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RATIONALE: Activin A receptor type II-like kinase-1 (ACVRL1, also known as ALK1) mutation is a cause of hereditary hemorrhagic telangiectasia (HHT) and/or heritable pulmonary arterial hypertension (PAH). OBJECTIVES: To describe the characteristics of patients with PAH carrying an ACVRL1 mutation. METHODS: We reviewed clinical, functional, and hemodynamic characteristics of 32 patients with PAH carrying an ACVRL1 mutation, corresponding to 9 patients from the French PAH Network and 23 from literature analysis. These cases were compared with 370 patients from the French PAH Network (93 with a bone morphogenetic protein receptor type 2 [BMPR2] mutation and 277 considered as idiopathic cases without identified mutation). Distribution of mutations in the ACVRL1 gene in patients with PAH was compared with the HHT Mutation Database. MEASUREMENTS AND MAIN RESULTS: At diagnosis, ACVRL1 mutation carriers were significantly younger (21.8 +/- 16.7 yr) than BMPR2 mutation carriers and noncarriers (35.7 +/- 14.9 and 47.6 +/- 16.3 yr, respectively; P < 0.0001). In seven of the nine patients from the French PAH Network, PAH diagnosis preceded manifestations of HHT. ACVRL1 mutation carriers had better hemodynamic status at diagnosis, but none responded to acute vasodilator challenge and they had shorter survival when compared with other patients with PAH despite similar use of specific therapies. ACVRL1 mutations in exon 10 were more frequently observed in patients with PAH, as compared with what was observed in the HHT Mutation Database (33.3 vs. 5%; P < 0.0001). CONCLUSIONS: ACVRL1 mutation carriers were characterized by a younger age at PAH diagnosis. Despite less severe initial hemodynamics and similar management, these patients had worse prognosis compared with other patients with PAH, suggesting more rapid disease progression. [ABSTRACT FROM AUTHOR]

RATIONALE: Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and pulmonary vascular resistance in the setting of portal hypertension. Survival results in PoPH are contrasting, and prognostic factors need to be identified. OBJECTIVES: To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival. METHODS: We retrospectively analyzed charts of all patients referred to the French Referral Center for pulmonary arterial hypertension with the diagnosis of PoPH between 1984 and 2004. MEASUREMENTS AND MAIN RESULTS: The study population comprised 154 patients; 57% male. Mean age at diagnosis was 49 +/- 11 years, 60% of patients were in New York Heart Association functional class III-IV, and mean 6-minute walk distance was 326 +/- 116 m. Hemodynamic measurements showed a mean pulmonary arterial pressure of 53 +/- 13 mm Hg, cardiac index of 2.9 +/- 0.9 L/min/m(2), and pulmonary vascular resistance of 752 +/- 377 dyn/s/cm(5). Portal hypertension was related to cirrhosis in 136 patients, with a severity assessed as follows: Child-Pugh class A 51%, Child-Pugh class B 38%, Child-Pugh class C 11%. Overall survival rates at 1, 3, and 5 yr were 88, 75, and 68%, respectively. Multivariate regression analysis individualized the presence and severity of cirrhosis and cardiac index as major independent prognostic factors. CONCLUSIONS: Prognosis in PoPH is mainly related to the presence and severity of cirrhosis and to cardiac function. The place of pulmonary arterial hypertension-specific therapies remains to be determined in the setting of PoPH. [ABSTRACT FROM AUTHOR]

Introduction: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are life-threatening conditions that can progress to death without treatment. Although strong medication adherence (MA) is known to enhance outcomes in chronic illnesses, its association with PAH and CTEPH was sporadically explored. This study aims to examine the MA of patients with PAH or CTEPH, identify factors associated with low adherence and explore the resulting outcomes., Methods: A systematic review was conducted by searching multiple databases (Medline, Embase, Cochrane Central, ClinicalTrials.gov, Scopus, Web of Science and Google Scholar) from 6 March 1998 to 6 July 2023. We included studies reporting MA as primary or secondary end-points. Study selection, data extraction and methodological quality assessment were performed in duplicate., Results: 20 studies involving 22 675 patients met the inclusion criteria. Heterogeneity was observed, particularly in the methods employed. MA means ranged from 0.62 to 0.96, with the proportion of patients exhibiting high MA varying from 40% (95% CI 35-45%) to 94% (95% CI 88-97%). Factors associated with low adherence included increased treatment frequency, time since diagnosis and co-payment. High MA seems to be associated with reduced hospitalisation rates, inpatient stays, outpatient visits and healthcare costs., Conclusions: This systematic review underscores the heterogeneity of MA across studies. Nevertheless, the findings suggest that high MA could improve patients' clinical outcomes and alleviate the economic burden. Identifying factors consistently associated with poor MA could strengthen educational efforts for these patients, ultimately contributing to improved outcomes., Competing Interests: Conflict of interest: A. Le Bozec, V. Korb-Savoldelli, C. Boiteau, M-C. Chaumais, C. Guignabert, A. Dechartres and S. Al Kahf have nothing to disclose. O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, and grants from GlaxoSmithKline. D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD. X. Jaïs reports grants and personal fees from Actelion and MSD, and grants from Bayer, outside the submitted work. M. Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, United Therapeutics and Acceleron. L. Savale reports grants, personal fees and non-financial support from Actelion and GSK, and personal fees and non-financial support from MSD and Bayer., (Copyright ©The authors 2024.)

Introduction: Pulmonary veno-occlusive disease (PVOD) is a rare and severe subtype of pulmonary arterial hypertension (PAH). Although European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines advise assessing PAH severity at baseline and during follow-up, no existing risk assessment methods have been validated for PVOD. This study aimed to identify prognostic factors, examine the impact of treatment strategies and evaluate risk assessment methods for PVOD patients., Methods: The study analysed all incident PVOD patients included in the French Pulmonary Hypertension Registry between 2006 and 2021. Survival was assessed based on initial treatment strategy and risk status and compared to a matched (age, sex, pulmonary vascular resistance) PAH group. Six risk assessment methods (number of four low-risk and three noninvasive low-risk variables, ESC/ERS guidelines three-strata and four-strata models, REVEAL 2.0 and Lite 2) were applied at baseline and early follow-up, and their accuracy was compared using Harrell's c-statistic., Results: Among the 327 included PVOD patients, survival rates at 1, 3 and 5 years were 86%, 50% and 27%, respectively. Multivariate analysis showed that only 6-min walk distance was associated with survival, with no significant difference based on initial treatment strategy. All six risk assessment methods could discriminate mortality risk, and the ESC/ERS four-strata model was the most accurate at both baseline and follow-up (C-index 0.64 and 0.74). PVOD survival rates were consistently lower than PAH when comparing baseline risk status using the ESC/ERS four-strata model., Conclusion: PVOD is associated with poor outcomes, and initial treatment strategies do not significantly affect survival. Risk assessment methods can be useful in predicting survival for PVOD patients., Competing Interests: Conflict of interest: A. Boucly reports grants or contracts from Acceleron, Janssen and MSD, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen, Merck, AOP Orphan and Ferrer, outside the submitted work; support for attending meetings and/or travel from Janssen and MSD, outside the submitted work. Conflict of interest: X. Jaïs reports grants or contracts from Acceleron, Janssen, MSD and Bayer HealthCare, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen, and MSD, outside the submitted work. Conflict of interest: M. Jevnikar reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen, outside the submitted work. Conflict of interest: A. Bourdin reports grants or contracts from AstraZeneca and Boehringer Ingelheim, outside the submitted work; consulting fees from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boeringher Ingelheim and Chiesi, outside the submitted work; support for attending meetings and/or travel from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, outside the submitted work; and participation on a data safety monitoring or advisory board for AB Science, outside the submitted work. Conflict of interest: A. Chaouat reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from GSK, MSD and Chiesi, outside the submitted work; and support for attending meetings and/or travel from Janssen and AstraZeneca, outside the submitted work. Conflict of interest: V. Cottin reports consulting fees from Ferrer/United Therapeutics, outside the submitted work; payment for lectures and consulting from Ferrer/United Therapeutics, outside the submitted work; participation on data and safety monitoring board for Galapagos, Galecto and GSK, outside the submitted work; and adjudication committee for Fibrogen, outside the submitted work. Conflict of interest: L. Bertoletti reports grant to the institution for research studies from MSD and Bayer, outside the submitted work; consulting fees from MSD, outside the submitted work; payments for honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from MSD, BMS/Pfizer, LEO-Pharma and Viatris, outside the submitted work; support for attending meetings and/or travel from Johnson and Johnson, BMS/Pfizer, and LEO-Pharma, outside the submitted work; participation on a data safety monitoring or advisory board for Bayer, outside the submitted work; receipt of medical writing services from BMS/Pfizer, outside the submitted work. Conflict of interest: L. Savale reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen, outside the submitted work; support for attending meetings and/or travel from Merck, outside the submitted work; and participation on a data safety monitoring or advisory board for Janssen, outside the submitted work. Conflict of interest: M. Humbert reports grants or contracts from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti, outside the submitted work; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti, Tiakis and United Therapeutics, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Janssen and Merck, outside the submitted work; and participation on a data safety monitoring or advisory board for Acceleron, Altavant, Janssen, Merck, and United Therapeutics, outside the submitted work. Conflict of interest: O. Sitbon reports grants or contracts from Acceleron (now MSD), AOP Orphan, Janssen (formerly Actelion) and MSD, outside the submitted work; consulting fees from Acceleron (now MSD), Altavant (now Enzyvant), AOP Orphan, Ferrer, Gossamer Bio, Janssen (formerly Actelion) and MSD, outside the submitted work; honoraria for speaking at conferences from AOP Orphan, Janssen (formerly Actelion), Ferrer and MSD, outside the submitted work; and honoraria received for Trial Steering Committee membership (topic: pulmonary hypertension) from Altavant (now Enzyvant), Gossamer Bio and Janssen (formerly Actelion), outside the submitted work. Conflict of interest: D. Montani reports grants or contracts from Acceleron, Janssen and Merck MSD, outside the submitted work; consulting fees from Acceleron, Janssen, Merck MSD and Ferrer, outside the submitted work; and payment or honoraria for speakers’ bureaus from Bayer, Janssen, Boehringer, Chiesi, GSK, Ferrer and Merck MSD, outside the submitted work., (Copyright ©The authors 2024.)

Aims: We aim to evaluate the clinical relevance and the prognostic value of arterial and venous renal Doppler in acute decompensated precapillary pulmonary hypertension (PH)., Methods and Results: The renal resistance index (RRI) and the Doppler-derived renal venous stasis index (RVSI) were monitored at admission and on Day 3 in a prospective cohort of precapillary PH patients managed in intensive care unit for acute right heart failure (RHF). The primary composite endpoint included death, circulatory assistance, urgent transplantation, or rehospitalization for acute RHF within 90 days following inclusion. Ninety-one patients were enrolled (58% female, age 58 ± 16 years). The primary endpoint event occurred in 32 patients (33%). In univariate logistic regression analysis, variables associated with RRI higher than the median value were non-variable parameters (age and history of hypertension), congestion (right atrial pressure and renal pulse pressure), cardiac function [tricuspid annular plane systolic excursion (TAPSE) and left ventricular outflow tract- velocity time integral], systemic pressures and NT-proBNP. Variables associated with RVSI higher than the median value were congestion (high central venous pressure, right atrial pressure, and renal pulse pressure), right cardiac function (TAPSE), severe tricuspid regurgitation, and systemic pressures. Inotropic support was more frequently required in patients with high RRI (P = 0.01) or high RVSI (P = 0.003) at the time of admission. At Day 3, a RRI value <0.9 was associated with a better prognosis after adjusting to the estimated glomerular filtration rate., Conclusion: Renal Doppler provides additional information to assess the severity of patients admitted to the intensive care unit for acute decompensated precapillary PH., Competing Interests: Conflict of interest: Over the last 3 years, J. Pichon declares no conflicts of interest. A. Roche declares no conflicts of interest. C. Fauvel reports grants or contracts from Pfizer and Novartis, consulting fees from Janssen and Payment or honoraria for lectures from Pfizer outside the submitted work. A. Boucly reports grants or contracts from Acceleron, Janssen, and MSD and Payment or honoraria for lectures from Janssen, Merck, and AOP Orphan outside the submitted work. O. Mercier reports grants or contracts from Edwards Lifescience, and consulting fees from MSD outside the submitted work. N. Ebstein declares no conflicts of interest. A. Beurnier declares no conflicts of interest. J. Cortese declares no conflicts of interest. M. Jevnikar declares no conflicts of interest. X. Jais declares grants or contracts from Acceleron, Janssen, Bayer, Merck, and payment or honoraria for lectures from Janssen and Merck outside the submitted work. M. Fartoukh reports grants or contracts from Funding: Fondation du Souffle (Profil COV), Funding: Fondation de l’AP-HP (Multicov trial), BioMérieux, and Payment or honoraria for lectures from Fisher & Paykel, BioMérieux, and Other financial or non-financial interests forme Pfizer outside the submitted work. E. Fadel declares no conflicts of interest. O. Sitbon reports honoraria for speaking, steering committees, and scientific advisory boards from Janssen, Bayer, Merck, Gossamer Bio, Ferrer, and United Therapeutics. D. Montani reports grants and personal fees from Acceleron, Janssen, Merck, and consulting fees from Accelron, Merck, Janssen, and payment or honoraria for lectures from Bayer, Janssen, and Merck outside the submitted work. G. Voiriot declares no conflicts of interest. M. Humbert reports grants and personal fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, and United Therapeutics and payment or honoraria from Janssen and Merck outside the submitted work. L. Savale reports personal fees from Janssen and Janssen and MSD outside the submitted work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Rationale: Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (MF). Objectives: To describe characteristics and outcomes of MPN-associated PH. Methods: We report clinical, functional, and hemodynamic characteristics, classification, and outcomes of patients with PV, ET, or primary MF in the French PH registry. Measurements and Main Results: Ninety patients with MPN (42 PV, 35 ET, 13 primary MF) presented with precapillary PH with severe hemodynamic impairment, with a median mean pulmonary arterial pressure and pulmonary vascular resistance of 42 mm Hg and 6.7 Wood units, respectively, and impaired clinical conditions, with 71% in New York Heart Association functional classes III/IV and having a median 6-minute-walk distance of 310 m. Half of the patients were diagnosed with chronic thromboembolic PH (CTEPH); the other half were considered to have group 5 PH. MF was preferentially associated with group 5 PH, whereas PV and ET were generally related to CTEPH. Proximal lesions were diagnosed in half of the patients with CTEPH. Thromboendarterectomy was performed in 18 selected patients with high risk of complications (5 early deaths). Overall survival at 1, 3, and 5 years was 67%, 50%, and 34% in group 5 PH and 81%, 66%, and 42% in CTEPH, respectively. Conclusions: PH is a life-threatening condition potentially occurring in MPN. There are multiple mechanisms, with equal diagnoses of CTEPH and group 5 PH. Physicians should be aware that PH strongly affects the burden of patients with MPN, especially in group 5 PH, with unknown pathophysiological mechanisms.

Background: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers., Methods: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues., Results: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P =0.037 and 1.263 [95% CI, 1.049-1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P =0.001 and 1.365 [95% CI, 1.185-1.573]; P <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P =0.009) and 0.17 (95% CI, 0.06-0.45; P <0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P =0.019) and 0.27 (95% CI, 0.09-0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin., Conclusions: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH., Competing Interests: Disclosures An academic patent application for these biomarkers has been filed. During the past 3 years, Dr Humbert reports grants and personal fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX and United Therapeutics, outside the submitted work. Dr Guignabert reports grants from Acceleron, Corteria, Structure therapeutics (ex ShouTi), and Janssen and grants and personal fees from Merck, outside the submitted work. Dr Howard reports honoraria for scientific advisory board from Acceleron (not related to the work). Dr Sitbon reports honoraria for speaking, steering committees, scientific advisory boards from Janssen, Bayer, Merck, Gossamer Bio, Ferrer, United Therapeutics. Dr Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work.

Background: Dyspnoea is a common persistent symptom after COVID-19. Whether it is associated with functional respiratory disorders remains unclear., Methods: We assessed the proportion and characteristics of patients with "functional respiratory complaints" (FRCs) (as defined by Nijmegen Questionnaire >22) among 177 post-COVID-19 individuals who benefited from outclinic evaluation in the COMEBAC study ( i.e. , symptomatic and/or intensive care unit (ICU) survivors at 4 months). In a distinct explanatory cohort of 21 consecutive individuals with unexplained post-COVID-19 dyspnoea after routine tests, we also analysed the physiological responses to incremental cardiopulmonary exercise testing (CPET)., Findings: In the COMEBAC cohort, 37 patients had significant FRCs (20.9%, IC95: 14.9-26.9). The prevalence of FRCs ranged from 7.2% (ICU patients) to 37.5% (non-ICU patients). The presence of FRCs was significantly associated with more severe dyspnoea, lower 6-min walk distance, more frequent psychological and neurological symptoms (cognitive complaint, anxiety, depression, insomnia and post-traumatic stress disorders) and poorer quality of life (all p<0.01). In the explanatory cohort, seven out of 21 patients had significant FRCs. Based on CPET, dysfunctional breathing was identified in 12 out of 21 patients, five out of 21 had normal CPET, three out of 21 had deconditioning and one out of 21 had evidence of uncontrolled cardiovascular disease., Interpretation: FRCs are common during post-COVID-19 follow-up, especially among patients with unexplained dyspnoea. Diagnosis of dysfunctional breathing should be considered in those cases., Competing Interests: Conflict of interest: A. Beurnier reports personal fees from Sanofi and AstraZeneca, outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Janssen and MSD, and grants, personal fees and nonfinancial support from GSK, outside the submitted work. Conflict of interest: X. Jaïs reports grants and personal fees from Janssen, grants and personal fees from MSD, and grants from Bayer and GSK, outside the submitted work. Conflict of interest: T. Gille reports personal fees from Roche SAS, and other support from Oxyvie (oxygen provider), Vivisol France (oxygen provider) and Menarini France, outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, AOP Orphan, Janssen, GSK and MSD; consulting fees from Altavant, Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; and participation on advisory boards for Acceleron, Altavant, Gossamer Bio, Janssen, MSD and Ferrer, all outside the submitted work. Conflict of interest: Marc Humbert reports grants from Acceleron, AOP Orphan, Janssen, Merck and Shou Ti; consulting fees from Acceleron, Aerovate, Altavant, AOP Orphan, Bayer, Chiesi, Ferrer, Janssen, Merck, MorphogenIX, Shou Ti and United Therapeutics; lecture honoraria from Janssen and Merck; and advisory board participation for Acceleron, Altavant, Janssen, Merck and United Therapeutics, all outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; and lecture honoraria from Bayer, Janssen and Merck, all outside the submitted work. Conflict of interest: All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH., Methods: This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients., Results: Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort., Conclusion: The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options., Competing Interests: Conflict of interest: A. Boucly reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and Merck, and travel support from Janssen, outside the submitted work. C. Guignabert reports grants from Acceleron, Janssen, Merck and ShouTi, and lecture honoraria from Merck, outside the submitted work. C. Rhodes reports support for the present manuscript from BHF fellowship (FS/15/59/31839), Academy of Medical Sciences Springboard fellowship (SBF004\1095); consulting fees from United Therapeutics and Janssen, travel support from United Therapeutics, a patent submitted for prognostic protein model from Imperial Innovations, and advisory board participation with United Therapeutics and Janssen, outside the submitted work. P. De Groote reports consulting fees and lecture honoraria from Janssen, outside the submitted work. G. Prévot reports lecture honoraria from Boehringer Ingelheim, Sanofi and Jansen, and travel support from Boehringer Ingelheim, outside the submitted work. E. Bergot reports lecture honoraria and travel support from Janssen, Actelion and GSK, outside the submitted work. A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim, consulting fees, lecture honoraria and travel support from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, and advisory board participation with AB Science; outside the submitted work. A. Beurnier reports lecture honoraria and travel support from Sanofi, outside the submitted work. X. Jaïs reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and MSD, and travel support from Janssen, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck, consulting fees from Acceleron, and lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. M.R. Wilkins reports support for the current manuscript from the British Heart Foundation and National Institute for Health Research; outside the submitted work, consulting fees from MorphogenIX, Actelion and Novartis, a patent under consideration on “Biomarker panel for pulmonary hypertension based on blood biomarkers”, and participation on advisory boards with Acceleron and GSK. M. Humbert reports support for the current manuscript from Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC EFORT) and ANR-15-RHUS-0002 (RHU BIOART-LUNG 2020); outside the submitted work, grants and consulting fees from Acceleron, Janssen and Merck, lecture honoraria from Janssen and Merck, and advisory board participation for Acceleron, Janssen, Merck and United Therapeutics. O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD, consulting fees from Gossamer Bio, Janssen and MSD, lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD, and advisory board participation for Acceleron, Janssen, MSD and Ferrer, outside the submitted work. L. Savale reports grants from Acceleron, Janssen and Merck, and lecture honoraria from GSK and Janssen, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

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.)

Background: The phenotype of pulmonary arterial hypertension (PAH) patients carrying SOX17 pathogenic variants remains mostly unknown., Methods: We report the genetic analysis findings, characteristics and outcomes of patients with heritable PAH carrying SOX17 variants from the French Pulmonary Hypertension Network., Results: 20 patients and eight unaffected relatives were identified. The median (range) age at diagnosis was 17 (2-53) years, with a female:male ratio of 1.5. At diagnosis, most of the patients (74%) were in New York Heart Association Functional Class III or IV with severe haemodynamic compromise, including a median pulmonary vascular resistance of 14.0 (4.2-31.5) WU. An associated congenital heart disease (CHD) was found in seven PAH patients (35%). Patients with CHD-associated PAH were significantly younger at diagnosis than PAH patients without CHD. Four patients (20%) suffered from recurrent haemoptysis requiring repeated arterial embolisations. 13 out of 16 patients (81%) for whom imaging was available displayed chest computed tomography abnormalities, including dilated, tortuous pulmonary vessels, ground-glass opacities as well as anomalies of the bronchial and nonbronchial arteries. After a median (range) follow-up of 47 (1-591) months, 10 patients underwent lung transplantation and one patient benefited from a heart-lung transplantation due to associated CHD. Histopathological analysis of lung explants showed a congested lung architecture with severe pulmonary arterial remodelling, subpleural vessel dilation and numerous haemorrhagic foci., Conclusions: PAH due to SOX17 pathogenic variants is a severe phenotype, frequently associated with CHD, haemoptysis and radiological abnormalities. Pathological assessment reveals severe pulmonary arterial remodelling and malformations affecting pulmonary vessels and thoracic systemic arteries., Competing Interests: Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. A. Boucly reports grants from Acceleron, Janssen and MSD; lecture honoraria from Janssen and Merck; travel support from Janssen; outside the submitted work. D. Bonnet reports grants and consulting fees from Janssen and Novartis; participation on an advisory board for Lupin; outside the submitted work. M. Humbert reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron, Janssen, Merck, Altavant, MorphogenIX and Bayer; lecture honoraria from Janssen and Merck; participation on advisory boards for Acceleron, Janssen, Merck and United Therapeutics; outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2022.)

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening complication of a pulmonary embolism (PE) whose incidence and predictors are not precisely determined., Objective: To determine the frequency and predictors for CTEPH after a first unprovoked PE., Patients/methods: In a randomized trial comparing an additional 18-month warfarin versus placebo in patients after a first unprovoked PE initially treated with vitamin K antagonist for 6 months, we applied recommended CTEPH screening strategies through an 8-year follow-up to determine cumulative incidence of CTEPH. CTEPH predictors were estimated using Cox models. Pulmonary vascular obstruction (PVO) and systolic pulmonary arterial pressure (sPAP) at PE diagnosis and 6 months were studied by receiver operating curves analysis. All CTEPH cases and whether they were incident or prevalent were adjudicated., Results: During a median follow-up of 8.7 years, nine CTEPH cases were diagnosed among 371 patients, with a cumulative incidence of 2.8% (95% confidence interval [CI] 0.95-4.64), and of 1.31% (95% CI 0.01-2.60) after exclusion of five cases adjudicated as prevalent. At PE diagnosis, PVO > 45% and sPAP > 56 mmHg were associated with CTEPH with a hazard ratio (HR) of 33.00 (95% CI 1.64-667.00, p = .02) and 12.50 (95% CI 2.10-74.80, p < .01), respectively. Age > 65 years, lupus anticoagulant antibodies and non-O blood groups were also predictive of CTEPH. PVO > 14% and sPAP > 34 mmHg at 6 months were associated with CTEPH (HR 63.90 [95% CI 3.11-1310.00, p < .01]and HR 17.2 [95% CI 2.75-108, p < .01])., Conclusion: After a first unprovoked PE, CTEPH cumulative incidence was 2.8% during an 8-year follow-up. PVO and sPAP at PE diagnosis and at 6 months were the main predictors for CTEPH diagnosis., (© 2022 International Society on Thrombosis and Haemostasis.)

Rationale: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with pulmonary endothelial dysfunction. There are limited data available on the outcomes of coronavirus disease (COVID-19) in patients with pulmonary hypertension (PH), a disease characterized by pulmonary endothelial dysfunction. Objectives: To describe characteristics and outcomes of patients with precapillary PH and COVID-19. Methods: We prospectively collected characteristics, management, and outcomes of adult patients with precapillary PH in the French PH network who had COVID-19 between February 1, 2020, and April 30, 2021. Clinical, functional, and hemodynamic characteristics of PH before COVID-19 were collected from the French PH registry. Measurements and Main Results: A total of 211 patients with PH (including 123 with pulmonary arterial hypertension, 47 with chronic thromboembolic PH, and 41 with other types of PH) experienced COVID-19, and 40.3% of them were outpatients, 32.2% were hospitalized in a conventional ward, and 27.5% were in an ICU. Among hospitalized patients ( n  = 126), 54.0% received corticosteroids, 37.3% high-flow oxygen, and 11.1% invasive ventilation. Right ventricular and acute renal failure occurred in 30.2% and 19.8% of patients, respectively. Fifty-two patients (all hospitalized) died from COVID-19. Overall mortality was 24.6% (95% CI [confidence interval], 18.8-30.5) and in-hospital mortality 41.3% (95% CI, 32.7-49.9). Nonsurvivors were significantly older, more frequently male and suffering comorbidities (diabetes, chronic respiratory diseases, systemic hypertension, chronic cardiac diseases, and/or chronic renal failure), and had more severe PH at their most recent evaluation preceding COVID-19 diagnosis (in terms of functional class and 6-minute-walk distance; all P  < 0.05). Use of pulmonary arterial hypertension therapy was similar between survivors and nonsurvivors. Conclusions: COVID-19 in patients with precapillary PH was associated with a high in-hospital mortality. The typical risk factors for severe COVID-19 and severity of PH were associated with mortality in this population.

Introduction: Contemporary risk assessment tools categorise patients with pulmonary arterial hypertension (PAH) as low, intermediate or high risk. A minority of patients achieve low risk status with most remaining intermediate risk. Our aim was to validate a four-stratum risk assessment approach categorising patients as low, intermediate-low, intermediate-high or high risk, as proposed by the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) investigators., Methods: We evaluated incident patients from the French PAH Registry and applied a four-stratum risk method at baseline and at first reassessment. We applied refined cut-points for three variables: World Health Organization functional class, 6-min walk distance and N-terminal pro-brain natriuretic peptide. We used Kaplan-Meier survival analyses and Cox proportional hazards regression to assess survival according to three-stratum and four-stratum risk approaches., Results: At baseline (n=2879), the four-stratum approach identified four distinct risk groups and performed slightly better than a three-stratum method for predicting mortality. Four-stratum model discrimination was significantly higher than the three-stratum method when applied during follow-up and refined risk categories among subgroups with idiopathic PAH, connective tissue disease-associated PAH, congenital heart disease and portopulmonary hypertension. Using the four-stratum approach, 53% of patients changed risk category from baseline compared to 39% of patients when applying the three-stratum approach. Those who achieved or maintained a low risk status had the best survival, whereas there were more nuanced differences in survival for patients who were intermediate-low and intermediate-high risk., Conclusions: The four-stratum risk assessment method refined risk prediction, especially within the intermediate risk category of patients, performed better at predicting survival and was more sensitive to change than the three-stratum approach., Competing Interests: Conflict of interest: A. Boucly reports personal fees from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc., grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, outside the submitted work. Conflict of interest: L. Savale reports personal fees from Actelion, personal fees from MSD, grants and personal fees from GSK, outside the submitted work. Conflict of interest: P. de Groote reports consulting fees from Actelion, Janssen, MSD, Novartis, Servier, Boehringer Ingelheim, Abbott, Boston, AstraZeneca, Bayer; lecture honoraria from Abbott, Vifor, MSD, Servier, Novartis, AstraZeneca, Actelion, Janssen, Medtronic; outside the submitted work. Conflict of interest: V. Cottin reports advisory board fees and non-financial support from Actelion, advisory board fees from Bayer/MSD, outside the submitted work. Conflict of interest: G. Prévot reports personal fees from Actelion and GSK, outside the submitted work. Conflict of interest: A. Chaouat reports consulting fees from GSK, Actelion and Bayer, outside the submitted work. Conflict of interest: F. Picard has nothing to disclose. Conflict of interest: D. Horeau-Langlard reports grants from Acceleron, outside the submitted work. Conflict of interest: A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim; consulting fees from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Amgen; lecture honoraria from AstraZeneca, GSK, Novartis, Boehringer Ingelheim, Chiesi, Sanofi Regeneron, Roche; travel support from Boehringer Ingelheim, Chiesi, Sanofi Regeneron, AstraZeneca, GSK, Roche; participation on advisory boards at AB science, AstraZeneca, GSK, Sanofi Regeneron, Novartis, Acceleron; and acted as investigator in clinical trials for Vertex, Abbvie, Galapagos, Fibrogen, Nuvaira, PulmonX, Gossamer, Acceleron; outside the submitted work. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: X. Jais reports grants from Bayer, Janssen and Merck; lecture honoraria from Janssen and Merck; outside the submitted work. Conflict of interest: G. Simonneau reports grants and personal fees from Janssen (formerly Actelion), Bayer and MSD; personal fees from Acceleron, outside the submitted work. Conflict of interest: D. Montani reports grants from Acceleron, Janssen and Merck; steering committee fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck; outside the submitted work. Conflict of interest: O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD; steering committee fees from Gossamer Bio, Janssen and MSD; lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD; advisory board participation at Acceleron, Janssen and MSD; outside the submitted work. Conflict of interest: M. Humbert reports grants, steering committee consulting fees, and advisory board participation from Acceleron, Janssen and Merck; lecture honoraria from AOP, Janssen and Merck; steering committee participation at United Therapeutics; outside the submitted work., (Copyright ©The authors 2022.)

Rationale: The characteristics of patients with respiratory complaints and/or lung radiologic abnormalities after hospitalisation for coronavirus disease 2019 (COVID-19) are unknown. The objectives were to determine their characteristics and the relationships between dyspnoea, radiologic abnormalities and functional impairment., Methods: In the COMEBAC (Consultation Multi-Expertise de Bicêtre Après COVID-19) cohort study, 478 hospital survivors were evaluated by telephone 4 months after hospital discharge, and 177 who had been hospitalised in an intensive care unit (ICU) or presented relevant symptoms underwent an ambulatory evaluation. New-onset dyspnoea and cough were evaluated, and the results of pulmonary function tests and high-resolution computed tomography of the chest were collected., Results: Among the 478 patients, 78 (16.3%) reported new-onset dyspnoea, and 23 (4.8%) new-onset cough. The patients with new-onset dyspnoea were younger (56.1±12.3 versus 61.9±16.6 years), had more severe COVID-19 (ICU admission 56.4% versus 24.5%) and more frequent pulmonary embolism (18.0% versus 6.8%) (all p≤0.001) than patients without dyspnoea. Among the patients reassessed at the ambulatory care visit, the prevalence of fibrotic lung lesions was 19.3%, with extent <25% in 97% of the patients. The patients with fibrotic lesions were older (61±11 versus 56±14 years, p=0.03), more frequently managed in an ICU (87.9 versus 47.4%, p<0.001), had lower total lung capacity (74.1±13.7 versus 84.9±14.8% pred, p<0.001) and diffusing capacity of the lung for carbon monoxide ( D LCO ) (73.3±17.9 versus 89.7±22.8% pred, p<0.001). The combination of new-onset dyspnoea, fibrotic lesions and D LCO <70% pred was observed in eight out of 478 patients., Conclusions: New-onset dyspnoea and mild fibrotic lesions were frequent at 4 months, but the association of new-onset dyspnoea, fibrotic lesions and low D LCO was rare., Competing Interests: Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: O. Meyrignac has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: X. Jaïs has nothing to disclose. Conflict of interest: T. Pham has nothing to disclose. Conflict of interest: L. Morin has nothing to disclose. Conflict of interest: A. Boucly has nothing to disclose. Conflict of interest: S. Bulifon has nothing to disclose. Conflict of interest: S. Figueiredo has nothing to disclose. Conflict of interest: A. Harrois has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: N. Noël has nothing to disclose. Conflict of interest: J. Pichon has nothing to disclose. Conflict of interest: A. Roche has nothing to disclose. Conflict of interest: A. Seferian has nothing to disclose. Conflict of interest: S. Soliman has nothing to disclose. Conflict of interest: J. Duranteau has nothing to disclose. Conflict of interest: L. Becquemont has nothing to disclose. Conflict of interest: X. Monnet has nothing to disclose. Conflict of interest: O. Sitbon has nothing to disclose. Conflict of interest: M-F. Bellin has nothing to disclose. Conflict of interest: M. Humbert has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: D. Montani has nothing to disclose., (Copyright ©The authors 2022.)

Objective: The diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is a major challenge as it is a curable cause of pulmonary hypertension (PH). Ventilation/Perfusion (V/Q) lung scintigraphy is the imaging modality of choice for the screening of CTEPH. However, there is no consensus on the criteria to use for interpretation. The aim of this study was to assess the accuracy of various interpretation criteria of planar V/Q scintigraphy for the screening of CTEPH in patients with PH., Methods: The eligible study population consisted of consecutive patients with newly diagnosed PH in the Brest University Hospital, France. Final diagnosis (CTEPH or non-CTEPH) was established in a referential center on the management of PH, based on the ESC/ERS guidelines and a minimum follow-up of 3 years. A retrospective central review of planar V/Q scintigraphy was performed by three nuclear physicians blinded to clinical findings and to final diagnosis. The number, extent (sub-segmental or segmental) and type (matched or mismatched) of perfusion defects were reported. Sensitivity and specificity were evaluated for various criteria based on the number of mismatched perfusion defects and the number of perfusion defects (regardless of ventilation). Receiver operating characteristic (ROC) curves were generated and areas under the curve (AUC) were calculated for both., Results: A total of 226 patients with newly diagnosed PH were analyzed. Fifty six (24.8%) were diagnosed with CTEPH while 170 patients (75.2%) were diagnosed with non-CTEPH. The optimal threshold was 2.5 segmental mismatched perfusion defects, providing a sensitivity of 100 % (95% CI 93.6-100%) and a specificity of 94.7% (95%CI 90.3-97.2%). Lower diagnostic cut-offs of mismatched perfusion defects provided similar sensitivity but lower specificity. Ninety five percent of patients with CTEPH had more than 4 segmental mismatched defects. An interpretation only based on perfusion provided similar sensitivity but a specificity of 81.8% (95%CI 75.3-86.9%)., Conclusion: Our study confirmed the high diagnostic performance of planar V/Q scintigraphy for the screening of CTEPH in patients with PH. The optimal diagnostic cut-off for interpretation was 2.5 segmental mismatched perfusion defects. An interpretation only based on perfusion defects provided similar sensitivity but lower specificity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Le Pennec, Tromeur, Orione, Robin, Le Mao, De Moreuil, Jevnikar, Hoffman, Savale, Couturaud, Sitbon, Montani, Jaïs, Le Gal, Salaün, Humbert and Le Roux.)

Pulmonary arterial hypertension (PAH) is a rare disease characterised by pulmonary vascular remodelling and elevated pulmonary pressure, which eventually leads to right heart failure and death. Registries worldwide have noted a female predominance of the disease, spurring particular interest in hormonal involvement in the disease pathobiology. Several experimental models have shown both protective and deleterious effects of oestrogens, suggesting that complex mechanisms participate in PAH pathogenesis. In fact, oestrogen metabolites as well as receptors and enzymes implicated in oestrogen signalling pathways and associated conditions such as BMPR2 mutation contribute to PAH penetrance more specifically in women. Conversely, females have better right ventricular function, translating to a better prognosis. Along with right ventricular adaptation, women tend to respond to PAH treatment differently from men. As some young women suffer from PAH, contraception is of particular importance, considering that pregnancy in patients with PAH is strongly discouraged due to high risk of death. When contraception measures fail, pregnant women need a multidisciplinary team-based approach. This article aims to review epidemiology, mechanisms underlying the higher female predominance, but better prognosis and the intricacies in management of women affected by PAH., Competing Interests: Conflict of interest: C. Cheron has nothing to disclose. Conflict of interest: S.A. McBride has nothing to disclose. Conflict of interest: F Antigny has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: M. Chouchana has nothing to disclose. Conflict of interest: M-C. Chaumais has nothing to disclose. Conflict of interest: X. Jaïs reports grants, personal fees and non-financial support from Actelion/Janssen, personal fees and non-financial support from MSD, and grants from Bayer, outside the submitted work. Conflict of interest: L. Bertoletti reports grants, personal fees and non-financial support from Actelion, MSD, Bayer, BMS/Pfizer and Léo-Pharma, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion; personal fees from Acceleron, Ferrer and Gossamer Bio; grants and personal fees from Bayer and MSD; and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, and personal fees from Novartis, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline; personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck; grants and personal fees from Acceleron, Actelion and Bayer, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer; personal fees from GSK, Pfizer, Chiesi and Boerhinger; grants, personal fees and non-financial support from MSD; and non-financial support from Acceleron, outside the submitted work., (Copyright ©The authors 2021.)

Background: Drugs approved for the treatment of pulmonary arterial hypertension (PAH) improve long-term outcomes. These drugs have pulmonary vasodilator properties which may potentially cause a decrease in arterial oxyhaemoglobin saturation ( S aO 2 ) in some patients. The present retrospective study of the French Pulmonary Hypertension Registry aimed to describe the clinical characteristics and outcomes of patients showing a ≥3% decrease in S aO 2 while treated with PAH drugs., Methods: We reviewed 719 PAH patients. The exclusion criteria were PAH associated with congenital heart disease and PAH with overt features of venous/capillaries involvement., Results: 173 (24%) patients had a ≥3% decrease in S aO 2 . At diagnosis, they were older with a lower diffusing capacity of the lung for carbon monoxide and a shorter 6-min walk distance compared with those who did not display a ≥3% decrease in S aO 2 . The percentage of patients meeting the European Society of Cardiology/European Respiratory Society (ESC/ERS) low-risk criteria at re-evaluation was significantly lower in those with a ≥3% decrease in S aO 2 and more patients started long-term oxygen therapy in this group (16% versus 5%; p<0.001). A ≥3% decrease in S aO 2 was associated with a poorer survival (hazard ratio 1.81, 95% CI 1.43-2.34; p<0.0001). In a multivariate Cox analysis, a ≥3% decrease in S aO 2 was a prognostic factor independent of age at diagnosis and ESC/ERS risk stratification at follow-up., Conclusions: When treated with PAH drugs, a large subset of patients experience a ≥3% decrease in S aO 2 , which is associated with worse long-term outcomes and reduced survival., Competing Interests: Conflict of interest: S. Valentin has nothing to disclose. Conflict of interest: A. Maurac has nothing to disclose. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion, grants and personal fees from Bayer and MSD, personal fees from Acceleron, Ferrer and Gossamer Bio, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Beurnier reports personal fees from Sanofi and AstraZeneca, outside the submitted work. Conflict of interest: E. Gomez has nothing to disclose. Conflict of interest: A. Guillaumot reports non-financial support from Actelion, AstraZeneca, Boehringer Ingelheim, MSD and Roche, outside the submitted work. Conflict of interest: L. Textoris has nothing to disclose. Conflict of interest: R. Fay has nothing to disclose. Conflict of interest: L. Savale reports personal fees and non-financial support from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: X. Jaïs reports grants from Bayer, grants, personal fees and non-financial support from Actelion/Janssen, personal fees from MSD, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GlaxoSmithKline, Pfizer, MSD and Chiesi, outside the submitted work. Conflict of interest: F. Picard reports personal fees from Novartis, outside the submitted work. Conflict of interest: J-F. Mornex reports personal fees and non-financial support from Actelion, grants, personal fees and non-financial support from GlaxoSmithKline, during the conduct of the study; grants, personal fees and non-financial support from LFB and CSL Behring, personal fees from Roche and Chiesi, outside the submitted work. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: F. Chabot reports non-financial support from Actelion, AstraZeneca, Boehringer Ingelheim and MSD, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline, grants and personal fees from Acceleron, Actelion and Bayer, personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck, outside the submitted work. Conflict of interest: A. Chaouat has received personal fees for lecturing and/or consulting from Actelion, Boehringer Ingelheim, Novartis, MSD and Chiesi, and research grants from Actelion and GlaxoSmithKline., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Rationale: The relationship between the initial treatment strategy and survival in pulmonary arterial hypertension (PAH) remains uncertain. Objectives: To evaluate the long-term survival of patients with PAH categorized according to the initial treatment strategy. Methods: A retrospective analysis of incident patients with idiopathic, heritable, or anorexigen-induced PAH enrolled in the French Pulmonary Hypertension Registry (January 2006 to December 2018) was conducted. Survival was assessed according to the initial strategy: monotherapy, dual therapy, or triple-combination therapy (two oral medications and a parenteral prostacyclin). Measurements and Main Results: Among 1,611 enrolled patients, 984 were initiated on monotherapy, 551 were initiated on dual therapy, and 76 were initiated on triple therapy. The triple-combination group was younger and had fewer comorbidities but had a higher mortality risk. The survival rate was higher with the use of triple therapy (91% at 5 yr) as compared with dual therapy or monotherapy (both 61% at 5 yr) ( P  < 0.001). Propensity score matching of age, sex, and pulmonary vascular resistance also showed significant differences between triple therapy and dual therapy (10-yr survival, 85% vs. 65%). In high-risk patients ( n  = 243), the survival rate was higher with triple therapy than with monotherapy or dual therapy, whereas there was no difference between monotherapy and double therapy. In intermediate-risk patients ( n  = 1,134), survival improved with an increasing number of therapies. In multivariable Cox regression, triple therapy was independently associated with a lower risk of death (hazard ratio, 0.29; 95% confidence interval, 0.11-0.80; P  = 0.017). Among the 148 patients initiated on a parenteral prostacyclin, those on triple therapy had a higher survival rate than those on monotherapy or dual therapy. Conclusions: Initial triple-combination therapy that includes parenteral prostacyclin seems to be associated with a higher survival rate in PAH, particularly in the youngest high-risk patients.

Busulfan is widely used to treat malignant diseases, particularly for therapeutic intensification prior to an autologous stem cell graft. Numerous side effects consecutive to busulfan are described, but few descriptions of pulmonary hypertension exist, while bronchiolitis obliterans remains a rare complication. We report the clinical observations of four patients from the French Pulmonary Hypertension Registry who experienced subacute pulmonary hypertension after receiving busulfan as preparation regimen before an autologous stem cell graft for malignancies (Hodgkin's disease, Ewing's sarcoma and primary large B cell lymphoma of the brain). Patients experienced severe pulmonary arterial hypertension 2 to 4.5 months after busulfan administration. Pulmonary hypertension improved after treatment with approved drugs for pulmonary arterial hypertension and/or corticosteroids. During the follow-up period, two patients developed chronic respiratory insufficiency due to interstitial lung disease, leading to double lung transplantation. The pathological assessment of explanted lungs revealed interstitial lung fibrosis with advanced bronchiolar lesions and severe pulmonary vascular damage. Three of the four patients were still alive after 36 to 80 months and the fourth died unexpectedly and suddenly after 5 months. In conclusion, PAH is a rare but severe complication associated with busulfan chemotherapy in adults. Histological examinations provide evidence for diffuse pulmonary vascular damage combined with interstitial lung injury in most cases., (© The Author(s) 2021.)

Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH., Competing Interests: Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion and GSK, and personal fees and non-financial support from MSD and Bayer, outside the submitted work. Conflict of interest: S. Akagi has nothing to disclose. Conflict of interest: L. Tu has nothing to disclose. Conflict of interest: A. Cumont has nothing to disclose. Conflict of interest: R. Thuillet has nothing to disclose. Conflict of interest: C. Phan has nothing to disclose. Conflict of interest: B. Le Vely has nothing to disclose. Conflict of interest: N. Berrebeh has nothing to disclose. Conflict of interest: A. Huertas has nothing to disclose. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: V. Cottin has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: C. Tromeur has nothing to disclose. Conflict of interest: A. Boucly reports personal fees and non-financial support from Actelion and personal fees from MSD, outside the submitted work. Conflict of interest: E.M. Jutant has nothing to disclose. Conflict of interest: O. Mercier has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, United Therapeutics and Acceleron, outside the submitted work. Conflict of interest: Y. Tamura has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Background: Heritable pulmonary arterial hypertension (PAH) is most commonly due to heterozygous mutations of the BMPR2 gene. Based on expert consensus, guidelines recommend annual screening echocardiography in asymptomatic BMPR2 mutation carriers. The main objectives of this study were to evaluate the characteristics of asymptomatic BMPR2 mutation carriers, assess their risk of occurrence of PAH and detect PAH at an early stage in this high-risk population., Methods: Asymptomatic BMPR2 mutation carriers underwent screening at baseline and annually for a minimum of 2 years (DELPHI-2 study; ClinicalTrials.gov: NCT01600898). Annual screening included clinical assessment, ECG, pulmonary function tests, 6-min walk distance, cardiopulmonary exercise testing, chest radiography, echocardiography and brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP level. Right heart catheterisation (RHC) was performed based on predefined criteria. An optional RHC at rest and exercise was proposed at baseline., Results: 55 subjects (26 males; median age 37 years) were included. At baseline, no PAH was suspected based on echocardiography and NT-proBNP levels. All subjects accepted RHC at inclusion, which identified two mild PAH cases (3.6%) and 12 subjects with exercise pulmonary hypertension (21.8%). At long-term follow-up (118.8 patient-years of follow-up), three additional cases were diagnosed, yielding a PAH incidence of 2.3% per year (0.99% per year in males and 3.5% per year in females). All PAH cases remained at low-risk status on oral therapy at last follow-up., Conclusions: Asymptomatic BMPR2 mutation carriers have a significant risk of developing incident PAH. International multicentre studies are needed to confirm that refined multimodal screening programmes with regular follow-up allow early detection of PAH., Competing Interests: Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GlaxoSmithKline, Pfizer, Chiesi, Boehringer and Incyte Biosciences France, grants, personal fees and nonfinancial support from MSD, nonfinancial support from Acceleron, outside the submitted work. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jaïs reports grants from Bayer, grants and personal fees from MSD, grants, personal fees and nonfinancial support from Actelion/Janssen, outside the submitted work. Conflict of interest: P. Laveneziana reports personal fees from Novartis France and Chiesi France, outside the submitted work. Conflict of interest: E.M.T. Lau reports grants and personal fees from Actelion and GlaxoSmithKline, outside the submitted work. Conflict of interest: A. Bouchachi has nothing to disclose. Conflict of interest: S. Hascoët reports grants and personal fees from Abbott, outside the submitted work. Conflict of interest: S. Gunther has nothing to disclose. Conflict of interest: L. Godinas has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: D. Chemla has nothing to disclose. Conflict of interest: P. Hervé has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: G. Simonneau reports personal fees from Bayer and Acceleron, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and nonfinancial support from Actelion Pharmaceuticals, personal fees from Acceleron Pharmaceuticals, AOP Orphan, Ferrer and Gossamer Bio, grants and personal fees from Bayer HealthCare and MSD, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: L. Savale reports personal fees and nonfinancial support from Actelion and Bayer, grants, personal fees and nonfinancial support from GlaxoSmithKline, nonfinancial support from MSD, outside the submitted work. Conflict of interest: M. Humbert reports grants, personal fees and nonfinancial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi, Teva and Merck, grants and personal fees from Acceleron, Actelion and Bayer, outside the submitted work., (Copyright ©The authors 2021. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: To determine whether preoperative systemic inflammation (defined by C-reactive protein [CRP] levels ≥10 mg/L) is associated with worse functional and hemodynamic status and poor early outcomes postendarterectomy in patients with chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: This study included 159 patients who underwent pulmonary endarterectomy from 2009 to 2013 (derivation cohort) and 238 patients from 2015 to 2016 (validation cohort) with CRP data from the national CTEPH registry. The correlations between proinflammatory markers (CRP, interleukins 1 and 6, fibrinogen, and leukocytes) and hemodynamics were assessed in the derivation cohort. Pre-, perioperative characteristics, and 30-day outcomes (ie, death or lung transplant or extracorporeal membrane oxygenation need or inotropic or vasopressor need ≥3 days) of patients with CRP levels ≥ or <10 mg/L were compared., Results: Median age of the derivation cohort was 63 [52-73] years with 48% female, 80% in New York Heart Association class III/IV. The validation cohort had similar demographics and disease severity. Patients with CRP ≥10 mg/L had greater resistance levels and lower cardiac index than those with CRP <10 mg/L in both cohorts. The primary endpoint was reached in 38% (derivation) and 42% (validation) of patients. In multivariable logistic regression analysis, CRP ≥10 mg/L was associated with the primary endpoint in both the derivation cohort (odd ratio, 2.49 [1.11-5.61], independently of New York Heart class class IV and aortic clamping duration) and the validation cohort (odd ratio, 1.89 [1.09-3.61], independently of age and aortic clamping duration)., Conclusions: Preoperative CRP ≥10 mg/L is independently associated with adverse early outcomes postendarterectomy., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Viral respiratory infections are the main causes of asthma exacerbation. The susceptibility of patients with asthma to develop an exacerbation when they present with severe pneumonia due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is unknown. The objective of this study was to investigate the characteristics and outcomes of asthmatic patients with coronavirus disease 2019 (COVID-19) pneumonia who required hospitalisation during the spring 2020 outbreak in Paris, France., Methods: A prospective cohort follow-up was carried out from 15 March to 15 April 2020 in Bicêtre Hospital, University Paris-Saclay, France. All hospitalised patients with a SARS-CoV-2 infection who reported a history of asthma were included., Results: Among 768 hospitalised patients, 37 (4.8%) reported a history of asthma, which had been previously confirmed by a pulmonologist in 85% of cases. These asthmatic patients were mainly female (70%) and nonsmokers (85%), with a median age of 54 years (interquartile range (IQR) 42-67 years). None of them presented with an asthma exacerbation. 22 (59%) had major comorbidities and 31 (84%) had a body mass index ≥25 kg·m -2 . The most common comorbidities were obesity (36%), hypertension (27%) and diabetes (19%). All patients had a confirmed diagnosis of COVID-19 pneumonia on computed tomography of the chest. Eosinopenia was a typical biological feature with a median count of 0 cells·mm -3 (IQR 0-0 cells·mm -3 ). 11 patients (30%) were admitted into the intensive care unit, with three deaths (8.1%) occurring in the context of comorbidities., Conclusion: Asthma patients were not overrepresented among those with severe pneumonia due to SARS-CoV-2 infection who required hospitalisation. The worst outcomes were observed mainly in patients with major comorbidities., Competing Interests: Conflict of interest: A. Beurnier has nothing to disclose. Conflict of interest: E-M. Jutant has nothing to disclose. Conflict of interest: M. Jevnikar has nothing to disclose. Conflict of interest: A. Boucly has nothing to disclose. Conflict of interest: J. Pichon has nothing to disclose. Conflict of interest: M. Preda has nothing to disclose. Conflict of interest: M. Frank has nothing to disclose. Conflict of interest: J. Laurent has nothing to disclose. Conflict of interest: C. Richard has nothing to disclose. Conflict of interest: X. Monnet has nothing to disclose. Conflict of interest: J. Duranteau has nothing to disclose. Conflict of interest: A. Harrois has nothing to disclose. Conflict of interest: M-C. Chaumais has nothing to disclose. Conflict of interest: M-F. Bellin has nothing to disclose. Conflict of interest: N. Noël has nothing to disclose. Conflict of interest: S. Bulifon has nothing to disclose. Conflict of interest: X. Jaïs has nothing to disclose. Conflict of interest: F. Parent has nothing to disclose. Conflict of interest: A. Seferian has nothing to disclose. Conflict of interest: L. Savale has nothing to disclose. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, grants and personal fees from Bayer, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: D. Montani has nothing to disclose. Conflict of interest: M. Humbert reports grants, personal fees and non-financial support from GlaxoSmithKline, personal fees from AstraZeneca, Novartis, Roche, Sanofi and Teva, outside the submitted work., (Copyright ©ERS 2020.)

Tyrosine kinase inhibitors (TKIs) targeting the Bcr-Abl oncoprotein revolutionised the treatment of chronic myelogenous leukaemia. Following the success of imatinib, second- and third-generation molecules were developed. Different profiles of kinase inhibition and off-target effects vary between TKIs, which leads to a broad spectrum of potential toxicities.Pulmonary complications are most frequently observed with dasatinib but all other Bcr-Abl TKIs have been implicated. Pleural effusions are the most frequent pulmonary complication of TKIs, usually associated with dasatinib and bosutinib. Pulmonary arterial hypertension is an uncommon but serious complication of dasatinib, which is often reversible upon discontinuation. Bosutinib and ponatinib have also been associated with pulmonary arterial hypertension, while imatinib has not. Rarely, interstitial lung disease has been associated with TKIs, predominantly with imatinib.Mechanistically, dasatinib affects maintenance of normal pulmonary endothelial integrity by generating mitochondrial oxidative stress, inducing endothelial apoptosis and impairing vascular permeability in a dose-dependent manner. The mechanisms underlying other TKI-related complications are largely unknown. Awareness and early diagnosis of the pulmonary complications of Bcr-Abl TKIs is essential given their seriousness, potential reversibility, and impact on future treatment options for the underlying chronic myelogenous leukaemia., Competing Interests: Conflict of interest: J. Weatherald reports grants, personal fees and non-financial support from Janssen Inc. and Actelion, personal fees and non-financial support from Bayer, personal fees from Novartis, grants from Alberta Lung Association, Canadian Vascular Network, European Respiratory Society and Canadian Thoracic Society, outside the submitted work. Conflict of interest: L. Bondeelle has nothing to disclose. Conflict of interest: M-C. Chaumais reports personal fees from Actelion, non-financial support from Bayer and Boehringer Ingelheim, outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: L. Savale reports personal fees from Actelion, grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees and non-financial support from Acceleron Pharmaceuticals, personal fees from Ferrer, Gossamer Bio and United Therapeutics, grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: P. Rousselot reports grants and personal fees from Pfizer and Incyte, grants from Britol Myers Squibb, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Acceleron, Merck, Morphogen IX and United Therapeutics, grants and personal fees from Actelion, Bayer and GSK, outside the submitted work. Conflict of interest: A. Bergeron reports grants from SOS oxygene, personal fees from Shire, Pfizer, MSD and Gilead, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work., (Copyright ©ERS 2020.)

Rationale: Pulmonary hypertension (PH) associated with neurofibromatosis type 1 (NF1) is a rare and largely unknown complication of NF1. Objectives: To describe characteristics and outcomes of PH-NF1. Methods: We reported the clinical, functional, radiologic, histologic, and hemodynamic characteristics, response to pulmonary arterial hypertension (PAH)-approved drugs, and transplant-free survival of patients with PH-NF1 from the French PH registry. Measurements and Main Results: We identified 49 PH-NF1 cases, characterized by a female/male ratio of 3.9 and a median (minimum-maximum) age at diagnosis of 62 (18-82) years. At diagnosis, 92% were in New York Heart Association functional class III or IV. The 6-minute-walk distance was 211 (0-460) m. Pulmonary function tests showed low Dl CO (30% [12-79%]) and severe hypoxemia (Pa O 2 56 [38-99] mm Hg). Right heart catheterization showed severe precapillary PH with a mean pulmonary artery pressure of 45 (10) mm Hg and a pulmonary vascular resistance of 10.7 (4.2) Wood units. High-resolution computed tomography images revealed cysts (76%), ground-glass opacities (73%), emphysema (49%), and reticulations (39%). Forty patients received PAH-approved drugs with a significant improvement in functional class and hemodynamic parameters. Transplant-free survival at 1, 3, and 5 years was 87%, 54%, and 42%, respectively, and four patients were transplanted. Pathologic assessment showed nonspecific interstitial pneumonia and major pulmonary vascular remodeling. Conclusions: PH-NF1 is characterized by a female predominance, a low Dl CO , and severe functional and hemodynamic impairment. Despite a potential benefit of PAH treatment, prognosis remains poor, and double-lung transplantation is an option for eligible patients.

Introduction: TBX4 mutation causes small patella syndrome (SPS) and/or pulmonary arterial hypertension (PAH). The characteristics and outcomes of PAH associated with TBX4 mutations are largely unknown., Methods: We report the clinical, functional, radiologic, histologic and haemodynamic characteristics and outcomes of heritable PAH patients carrying a TBX4 mutation from the French pulmonary hypertension (PH) network., Results: 20 patients were identified in 17 families. They were characterised by a median age at diagnosis of 29 years (0-76 years) and a female to male ratio of three. Most of the patients (70%) were in New York Heart Association (NYHA) functional class III or IV with a severe haemodynamic impairment (median pulmonary vascular resistance (PVR) of 13.6 (6.2-41.8) Wood units). Skeletal signs of SPS were present in 80% of cases. Half of the patients had mild restrictive or obstructive limitation and diffusing capacity of the lung for carbon monoxide ( D LCO ) was decreased in all patients. High-resolution computed tomography (HRCT) showed bronchial abnormalities, peri-bronchial cysts, mosaic distribution and mediastinal lymphadenopathies. PAH therapy was associated with significant clinical improvement. At follow-up (median 76 months), two patients had died and two had undergone lung transplantation. One-year, three-year and five-year event-free survival rates were 100%, 94% and 83%, respectively. Histologic examination of explanted lungs revealed alveolar growth abnormalities, major pulmonary vascular remodelling similar to that observed in idiopathic pulmonary arterial hypertension (IPAH) and accumulation of cholesterol crystals within the lung parenchyma., Conclusion: PAH due to TBX4 mutations may occur with or without skeletal abnormalities across a broad age range from birth to late adulthood. PAH is usually severe and associated with bronchial and parenchymal abnormalities., Competing Interests: Conflict of interest: P. Thoré has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, and grants from Bayer, outside the submitted work. Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion, grants and personal fees from MSD, and non-financial support from GSK, outside the submitted work. Conflict of interest: M-R. Ghigna has nothing to disclose. Conflict of interest: M. Eyries has nothing to disclose. Conflict of interest: M. Levy has nothing to disclose. Conflict of interest: C. Ovaert has nothing to disclose. Conflict of interest: A. Servettaz has nothing to disclose. Conflict of interest: A. Guillaumot has nothing to disclose. Conflict of interest: C. Dauphin has nothing to disclose. Conflict of interest: C. Chabanne has nothing to disclose. Conflict of interest: E. Boiffard has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for advisory board work and non-financial (travel) support from Actelion, grants and personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Boehringer Ingelheim, personal fees for advisory board work and data monitoring committee work from Bayer/MSD and Galapagos, personal fees for advisory board work from Gilead and Novartis, personal fees for advisory board work, lectures and steering committee work, as well as non-financial (travel) support from Roche SAS, personal fees for lectures and non-financial (travel) support from Sanofi, personal fees for steering committee work and data monitoring committee work from Promedior, and personal fees for data monitoring committee work from Celgene and Galecto, outside the submitted work. Conflict of interest: F.Perros has nothing to disclose. Conflict of interest: G. Simonneau reports grants, personal fees and non-financial support from Actelion, Bayer, GSK and Merck, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer HealthCare and MSD, personal fees from Acceleron Pharmaceuticals, Ferrer, Gossamer Bio and United Therapeutics, and grants from GlaxoSmithKline, outside the submitted work. Conflict of interest: F. Soubrier has nothing to disclose. Conflict of interest: D. Bonnet reports personal fees for advisory board work and steering committee work from Actelion Pharmaceuticals, Eli Lilly and Novartis, outside the submitted work. Conflict of interest: M. Remy-Jardin has nothing to disclose. Conflict of interest: A. Chaouat has nothing to disclose. Conflict of interest: M. Humbert reports personal fees from Acceleron, Actelion, MSD and United Therapeutics, and grants and personal fees from Bayer and GSK, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work., (Copyright ©ERS 2020.)