Pediatric Pulmonary Arterial Hypertension Research Articles

The Glu86 Residue in TBX4 Proves Critical for Human Lung Development

ABSTRACTT‐box transcription factors are a group of evolutionarily conserved T‐box‐containing regulators of mesoderm specification and development. Heterozygous single nucleotide variants (SNVs) or copy‐number variant (CNV) deletions involving dosage‐sensitive TBX4 have been associated with pulmonary arterial hypertension (PAH), ischiocoxopodopatellar syndrome with or without PAH, and lethal lung developmental disorders (LLDDs), including acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD), and other unspecified primary pulmonary hypoplasias. Loss‐ and gain‐of‐function variants have been proposed to cause pediatric PAH and LLDDs, and adult forms of PAH, respectively. Of more than 50 missense SNVs scattered across the entire TBX4, only three have been reported in patients with LLDDs, all mapping to the T‐box domain. Here, we report a recurrence of a pathogenic substitution Glu86Lys identified in an unrelated patient with AcDys. In silico predictions of the conformational changes of TBX4 resulting from this and another substitution, Glu86Gln, suggest the loss of most intermolecular hydrogen bonds involving residue 86, including those with Tyr230 that directly interact with DNA. Functional assays on the TBX4 variants in fetal lung fibroblasts confirmed their deleterious character. We propose that Glu86 is critically involved in maintaining TBX4 structure and function essential for airway branching during early stages of human lung development. Substitutions of this residue may act in a dominant negative manner, leading to AcDys and CAD.

Actigraphy Study Endpoints to Reduce Sample Size and Facilitate Drug Development for Pediatric Pulmonary Arterial Hypertension

To investigate the feasibility of using actigraphy to measure physical activity (pA) and heart rate variability (HRV) as study endpoints in pediatric pulmonary arterial hypertension (PAH) and to compare their performance to six-minute-walk distance (6MWD), a common primary endpoint used in PAH clinical trials in adults and children who can walk and understand the test process. We conducted a prospective, multicenter, non-interventional study in pediatric PAH patients and healthy children. Actiheart™ and Fitbit Charge 2™ recorded pA and heart rate (HR) data. HRV was defined as standard deviation of daily HR. Actigraphy pA and HRV and 6MWD from the same subjects were analyzed to compare children with PAH with controls, and Panama functional classification (FC) III versus II. Power/sample size simulations were conducted to detect hypothetical treatment effect equivalent to differences seen between FC III and FC II. We enrolled 116 children; 90 and 98 adhered with Actiheart and Fitbit, respectively. Actigraphy daily pA was ∼36% lower (P<0.05) and daily HRV was ∼18% lower (P<0.05) in children with PAH (n=62) than healthy controls (n=54). Daily pA and daily HRV trended ∼17% lower in FC III than FC II, whereas 6MWD showed little difference. Simulation at 80% power showed that pA required 175 subjects per group and HRV required 40 per group to detect the difference/effect, whereas 6MWD required over our maximum sample size of 200. Actigraphy is a feasible measure in pediatric PAH. Compared with 6MWD, pA and HRV may be more sensitive in differentiating Panama FC III from II. HRV may improve actigraphy's utility in pediatric PAH.

Genetic burden in neonatal and pediatric-onset pulmonary hypertension: a single-center retrospective study using exome sequencing in a Chinese population

ObjectiveThis single-center retrospective study aimed to investigate the genetic factors contributing to neonatal and pediatric pulmonary hypertension in a Chinese population using trio whole-exome sequencing (trio-WES). MethodThis retrospective analysis reviewed the clinical and genetic profiles of children under 18 years of age diagnosed with pulmonary hypertension between March 2017 and March 2022. The diagnosis of pediatric pulmonary hypertension was confirmed through echocardiography and catheterization. Trio-WES was performed on the patients and their parents after obtaining informed consent. ResultsA total of 51 children with neonatal and pediatric pulmonary hypertension were included, comprising 20 with pediatric pulmonary arterial hypertension and 31 with persistent pulmonary hypertension of the newborn. Trio-WES detected 16 pathogenic or likely pathogenic variants in 14 patients across nine genes, including: BMPR2 (n=2), CHD7 (n=2), FOXF1 (n=2), MED13L (n=1), TNNI3 (n=2), ALMS1 (n=1), KMT2D (n=2), NKX2-1 (n=1), NONO (n=1), and CACNA1E (n=1). In addition, two patients exhibited de novo pathogenic copy number variations. ConclusionOur findings demonstrate the significant diagnostic value of trio-WES in pediatric pulmonary hypertension, supporting its recommendation for these patients.

Extracorporeal membrane oxygenation (ECMO) support for children with pulmonary hypertension: A single-institutional experience of outcomes.

Pediatric pulmonary arterial hypertension (PAH) can present with a wide spectrum of disease severity. Pulmonary hypertension (PH) crises can lead to acute decompensation requiring extracorporeal membrane oxygenation (ECMO) support, including extracorporeal cardiopulmonary resuscitation (eCPR). We evaluated outcomes for pediatric PH patients requiring ECMO. A single-institution retrospective review of pediatric PAH patients with World Symposium on PH (WSPH) groups 1 and 3 requiring ECMO cannulation from 2010 through 2022 (n = 20) was performed. Primary outcome was survival to hospital discharge. Secondary outcomes were survival to decannulation and 1-year survival. Of 20 ECMO patients, 16 (80%) survived to decannulation and 8 (40%) survived to discharge and 1 year follow up. Of three patients who had two ECMO runs; none survived. There were five patients who had eCPR for the first run; one survived to discharge. The univariate logistic regression model showed that venovenous ECMO was associated with better survival to hospital discharge than venoarterial ECMO, (OR: 0.12, 95% CI: 0.01-0.86, p = 0.046). PH medications (administered before, during, or after ECMO) were not associated with survival to discharge. For children with decompensated PAH requiring ECMO, mortality rate is high, and management is challenging. While VA ECMO is the main configuration for decompensated PH, VV ECMO could be considered if there is adequate ventricular function, presence of a systemic to pulmonary shunt, or an intercurrent treatable illness to improve survival to discharge. A multidisciplinary approach with requisite expertise should be utilized on a case-by-case basis until more reliable data is available to predict outcomes.

The Pulmonary Artery Pulsatility Index Provides No Additional Prognostic Information in Pediatric Pulmonary Arterial Hypertension.

The pulmonary artery pulsatility index (PAPi, calculated as (SPAP - DPAP)/mRAP) has been suggested as a measure of right ventricular-vascular coupling (RVVC) and as a prognostic parameter in cardiovascular conditions, particularly right ventricular failure. This retrospective study investigated the relationship between the PAPi and its components with disease severity parameters, the RVVC, and clinical outcomes in children with pulmonary arterial hypertension (PAH). We analyzed data from 111 children from the Dutch National Registry with PAH. The PAPi (median 6.0 [3.9-8.3]) was calculated from heart catheterization data and the RVVC was determined as the TAPSE/sPAP ratio via echocardiography (0.25 ± 0.12 mm/mmHg). Disease severity was characterized by clinical, hemodynamic, and laboratory data. Cox proportional hazard modeling assessed the PAPi's predictive value for transplant-free survival. There was no correlation between the RVVC and PAPi (R = -0.208, p = 0.111, n = 60). The PAPi correlated negatively with uric acid (R = -0.387, p < 0.001) but not with other disease severity parameters. Mean right atrial pressure correlated with multiple disease severity indicators. Transplant-free survival rates at 1, 3, and 5 years were 87%, 79%, and 73%, respectively. Neither the PAPi nor its components correlated with transplant-free survival. In conclusion, the PAPi does not correlate with the RVVC and this study could not demonstrate any prognostic value of the PAPi regarding disease severity or outcomes in children with PAH, challenging its utility in this population.

Embracing the challenges of neonatal and paediatric pulmonary hypertension.

Paediatric pulmonary arterial hypertension (PAH) shares common features with adult disease, but is associated with several additional disorders and challenges that require unique approaches. This article discusses recent advances, ongoing challenges and distinct approaches for caring for infants and children with PAH, as presented by the paediatric task force of the 7th World Symposium on Pulmonary Hypertension. We provide updates on diagnosing, classifying, risk-stratifying and treating paediatric pulmonary hypertension (PH) and identify critical knowledge gaps. An updated risk stratification tool and treatment algorithm is provided, now also including strategies for patients with associated cardiopulmonary conditions. Treatment of paediatric PH continues to be hindered by the lack of randomised controlled clinical trials. The challenging management of children failing targeted PAH therapy is discussed, including balloon atrial septostomy, lung transplantation and pulmonary-to-systemic shunt (Potts). A novel strategy using a multimodal approach for the management of PAH associated with congenital heart diseases with borderline pulmonary vascular resistance is included. Advances in diagnosing neonatal PH, especially signs and interpretation of PH by echocardiography, are highlighted. A team approach to the rapidly changing physiology of neonatal PH is emphasised. Challenges in drug approval are discussed, particularly the challenges of designing accurate paediatric clinical trials with age-appropriate end-points and adequate enrolment.

Safety and Effectiveness of Selexipag in Pediatric Pulmonary Hypertension: A Retrospective Multicenter Cohort Study

ObjectiveTo describe the safety and effectiveness of treating pediatric patients who have pulmonary arterial hypertension (PAH) with selexipag in a real-world, multi-center cohort, given that data supporting its use in pediatric PAH are sparse. Study designWe report a multi-center, retrospective, cohort study of children with PAH treated with selexipag. Demographic and clinical variables were extracted from the medical records. Clinical parameters were analyzed at 3 timepoints: pre-selexipag, 3-12 months post-selexipag, and >12 months follow-up. ResultsEighty-seven patients were included, 32 received selexipag as add-on to background therapy, and 55 transitioned from another prostanoid. Median starting and final doses were 4.7 and 28.5 μg/kg/dose BID, respectively. Add-on patients demonstrated improved indexed pulmonary to systemic vascular resistance ratio after selexipag initiation (PVRi/SVRi, 0.62v0.53, p=0.034) with a lower average mean pulmonary artery pressure (MPAP, 46v39 mmHg, p=NS), and oxygen consumption (VO2 max 27.8v30.9 mL/kg/min, p=NS). Transition patients demonstrated stable MPAP (47v45 mmHg, p=NS) and a lower mean PVRi (10.9v8.2 Wood units*m2, p=NS) but late functional worsening in some with VO2 max decreased at follow-up (26.0v19.5 ml/kg/min). Side effects were noted in 40% of the cohort but prompted discontinuation in only 2%. ConclusionsIn a large, multi-center cohort, the oral prostacyclin agonist selexipag demonstrates favorable tolerability and effectiveness. Add-on patients demonstrated early hemodynamic improvement. Transition patients demonstrated early stability with risk of late functional worsening, highlighting the importance of ongoing monitoring.

Collagen 18A1/Endostatin Expression in the Progression of Right Ventricular Remodeling and Dysfunction in Pulmonary Arterial Hypertension.

Numerous studies have demonstrated that endostatin (ES), a potent angiostatic peptide derived from collagen type XVIII α 1 chain and encoded by COL18A1, is elevated in pulmonary arterial hypertension (PAH). It is important to note that elevated ES has consistently been associated with altered hemodynamics, poor functional status, and adverse outcomes in adult and pediatric PAH. This study used serum samples from patients with Group I PAH and plasma and tissue samples derived from the Sugen/hypoxia rat pulmonary hypertension model to define associations between COL18A1/ES and disease development, including hemodynamics, right ventricle (RV) remodeling, and RV dysfunction. Using cardiac magnetic resonance imaging and advanced hemodynamic assessments with pressure-volume loops in patients with PAH to assess RV-pulmonary arterial coupling, we observed a strong relationship between circulating ES levels and metrics of RV structure and function. Specifically, RV mass and the ventricular mass index were positively associated with ES, whereas RV ejection fraction and RV-pulmonary arterial coupling were inversely associated with ES levels. Our animal data demonstrate that the development of pulmonary hypertension is associated with increased COL18A1/ES in the heart as well as the lungs. Disease-associated increases in COL18A1 mRNA and protein were most pronounced in the RV compared with the left ventricle and lung. COL18A1 expression in the RV was strongly associated with disease-associated changes in RV mass, fibrosis, and myocardial capillary density. These findings indicate that COL18A1/ES increases early in disease development in the RV and implicates COL18A1/ES in pathologic RV dysfunction in PAH.

The Current Strategy in Managing Congenital and Structural Heart Disease: Find and Treat Them Appropriately

Significant progress has been made in diagnosing and treating congenital heart defects (CHDs) over the past five decades. Notable advancements include pulse oximetry screening for critical CHDs in newborns and percutaneous, catheter-based procedures, improving outcomes even in developing nations. Recent studies demonstrate favorable outcomes with device closure of acyanotic CHDs, with non-fluoroscopy techniques adopted to minimize radiation risks. Positive results are observed with right ventricular outflow tract (RVOT) stent palliation for late-presenting cyanotic congenital heart diseases such as tetralogy of Fallot (TOF). Novel interventions like reverse Potts shunt anastomosis show promise in managing pediatric pulmonary arterial hypertension (PAH), while prophylactic treatments effectively reduce postoperative arrhythmias. Fontan procedure significantly enhances survival rates for individuals with single functional ventricles, although challenges arise with aging populations. In developed countries, fetal cardiac interventions utilizing advanced imaging techniques allow for early detection and preventive interventions, reducing secondary complications. Keyword: Fetal Intervention, Fontan, Non-Fluoroscopy, Percutaneous, Reverse Potts, Rheumatic Heart Disease, RVOT Stenting.

Demographic, hemodynamic characteristics, and therapeutic trends of pulmonary hypertension patients: The Pulmonary Hypertension Mexican registry (REMEHIP).

Data on demographic characteristics and therapeutic approaches in Latin American pulmonary arterial hypertension (PAH) patients are scarce. Pulmonary Hypertension Mexican registry (REMEHIP) is a multicenter Mexican registry of adult and pediatric patients, including prevalent and incident cases. Objective: assess clinical characteristics, treatment trends, and in-hospital outcomes. Inclusion: age >2 years, diagnosis of pulmonary hypertension(PH) (groups 1 and 4),right heart catheterization with mPAP ≥25 mmHg, PWP ≤ 15 mmHg, and PVR > 3 Wood unit(WU). We included 875 PH patients, 619 adults, 133 pediatric idiopathic PAH (IPAH), and 123 chronic thromboembolic pulmonary hypertension (CTEPH) patients. We enrolled 48.4% of the incident and 51.6% of the prevalent adult and pediatric patients. PAH adults: age 43 ± 15, females 81.9%, functional class (FC) (I/II) 66.5%, 6-min walk distance (6MWD)378 ± 112 m, mPAP 57.3 ± 19.0 mmHg, confidence interval (CI) 3.3 ± 1.5 L/min/m2, PVR 12.0 ± 8.1 WU. PAH pediatrics: age 9 ± 5, females 51.1%, FC (I/II) 85.5%, 6MWD 376 ± 103 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 16.4 ± 13.5 WU. CTEPH: age 44 ± 17, females 56.1%, FC (I/II) 65.5%, 6MWD 369 ± 126 m, mPAP 49.7 ± 13.4 mmHg, CI 2.6 ± 0.9 L/min/m2, PVR 10.5 + 6.5 WU. When we analyzed the IPAH group separately, it sustained a high functional class I/II incidence. REMEHIP shows better functional class in young females with severe PAH than in American and European patients. Also, PAH pediatric patients had a better functional class than other registries. However, our registry also shows that our population's access to specific pharmacologic treatments is still far from optimal.

Prognostic and diagnostic utility of interleukin-6 in pediatric pulmonary arterial hypertension — a case-control study

Pulmonary arterial hypertension (PAH) in pediatrics is a progressive disease with significant vascular remodeling, right sided heart failure, and death if left untreated. Elevated interleukin-6 (IL-6) level in PAH patients is taken as an independent predictor of adverse outcome including mortality. The aim of this study was to investigate and compare serum levels of IL-6 in children with PAH and healthy matched controls, and correlate between IL-6 and degree of PAH, as well as mortality. IL-6 was measured by ELISA in serum samples in 40 children with PAH (age 1–12 years) and 40 age and sex-matched healthy controls. There was a statistically significant increase in IL-6 level among PAH cases compared with the controls (1.85 ng/L vs 1.30 ng/L, p-value = 0.004). IL-6 at cut off point 1.45 ng/L significantly predict pulmonary hypertension in children (AUC = 0.685, 75% sensitivity, and 65% specificity with p = 0.002). There was no statistically significant association between IL-6 level and degree of PAH (p = 0.218). There was no statistically significant association between IL-6 level and mortality (p = 0.662). Conclusion: IL-6 significantly predict PAH in pediatrics but there is no association between IL-6 level and degree of PAH or mortality. IL-6 may provide a less costly and less invasive method for disease detection.What is Known:• Definitive diagnosis of PAH is made by right heart catheterization, while echocardiography is the gold standard for tracking the course of the disease.What is New:• It was assumed that children with a diagnosis of PAH would have higher serum IL-6 levels than controls. Furthermore, an adverse relationship between the blood IL-6 level and PPAH was predicted.

Actigraphy methodology in the Kids Mod PAH trial: Physical activity as a functional endpoint in pediatric clinical trials.

Pulmonary vasodilator treatment can improve hemodynamics, right ventricular function, symptoms, and survival in pediatric pulmonary hypertension (PH). However, clinical trial data are lacking due to many constraints. One major limitation is the lack of relevant trial endpoints reflective of hemodynamics or functional status in patients in whom standard exercise testing is impractical, unreliable, or not reproducible. The Kids Mod PAH trial (Mono- vs. Duo Therapy for Pediatric Pulmonary Arterial Hypertension) is an ongoing multicenter, Phase III, randomized, open-label, pragmatic trial to compare the safety and efficacy of first-line combination therapy (sildenafil and bosentan) to first-line monotherapy (sildenafil alone) in 100 pediatric patients with PH across North America. Investigators will measure participants' physical activity with a research-grade, wrist-worn actigraphy device at multiple time points as an exploratory secondary outcome. Vector magnitude counts per minute and activity intensity will be compared between the treatment arms. By directly and noninvasively measuring physical activity in the ambulatory setting, we aim to identify a novel, simple, inexpensive, and highly reproducible approach for quantitative assessment of exercise tolerance in pediatric PH. These data will increase the field's understanding of the effect of pulmonary vasodilator treatment on daily activity - a quantitative measure of functional status and wellbeing in pediatric PH and a potential primary outcome for future clinical trials in children with cardiopulmonary disorders.

Thirty years of surgical management of pediatric pulmonary hypertension: Mid-term outcomes following reverse Potts shunt and transplantation

BackgroundReverse Potts shunt (RPS) and lung or heart–lung transplantation are life-extending surgical interventions for pediatric patients with severe pulmonary arterial hypertension (PAH). Robust criteria for identifying patients who will benefit from these procedures remain elusive. Based on 30 years of experience, we sought to refine the surgical indications. MethodsThis single-center retrospective cohort study included 61 consecutive pediatric patients with PAH managed by RPS (2004-2020) or transplantation (1988-2020). Their mid-term outcomes were assessed. ResultsCompared with the 20 patients managed by RPS, the 41 transplant waitlist patients, of whom 28 were transplanted, were older (14.9 vs 8.0 years, P = .0001), had worse right ventricular impairment (tricuspid annular plane systolic excursion, 12.5 mm vs 18.0 mm, P = .03), and were managed later in the evolution of the disease (6.0 vs 1.7 years, P = .002). After implementation of a high-priority allocation program in 2007, waitlist mortality decreased from 52.6% to 13.6% (P = .02) and 5-year survival increased from 57.1% to 74.7% after RPS and 55.6% to 77.2% after transplantation. At a median follow-up of 8.6 years after RPS and 5.9 years after transplantation, functional capacity had improved significantly, and PAH-specific drug requirements had diminished markedly in the RPS group. Two patients successfully underwent double-lung transplant 6 and 9 years after RPS. ConclusionsIn selected children with suprasystemic PAH, RPS is associated with functional capacity improvements and decreased pharmacotherapy needs over the midterm. RPS deserves consideration earlier in the course of pediatric PAH, with transplantation being performed in the event of refractory RV failure.

Rapidly Progressive Idiopathic Pulmonary Arterial Hypertension in a Paediatric Patient Treated with Lung Transplantation.

Pulmonary arterial hypertension (PAH) is a rare heterogeneous disorder in the paediatric population which is mostly associated with congenital heart disease. The management of paediatric idiopathic PAH (IPAH) is difficult due to insufficient comparative data and depends on the results of evidence-based adult studies with several pulmonary vasodilators, as well as the clinical experiences of paediatric experts. Our aim was to present the case of a 9-year-old girl who underwent several methods of treatment, including pharmacotherapy with a significant reaction to treprostinil, as well as bilateral lung transplantation. The patient's treatment was distinguished by the fact that the dose escalation was as rapid as that observed in the adult population. Due to the limited current evidence and knowledge, the initiation of treatment for these patients remains an individual choice. On the grounds of the number of non-specific symptoms, the diagnosis of this patient was a long process and based mainly on the differential diagnosis. The purpose of this paper is to study this example in order to highlight the importance of early symptoms and the quick implementation of intensive treatment. The applied methods may be useful in doubtful diagnosis processes and treatment procedures in the paediatric population.

Transcatheter Ductus Arteriosus Stenting for Acute Pediatric Pulmonary Arterial Hypertension is Associated with Improved Right Ventricular Echocardiography Strain.

Interventional therapies for severe pulmonary arterial hypertension (PAH) can provide right ventricular (RV) decompression and preserve cardiac output. Transcatheter stent placement in a residual ductus arteriosus (PDA) is one potentially effective option in critically ill infants and young children with PAH. We sought to assess recovery of RV function by echocardiographic strain in infants and young children following PDA stenting for acute PAH. Retrospective review of patients < 2years old who underwent PDA stenting for acute PAH. Clinical data were abstracted from the electronic medical record. RV strain (both total and free wall components) was assessed from echocardiographic images at baseline and 3, 6, and 12months post-intervention, as well as at last echocardiogram. Nine patients underwent attempted ductal stenting for PAH. The median age at intervention was 38days and median weight 3.7kg. One-third (3of 9) of patients had PAH associated with a congenital diaphragmatic hernia. PDA stents were successfully deployed in eight patients. Mean RV total strain was - 14.9 ± 5.6% at baseline and improved to - 23.8 ± 2.2% at 6 months post-procedure (p < 0.001). Mean free wall RV strain was - 19.5 ± 5.4% at baseline and improved to - 27.7 ± 4.1% at 6 months (p = 0.002). Five patients survived to discharge, and four patients survived 1 year post-discharge. PDA stenting for severe, acute PAH can improve RV function as assessed by strain echocardiography. The quantitative improvement is more prominent in the first 6 months post-procedure and stabilizes thereafter.

Cost-utility of ambrisentan and bosentan for pediatric pulmonary arterial hypertension

ABSTRACT Introduction Despite the increasing evidence supporting the efficacy of ambrisentan and bosentan in improving functional classes among pediatric patients with pulmonary arterial hypertension (PAH), there is a lack of information regarding their cost implications. Therefore, the objective of this study is to assess the cost-utility of bosentan compared to ambrisentan for the treatment of pediatric patients with PAH in Colombia. Methods We employed a Markov model to estimate the costs and quality-adjusted life-years (QALYs) associated with the use of ambrisentan or bosentan in pediatric patients diagnosed with pulmonary arterial hypertension (PAH). To ensure the reliability of our findings, we conducted sensitivity analyses to assess the robustness of the model. In our cost-effectiveness analysis, we evaluated the outcomes at a willingness-to-pay (WTP) threshold of US$5,180. Results The expected annual cost per patient receiving ambrisentan was estimated to be $16,055 (95% CI 15,937 –16,172), while for bosentan it was $14,503 (95% CI 14,489 –14,615). The QALYs per person estimated for ambrisentan were 0.39 (95% CI 0.381–0.382), whereas for bosentan it was 0.40 (95% CI 0.401–0.403). Conclusion Our economic evaluation shows that ambrisentan is not cost-effective regarding bosentan to in treating pulmonary arterial hypertension in C.

Bilateral lung transplantation for pediatric pulmonary arterial hypertension: perioperative management and one-year follow-up.

Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes. Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020. Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic (n = 4) or heritable PAH (n = 4), PAH associated with congenital heart disease (n = 2), pulmonary veno-occlusive disease (n = 1), and pulmonary capillary hemangiomatosis (n = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months). LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading.

Pediatric pulmonary arterial hypertension due to a novel homozygous GDF2 missense variant affecting BMP9 processing and activity.

Pulmonary arterial hypertension (PAH) is a rare and severe disorder characterized by progressive pulmonary vasculopathy. Growth differentiation factor (GDF)2 encodes the pro-protein bone morphogenetic protein (BMP) 9, activated after cleavage by endoproteases into an active mature form. BMP9, together with BMP10, are high-affinity ligands of activin receptor-like kinase 1 (ALK1) and BMP receptor type II (BMPR2). GDF2 mutations have been reported in idiopathic PAH with most patients being heterozygous carriers although rare homozygous cases have been described. The link between PAH occurrence and BMP9 or 10 expression level is still unclear. In this study, we describe a pediatric case of PAH also presenting with telangiectasias and epistaxis. The patient carries the novel homozygous GDF2 c.946A > G mutation, replacing the first arginine of BMP9's cleavage site (R316) by a glycine. We show that this mutation leads to an absence of circulating mature BMP9 and mature BMP9-10 heterodimers in the patient's plasma although pro-BMP9 is still detected at a similar level as controls. In vitro functional studies further demonstrated that the mutation R316G hampers the correct processing of BMP9, leading to the secretion of inactive pro-BMP9. The heterozygous carriers of the variant were asymptomatic, similarly to previous reports, reinforcing the hypothesis of modifiers preventing/driving PAH development in heterozygous carriers.

Cardiac Magnetic Resonance Derived Left Ventricular Eccentricity Index and Right Ventricular Mass Measurements Predict Outcome in Children with Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is associated with increased right ventricular (RV) afterload, affecting RV remodeling and RV performance, a major determinant of outcome in PAH-patients. In children with PAH, treatment strategy is guided by risk stratification where noninvasive prognosticators are highly needed. The prognostic value of RV characteristics derived by cardiac magnetic resonance (CMR) has been scarcely studied in pediatric PAH. We aimed to identify CMR-derived morphometric and functional RV characteristics prognostic for outcome in children with PAH. From the Dutch National cohort, thirty-eight children with either idiopathic/heritable PAH (IPAH/HPAH) or PAH associated with congenital heart disease (PAH-CHD), who underwent CMR, were included (median (interquartile range) [IQR] age 13.0 years (10.8-15.0), 66% females). Patients had severe PAH, characterized by their World Health Organization Functional Class, increased N-terminal pro-B-type natriuretic peptide and high pulmonary arterial pressure and pulmonary vascular resistance index at time of CMR. RV-ejection fraction (RVEF), indexed RV-mass (RVMi), the ratio between RV and LV mass (RVM/LVM-ratio) and left ventricular eccentricity index (LVEI) all correlated with transplant-free survival from time of CMR. These correlations could not be confirmed in the PAH-CHD group. This study shows that CMR-derived measures reflecting RV function and remodeling (LVEI, RVMi, RVM/LVM-ratio, RVEF) predict transplant-free survival in children with IPAH/HPAH and may be included in risk stratification scores in pediatric PAH.

(1) Severe Pediatric Pulmonary Arterial Hypertension. Long-Term Outcomes of Reverse Potts Shunt and Transplantation

(1) Severe Pediatric Pulmonary Arterial Hypertension. Long-Term Outcomes of Reverse Potts Shunt and Transplantation