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Background: Exercise hemodynamics are recommended for early detection of pulmonary arterial hypertension (PAH) and have been suggested to be predictive of future development of PAH in high-risk populations such as BMPR2 mutation carriers. However, the optimal exercise hemodynamic screening parameter remains to be determined. Recent data suggest that pulmonary vascular distensibility (α) may serve as a useful parameter for early detection of PAH., Research Question: What is the value of exercise hemodynamics, including α, for predicting the occurrence of PAH during long-term follow-up in BMPR2 mutation carriers?, Study Design and Methods: Fifty-two asymptomatic BMPR2 mutation carriers who underwent symptom-limited exercise hemodynamic assessment were followed up for a median of 10 years. The impact of hemodynamics at rest and exercise, presence of exercise pulmonary hypertension, and α on occurrence of PAH during long-term follow-up were assessed., Results: During long-term follow-up, five patients developed PAH. Patients who developed PAH showed a significantly lower α (0.8 ± 0.4%/mm Hg) than patients without PAH (1.8 ± 0.8%/mm Hg; P = .008). The only hemodynamic parameter that predicted the occurrence of PAH during long-term follow-up at regression analysis was α. Receiver operating characteristic analysis showed that α ≤ 1.5%/mm Hg predicted PAH occurrence with a specificity of 75% and sensitivity of 100%., Interpretation: The results of this study indicate that before development of PAH in BMPR2 mutation carriers, α is reduced markedly and may serve as a useful parameter in the setting of early disease detection. Given the low event rate, caution is warranted in interpreting these results, highlighting the need for validation studies., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: C. G. has received compensation for scientific symposia from AstraZeneca, AOPHealth, Cordis, Janssen, and MSD; speaker fees from AOPHealth, AstraZeneca, Janssen, and Ferrer; and an educational grant from OrphaCare. A. Beurnier has received speaker fees from AstraZeneca and Sanofi Aventis. X. J. has received speaker fees from Janssen and MSD and research grants from Acceleron, Bayer, Janssen, and MSD. E. M. T. L. has received speaker fees from Janssen and GlaxoSmithKline and research grants from Janssen and has served as an advisory board member for Janssen. M. J. has received speaker fees from Janssen. A. Boucly has received compensation for scientific symposia from Janssen and MSD, speaker fees from Janssen, MSD, AOPHealth and Ferrer, and research grants from Acceleron, Janssen and MSD. H. J. B. has received speaker fees and research grants from Janssen, MSD, and Ferrer and consultancy fees from Novartis and was supported by the Dutch Cardiovascular Alliance [Grant 01-001-2017-B010, DOLPHIN-GENESIS]. G. S. has received speaker and consultancy fees from Janssen, Bayer, GlaxoSmithKline, MSD, and Pfizer and research grants from Janssen and has served as a steering committee member for Janssen. O. S. has received speaker fees from AOPHealth, Janssen, Ferrer, and MSD; consultancy fees from Acceleron, Altavant, AOPHealth, Ferrer, Gossamer Bio, Janssen, and MSD; and research grants from Acceleron, AOPHealth, Janssen, and MSD; and has served as an advisory board member for Altavant, Gossamer Bio, Janssen, and MSD. L. S. has received compensation for scientific symposia from Janssen and MSD and speaker fees from Janssen and has served as an advisory board member for Janssen. M. H. has received speaker fees from Janssen and MSD; consultancy fees from Acceleron, Aerovate, Altavant, AOPHealth, Bayer, Chiesi, Ferrer, Janssen, MSD, MorphogenIX, Shou Ti, Tiakis, and United Therapeutics; and research grants from Acceleron, AOPHealth, Janssen, MSD, and Shou Ti; and has served as an advisory board member for Acceleron, Altavant, Janssen, MSD, and United Therapeutics. D. M. has received speaker fees from Bayer, Janssen, and MSD; consultancy fees from Acceleron, Janssen, and MSD; and research grants from Acceleron, Janssen, and MSD. None declared (P. H., B. G., S. G., A. Bouchachi, D. C.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., Competing Interests: Declaration of interests H-AG has received fees for serving as a board member for AbbVie, Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer. GS has received consultancy fees, lecture fees and travel support from Actelion Pharmaceuticals, Bayer, Merck, GlaxoSmithKline, and Pfizer; and grant support and fees for serving on a steering committee from Actelion Pharmaceuticals and Bayer. AMD’A has received fees for organising Masters-level courses, lecture fees and writing assistance from Bayer and Merck; and fees for serving on steering committees from Actelion Pharmaceuticals. PF has received fees for serving on an adjudication committee for Actelion Pharmaceuticals. LSH has received consultancy fees from Endotronix; fees for serving on steering committees from Actelion Pharmaceuticals, Bristol-Myers Squibb, and BTG plc; lecture fees, fees for serving on advisory boards, and travel support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, and Merck; grant support from Bayer; and departmental funding from Actelion Pharmaceuticals. XJ has received fees for serving on an adjudication committee for Actelion Pharmaceuticals; grant support from Actelion Pharmaceuticals and GlaxoSmithKline; and personal fees from Actelion Pharmaceuticals, GlaxoSmithKline, and Merck. DPJ has received fees for serving on a steering committee for Actelion Pharmaceuticals and lecture fees from Bayer. Z-CJ has received consultancy fees, lecture fees and fees for serving on a steering committee from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Lee's Pharmaceuticals, and Pfizer; fees for serving on an adjudication committee from Actelion Pharmaceuticals; and grant support from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Pfizer, The National Science Fund for Distinguished Young Scholars (81425002), CAMS Innovation Fund for Medical Sciences (2016-I2M-1-002), and The National Key Research and Development Program of China (No. 2016YFC0901502). MMM has received fees for serving on an adjudication committee for Actelion Pharmaceuticals and consultancy fees from Bayer. NM is an employee of Actelion Pharmaceuticals. EM has received consultancy fees from Actelion Pharmaceuticals, Bayer, Merck, and GlaxoSmithKline; lecture fees from Actelion Pharmaceuticals, Bayer, Merck, Pfizer, and GlaxoSmithKline; and fees for serving on a steering committee for Actelion Pharmaceuticals. KP and DR are employees of and hold stock in Actelion Pharmaceuticals. NHK has received consultancy fees from Actelion Pharmaceuticals, Arena, Bayer, Merck, and SteadyMed; lecture fees from Actelion Pharmaceuticals and Bayer; fees for serving on a steering committee for Actelion Pharmaceuticals; and grant support from Bellerophon, Eiger, Gilead, Lung Biotechnology, and Sonivie., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. Important advances have enabled better understanding, characterisation, and treatment of this condition. Guidelines recommending systematic follow-up after acute pulmonary embolism, and the insight that CTEPH can mimic acute pulmonary embolism on initial presentation, have led to the definition of CTEPH imaging characteristics, the introduction of artificial intelligence diagnosis pathways, and thus the prospect of easier and earlier CTEPH diagnosis. In this Series paper, we show how the understanding of CTEPH as a sequela of inflammatory thrombosis has driven successful multidisciplinary management that integrates surgical, interventional, and medical treatments. We provide imaging examples of classical major vessel targets, describe microvascular targets, define available tools, and depict an algorithm facilitating the initial treatment strategy in people with newly diagnosed CTEPH based on a multidisciplinary team discussion at a CTEPH centre. Further work is needed to optimise the use and combination of multimodal therapeutic options in CTEPH to improve long-term outcomes for patients., Competing Interests: Declaration of interests MD reports research grants from Janssen; and speaker and consultancy fees from Altavant, Acceleron, AOP, Bayer, Ferrer, Gossamer, INARI, Janssen, United Therapeutics, and MSD, outside of the submitted work and all paid to her institution. She is holder of a Janssen Chair for Pulmonary Hypertension at the KU Leuven. MdP reports speaker fees and consultancy honoraria from AstraZeneca and BMS; speaker fees from Bayer; and consultancy honoraria from Merck and Roche. XJ reports research grants from Janssen, MSD, and Bayer HealthCare; and speaker fees from Janssen and MSD, outside of the submitted work. DPJ reports speaker and consultancy fees from Janssen, outside of the submitted work. IML has relationships with drug companies, including AOP-Health, Actelion-Janssen, MSD, United Therapeutics, Pulnovo, Medtronic, Neutrolis and Sanofi; in addition to being an investigator in trials involving these companies, relationships include consultancy service, research grants, and membership of scientific advisory boards. HM reports research grants from Nippon Shinyaku; speaker and consultancy fees from Bayer, Janssen, and MSD; and speaker fees from Kaneka Medix, Mochida, Nippon Shinyaku, and Niprol, outside of the submitted work. LJM participated in an advisory board on CTEPH imaging for Janssen. GS has received advisory board and speaker fees from Acceleron, Bayer, Janssen, MSD, and Merck. CBW reports speaker fees from Actelion/Janssen, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, OrphaCare, and Pfizer; and consultancy honoraria from Actelion/Janssen and MSD. NHK has received 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, outside of the submitted work. RQ declares no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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.)

Background: Riociguat and balloon pulmonary angioplasty (BPA) are treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However, randomised controlled trials comparing these treatments are lacking. We aimed to evaluate the efficacy and safety of BPA versus riociguat in patients with inoperable CTEPH., Methods: In this phase 3, multicentre, open-label, parallel-group, randomised controlled trial done in 23 French centres of expertise for pulmonary hypertension, we enrolled treatment-naive patients aged 18-80 years with newly diagnosed, inoperable CTEPH and pulmonary vascular resistance of more than 320 dyn·s/cm 5 . Patients were randomly assigned (1:1) to BPA or riociguat via a web-based randomisation system, with block randomisation (block sizes of two or four patients) without stratification. The primary endpoint was change in pulmonary vascular resistance at week 26, expressed as percentage of baseline pulmonary vascular resistance in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of riociguat or had at least one BPA session. Patients who completed the RACE trial continued into an ancillary 26-week follow-up during which symptomatic patients with pulmonary vascular resistance of more than 320 dyn·s/cm 5 benefited from add-on riociguat after BPA or add-on BPA after riociguat. This trial is registered at ClinicalTrials.gov, NCT02634203, and is completed., Findings: Between Jan 19, 2016, and Jan 18, 2019, 105 patients were randomly assigned to riociguat (n=53) or BPA (n=52). At week 26, the geometric mean pulmonary vascular resistance decreased to 39·9% (95% CI 36·2-44·0) of baseline pulmonary vascular resistance in the BPA group and 66·7% (60·5-73·5) of baseline pulmonary vascular resistance in the riociguat group (ratio of geometric means 0·60, 95% CI 0·52-0·69; p<0·0001). Treatment-related serious adverse events occurred in 22 (42%) of 52 patients in the BPA group and five (9%) of 53 patients in the riociguat group. The most frequent treatment-related serious adverse events were lung injury (18 [35%] of 52 patients) in the BPA group and severe hypotension with syncope (two [4%] of 53 patients) in the riociguat group. There were no treatment-related deaths. At week 52, a similar reduction in pulmonary vascular resistance was observed in patients treated with first-line riociguat or first-line BPA (ratio of geometric means 0·91, 95% CI 0·79-1·04). The incidence of BPA-related serious adverse events was lower in patients who were pretreated with riociguat (five [14%] of 36 patients vs 22 [42%] of 52 patients)., Interpretation: At week 26, pulmonary vascular resistance reduction was more pronounced with BPA than with riociguat, but treatment-related serious adverse events were more common with BPA. The finding of fewer BPA-related serious adverse events among patients who were pretreated with riociguat in the follow-up study compared with those who received BPA as first-line treatment points to the potential benefits of a multimodality approach to treatment in patients with inoperable CTEPH. Further studies are needed to explore the effects of sequential treatment combining one or two medications and BPA in patients with inoperable CTEPH., Funding: Programme Hospitalier de Recherche Clinique of the French Ministry of Health and Bayer HealthCare., Translation: For the French translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests XJ, PB, HB, MJ, LS, OS, FP, CP, LG, EF, DM, MH, and GS report grants from the French Ministry of Health and Bayer HealthCare, during the conduct of the study. XJ reports grants from Acceleron, Janssen, and Merck Sharp & Dohme (MSD); personal fees from Janssen and MSD; and non-financial support from Janssen, outside of this study. MC reports personal fees from Menarini, and non-financial support from France Oxygène and Actelion, outside of this study. AC reports grants from Actelion and GlaxoSmithKline; personal fees from MSD, Chiesi, and GlaxoSmithKline; and non-financial support from Asten Santé, Johnson & Johnson, Chiesi, and Boehringer Ingelheim, outside of this study. VC reports grants from Boehringer Ingelheim; personal fees from Boehringer Ingelheim, Roche, Galapagos, Galecto, Shionogi, Fibrogen, RedX, Promedior, Celgene, Bristol Myers Squibb, and PureTech; and non-financial support from Boehringer Ingelheim and Roche, outside of this study. PDG reports personal fees from Bayer HealthCare and MSD, outside of this study. LS reports grants from Janssen, MSD, and GlaxoSmithKline; personal fees from Janssen and MSD; and non-financial support from Janssen, outside of this study. OS reports grants from GlaxoSmithKline, Acceleron, Janssen, and MSD; and personal fees from Gossamer Bio, Janssen, AOP Orphan, Ferrer, Acceleron, and MSD, outside of this study. FP reports grants from Acceleron, MSD, and Janssen; personal fees from MSD and Bayer HealthCare; and non-financial support from Bayer HealthCare, outside of this study. CT reports personal fees from Bayer HealthCare, Janssen, and GlaxoSmithKline; and non-financial support from Orkyn and Bayer HealthCare, outside of this study. EF reports personal fees from MSD, outside of this study. DM reports grants from Acceleron, Janssen, and MSD; and personal fees from Acceleron, Bayer HealthCare, Janssen, and MSD, outside of this study. MH reports grants from the French National Research Agency, Acceleron, Janssen, and MSD; and personal fees from Acceleron, Janssen, MSD, and United Therapeutics, outside of this study. GS reports personal fees from Acceleron, Janssen, MSD, and Bayer HealthCare, outside of this study. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: It is unknown whether pulmonary arterial hypertension (PAH) risk stratification instruments could be helpful to support the decision to list a patient for lung transplantation (LT). Our aim was to evaluate contemporary risk assessment tools in a cohort of PAH patients listed for LT., Methods: Consecutive PAH patients (without pulmonary veno-occlusive disease or unrepaired congenital heart disease) listed for LT at the French Pulmonary Hypertension Reference Center between January 2006 and December 2018 were included. At the time of listing, risk stratification was assessed using the ESC/ERS criteria, the REVEAL Lite 2 score and the COMPERA 2.0 method. The primary end point was overall survival after LT listing. Secondary outcome measures were mortality on waiting list and posttransplant survival., Results: One hundred and two patients were enrolled (mean age 38 ± 13 years, 69% females). Overall survival after listing was 72%, 58% and 46% at 1, 3 and 5 years respectively. Survival after LT listing was lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0001) and the REVEAL Lite 2 score (p = 0.04). The COMPERA 2.0 method discriminated post-listing survival of patients at high-risk, intermediate-high and intermediate-low risk (p = 0.04). The proportion of patients requiring urgent transplantation and extracorporeal life support as a bridge to transplantation was higher in the "high-risk" patients. Posttransplant survival was significantly lower in "high-risk" patients according to the ESC/ERS criteria (p = 0.0004)., Conclusions: High-risk PAH patients at the time of LT listing have poor outcomes, suggesting that LT should be considered earlier in the course of PAH remaining refractory to triple combination therapy with a parenteral prostacyclin., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported., Research Question: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD?, Study Design and Methods: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum)., Results: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m 2 ), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively., Interpretation: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH., Methods: Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined., Results: Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively)., Conclusion: Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes., Lay Summary: Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation., Competing Interests: Conflict of interest LS reports grants and personal fees from Actelion, grants and personal fees from MSD, grants and personal fees from GSK, outside the submitted work. MH reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants from GSK, grants and personal fees from MSD, personal fees from Ferrer, personal fees from Acceleron, outside the submitted work. GS reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants from GSK, grants and personal fees from MSD, outside the submitted work. OS reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants from GSK, grants and personal fees from MSD, personal fees from Ferrer, personal fees from Gossamer Bio, personal fees from Acceleron, outside the submitted work. DM reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from MSD, outside the submitted work. PDG reports personal fees from Actelion, MSD, Bayer, outside the submitted work. XJ reports grants and personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, outside the submitted work. DS reports personal fees from Intercept, personal fees from Biotest, personal fees from Abbvie , personal fees from Gilead sciences, outside the submitted work. PDG reports personal fees and non-financial support from ACTELION, personal fees and non-financial support from BAYER - MSD, personal fees and non-financial support from NOVARTIS, personal fees and non-financial support from VIFOR, personal fees from ABBOTT, personal fees and non-financial support from SERVIER, personal fees from ASTRA-ZENECA, non-financial support from AMGEN, outside the submitted work. NL reports personal fees and other from MSD, personal fees from AMICUS THERAPEUTICS, other from BMS, personal fees from NOVARTIS, personal fees from ASTRA-ZENECA, personal fees from BAYER, personal fees from AKCEA, outside the submitted work. MG, NE, MF, MJ, SR, DHL, CT, CC, GP, AC, PM, EAM, BD, RT, CB, HB, ACS, MR, NF, SP, DB, PM, VC, EB, AC, FD, CF, PH, JCDV have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH., Methods: From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed., Results: In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p < 0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival., Conclusions: Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The role of decreased pulmonary arterial (PA) compliance (C), equivalent to increased PA stiffness (1/C), as a critical determinant of right ventricular dysfunction and prognosis has been emphasized in pulmonary arterial hypertension (PAH)., Methods: This study retrospectively reviewed all incident patients diagnosed with idiopathic PAH according to right heart catheterization who were enrolled in the French Pulmonary Arterial Hypertension Network registry between 2006 and 2016 and who had complete baseline data allowing calculation of stiffness (PA pulse pressure/stroke volume index)., Results: In the 719 patients included (median age: 66 years; 53.7% female), PA stiffness was 1.49 mm Hg × m 2 /mL (interquartile ratio: 1.08-2.04 mm Hg × m 2 /mL). Stiffness was related to mean pulmonary artery pressure (mPAP) (r 2  = 0.33) and heart rate (r 2  = 0.15) but not to age or sex. Higher PA stiffness and higher pulmonary vascular resistance (PVR) were documented in high-risk vs low-risk patients, as defined according to the European Society of Cardiology/European Respiratory Society guidelines. The dispersion of the PVR × C product was as variable as patient age and mPAP, and C could not be estimated on the basis of PVR alone (95% limits of agreement of the bias: -50% to 54%). Although transplant-free survival differed across PA stiffness quartiles (P = .04), stiffness was not an independent predictor of long-term outcome (median follow-up duration: 2.43 years)., Conclusions: In incident idiopathic PAH, PA stiffness was related to mPAP and heart rate, and this finding outperformed the potential influences of age and sex. Baseline PA stiffness did not independently predict outcome. The great dispersion of the PVR × C product implied that PVR and PA stiffness were differently affected by the disease process., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Background: An obesity paradox, wherein patients who are obese have lower mortality, has been described in cardiopulmonary diseases, including pulmonary arterial hypertension (PAH). Our objective was to determine whether obesity and BMI are associated with mortality in patients with PAH., Methods: We assessed incident patients with idiopathic, drug-induced, and heritable PAH from the French Pulmonary Hypertension Network registry. Cox regression and Kaplan-Meier analysis were used to assess the association between BMI and obesity with all-cause mortality., Results: Of 1,255 patients included, 30% were obese. A higher proportion of women (65.1% vs 53.4%, P < .01), drug-induced PAH (28.9% vs 9.2%, P < .01), systemic hypertension, diabetes, and hypothyroidism were present in the obese group. More obese patients were in New York Heart Association class III (66.4% vs 57.1%), fewer were class IV (11.8% vs 16.9%, P < .01), and 6-min walk distance was lower (276 ± 121 vs 324 ± 146, P < .01). Right atrial pressure, pulmonary wedge pressure, and cardiac index were higher, whereas pulmonary vascular resistance was lower in patients who were obese. Neither BMI (hazard ratio [HR], 0.99; 95% CI, 0.97-1.01; P = .41) nor obesity (HR, 1.0; 95% CI, 0.99-1.01; P = .46) were associated with mortality in multivariable analyses. There was a significant interaction between age and obesity such that mortality increased among patients < 65 years of age who were morbidly obese (HR, 3.01; 95% CI, 1.56-5.79; P = .001)., Conclusions: Obesity was not associated with mortality in the overall population, but there was an age-obesity interaction with increased mortality among young patients who were morbidly obese. These results have implications for active weight management in younger patients who are morbidly obese who are otherwise candidates for lung transplantation., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Heritable pulmonary veno-occlusive disease (PVOD) is linked to mutations in the eukaryotic initiation factor 2 alpha kinase 4 (EIF2AK4) gene, leading to a loss of general control nonderepressible 2 (GCN2). The role of GCN2 expression in pulmonary vascular remodeling remains obscure. We sought to identify specific histologic and biologic features in heritable PVOD., Methods: Clinical data and lung histology of 24 PVOD patients (12 EIF2AK4 mutation carriers, 12 non-carriers) were submitted to systematic histologic analysis and semiautomated morphometry. GCN2 expression was quantified by Western blotting in 24 PVOD patients, 44 patients with pulmonary arterial hypertension (PAH; 23 bone morphogenetic protein receptor type II [BMPR2] mutation carriers, 21 non-carriers), and 3 experimental pulmonary hypertension models., Results: PVOD patients showed a significant decrease of pulmonary arterial patency (p < 0.0001) compared with healthy controls. Histology of EIF2AK4 mutation carriers was distinctive from non-carriers regarding (1) arterial remodeling, with significantly more severe intimal fibrosis (p = 0.001), less severe medial hypertrophy (p = 0.001), and (2) stronger muscular hyperplasia of interlobular septal veins (p = 0.002). GCN2 expression was abolished in heritable PVOD (p < 0.0001), but also importantly decreased in sporadic PVOD (p = 0.03) as well as in heritable (p = 0.002) and idiopathic PAH (p = 0.003); moreover, GCN2 was abolished in 2 experimental pulmonary hypertension models and importantly decreased in 1 model (p < 0.0001 for all models)., Conclusions: Pulmonary arterial remodeling in PVOD is present to an important extent. A significant decrease of GCN2 expression is a common denominator of all tested groups of PVOD and PAH, including their respective experimental models. Our results underline specific morphologic and biologic similarities between PAH and PVOD and let us consider both conditions rather in one large spectrum of disease than as two distinct and clear-cut entities., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Cardiopulmonary exercise testing (CPET) is frequently used for the evaluation of patients with pulmonary hypertension (PH). Non-operable distal chronic thromboembolic pulmonary hypertension (CTEPH) represents a unique subgroup of PH where microvascular disease resembling pulmonary arterial hypertension (PAH) may predominate and efficacious medical therapy is now available. However, little is known regarding the detailed CPET profile of patients with distal CTEPH, and whether ventilation and gas exchange responses are different from PAH., Methods: Forty-nine consecutive patients with non-operable distal CTEPH according to multidisciplinary team assessment and 45 PAH patients underwent CPET and right heart catheterization. Patients were followed up for a median of 3.2 years (interquartile range: 1.8 to 4.4)., Results: Pulmonary hemodynamics were similar in distal CTEPH and PAH groups, but patients with distal CTEPH achieved a lower percent predicted peak oxygen consumption (59 ± 13% vs 66 ± 14%, p < 0.05). At peak exercise, higher physiologic dead-space fraction (VD/VT) (0.45 ± 0.07 vs 0.35 ± 0.07, p < 0.0001) and higher arterial-to-end-tidal carbon dioxide gradient (9 ± 3 vs 5 ± 3 mm Hg, p < 0.0001) were observed in distal CTEPH compared with PAH. Ventilatory efficiency, expressed as VE/VCO 2 slope, was also more impaired in distal CTEPH (52.2 ± 10.1 vs 43.8 ± 8.4 liters/min, p < 0.0001). In the distal CTEPH group only, higher VD/VT was associated with lower peak oxygen consumption (r = -0.46, p = 0.003) and worse survival., Conclusions: Compared with PAH, a distinct pattern of response to exercise was observed in distal CTEPH, characterized by increased dead-space ventilation that resulted in worse ventilatory efficiency and greater impairment of exercise capacity. In distal CTEPH, dead-space ventilation correlated with exercise capacity and was associated with survival., (Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar., Methods: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm 5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292., Findings: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 73·0% of baseline in the macitentan group and to 87·2% in the placebo group (geometric means ratio 0·84, 95% CI 0·70-0·99, p=0·041). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%])., Interpretation: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated., Funding: Actelion Pharmaceuticals Ltd., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Since 2006 and 2007, patients in France with severe pulmonary hypertension (PH) who are at imminent risk of death, despite optimal treatment in the intensive care unit, are placed on a high-priority list (HPL) for heart-lung transplantation (HLT) or double-lung transplantation (DLT). We assessed the effect of this approach on the waiting list and outcomes after transplantation., Methods: We conducted a single-center, retrospective, before-and-after study of consecutive patients with severe group 1, 1', or 4 PH listed for DLT or HLT between 2000 and 2013 (ie, 6 years before and 6 years after HPL implementation)., Results: We included 234 patients. HPL implementation resulted in a significant decrease of the cumulative incidence of death on the waiting list at 1 and 2 years (p < 0.0001). The cumulative incidence of transplantation increased significantly from 48% to 76% after 2 years (p < 0.0001). Overall survival after transplantation was not significantly different between the pre-HPL and post-HPL era. In the HPL period, patients on the regular list who received a transplant had a nonsignificant trend toward improved overall survival compared with those on the HPL who received a transplant (at 1, 2, 3, and 5 years: 85%, 77%, 72%, and 72% vs 67%, 61%, 58%, and 50%; p = 0.053). Finally, survival after listing improved significantly after HPL implementation (at 1, 2, 3, and 5 years: 69%, 62%, 58%, and 54% vs 54%, 45%, 34%, and 26% before the HPL; p < 0.001)., Conclusions: HPL implementation was followed by higher survival of PH patients after registration on the DLT or HLT waiting list and by a higher cumulative incidence of transplantation among waiting-list patients., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on the clinical phenotypes and outcomes of PVOD/PCH., Methods: We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicêtre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specific therapy for pulmonary arterial hypertension was defined by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m 2 at the first reassessment after initiation of specific therapy for pulmonary arterial hypertension., Findings: We obtained data from Jan 1, 2003, to June 1, 2016, and identified 94 patients with sporadic or heritable PVOD/PCH (confirmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years [range 0-50.3] vs 60·0 years [6·7-81·4] years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in five (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefined criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No significant differences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated post-transplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively., Interpretation: Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients., Funding: None., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Extracorporeal life support (ECLS) can be used to sustain patients having cardiorespiratory failure after pulmonary endarterectomy (PEA). We aimed to assess outcomes and to identify factors associated with short-term survival among patients who required ECLS after PEA., Methods: We reviewed the charts of consecutive patients who required ECLS after PEA between 2005 and 2013 at our institution. Patients with failed PEA were scheduled for heart-lung transplantation, and patients with potentially reversible hemodynamic or respiratory failure were given appropriate supportive care until recovery., Results: Of the 829 patients who underwent PEA, 31 (3.7%) required postoperative ECLS. Of these, 23 continued to receive support, and 8 were listed for heart-lung transplantation during ECLS. Overall inhospital survival was 48.4% (15 of 31). Of patients listed for transplantation, 2 died while on support; 4 of the 6 patients undergoing transplantation lived to hospital discharge. Of the 23 supportive care patients, 11 (47.8%) were alive at hospital discharge. The factors associated with survival were younger age (p = 0.02), larger post-PEA decrease in mean pulmonary artery pressure (p = 0.020), lower post-PEA total pulmonary resistance (p = 0.008), and pure respiratory failure related to reperfusion edema or airway bleeding (p = 0.003)., Conclusions: Extracorporeal life support may be useful to support patients with complications after PEA either to recovery or to salvage transplantation., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Combined diffusion capacity of the lung for carbon monoxide (DLco) and nitric oxide (DLno) measurements allow for the estimation of pulmonary capillary blood volume (Vc) and alveolar membrane diffusion (Dm). The clinical usefulness of these measurements in pulmonary hypertension (PH) is unclear., Methods: Combined DLco and DLno were measured in 290 consecutive patients with precapillary PH (pulmonary arterial hypertension (PAH), n = 153; pulmonary veno-occlusive disease (PVOD), n = 33; and chronic thromboembolic pulmonary hypertension (CTEPH), n = 104). Clinical correlates of Vc and Dm were assessed in a sub-group of PAH patients without comorbidities., Results: PVOD patients compared with PAH and CTEPH patients displayed the lowest values of Vc (29.4 ± 16.8 ml vs 56.3 ± 26.5 ml vs 56.9 ± 26.2 ml, p < 0.01, respectively) and Dm (27.7 ± 11.6 ml/mm Hg/min vs 43.4 ± 14.8 ml/mm Hg/min vs 44.7 ± 17.7 ml/mm Hg/min, p < 0.01, respectively). The DLno/DLco ratio was highest in the PVOD group (5.82 ± 2.04 vs 4.95 ± 1.31 vs 5.16 ± 1.58, p < 0.05). In a sub-set of 69 PAH patients without comorbidities, Vc and Dm correlated significantly with functional capacity (6-minute walking distance, oxygen consumption) and New York Heart Association Functional Classification but not with invasive hemodynamics. Only Dm was significantly associated with survival. On receiver operating characteristic curve analysis, Vc, Dm, and DLno/DLco were not superior to DLco for discriminating PVOD from PAH or CTEPH., Conclusions: PVOD patients display higher values of the DLno/DLco ratio compared with PAH and CTEPH, suggesting proportionally greater reduction in Vc relative to Dm. However, partitioning of diffusion failed to be more clinically relevant than conventional DLco for detection of PVOD., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH)., Methods: Distensibility α during exercise (percentage change in vessel diameter per mm Hg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n = 33) were compared with control subjects (n = 26) and PVD with overt resting PH (PVD-PH) (n = 31)., Results: Resting mean pulmonary artery pressure (mPpa) levels were 14 ± 4, 20 ± 3, and 34 ± 10 mm Hg with corresponding exercise mPpa-cardiac output slopes of 1.5 ± 0.6, 3.5 ± 0.9, and 5.7 ± 3.2 mm Hg/L/min for control subjects and the PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of -4.5 to 4.5 mm Hg between calculated and measured mPpa. Distensibility α was lowest in the PVD-PH group, intermediate in the PVD-noPH group, and highest in control subjects (0.25 ± 0.14%/mm Hg vs 0.45 ± 0.24%/mm Hg vs 1.40 ± 0.45%/mm Hg, P < .0001). Distensibility α discriminated PVD-noPH from control subjects with a sensitivity of 88% and a specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH, with a strictly normal resting mPpa ≤ 20 mm Hg., Conclusions: Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The usefulness of α as a novel vascular index for the early detection of PVD warrants further validation., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: A novel formulation of bosentan was evaluated in children with pulmonary arterial hypertension (PAH) in FUTURE-1, which characterized its pharmacokinetic and clinical profile. The subsequent phase III, open-label, long-term extension study, FUTURE-2, aimed to provide long-term tolerability, safety and exploratory efficacy data., Methods: Children (≥2 and <12 years) with idiopathic or heritable PAH, who completed 12-week treatment in FUTURE-1 and for whom bosentan was considered beneficial were enrolled, and continued to receive bosentan 4 mg/kg twice-daily, which could be down-titrated to 2mg/kg if not tolerated. Safety and tolerability were evaluated via treatment-emergent adverse events (AEs), serious AEs, growth, and laboratory measurements. Exploratory efficacy endpoints included time to PAH worsening and long-term survival. All analyses were conducted on pooled data of both studies., Results: 36 patients were enrolled in FUTURE-1 and 33 continued in FUTURE-2. The overall median duration of exposure to bosentan was 27.7 (range 1.9-59.6) months. Treatment-emergent AEs occurred in 32 (88.9%) patients; AEs considered treatment-related in 15 (41.7%) patients. Of 51 serious AEs, three were considered treatment-related: two incidences of reported PAH worsening and one of autoimmune hepatitis. Six deaths occurred; none were considered treatment-related. Kaplan-Meier event-free estimates of PAH worsening were 78.9% and 73.6% at 2 and 4 years, respectively., Conclusions: The pediatric bosentan formulation was generally well tolerated, its safety profile comparable to that of the adult formulation when used in children. The results are in line with the efficacy profile of bosentan in previous pediatric and adult PAH studies of shorter duration., (Copyright © 2015. Published by Elsevier Ireland Ltd.)

Background: Various cardiovascular magnetic resonance (CMR) imaging indices are used to assess pulmonary hypertension (PH; mean pulmonary artery pressure ≥ 25 mm Hg). We compared the value of CMR indices to diagnose precapillary PH in treatment-naive patients evaluated for the first time for known or suspected pulmonary vascular disease., Methods: Right heart catheterization and CMR were performed within 48 hours of each other in 85 consecutive subjects. The tricuspid annular plane systolic excursion, right ventricular (RV) fractional area change (RVFAC), RV ejection fraction, systolic eccentricity index, and RV end-diastolic area over left ventricular end-diastolic area ratio were calculated. The pulmonary artery trunk diameter, main pulmonary artery relative area change, and mean flow velocity were also calculated., Results: There were 20 non-PH subjects (14 women/6 men, 55 ± 14 years of age, mean pulmonary artery pressure [mPAP] = 20 ± 4 mm Hg) and 65 precapillary PH subjects (32 women/33 men, 60 ± 15 years of age; P = not significant; mPAP = 46 ± 12 mm Hg; 54% with chronic thromboembolic PH). All CMR indices showed essentially the same (good) value to rule in precapillary PH. The RV end-diastolic area over left ventricular end-diastolic area ratio and RVFAC, which are relatively easy to measure, had a large area under the receiver operating characteristic curve (0.93, with optimal cut-off > 0.96, and 0.92, with optimal cut-off ≤ 35%, respectively), not significantly different from RV ejection fraction. In addition, RVFAC > 45% was documented in none of 65 PH and in 10 of 20 non-PH; thus, in a population similar to ours, RVFAC measurement could potentially have avoided unnecessary catheterization in 50% of non-PH subjects., Conclusions: In treatment-naive subjects in whom pulmonary vascular disease is highly suspected, right-sided CMR indices distinguish between PH and non-PH patients. RVFAC might have particular value in excluding precapillary PH., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling., Methods: This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain., Results: We identified 171 carriers affected with PAH with a mutated BMPR2. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 ± 12.1 years and 35.7 ± 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 ± 3.5 and 17.4 ± 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain., Conclusions: Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins and a dismal prognosis. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal models (mouse, rat, and rabbit). Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (43.2%). In three different animal models, cyclophosphamide was able to induce PH on the basis of hemodynamic, morphological, and biological parameters. In these models, histopathological assessment confirmed significant pulmonary venous involvement highly suggestive of PVOD. Together, clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon, but severe, pulmonary vascular complication of alkylating agents., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated., Methods: This observational study evaluated newly diagnosed (≤1 year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment., Results: After 4 months of epoprostenol therapy, improvement was observed for treatment naïve patients (n=43) and for patients who had received previous PAH-specific therapy (n=35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p<0.0001) and 41 m (p=0.03), cardiac index increased by 1.2 (p<0.0001) and 0.5 L·min(-1)·m(-2) (p=0.006), and pulmonary vascular resistance decreased by 700 (p<0.0001) and 299 dyn·s·cm(-5) (p=0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p=0.03). The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3 years, respectively)., Conclusions: First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Novel noninvasive tools may improve the management of patients with pulmonary hypertension (PH) experiencing heart failure. Major right ventricle overload leads to decreased stroke volume, which shortens left ventricular ejection time (LVET). Our arterial tonometry study tested the hypothesis that LVET carries prognostic value in patients with precapillary PH with heart failure., Methods: Clinical, biologic, and radial artery tonometry variables were prospectively obtained at admission and at day 3 to 5 in 53 consecutive patients with PH admitted to our ICU for clinical deterioration. LVET was measured from the reconstructed aortic pressure curve., Results: Overall ICU mortality (median stay, 5 days) was 17%. At admission, the LVET was shorter in patients with unfavorable outcome (median, 228 milliseconds [25th-75th percentiles, 212-278 milliseconds] vs 257 milliseconds [237-277 milliseconds], P = .032), whereas other tonometric indices were similar. The LVET at entry (237 milliseconds) had 73% sensitivity and 89% specificity for identifying death in the ICU. Other prognostic factors at admission were higher serum levels of brain natriuretic peptide (BNP) and creatinine and lower natremia. Dobutamine requirement, higher furosemide dose, and higher oxygen flow were associated with unfavorable outcome. At the second evaluation, higher serum levels of creatinine and BNP, higher furosemide dose and oxygen flow, and dobutamine or norepinephrine requirement were associated with poor outcome. The change in LVET between admission and follow-up measurement was not associated with outcome. The 90-day mortality was 28%., Conclusions: Shortened LVET at ICU admission was a prognostic factor in patients with precapillary PH with heart failure. Previously documented prognostic factors were also confirmed in this cohort.

Background: The occurrence and mechanisms of nocturnal hypoxemia in precapillary pulmonary hypertension (PH) are not clearly defined., Methods: In an observational, prospective, and transversal design, we studied 46 clinically stable patients with PH and a BMI < 35 kg/m(2), an FEV(1) > 60% predicted, and idiopathic pulmonary arterial hypertension (n = 29) or chronic thromboembolic pulmonary hypertension (n = 17). They underwent nocturnal polysomnography with transcutaneous capnography., Results: Most patients (69.6%) had New York Heart Association functional class II disease. Mean pulmonary artery pressure was 44 ± 13 mm Hg, and the cardiac index was 3.2 ± 0.6 L/min/m(2). Duration of sleep time spent with oxygen saturation as measured by pulse oximetry <90% was 48.9% ± 35.9%, and 38 of 46 patients (82.6%) had nocturnal hypoxemia. Mean apnea-hypopnea index was 24.9 ± 22.1/h, and 41 patients (89%) had sleep apnea. The major mechanism of nocturnal hypoxemia was a ventilation/perfusion mismatch alone or associated with obstructive apneic events. Multivariate logistic regression identified both FEV(25%-75%) (OR, 0.9519; 95% CI, 0.9089-0.9968; P = .036) and mean pulmonary artery pressure (OR, 1.1068; 95% CI, 1.0062-1.2175; P = .037) as significant predictors of nocturnal hypoxemia. Clinical symptoms were not predictive of nocturnal hypoxemia., Conclusions: The occurrence of nocturnal hypoxemia is high in PH and should be screened for systematically. Further studies are needed to determine the impact of nocturnal hypoxemia on the outcome of patients with PH., Trial Registry: ClinicalTrials.gov; No.: NCT01371669; URL: www.clinicaltrials.gov

Background: Precapillary pulmonary hypertension (PH) is a complication of pulmonary Langerhans cell histiocytosis (PLCH) associated with increased mortality. However, outcomes and efficacy of pulmonary arterial hypertension (PAH) therapies in patients with PH complicating PLCH(PLCH-PH) remain unknown., Methods: Consecutive patients with PLCH with PH confirmed by right-sided heart catheterization were included in the study. Characteristics at baseline and during follow-up as well as survival were analyzed., Results: Twenty-nine patients were studied. Baseline characteristics of patients with PLCH-PH wereas follows: 83% of patients in World Health Organization (WHO) functional class III to IV, mean 6-min walk distance of 355 ±95 m, mean pulmonary arterial pressure (mPAP) of 45 ±14 mm Hg,cardiac index of 3.2± 0.9 L/min/m 2 , and pulmonary vascular resistance (PVR) of 555 ±253 dyne/s/cm 5. Use of PAH therapy in 12 patients was followed by an improvement in mPAP (56±14 mm Hg and 45±12 mm Hg, P 5 .03) and PVR (701±239 dyne/s/cm 5 and 469±210 dyne/s/cm 5 , P = .01) between baseline and follow-up evaluations. No significant oxygen worsening was observed in the treated group. The 1-, 3-, and 5-year survival estimates of the 29 patients were 96%, 92%, and 73%,respectively. Except a trend toward a better survival rate associated with the use of PAH therapy,WHO functional class was the only variable significantly associated with death., Conclusions: In this group of patients, PAH therapies improved hemodynamics without oxygen worsening or pulmonary edema. WHO functional class was the only prognostic factor identified.Prospective clinical trials focusing on this population of patients are warranted

Background: Recent guidelines have proposed first-line combination therapy as a potential strategy for the treatment of functional class IV pulmonary arterial hypertension (PAH)., Methods: We analyzed efficacy and safety of upfront epoprostenol and bosentan combination therapy in consecutive patients with idiopathic, heritable, or anorexigen-associated PAH and compared outcomes with matched controls treated by epoprostenol monotherapy., Results: Data for 16 functional class III patients and 7 functional class IV patients were analyzed. Baseline 6-minute walk distance (6MWD) was 287 ± 133 meters, mean pulmonary artery pressure was 65 ± 12 mm Hg, cardiac index was 1.8 ± 0.3 L/min/m(2), and pulmonary vascular resistance (PVR) was 1493 ± 398 dynes/sec/cm(5). After 4 months, 6MWD and PVR significantly improved to 421 ± 100 meters and 784 ± 364 dynes/sec/cm(5), respectively. These improvements were maintained long-term (30 ± 19 months). At 1, 2, 3, and 4 years, overall survival estimates were 100%, 94%, 94%, and 74%, and transplant-free survival estimates were 96%, 85%, 77%, and 60%, respectively. Compared with matched controls started on epoprostenol monotherapy, there was a trend to an improvement in overall survival (p = 0.07)., Conclusions: Initial combination therapy with epoprostenol and bosentan in patients with severe PAH is associated with improvements in important outcomes such as functional class, exercise capacity, and hemodynamics. This combination strategy might also favorably affect overall and transplant-free survival., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO(2) at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice., (Copyright (c) 2010. Published by Elsevier Ltd.)

The last decade has witnessed a remarkable increase in the number of effective treatment options available for the management of patients with pulmonary arterial hypertension. In this regard, agents belonging to the therapeutic classes that specifically target the prostacyclin, endothelin and nitric oxide pathways have shown the greatest efficacy in clinical studies to date. These various drug treatments have individually been shown to confer improvements in symptoms, exercise capacity, pulmonary haemodynamics and possibly survival in different patient subgroups. However, pulmonary arterial hypertension is characterised by dysregulation of a variety of pathways. In addition, disease worsening is inevitable for the majority of patients receiving monotherapy. As a consequence, there is increasing interest in the use of treatment combinations in order to target multiple targets with the aim of restoring normal pulmonary vascular function in order to improve clinical status. Indeed, use of multiple specific-treatment regimens is now part of routine clinical practice and is emphasized in recently published therapeutic guidelines. This review details the rationale for the different combination strategies and examines the clinical evidence in favour of some of the approaches that have been evaluated., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Background: At diagnosis of pulmonary arterial hypertension (PAH), some patients are considered to have a "near-normal" 6-min walk distance (6MWD) (ie, > 450 m). Because they are generally excluded from randomized controlled trials, little is known about these patients., Methods: We analyzed the baseline characteristics and treatment responses of 49 consecutive patients with a 6MWD > 450 m at the time of newly diagnosed PAH. Data from this cohort were then compared with data from hemodynamically matched patients with a 6MWD < or = 450 m., Results: Patients with a 6MWD > 450 m were either in World Health Organization (WHO) functional class (FC) II (n = 23) or III (n = 26) at baseline. Compared with patients in FC II, those in FC III had more severe hemodynamic impairment (ie, a lower cardiac index and higher pulmonary vascular pressures and resistance) but similar 6MWD. At first evaluation after initiation of PAH-specific treatment (3-6 months), FC improved (FC I-II: n = 38; FC III: n = 11, P < .005) and cardiac index increased. However, 6MWD remained unchanged. Compared with matched patients with a 6MWD < or = 450 m (n = 98), individuals with a 6MWD > 450 m were approximately 9 years younger (P = .0006) and had a lower BMI (P = .0009)., Conclusions: Anthropometric characteristics such as younger age and lower BMI may explain higher 6MWD in some PAH patients. In the cohort of patients with a 6MWD > 450 m, hemodynamic indices and WHO FC were more sensitive than 6MWD in detecting changes secondary to PAH-specific treatments.

Background: The POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal immunoglobulin, Skin changes) syndrome is a rare disease that entails a specific risk for pulmonary arterial hypertension., Methods and Results: We report on 2 patients who suffered from POEMS syndrome and pulmonary arterial hypertension for whom a detailed hemodynamic pulmonary study was obtained before and after steroid treatment. Patient 1 had defined post-capillary pulmonary hypertension (PH) ascribed to an abnormally high cardiac output. Patient 2 suffered from severe pre-capillary PH. Under high-dose steroids treatment, clinical symptoms disappeared and PH assessment by sequential hemodynamic study showed a clear-cut improvement in both patients., Conclusion: First-line therapy should include corticosteroids in POEMS syndrome-related PH.

Study Objective: Immune and inflammatory mechanisms could play a significant role in pulmonary arterial hypertension (PAH) genesis or progression, especially in patients with connective tissue diseases. Immunosuppressive therapy should be better evaluated in this setting., Study Design: Monocentric retrospective study., Patients: We reviewed the clinical and hemodynamic effects of immunosuppressants administered as first-line monotherapy to 28 consecutive patients with connective tissue disease-associated PAH., Interventions: All patients received a monthly IV bolus of cyclophosphamide, 600 mg/m2, for at least 3 months, and 22 of 28 patients received systemic glucocorticosteroids. Responders to immunosuppressive therapy were defined as patients who remained in New York Heart Association (NYHA) functional class I or II with sustained hemodynamic improvement after at least 1 year of immunosuppressive therapy without addition of prostanoids, phosphodiesterase type 5 inhibitors, or endothelin receptor antagonists., Results: Eight of 28 patients (systemic lupus erythematosus [SLE], n = 5; mixed connective tissue disease [MCTD], n = 3) [29%] were responders. These patients had a significantly improved 6-min walking distance (available in five patients) and a significant improvement in hemodynamic function. No patients with systemic sclerosis responded, while 5 of 12 patients with SLE and 3 of 8 patients with MCTD did respond. Survival analysis indicated that responders had a better survival than nonresponders. Patients with a lower baseline NYHA functional class and better baseline pulmonary hemodynamics (p < 0.05) were more likely to benefit from immunosuppressive therapy., Conclusion: PAH associated with SLE or MCTD might respond to a treatment combining glucocorticosteroids and cyclophosphamide.

Purpose: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis and vascular remodeling of small pulmonary arteries inducing a fixed pulmonary arterial obstruction and persistent elevation of pulmonary arterial resistance. Conventional treatment is based on simple measures (exercise limitation) and non-specific drugs (warfarine, diuretics, oxygen)., Current Knowledge and Key Points: Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients, presumably because fixed pulmonary arteriopathy predominate over vasoconstriction. Intravenous prostacyclin (epoprostenol) and endothelin receptor antagonists have vasodilator and antiproliferative properties. Epoprostenol therapy has resulted in significant improvements in prognosis of this disease and this drug remains the first-line treatment of the most severe patients. Bosentan is an interesting first-line treatment for NYHA functional class III patients. Availability of novel specific drugs (endothelin receptor type A antagonists, prostacyclin analogues, type 5 phosphodiesterase inhibitors) open new perspectives in treatment of PAH. The long-term benefit of these drugs remains to be evaluated and their respective place in treatment of these patients is still uncertain. We here present the different therapeutic alternatives available in the PAH and propose an algorithm for treatment of these patients., Future Prospects and Projects: The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension.