromosomal or genetic anomalies, and 6.5% (15/231) terminations of pregnancy were observed. Total CHD prevalence was 68.4 [95% CI: 67.9–68.8] per 10,000, while live birth prevalence was 65.2 [95% CI: 64.7–65.7] per 10,000. Total infant mortality was 9.4/10,000 live births [95% CI 9.1–9.7], with highest rates for functionally univentricular hearts (FUH). Interpretation: A distinct profile for CHD is highlighted in French Guiana with elevated mortality linked to FUH. A potential determinant of the recognized excess mortality risk might be the presence of chromosomal or genetic anomalies in about a fifth of all CHD. This helps us to better understand CHD burden in this part of South America and provides future keys towards reducing CHD-related infant mortality. Funding: The authors received no financial support for the present research, authorship, and/or publication of this article.

Abstract Background Recent studies have shown the implication of the ROBO-SLIT pathway in heart development. Within this study, we aimed to further assess the implication of the ROBO and SLIT genes mainly in bicuspid aortic valve (BAV) and other human congenital heart defects (CHD). Methods We have analyzed a cohort of singleton exome sequencing data comprising 40 adult BAV patients, 20 pediatric BAV patients generated by the Pediatric Cardiac Genomics Consortium, 10 pediatric cases with tetralogy of Fallot (ToF), and one case with coarctation of the aorta. A gene-centered analysis of data was performed. To further advance the interpretation of the variants, we intended to combine more than 5 prediction tools comprising the assessment of protein structure and stability. Results A total of 24 variants were identified. Only 4 adult BAV patients (10%) had missense variants in the ROBO and SLIT genes. In contrast, 19 pediatric cases carried variants in ROBO or SLIT genes (61%). Three BAV patients with a severe phenotype were digenic. Segregation analysis was possible for two BAV patients. For the homozygous ROBO4: p.(Arg776Cys) variant, family segregation was consistent with an autosomal recessive pattern of inheritance. The ROBO4: c.3001 + 3G > A variant segregates with the affected family members. Interestingly, these variants were also found in two unrelated patients with ToF highlighting that the same variant in the ROBO4 gene may underlie different cardiac phenotypes affecting the outflow tract development. Conclusion Our results further reinforce the implication of the ROBO4 gene not only in BAV but also in ToF hence the importance of its inclusion in clinical genetic testing. The remaining ROBO and SLIT genes may be screened in patients with negative or inconclusive genetic tests.

Diastolic dysfunction refers to a structural or functional abnormality of the left ventricle, resulting in impaired filling of the heart. Severe diastolic dysfunction can lead to congestive heart failure even when the left ventricle systolic function is normal. Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of the hospitalizations for acute heart failure in the adult population but the clinical recognition and understanding of HFpEF in children is poor. The condition is certainly much less frequent than in the adult population but the confirmatory diagnosis of diastolic dysfunction in children is also challenging. The underlying causes of HFpEF in children are diverse and differ from the main cause in adults. This review addresses the underlying causes and prognostic factors of HFpEF in children. We describe the pulmonary hypertension profiles associated with this cardiac condition. We discuss diagnosis difficulties in clinical practice, and we provide a simplified diagnostic algorithm for HFpEF in children.

Le goût de Gérard Pesson (1958*) pour les berceuses est loin d’être anecdotique. Il s’articule à tout un univers poétique où l’intime et le rapport à l’enfance ont toujours été prisés et recherchés. Outre ses émissions sur France musique, où les berceuses avaient une place à part, le compositeur est aussi l’auteur de sept pièces de ce genre. L’étude de ce corpus met en évidence quelques universaux stylistiques (telle que l’oscillation) et déplace la question de la vocalité dans une écriture proprement instrumentale. Aussi, la berceuse pessonienne n’est pas que consolation, mais semble refléter, à l’intérieur même de la musique, l’inquiétude portée par celui qui s’endort. L’étude entend ouvrir la question du bercement pour faire de celui-ci un trait stylistique qui dépasse le strict cadre de la berceuse, jusqu’à faire de celle-ci l’un des topoï volontiers réutilisés par Gérard Pesson au fil de ses œuvres.

Abstract Background Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4 gene. The natural history of MS remains incompletely understood. Methods We recruited in a longitudinal retrospective study patients with molecular confirmed MS from the French reference center for rare skeletal dysplasia. We described natural history by chaining data from medical reports, clinical data warehouse, medical imaging and photographies. Results We included 12 patients. The median age was 22 years old (y/o). Intrauterine and postnatal growth retardation were consistently reported. In preschool age, neurodevelopment disorders were reported in 80% of children. Specifics facial and skeletal features, thickened skin and joint limitation occured mainly in school age children. The adolescence was marked by the occurrence of pulmonary arterial hypertension (PAH) and vascular stenosis. We reported for the first time recurrent strokes from the age of 26 y/o, caused by a moyamoya syndrome in one patient. Two patients died at late adolescence and in their 20 s respectively from PAH crises and mesenteric ischemia. Conclusion Myhre syndrome is a progressive disease with severe multisystemic impairement and life-threathning complication requiring multidisciplinary monitoring.

Dilated cardiomyopathy (DCM) is the most common childhood cardiomyopathy and is associated with considerable early mortality. Heart transplantation is often the only viable life-saving option. Pulmonary artery banding (PAB) has been recently proposed as a bridge or alternative to transplantation for DCM. In our cohort, PAB was selectively addressed to heritable DCM or DCM with congenital left ventricle aneurysm (CLVA). This study aimed to describe the clinical evolution and left ventricle reverse remodeling (LVRR) over time (6 months and 1 year after surgery). Ten patients with severe DCM received PAB between 2016 and 2021 and underwent clinical and postoperative echocardiography follow-ups. The median age at PAB was p < 0.05; LV ejection fraction: 23.8 ± 5.8 to 44.5 ± 13.1 (p < 0.05)). PAB might be useful as part of the armamentarium available in infants and toddlers with severe DCM not sufficiently responding to medical treatment with limited probability of spontaneous recovery.

While rare, SARS-CoV-2-infected children can develop severe COVID-19 (ARDS) or inflammatory syndrome (MIS-C). Here, the authors use proteomics to characterize hundreds of blood proteins and identify key biological pathways that differentiate MIS-C and ARDS.

Background Right heart catheterization (RHC) is a high‐risk procedure in children with pulmonary arterial hypertension without clear guidelines for the indications and targets of invasive reassessment. Our objectives are to define the aims of repeated RHC and evaluate the correlation between noninvasive criteria and hemodynamic parameters. Methods and Results Clinical and hemodynamic characteristics from 71 incident treatment‐naïve children (median age 6.2 years) with pulmonary arterial hypertension who had a baseline and reevaluation RHC were analyzed. Correlations between noninvasive predictors and hemodynamic parameters were tested. Adverse outcomes were defined as death, lung transplantation, or Potts shunt. At baseline, pulmonary vascular resistance index (hazard ratio [HR] 1.07 per 1 WU·m2 increase [95% CI, 1.02–1.12], P=0.002), stroke volume index (HR 0.95 per 1 L·min−1·m−2 increase [95% CI, 0.91–0.99], P=0.012), pulmonary artery compliance index (HR 0.16 per 1 mL·mm Hg−1·m−2 increase [95% CI, 0.051–0.52], P=0.002), and right atrial pressure (HR, 1.31 per 1 mm Hg increase [95% CI, 1.01–1.71], P=0.043) were associated with adverse outcomes. Pulmonary vascular resistance index, pulmonary artery compliance index, and right atrial pressure were still associated with a worse outcome at second RHC. Noninvasive criteria accurately predicted hemodynamic evolution; however, 70% of the patients who had improved based on noninvasive criteria still presented at least 1 “at risk” hemodynamics at second RHC. Conclusions Pulmonary vascular resistance index, pulmonary artery compliance index, and right atrial pressure are solid predictors of adverse outcomes in pediatric pulmonary arterial hypertension and potential therapeutic targets. Noninvasive criteria accurately predict the evolution of hemodynamic parameters, but insufficiently. Repeated RHC are helpful to identify children with persistent higher risk after treatment introduction.

Objectives To evaluate bare-metal Optimus and polytetrafluoroethylene (PTFE)-covered Optimus-CVS balloon-expandable, cobalt–chromium, hybrid cell–designed stents in congenital heart disease (CHD) interventions.Methods Retrospective multicentre review of patients with CHD receiving Optimus stents. Stent mechanical behaviour, clinical indications and outcomes were assessed.Results 183 stents (49.2% XXL/15-ZIG, 33.3% XL/12-ZIG, 17.5% L/9-ZIG) were implanted (98.9% success rate, 2.3% serious procedural complication rate) in 170 patients (57.6% men, 64.1% adults), median age 23.6 years (IQR, 15.2–39.2) and weight 63.5 kg (IQR, 47–75.7). Indications were right ventricular outflow tract stand-alone stenting or before revalvulation (62.4%), aortic coarctation treatment (15.3%), Fontan-circuit fenestration closure (12.4%) and miscellaneous (10%). 86/170 (50.6%) patients had PTFE-covered stenting (50% prophylactic). In 86/170 (50.6%) patients with stenotic lesions, median percentage of achieved stent expansion was 93.4% (IQR, 85.5%–97.7%), median gradient decreased from 28 mm Hg (IQR, 19–41) to 5 mm Hg (IQR, 1–9) (p

BackgroundTranscatheter Potts shunt (TPS) is a palliation alternative for children with severe pulmonary arterial hypertension (PAH). Debates on the long-term outcomes remain unsolved.ObjectivesTo evaluate long-term clinical and procedural outcomes of TPS intervention.MethodsSingle-center retrospective data review of children with severe PAH who had TPS between 2009 and 2018. Patients who died per-operatively and early post-procedure were excluded. Long-term outcomes of survivors were evaluated.ResultsOut of 13 identified patients (53.8% males), 7 had endovascular stenting of probe/patent arterial ducts, while 6 individuals had aorta-to-pulmonary radiofrequency perforation and covered stent placement. Compared to baseline, the overall clinical condition significantly improved at discharge (p < 0.001) and stayed better at the last visit (p < 0.05) despite frequent clinical worsening events across follow-up. Improvement in functional class across follow-up was significant (p < 0.001). There was, however, no significant improvement in other disease markers (TPASE, 6MWD z-scores, and NT-proBNP levels) or reduction in PAH medications. The median follow-up was 77.4 months (IQR, 70.7–113.4). Survival was 100% at 1 year and 92.3% at 6 years. Freedom from reinterventions was 77% at 1 year and 21% at 6 years. Nine (69.2%) patients had stent reinterventions at a median of 25 months (IQR, 9.5–56) postoperative. Balloon dilatation and restenting were performed in 53.8% and 46.2% of patients, respectively. High-pressure post-dilatation of implanted stents was performed in 53.8% of patients during TPS intervention for incomplete stent expansion and/or residual pressure gradient and was associated with higher rates of reinterventions (p = 0.021). Stent malfunctioning was present in 46.2% of patients at last follow-up. Two patients are listed for heart-lung transplantation.ConclusionSurvivors of TPS procedures experience significant improvement in functional class that can be durable. Clinical worsening and stent malfunctioning are frequent morbid events indicating recurrent transcatheter reinterventions throughout follow-up. Six-year survival is, however, satisfactory.

Abstract Background Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. Methods The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease’s clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. Discussion After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 ).

Background: A pulmonary sequestration (PS) is an area of bronchopulmonary tissue with aberrant arterial supply. Transcatheter occlusion of PSs is an appealing treatment option, but data on outcomes remain scarce. We aim to describe our experience with transcatheter management of PS in infants and children. Methods: Retrospective review of clinical data of all patients with suspected PS sent for diagnostic and/or interventional cardiac catheterization at our institution between January 1999 and May 2021. Procedural considerations, techniques, standard safety, and outcomes were assessed. Results: We identified 71 patients (52.1% males), with median age and weight of 4.9 months (IQR, 2.1–26.6) and 4.2 kg (IQR, 3.9–12.1), respectively. Sixty-one (86%) patients had associated congenital heart defects (CHDs). Forty-two (59%) patients had pulmonary arterial hypertension (PAH) at the time of diagnosis. Fifty-three (74.7%) patients underwent embolization of the PS feeding vessel using microcoils and/or vascular plugs, and eight (15.1%) of these were neonates who presented with severe PAH and cardiac failure. Two patients had large feeding vessels and were treated surgically. Sixteen (22.5%) patients with small feeding vessels received conservative management. At median follow-up of 36.4 months (IQR, 2.1–89.9), seven patients had died, 24 patients had CHD corrective surgeries, 26 patients had redo catheterizations, and five patients had persistent PAH. No PS surgical resection was needed, and no infection of the remaining lung tissue occurred. Conclusions: Transcatheter assessment and treatment of PSs is a safe and effective procedure. Neonates with large PSs are severely symptomatic and improve remarkably after PS closure. PS embolization and surgical repair of associated CHDs generally leads to the normalization of pulmonary pressures.

Background: Fetal tachyarrhythmia is a condition that may lead to cardiac dysfunction, hydrops, and death. Despite a transplacental treatment, failure to obtain or maintain sinus rhythm may occur. Objective: We aimed to analyze the perinatal outcomes of sustained fetal tachyarrhythmias after in utero treatment. Methods: We performed a retrospective evaluation of 69 cases with sustained fetal tachyarrhythmia. We compared the perinatal and long-term outcomes of prenatally converted and drug-resistant fetuses. Tachyarrhythmia subtypes were also evaluated. Results: Conversion to sinus rhythm was obtained in 74% of cases; 26% of cases were drug-resistant and delivered arrhythmic. Three perinatal deaths occurred in both groups (6.7% vs 17%, P = .34). Neonates delivered arrhythmic were more frequently admitted to neonatal intensive care units (75% vs 31%, P < .01), and their hospital stay was longer (20.9 vs 6.64 days, P < .001). Multiple neonatal recurrences (81% vs 11%, P < .001), temporary hemodynamic dysfunction or heart failure (50% vs 6.7%, P < .001), and postnatal use of a combination treatment (44% vs 13%, P = .028) were also more frequent in this population. Beyond the neonatal period, rates of recurrences within the first 16 months were higher in drug-resistant fetuses (HR = 16.14, CI 95% [4.485; 193.8], P < .001). In this population, postnatal electrocardiogram revealed an overrepresentation of rare mechanisms, especially permanent junctional reciprocating tachycardia (PJRT) (31%). Conclusion: Prenatal conversion to stable sinus rhythm is a major determinant of perinatal and long-term outcomes in fetal tachyarrhythmias. The underlying electrophysiological mechanisms have a major role in predicting these differential outcomes with an overrepresentation of PJRT in the drug-resistant population.

Although the left ventricular assist device is an important bridge to heart transplantation for patients with end-stage heart failure, it can also be a source of embolic stroke. We present a case of late intracranial mechanical thrombectomy performed for embolic stroke beyond the recommended 6 h, thus allowing for heart transplantation 4 days after intracranial mechanical thrombectomy. (Level of Difficulty: Advanced.)

Abstract Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT–CHILD (NCT02562235), a multicenter, single‐arm, 24‐week, open‐label, Phase 3 study. Patients aged 6–17 years in World Health Organization functional class (WHO‐FC) I–III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5–2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty‐four patients (mean age 12.8 years), 18 of whom were in WHO‐FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study‐drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6‐minute walking distance was 23 ± 69 m (n = 19), and mean decrease in NT‐proBNP was –66 ± 585 pg/ml (n = 14). There was no change in WHO‐FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals.

Abstract Aims Potts shunt has been proposed as a bridge or alternative to lung transplantation for children with severe and drug‐refractory suprasystemic pulmonary arterial hypertension (PAH). We describe the management of the atrial shunt when a Potts shunt is planned in refractory PAH. Methods and results We report a case series of children in whom a Potts shunt was done for severe PAH associated with an atrial septal defect to illustrate the different clinical and haemodynamic scenarios. Five children (2 to 13 years) underwent a Potts shunt: three surgical, one percutaneous Potts shunt, and one percutaneous stenting of a restrictive arterial duct. All had associated atrial septal defect. Those who had generalized cyanosis before the procedure had a complicated postoperative course and required longer ventilatory and inotropic support, except the one who had atrial septal defect closure before the Potts shunt. One of the three cyanotic patients died. Two patients with left‐to‐right shunt before the Potts shunt had an uncomplicated postoperative course. Conclusions Shunt physiology is only partially predictable after the Potts shunt in children with PAH and atrial septal defect. Abrupt drop in left ventricle preload while the right ventricle is decompressed can potentially be prevented by atrial septal defect closure prior to the Potts shunt.

Abstract Aims In univentricular hearts, selective lung vasodilators such as phosphodiesterase type 5 (PDE5) inhibitors would decrease pulmonary resistance and improve exercise tolerance. However, the level of evidence for the use of PDE5 inhibitors in patients with a single ventricle (SV) remains limited. We present the SV‐INHIBITION study rationale, design, and methods. Methods and results The SV‐INHIBITION trial is a nationwide multicentre, randomized, double blind, placebo‐controlled, Phase III study, aiming to evaluate the efficacy of sildenafil on the ventilatory efficiency during exercise, in teenagers and adult patients (>15 years old) with an SV. Patients with a mean pulmonary arterial pressure >15 mmHg and a trans‐pulmonary gradient >5 mmHg, measured by cardiac catheterization, will be eligible. The primary outcome is the variation of the VE/VCO2 slope, measured by a cardiopulmonary exercise test, between baseline and 6 months of treatment. A total of 50 patients are required to observe a decrease of 5 ± 5 points in the VE/VCO2 slope, with a power of 90% and an alpha risk of 5%. The secondary outcomes are clinical outcomes, oxygen saturation, 6 min walk test, SV function, NT‐proBNP, peak VO2, stroke volume, mean pulmonary arterial pressure, trans‐pulmonary gradient, SF36 quality of life score, safety, and acceptability. Conclusions The SV‐INHIBITION study aims to answer the question whether PDE5 inhibitors should be prescribed in patients with an SV. This trial has been built focusing on the three levels of research defined by the World Health Organization: disability (exercise tolerance), deficit (SV function), and handicap (quality of life).

Background: The use of covered stents (CVS) in congenital heart disease (CHD) interventions is increasing but intrinsic properties of commercially available material remain not optimal. The Optimus-CVS™ (AndraTec GmbH, Koblenz, Germany) is a new balloon-expandable, non-premounted, Cobalt–Chromium stent with patented hybrid-cell design, innovative end-free Nano-PTFE sandwich-covering, and competitive deliverability features. Methods and results: Three patients with CHD received Optimus-CVS during December 2020 at our institution. Indications for CVS implantation were relief of complex aortic recoarctation (57 ​mm long Optimus-CVS-XL), treatment of intra-stent intimal proliferation in Fontan circulation (48 ​mm long Optimus-CVS-XXL), and as a bail-out for conduit rupture during pulmonary valve implantation (33 ​mm long Optimus-CVS-XXL). Procedures were successful and straightforward. Target diameter was achieved and stent shortening was minimal and as expected. No stent failure was recorded on short-term follow-up. Conclusions: Optimus-CVS appears to be a reliable high-performing CVS alternative in major CHD situations where CVS are needed. Optimus-CVS offers interesting construction characteristics, smart covering design, and the largest portfolio in terms of diameters and length optimizing lesion care and improving outcomes.

Mortality outcomes of children with isolated neonatally operated congenital heart defects (CHDs) born with a low (LBW), moderately low (MLBW) or very-low birthweight (VLBW) remain ambiguous. We searched Medline and Embase (inception until October 2021) and included studies that evaluated early mortality. The risk of bias was assessed using the Critical Appraisal Skills Program cohort checklist. Meta-analysis involved random-effects models. We explored variability in mortality across birthweight subgroups, CHD types, and study designs. From 2035 reports, we included 23 studies in qualitative synthesis, and the meta-analysis included 11 studies (1658 CHD cases), divided into 30 subcohorts. The risk of bias was low in 4/11 studies included in the meta-analysis. Summary mortality before discharge or within one month after surgery was 37% (95%CI 27–47). Early mortality varied by birthweight (VLBW 56%, MLBW 15%, LBW 16%; p = 0.003) and CHD types (hypoplastic left heart syndrome (HLHS) 50%, total anomalous pulmonary venous return (TAPVR) 47%, transposition of the great arteries (TGA) 34%, coarctation of the aorta (CoA) 16%; p = 0.13). Mortality was higher in population-based studies (49% vs. 10%; p = 0.006). One-third of infants born with neonatally operated isolated CHDs and LBW, MLBW, or VLBW died within 30 days after surgery. Mortality varied across infant and study characteristics. These results may help clinicians assess neonatal prognosis. PROSPERO registration CRD42020170289.

Introduction: Patent ductus arteriosus (PDA) is common in preterm infants and contributes to morbidity and mortality. Several studies have shown the feasibility and safety of percutaneous PDA closure. Minimally invasive surgical ligation by anterior thoracotomy is an alternative, bedside technique for PDA closure in very low birth weight preterm infants. Our study aimed to compare short- and medium-term morbidity and mortality between anterior minithoracotomy and transcatheter PDA closure.Methods: From 2010 to 2020, 92 preterm infants

Purpose The COCCINELLE study is a nationwide retrospective French cohort set up to evaluate the risk of cancer in patients who undergone cardiac catheterisation (CC) procedures for diagnosis or treatment of congenital heart disease during childhood.Participants Children who undergone CC procedures from 1 January 2000 to 31 December 2013, before the age of 16 in one of the 15 paediatric cardiology departments which perform paediatric CC in mainland France were included. The follow-up started at the date of the first recorded CC procedure until the exit date, that is, the date of death, the date of first cancer diagnosis, the date of the 18th birthday or the 31 December 2015, whichever occurred first. The cohort was linked to the National Childhood Cancer Registry to identify patients diagnosed with cancer and with the French National Directory for the Identification of Natural Persons to retrieve the patients’ vital status.Findings to date A total of 17 104 children were included in the cohort and followed for 110 335 person-years, with 22 227 CC procedures collected. Among the patients, 81.6% received only one procedure. Fifty-nine cancer cases were observed in the cohort. Standardised incidence ratios (SIRs) were increased for all-cancer (SIR=3.8, 95% CI: 2.9 to 4.9), leukaemia (SIR=3.3, 95% CI: 2.0 to 5.4), lymphoma (SIR=14.9, 95% CI: 9.9 to 22.5) and solid cancers excluding central nervous system (CNS) tumours (SIR=3.3, 95% CI: 2.0 to 5.5) compared with the general population.Future plans Dose reconstruction is currently underway to estimate individual cumulative doses absorbed to relevant organs, including red bone marrow and brain for respectively haematologic disorders and CNS tumours risk estimation. A dose–response analysis will be conducted with consideration to confounding factors such as age at exposure, gender, predisposing factors to cancer and other sources of medical diagnostic low-dose ionising radiation.

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to

This study evaluated the efficacy and safety of tadalafil in pediatric patients with pulmonary arterial hypertension. This phase-3, international, randomized, multicenter (24 weeks double-blind placebo-controlled period; two-year, open-labeled extension period), add-on (patient’s current endothelin receptor antagonist therapy) study included pediatric patients aged

Background and Objectives: Congenital heart defects (CHD) and growth restriction at birth are two major causes of childhood and adult morbidity and mortality. The aim of this study was to assess the overall risk of growth restriction at birth, as measured by its imperfect proxy small (< 10th percentile) for gestational age (SGA), for newborns with CHD.Methods: Using data from a population-based cohort of children born with CHD, we assessed the risk of growth restriction at birth using SGA and severe SGA (3rd percentile). To compare the odds of SGA and severe SGA across five specific major CHD, we used ordinal logistic regression using isolated, minor (non-operated) ventricular septal defect (VSD) as the control group.Results: The overall proportion of SGA for “isolated” CHD (i.e., those not associated with other anomalies) was 13% (95% CI, 12–15%), which is 30% higher than what would be expected in the general population (i.e., 10%). The risk of severe SGA was 5% (95% CI, 4–6%) as compared with the expected 3% in the general population. There were substantial differences in the risk of overall SGA and more so severe SGA across the different CHD. The highest risk of SGA occurred for Tetralogy of Fallot (adjusted OR 2.7, 95% CI, 1.3–5.8) and operated VSD (adjusted OR 2.1, 95% CI, 1.1–3.8) as compared with the control group of minor (non-operated) VSD.Conclusion: The overall risks of both SGA and severe SGA were higher in isolated CHD than what would be expected in the general population with substantial differences across the subtypes of CHD. These results may provide a clue for understanding the underlying mechanisms of the relation between alterations in fetal circulation associated with different types of CHD and their effects on fetal growth.

Objectives: To evaluate safety, efficacy, and technical advantages of Amplatzer™ Trevisio™ intravascular delivery system (ATIDS) in percutaneous atrial septal defect (ASD) closure in children.Background: The Trevisio™ is a novel delivery system designed for accurate and facilitated implantation of Amplatzer™ devices. There are no published clinical reports so far.Methods: During September 2020, 9 children with anatomically challenging ASDs underwent attempted transcatheter closure using ATIDS to deliver Amplatzer™ Septal occluders (ASO). All interventions were performed under general anesthesia, trans-esophageal echocardiography (TOE), and fluoroscopic guidance. Standard safety, immediate, and 60-days outcomes were prospectively assessed.Results: The median age was 8.1 (5.1–16.9) years and the median bodyweight was 30 (18–63) kg. Six patients had isolated secundum-type ASDs with absent anterosuperior rims including one with an aneurysmal septum. Three patients had unclassical defects associated with complex congenital heart anomalies. Eight devices were delivered from the femoral vein and the jugular vein was accessed in one patient with interrupted inferior caval vein and azygos continuation. All implantations were successful. The shape, position, and orientation of the ASO were identical before and after release on TOE and fluoroscopy. There was no device embolization or serious complication following closure. Complete shunt closure was confirmed on follow-up.Conclusions: We report the first clinical experience with ATIDS in transcatheter ASD pediatric closures. Safety and efficacy were witnessed in our case-series. The major advantage of reduced-tension deployment and reliable precision in device positioning is highly beneficial in challenging anatomies and unusual access.

Congenital heart disease (CHD) is a frequent occurrence, with a prevalence rate of almost 1% in the general population. However, the pathophysiology of the anomalous heart development is still unclear in most patients screened. A definitive genetic origin, be it single-point mutation or larger chromosomal disruptions, only explains about 35% of identified cases. The precisely choreographed embryology of the heart relies on timed activation of developmental molecular cascades, spatially and temporally regulated through epigenetic regulation: chromatin conformation, DNA priming through methylation patterns, and spatial accessibility to transcription factors. This multi-level regulatory network is eminently susceptible to outside disruption, resulting in faulty cardiac development. Similarly, the heart is unique in its dynamic development: growth is intrinsically related to mechanical stimulation, and disruption of the intrauterine environment will have a direct impact on fetal embryology. These two converging axes offer new areas of research to characterize the cardiac epigenetic regulation and identify points of fragility in order to counteract its teratogenic consequences.

Background: Recent advances in the field of congenital heart disease (CHD) have significantly improved the overall prognosis. Now more attention is being given to health-related quality of life (HRQoL) and promotion of physical activity. Non-invasive relaxation therapy may be effective in cardiac patients concerned with exercise-induced dyspnoea. The SOPHROCARE randomised trial aims to assess the impact of Caycedian Sophrology on cardiopulmonary fitness in adolescents and young adults with CHD. Methods: The SOPHROCARE trial is a nationwide, multicentre, randomised, controlled study in CHD patients aged from 13 to 25 years old. Patients will be randomised into 2 groups (8 Sophrology group sessions vs. no intervention). The primary outcome is the change in percent predicted maximum oxygen uptake (VO2max) between baseline and 12-month follow-up. A total of 94 patients in each group is required to observe a significant increase of 10% in VO2max with a power of 80% and an alpha risk of 5%. The secondary outcomes are: clinical outcomes, cardiopulmonary exercise test parameters (VE/VCO2 slope, ventilatory anaerobic threshold, oxygen pulse, respiratory response to hypercapnia), health-related quality of life score (PedsQL), physical and psychological status. Conclusion: After focusing on the survival in CHD, current research is opening on secondary prevention and patient-related outcomes. We sought to assess in the SOPHROCARE trial, if a Sophrology program, could improve exercise capacity and quality of life in youth with CHD. Trial registration: Clinicaltrials.gov (NCT03999320). Keywords: Sophrology, Congenital heart defect, Exercise capacity, Health-related quality of life, VO2max, Relaxation

Abstract Background Venous thromboembolism (VTE) in young children is not well documented. Methods Clinicians from 12 institutions retrospectively evaluated the presentation, therapeutic management, and outcome of VTE in children younger than 2 years seen in 2011–2016. Feasibility of recruiting these children in EINSTEIN-Jr. phase III, a randomized trial evaluating rivaroxaban versus standard anticoagulation for VTE, was assessed. Results We identified 346 children with VTE, of whom 227 (65.6%) had central venous catheter-related thrombosis (CVC-VTE), 119 (34.4%) had non-CVC-VTE, and 156 (45.1%) were younger than 1 month. Of the 309 children who received anticoagulant therapy, 86 (27.8%) had a short duration of therapy (i.e.

Abstract Background A ventricular septal defect (VSD) is an integral part of most congenital heart defects (CHD). To determine the prevalence of VSD in various types of CHD and the distribution of their anatomic types. Methods We reviewed 1178 heart specimens with CHD from the anatomic collection of the French Reference Centre for Complex Congenital Heart Defects. During the morphologic study a special attention was paid to the localisation of the VSD viewed from the right ventricular side. The VSDs were classified as muscular, central perimembranous, outlet located between the two limbs of the septal band, and inlet. The specimens were classified according to the 9 categories and 23 subcategories of the anatomic and clinical classification of CHD1 (ACC-CHD). Results Ventricular septum was almost always intact in anomalies of pulmonary veins (4/73, 5%), Ebstein anomaly (3/21, 14%), and double-inlet right ventricle (DIRV, 1/10, 10%). There was always a VSD in tetralogy of Fallot and variants (TOF, 123 cases) and common arterial trunk (CAT, 55 cases), always of the outlet type. There was almost always a VSD in double inlet left ventricle (33/34, 97%, always muscular), congenitally corrected transposition of great arteries (ccTGA, 23/24, 96%), interrupted aortic arch (IAA, 25/27, 93%), and double outlet right ventricle (DORV, 92/106, 87%). A VSD was found in 68% of aortic coarctation (CoA, 43/63), 62% of heterotaxy syndromes (21/34), 54% of transposition of the great arteries (TGA, 104/194). The VSD was located between the two limbs of the septal band in 100% of TOF and CAT, 80% of IAA, 77% of DORV, 82% of DD. The VSD was of the inlet type in 17% of cc TGA and in 71% of heterotaxy syndromes. In TGA, the VSD was outlet in 40%, central perimembranous in 25%, muscular in 25%, inlet in 10%. In CoA, the VSD was outlet in 44%, central perimembranous in 35%, muscular in 21%. In the 10% hearts with isolated VSD, the distribution was outlet in 44%, central perimembranous in 36%, muscular in 18%, and inlet in 2%. Conclusion The anatomic distribution of VSD is similar in isolated VSD, CoA and TGA, while the VSD is predominantly outlet in outflow tract defects except TGA. This reinforces the allegedly different mechanisms in TGA and cardiac neural crest defects. This anatomic approach could provide new insights in the grouping and aetiology of CHD.

(1) Background: Transcatheter closure of the patent arterial duct (TCPDA) in preterm infants is an emerging procedure. Patent arterial duct (PDA) spontaneous closure after failed TCPDA attempts is seen but reasons and outcomes are not reported; (2) Methods: We retrospectively included all premature infants

Common arterial trunk (CAT) is a rare congenital heart disease that is commonly included into the spectrum of conotruncal heart defects. CAT is rarely associated with functionally univentricular hearts, and only few cases have been described so far. Here, we describe the anatomical characteristics of CAT associated with a univentricular heart diagnosed in children and fetuses referred to our institution, and we completed the anatomical description of this rare condition through an extensive review of the literature. The complete cohort ultimately gathered 32 cases described in the literature completed by seven cases from our unit (seven fetuses and one child). Four types of univentricular hearts associated with CAT were observed: tricuspid atresia or hypoplastic right ventricle in 16 cases, mitral atresia or hypoplastic left ventricle in 12 cases, double-inlet left ventricle in 2 cases, and unbalanced atrioventricular septal defect in 9 cases. Our study questions the diagnosis of CAT as the exclusive consequence of an anomaly of the wedging process, following the convergence between the embryonic atrioventricular canal and the common outflow tract. We confirm that some forms of CAT can be considered to be due to an arrest of cardiac development at the stages preceding the convergence.

We propose an asymmetric synthesis of functionalized cyclopentanoids bearing up to four stereogenic centers from easily accessible nitroalkenes and unsaturated aldehydes. The overall sequence includes an enantioselective organocatalytic Michael addition and a [3 + 2]-heterocyclization between an in situ generated silylnitronate and the unactivated double bond. Finally, the fused isoxazoline can be further transformed to various cyclopentanoids. [ABSTRACT FROM AUTHOR]

Abstract Background Congenital heart defects (CHD) and preterm birth (PTB) are major causes of infant mortality. However, limited data exist on risk of mortality associated with PTB for newborns with CHD. Our objective was to assess impact of PTB on risk of infant mortality for newborns with CHD, while taking into account the role of associated anomalies and other potentially confounding factors. Methods We used data on 2172 live births from a prospective population-based cohort study of CHD (the EPICARD Study) and compared neonatal, post-neonatal and overall infant mortality for infants born at

Background: 3D technology support is an emerging technology in the field of congenital heart diseases (CHD). The goals of 3D printings or models is mainly a better analysis of complex anatomies to optimize the surgical repair or intervention planning.Method: We performed a systematic review to evaluate the accuracy and reliability of CHD modelization and 3D printing, as well as the proof of concept of the benefit of 3D printing in planning interventions.Results: Correlation studies showed good results with anatomical measurements. This technique can therefore be considered reliable with the limit of the operator's subjectivity in modelizing the defect. In cases series, the benefits of the 3D technology have been shown for describing the vessels anatomy and guiding the surgical approach. For intra-cardiac complex anatomy, 3D models have been shown helpful for the planification of intracardiac repair. However, there is still lack of evidence based approach for the usefulness of 3D models in CHD in changing outcomes after surgery or interventional procedures due to the difficulty to design a prospective study with comprehensive and clinically meaningful end-points.Conclusion: 3D technology can be used to improve the understanding of anatomy of complex CHD and to guide surgical strategy. However, there is a need to design clinical studies to identify the place of this approach in the current clinical practice.

Incontinentia pigmenti (IP) is a multisystemic disorder in which pulmonary arterial hypertension (PAH) is a severe and rarely reported association. The prognosis has been poor in reported cases. In our patient, IP was diagnosed during the neonatal period with a combination of cutaneous, ophthalmic, and neurological symptoms. The infant experienced severe collapse with bradycardia during general anesthesia to treat retinal telangiectasia. Echocardiography after resuscitation revealed suprasystemic pulmonary hypertension (PH). Right heart catheterization (RHC) confirmed precapillary PAH not responding to acute vasodilatation test. Lung biopsy was performed to exclude alveolo-capillary dysplasia. Upfront triple therapy with endothelin receptor antagonist, PDE5 inhibitors, and prostacyclin was started. Due to a potential inflammatory mechanism of this acute PAH in the setting of IP, TNF-alpha blockers and steroids were associated. The evolution was favorable with progressive normalization of the pulmonary artery pressure confirmed by RHC after six months. Doses of PAH drugs were tapered down, and finally all PAH treatments could be stopped after 18 months. Subsequent controls including physical exams and echocardiograms did not show signs of PH. This unusual reversible case of pediatric PAH without associated congenital heart disease or portal hypertension highlights the potential reversibility of pediatric PH when an inflammatory mechanism can be suspected. This is the first reported case of non-fatal isolated PAH associated with IP.

An unusual case of a rare vascular ring, which has been called right aortic arch with aberrant left innominate artery, is presented. The appearance of this case led to the realization that there is really no innominate artery present in this anomaly but only the left dorsal aorta. We present a clarification of the nature and likely development of the vessels present.

BACKGROUND: Antiretroviral therapy (ART) has major benefits during pregnancy, both for maternal health and to prevent mother-to-child transmission of HIV. Safety issues, including teratogenic risk, need to be evaluated. We estimated the prevalence of birth defects in children born to HIV-infected women receiving ART during pregnancy, and assessed the independent association of birth defects with each antiretroviral (ARV) drug used. METHODS AND FINDINGS: The French Perinatal Cohort prospectively enrolls HIV-infected women delivering in 90 centers throughout France. Children are followed by pediatricians until 2 y of age according to national guidelines. We included 13,124 live births between 1994 and 2010, among which, 42% (n = 5,388) were exposed to ART in the first trimester of pregnancy. Birth defects were studied using both European Surveillance of Congenital Anomalies (EUROCAT) and Metropolitan Atlanta Congenital Defects Program (MACDP) classifications; associations with ART were evaluated using univariate and multivariate logistic regressions. Correction for multiple comparisons was not performed because the analyses were based on hypotheses emanating from previous findings in the literature and the robustness of the findings of the current study. The prevalence of birth defects was 4.4% (95% CI 4.0%-4.7%), according to the EUROCAT classification. In multivariate analysis adjusting for other ARV drugs, maternal age, geographical origin, intravenous drug use, and type of maternity center, a significant association was found between exposure to zidovudine in the first trimester and congenital heart defects: 2.3% (74/3,267), adjusted odds ratio (AOR) = 2.2 (95% CI 1.3-3.7), p = 0.003, absolute risk difference attributed to zidovudine +1.2% (95% CI +0.5; +1.9%). Didanosine and indinavir were associated with head and neck defects, respectively: 0.5%, AOR = 3.4 (95% CI 1.1-10.4), p = 0.04; 0.9%, AOR = 3.8 (95% CI 1.1-13.8), p = 0.04. We found a significant association between efavirenz and neurological defects (n = 4) using the MACDP classification: AOR = 3.0 (95% CI 1.1-8.5), p = 0.04, absolute risk +0.7% (95% CI +0.07%; +1.3%). But the association was not significant using the less inclusive EUROCAT classification: AOR = 2.1 (95% CI 0.7-5.9), p = 0.16. No association was found between birth defects and lopinavir or ritonavir with a power >85% for an odds ratio of 1.5, nor for nevirapine, tenofovir, stavudine, or abacavir with a power >70%. Limitations of the present study were the absence of data on termination of pregnancy, stillbirths, tobacco and alcohol intake, and concomitant medication. CONCLUSIONS: We found a specific association between in utero exposure to zidovudine and heart defects; the mechanisms need to be elucidated. The association between efavirenz and neurological defects must be interpreted with caution. For the other drugs not associated with birth defects, the results were reassuring. Finally, whatever the impact that some ARV drugs may have on birth defects, it is surpassed by the major role of ART in the successful prevention of mother-to-child transmission of HIV. Please see later in the article for the Editors' Summary.

BackgroundAbnormalities of the fetal pulmonary vasculature may affect lung morphogenesis. Postnatal studies have suggested that pulmonary hypoplasia (PH) may be associated with congenital heart diseases (CHDs).ObjectiveTo determine the prevalence of PH associated with CHDs, and to evaluate whether CHDs with right outflow obstruction were associated with the highest risk of lung growth impairment.MethodsBetween January 2006 and December 2010, fetuses with CHD obtained following the termination of pregnancies due to fetal abnormalities were examined in a prospective manner for the detection of heart and lung defects. CHDs were classified into five pathophysiological groups. Lung weight (LW), body weight (BW), and LW/BW ratio were analyzed for each case. The expression of CD31 and VEGF in the lung was evaluated by immunohistochemistry.ResultsFetuses with CHDs and right outflow obstruction had significantly lower LW for a given BW, and significantly lower LW/BW ratios for a given gestational age. When defining PH as a fetal LW/BW ratio ConclusionCHDs with right outflow obstruction are a significant risk factor for prenatally acquired PH. The occurrence of fetal PH is not correlated with abnormalities of the pulmonary vasculature, suggesting the involvement of perfusion-independent mechanisms.

Hypoxia is a common feature in children with sickle cell disease (SCD) that is inconsistently associated with painful crises and acute chest syndrome. To assess the prevalence and risk factors of hypoxia, we recorded daytime, nocturnal, and postexercise pulse oximetry (SpO2) values in 39 SCD patients with a median age of 10.8 years. Median daytime SpO2 was 97% (range, 89%-100%), and 36% of patients had daytime hypoxia defined as SpO2

BACKGROUND: Pulmonary vasodilators in general and prostacyclin analogues in particular have improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cell (CEC) level could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that an efficient PAH-specific vasodilator therapy might decrease CEC level. METHODS/RESULTS: CECs were prospectively quantified by immunomagnetic separation with mAb CD146-coated beads in peripheral blood from children with idiopathic PAH (iPAH, n = 30) or PAH secondary to congenital heart disease (PAH-CHD, n = 30): before, after treatment and during follow up. Controls were 23 children with reversible PAH. Oral treatment with endothelin receptor antagonists (ERA) and/or phosphodiesterase 5 inhibitors (PDE5) significantly reduced CEC counts in children. In 10 children with refractory PAH despite oral combination therapy, subcutaneous (SC) treprostinil was added and we observed a significant decrease in CEC counts during the first month of such treatment. CECs were quantified during a 6 to 36 month-follow-up after initiation of SC treprostinil and we found that CEC counts changed over time, with rising counts always preceding clinical deterioration. CONCLUSION: CECs might be useful as a biomarker during follow-up of pediatric iPAH and PAH-CHD to assess response to treatment and to anticipate clinical worsening.

Impairment of endothelial-dependent vasodilation has been demonstrated in adults with sickle cell anemia (SCA). We enrolled 21 SCA children, mean age 10.4±3.3 yrs, and 23 Afro-Caribbean controls. We examined flow-mediated (FMD) and nitroglycerine-mediated (GTNMD) dilation of the brachial artery, using echotracking techniques, and measured intima-media thickness (IMT) and mechanical properties of the common carotid artery. FMD was significantly decreased in SCA children vs controls (5.6±0.2 vs 8.0±0.2%, p=0.008), while IMT, stiffness of the common carotid artery, and GTNMD were comparable. In conclusion, endothelial dysfunction is present as early as childhood in SCA patients.