Eric D. Austin

Pulmonary hypertension (BPD‐PH) associated with bronchopulmonary dysplasia (BPD) in preterm infants associates with high morbidity and mortality within the first 2 years of life. In a previous unbiased study, we identified a panel of 16 miRNAs in tracheal aspirates (TA) that were differentially expressed in extremely low gestational age newborns (ELGANs) with BPD‐PH compared to those with BPD but no PH. To explore the predictive potential of these candidate miRNAs, we studied them in TA exosomes from 7‐day‐old ELGANs and through logistic regression calculated the predictive area under the receiver operating characteristic curve (AUROC) to diagnose BPD‐PH at 36 weeks post menstrual age (PMA). AUROC of TA miRNAs was 0.76 with sensitivity and specificity of 93% and 54%, respectively. Adding sex and gestational age to the variables improved the AUROC to 0.78 with sensitivity and specificity of 88% and 62%, respectively. Due to challenges of obtaining TA in noninvasively ventilated infants, we collected saliva samples from ELGANs at 7 days of age and compared the log expression of these target miRNAs in both biofluids and found a significant correlation in their expression (pearson r = 0.92, p < 0.001). We calculated the predictive AUROC of these candidate miRNAs to diagnose BPD‐PH at 36 weeks PMA. AUROC of these miRNAs in saliva was = 0.85 with sensitivity and specificity of 72% and 82%, respectively; addition of biological sex and gestational age improved AUROC to 0.86 with sensitivity and specificity of 76% and 79%, respectively. Leave‐one‐sample‐out sensitivity analysis demonstrated stable training performance with reduced performance in testing samples, supporting the need for validation in larger independent cohorts. In conclusion, early salivary miRNAs have great potential for risk stratification of ELGANs to develop BPD‐PH, while also providing the opportunity to identify target molecules and mechanisms that modulate molecular function.

The role of antithrombotic therapy in pulmonary hypertension (PH) remains uncertain, with conflicting adult data and limited pediatric evidence. This study aimed to describe real‐world antithrombotic use in pediatric PH utilizing Pediatric Pulmonary Hypertension Network (PPHNet) registry data and a survey of PPHNet centers. We analyzed data of 1,716 patients from the PPHNet registry (2014–2024), comparing characteristics of those who received aspirin or warfarin with those who did not. A survey on real‐world antithrombotic use was also distributed to 12 North American PPHNet centers in 2023. Eighteen percent of subjects received aspirin and 7% received warfarin. Patients who received aspirin or warfarin were more likely to have idiopathic/heritable PH. Aspirin or warfarin‐treated patients demonstrated higher‐risk features as evidenced by use of PH‐targeted triple therapy (aspirin vs. no aspirin: 22% vs. 9%, p < 0.01; warfarin vs. no warfarin: 31% vs. 10%; p < 0.01) and higher mortality over a median follow‐up of 3.2 years (aspirin vs. no aspirin: 14% vs. 9%, p = 0.008; warfarin vs. no warfarin: 19% vs. 9%, p = 0.001). Center‐specific aspirin and warfarin use varied widely. Survey data demonstrated general agreement that antithrombotic therapy was not indicated for patients at lowest risk and probably indicated for patients at highest risk, but management of intermediate‐risk patients varied considerably. Antithrombotic therapy is used infrequently in pediatric PH and primarily reserved for high‐risk patients, with significant variation across centers. These findings highlight the need for further research to define which patients may benefit and guide evidence‐based practice.

Background: Pediatric‐onset pulmonary hypertension (PH) is a rare, progressive pulmonary vascular disease associated with high mortality. In cases unresponsive to pharmacological therapy with a severe cardiorespiratory phenotype, lung transplantation (LT) remains the final treatment option. Although LT for pediatric PH is considered a procedure with elevated risk, it has been successfully performed in this population. Case Presentation: A 3‐year‐old boy underwent uncomplicated LT for fulminant TBX4 ‐associated PH and developed hyperacute allograft failure requiring plasmapheresis, augmentation of immunosuppression, and the use of a monoclonal complement inhibitor. Despite extensive treatment the patient died 46 days after LT. Retrospective analysis of the serum sample taken at time of transplant prior to reperfusion was positive for six non‐histocompatibility antibodies: Sjogren syndrome antigen B, thyroglobulin, glutathione S‐transferase Theta‐1, colony stimulating factor 2, intracellular adhesion molecule 1, and interferon gamma that were not present in other pediatric thoracic transplant recipients. Conclusions: Hyperacute allograft rejection is extremely rare in LT recipients and its occurrence in this patient implies the need for further characterization of non‐HLA antibody‐associated LT rejection.

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies. In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA -related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.

BACKGROUND: Risk prediction is fundamental to pulmonary hypertension (PH) guideline-based care, yet pediatric-specific risk prediction models remain limited, relying primarily on single predictors, expert opinion, or application of adult models to children. The authors developed and externally validated a data-driven 1-year risk prediction model for pediatric PH. METHODS: Pediatric patients with PH (n=345; World Symposium on Pulmonary Hypertension groups 1 and 3) enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014–2020; 50.4% male; median age, 4.9 years [interquartile range, 1.9–10.3]) were split into training (80%) and test cohorts (20%). The Dutch National Registry for Pulmonary Hypertension in Childhood (n=155 [1993–2020]) and the Spanish Registry of Pediatric Pulmonary Hypertension (n=327 [2009–2023]) were used for external validation. From 176 variables, BorutaSHAP feature selection with random forest identified 16 predictors for a 1-year outcome of time to death, transplant, Potts shunt, or atrial septostomy, modeled using extreme gradient boosting. Performance was assessed with the area under the receiver operating characteristic curve, confusion matrices, calibration, and Kaplan-Meier event-free survival. RESULTS: The final model achieved an area under the receiver operating characteristic curve of 0.90 (0.79–0.97) and 99% (96%–99%) negative predictive value in testing, dividing participants into 3 groups with strong outcome discrimination. External validation showed an area under the receiver operating characteristic curve of 0.76 (Dutch National Registry for Pulmonary Hypertension in Childhood, 0.70–0.81) and 0.77 (Spanish Registry of Pediatric Pulmonary Hypertension, 0.73–0.82) with negative predictive values of 93% (93%–97%) and 96% (93%–97%), respectively. Kaplan-Meier analysis significantly differentiated outcomes by risk group. CONCLUSIONS: This multicenter, validated model provides good 1-year risk prediction in pediatric PH across World Symposium on Pulmonary Hypertension groups 1 and 3, providing a robust tool for clinical risk stratification to guide therapy and addressing a gap in pediatric PH care.

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal‑dominant vascular disease characterized by telangiectasias and visceral arteriovenous malformations (AVMs), commonly in the lungs, liver, and brain. HHT is linked to mutations in the genes Activin A Receptor Like Type 1 (ACVRL1), Endoglin (ENG), and SMAD Family Member 4 (SMAD4). The ACVRL1 gene encodes the receptor ACVRL1 (Activin A Receptor Like Type 1), also known as ALK1 (Activin Receptor‐Like Kinase 1), and belongs to the Transforming Growth Factor‐Beta (TGFβ) Superfamily of receptors. Approximately 20% of patients with ACVRL1‐associated HHT develop pulmonary arterial hypertension (PAH). [1] In pediatric PAH cohorts, ACVRL1 mutations account for nearly 10% of identified genetic variants. [2] The reduced penetrance of PAH among ACVRL1 mutation carriers suggests that additional modifiers account for PAH development. [3]. Given the relevance of the bone‑morphogenetic‑protein (BMP) pathway to the pathogenesis of PAH, and the intimate relationship of TGFβ superfamily signaling partners including ACVRL1 and BMPR2, genes which modify BMP‐TGFβ signaling balance may contribute to PAH development in children with ACVRL1‑positive HHT. One such gene is SMAD9 (Receptor Regulated SMAD 9); the protein product of SMAD 9 (SMAD8) which mediates downstream TGFβ signaling. Herein, we report what we believe to be the youngest reported case of PAH in ACVRL1‑mediated HHT, in a patient who co‑harbors a SMAD9 mutation.

Preterm birth survivors reaching adulthood are a growing population, with bronchopulmonary dysplasia (BPD), the chronic lung disease of prematurity, common among this cohort. Infants with BPD are at increased risk for pulmonary vascular disease (PVD) including the development of pulmonary hypertension (PH). We present three preterm patients with a history of BPD‐associated PH (BPD‐PH) with monitoring throughout their childhood and young adulthood, highlighting the variation in management and late outcomes of each patient. Resolution of PH is reported on transthoracic echocardiogram (TTE) in all patients early in their life. Long‐term follow‐up was discontinued for one patient, while long‐term monitoring in the other two individuals showed evidence of cardiopulmonary complications requiring PH‐specialty management. The burden of cardiopulmonary disease associated with prematurity exists beyond early childhood and further research on the long‐term management of this population is necessary to mitigate complications.

Extract Noonan syndrome is an autosomal dominant genetic condition with multisystem involvement and an estimated prevalence of one in 1000 to 2500 live births [1]. Its unifying biological feature is dysregulation of the RAS/MAP kinase signalling pathway with pathogenic variants most commonly found in PTPN11 (∼50%), SOS1 (10%), RAF1 (5–15%) and RIT1 (10%) [2, 3]. Cardiovascular manifestations are among the most clinically significant features, including pulmonary stenosis in 50–60% of individuals, hypertrophic cardiomyopathy in 20%, and secundum-type atrial septal defects in 6–10% [3]. Shareable abstract The study of Noonan syndrome by Grynblat and co-workers serves as an essential foundation and lays the groundwork for collaborative research directed at addressing numerous areas of need for patients and families impacted by this condition https://bit.ly/4bfkxud

Background: Echocardiography is a non-invasive test that is readily used to detect pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) and right ventricular failure (RVF). However, the most feasible, reproducible and accurate parameters to measure and use for guidance in addressing patient care have not been established and may differ between subspecialties. Methods: We surveyed members of the BPD Collaborative to determine how different care providers clinically evaluate infants for BPD-PH and RVF. Perceived challenges and obstacles that limit the utility of echocardiography are also reported. Results: Of the 108 survey respondents from ~45 centers, 55.6% were neonatologists, 18.5% were pediatric pulmonologists or pediatric intensive care physicians, 15.7% were pediatric cardiologists or pulmonary hypertension specialists, and 10.2% were other providers. Responses revealed discrepancies between specialists concerning the use of standard echocardiographic protocols and parameters that can be measured serially with relative ease, metrics that should be used to best define and distinguish the severity of BPD-PH or RVF, and parameter values that should be used to determine whether changes in PH-targeted medical therapies, hemodynamic or respiratory support are needed. Free text responses identified patient-, protocol-, cardiology-, technician-, and BPD-PH definition-related obstacles that may limit the reliable utility of echocardiography. Conclusions: Although most providers agree that echocardiography is feasible and of value, variability exists between subspecialists and centers, suggesting the need for improved standardization of imaging protocols and BPD-PH definition, consistent test interpretation, and effective communication of results to improve the reproducibility and accuracy of echocardiography in infants with BPD.

Advances in tissue biology have revealed remarkable transcriptomic heterogeneity of endothelial cells between and within organ systems. This necessitates more precise models of organ-specific endothelium to understand the pathogenesis of genetic vascular disorders, such as pulmonary hypertension (PH), where gene-disease associations have implicated endothelial cell dysfunction as a key driver of disease pathogenesis. Towards this end, human induced pluripotent stem cells (hiPSCs) hold immense promise for PH disease modeling where hiPSCs are generated from an affected individual and undergo gene correction to generate syngeneic controls that can be differentiated to endothelial cells (hiEndos), providing a limitless source of material for downstream studies; however, the ability to generate lung-specific hiEndos to model pulmonary vascular disease has been limited. To overcome this challenge, we developed a chimeric human-mouse lung vascular model wherein hiEndos are first patterned via BMP9-induced signaling towards a lung-like molecular phenotype in vitro and are then intravenously transplanted into the mouse lung vasculature in vivo to generate orthotopic lung-specific endothelium for downstream studies. Transplanted pre-patterned hiEndos form functional connections to the native mouse lung vasculature and upregulate differentiated lung-specific molecular cell subtype profiles that include capillary- and arterial-like cell populations. To apply this approach for disease modeling, we generated new hiPSC lines by reprogramming fibroblasts from individuals of the 2001 landmark cohort of BMPR2 gene variant-associated PH and developed a novel in vivo competitive lung endothelial reconstitution assay to quantify functional and molecular differences between human BMPR2 -variant vs syngeneic gene-corrected/edited hiEndos. Our approach revealed novel insights into PH disease pathogenesis, not previously evident with prior models, including BMPR2 variant-induced in vivo defects in human lung capillary gene expression, elevated lncRNA H19 expression, increased AHR signaling, and diminished functional capacity to repopulate the pulmonary vascular endothelium.