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Objective(s): To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. Data sources: Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. Review methods: The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. Results: In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12–18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6–110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20–99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13–1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07–1.18), 0.21 (95% CI 0.03–1.76), 0.18 (95% CI 0.02–1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were £277,000/quality-adjusted life-year (QALY) for FCIII and £343,000/QALY for FCIV patients for epoprostenol, £101,000/QALY for iloprost, £27,000/QALY for bosentan and £25,000/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. Conclusion(s): All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening and debilitating disease affecting up to 5% of survivors of pulmonary embolism. Diagnostic testing is important to distinguish it from other forms of pulmonary hypertension and to assess the feasibility of pulmonary endarterectomy. This review provides an up-to-date perspective on the diagnosis and assessment of the disease. Patients with CTEPH often have a history of pulmonary embolism, deep-vein thrombosis, thrombophilia, splenectomy, ventriculo-atrial shunt, inflammatory bowel disease or malignancy. Chest radiography may reveal pulmonary infarcts. CTEPH is often diagnosed as a wedge-shaped perfusion defect with normal ventilation scan during ventilation–perfusion scintigraphy, but multi-slice computed tomography angiography may be needed for differential diagnosis. Right heart catheterisation is required for diagnostic confirmation. Suitability for surgery is assessed by evaluating the number of obstructed vessels which could be disobliterated in the context of the pulmonary vascular resistance. Pulmonary vascular resistance that is out of proportion to evident obstructions is indicative of distal disease. Conventional pulmonary angiography, multi-slice computed tomography angiography and, potentially, magnetic resonance imaging can aid the decision to operate, but risk stratification systems are needed. In conclusion, CTEPH can be cured surgically, providing that patients are diagnosed and assessed using the appropriate techniques.

Background: An increasing number of patients with pulmonary arterial hypertension (PAH) have cardiovascular comorbidities. However, the effects of comorbidities on responses to PAH treatment are not well understood., Research Question: Do cardiovascular comorbidities in patients with PAH influence the efficacy and tolerability of inhaled or oral treprostinil?, Study Design and Methods: All patients from phase 3 studies TRIUMPH (N = 235) and FREEDOM-EV (N = 690) were included in this post hoc analysis and were classified as having 0, ≥1, or ≥2 cardiovascular comorbidities of interest based on patients' medical histories. The mean difference in 6-minute walk distance (6MWD) and N-terminal pro-brain natriuretic peptide (NT-proBNP) from baseline to Week 12 was assessed for TRIUMPH and the risk and incidence of clinical worsening was assessed for patients in FREEDOM-EV. Adverse events (AEs) were summarized for each comorbidity grouping for TRIUMPH and FREEDOM-EV., Results: In TRIUMPH, there were 79, 156, and 88 patients with 0, ≥1, and ≥2 comorbidities, respectively. Patients on inhaled treprostinil had improvements in 6MWD, with numerically similar improvements for comorbidity subgroups (0: 26 m, P = 0.020; ≥1: 22 m, P = 0.006; ≥2: 21.6 m, P = 0.043). Significant reductions in NT-proBNP were also seen in all subgroups. In FREEDOM-EV, there were 375, 315, and 166 patients with 0, ≥1, and ≥2 comorbidities, respectively. Regardless of comorbidities, patients on oral treprostinil had a significantly reduced risk of clinical worsening compared with placebo (0: 36% reduction, P = 0.034; ≥1: 41% reduction, P = 0.014; ≥2: 45% reduction, P = 0.026). In TRIUMPH and FREEDOM-EV, AE profiles were typical for this class of medication regardless of the number of comorbidities. A sensitivity analysis using a subset of comorbidities confirmed the findings of our primary analysis., Interpretation: This post hoc analysis suggests that patients with PAH and cardiovascular comorbidities can benefit from combination therapy with inhaled or oral treprostinil., (Copyright © 2024. Published by Elsevier Inc.)

Background: Risk prediction tools are routinely utilised in cardiothoracic surgery but have not been developed for pulmonary endarterectomy (PEA). There is no data on whether patients undergoing PEA may benefit from a tailored risk modelling approach. We develop and validate a clinically-usable tool to predict PEA 90-day mortality (90 DM) with the secondary aim of informing factors that may influence five-year mortality (5 YM) and improvement in patient-reported outcomes (PROchange) using common clinical assessment parameters. Derived model predictions were compared to those of the currently most widely implemented cardiothoracic surgery risk tool, EuroSCORE II., Methods: Consecutive patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH) between 2007 and 2018 (n=1334) were included in a discovery dataset. Outcome predictors included an intentionally broad array of variables, incorporating demographic, functional and physiological measures. Three statistical models (linear regression, penalised linear regression and random forest) were considered per outcome, each calibrated, fitted and assessed using cross-validation, ensuring internal consistency. The best predictive models were incorporated into an open-source PEA risk tool and validated using a separate prospective PEA cohort from 2019 to 2021 (n=443) at the same institution., Results: Random forest models had the greatest predictive accuracy for all three outcomes. Novel risk models had acceptable discriminatory ability for outcome 90 DM (AUROC 0.82) outperforming that of EuroSCORE II (AUROC 0.65). CTEPH related factors were important for outcome 90 DM but 5 YM was driven by non-CTEPH factors, dominated by generic cardiovascular risk. We were unable to accurately predict a positive improvement in PRO status (AUROC 0.47)., Conclusions: Operative mortality from PEA can be predicted pre-operatively to a potentially clinically useful degree. Our validated models enable individualised risk stratification at clinician point-of-care to better inform shared decision making., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Pulmonary hypertension (PH) associated with chronic lung disease (CLD) is both common and underrecognised. The presence of PH in the setting of lung disease has been consistently shown to be associated with worse outcomes. Recent epidemiological studies have advanced understanding of the heterogeneity of this patient population and shown that defining both the specific type of CLD as well as the severity of PH ( i.e. deeper phenotyping) is necessary to inform natural history and prognosis. A systematic diagnostic approach to screening and confirmation of suspected PH in CLD is recommended. Numerous uncontrolled studies and one phase 3 randomised, controlled trial have suggested a benefit in treating PH in some patients with CLD, specifically those with fibrotic interstitial lung disease (ILD). However, other studies in diseases such as COPD-PH showed adverse outcomes with some therapies. Given the expanding list of approved pharmacological treatments for pulmonary arterial hypertension, developing a treatment algorithm for specific phenotypes of CLD-PH is required. This article will summarise existing data in COPD, ILD and other chronic lung diseases, and provide recommendations for classification of CLD-PH and approach to the diagnosis and management of these challenging patients., Competing Interests: Conflict of interest: O.A. Shlobin reports consultancy fees from United Therapeutics, Merck, Janssen and Aerami, payment or honoraria for lectures, presentations, manuscript writing or educational events from Ferrera and United Therapeutics, participation on a data safety monitoring board or advisory board with Janssen, and leadership roles with ACCP/Chest and World Symposium on Pulmonary Hypertension task force. Y. Adir reports consultancy fees and payment or honoraria for lectures, presentations, manuscript writing or educational events from MSD Israel and Bayer Israel, support for attending meetings from BI Israel and RAFA Israel, and participation on a data safety monitoring board or advisory board with MSD, GB and Acceleron. J.A. Barbera reports grants from Merck Sharp & Dome and Ferrer International, consultancy fees from Merck Sharp & Dome, Janssen-Cilag and Ferrer International, payment or honoraria for lectures, presentations, manuscript writing or educational events from Merck Sharp & Dome, Janssen-Cilag, Ferrer International and AOP Orphan, support for attending meetings from Merck Sharp & Dome and Janssen-Cilag, and a leadership role with the World Symposium on Pulmonary Hypertension task force. V. Cottin reports consultancy fees and payment or honoraria for lectures, presentations, or educational events from Ferrer/United Therapeutics. S. Harari reports consultancy fees from Roche-Boehringer Ingelheim, payment or honoraria for lectures, presentations, manuscript writing or educational events from Boehringer Ingelheim, participation on a data safety monitoring board or advisory board “Prise en charge pragmatique de la fibrose pulmonaire idiopathique en progression: essai randomisé PROGRESSION-IPF”, and leadership roles with the World Symposium on Pulmonary Hypertension task force, FERS of the ERS and officer of the society, and FATS of the ATS. E-M. Jutant reports consultancy fees from Chiesi, payment or honoraria for lectures, presentations, manuscript writing or educational events from Chiesi, GSK, MSD and AstraZeneca, support for attending meetings from Janssen and MSD, and a leadership role with the World Symposium on Pulmonary Hypertension task force. J. Pepke-Zaba reports grants from MSD, consultancy fees from MSD, Janssen, Gossamer and Ferrer, support for attending meetings from Janssen, and a leadership role with the World Symposium on Pulmonary Hypertension task force. H-A. Ghofrani reports consultancy fees from Gossamer Bio, Inc., Aerovate, Altavant, Bayer AG, Attgeno, Janssen/Actelion, MSD/Acceleron, Pfizer, Liquidia, Morphic and Keros, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer AG, Janssen/Actelion, Gossamer Bio, Keros and MSD/Acceleron, participation on a data safety monitoring board or advisory board with Aerovate, Altavant, Attgeno, Janssen/Actelion, Insmed, MSD/Acceleron, Pfizer and Bayer AG, and the following financial (or non-financial) interests: the author's spouse is and employee of Liquidia. R. Channick reports consultancy fees from Bayer, Merck, Gossamer, Respira and Janssen, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer and Janssen, and participation on a data safety monitoring board or advisory board with Altavant., (Copyright ©The authors 2024.)

Background: The European Chronic Thromboembolic Pulmonary Hypertension (CTEPH) registry, conducted between 2007 and 2012, reported the major impact of pulmonary endarterectomy (PEA) on the long-term survival of patients with CTEPH. Since then, 2 additional treatments for inoperable CTEPH have become available: balloon pulmonary angioplasty (BPA), and an approved oral drug therapy with the guanylate cyclase stimulator riociguat. The current registry aimed to evaluate the effect of these new therapeutic approaches in a worldwide context., Methods: Participation in this international global registry included 34 centers in 20 countries. Between February 2015 and September 2016, 1009 newly diagnosed, consecutive patients were included and followed until September 2019., Results: Overall, 605 patients (60%) underwent PEA and 185 (18%) underwent BPA; 76% of the 219 remaining patients not receiving mechanical intervention (ie, neither PEA nor BPA) were treated with pulmonary hypertension drugs. Of patients undergoing PEA and BPA, 38% and 78% also received drugs for pulmonary hypertension, respectively. Median age at diagnosis was higher in the BPA and No PEA/BPA groups than in the PEA group: 66 and 69, respectively, versus 60 years. Pulmonary vascular resistance (PVR) was similar in all groups, with an average of 643 dynes.s.cm -5 . During the observation period (>3 years; ≤5.6 years), death was reported in 7%, 11%, and 27% of patients treated by PEA and BPA, and those receiving no mechanical intervention ( P <0.001). In Kaplan-Meier analysis, 3-year survival was 94%, 92%, and 71% in the 3 groups, respectively. PEA 3-year survival improved by 5% from that observed between 2007 and 2012. There was no survival difference in patients receiving vitamin K antagonists and non-vitamin K oral anticoagulants ( P =0.756). In Cox regression, reduced mortality was associated with: PEA and BPA in the global cohort; history of venous thromboembolism and lower PVR in the PEA group; lower right atrial pressure in the BPA group; and use of pulmonary hypertension drugs, oxygen therapy, and lower right atrial pressure, as well as functional class in the group receiving no mechanical intervention., Conclusions: This second international CTEPH registry reveals important improvement in patient survival since the introduction of BPA and an approved drug for pulmonary hypertension. The type of anticoagulation regimen did not influence survival., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02656238., Competing Interests: M.D. reports research grants from Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD outside the submitted work, and all paid to her institution. She was holder of a Janssen chair for pulmonary hypertension at the KU Leuven. J.P.Z. reports research grants from MSD and consultant fees from Ferrer, Gossamer, Janssen outside submitted work. S.G. reports speaker fees or consultant honoraria from Actelion/Janssen, Bayer AG, MSD, and Pfizer. D.P.J. reports speaker fees and consultancy fees from Janssen outside this submitted work. D.G.K. reports speaker fees, consultancy fees, or funding to attend meetings from Acceleron, Altavant, Ferrer, Janssen, Gossamer, MSD and United Therapeutics and research support from Ferrer and Janssen, all outside of the submitted work. N.H.K. reports receiving speaker fees from Bayer and Janssen; consultancy fees from Bayer, Janssen, Merck, Polarean, Pulnovo, and United Therapeutics; and research support from Altavant and Gossamer Bio. All disclosed fees and support are outside the submitted work. M.M.M. reports consultancy fees and royalties from Wexler Surgical and consultancy fees from Actelion/Janssen and Johnson & Johnson. H.M. reports research grants from Nippon Shinyaku; speaker and consultant fees from Bayer, Janssen, and MSD; speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Nipro, all outside of the submitted work. J.S.O.A. reports personal fees from Bayer and MSD. R.S.K. reports having received speaker fees from AOP Health, Actelion/Janssen, and MSD, all outside of the submitted work. GS reports receiving advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. C.B.W. reports speaker fees or consultant honoraria from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer. E.M. reports receiving consultancy or speaker fees from Actelion/Janssen, Bayer, and MSD. I.M.L. has relationships with drug companies including AOP Health, Actelion/Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis, and Sanofi; in addition to being investigator in trials involving these companies, relationships include consultancy services, research grants, and membership of scientific advisory boards. The other authors report no conflicts.

Competing Interests: We declare no competing interests.

Background: SELECT was the first global randomised controlled trial of selexipag with standard of care in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension., Methods: SELECT was a multicentre, randomised, double-blind, placebo-controlled, parallel-group, group-sequential, phase 3 study (ClinicalTrials.gov: NCT03689244). Adults aged ≤85 years in World Health Organization Functional Class I-IV, with a 6-min walk distance of 100-450 m, were randomised (1:1) to receive selexipag (200-1600 µg twice daily titration until individual maximum tolerated dose)+standard of care or placebo+standard of care. Patients were recruited into the haemodynamic set (first 91 randomised patients to undergo right heart catheterisation (RHC); week 20) or non-haemodynamic cohort (remaining patients, no RHC required). The primary end-point was percent of baseline pulmonary vascular resistance (PVR; week 20). Safety was also assessed., Results: Of 321 patients screened, 128 were randomised (haemodynamic set n=91 (selexipag n=47; placebo n=44)). In the haemodynamic set, 29 (31.9%) patients had previous pulmonary endarterectomy (PEA), 20 (22.0%) balloon pulmonary angioplasty (BPA), and 14 (15.4%) both PEA and BPA; 28 (30.8%) were inoperable. The independent data monitoring committee recommended to stop the study for futility as no statistically significant difference was observed for the primary end-point (between-treatment geometric least squares mean ratio of PVR: 0.95, 95% CI 0.84-1.07; p=0.412). Adverse events were reported in 63 (98.4%) and 53 (82.8%) patients for selexipag and placebo, respectively., Conclusions: SELECT was discontinued for futility, as no treatment effect on the primary end-point (PVR) was observed. Safety data were consistent with the established safety profile of selexipag, with no new safety signals identified., Competing Interests: Conflict of interest: N.H. Kim has consulted for, received research grants from or spoken for Janssen, Bayer, Merck, United Therapeutics, Enzyvant, Gossamer Bio, Polarean and Pulnovo. R. Channick has consulted for, received research grants from or spoken for Janssen, Bayer, United Therapeutics, Respira, Third Pole, Merck, Aria CV and Gossamer. M. Delcroix reports research grants from Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics and MSD, outside the submitted work, and all paid to her institution; and is holder of a Janssen Chair for Pulmonary Hypertension at KU Leuven. M. Madani has served as a consultant and has received fees from Wexler Surgical, Janssen, Bayer and MSD. J. Pepke-Zaba reports research grants from MSD and consultant fees from Ferrer, Gossamer, Janssen, United Therapeutics and MSD. V. Easton, S. Gesang and D. Richard are employees of Johnson & Johnson and own shares in the company. J.I. Borissoff is an employee of Johnson & Johnson. H-A. Ghofrani reports consultancy fees from Gossamer Bio, Inc., Aerovate, Altavant, Bayer AG, Attgeno, Janssen/Actelion, MSD/Acceleron, Pfizer, Liquidia, Morphic and Keros, payment or honoraria for lectures, presentations, manuscript writing or educational events from Bayer AG, Janssen/Actelion, Gossamer Bio, Keros and MSD/Acceleron, participation on a data safety monitoring board or advisory board with Aerovate, Altavant, Bayer AG, Attgeno, Janssen/Actelion, Insmed, MSD/Acceleron and Pfizer; H-A. Ghofrani's spouse is an employee of Liquidia., (Copyright ©The authors 2024.)

Background: Previous studies have demonstrated the safety of pulmonary endarterectomy (PEA) across body mass index (BMI) strata. However, long-term survival and patient-reported outcome measures by BMI strata remain unknown. We examined the impact of preoperative BMI on long-term survival, QOL, and functional outcomes for patients undergoing PEA for chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: Retrospective review of 2,004 patients from the UK National Cohort between 2007 and 2021 undergoing PEA for CTEPH (mean pulmonary artery pressure >20 mm Hg and pulmonary vascular resistance >160 dynes). Patients were stratified into BMI<20, 20 to 29, 30 to 39, 40 to 49, and 50+. All-cause mortality was the primary outcome measure. Secondary outcome measures were 3- to 6-month postoperative hemodynamics, 6-minute walk distance (6MWD), New York Heart Association (NYHA) class, and Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) scores., Results: Hemodynamics and 6MWD at 3 to 6 months were similar across BMI strata. Patients with BMI 50+ reported the highest incidence of postoperative NYHA III/IV limitation (53.3%, p < 0.001) and the highest residual symptom burden by CAMPHOR (p < 0.001). Five-year survival was lowest in patients with BMI 50+ (70.2%) and BMI<20 (73.4%), while highest in BMI 30 to 39 (88.2%, p = 0.008). Ten-year Kaplan-Meier estimates predicted the lowest survival in BMI 50+ and BMI<20., Conclusions: PEA remains safe and effective for all patients regardless of BMI. Despite similar hemodynamic outcomes, patients with BMI 50+ are at the greatest risk of long-term all-cause mortality, and patients with BMI 50+ experience residual symptomatic limitation., (Copyright © 2024 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary embolism (PE) is a well-recognised complication of coronavirus disease 2019 (COVID-19) infection, and chronic thromboembolic pulmonary disease with and without pulmonary hypertension (CTEPD/CTEPH) are potential life-limiting consequences. At present the burden of CTEPD/CTEPH is unclear and optimal and cost-effective screening strategies yet to be established., Methods: We evaluated the CTEPD/CTEPH referral rate to the UK national multidisciplinary team (MDT) during the 2017-2022 period to establish the national incidence of CTEPD/CTEPH potentially attributable to COVID-19-associated PE with historical comparator years. All individual cases of suspected CTEPH were reviewed by the MDT for evidence of associated COVID-19. In a separate multicentre cohort, the risk of developing CTEPH following hospitalisation with COVID-19 was calculated using simple clinical parameters at a median of 5 months post-hospital discharge according to existing risk scores using symptoms, ECG and N-terminal pro-brain natriuretic peptide., Results: By the second year of the pandemic, CTEPH diagnoses had returned to the pre-pandemic baseline (23.1 versus 27.8 cases per month; p=0.252). Of 334 confirmed CTEPD/CTEPH cases, four (1.2%) patients were identified to have CTEPH potentially associated with COVID-19 PE, and a further three (0.9%) CTEPD without PH. Of 1094 patients (mean age 58 years, 60.4% male) hospitalised with COVID-19 screened across the UK, 11 (1.0%) were at high risk of CTEPH at follow-up, none of whom had a diagnosis of CTEPH made at the national MDT., Conclusion: A priori risk of developing CTEPH following COVID-19-related hospitalisation is low. Simple risk scoring is a potentially effective way of screening patients for further investigation., Competing Interests: Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is Chief Editor of the European Respiratory Journal. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024.)

Introduction: In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable., Methods: Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan-Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards., Results: Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46-0.91, p = 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (p < 0.0001), 6MWD improvements of + 84 m (p < 0.0001), and a reduction in NT-proBNP of - 778 pg/mL (p = 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV., Conclusion: Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains., Clinical Trial Registration: ClinicalTrials.gov identifier NCT01560637., (© 2023. The Author(s).)

Chronic thromboembolic pulmonary disease (CTEPD) is a complication of pulmonary embolism (PE). We conducted an online survey of UK PE-treating physicians to understand practices in the follow-up of PE and awareness of CTEPD. The physicians surveyed ( N = 175) included 50 each from cardiology, respiratory and internal medicine, plus 25 haematologists. Most (89%) participants had local guidelines for PE management, and 65% reported a PE follow-up clinic, of which 69% were joint clinics. Almost half (47%) had a protocol for the investigation of CTEPD. According to participants, 129 (74%) routinely consider a diagnosis of CTEPD and 97 (55%) routinely investigate for CTEPD, with 76% of those 97 participants investigating in patients who are symptomatic at 3 months and 22% investigating in all patients. This survey demonstrated variability in the follow-up of PE and the awareness of CTEPD and its investigation. The findings support the conduct of a national audit to understand the barriers to the timely detection of CTEPD.

Pulmonary arterial hypertension (PAH) is characterised by pulmonary vascular remodelling causing premature death from right heart failure. Established DNA variants influence PAH risk, but susceptibility from epigenetic changes is unknown. We addressed this through epigenome-wide association study (EWAS), testing 865,848 CpG sites for association with PAH in 429 individuals with PAH and 1226 controls. Three loci, at Cathepsin Z (CTSZ, cg04917472), Conserved oligomeric Golgi complex 6 (COG6, cg27396197), and Zinc Finger Protein 678 (ZNF678, cg03144189), reached epigenome-wide significance (p < 10 -7 ) and are hypermethylated in PAH, including in individuals with PAH at 1-year follow-up. Of 16 established PAH genes, only cg10976975 in BMP10 shows hypermethylation in PAH. Hypermethylation at CTSZ is associated with decreased blood cathepsin Z mRNA levels. Knockdown of CTSZ expression in human pulmonary artery endothelial cells increases caspase-3/7 activity (p < 10 -4 ). DNA methylation profiles are altered in PAH, exemplified by the pulmonary endothelial function modifier CTSZ, encoding protease cathepsin Z., (© 2024. The Author(s).)

Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional microvasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) with increased pulmonary arterial pressure and pulmonary vascular resistance, which, if left untreated, can lead to right heart failure and death. The pathobiology of CTEPH has been challenging to unravel due to its rarity, possible interference of results with anticoagulation, difficulty in selecting the most relevant study time point in relation to presentation with acute pulmonary embolism (PE), and lack of animal models. In this article, we review the most relevant multifaceted cross-talking pathogenic mechanisms and advances in understanding the pathobiology in CTEPH, as well as its challenges and future direction. There appears to be a genetic background affecting the relevant pathological pathways. This includes genetic associations with dysfibrinogenemia resulting in fibrinolysis resistance, defective angiogenesis affecting thrombus resolution, and inflammatory mediators driving chronic inflammation in CTEPH. However, these are not necessarily specific to CTEPH and some of the pathways are also described in acute PE or deep vein thrombosis. In addition, there is a complex interplay between angiogenic and inflammatory mediators driving thrombus non-resolution, endothelial dysfunction, and vascular remodeling. Furthermore, there are data to suggest that infection, the microbiome, circulating microparticles, and the plasma metabolome are contributing to the pathobiology of CTEPH.

Competing Interests: Competing interests: None declared.

Pulmonary endarterectomy (PEA) is the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (PH), provided lesions are proximal enough in the pulmonary vasculature to be surgically accessible and the patient is well enough to benefit from the operation in the longer term. It is a major cardiothoracic operation, requiring specialized techniques and instruments developed over several decades to access and dissect out the intra-arterial fibrotic material. While in-hospital operative mortality is low (<5%), particularly in high-volume centers, careful perioperative management in the operating theater and intensive care is mandatory to balance ventricular performance, fluid balance, ventilation, and coagulation to avoid or treat complications. Reperfusion pulmonary edema, airway hemorrhage, and right ventricular failure are the most problematic complications, often requiring the use of extracorporeal membrane oxygenation to bridge to recovery. Successful PEA has been shown to improve both morbidity and mortality in large registries, with survival >70% at 10 years. For patients not suitable for PEA or with residual PH after PEA, balloon pulmonary angioplasty and/or PH medical therapy may prove beneficial. Here, we describe the indications for PEA, specific surgical and perioperative strategies, postoperative monitoring and management, and approaches for managing residual PH in the long term., Competing Interests: D.P.J. reports Honoraria and consulting fees from Actelion J&J; membership of CTEPH executive board. J.P.-Z. receipts grants from MSD and Actelion J&J; membership of advisory board for Actelion J&J and Ferrer., (Thieme. All rights reserved.)

Background and Aims: Interventional studies in pulmonary arterial hypertension completed to date have shown to be effective in symptomatic patients with significantly elevated mean pulmonary artery pressure (mPAP) (≥25 mmHg) and pulmonary vascular resistance (PVR) > 3 Wood Unit (WU). However, in health the mPAP does not exceed 20 mmHg and PVR is 2 WU or lower, at rest. The ESC/ERS guidelines have recently been updated to reflect this. There is limited published data on the nature of these newly defined populations (mPAP 21-24 mmHg and PVR >2-≤3 WU) and the role of comorbidity in determining their natural history. With the change in guidelines, there is a need to understand this population and the impact of the ESC/ERS guidelines in greater detail., Methods: A retrospective nationwide evaluation of the role of pulmonary haemodynamics and comorbidity in predicting survival among patients referred to the UK pulmonary hypertension (PH) centres between 2009 and 2017. In total, 2929 patients were included in the study. Patients were stratified by mPAP (<21 mmHg, 21-24 mmHg, and ≥25 mmHg) and PVR (≤2 WU, > 2-≤3 WU, and >3 WU), with 968 (33.0%) in the mPAP <21 mmHg group, 689 (23.5%) in the mPAP 21-24 mmHg group, and 1272 (43.4%) in the mPAP ≥25 mmHg group., Results: Survival was negatively correlated with mPAP and PVR in the population as a whole. Survival in patients with mildly elevated mPAP (21-24 mmHg) or PVR (>2-≤3WU) was lower than among those with normal pressures (mPAP <21 mmHg) and normal PVR (PVR ≤ 2WU) independent of comorbid lung and heart disease [hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.14-1.61, P = .0004 for mPAP vs. HR 1.28, 95% CI 1.10-1.49, P = .0012 for PVR]. Among patients with mildly elevated mPAP, a mildly elevated PVR remained an independent predictor of survival when adjusted for comorbid lung and heart disease (HR 1.33, 95% CI 1.01-1.75, P = .042 vs. HR 1.4, 95% CI 1.06-1.86, P = .019). 68.2% of patients with a mPAP 21-24 mmHg had evidence of underlying heart or lung disease. Patients with mildly abnormal haemodynamics were not more symptomatic than patients with normal haemodynamics. Excluding patients with heart and lung disease, connective tissue disease was associated with a poorer survival among those with PH. In this subpopulation evaluating those with a mPAP of 21-24 mmHg, survival curves only diverged after 5 years., Conclusions: This study supports the change in diagnostic category of the ESC/ERS guidelines in a PH population. The newly included patients have an increased mortality independent of significant lung or heart disease. The majority of patients in this new category have underlying heart or lung disease rather than an isolated pulmonary vasculopathy. Mortality is higher if comorbidity is present. Rigorous phenotyping will be pivotal to determine which patients are at risk of progressive vasculopathic disease and in whom surveillance and recruitment to studies may be of benefit. This study provides an insight into the population defined by the new guidelines., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Competing Interests: JP-Z serves on advisory boards for Janssen, MSD, Gossamer, and United Therapeutics. JN declares no competing interests.

Background: We describe baseline characteristics, disease progression and mortality in chronic thromboembolic pulmonary disease patients as a function of mean pulmonary artery pressure (mPAP) according to new and previous definitions of pulmonary hypertension., Methods: All patients diagnosed with chronic thromboembolic pulmonary disease between January, 2015 and December, 2019 were dichotomized according to initial mPAP: ≤ 20 mmHg ('normal') vs 21-24 mmHg ('mildly-elevated'). Baseline features were compared between the groups, and pairwise analysis performed to determine changes in clinical endpoints at 1-year, excluding those who underwent pulmonary endarterectomy or did not attend follow-up. Mortality was assessed for the whole cohort over the entire study period., Results: One hundred thirteen patients were included; 57 had mPAP ≤ 20 mmHg and 56 had mPAP 21-24 mmHg. Normal mPAP patients had lower pulmonary vascular resistance (1.6 vs 2.5WU, p < 0.01) and right ventricular end-diastolic pressure (5.9 vs 7.8 mmHg, p < 0.01) at presentation. At 3 years, no major deterioration was seen in either group. No patients were treated with pulmonary artery vasodilators. Eight had undergone pulmonary endarterectomy. Over 37 months median follow-up, mortality was 7.0% in the normal mPAP group and 8.9% in the mildly-elevated mPAP group. Cause of death was malignancy in 62.5% of cases., Conclusions: Chronic thromboembolic pulmonary disease patients with mild pulmonary hypertension have statistically higher right ventricular end-diastolic pressure and pulmonary vascular resistance than those with mPAP ≤ 20 mmHg. Baseline characteristics were otherwise similar. Neither group displayed disease progression on non-invasive tests up to 3 years. Mortality over 37 months follow-up is 8%, and mainly attributable to malignancy. Further prospective study is required to validate these findings., (Copyright © 2023 International Society for the Heart and Lung Transplantation. All rights reserved.)

Pulmonary endarterectomy (PEA) may not achieve full clearance of vascular obstructions in patients with more distal chronic thromboembolic pulmonary hypertension (CTEPH). Balloon pulmonary angioplasty (BPA) may be indicated to treat these residual vascular lesions. We compared whether patients post-PEA (PP) treated by BPA derived similar benefit to those who had inoperable CTEPH (IC), and assessed predictors of BPA response after surgery. We treated 109 patients with BPA-89 with IC and 20 PP. Serial right heart catheterization performed at baseline (immediately before BPA) and 3 months after completing BPA, compared pulmonary vascular resistance (PVR), mean pulmonary artery pressure (mPAP) as well as change in WHO functional class and 6-minute walk distance. We also assessed the impact of total thrombus tail length (TTTL) from photographed PEA surgical specimens and PP computed tomography pulmonary angiography (CTPA)-quantified residual disease burden on BPA response. PP and IC groups did not differ significantly in terms of demographics, baseline hemodynamics or procedural characteristics. However, IC derived greater hemodynamic benefit from BPA: ΔPVR (-27.9 ± 20.2% vs. -13.9 ± 23.9%, p  < 0.05) and ΔmPAP (-17.1 ± 14.4% vs. -8.5 ± 18.0%, p  < 0.05). There was a negative correlation between pre-BPA PVR and TTTL ( r  = -0.47, p  < 0.05) which persisted post-BPA. PVR, mPAP, WHO FC and 6MWD were not improved significantly post-BPA in PP patients. BPA response was not related to TTTL terciles or CTPA-quantified residual disease burden. Patients PP experienced inferior response to BPA, despite similar baseline and procedural characteristics to IC. BPA does not abolish the relationship between TTTL and postsurgical PVR in PP patients, suggesting that BPA is less effective in treating residual PH after surgery in an experienced surgical center., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Chronic thromboembolic pulmonary hypertension occurs in a proportion of patients with prior acute pulmonary embolism and is characterised by breathlessness, persistently raised pulmonary pressures and right heart failure. Surgical pulmonary endarterectomy (PEA) offers significant prognostic and symptomatic benefits for patients with proximal disease distribution. For those with inoperable disease, management options include balloon pulmonary angioplasty (BPA) and medical therapy. Current clinical practice relies on the evaluation of pulmonary haemodynamics to assess disease severity, timing of and response to treatment. However, pulmonary haemodynamics correlate poorly with patient symptoms, which are influenced by right ventricular tolerance of the increased afterload. How best to manage symptomatic patients with chronic thromboembolic pulmonary disease (CTEPD) in the absence of pulmonary hypertension is not resolved.Right ventricular-pulmonary artery coupling (RV-PAC) describes the energy transfer within the whole cardiopulmonary unit. Thus, it can identify the earliest signs of decompensation even before pulmonary hypertension is overt. Invasive measurement of coupling using pressure volume loop technology is well established in research settings. The development of efficient and less invasive measurement methods has revived interest in coupling as a viable clinical tool. Significant improvement in RV-PAC has been demonstrated after both PEA and BPA. Further studies are required to understand its clinical utility and prognostic value, in particular, its potential to guide management in patients with CTEPD. Finally, given the reported differences in coupling between sexes in pulmonary arterial hypertension, further work is required to understand the applicability of proposed thresholds for decoupling in therapeutic decision making., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To develop a suite of quality indicators (QIs) for the evaluation of the care and outcomes for adults with pulmonary arterial hypertension (PAH)., Methods and Results: We followed the European Society of Cardiology (ESC) methodology for the development of QIs. This included (i) the identification of key domains of care for the management of PAH, (ii) the proposal of candidate QIs following systematic review of the literature, and (iii) the selection of a set of QIs using a modified Delphi method. The process was undertaken in parallel with the writing of the 2022 ESC/European Respiratory Society (ERS) guidelines for the diagnosis and treatment of pulmonary hypertension and involved the Task Force chairs, experts in PAH, Heart Failure Association (HFA) members and patient representatives. We identified five domains of care for patients with PAH: structural framework, diagnosis and risk stratification, initial treatment, follow-up, and outcomes. In total, 23 main and one secondary QIs for PAH were selected., Conclusion: This document presents the ESC QIs for PAH, describes their development process and offers scientific rationale for their selection. The indicators may be used to quantify and improve adherence to guideline-recommended clinical practice and improve patient outcomes., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Introduction: Chronic thromboembolic pulmonary hypertension (CTEPH) is an underdiagnosed disease of uncertain etiology. Altered endothelial homeostasis, defective angiogenesis and inflammation are implicated. Angiopoietin 2 (Ang2) impairs acute thrombus resolution and is associated with vasculopathy in idiopathic pulmonary arterial hypertension., Methods: We assessed circulating proteins associated with these processes in serum from patients with CTEPH (n = 71) before and after pulmonary endarterectomy (PEA), chronic thromboembolic pulmonary disease without pulmonary hypertension (CTEPD, n = 9) and healthy controls (n = 20) using Luminex multiplex arrays. Comparisons between groups were made using multivariable rank regression models. Ang2 and high-sensitivity C-reactive protein (hsCRP) were measured in a larger validation dataset (CTEPH = 277, CTEPD = 26). Cox proportional hazards models were used to identify markers predictive of survival., Results: In CTEPH patients, Ang2, interleukin (IL) 8, tumor necrosis factor α, and hsCRP were elevated compared to controls, while vascular endothelial growth factor (VEGF) c was lower (p < 0.05). Ang2 fell post-PEA (p < 0.05) and was associated with both pre- and post-PEA pulmonary hemodynamic variables and functional assessments (p < 0.05). In the validation dataset, Ang2 was significantly higher in CTEPH compared to CTEPD. Pre-operative hsCRP was an independent predictor of mortality., Conclusions: We hypothesize that CTEPH patients have significant distal micro-vasculopathy and consequently high circulating Ang2. Patients with CTEPD without pulmonary hypertension have no discernible distal micro-vasculopathy and therefore have low circulating Ang2. This suggests Ang2 may be critical to CTEPH disease pathogenesis (impaired thrombus organization and disease severity)., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by chronic organised fibrotic clots, despite adequate anticoagulation. The pulmonary hypertension is also caused by concomitant microvasculopathy which may progress without timely treatment. Timely and accurate diagnosis requires the combination of imaging and haemodynamic assessment. Optimal therapy should be individualised to each case and determined by an experienced multidisciplinary CTEPH team with the ability to offer all current treatment modalities. This report summarises current knowledge and presents key messages from the International CTEPH Conference, Bad Nauheim, Germany, 2021. Sessions were dedicated to 1) disease definition; 2) pathophysiology, including the impact of the hypertrophied bronchial circulation, right ventricle (dys)function, genetics and inflammation; 3) diagnosis, early after acute pulmonary embolism, using computed tomography and perfusion techniques, and supporting the selection of appropriate therapies; 4) surgical treatment, pulmonary endarterectomy for proximal and distal disease, and peri-operative management; 5) percutaneous approach or balloon pulmonary angioplasty, techniques and complications; and 6) medical treatment, including anticoagulation and pulmonary hypertension drugs, and in combination with interventional treatments. Chronic thromboembolic pulmonary disease without pulmonary hypertension is also discussed in terms of its diagnostic and therapeutic aspects., Competing Interests: Conflict of interest: E. Fadel, G. Martinez, G. Simonneau, K. Salaunkey, N. Screaton and P. Brénot have no conflicts of interest to declare. A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012–08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610); his institute received speakers fees from Johnson & Johnson, MSD, Actelion, Bayer and Ferrer in the past 3 years; and he served as a member of the scientific advisory boards of Morphogen-X, Ferrer, Gossamer Bio Services Inc. and Johnson & Johnson. C.B. Wiedenroth has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD and Pfizer. D.P. Jenkins is on the adjudication committees for the SELECT and Maciteph studies (Actelion), and has received fees for lectures on CTEPH from Actelion. E. Mayer has received speaker or consulting fees from Actelion/Janssen, Bayer and MSD. F.A. Klok has received research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Leo Pharma, Actelion, the Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, the Dutch Heart Foundation and the Horizon Europe Program, unrelated to the current work and paid to his institution. H.A. Ghofrani has received grants/research support from Actelion, Janssen, Bayer, Gossamer, Acceleron; honoraria or consultation fees from Actelion, Janssen, Bayer, Gossamer, Acceleron, Pfizer, Novartis and MSD; and participated in a company sponsored speaker's bureau for Actelion, Janssen, Bayer, Gossamer, Pfizer, Novartis and MSD. H. Matsubara has received honoraria for lectures from Janssen Pharmaceutical KK, Bayer Yakuhin Ltd, Nippon Shinyaku Co Ltd, Mochida Pharmaceutical Co. Ltd and Kaneka Medix Corporation. I.M. Lang has a financial interest with Actelion/Janssen, AOP Orphan, Medtronic, Daiichi Sankyo, Neutrolis, United Therapeutics and Ferrer that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. J. Pepke-Zaba has received speaker or consulting fees from Actelion/Janssen, Bayer, MSD and Ferrer, and a research grant from MSD, all outside submitted work. M.C. McInnis reports honoraria from Bayer and Boehringer Ingelheim, unrelated to the current work. M. Delcroix reports research grants from Actelion/Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Daiichi Sankyo, Bayer, Ferrer, Gossamer and MSD, outside the submitted work, and all paid to her institution. She is holder of the Janssen Chair for Pulmonary Hypertension at KU Leuven. M.M. Hoeper reports fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. M.M. Madani is a consultant for Actelion. M. Toshner reports grants and personal fees from Bayer, personal fees from MSD, grants and personal fees from Actelion, and personal fees from GSK within the last 5 years. N.H. Kim has served as consultant for Bayer, Janssen, Merck and United Therapeutics. S. Guth has received speaker fees and/or consultant honoraria from Actelion, Bayer, GSK, MSD and Pfizer. X. Jaïs reports grants from the French Ministry of Health and Bayer Healthcare, during the conduct of the study; grants from Acceleron, Janssen and MSD; personal fees from Janssen and MSD; and non-financial support from Janssen., (Copyright ©The authors 2023.)

Rationale: Despite the increased recognition of TBX4 (T-BOX transcription factor 4)-associated pulmonary arterial hypertension (PAH), genotype-phenotype associations are lacking and may provide important insights. Objectives: To compile and functionally characterize all TBX4 variants reported to date and undertake a comprehensive genotype-phenotype analysis. Methods: We assembled a multicenter cohort of 137 patients harboring monoallelic TBX4 variants and assessed the pathogenicity of missense variation ( n  = 42) using a novel luciferase reporter assay containing T-BOX binding motifs. We sought genotype-phenotype correlations and undertook a comparative analysis with patients with PAH with BMPR2 (Bone Morphogenetic Protein Receptor type 2) causal variants ( n  = 162) or no identified variants in PAH-associated genes ( n  = 741) genotyped via the National Institute for Health Research BioResource-Rare Diseases. Measurements and Main Results: Functional assessment of TBX4 missense variants led to the novel finding of gain-of-function effects associated with older age at diagnosis of lung disease compared with loss-of-function effects ( P  = 0.038). Variants located in the T-BOX and nuclear localization domains were associated with earlier presentation ( P  = 0.005) and increased incidence of interstitial lung disease ( P  = 0.003). Event-free survival (death or transplantation) was shorter in the T-BOX group ( P  = 0.022), although age had a significant effect in the hazard model ( P  = 0.0461). Carriers of TBX4 variants were diagnosed at a younger age ( P  < 0.001) and had worse baseline lung function (FEV 1 , FVC) ( P  = 0.009) than the BMPR2 and no identified causal variant groups. Conclusions: We demonstrated that TBX4 syndrome is not strictly the result of haploinsufficiency but can also be caused by gain of function. The pleiotropic effects of TBX4 in lung disease may be in part explained by the differential effect of pathogenic mutations located in critical protein domains.