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BACKGROUND: The placement of a pulmonary-to-systemic arterial shunt in children with severe pulmonary hypertension (PH) has been demonstrated, in relatively small studies, to be an effective palliation for their disease.OBJECTIVES: The aim of this study was to expand upon these earlier findings using an international registry for children with PH who have undergone a shunt procedure.METHODS: Retrospective data were obtained from 110 children with PH who underwent a shunt procedure collected from 13 institutions in Europe and the United States.RESULTS: Seventeen children died in-hospital postprocedure (15%). Of the 93 children successfully discharged home, 18 subsequently died or underwent lung transplantation (20%); the mean follow-up was 3.1 years (range: 25 days to 17 years). The overall 1- and 5-year freedom from death or transplant rates were 77% and 58%, respectively, and 92% and 68% for those discharged home, respectively. Children discharged home had significantly improved World Health Organization functional class (P < 0.001), 6-minute walk distances (P = 0.047) and lower brain natriuretic peptide levels (P < 0.001). Postprocedure, 59% of children were weaned completely from their prostacyclin infusion (P < 0.001). Preprocedural risk factors for dying in-hospital postprocedure included intensive care unit admission (hazard ratio [HR]: 3.2; P = 0.02), mechanical ventilation (HR: 8.3; P < 0.001) and extracorporeal membrane oxygenation (HR: 10.7; P < 0.001).CONCLUSIONS: A pulmonary-to-systemic arterial shunt can provide a child with severe PH significant clinical improvement that is both durable and potentially free from continuous prostacyclin infusion. Five-year survival is comparable to children undergoing lung transplantation for PH. Children with severely decompensated disease requiring aggressive intensive care are not good candidates for the shunt procedure.

Background A structured transition provides a framework of care that bridges the gap between paediatric and adult medicine. It is essential for achieving continuity of care and providing support and education around the challenging period of adolescence for young people with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD). Presentation In this review of transition care in PAH-CHD, we evaluate the evidence supporting a structured programme of transition care and review the current principles and ‘best practice’ standards for transition in the UK. In the second part of the review, we highlight some important areas of education that are relevant to adolescents with PAH-CHD, including health education, exercise and participation in sports, pregnancy and contraception, employment, and driving. Conclusions As the number of young people embarking on transition continues to increase, the challenge is set to continue to improve the quality of care for our patients within the framework of available resources.

Rationale: Pediatric pulmonary hypertension is an important cause of childhood morbidity and mortality, but there are limited data on the range of associated diseases, contributions of different pulmonary hypertension subtypes, therapeutic strategies, and clinical outcomes in children. Objectives: To report the 20-year experience of a large UK National Pediatric Pulmonary Hypertension Service focusing on epidemiology and clinical outcomes. Methods: Consecutive patients presenting between 2001 and 2021 were included and survival analysis was performed for incident patients. Measurements and Main Results: Of 1353 patients assessed, a pulmonary hypertension diagnosis was made in 1101(81.4%) patients (51% female, median age 2.6[IQR 0.8-8.2] years). The most common form was pulmonary arterial hypertension in 48%, followed by 32.3% with pulmonary hypertension due to lung disease. Multiple contributory causes of pulmonary hypertension were common, with 16.9% displaying features of more than one diagnostic group. The annual incidence of childhood pulmonary hypertension was 3.5(95%CI 3.3-3.8)/million children, and the prevalence was 18.1(95%CI 15.8-20.4)/million. The incidence was highest for pulmonary hypertension due to lung disease in infancy (15.0[95%CI 12.7-17.2]/million/year). Overall, 82.4% patients received pulmonary arterial hypertension therapy and escalation to triple therapy during follow-up was required in 13.1%. In 970(88.1%) incident patients, transplant-free survival was 86.7%(95%CI:84.5-89%) at 1, and 68.6%(95%CI:64.7-72.6%) at 10 years. Pulmonary hypertension due to left heart disease had the lowest survival (hazard ratio 2.0, 95%CI:1.36-2.94, p

In children with single ventricle physiology, increased pulmonary vascular resistance may impede surgical progression or result in failing single ventricle physiology. The use of pulmonary vasodilators has been suggested as a potential therapy. However, knowledge on indication, dosage, and effect is limited. A retrospective case notes review of all (n = 36) children with single ventricle physiology, treated with pulmonary vasodilators by the UK Pulmonary Hypertension Service for Children 2004–2017. Therapy was initiated in Stage 1 (n = 12), Glenn (n = 8), or TCPC (n = 16). Treatment indications were high mean pulmonary arterial pressure, cyanosis, reduced exercise tolerance, protein-losing enteropathy, ascites, or plastic bronchitis. Average dose of sildenafil was 2.0 mg/kg/day and bosentan was 3.3 mg/kg/day. 56% had combination therapy. Therapy was associated with a reduction of the mean pulmonary arterial pressure from 19 to 14 mmHg (n = 17, p n = 16, p

Introduction:Infants with isolated atrial septal defects are usually minimally symptomatic, and repair is typically performed after infancy. Early repair may be considered if there is high pulmonary blood flow and reduced respiratory reserve or early signs of pulmonary hypertension. Our aim was to review the characteristics and outcomes of a cohort of patients who underwent infant repair at our institute.Methods:The study included 56 infants (28 female, 19 trisomy 21) with isolated atrial septal defect (age: 8 months (1.5–12), weight: 6 kg (2.8–7.5), echo Qp/Qs: 1.9 ± 0.1) who underwent surgical closure (20 fenestrated). Three groups were identified: 1) chronic lung disease and pulmonary hypertension (group A: n = 28%); 2) acutely unwell infants with pulmonary hypertension but no chronic lung disease (group B: n = 20, 36%); and 3) infants with refractory congestive heart failure without either pulmonary hypertension or chronic lung disease (group C: n = 9, 16%).Results:Post-operatively, pulmonary hypertension infants (47/56) showed improvement in tricuspid annular plane systolic excursion z-score (p < 0.001) and right ventricular systolic/diastolic duration ratio (p < 0.05). All ventilator (14.3%) or oxygen-dependent (31.6%) infants could be weaned within 2 weeks after repair. One year later, weight z-score increased in all patients and by +1 in group A, +1.3 in group B and +2 in group C. Over a median follow-up of 1.4 years, three patients died, four patients continued to have pulmonary hypertension evidence and two remained on targeted pulmonary hypertension therapy.Conclusion:Atrial septal defect repair within the first year may improve the clinical status and growth in infants with early signs of pulmonary hypertension or those requiring respiratory support and facilitate respiratory management.

Background The Fontan circulation is a successful operative strategy for abolishing cyanosis and chronic volume overload in patients with congenital heart disease with single ventricle physiology. “Fontan failure” is a major cause of poor quality of life and mortality in these patients. We assessed the number and clinical characteristics of adult patients with Fontan physiology receiving pulmonary arterial hypertension (PAH) therapies across specialist centers in the United Kingdom. Methods and Results We identified all adult patients with a Fontan‐type circulation under active follow‐up in 10 specialist congenital heart disease centers in England and Scotland between 2009 and 2019. Patients taking PAH therapies were matched to untreated patients. A survey of experts was also performed. Of 1538 patients with Fontan followed in specialist centers, only 76 (4.9%) received PAH therapies during follow‐up. The vast majority (90.8%) were treated with a phosphodiesterase‐5 inhibitor. In 33% of patients, PAH therapies were started after surgery or during hospital admission. In the matched cohort, treated patients were more likely to be significantly limited, have ascites, have a history of protein‐losing enteropathy, or receive loop diuretics ( P P =0.01), with no other changes in clinical parameters or safety issues. Conclusions PAH therapies are used in adult patients with Fontan circulation followed in specialist centers, targeting individuals with advanced disease or complications. Follow‐up suggests stabilization of the clinical status after 12 months of therapy.

Background/Introduction Pulmonary arterial hypertension (PAH) is a common complication of congenital heart disease (CHD) in children and is associated with significant morbidity and mortality. The impact of different phenotypes on management and survival remains unclear. Purpose To examine the clinical features, management and outcomes of paediatric PAH-CHD patients based on the 20-year experience of the UK National Paediatric Pulmonary Hypertension (PH) Service. Methods Consecutive PAH-CHD patients entering the service between January 2001 and January 2021 were included and classified into: Eisenmenger syndrome (ES, group A), PAH related to a significant systemic-pulmonary shunt (group B), PAH with small or co-incidental CHD (group C) and PAH following defect repair (group D). Incident patients (without pre-existing PAH) were included in survival analysis. Results Of the overall PH paediatric cohort of 1104 patients, 819 (74.2%) had co-existing CHD and 354 (32.1%) patients received a diagnosis of PAH-CHD: 57.1% female, median [IQR] 4.6 [1.7–10.9] years. Group D PAH-CHD was the commonest subgroup, accounting for 36%, while the least frequent subtype was group C (14%). Group A and group B PAH-CHD represented 26% and 24%, respectively. Down syndrome was present in over one third (122, 34.5%) of PAH-CHD patients and was more commonly associated with ES (p=0.02). PAH therapy was started in 79.9% of PAH-CHD patients. At the end of follow-up, patients with group C PAH-CHD were more likely to be on combination therapy than any other group (64.6% vs. 28.4%, p The subgroup distribution of PAH-CHD at diagnosis changed from the early (2000–2005) to late (2015–2020) period (Figure 1). The proportion of ES patients decreased from 43.4% to 14.6% of PAH-CHD (p Transplant-free survival in PAH-CHD was 90.9% (95% CI: 87.8–94%) at 1 year, 77.9% (95% CI: 73.1–83.1%) at 5 years, and 74.9% (95% CI: 69.6–80.7%) at 10 years (Figure 2). Group C PAH-CHD had a lower transplant-free survival than the other 3 groups (HR 2.54, 95% CI: 1.51–4.28, p=0.0005). There was no difference in outcome between group A and group D PAH-CHD (HR 1.19, 95% CI: 0.62–2.28, p=0.6). Conclusions Repaired PAH-CHD, not ES, was the most common subtype in this large paediatric cohort. Over time, there were fewer ES patients and more “operable” patients with left-right shunts, suggesting an improvement in early diagnosis and management. Despite widespread use of PAH therapy, PAH-CHD remains a life-limiting disease with the poorest outcomes in PAH with co-incidental CHD. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Dr Constantine received a personal PhD fellowship grant (CHAMPION PhD Fellowship) Figure 1Figure 2

Introduction Pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) is a progressive, life-limiting disease. Areas covered In this paper, we review the classification and pathophysiology of PAH-CHD, including the mechanisms of disease progression and multisystem effects of disease. We evaluate current strategies of risk stratification and the use of biological markers of disease severity, and review principles of management of PAH-CHD. The indications, timing, and the content of advanced heart failure assessment and transplant listing are discussed, along with a review of the types of transplant and other forms of available circulatory support in this group of patients. Finally, the integral role of advance care planning and palliative care is discussed. Expert opinion/commentary All patients with PAH-CHD should be followed up in expert centers, where they can receive appropriate risk assessment, PAH therapy, and supportive care. Referral for transplant assessment should be considered if there continue to be clinical high-risk features, persistent symptoms, or acute heart failure decompensation despite appropriate PAH specific therapy. Expert management of PAH-CHD patients, therefore, requires vigilance for these features, along with a close relationship with local advanced heart failure services and a working knowledge of listing criteria, which may disadvantage congenital heart disease patients.

Supplemental Digital Content is available in the text., Background: Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH, we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods: We analyzed 13 037 participants enrolled in the NBR study (NIHR BioResource—Rare Diseases), of which 1148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension, we used the Bayesian rare variant association method BeviMed. Results: Heterozygous, high impact, likely loss-of-function variants in the kinase insert domain receptor (KDR) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (posterior probability=0.989) and older age at diagnosis (posterior probability=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the 5 patients harboring these predicted deleterious variants in KDR. Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions: The Bayesian inference approach allowed us to independently validate KDR, which encodes for the VEGFR2 (vascular endothelial growth factor receptor 2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

International audience; Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor.Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH.Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260).Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations.Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Risk stratification can be defined as clinical assessment and investigation with the purpose of determining a person’s risk of suffering a particular outcome and thereby guiding the need for preventative intervention (McGraw-Hill Concise Dictionary of Modern Medicine 2002). The need for risk stratification comes from the realisation that although the presence of pulmonary arterial hypertension significantly impairs survival, the degree of impairment can vary across the population of patients by as much as an order of magnitude.

Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 ( BMPR2 ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( EIF2AK4 ) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (K co ; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low K co and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

OBJECTIVES: Paediatric pulmonary arterial hypertension (PAH) after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA) is a clinically recognised entity with an estimated incidence of 0.6%-1.0%. Nevertheless, a clinical characterisation is lacking. We present an international cohort of children with PAH after neonatal ASO for TGA and describe epidemiology and clinical course.METHODS: Data were collected of children with PAH after neonatal ASO (≤6 weeks after birth) for simple TGA without residual shunt defects, identified in four national paediatric PAH networks in Europe and one US referral centre.RESULTS: Twenty-five children were identified between 1989 and 2014. In 17 children (68%), PAH was detected CONCLUSIONS: The occurrence of PAH after ASO for TGA represents a specific association. PAH onset may be early or late after ASO, with similar fatal course from first PAH detection. Mechanisms leading to PAH in this association are unknown, but may include abnormal prenatal pulmonary haemodynamics and/or genetic susceptibility. Routine, lifelong follow-up for children who undergo ASO for TGA should include screening for PAH.

Mutations in more than 250 genes are implicated in inherited retinal dystrophy; the encoded proteins are involved in a broad spectrum of pathways. The presence of unsolved families after highly parallel sequencing strategies suggests that further genes remain to be identified. Whole-exome and -genome sequencing studies employed here in large cohorts of affected individuals revealed biallelic mutations in ARHGEF18 in three such individuals. ARHGEF18 encodes ARHGEF18, a guanine nucleotide exchange factor that activates RHOA, a small GTPase protein that is a key component of tight junctions and adherens junctions. This biological pathway is known to be important for retinal development and function, as mutation of CRB1, encoding another component, causes retinal dystrophy. The retinal structure in individuals with ARHGEF18 mutations resembled that seen in subjects with CRB1 mutations. Five mutations were found on six alleles in the three individuals: c.808A>G (p.Thr270Ala), c.1617+5G>A (p.Asp540Glyfs ∗ 63), c.1996C>T (p.Arg666 ∗ ), c.2632G>T (p.Glu878 ∗ ), and c.2738_2761del (p.Arg913_Glu920del). Functional tests suggest that each disease genotype might retain some ARHGEF18 activity, such that the phenotype described here is not the consequence of nullizygosity. In particular, the p.Thr270Ala missense variant affects a highly conserved residue in the DBL homology domain, which is required for the interaction and activation of RHOA. Previously, knock-out of Arhgef18 in the medaka fish has been shown to cause larval lethality which is preceded by retinal defects that resemble those seen in zebrafish Crumbs complex knock-outs. The findings described here emphasize the peculiar sensitivity of the retina to perturbations of this pathway, which is highlighted as a target for potential therapeutic strategies.

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.

Introduction Abnormal endothelial morphological adaptation to shear stress is a feature of pulmonary arterial hypertension (PAH) but the mechanisms responsible are poorly understood. In this study, we explored whether BMPRII loss mediates abnormal human pulmonary artery endothelial cell (HPAEC) adaptation to laminar shear stress and investigate gene expression of shear-sensitive Rho GTPases (RhoA, Rac1 and CDC42), known for their involvement in cytoskeletal reorganisation. Methods HPAECs were transfected with BMPRII siRNA (siBMPRII) or control siRNA (siControl). Laminar shear stress acting on HPAECs was modelled using a parallel-plate fluid flow chamber (ibdi). siControl and siBMPRII-transfected HPAECs were exposed to unidirectional shear stress (15 dyn/cm2) for 72 hours. Phase-contrast and confocal microscopy were used to assess cell morphology and orientation. Gene expression of RhoA, Rac1 and CDC42 were quantified using qPCR. Results siControl-transfected HPAECs subjected to shear stress significantly elongated (length-to-width ratio 1.90±0.227 versus 4.12±0.133, p Conclusion Inactivating mutations in the BMPRII gene may contribute to PAH by engendering abnormal pulmonary artery endothelial shear adaptation.

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects (n = 120) and patients with idiopathic PAH (n = 260). Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro, BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

The aim of this study was to determine practice patterns and inter-institutional variability in how acute vasoreactivity testing (AVT) is performed and interpreted in pediatrics throughout the world. A survey was offered to physicians affiliated with the Pediatric & Congenital Heart Disease Taskforce of the Pulmonary Vascular Research Institute (PVRI), the Pediatric Pulmonary Hypertension Network (PPHNET), or the Spanish Registry for Pediatric Pulmonary Hypertension (REHIPED), from February to December 2016. The survey requested data about the site-specific protocol for AVT and subsequent management of pediatric patients with idiopathic pulmonary arterial hypertension (IPAH) or heritable PAH (HPAH). Twenty-eight centers from 13 countries answered the survey. AVT is performed in most centers using inhaled nitric oxide (iNO). Sitbon criteria was used in 39% of the centers, Barst criteria in 43%, and other criteria in 18%. First-line therapy for positive AVT responders in functional class (FC) I/II was calcium channel blocker (CCB) in 89%, but only in 68% as monotherapy. Most centers (71%) re-evaluated AVT-positive patients hemodynamics after 6-12 months; 29% of centers re-evaluated based only on clinical criteria. Most centers (64%) considered a good response as remaining in FC I or II, with near normalization of pulmonary arterial pressure and pulmonary vascular resistance, but a stable FC I/II alone was sufficient criteria in 25% of sites. Protocols and diagnostic criteria for AVT, and therapeutic approaches during follow-up, were highly variable across the world. Reported clinical practice is not fully congruent with current guidelines, suggesting the need for additional studies that better define the prognostic value of AVT for pediatric IPAH patients.

Pulmonary hypertension is a complex and progressive condition that is either idiopathic or heritable, or associated with one or multiple health conditions, with or without congenital or acquired cardiovascular disease. Recent developments have tremendously increased the armamentarium of diagnostic and therapeutic approaches in children and young adults with pulmonary hypertension that is still associated with a high morbidity and mortality. These modalities include non-invasive imaging, pharmacotherapy, interventional and surgical procedures, and supportive measures. The optimal, tailored diagnostic and therapeutic strategies for pulmonary hypertension in the young are rapidly evolving but still face enormous challenges: Healthcare providers need to take the patient’s age, development, disease state, and family concerns into account when initiating advanced diagnostics and treatment. Therefore, there is a need for guidance on core and advanced medical training in paediatric pulmonary hypertension. The Association for European Paediatric and Congenital Cardiology working group “pulmonary hypertension, heart failure and transplantation” has produced this document as an expert consensus statement; however, all recommendations must be considered and applied in the context of the local and national infrastructure and legal regulations.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11–6.47) per 3 μg·m−3; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44–13.36) per 3 μg·m−3; p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500–1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

Background and purpose Beraprost is a prostacyclin analogue and IP receptor agonist which is approved to treat pulmonary arterial hypertension (PAH) in Asia. The beraprost-314d isomer (esuberaprost) is one of four stereoisomers contained within the racemic mixture of beraprost. The pharmacological profile of esuberaprost is now evaluated to determine how stereoisomer separation affects its potency and mode of action in functional assays. Experimental approach Vascular tone was assessed using wire myography in rat and human distal pulmonary arteries (PAs) pre-contracted with U46619 (100 nM). HEK-293 cells stably expressing the human IP receptor (HEK-293-IP) and pulmonary arterial smooth muscle cells (PASMCs) derived from PAH patients were used to assess cyclic AMP (cAMP) generation and cell proliferation, respectively. Key results Esuberaprost relaxed rat PAs with a 5-fold greater potency compared with beraprost, and effects were strongly inhibited by RO3244794 (IP receptor antagonist) or L-NAME (NO synthase inhibitor). Esuberaprost caused EP3 receptor-dependent vasoconstriction at high concentrations ≥ 1000 nM, but contractions were 50% lower compared to beraprost. In HEK-293-IP cells, esuberaprost was 26-fold more potent (EC50 0.4 nM) at increasing cAMP than beraprost. In human PASMCs, esuberaprost was 40-fold more potent than beraprost at inhibiting cell proliferation (EC50 3 nM versus 120 nM), contrasting the 5-fold potency difference for cAMP elevation. Antiproliferative effects of esuberaprost appeared more dependent on NO than on the IP receptor. In PAs from patients with pulmonary hypertension, esuberaprost, caused some relaxation whereas beraprost instead produced a weak contraction. Conclusions and implications Stereoisomer separation of beraprost has a significant effect on the pharmacology of the individual isomer, esuberaprost, identified in vitro as a highly potent prostanoid IP receptor agonist.

Introduction A major breakthrough in the understanding the pathobiology of pulmonary arterial hypertension (PAH) was the identification of heterozygous disease-causing mutations in the BMPR2gene. Recently, mutations were also identified in GDF2, which encodes the ligand for BMPR2 (Graf S et al.,2018). We hypothesised that patients harbouring mutations in BMPR2and GDF2show distinct phenotypes from patients without mutations in previously established disease genes. Methods A total of 1077 cases of idiopathic and heritable PAH were recruited to NIHR Bioresource-Rare Diseases PAH study and underwent whole genome sequencing. Phenotypic diagnostic information was prospectively collected. Results Of 1077 patients recruited, 162 had heterozygous mutations in BMPR2 and 10 patients had heterozygous GDF2 mutations, including 2 patients with large deletions at the GDF2 locus not previously described. Plasma GDF2 levels were significantly lower in GDF2mutation carriers than in healthy controls (79.2 (22.3)vs.202 (35.2);p Conclusions We report deletions at the GDF2 locus and reduced plasma GDF2 levels in patients with pathogenic mutations, supporting the functional significance of these mutations. BMPR2 mutation carriers had earlier disease onset, more severe haemodynamics and altered blood test parameters. GDF2 mutation carriers were indistinguishable from PAH patients without disease-causing mutations and showed no features of HHT or vascular anomaly syndromes. On behalf of UK PAH Cohort Study Consortium, NIHR BioResource – Rare Disease Consortium

Background— Chronic thromboembolic pulmonary hypertension results from incomplete resolution of pulmonary emboli. Pulmonary endarterectomy (PEA) is potentially curative, but residual pulmonary hypertension following surgery is common and its impact on long-term outcome is poorly understood. We wanted to identify factors correlated with poor long-term outcome after surgery and specifically define clinically relevant residual pulmonary hypertension post-PEA. Methods and Results— Eight hundred eighty consecutive patients (mean age, 57 years) underwent PEA for chronic thromboembolic pulmonary hypertension. Patients routinely underwent detailed reassessment with right heart catheterization and noninvasive testing at 3 to 6 months and annually thereafter with discharge if they were clinically stable at 3 to 5 years and did not require pulmonary vasodilator therapy. Cox regressions were used for survival (time-to-event) analyses. Overall survival was 86%, 84%, 79%, and 72% at 1, 3, 5, and 10 years for the whole cohort and 91% and 90% at 1 and 3 years for the recent half of the cohort. The majority of patient deaths after the perioperative period were not attributable to right ventricular failure (chronic thromboembolic pulmonary hypertension). At reassessment, a mean pulmonary artery pressure of ≥30 mm Hg correlated with the initiation of pulmonary vasodilator therapy post-PEA. A mean pulmonary artery pressure of ≥38 mm Hg and pulmonary vascular resistance ≥425 dynes·s −1 ·cm −5 at reassessment correlated with worse long-term survival. Conclusions— Our data confirm excellent long-term survival and maintenance of good functional status post-PEA. Hemodynamic assessment 3 to 6 months and 12 months post-PEA allows stratification of patients at higher risk of dying of chronic thromboembolic pulmonary hypertension and identifies a level of residual pulmonary hypertension that may guide the long-term management of patients postsurgery.

Cardiac catheterization is important in the diagnosis and risk stratification of pulmonary hypertensive vascular disease (PHVD) in children. Acute vasoreactivity testing provides key information about management, prognosis, therapeutic strategies, and efficacy. Data obtained at cardiac catheterization continue to play an important role in determining the surgical options for children with congenital heart disease and clinical evidence of increased pulmonary vascular resistance. The Pediatric and Congenital Heart Disease Task Forces of the Pulmonary Vascular Research Institute met to develop a consensus statement regarding indications for, conduct of, acute vasoreactivity testing with, and pitfalls and risks of cardiac catheterization in children with PHVD. This document contains the essentials of those discussions to provide a rationale for the hemodynamic assessment by cardiac catheterization of children with PHVD.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

Next-generation sequencing has been invaluable in the elucidation of the genetic etiology of many subtypes of intellectual disability in recent years. Here, using exome sequencing and whole-genome sequencing, we identified three de novo truncating mutations in WAS protein family member 1 (WASF1) in five unrelated individuals with moderate to profound intellectual disability with autistic features and seizures. WASF1, also known as WAVE1, is part of the WAVE complex and acts as a mediator between Rac-GTPase and actin to induce actin polymerization. The three mutations connected by Matchmaker Exchange were c.1516C>T (p.Arg506Ter), which occurs in three unrelated individuals, c.1558C>T (p.Gln520Ter), and c.1482delinsGCCAGG (p.Ile494MetfsTer23). All three variants are predicted to partially or fully disrupt the C-terminal actin-binding WCA domain. Functional studies using fibroblast cells from two affected individuals with the c.1516C>T mutation showed a truncated WASF1 and a defect in actin remodeling. This study provides evidence that de novo heterozygous mutations in WASF1 cause a rare form of intellectual disability. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:1 pages:144-153 ispartof: location:United States status: published

Congenital heart disease is a major cause of pulmonary arterial hypertension (PAH) and this can largely be prevented by early repair. PAH in the presence of systemic-to-pulmonary communication, leads to shunt reversal and cyanosis, with multiple systemic consequences (Eisenmenger syndrome). Congenital heart disease patients with PAH are vulnerable and are at high risk from non-cardiac surgery, pregnancy, and inappropriate medical treatment (e.g. excessive venesection). Survival is reduced, but is better than in idiopathic PAH. Recommendations for surgery should be based on careful assessment by experts. Modern PAH pharmacotherapy is showing promise in improving quality of life.

BackgroundCardiopulmonary exercise testing helps prognosticate and guide treatment in adults with pulmonary hypertension. Concerns regarding its feasibility and safety limit its use in children with pulmonary hypertension. We aimed to assess the feasibility and safety of cardiopulmonary exercise testing in a large paediatric pulmonary hypertension cohort.MethodsWe reviewed all consecutive cardiopulmonary exercise tests performed between March, 2004 and November, 2013. The exclusion criteria were as follows: height 2 saturation.ResultsA total of 98 children underwent 167 cardiopulmonary exercise tests. The median age was 14 years (inter-quartile range 10–15 years). Peak oxygen uptake was 20.4±7.3 ml/kg/minute, corresponding to 51.8±18.3% of the predicted value. Peak respiratory quotient was 1.08±0.16. All the tests except two were maximal, being terminated prematurely for clinical reasons. Baseline Oxygen saturation was 93.3±8.8% and was 81.2±19.5% at peak exercise. A drop in arterial O2 saturation >20% was observed in 23.5% of the patients. Moreover, five patients (3.0%) experienced dizziness, one requiring termination of cardiopulmonary exercise testing; five children (3.0%) experienced chest pain, with early cardiopulmonary exercise test termination in one patient. No significant arrhythmias or electrocardiogram changes were observed.ConclusionExercise testing in non-severely symptomatic children with pulmonary hypertension is safe and practical, and can be performed in a large number of children with pulmonary hypertension in a controlled environment with an experienced team. Side-effects were not serious and were resolved promptly with test termination.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlie most heritable forms of PAH. Since the missing heritability likely involves genetic variation confined to small numbers of cases, we performed whole genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses revealed significant overrepresentation of rare variants in novel genes, namely ATP13A3, AQP1 and SOX17, and provided independent validation of a critical role for GDF2 in PAH. We provide evidence for familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, led to reduced secretion from transfected cells. In addition, we identified pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings provide new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Pulmonary arterial hypertension (PAH) is a frequently diagnosed complication in patients with congenital heart disease (CHD). The majority of the cases involve patients with nonrestrictive congenital cardiac shunts with unprotected pulmonary blood flow. Exposure of the pulmonary vasculature to increased blood flow and pressure results in vascular remodelling and eventually established pulmonary vascular disease. Despite advances in the understanding of the pulmonary vascular disease, advances in surgical repair of congenital heart disease and the development of drug therapies, PAH still occurs after successful corrective surgery in patients with CHD and results in significant morbidity and mortality. In this chapter, we discuss the pathogenesis, presentation, natural history and management of PAH in patients with previous surgical or percutaneous repair of CHD.

Aim Interstitial lung disease (ILD) in infants represents a rare and heterogenous group of disorders, distinct from those occurring in adults. In recent years a new entity within this category is being recognized, namely filamin A (FLNA) mutation related lung disease. Our aims are to describe the clinical and radiological course of patients with this disease entity to aid clinicians in the prognostic counseling and management of similar patients they may encounter. Method A retrospective case note review was conducted of all patients treated at our institution (a specialist tertiary referral childrens’ center) for genetically confirmed FLNA mutation related lung disease. The clinical presentation, evolution, management and radiological features were recorded and a medical literature review of Medline indexed articles was conducted. Results We present a case series of four patients with interstitial lung disease and genetically confirmed abnormalities within the FLNA gene. Their imaging findings all reveal a pattern of predominantly upper lobe overinflation, coarse pulmonary lobular septal thickening and diffuse patchy atelectasis. The clinical outcomes of our patients have been variable ranging from infant death, lobar resection and need for supplemental oxygen and bronchodilators. Conclusion The progressive nature of the pulmonary aspect of this disorder and need for early aggressive supportive treatment make identification crucial to patient management and prognostic counseling.

Background—Conventional cardiopulmonary exercise testing can objectively measure exercise intolerance but cannot provide comprehensive evaluation of physiology. This requires additional assessment of cardiac output and arteriovenous oxygen content difference. We developed magnetic resonance (MR)–augmented cardiopulmonary exercise testing to achieve this goal and assessed children with right heart disease.Methods and Results—Healthy controls (n=10) and children with pulmonary arterial hypertension (PAH; n=10) and repaired tetralogy of Fallot (n=10) underwent MR-augmented cardiopulmonary exercise testing. All exercises were performed on an MR-compatible ergometer, and oxygen uptake was continuously acquired using a modified metabolic cart. Simultaneous cardiac output was measured using a real-time MR flow sequence and combined with oxygen uptake to calculate arteriovenous oxygen content difference. Peak oxygen uptake was significantly lower in the PAH group (12.6±1.31 mL/kg per minute;P=0.01) and trended toward lower in the tetralogy of Fallot group (13.5±1.29 mL/kg per minute;P=0.06) compared with controls (16.7±1.37 mL/kg per minute). Although tetralogy of Fallot patients had the largest increase in cardiac output, they had lower resting (3±1.2 L/min per m2) and peak (5.3±1.2 L/min per m2) values compared with controls (resting 4.3±1.2 L/min per m2and peak 6.6±1.2 L/min per m2) and PAH patients (resting 4.5±1.1 L/min per m2and peak 5.9±1.1 L/min per m2). Both the PAH and tetralogy of Fallot patients had blunted exercise–induced increases in arteriovenous oxygen content difference. However, only the PAH patients had significantly reduced peak values (6.9±1.3 mlO2/100 mL) compared with controls (8.4±1.4 mlO2/100 mL;P=0.005).Conclusions—MR-augmented cardiopulmonary exercise testing is feasible in both healthy children and children with cardiac disease. Using this novel technique, we have demonstrated abnormal exercise patterns in oxygen uptake, cardiac output, and arteriovenous oxygen content difference.

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter ≤2.5 μm3 (PM2.5), nitrogen dioxide (NO2) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK PAH national Cohort study. Associations with transplant-free survival and pulmonary hemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori.Higher estimated exposure to PM2.5 was associated with higher risk of death or lung transplant (Unadjusted hazard ratio (HR) 2.68; 95% CI 1.11-6.47 per 3 μg·m-3, p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38; 95% CI 1.44-13.36 per 3 μg·m-3, p=0.009). No associations were found between NO2 exposure or other traffic pollution indicators and transplant-free survival Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the ERS/ESC risk categories as well as pulmonary hemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM2.5 exposure may independently predict shorter transplant-free survival.

Background— There are very few validated prognostic markers in pediatric pulmonary hypertension. Cardiac MRI is a useful, noninvasive method for determining prognosis in adults. The present study is the first to assess its prognostic value in children. Methods and Results— A total of 100 children with pulmonary hypertension (median, 10.4 years; range, 0.5–17.6 years) were evaluated (idiopathic, n=60; repaired congenital heart disease, n=22; miscellaneous, n=18). In all patients, ventricular volumes and great vessel flow were measured. Volumetric data were obtained using retrospectively gated cine imaging (n=37) or real-time imaging (n=63), depending on the patient’s ability to hold his or her breath. During a median follow-up of 1.9 years, 11 patients died and 3 received lung transplantation. Of the cardiac MR parameters measured, right ventricular ejection fraction and left ventricular stroke volume index were most strongly predictive of survival on univariate analysis (2.6- and 2.5-fold increase in mortality for every 1-SD decrease, respectively; P Conclusions— Cardiac MR measures correlate with clinical status and prognosis in children with pulmonary hypertension. Cardiac MR is feasible and may be useful in clinical decision making in pediatric pulmonary hypertension.

The European Paediatric Pulmonary Vascular Disease (PVD) Network is a registered, non-profit organisation that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of paediatric pulmonary hypertensive vascular disease, including specific forms such as pulmonary arterial hypertension (PAH)-congenital heart disease, pulmonary hypertension (PH) associated with bronchopulmonary dysplasia, persistent PH of the newborn, and related cardiac dysfunction. Methods The writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990–2015) and held five face-to-face meetings with votings. Clinical trials, guidelines, and reviews limited to paediatric data were searched using the terms ‘pulmonary hypertension’ and 5–10 other keywords, as outlined in the other nine articles of this special issue. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on paediatric data only, or on adult studies that included >10% children. Results A total of 9 original consensus articles with graded recommendations (COR/LOE) were developed, and are summarised here. The topics included diagnosis/monitoring, genetics/biomarker, cardiac catheterisation, echocardiography, cardiac magnetic resonance/chest CT, associated forms of PH, intensive care unit/ventricular assist device/lung transplantation, and treatment of paediatric PAH. Conclusions The multipaper expert consensus statement of the European Paediatric PVD Network provides a specific, comprehensive, detailed but practical framework for the optimal clinical care of children with PH.

The aim of the present study was to evaluate a 5-yr experience of bosentan in children with pulmonary arterial hypertension (PAH). A retrospective, observational study was made of children in the UK Pulmonary Hypertension Service for Children (Great Ormond Street Hospital for Children, London, UK) who were given bosentan as monotherapy or in combination, from February 2002 to May 2008 and followed up for ≥ 6 months. Detailed studies were made of 101 children with idiopathic PAH (IPAH) (n = 42) and PAH associated with congenital heart disease (n = 59). Before treatment, World Health Organization (WHO) functional class, 6-min walk distance (6MWD), height, weight and haemodynamic data were determined. Evaluations were analysed after 6 months and annually to a maximum of 5 yrs. Median duration of treatment was 31.5 months. Initial improvement in WHO functional class and 6MWD was maintained for up to 3 yrs. Height and weight increased but the z-scores did not improve. After 3 yrs, bosentan was continued as monotherapy in only 21% of children with IPAH, but in 69% of repaired cases and 56% of those with Eisenmenger syndrome. The Kaplan-Meier survival estimates for the 101 patients were 96, 89, 83 and 60% at 1, 2, 3 and 5 yrs, respectively. A treatment regime that includes bosentan is safe and appears to be effective in slowing disease progression in children with PAH.

Prostacyclins are extensively used to treat pulmonary arterial hypertension (PAH), a life-threatening disease involving the progressive thickening of small pulmonary arteries. Although these agents are considered to act therapeutically via the prostanoid IP receptor, treprostinil is the only prostacyclin mimetic that potently binds to the prostanoid EP2 receptor, the role of which is unknown in PAH. We hypothesised that EP2 receptors contribute to the anti-proliferative effects of treprostinil in human pulmonary arterial smooth muscle cells (PASMCs), contrasting with selexipag, a non-prostanoid selective IP agonist. Human PASMCs from PAH patients were used to assess prostanoid receptor expression, cell proliferation, and cyclic adenosine monophosphate (cAMP) levels following the addition of agonists, antagonists or EP2 receptor small interfering RNAs (siRNAs). Immunohistochemical staining was performed in lung sections from control and PAH patients. We demonstrate using selective IP (RO1138452) and EP2 (PF-04418948) antagonists that the anti-proliferative actions of treprostinil depend largely on EP2 receptors rather than IP receptors, unlike MRE-269 (selexipag-active metabolite). Likewise, EP2 receptor knockdown selectively reduced the functional responses to treprostinil but not MRE-269. Furthermore, EP2 receptor levels were enhanced in human PASMCs and in lung sections from PAH patients compared to controls. Thus, EP2 receptors represent a novel therapeutic target for treprostinil, highlighting key pharmacological differences between prostacyclin mimetics used in PAH.