Acute lung injury (ALI) involves inflammatory cytokines and chemokines, resulting in lung and multiple organ injuries. This study explored the mechanism of mitophagy and cGAS/STING pathway in oleic acid (OA)-induced ALI....Acute lung injury (ALI) involves inflammatory cytokines and chemokines, resulting in lung and multiple organ injuries. This study explored the mechanism of mitophagy and cGAS/STING pathway in oleic acid (OA)-induced ALI. Mice and pulmonary microvascular endothelial cells were divided into four groups: control group (Con), ALI group, control group (FCon), and ALI group (F-ALI). After 24 h of modeling, proceed with tissue collection. Lung tissues were stained using hematoxylin eosin. Autophagosomes were observed by electron microscope and mtDNA was detected by qPCR. Western blot was used to analyze protein expression of pathways cGAS, STING, pTBK1, pIRF3, and pNF-κB. Serum IFN-β expression was detected by ELISA. Cellular morphological changes were observed using microscopy. LDH level, cGAS, and STING in endothelial cells were observed. Compared with control group, pathological changes in ALI group were significantly aggravated. Expressions of serum IFN-β, cGAS, STING, pTBK1, pIRF3, and pNF-κB in lung tissues of ALI mice were significantly higher than control group. After OA, the morphology of lung microvascular endothelial cells changed and LDH expression increased. After FUNDC1 gene was knocked out to inhibit mitophagy, autophagosomes were significantly reduced and mtDNA increased. Expressions of pathway proteins in lung tissues and cells of ALI group were higher than those of wild-type ALI group. Serum IFN-β expression also increased. Silencing FUNDC1 inhibits mitophagy. Subsequently, accumulated mtDNA activates cGAS/STING pathway, aggravating ALI pathological damage and inflammation, suggesting that mitophagy may provide protection in OA-induced ALI through cGAS/STING pathway.
Conde-Camacho R, Orozco-Levi M, Londoño A
… +9 more, Gómez-Palau R, Tuta-Quintero E, Naranjo A, Díaz K, De Luque J, Goldfeder S, Giraldo-Cadavid LF, Guerrero MC, Red Colombiana de Hipertensión Pulmonar – HAPredCo.
Pulmonary arterial hypertension (PAH) in intermediate-risk patients poses a challenge for clinicians, particularly in determining the optimal timing for escalating pharmacological treatment. We conducted a multicenter cr...Pulmonary arterial hypertension (PAH) in intermediate-risk patients poses a challenge for clinicians, particularly in determining the optimal timing for escalating pharmacological treatment. We conducted a multicenter cross-sectional study that analyzed data from the Colombian Pulmonary Hypertension Network (HAPredCO) on patients diagnosed with PAH. Participants were stratified into low- and high-intermediate risk groups using the four-level ESC/ERS score, which incorporates optimized cutoff values for WHO functional class (WHO FC), the 6-min walk test (6MWT), and N-terminal pro-brain natriuretic peptide (NT-proBNP)/brain natriuretic peptide (BNP) concentration. A bivariate analysis was conducted to compare study variables at baseline and during clinical follow-up. Additionally, a survival analysis was performed using Kaplan-Meier curves to compare outcomes between the intermediate-risk groups. A total of 175 patients were analyzed, with a mean age of 44.85 years (SD 15.5), of which 86% (150/175) were women. In the baseline, a total of 75% (131/175) were classified as intermediate-low-risk. In clinical follow-up, 40% (61/154) were classified as intermediate-low-risk, 21% (32/154) were classified as intermediate-low-risk, 23% (35/154) were classified as intermediate-low-risk, and 16% (26/154) as intermediate-high-risk. At baseline, WHO FC III was 61% (107/174), compared to 35% (56/154) at follow-up ( = 0.083). The use of bosentan decreased from 36% (63/175) to 28% (46/154) ( < 0.001), while ambrisentan increased from 18% (31/175) to 30% (47/154), and macitentan increased from 25% (44/175) to 36% (57/154). The use of parenteral prostanoids and selexipag increased by 20% (4% vs. 24%) and 3% (1% vs. 4%) during clinical follow-up, respectively. Overall survival at 1 year of follow-up was 96%, at 2 years 92%, and at 3 years 88%. The survival rates at 1, 2, and 3 years were 98%, 95%, and 90% in the intermediate-low-risk group, and 90%, 80%, and 80% in the intermediate-high-risk group. In this real-world study of PAH in the Colombian HAPredCO registry, the median survival in the intermediate-low-risk group was slightly higher than in the intermediate-high-risk group. At baseline, most patients were classified as intermediate-low-risk. However, during clinical follow-up, risk distribution changed, with a notable proportion shifting across different risk categories.
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent obstruction and vascular remodeling of the pulmonary arteries following pulmonary thromboembolism (PTE), diagnosed after a minimum of 3...Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent obstruction and vascular remodeling of the pulmonary arteries following pulmonary thromboembolism (PTE), diagnosed after a minimum of 3 months of therapeutic anticoagulation. Disease progression from PTE to CTEPH takes place in the pulmonary circulation, where the vascular microenvironment is composed of a fluid portion that includes blood cells and components of the fibrinolytic system, and various vascular cells, including endothelial and smooth muscle cells. Following PTE, the homeostasis of the pulmonary vascular microenvironment is disrupted, leading to the accumulation of inflammatory mediators and immune cells at the site of thrombosis. Platelets are also involved in the regulation of coagulation and inflammation, and functional changes such as impaired fibrinolysis are observed. Subsequently, endothelial cell dysfunction and smooth muscle cell dysregulation lead to delayed thrombus resolution and pulmonary vascular remodeling, eventually resulting in CTEPH. Early intervention targeting the aberrant vascular microenvironment may thwart or mitigate the transition from PTE to CTEPH. Here, we discuss the development of CTEPH from the perspective of the pulmonary vascular microenvironment and examine its related biomarkers and therapeutic methods for CTEPH diagnosis and treatment.
Segmental pulmonary hypertension (PH) in congenital heart disease remains poorly understood with data limited to case studies. We performed a retrospective, single center study in children treated with PH medications aft...Segmental pulmonary hypertension (PH) in congenital heart disease remains poorly understood with data limited to case studies. We performed a retrospective, single center study in children treated with PH medications after unifocalization/pulmonary artery reconstruction for major aortopulmonary collaterals (MAPCA). Drug response was determined by hemodynamic changes across at least two cardiac catheterizations. Mechanical properties of the segmental arteries were quantified by distensibility, stiffness, and augmentation indices. Twenty-five patients were included (8 surgical shunt, 17 complete repair), with 76% considered responsive to PH medications based on the relative decrease in maximum segmental mean pulmonary artery pressure (mPAP). At a median duration of 14 months (Q1-Q3 9.5-29), mPAP decreased from 33 mmHg (28-38) to 23 mmHg (21-32) ( < 0.001) with no significant change in blood flow distribution by lung perfusion scintigraphy. Subgroup analysis demonstrated a trend towards a larger percent decrease in mPAP of 35% (18-45) on dual therapy compared to 23% (Q1-Q3 3-36) on monotherapy ( = 0.16). In repaired patients, arterial distensibility at initial catheterization correlated with residual elevation in mPAP at follow-up ( 0.687, < 0.001), with distensibility < 1.7%/mmHg associated with treatment failure. Among the lowest distensibility values were patients with mutations, and among patients with extended follow-up, progressive increase in mPAP was identified only in those with hereditary PH-associated mutations. Children with segmental PH following pulmonary artery reconstruction can be successfully treated with PH medications. Although treatment efficacy may be limited in patients with high vascular stiffness and those with pathologic vascular mutations.
Pulmonary hypertension (PH) carries a poor prognosis and a high mortality. Loss of pulmonary arterial compliance (PAC) plays a significant role in the development of PH and is an early predictor of mortality. Currently,...Pulmonary hypertension (PH) carries a poor prognosis and a high mortality. Loss of pulmonary arterial compliance (PAC) plays a significant role in the development of PH and is an early predictor of mortality. Currently, there are no therapeutic options to overcome the loss of PAC. Aria CV (Saint Paul, MN) has developed a device to augment PAC. The device consists of a 20-cc balloon and anchor that can be implanted in the pulmonary artery using a minimally invasive procedure, a catheter, and a gas reservoir. Computed tomography imaging of 46 patients from the ASPIRE database and cadaver studies ( = 7) were used to ascertain device fit and optimize surgical procedure. Aria CV devices ( = 6) were tested for simulated use, durability, and PAC augmentation. Animal studies were conducted to demonstrate device safety in the deflated state ( = 9), and gas embolism due to simulated balloon rupture ( = 5). A chronic bovine model of PH was used to demonstrate PAC augmentation ( = 3). Chronic animal studies ( = 8, 30-days) were conducted to demonstrate long-term device safety and biocompatibility per ISO 10993 standards. In-silico fit and cadaver studies demonstrated that the device could be successfully implanted in the PA for a wide range of patients. In vitro and bovine models of PH demonstrated that the chronic Aria CV device enhanced PAC by > 0.4 ml/mmHg, which matched the PAC enhancement observed in 28 human patients with a short-term Aria CV device. The device passed all required durability, safety, and biocompatibility testing and is enrolling patients in a Food and Drug Administration (FDA) approved clinical trial (ASPIRE PH, NCT04555161).
Iron deficiency (ID) is prevalent in pulmonary hypertension(PH), but there is no consensus on ID definition and its possible correlation to prognostic markers. Hence, in this study, PH-patients were recruited at the Univ...Iron deficiency (ID) is prevalent in pulmonary hypertension(PH), but there is no consensus on ID definition and its possible correlation to prognostic markers. Hence, in this study, PH-patients were recruited at the University Hospital Zurich from May 2019 to April 2021. Clinical and hemodynamic characteristics were recorded at inclusion and venous blood samples were taken. ID was defined as: (i) ferritin-ID: ferritin< 100 µg/L or 100-299 µg/L plus a transferrin saturation (TSAT) < 20%; (ii) TSAT-ID: a TSAT < 20% (males)/< 15% (females) and (iii) TFRI-ID: a transferrin receptor index (TFRI) > 3.2/ > 2.0 depending on CRP < / > 5 mg/L. 94 patients (52% female, mean age 62.9 ± 14.6 years) with pulmonary arterial hypertension(48%), PH associated with lung disease (20%) or chronic thromboembolic PH (32%) were included. Sixty-seven percent fulfilled criteria for ferritin-ID, 35% for TSAT-ID, and 13% for TFRI-ID. Mean pulmonary arterial pressure (mPAP) was elevated in TFRI-ID patients compared to non-ID (50 ± 12.2 mmHg vs. 35.9 ± 11.7 mmHg); however, after correction for age, sex, PH-type, and anticoagulation, the difference was nonsignificant ( = 0.085). NT-proBNP was significantly higher in TFRI-ID-positive (1237 ± 1166 pg/mL vs. 334 ± 417 pg/mL, = 0.004). No significant differences were found for ferritin-ID and TSAT-ID ( > 0.05). Six-minute walk distance (6MWD) was reduced for both TSAT-ID (402 ± 133 m vs. 469 ± 152 m, = 0.006) and TFRI-ID (370 ± 112 m vs. 459 ± 151 m, = 0.052), but not for ferritin-ID ( > 0.05). In conclusion, TFRI-ID is seemingly associated with clinical markers of right heart parameters and disease severity. This could not be seen with the currently recommended ferritin-ID-definition or TSAT-ID. More data is needed to assess the use of the TFRI-ID instead of the ferritin-ID-definition as a method to identify PH-patients at risk and as a threshold for iron substitution.
Awareness of health disparities that exist across different self-identified racial and ethnic groups are essential to developing interventions that improve the quality of care of patients with rare diseases such as pulmo...Awareness of health disparities that exist across different self-identified racial and ethnic groups are essential to developing interventions that improve the quality of care of patients with rare diseases such as pulmonary arterial hypertension (PAH). We sought to determine whether there are important differences in clinical characteristics and illness severity at the time of PAH diagnosis among different racial/ethnic groups. 110 patients followed at the University of Illinois Health Pulmonary Hypertension Clinic diagnosed with PAH between 2010 and 2019 were enrolled in our retrospective cohort study. Self-reported race, ethnicity, ZIP code, and standard clinical measures were obtained from the electronic medical record. Comparisons of clinical severity, hemodynamic measurements, social vulnerability, income, and timing of diagnostic testing were made between non-Hispanic Black and non-Black subjects. Our data shows that PAH is more severe at the time of diagnosis in non-Hispanic Black patients compared to non-Black patients, by both clinical and hemodynamic assessments. Tricuspid regurgitant velocity correlated poorly with invasive hemodynamics in non-Hispanic Black patients, yet measures of RV performance were worse than non-Black counterparts. Increased social vulnerability and income inequality was evident between the groups. When compared to non-Black patients, there were significant delays between abnormal echocardiogram findings and completion of diagnostic catheterization. These results implicate concerning health disparities in non-Hispanic Black patients with PAH. More severe disease at time of diagnosis and longer delays from time of symptom onset to PAH diagnosis have both been associated with increased mortality in this population and future work should be aimed at comprehensive strategies to reduce this disparity.
To evaluate current digital inclusion in the Scottish pulmonary hypertension population, a paper questionnaire was offered to the entirety of patients with pulmonary arterial hypertension in Scotland. The Scottish Index...To evaluate current digital inclusion in the Scottish pulmonary hypertension population, a paper questionnaire was offered to the entirety of patients with pulmonary arterial hypertension in Scotland. The Scottish Index of Multiple Deprivation was used to stratify patients into deprivation deciles. 464 patients returned questionnaires (86%). 91% had reliable internet access. 89% had access to an internet-enabled device. 71% used the internet daily. The most common barriers to increased internet usage were confidence with technology (19%) and lack of perceived personal benefit (7%). 54% would like virtual healthcare to complement in person review and 58% would like to monitor their health digitally. Older patients were less likely to use the internet and had less desire for virtual healthcare. Rural living did not negatively impact access to the internet. Younger, more rural, and less deprived patients currently use and desire more online exercise. Deprived patients were less likely to have internet access or internet enabled devices, more likely to have no device or a mobile without internet, and had less desire for virtual healthcare or digital health monitoring. Most patients have the means of accessing the internet and support virtual healthcare in addition to direct clinician contact. However, digital engagement was lower in older and more deprived patients. The high response rate supports paper over online survey methodology for future digital inclusion research. Future digital healthcare strategies need to integrate this knowledge to minimize age- and deprivation-related inequity.
Pulmonary arterial hypertension (PAH) is a disorder characterized by progressive remodeling of small pulmonary arteries, leading to increased pulmonary vascular resistance, right ventricular failure and premature death (...Pulmonary arterial hypertension (PAH) is a disorder characterized by progressive remodeling of small pulmonary arteries, leading to increased pulmonary vascular resistance, right ventricular failure and premature death (1-2). Over the past 30 years, significant advancements have been made in the treatment of PAH, including the recent approval of sotatercept, a first-in-class fusion protein that acts as a ligand trap for activins and growth differentiation factors, which are key players in the transforming growth factor β (TGF-β) superfamily (3-4). Sotatercept improves exercise capacity, as assessed by 6-min walk distance and World Health Organization (WHO) functional class, reduces pulmonary vascular resistance and NT-pro brain natriuretic peptide, and improves the simplified French risk score while extending the time to death or nonfatal clinical worsening (3). The 7th World Symposium in pulmonary hypertension recommends the addition of sotatercept as an option in PAH patients who have not achieved low risk despite combination therapy with at least an endothelin receptor antagonist and phosphodiesterase type-5 inhibitor, in intermediate or high-risk patients. The STELLAR study of sotatercept in PAH patients demonstrated the efficacy of this medication in patients receiving background therapy (3). In fact, 34% of the patients were on double and 60% of the patients on triple therapy. Interestingly 40% were on prostacyclin infusion therapy (3). Post-hoc analysis of the stellar study showed a beneficial effect for those on double or triple background PAH therapy as well as those receiving prostacyclin infusion at baseline (1,5). It remains unclear if the addition of sotatercept to other PAH treatments may have unexpected complications. It is possible that by rebalancing the proliferative/antiproliferative effects in the pulmonary circulation, the effect of other treatments for PAH may become excessive, particularly when parenteral prostacyclin is used at high doses. This phenomenon may manifest with the typical characteristics of prostacyclin overdose, including enhanced side effects and high cardiac output heart failure. Hereby we describe a patient with PAH on triple PAH-specific therapy, who after the initiation of sotatercept developed a large pericardial effusion and high cardiac output heart failure.
Evidence on the predictive ability of risk assessment models for event-free survival (EFS) in patients with pulmonary arterial hypertension is scarce. We aimed to investigate the relationship between risk status at 6 mon...Evidence on the predictive ability of risk assessment models for event-free survival (EFS) in patients with pulmonary arterial hypertension is scarce. We aimed to investigate the relationship between risk status at 6 months after diagnosis (6 M) and EFS, by three risk models: Multicomponent Improvement (MCI), ESC/ERS 4-Strata Risk (4SR), and noninvasive French PH Registry Score (FRS). Data collected in the Swedish PAH Registry 2008-2021 were used. The study population was risk-stratified at 6 M according to each model. Information on PAH-related hospitalization (HOSP) was collected from the National Patient Register. EFS was defined as survival without occurrence of: (1) HOSP; (2) initiation of parenteral prostacyclin therapy or dose increase ≥ 10%; (3) lung transplantation. The association between risk and EFS was evaluated by Kaplan-Meier estimates and Cox proportional models. The analysis included 411 incident patients, median age 66 y [50, 73]. Median survival time was 3.5 y [1.7; 5.4], and cumulative EFS was 55%. In a Cox proportional regression adjusted for age, eGFR, obesity, atrial fibrillation, and systemic hypertension, EFS was higher in patients who: (1) achieved two or three MCI criteria compared to one or no MCI criterion (HR 0.58; CI 0.39-0.84, = 0.005); (2) were assessed as low, intermediate-low, or intermediate-high compared to high risk (HR 0.16; CI 0.09-0.28, < 0.001); or (3) fulfilled one, two, or three low-risk FRS criteria, compared to no low-risk criterion (HR 0.29; CI 0.19-0.43, < 0.001). Performing a risk assessment 6 months after diagnosis effectively predicts the likelihood of EFS in the studied population, highlighting its prognostic value.
Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by small artery occlusion, increased pulmonary vascular resistance, and right heart failure. HSPH1, a member of the heat shock protein...Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by small artery occlusion, increased pulmonary vascular resistance, and right heart failure. HSPH1, a member of the heat shock protein family, has been shown to inhibit protein aggregation but its role in PAH remains unclear. The purpose of this study was to explore the expression pattern and potential mechanism of HSPH1 in PAH, and to provide new diagnostic markers for PAH. In the study differentially expressed genes from two GEO microarray datasets (GSE53408, GSE113439) were analyzed to identify potential biomarkers for PAH. The expression of HSPH1 in normal lung tissue and pulmonary hypertension tissue was verified by bioinformatics and various experiments. This study also validated the potential mechanism of action of HSPH1 in PAH through transfection techniques. In addition, clinical correlation analysis was used to verify whether HSPH1 was correlated with clinical indicators (age, smoking history, hypertension, SII, NLR, PLR). The results showed that the protein level of HSPH1 was significantly increased in the pulmonary artery tissue of rats with pulmonary hypertension. In the plasma of patients with clinical PAH, the expression of HSPH1 mRNA was also observed to be significantly increased, and its expression was also associated with inflammatory markers such as NLR, PLR and SII. In addition, wet experiments found that HSPH1 could promote the proliferation of pulmonary artery smooth muscle cells, promote epithelial-mesenchymal transformation and inhibit apoptosis. These findings suggest that HSPH1 plays a crucial role in PAH progression and may serve as a potential diagnostic biomarker for the disease.
The objective of this study is to assess the effect of subcutaneous treprostinil (TRE) administered peri-operatively after Fontan operation on chest tube duration (CTD), hospital length of stay (LOS), and post-operative...The objective of this study is to assess the effect of subcutaneous treprostinil (TRE) administered peri-operatively after Fontan operation on chest tube duration (CTD), hospital length of stay (LOS), and post-operative hemodynamics. This is a single center randomized, blinded, placebo-controlled study of pediatric patients with single ventricle congenital heart disease undergoing Fontan operation between September 2015 and September 2019. Patients were randomized to receive subcutaneous TRE (target dose 10 ng/kg/min) or saline placebo starting intraoperatively through post-operative day 7. Baseline demographics, pre-operative hemodynamics, and peri-operative clinical details were collected. The primary outcome was CTD. Secondary outcomes included hospital LOS and hemodynamics. Thirty-four patients were randomized, 16 to TRE and 18 to saline placebo. Baseline characteristics were similar between groups, including pre-operative hemodynamics. Patients receiving TRE had increased risk for longer CTD (median CTD 8 vs. 7 days compared to placebo [IQR: 7-12.5, 5-8 days, respectively] with a relative risk (RR) of 1.29 (95% CI: 1.02, 1.64; = 0.03)) and increased risk for longer hospital LOS (median LOS 11 vs. 9 days compared to placebo [IQR: 9.5-14.5, 8-10 days, respectively] with a RR of 1.23 (95% CI: 1.00, 1.51; = 0.05)). Patients receiving TRE had higher median Fontan pressure at post-operative hour 12 (13 mmHg [IQR: 12.5-15.0] vs. 10.5 mmHg [IQR: 8.0-12.5]; < 0.01 on repeated measure analysis model) and greater transpulmonary gradient at post-operative hour 12 (7.0 mmHg [IQR: 5.0-9.5] vs. 4.0 mmHg [IQR: 3.5-5.0]; < 0.01 on repeated measure analysis model) compared to placebo. Peri-operative subcutaneous TRE did not reduce CTD or hospital LOS after Fontan operation and did not exert significant beneficial effects on post-operative hemodynamics. Accordingly, TRE at a dose of 10 ng/kg/min is not recommended for routine use in immediate post-operative Fontan management.
Interstitial lung disease (ILD) complicated by pulmonary hypertension (PH) is associated with poor outcomes. However, real-world data characterizing the hemodynamic profiles of ILD patients undergoing right heart cathete...Interstitial lung disease (ILD) complicated by pulmonary hypertension (PH) is associated with poor outcomes. However, real-world data characterizing the hemodynamic profiles of ILD patients undergoing right heart catheterization (RHC) remain limited. We retrospectively analyzed ILD patients who underwent RHC between 2006 and 2024. Hemodynamic profiles were assessed according to the 5th, 6th, and 7th World Symposium on Pulmonary Hypertension (WSPH) definitions and for severe PH (pulmonary vascular resistance [PVR] > 5 Wood units). Correlations between pulmonary function testing (PFT) variables and PVR were explored, and baseline characteristics were compared across groups stratified by PH severity. There were 3541 ILD patients evaluated of whom 12.2% underwent RHC. Among 371 patients with available RHC data and pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg, 49.6%, 54.4%, and 69.4% met the 5th, 6th, and 7th WSPH criteria for precapillary PH, respectively, while 31.3% exhibited severe PH. Correlations between diffusing capacity for carbon monoxide (DLco)%, and forced vital capacity (FVC)%/DLco% ratio with PVR were weak. Our findings highlight the heterogeneous hemodynamic landscape of ILD-PH in clinical practice and underscore the need for heightened vigilance and lower thresholds for RHC. These real-world data can inform future clinical trial design, screening strategies, and management decisions for ILD-PH.
As with adult pulmonary hypertension (PH), high morbidity and mortality persist with diverse types of paediatric PH. Despite major advances in pharmacologic therapies based on extensive studies in adult PH, few drugs hav...As with adult pulmonary hypertension (PH), high morbidity and mortality persist with diverse types of paediatric PH. Despite major advances in pharmacologic therapies based on extensive studies in adult PH, few drugs have been comprehensively studied in neonates, infants, and children, leaving current paediatric PH care largely dependent on small observational studies and extrapolation of evidence from adult clinical trials. Challenges in developing successful clinical trials in children include the need to define distinct disease phenotypes with well-characterised natural history and outcomes, the lack of established age- and disease-specific study endpoints, small and heterogeneous paediatric populations, and the common off-label use of PH-targeted drug therapies without regulatory approval. From a regulatory perspective, sufficient studies of safety, pharmacokinetics, and pharmacodynamics in neonates and young children are often lacking, and the potential role for bridging biomarkers has been underexplored. Additional opportunities include developing innovative trial designs, employing real-world data from existing registries, and fostering collaborations among sponsors, regulatory authorities, physicians, patients, and their families. By reducing reliance on off-label drug use and leveraging paediatric PH registry data, this approach offers a path toward more effective and evidence-based treatment protocols for paediatric patients. This review provides an overview of integrated international perspectives from an interprofessional platform that includes academia, the pharmaceutical industry, and regulatory agencies surrounding the future design of clinical trials for paediatric PH. Ongoing evaluation and adaptation of these strategies will be essential for ensuring that paediatric PH patients receive the highest standard of care.