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Rationale: Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. Objectives: To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-associated pulmonary arterial hypertension and to determine the changes in presentations and survival over the past decade in the United Kingdom and Ireland. Methods: All consecutive newly diagnosed patients from 2001 to 2009 were identified prospectively. Measurements and Main Results: A total of 482 patients (93% idiopathic, 5% heritable, and 2% anorexigen-associated pulmonary arterial hypertension) were diagnosed, giving rise to an estimated incidence of 1.1 cases per million per year and prevalence of 6.6 cases per million in 2009. Younger patients (age ≤ 50 yrs) had shorter duration of symptoms, fewer comorbidities, better functional and exercise capacity, higher percent diffusing capacity of carbon monoxide, more severe hemodynamic impairment, but better survival compared with older patients. In comparison with the earlier cohorts, patients diagnosed in 2007-2009 were older, more obese, had lower percent diffusing capacity of carbon monoxide,(,) and more comorbidities, but better survival. Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL) equation, REVEAL risk score, and Pulmonary Hypertension Connection Registry survival equation accurately predicted survival of our incident cohort at 1 year. Conclusions: This study highlights the influence of age on phenotypes of incident pulmonary arterial hypertension and has shown the changes in demographics and epidemiology over the past decade in a national setting. The results suggest that there may be two subtypes of patients: the younger subtype with more severe hemodynamic impairment but better survival, compared with the older subtype who has more comorbidities. [ABSTRACT FROM AUTHOR]

Rationale: Pulmonary arterial hypertension in association with connective tissue disease (CTD-PAH) has historically had a poor prognosis, with a 1-year survival rate among patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available.Objectives: To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hypertension service.Methods: National registry of all incident cases of CTD-PAH diagnosed consecutively between January 2001 and June 2006.Measurements and Main Results: Patients with CTD-PAH (429; 73% SSc-PAH) were diagnosed by a catheter-based approach. One- and 3-year survival rates were 78 and 47% for patients with isolated SSc-PAH. Survival was worse for those with respiratory disease-associated SSc-PAH (3-yr survival, 28%; P = 0.005) whereas survival among patients with exercise-induced SSc-PAH was superior (3-yr survival, 86%; P = < 0.001). Age, sex, mixed venous oxygen saturation, and World Health Organization functional class were independent predictors of survival in isolated SSc-PAH. Nineteen percent of patients with exercise-induced SSc-PAH and 39% of patients with isolated SSc-PAH who were in functional classes I and II had evidence of disease progression. The prevalence of diagnosed SSc-PAH is 2.93 per 1 million. The 3-year survival rate of 75% for those with pulmonary arterial hypertension associated with systemic lupus erythematosus (SLE-PAH) was significantly better than that for patients with SSc-PAH (P = 0.01).Conclusions: Survival of patients with SSc-PAH in the modern treatment era is better than in historical series. A significant proportion of patients with mild functional impairment or exercise-induced SSc-PAH have evidence of disease progression. Survival of patients with respiratory disease-associated pulmonary hypertension is inferior. SLE-PAH has a better prognosis than SSc-PAH. [ABSTRACT FROM AUTHOR]

Rationale: The management of chronic thromboembolic pulmonary hypertension (CTEPH) has changed over recent years with the growth of pulmonary endarterectomy surgery and the availability of disease-modifying therapies.Objectives: To investigate the prognosis of CTEPH in a national setting during recent years.Methods: All incident cases diagnosed in one of the five pulmonary hypertension centers in the United Kingdom between January 2001 and June 2006 were identified prospectively. Information regarding baseline characteristics, treatment, and follow-up was subsequently collected from hospital records.Measurements and Main Results: A total of 469 patients received a diagnosis, of whom 148 (32%) had distal, nonsurgical disease. One- and three-year survival from diagnosis was 82 and 70% for patients with nonsurgical disease and 88 and 76% for those treated surgically (P = 0.023). Initial functional improvement in patients with nonsurgical disease was noted but did not persist at 2 years. Significant functional and hemodynamic improvements were seen in surgically treated patients with an increase in six-minute-walk distance of 105 m (P < 0.001) at 3 months. Five-year survival from surgery in the 35% of patients who survived to 3 months but had persistent pulmonary hypertension was 94%.Conclusions: The prognosis in nonsurgical disease has improved. We have confirmed the previously described good outcome in surgically treated disease. However, we have also demonstrated that the long-term prognosis for patients who have persistent pulmonary hypertension at 3 months after surgery is good. The observed improvements in outcome during the modern treatment era reinforce the importance of identifying patients with this increasingly treatable condition. [ABSTRACT FROM AUTHOR]

Background: Data obtained in human lung tissue and preclinical models suggest that oxidative stress and increased apoptosis signal-regulating kinase 1 (ASK1) activity might have a prominent role in the pathobiology of pulmonary arterial hypertension (PAH). The purpose of this study was to determine the efficacy, safety, and tolerability of the ASK1 inhibitor selonsertib compared with placebo in patients with PAH., Methods: We did a randomised, double-blind, placebo-controlled, phase 2 trial at 46 centres located in Canada, France, Germany, Italy, the Netherlands, Spain, the UK, and the USA. Participants were aged 18-75 years and had an established diagnosis of idiopathic or hereditary PAH, or PAH associated with connective tissue disease, drugs or toxins, human immunodeficiency virus, or repaired congenital heart defects. Patients were stratified by PAH aetiology and background therapy, and randomly assigned (1:1:1:1) using an interactive voice-response or web-response system to placebo or selonsertib 2 mg, 6 mg, or 18 mg administered orally once daily. Both placebo and selonsertib were in tablet form. The primary efficacy endpoint was change in pulmonary vascular resistance, measured by right heart catheterisation, from baseline to week 24 in the full analysis set. Pair-wise comparisons between each of the selonsertib groups and the placebo group were made with a stratified Wilcoxon (van Elteren) rank sum test for participants without major protocol deviations who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02234141., Findings: Between Dec 3, 2014, and Nov 13, 2015, 151 patients were enrolled and randomly assigned. Of 150 participants who received selonsertib or placebo, 134 (89%) completed 24 weeks of the randomly assigned treatment; all were on background PAH therapy (138 [92%] on combination therapy). 90 (60%) patients were in functional class II and 60 (40%) in functional class III. Mean baseline pulmonary vascular resistance was 772 (SD 334) dyn·s/cm 5 . Change in pulmonary vascular resistance was 6·0 dyn·s/cm 5 (SD 28·0; n=31) for placebo, and 35·0 (35·4) dyn·s/cm 5 (n=35; p=0·21 vs placebo) for 2 mg selonsertib, -28·0 (30·2) dyn·s/cm 5 (n=34; p=0·27 vs placebo) for 6 mg selonsertib, and -21·0 (37·9) dyn·s/cm 5 (n=36; p=0·60 vs placebo) for 18 mg selonsertib. The most frequent adverse events were headache (17 [15%]), abnormal dreams (eight [7%]), nausea (seven [6%]), and diarrhoea (seven [6%]) in the selonsertib groups, and headache (six [16%]), nausea (five [14%]), and diarrhoea (two [5%]) in the placebo group. Serious adverse events occurred in 23 (20%) of 113 selonsertib-treated patients and seven (19%) of 37 patients who received placebo., Interpretation: Selonsertib once daily for 24 weeks did not lead to a significant reduction in pulmonary vascular resistance or to clinical improvement in patients with PAH, but appeared to be safe and well tolerated. Although these data do not support the clinical use of selonsertib in PAH, further study of the potential of targeting the ASK1-p38 pathway in PAH is warranted., Funding: Gilead Sciences., Competing Interests: Declaration of interests SR reports remuneration for lectures and consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, Bristol-Myers Squibb, Ferrer, Janssen, Merck Sharp & Dohme, Novartis, Pfizer, United Therapeutics, and Vifor; and grants to his institution from Actelion, AstraZeneca, Bayer, Novartis, and United Therapeutics. JF reports remuneration for lectures and consultancy from Actelion, Gilead, and United Therapeutics. VVM reports grant support from Acceleron, Actelion, Gilead, Reata, Sonovie, and United Therapeutics; and remuneration for scientific consulting from Acceleron, Actelion, Altavant, Caremark, CiVi Biopharma, Gossamer Bio, Liquidia, Limited Liability Company, and United Therapeutics. FR has received remuneration for consultancy and advisory roles, and research grants from Actelion, Bayer, Gilead, and United Therapeutics. TJL has received personal fees for lectures and consultancy from Acceleron Pharma, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, Merck Sharp & Dohme, Pfizer, and United Therapeutics; and grants to his institution from Acceleron Pharma, Actelion, Bayer, Bellerophon, Gilead, Janssen-Cilag, Pfizer, and United Therapeutics. RJW has received research grants from Bayer, Gilead, Merck Sharp & Dohme, PhaseBio, and United Therapeutics; and reports personal fees for consultancy from Altavant, Bayer, Gilead, Merck Sharp & Dohme, and PhaseBio. AJP has received research grants assistance with travel and honoraria from Actelion, Bayer, Gilead, GlaxoSmithKline, and Merck Sharp & Dohme. FG reports remuneration for lectures from Actelion, Bayer, Janssen, and Merck Sharp & Dohme; and grants to his institution from Actelion, Bayer, and Janssen. RE is an employee of Gilead. GB and CS are former employees of Gilead. CS reports consulting fees from Respira. RPF has received reimbursement for travel to investigator meetings and advisory board meetings from Actelion, Gilead, and United Therapeutics; and consulting fees from Actelion and Liquidia., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: This prospective, randomized, controlled, multicentre study aimed to evaluate efficacy and safety of exercise training in patients with pulmonary arterial (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)., Methods and Results: For the first time a specialized PAH/CTEPH rehabilitation programme was implemented in 11 centres across 10 European countries. Out of 129 enrolled patients, 116 patients (58 vs. 58 randomized into a training or usual care control group) on disease-targeted medication completed the study [85 female; mean age 53.6 ± 12.5 years; mean pulmonary arterial pressure 46.6 ± 15.1 mmHg; World Health Organization (WHO) functional class II 53%, III 46%; PAH n = 98; CTEPH n = 18]. Patients of the training group performed a standardized in-hospital rehabilitation with mean duration of 25 days [95% confidence interval (CI) 17-33 days], which was continued at home. The primary endpoint, change of 6-min walking distance, significantly improved by 34.1 ± 8.3 m in the training compared with the control group (95% CI, 18-51 m; P < 0.0001). Exercise training was feasible, safe, and well-tolerated. Secondary endpoints showed improvements in quality of life (short-form health survey 36 mental health 7.3 ± 2.5, P = 0.004), WHO-functional class (training vs. control: improvement 9:1, worsening 4:3; χ2P = 0.027) and peak oxygen consumption (0.9 ± 0.5 mL/min/kg, P = 0.048) compared with the control group., Conclusion: This is the first multicentre and so far the largest randomized, controlled study on feasibility, safety, and efficacy of exercise training as add-on to medical therapy in PAH and CTEPH. Within this study, a standardized specialized training programme with in-hospital start was successfully established in 10 European countries., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background: Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality., Methods: Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850., Findings: Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period., Interpretation: Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality., Funding: Bayer AG, Merck Sharp & Dohme., Competing Interests: Declaration of interests MMH has received fees for consultations and lectures from Acceleron, Actelion, Bayer, Janssen, Merck Sharpe & Dohme (MSD), and Pfizer. HA-H is an investigator of clinical studies with Actelion, Bayer AG, and Pfizer. RLB reports grants from Bellerophon, Bayer AG, Actelion, and EIGER. PAC reports grants and personal fees from Bayer AG, Actelion, and GlaxoSmithKline (GSK). JSRG reports grants and personal fees from Actelion, Bayer AG, United Therapeutics, and MSD, personal fees from Arena, Bellopheron, Acceleron, Complexa, and Pfizer, and grants from GSK and Amco. EG reports fees for lectures and consultations from Actelion, Bayer AG, GSK, MSD, United Therapeutics, and Pfizer. PJ reports personal fees from Actelion, Bayer AG, Reata Pharmaceuticals, AOP Orphan, and MSD, and is an investigator for Actelion, Bayer AG, and Reata Pharmaceuticals. JRK reports that his institution has received grant support for clinical trials and basic science research in pulmonary hypertension from Actelion, Bayer, Lung Biotechnology, and United Therapeutics. DL reports honoraria, consultation fees, research support, and travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, and United Therapeutics. VVM has received research support or grants from Acceleron Pharma, Actelion, Bayer AG, Reata Pharmaceuticals, SoniVie, and United Therapeutics, and has served as a consultant and on advisory committees for Acceleron, Actelion, Altavant, Bayer, Caremark, CiVi BioPharma, Gossamer, Liquidia, and United Therapeutics. GMBM reports lecture and consultation fees from Bayer AG, Eli Lilly, and GSK. ASP reports fees for research grants, support for travel to meetings, and honoraria from Actelion, Bayer AG, GSK, MSD, Pfizer, and United Therapeutics. TP reports grants and personal fees from Actelion–Janssen, grants from United Therapeutics, Reata Pharmaceuticals, and Bayer, and personal fees from Bayer and Pfizer. SR reports remunerations for lectures and consultancy from Abbott, Acceleron, Actelion, Arena, Bayer, Bristol-Myers Squibb, Ferrer, GSK, Janssen, MSD, Novartis, Pfizer, and United Therapeutics, and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. AV-N 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, funding outside of the current study), has received speakers fees from Johnson & Johnson and Ferrer in the past 3 years, and served as a member of the scientific advisory board of Morphogen-XI. RJW reports grants and personal fees from Bayer AG and personal fees from MSD. MC, FK, CM, and KP are employees of Bayer AG. HAG reports personal fees and consultancy fees from Actelion, Bayer AG, GSK, Novartis, and Pfizer, consultancy fees from Bellerophon Pulse Technologies and MSD, and grants from Deutsche Forschungsgemeinschaft. GS reports personal fees and non-financial support from Actelion, Bayer, and MSD. S-AC, CDV, and JO-A declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Health-related quality of life (HRQoL) scores assess symptom burden in pulmonary arterial hypertension (PAH) but data regarding their role in prognostication and risk stratification are limited. We assessed these relationships using the emPHasis-10 HRQoL measure.1745 patients with idiopathic PAH (IPAH), drug-induced PAH (DPAH), heritable PAH (HPAH) (collectively "(I/D/H)PAH"), or connective tissue disease-associated PAH (CTD-PAH), who had completed emPHasis-10 questionnaires at one of six UK referral centres between 2014 and 2017, were identified. Correlations with exercise capacity and World Health Organization (WHO) functional class were assessed, and exploratory risk stratification thresholds were tested.Moderate correlations were seen between emPHasis-10 scores and 6-min walk distance (r=-0.546), incremental shuttle walk distance (r=-0.504) and WHO functional class (r=0.497) (all p<0.0001). Distribution of emPHasis-10 score differed significantly between each WHO functional class (all p<0.0001). On multivariate analysis, emPHasis-10 score, but not WHO functional class, was an independent predictor of mortality. In a risk stratification approach, scores of 0-16, 17-33 and 34-50 identified incident patients with 1-year mortality of 5%, 10% and 23%, respectively. Survival of patients in WHO functional class III could be further stratified using an emPHasis-10 score ≥34 (p<0.01). At follow-up, patients with improved emPHasis-10 scores had improved exercise capacity (p<0.0001) and patients who transitioned between risk groups demonstrated similar survival to patients originally in those risk groups.The emPHasis-10 score is an independent prognostic marker in patients with (I/D/H)PAH or CTD-PAH. It has utility in risk stratification in addition to currently used parameters. Improvement in emPHasis-10 score is associated with improved exercise capacity., Competing Interests: Conflict of interest: R.A. Lewis reports non-financial support for meeting attendance from Actelion Pharmaceuticals, outside the submitted work. Conflict of interest: I. Armstrong has nothing to disclose. Conflict of interest: C. Bergbaum has nothing to disclose. Conflict of interest: M.J. Brewis has nothing to disclose. Conflict of interest: J. Cannon has nothing to disclose. Conflict of interest: A. Charalampopoulos reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees and non-financial support from Novartis, and grants from Bayer and GSK, outside the submitted work. Conflict of interest: A.C. Church has nothing to disclose. Conflict of interest: J.G. Coghlan has nothing to disclose. Conflict of interest: R.J. Davies has nothing to disclose. Conflict of interest: K. Dimopoulos has nothing to disclose. Conflict of interest: C. Elliot reports personal fees for advisory board work and lectures from Actelion Pharmaceuticals, GlaxoSmithKline and Bayer, as well as grants from Pfizer, Actelion Pharmaceuticals and Bayer, outside the submitted work. Conflict of interest: J.S.R. Gibbs reports personal fees from Acceleron, Arena, Bayer, Complexa, Pfizer and GSK, as well as grants and personal fees from Actelion and United Therapeutics, outside the submitted work. Conflict of interest: W. Gin-Sing has nothing to disclose. Conflict of interest: G. Haji has nothing to disclose. Conflict of interest: A.G. Hameed has nothing to disclose. Conflict of interest: L.S. Howard has nothing to disclose. Conflict of interest: M.K. Johnson reports grants and personal fees for meeting attendance, lectures and advisory board work from Actelion and MSD, outside the submitted work. Conflict of interest: A. Kempny has nothing to disclose. Conflict of interest: D.G. Kiely reports grants, personal fees and non-financial support from Actelion, Bayer and GSK, as well as personal fees and non-financial support from MSD, outside the submitted work. Conflict of interest: F. Lo Giudice has nothing to disclose. Conflict of interest: C. McCabe has nothing to disclose. Conflict of interest: A.J. Peacock has nothing to disclose. Conflict of interest: O. Peleyeju has nothing to disclose. Conflict of interest: J. Pepke-Zaba has nothing to disclose. Conflict of interest: G. Polwarth has nothing to disclose. Conflict of interest: L. Price reports educational grants from Actelion J&J, during the conduct of the study. Conflict of interest: I. Sabroe reports grants and personal fees for advisory board work from AstraZeneca, as well as grants from GSK, outside the submitted work. Conflict of interest: B.E. Schreiber has nothing to disclose. Conflict of interest: K. Sheares reports educational support from Actelion, Bayer and GSK, as well as personal fees for lectures and consultancy from Actelion, outside the submitted work. Conflict of interest: D. Taboada reports fees for lectures and education and travel grants from Actelion, Bayer, GlaxoSmithKline, Lilly, MDS and Pfizer, outside the submitted work. Conflict of interest: A.A.R. Thompson reports grants from the British Heart Foundation (Intermediate Clinical Fellowship FS/18/13/3328), during the conduct of the study, as well as non-financial support for travel to meetings from Actelion Pharmaceuticals Ltd, outside the submitted work. Conflict of interest: M.R. Toshner has nothing to disclose. Conflict of interest: I. Wanjiku has nothing to disclose. Conflict of interest: S.J. Wort has nothing to disclose. Conflict of interest: J. Yorke has nothing to disclose. Conflict of interest: R. Condliffe reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and Bayer, as well as grants from GSK, outside the submitted work., (Copyright ©ERS 2021.)

Pulmonary arterial hypertension, group 1 of the pulmonary hypertension disease family, involves pulmonary vascular remodelling, right ventricular dysfunction and cardiac failure. Oxidative stress, through activation of mitogen-activated protein kinases is implicated in these changes. Inhibition of apoptosis signal-regulating kinase 1, an apical mitogen-activated protein kinase, prevented pulmonary arterial hypertension developing in rodent models. Here, we investigate apoptosis signal-regulating kinase 1 in pulmonary arterial hypertension by examining the impact that its inhibition has on the molecular and cellular signalling in established disease. Apoptosis signal-regulating kinase 1 inhibition was investigated in in vivo pulmonary arterial hypertension and in vitro pulmonary hypertension models. In the in vivo model, male Sprague Dawley rats received a single subcutaneous injection of Sugen SU5416 (20 mg/kg) prior to two weeks of hypobaric hypoxia (380 mmHg) followed by three weeks normoxia (Sugen/hypoxic), then animals were either maintained for three weeks on control chow or one containing apoptosis signal-regulating kinase 1 inhibitor (100 mg/kg/day). Cardiovascular measurements were carried out. In the in vitro model, primary cultures of rat pulmonary artery fibroblasts and rat pulmonary artery smooth muscle cells were maintained in hypoxia (5% O 2 ) and investigated for proliferation, migration and molecular signalling in the presence or absence of apoptosis signal-regulating kinase 1 inhibitor. Sugen/hypoxic animals displayed significant pulmonary arterial hypertension compared to normoxic controls at eight weeks. Apoptosis signal-regulating kinase 1 inhibitor decreased right ventricular systolic pressure to control levels and reduced muscularised vessels in lung tissue. Apoptosis signal-regulating kinase 1 inhibition was found to prevent hypoxia-induced proliferation, migration and cytokine release in rat pulmonary artery fibroblasts and also prevented rat pulmonary artery fibroblast-induced rat pulmonary artery smooth muscle cell migration and proliferation. Apoptosis signal-regulating kinase 1 inhibition reversed pulmonary arterial hypertension in the Sugen/hypoxic rat model. These effects may be a result of intrinsic changes in the signalling of adventitial fibroblast., (© The Author(s) 2020.)

Patients classified as idiopathic pulmonary arterial hypertension (defined as Group 1 on European Respiratory Society (ERS)/European Cardiac Society (ESC) criteria) may have evidence of minor co-existing lung disease on thoracic computed tomography. We hypothesised that these idiopathic pulmonary arterial hypertension patients ( IPAH lung disease ) are a separate subgroup of idiopathic pulmonary arterial hypertension with different phenotype and outcome compared with idiopathic pulmonary arterial hypertension patients without co-existing lung disease ( IPAH no lung disease ). Patients with ' IPAH lung disease ' have been eligible for all clinical trials of Group 1 patients because they have normal clinical examination and normal spirometry but we wondered whether they responded to treatment and had similar survival to patients with ' IPAH no lung disease '. We described the outcome of the cohort of patients with ' IPAH no lung disease ' in a previous paper. Here, we have compared incident ' IPAH lung disease ' patients with ' IPAH no lung disease ' patients diagnosed concurrently in all eight Pulmonary Hypertension centres in the UK and Ireland between 2001-2009. Compared with ' IPAH no lung disease ' ( n  = 355), ' IPAH lung disease ' patients ( n  = 137) were older, less obese, predominantly male, more likely to be current/ex-smokers and had lower six-minute walk distance, lower % predicted diffusion capacity for carbon monoxide, lower mean pulmonary arterial pressure and lower pulmonary vascular resistance index. After three months of pulmonary hypertension-targeted treatment, six-minute walk distance improved equally in ' IPAH lung disease ' and ' IPAH no lung disease '. However, survival of ' IPAH lung disease ' was lower than ' IPAH no lung disease ' (one year survival: 72% compared with 93%). This survival was significantly worse in ' IPAH lung disease ' even after adjusting for age, gender, smoking history, comorbidities and haemodynamics. ' IPAH lung disease ' patients had similar short-term improvement in six-minute walk distance with anti-pulmonary arterial hypertension therapy but worse survival compared with ' IPAH no lung disease ' patients. This suggests that ' IPAH lung disease ' are a separate phenotype and should not be lumped with ' IPAH no lung disease ' in clinical trials of Group 1 pulmonary arterial hypertension., (© The Author(s) 2020.)

Rationale: Recently, rare heterozygous mutations in GDF2 were identified in patients with pulmonary arterial hypertension (PAH). GDF2 encodes the circulating BMP (bone morphogenetic protein) type 9, which is a ligand for the BMP2 receptor. Objectives: Here we determined the functional impact of GDF2 mutations and characterized plasma BMP9 and BMP10 levels in patients with idiopathic PAH. Methods: Missense BMP9 mutant proteins were expressed in vitro and the impact on BMP9 protein processing and secretion, endothelial signaling, and functional activity was assessed. Plasma BMP9 and BMP10 levels and activity were assayed in patients with PAH with GDF2 variants and in control subjects. Levels were also measured in a larger cohort of control subjects ( n  = 120) and patients with idiopathic PAH ( n  = 260). Measurements and Main Results: We identified a novel rare variation at the GDF2 and BMP10 loci, including copy number variation. In vitro , BMP9 missense proteins demonstrated impaired cellular processing and secretion. Patients with PAH who carried these mutations exhibited reduced plasma levels of BMP9 and reduced BMP activity. Unexpectedly, plasma BMP10 levels were also markedly reduced in these individuals. Although overall BMP9 and BMP10 levels did not differ between patients with PAH and control subjects, BMP10 levels were lower in PAH females. A subset of patients with PAH had markedly reduced plasma levels of BMP9 and BMP10 in the absence of GDF2 mutations. Conclusions: Our findings demonstrate that GDF2 mutations result in BMP9 loss of function and are likely causal. These mutations lead to reduced circulating levels of both BMP9 and BMP10. These findings support therapeutic strategies to enhance BMP9 or BMP10 signaling in PAH.

Cardiac magnetic resonance-derived ventricular variables are predictive of mortality in pulmonary arterial hypertension. Rodent models which emphasize ventricular function, allowing serial monitoring, are needed to identify pathophysiological features and novel therapies for pulmonary arterial hypertension. We investigated longitudinal changes in the Sugen-hypoxia model during disease progression. Sprague Dawley rats ( n  = 32) were divided into two groups. (1) Sugen-hypoxia: a dose of subcutaneous Sugen-5416 and placed in hypobaric hypoxia for two weeks followed by normoxia for three weeks. (2) Normoxia: maintained at normal pressure for five weeks. Rats were examined at five or eight weeks with right-heart catheter, cardiac magnetic resonance, and autopsy. Compared to normoxic controls (23.9 ± 4.1 mmHg), right ventricular systolic pressure was elevated in Sugen-hypoxia rats at five and eight weeks (40.9 ± 15.5 mmHg, p  = 0.026; 48.9 ± 9.6 mmHg, p  = 0.002). Right ventricular end-systolic volume index was increased in eight weeks Sugen-hypoxia (0.28 ± 0.04 µlcm -2 , p  = 0.003) compared to normoxic controls (0.18 ±0.03 mlcm -2 ). There was progressive dilatation of the right ventricular at eight weeks Sugen-hypoxia compared to normoxic controls (0.75 ± 0.13 µlcm -2 vs 0.56 ± 0.1 µlcm -2 p  = 0.02). Ventricle mass index by cardiac magnetic resonance at five weeks (0.34 ± 0.06, p  = 0.003) and eight weeks Sugen-hypoxia (0.34 ± 0.06, p  = 0.002) were higher than normoxic controls (0.21 ± 0.04). Stroke volume, right ventricular ejection fraction, and left ventricular variables were preserved in Sugen-hypoxia. Ventricular changes during the course of illness in a pulmonary arterial hypertension rodent model can be examined by cardiac magnetic resonance. These changes including right ventricular hypertrophy and subsequent dilatation are similar to those seen in pulmonary arterial hypertension patients. Despite the persisting pulmonary hypertension, there are features of adaptive cardiac remodeling through the study duration., (© The Author(s) 2020.)

Background: The purpose of this study was to compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction., Methods: Treatment-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event., Results: Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients., Conclusions: Efficacy of initial combination therapy vs pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients., (Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

While traffic and air pollution exposure is associated with increased mortality in numerous diseases, its association with disease severity and outcomes in pulmonary arterial hypertension (PAH) remains unknown.Exposure to particulate matter with a 50% cut-off aerodynamic diameter ≤2.5 μm (PM 2.5 ), nitrogen dioxide (NO 2 ) and indirect measures of traffic-related air pollution (distance to main road and length of roads within buffer zones surrounding residential addresses) were estimated for 301 patients with idiopathic/heritable PAH recruited in the UK National Cohort Study of Idiopathic and Heritable PAH. Associations with transplant-free survival and pulmonary haemodynamic severity at baseline were assessed, adjusting for confounding variables defined a priori Higher estimated exposure to PM 2.5 was associated with higher risk of death or lung transplant (unadjusted hazard ratio (HR) 2.68 (95% CI 1.11-6.47) per 3 μg·m -3 ; p=0.028). This association remained similar when adjusted for potential confounding variables (HR 4.38 (95% CI 1.44-13.36) per 3 μg·m -3 ; p=0.009). No associations were found between NO 2 exposure or other traffic pollution indicators and transplant-free survival. Conversely, indirect measures of exposure to traffic-related air pollution within the 500-1000 m buffer zones correlated with the European Society of Cardiology/European Respiratory Society risk categories as well as pulmonary haemodynamics at baseline. This association was strongest for pulmonary vascular resistance.In idiopathic/heritable PAH, indirect measures of exposure to traffic-related air pollution were associated with disease severity at baseline, whereas higher PM 2.5 exposure may independently predict shorter transplant-free survival., Competing Interests: Conflict of interest: E. Sofianopoulou has nothing to disclose. Conflict of interest: S. Kaptoge reports grants from UK Medical Research Council and British Heart Foundation, during the conduct of the study. Conflict of interest: S. Gräf has nothing to disclose. Conflict of interest: C. Hadinnapola has nothing to disclose. Conflict of interest: C.M. Treacy has nothing to disclose. Conflict of interest: C. Church has nothing to disclose. Conflict of interest: G. Coghlan has nothing to disclose. Conflict of interest: J.S.R. Gibbs reports grants and personal fees from Actelion, Bayer, GSK and MSD, personal fees from Arena, Bellerophon, Complexa and Pfizer, grants from Amco and United Therapeutics, outside the submitted work. Conflict of interest: M. Haimel has nothing to disclose. Conflict of interest: L.S. Howard has nothing to disclose. Conflict of interest: M. Johnson reports grants and personal fees for attendance at meeting and lectures from Actelion, Bayer, GSK and MSD, outside the submitted work. Conflict of interest: D.G. Kiely reports grants, personal fees and nonfinancial support from Actelion, Bayer and GSK, personal fees and nonfinancial support from MSD, outside the submitted work. Conflict of interest: A. Lawrie reports grants and personal fees from Actelion and GSK, grants from British Heart Foundation and UK Medical Research Council, outside the submitted work. Conflict of interest: J. Lordan has nothing to disclose. Conflict of interest: R.V. MacKenzie Ross has nothing to disclose. Conflict of interest: J.M. Martin has nothing to disclose. Conflict of interest: S. Moledina has nothing to disclose. Conflict of interest: M. Newnham reports education support (travel, registration and accommodation) to attend conferences from MSD and GSK, outside the submitted work. Conflict of interest: A.J. Peacock reports grants and personal fees from Actelion and Bayer, personal fees from GSK, grants from Gilead, outside the submitted work. Conflict of interest: L.C. Price has nothing to disclose. Conflict of interest: C.J. Rhodes has nothing to disclose. Conflict of interest: J. Suntharalingam has nothing to disclose. Conflict of interest: E.M. Swietlik has nothing to disclose. Conflict of interest: M.R. Toshner has nothing to disclose. Conflict of interest: J. Wharton reports personal fees for advisory board work from Actelion, outside the submitted work. Conflict of interest: M.R. Wilkins has nothing to disclose. Conflict of interest: S.J. Wort reports grants and personal fees from Actelion and Bayer, personal fees from GSK and MSD, outside the submitted work. Conflict of interest: J. Pepke-Zaba (or her institution) received research, education grants from Actelion, Merck and Bayer; and has served on advisory boards for Actelion, Merck, Bayer and GSK. Conflict of interest: R. Condliffe reports personal fees for advisory board work from Actelion, Bayer and MSD, during the conduct of the study. Conflict of interest: P.A. Corris reports grants and personal fees from Actelion and Bayer, personal fees from MSD, outside the submitted work. Conflict of interest: E. Di Angelantonio reports grants from European Commission Framework 7, European Research Council, British Heart Foundation, UK Medical Research Council and National Institute for Health Research, during the conduct of the study; grants from NHS Blood and Transplant, outside the submitted work. Conflict of interest: S. Provencher has nothing to disclose. Conflict of interest: N.W. Morrell reports personal fees from GSK and Johnson & Johnson/Actelion, outside the submitted work., (Copyright ©ERS 2019.)

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes., Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses., Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10 -15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10 -20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10 -12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity., Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials., Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objectives of this European Respiratory Society task force were to summarise current studies, to develop strategies for future research and to increase availability and awareness of exercise training for pulmonary hypertension (PH) patients.An evidence-based approach with clinical expertise of the task force members, based on both literature search and face-to-face meetings was conducted. The statement summarises current knowledge and open questions regarding clinical effects of exercise training in PH, training modalities, implementation strategies and pathophysiological mechanisms.In studies (784 PH patients in total, including six randomised controlled trials, three controlled trials, 10 prospective cohort studies and four meta-analyses), exercise training has been shown to improve exercise capacity, muscular function, quality of life and possibly right ventricular function and pulmonary haemodynamics. Nevertheless, further studies are needed to confirm these data, to investigate the impact on risk profiles and to identify the most advantageous training methodology and underlying pathophysiological mechanisms.As exercise training appears to be effective, cost-efficient and safe, but is scarcely reimbursed, support from healthcare institutions, commissioners of healthcare and research funding institutions is greatly needed. There is a strong need to establish specialised rehabilitation programmes for PH patients to enhance patient access to this treatment intervention., Competing Interests: Conflict of interest: E. Grünig reports grants and personal fees from Actelion and Bayer/MSD, grants from GSK, United Therapeutics and Novartis, and personal fees from SCOPE, OrPha Swiss GmbH and Zurich Heart House, outside the submitted work. Conflict of interest: C. Eichstaedt has nothing to disclose. Conflict of interest: J-A. Barberà has nothing to disclose. Conflict of interest: N. Benjamin reports personal fees for speaking from Bayer and Actelion, outside the submitted work. Conflict of interest: I. Blanco has nothing to disclose. Conflict of interest: E. Bossone has nothing to disclose. Conflict of interest: A. Cittadini has nothing to disclose. Conflict of interest: G. Coghlan has nothing to disclose. Conflict of interest: P. Corris reports grants and personal fees from Actelion and Bayer, and personal fees from MSD, outside the submitted work. Conflict of interest: M. D'Alto has nothing to disclose. Conflict of interest: A. D'Andrea has nothing to disclose. Conflict of interest: M. Delcroix has nothing to disclose. Conflict of interest: F. de Man has nothing to disclose. Conflict of interest: S. Gaine reports personal fees from Actelion, United Therapeutics, MSD and GSK, outside the submitted work. Conflict of interest: S. Ghio has nothing to disclose. Conflict of interest: S. Gibbs reports grants and personal fees from Actelion, Bayer and MSD, personal fees from Arena, Bellopheron, Acceleron, Complexa and Pfizer, and grants from GSK, Amco and United Therapeutics, during the conduct of the study. Conflict of interest: L. Gumbiene has nothing to disclose. Conflict of interest: L.S. Howard has nothing to disclose. Conflict of interest: M. Johnson reports research grants and personal fees for attendance at meeting and speaking from Actelion, Bayer, GSK and MSD, outside the submitted work. Conflict of interest: E. Jurevičienė has nothing to disclose. Conflict of interest: D.G. Kiely reports grants, personal fees and non-financial support from Actelion, Bayer and GSK, and personal fees and non-financial support from MSD, outside the submitted work. Conflict of interest: G. Kovacs reports personal fees for lecturing, travel support and advisory board work from Actelion and MSD, personal fees for lecturing and advisory board work from GSK, personal fees for lecturing, consultancy and advisory board work from Boehringer Ingelheim and Chiesi, personal fees for lecturing and travel support from Bayer, and personal fees for lecturing from Pfizer and Novartis, outside the submitted work. Conflict of interest: A. MacKenzie has nothing to disclose. Conflict of interest: A.M. Marra reports a grant for Young Researcher (Principal Investigator “Ricerca Finalizzata under 40” n. GR-2016-02364727) from the Italian Healthcare Ministry, and personal fees for lecturing from Bayer Healthcare, during the conduct of the study. Conflict of interest: N. McCaffrey has nothing to disclose. Conflict of interest: P. McCaughey has nothing to disclose. Conflict of interest: R. Naeije has nothing to disclose. Conflict of interest: H. Olschewski reports personal fees and non-financial support from Bayer, MSD, Pfizer and Novartis, grants, personal fees and non-financial support from Actelion, grants from Inventiva, and personal fees from Bellerophon, outside the submitted work; and is a part time employee of Ludwig Boltzmann Insitute for Lung Vascular Research. Conflict of interest: J. Pepke-Zaba or her institution have received educational/research grants and J. Pepke-Zaba serves on advisory boards for Actelion, Merck, Bayer and GSK. Conflict of interest: A. Reis has nothing to disclose. Conflict of interest: M. Santos has nothing to disclose. Conflict of interest: S. Saxer has nothing to disclose. Conflict of interest: R.M. Tulloh has received honoraria and speaker fees from Actelion, Pfizer, Bayer and GSK. Conflict of interest: S. Ulrich reports grants from Swiss National Science Foundation and Zurich Lung, grants and personal fees from Actelion SA and Orpha Swiss, and personal fees from MSD SA, outside the submitted work. Conflict of interest: A. Vonk Noordegraaf reports speaker fees from Actelion, and grants from MSD, Actelion and GSK, outside the submitted work. Conflict of interest: A.J. Peacock reports grants from Actelion, Bayer and GSK, and personal fees from MSD and Arena, outside the submitted work., (Copyright ©ERS 2019.)

Background: In the randomized, double-blind, event-driven AMBITION study, initial combination therapy with ambrisentan and tadalafil was associated with a 50% reduction in risk of clinical failure (first occurrence of all-cause death, hospitalization for worsening pulmonary arterial hypertension [PAH], disease progression, or unsatisfactory long-term clinical response) vs pooled monotherapy. These results were primarily driven by a reduction in PAH-related hospitalization in the combination therapy group, although a significant effect was not observed in a post-hoc analysis of all-cause hospitalization., Methods: The effect of initial combination therapy with ambrisentan and tadalafil in AMBITION was further explored to study PAH-related hospitalization, which was not reported in the primary publication., Results: Initial combination therapy was associated with a 63% reduction in risk of PAH-related hospitalization when compared with pooled monotherapy (hazard ratio [HR] 0.372, 95% confidence interval [CI] 0.217 to 0.639, p = 0.0002). For every 9 patients treated with combination therapy vs monotherapy, 1 PAH-related hospitalization could be prevented over a 1-year period. Serious adverse events leading to hospitalization, not necessarily PAH-related, occurred in 87 of 253 (34%) and 89 of 247 (36%) of patients on combination therapy and pooled monotherapy, respectively (post-hoc summary)., Conclusions: Initial combination therapy with ambrisentan and tadalafil was found to reduce the risk of PAH-related hospitalization by 63% compared with pooled monotherapy., (Copyright © 2018. Published by Elsevier Inc.)

Pulmonary hypertension (PH) frequently complicates the course of patients with various forms of chronic lung disease (CLD). CLD-associated PH (CLD-PH) is invariably associated with reduced functional ability, impaired quality of life, greater oxygen requirements and an increased risk of mortality. The aetiology of CLD-PH is complex and multifactorial, with differences in the pathogenic sequelae between the diverse forms of CLD. Haemodynamic evaluation of PH severity should be contextualised within the extent of the underlying lung disease, which is best gauged through a combination of physiological and imaging assessment. Who, when, if and how to screen for PH will be addressed in this article, as will the current state of knowledge with regard to the role of treatment with pulmonary vasoactive agents. Although such therapy cannot be endorsed given the current state of findings, future studies in this area are strongly encouraged., Competing Interests: Conflict of interest: S.D. Nathan is a consultant for and has received research funding from Bellerophon, United Therapeutics and Bayer Pharmaceuticals; is a consultant for Third Pole and Actelion, and is a consultant for, has received research funding from and is on the speakers’ bureau of Roche-Genentech and Boehringer Ingelheim. Conflict of interest: J.A. Barbera reports grants and personal fees from Actelion and MSD, personal fees from Arena, and grants from Bayer and GSK, outside the submitted work. Conflict of interest: S.P. Gaine reports personal fees from Actelion, United Therapeutics, MSD and GSK, outside the submitted work. Conflict of interest: S. Harari has received grants for research and speakers fees from Actelion, Boehringer Ingelheim and Roche. Conflict of interest: F.J. Martinez has received grants from the NIH (IPF UO1, COPD UO1/RO1); personal fees, honoraria and non-personal travel support from the American College of Chest Physicians, Continuing Education, ConCert, Inova Fairfax Health System, MD Magazine, Miller Communications, National Association for Continuing Education, Novartis, Pearl Pharmaceuticals, PeerView Communications, Prime Communications, Puerto Rican Respiratory Society, Roche, Sunovion, Theravance, Potomac, University of Alabama Birmingham and Zambon; personal fees and non-personal or non-financial travel support from AstraZeneca; personal fees, non-personal travel support, and non-financial support for data and safety monitoring board work from Boehringer Ingelheim; personal fees, honoraria, non-personal travel support, and non-financial support for data and safety monitoring board work from Genentech and GlaxoSmithKline; personal fees and honoraria from Columbia University, Integritas, Methodist Hospital Brooklyn, New York University, Unity, UpToDate, WebMD/MedScape, Western Connecticut Health Network, Academic CME, Patara, PlatformIQ, American Thoracic Society, Rockpointe and Rare Disease Healthcare Communications; non-personal travel support from Nitto; personal fees, honoraria, travel support and non-personal travel support from Chiesi; personal fees, honoraria and travel support from Physicians Education Resource and Teva; honoraria and travel support from Canadian Respiratory Network; personal fees from France Foundation; and has participated on scientific advisory boards (no direct financial compensation) for ProterrixBio and Bridge Biotherapeutics; participated on IPF study steering committees (no direct financial compensation) for Afferent/Merck, Gilead, Veracyte, Prometic, Bayer and ProMedior; and participated on an IPF study steering committee and data safety monitoring board (no direct financial compensation) for Biogen. Conflict of interest: H. Olschewski reports personal fees and non-financial support from Bayer, MSD, Pfizer and Novartis, grants, personal fees and non-financial support from Actelion, grants from Inventiva, and personal fees from Bellerophon, outside the submitted work; and is part-time employee of the Ludwig Boltzmann Institute for Lung Vascular Research. Conflict of interest: K.M. Olsson received fees for talks and consulting work from Actelion, Bayer, GSK, Pfizer and United Therapeutics. Conflict of interest: A.J. Peacock has received research grants and personal fees from Actelion Pharmaceuticals, Bayer, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work. Conflict of interest: J. Pepke-Zaba is a member of the advisory boards for Actelion, Merck, Bayer and GSK, has received grants, personal fees and non-financial support from Actelion, Merck and Bayer, and personal fees from GSK. Conflict of interest: S. Provencher has received research grants from Actelion Pharmaceuticals and Boehringer Ingelheim, and has received speaker fees from Actelion Pharmaceuticals. Conflict of interest: N. Weissmann has nothing to disclose. Conflict of interest: W. Seeger has received consultancy fees from Bayer AG, United Therapeutics, Liquidia, Vectura and Novartis., (Copyright ©ERS 2019.)

Background: In pulmonary arterial hypertension (PAH), pathological changes in pulmonary arterioles progressively raise pulmonary artery pressure and increase pulmonary vascular resistance, leading to right heart failure and high mortality rates. Recently, the first potassium channelopathy in PAH, because of mutations in KCNK3, was identified as a genetic cause and pharmacological target., Methods: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis., Results: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide., Conclusions: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of unresolved organised pulmonary emboli/thrombi obstructing the major pulmonary arteries. The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE). This was a population-based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012. CTEPH was assessed using a rigorous case-ascertainment algorithm. Risk factors for CTEPH were studied using a nested case-control approach by matching CTEPH cases to VTE patients without CTEPH. Adjusted odds ratios (OR) of comorbidities were estimated from conditional logistic regression. During 81,413 person-years of follow-up among 23,329 patients with first VTE (mean follow-up 3.5 years; maximum 11.0 years) 283 patients were diagnosed with CTEPH (incidence rate 3.5 per 1000 person-years); cumulative incidence was 1.3% and 3.3% at 2 and 10 years after pulmonary embolism, and 0.3% and 1.3% following deep vein thrombosis (DVT), respectively. Risk factors for CTEPH included age over 70, OR 2.04 (95% CI 1.23 to 3.38), female gender, 1.44 (1.06 to 1.94), pulmonary embolism at first VTE, 3.11 (2.23 to 4.35), subsequent pulmonary embolism and DVT, 3.17 (2.02 to 4.96) and 2.46 (1.34 to 4.51) respectively, chronic obstructive pulmonary disease 3.17 (2.13 to 4.73), heart failure 2.52 (1.76 to 3.63) and atrial fibrillation, 2.42 (1.71 to 3.42). CTEPH develops most commonly after pulmonary embolism and less frequently after DVT. Awareness of risk factors may increase referrals to specialised centres for confirmation of CTEPH and initiation of specific treatment.

Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.

Apelin agonism causes systemic vasodilatation and increased cardiac contractility in humans, and improves pulmonary arterial hypertension (PAH) in animal models. Here, the authors examined the short-term pulmonary hemodynamic effects of systemic apelin infusion in patients with PAH. In a double-blind randomized crossover study, 19 patients with PAH received intravenous (Pyr 1 )apelin-13 and matched saline placebo during invasive right heart catheterization. (Pyr 1 )apelin-13 infusion caused a reduction in pulmonary vascular resistance and increased cardiac output. This effect was accentuated in the subgroup of patients receiving concomitant phosphodiesterase type 5 inhibition. Apelin agonism is a novel potential therapeutic target for PAH. (Effects of Apelin on the Lung Circulation in Pulmonary Hypertension; NCT01457170).

Background: Non-invasive methods of measuring cardiac output are highly desirable in pulmonary arterial hypertension (PAH). We therefore sought to validate impedance cardiography (ICG) against thermodilution (TD) and cardiac magnetic resonance (CMR) in the measurement of cardiac output in patients under investigation for PAH., Methods: A prospective, cross-sectional study was performed to compare single-point measurements of cardiac output obtained by impedance cardiography (CO ICG ) technology (PhysioFlow ® ) with (i) contemporaneous TD measurements (CO TD ) at rest and steady-state exercise during right heart catheterization and (ii) CMR measurements (CO CMR ) at rest obtained within 72 h., Results: Paired CO ICG and CO TD measurements were obtained in 25 subjects at rest and 16 subjects at exercise. CO CMR measurements were obtained in 16 subjects at rest. There was unsatisfactory correlation and agreement between CO ICG and CO TD at rest (r = 0·42, P = 0·035; bias: 1·21 l min -1 , 95% CI: -2·33 to 4·75 l min -1 ) and exercise (r = .65, P = .007; bias: 1·41 l min -1 ; 95% CI: -3·99 to 6·81 l min -1 ) and in the change in CO ICG and CO TD from rest to exercise (r = 0·53, P = 0·033; bias: 0·76 l min -1 , 95% CI: -3·74 to 5·26 l min -1 ). There was also a lack of correlation and unsatisfactory agreement between resting CO ICG and CO CMR (r = 0·38, P = 0·1; bias: 1·40 l min -1 , 95% CI: -2·48 to 5·28 l min -1 ). In contrast, there was close correlation and agreement between resting CO TD and CO CMR (r = 0·87, P<0·001; bias: -0·16 l min -1 , 95% CI: -1·97 to 1·65)., Conclusions: In a representative population of patients under investigation for PAH, ICG showed insufficient qualitative and quantitative value in the measurement of resting and exercise cardiac output when compared with TD and CMR., (© 2017 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Clinical assessment of right ventricular (RV) contractility in diseases such as pulmonary arterial hypertension (PAH) has been hindered by the lack of a robust methodology. Here, a novel, clinically viable, single-beat method was developed to assess end-systolic elastance (E es ), a measure of right ventricular (RV) contractility. We hypothesized that this novel approach reduces uncertainty and interobserver variability in the estimation of the maximum isovolumic pressure (P iso ), the key step in single-beat methods. The new method was designed to include a larger portion of the RV pressure data and minimize subjective adjustments by the operator. Data were obtained from right heart catheterization of PAH patients in a multicenter prospective study ( data set 1) and a single-center retrospective study ( data set 2). To obtain P iso , three independent observers used an established single-beat method (based on the first derivative of the pressure waveform) and the novel method (based on the second derivative). Interobserver variability analysis included paired t-test, one-way ANOVA, interclass correlation (ICC) analysis, and a modified Bland-Altman analysis. The P iso values obtained from the two methods were linearly correlated for both data set 1 ( R 2  = 0.74) and data set 2 ( R 2  = 0.91). Compared with the established method, the novel method resulted in smaller interobserver variability ( P < 0.001), nonsignificant differences between observers, and a narrower confidence interval. By reducing uncertainty and interobserved variability, this novel approach may pave the way for more effective clinical management of PAH. NEW & NOTEWORTHY A novel methodology to assess right ventricular contractility from clinical data is demonstrated. This approach significantly reduces interobserver variability in the analysis of ventricular pressure data, as demonstrated in a relatively large population of subjects with pulmonary hypertension. This study may enable more accurate clinical monitoring of systolic function in subjects with pulmonary hypertension.

Several demographic and clinical factors have prognostic significance in idiopathic pulmonary arterial hypertension (IPAH). Studies in China and the USA have suggested an association between low socioeconomic status and reduced survival. The impact of social deprivation on IPAH survival in the UK is not known.280 patients with IPAH and hereditary PAH (HPAH) attending the Scottish Pulmonary Vascular Unit (Glasgow, UK) were assigned to social deprivation quintiles using the Scottish Index of Multiple Deprivation database. The association between survival and social deprivation quintile was assessed using Cox proportional hazards regression analysis.The distribution of IPAH/HPAH patients was more socially deprived than would be expected based on Scottish citizenry as a whole (Chi-squared 16.16, p=0.003), suggesting referral and access to care is not impeded by socioeconomic status. Univariate analysis demonstrated no significant association between social deprivation and survival (p=0.81), and this association failed to reach significance with inclusion of time, sex and age as covariates in the model (p=0.23). There were no statistically significant correlations between social deprivation and baseline clinical variables of prognostic importance except for age, sex and quality of life.Social deprivation is not a significant referral barrier or prognostic factor for IPAH and HPAH in Scotland., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

Pulmonary hypertension (PH) is a progressive illness characterized by elevated pulmonary artery pressure; however, the main cause of mortality in PH patients is right ventricular (RV) failure. Historically, improving the hemodynamics of pulmonary circulation was the focus of treatment; however, it is now evident that cardiac response to a given level of pulmonary hemodynamic overload is variable but plays an important role in the subsequent prognosis. Non-invasive tests of RV function to determine prognosis and response to treatment in patients with PH is essential. Although the right ventricle is the focus of attention, it is clear that cardiac interaction can cause left ventricular dysfunction, thus biventricular assessment is paramount. There is also focus on the atrial chambers in their contribution to cardiac function in PH. Furthermore, there is evidence of regional dysfunction of the two ventricles in PH, so it would be useful to understand both global and regional components of dysfunction. In order to understand global and regional cardiac function in PH, the most obvious non-invasive imaging techniques are echocardiography and cardiac magnetic resonance imaging (CMRI). Both techniques have their advantages and disadvantages. Echocardiography is widely available, relatively inexpensive, provides information regarding RV function, and can be used to estimate RV pressures. CMRI, although expensive and less accessible, is the gold standard of biventricular functional measurements. The advent of 3D echocardiography and techniques including strain analysis and stress echocardiography have improved the usefulness of echocardiography while new CMRI technology allows the measurement of strain and measuring cardiac function during stress including exercise. In this review, we have analyzed the advantages and disadvantages of the two techniques and discuss pre-existing and novel forms of analysis where echocardiography and CMRI can be used to examine atrial, ventricular, and interventricular function in patients with PH at rest and under stress.

Daily physical activity is reduced in precapillary pulmonary hypertension (PH), but the underlying mechanisms are inadequately explored. We sought to investigate clinical and physiological relations of daily physical activity and profile differences between less and more active patients with precapillary PH. A prospective, cross-sectional study of 20 patients with precapillary PH who undertook 1 ) a comprehensive clinical assessment, 2 ) a preliminary treadmill test, 3 ) 7-day monitoring of daily walking intensity with triaxial accelerometry, and 4 ) a personalized treadmill test corresponding to the individual patient mean daily walking intensity with real-time physiological measurements. Significant clinical correlations with individual patient mean walking intensity [1.71 ± 0.27 (SD) m/s 2 ] were observed for log-transformed N-terminal probrain natriuretic peptide (log NT-proBNP; r = -0.75, P = <.001), age ( r = -0.70, P = 0.001), transfer factor for carbon monoxide %predicted ( r = 0.51, P = 0.022), and 6-min walk distance ( r = 0.50, P = 0.026). Significant physiological correlations were obtained for heart rate reserve ( r = 0.68, P = 0.001), quadriceps tissue oxygenation index (Q-[Formula: see text]; r = 0.58, P = 0.008), change in Q-[Formula: see text] from rest ( r = 0.60, P = 0.006), and ventilatory equivalent for oxygen uptake ( r = -0.56, P = 0.013). Stepwise multiple regression analyses retained log NT-proBNP ( R 2 = 0.55), heart rate reserve ( R 2 = 0.44), and Q-[Formula: see text] ( R 2 = 0.13) accounting for a significant variance in individual walking intensity. Less active patients had greater physical activity-induced cardiopulmonary impairment, worse quadriceps oxygenation profile, and compromised health-related quality of life compared with more active patients. These preliminary findings suggest a significant relation between right ventricular and peripheral muscle oxygenation status and reduced daily physical activity in precapillary PH. Further research is warranted to unravel the physiological determinants, establish clinical predictors, and identify beneficial interventions. NEW & NOTEWORTHY Daily physical activity holds promise to be a meaningful, patient-related outcome measure in pulmonary hypertension. In this study, novel findings in a representative sample of patients with precapillary pulmonary hypertension link reduced daily walking activity, as measured by triaxial accelerometry, with compromised right ventricular and pulmonary vascular status, peripheral muscle oxygenation, and health-related quality of life, providing a preliminary insight into the physiological mechanisms and clinical predictors of daily physical activity in precapillary pulmonary hypertension., (Copyright © 2017 the American Physiological Society.)

Background: Patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH), in particular systemic sclerosis (SSc), had an attenuated response compared with idiopathic PAH in most trials. Thus, there is uncertainty regarding the benefit of PAH-targeted therapy in some forms of CTD-PAH., Objective: To explore the safety and efficacy of initial combination therapy with ambrisentan and tadalafil versus ambrisentan or tadalafil monotherapy in patients with CTD-PAH and SSc-PAH enrolled in the AMBITION trial., Methods: This was a post hoc analysis of patients with CTD-PAH and SSc-PAH from AMBITION, an event-driven, double-blind trial in patients with WHO functional class II/III PAH. Treatment-naive patients were randomised 2:1:1 to once-daily initial combination therapy with ambrisentan plus tadalafil or monotherapy with ambrisentan or tadalafil, respectively. The primary endpoint was time to the first clinical failure event (first occurrence of death, hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response)., Results: In the primary analysis set (N=500), 187 patients had CTD-PAH, of whom 118 had SSc-PAH. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in each subgroup: CTD-PAH (HR 0.43 (95% CI 0.24 to 0.77)) and SSc-PAH (0.44 (0.22 to 0.89)). The most common AE was peripheral oedema, which was reported more frequently with initial combination therapy than monotherapy in the two PAH subgroups. The relative frequency of adverse events between those on combination therapy versus monotherapy was similar across subgroups., Conclusions: This post hoc subgroup analysis provides evidence that CTD-PAH and SSc-PAH patients benefit from initial ambrisentan and tadalafil combination therapy., Trial Registration Number: NCT01178073, post results., Competing Interests: Competing interests: JGC: grants and personal fees from Actelion and GlaxoSmithKline; personal fees from Bayer, Endotronix, Pfizer and United Therapeutics. NG: grants and personal fees from Actelion, Bayer, GlaxoSmithKline and Pfizer. JAB: personal fees from Actelion, Almirall, Bayer, GlaxoSmithKline and Pfizer; grants from Actelion, Bayer, GlaxoSmithKline and Pfizer. AEF: funds for the conduct of the study from Baylor College of Medicine; honoraria and travel/lodging expense for participating on the study's Steering Committee; grants from Actelion, Bayer, Gilead and United Therapeutics; personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; non-financial support from Bayer and Novartis. H-AG: grants from Actelion, Bayer, Novartis and Pfizer; board membership and consultancy for Actelion, Bayer, GlaxoSmithKline, Merck, Novartis, Pfizer and Takeda; consultancy for Lilly; payment for lectures from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer. MMH: personal fees from Actelion, Bayer, Gilead, GlaxoSmithKline, Merck and Pfizer. MK: grants and personal fees from Actelion, Bayer and Pfizer; personal fees from GlaxoSmithKline. VVM: grants and personal fees from Actelion, Bayer, Gilead, Ikaria and United Therapeutics; grants from Novartis; personal fees from Steadymed and Akros. AJP: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline; personal fees from United Therapeutics. GS: grants and personal fees from Actelion, Bayer, Gilead and GlaxoSmithKline. J-LV: grants from Actelion and GlaxoSmithKline; speaker fees from Actelion, Bayer, GlaxoSmithKline and Pfizer; advisory board honoraria from Actelion and Merck. CB: employee of Gilead; stock options in Gilead. HG: former employee of Gilead; patent pending in relation to the use of selective ERA's and PDE5 inhibitors. KLM: employee of Gilead; stock options in Gilead. JHNH: employee of GlaxoSmithKline; stock options in GlaxoSmithKline. JL: employee of GlaxoSmithKline. LJR: personal fees from Gilead., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background: Portopulmonary hypertension (PoPH) is a rare condition associated with poor survival, and the effect of modern therapies that target pulmonary arterial hypertension (PAH) on long-term outcome is unknown. This study investigated the baseline characteristics and survival in the cohort of patients diagnosed with PoPH in the United Kingdom National Pulmonary Hypertension Service., Methods: A retrospective review was conducted of all incident treatment-naïve patients with PoPH within the United Kingdom national registry diagnosed between January 2001 and December 2010., Results: Patients with PoPH (n = 110) had survival rates of 85%, 60%, and 35% at 1, 3, and 5 years. The prevalence of PoPH was 0.85 cases/1 million. Mean age at diagnosis was 53 ± 12 years, with a balanced distribution in gender. Alcohol (n = 57) and hepatitis C (n = 10) were the most common causes of portal hypertension. Phosphodiesterase V inhibitors were the most frequently used targeted therapy, in 63.6% (n = 70) of patients, endothelin receptor antagonists were used in 10% (n = 11) and prostacyclin analogs in 12.7% (n = 14). Univariate and multivariate analysis of baseline characteristics did not demonstrate a significant influence of severity of portal hypertension or liver cirrhosis, World Health Organization Functional Class, cardiopulmonary hemodynamics, or year of diagnosis on survival., Conclusions: Survival of patients with PoPH remains poor despite targeted therapy and worse than patients with idiopathic PAH. The benefit of PAH therapies in PoPH on long-term morbidity and mortality outcomes needs further consideration and study., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

In pulmonary hypertension (PH), right ventricular (RV) performance determines survival. Pulmonary artery (PA) stiffening is an important biomechanical event in PH and also predicts survival based on the PA relative area change (RAC) measured at rest using magnetic resonance imaging (MRI). In this exploratory study, we sought to generate novel hypotheses regarding the influence of stress RAC on PH prognosis and the interaction between PA stiffening, RV performance and survival. Fifteen PH patients underwent dobutamine stress-MRI (ds-MRI) and right heart catheterization. RAC REST , RAC STRESS , and ΔRAC (RAC STRESS - RAC REST ) were correlated against resting invasive hemodynamics and ds-MRI data regarding RV performance and RV-PA coupling efficiency (n' vv [RV stroke volume/RV end-systolic volume]). The impact of RAC, RV data, and n' vv on ten-year survival were determined using Kaplan-Meier analysis. PH patients with a low ΔRAC (<-2.6%) had a worse long-term survival (log-rank P = 0.045, HR for death = 4.46 [95% CI = 1.08-24.5]) than those with ΔRAC ≥ -2.6%. Given the small sample, these data should be interpreted with caution; however, low ΔRAC was associated with an increase in stress diastolic PA area indicating proximal PA stiffening. Associations of borderline significance were observed between low RAC STRESS and low n' vvSTRESS , Δη' VV , and ΔRVEF. Further studies are required to validate the potential prognostic impact of ΔRAC and the biomechanics potentially connecting low ΔRAC to shorter survival. Such studies may facilitate development of novel PH therapies targeted to the proximal PA.

Background: The VOLibris Tracking (VOLT) Study was an open-label, prospective, observational, multicenter, post-marketing registry program designed to more fully characterize the safety profile of ambrisentan for the treatment of pulmonary arterial hypertension (PAH). The key outcome was the incidence of aminotransferase elevations >3× the upper limit of normal (ULN)., Methods: In total, 999 patients from 115 centers in 15 countries, who were prescribed ambrisentan for the treatment of PAH (Functional Class II and III) between 30 June 2008 and 13 May 2011, were enrolled. Of these, 238 had PAH associated with connective tissue disease (PAH-CTD) and 220 had no prior PAH-specific therapy. Routine clinical monitoring data were collected by physicians., Results: The incidence of both alanine and aspartate aminotransferase events (>3× ULN) was 0.02 per patient-year (95% confidence interval 0.015 to 0.027). Similar results were reported for the PAH-CTD and PAH-specific-therapy-naive subgroups. Overall, 514 (52%) patients reported treatment-emergent adverse events of special interest, most commonly edema/fluid retention (249, or 25%) and anemia (143, or 14%)., Conclusions: Data from the VOLT study indicate no new ambrisentan-related safety signals. Ambrisentan was not associated with increases in liver function test abnormalities above the assumed background incidence of 1.5% per year, and the observed safety profile of ambrisentan was consistent with previously published data., (Copyright © 2017 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is a heterogeneous disorder with high mortality., Methods: We conducted a comprehensive study of plasma metabolites using ultraperformance liquid chromatography mass spectrometry to identify patients at high risk of early death, to identify patients who respond well to treatment, and to provide novel molecular insights into disease pathogenesis., Results: Fifty-three circulating metabolites distinguished well-phenotyped patients with idiopathic or heritable PAH (n=365) from healthy control subjects (n=121) after correction for multiple testing (P<7.3e-5) and confounding factors, including drug therapy, and renal and hepatic impairment. A subset of 20 of 53 metabolites also discriminated patients with PAH from disease control subjects (symptomatic patients without pulmonary hypertension, n=139). Sixty-two metabolites were prognostic in PAH, with 36 of 62 independent of established prognostic markers. Increased levels of tRNA-specific modified nucleosides (N2,N2-dimethylguanosine, N1-methylinosine), tricarboxylic acid cycle intermediates (malate, fumarate), glutamate, fatty acid acylcarnitines, tryptophan, and polyamine metabolites and decreased levels of steroids, sphingomyelins, and phosphatidylcholines distinguished patients from control subjects. The largest differences correlated with increased risk of death, and correction of several metabolites over time was associated with a better outcome. Patients who responded to calcium channel blocker therapy had metabolic profiles similar to those of healthy control subjects., Conclusions: Metabolic profiles in PAH are strongly related to survival and should be considered part of the deep phenotypic characterization of this disease. Our results support the investigation of targeted therapeutic strategies that seek to address the alterations in translational regulation and energy metabolism that characterize these patients., (© 2016 The Authors.)

Pulmonary vascular and cardiac impairment is increasingly appreciated as a major adverse factor in the natural history of interstitial lung disease. This clinically orientated review focuses on the current concepts in the pathogenesis, pathophysiology and implications of the detrimental sequence of increased pulmonary vascular resistance, pre-capillary pulmonary hypertension and right heart failure in interstitial lung disease, and provides guidance on its management., (Copyright ©ERS 2017.)

Background: In treatment-naive patients with pulmonary arterial hypertension, initial combination therapy with ambrisentan and tadalafil reduces the risk of clinical failure events compared with monotherapy. We did this secondary analysis to further investigate the effect of combination therapy on survival., Methods: We analysed survival data from the modified intention-to-treat population of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial. AMBITION was a multicentre, randomised, double-blind study, in which treatment-naive patients with pulmonary arterial hypertension were randomly assigned in a 2:1:1 ratio and received combination therapy with ambrisentan and tadalafil, ambrisentan and placebo, or tadalafil and placebo. We did a prespecified analysis of all mortality events from randomisation to the end of the study, including patients who discontinued their assigned treatment. In a post-hoc analysis, we analysed survival at 7 days after the termination of each individual patient's randomised treatment. We used Cox proportional hazard regression, Kaplan-Meier survival estimates, and the stratified log-rank test to compare the survival of patients receiving initial combination therapy or initial monotherapy., Findings: The study population consisted of 605 patients with pulmonary arterial hypertension who were randomly assigned and received combination therapy (n=302) or monotherapy (n=303; 152 patients assigned to ambrisentan monotherapy and 151 patients to tadalafil monotherapy). At the end of the study, 29 (10%) of 302 patients in the combination therapy group had died compared with 41 (14%) of 303 patients in the monotherapy group (hazard ratio 0·67, 95% CI 0·42-1·08; stratified log-rank p=0·10). At 7 days after the end of randomised treatment, fewer patients had died in the combination therapy group (3 [1%] of 302 patients) compared with the monotherapy group (13 [4%] of 303 patients; hazard ratio 0·21, 95% CI 0·06-0·73)., Interpretation: These data indicate that initial combination therapy might be associated with a survival advantage compared with initial monotherapy in patients with newly diagnosed pulmonary arterial hypertension. This hypothesis needs to be addressed in future studies., Funding: Gilead, GlaxoSmithKline., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Right ventricular (RV) function is a major determinant of outcome in pulmonary arterial hypertension (PAH). However, uncertainty persists about the optimal method of evaluation., Methods: We measured RV end-systolic and end-diastolic volumes (ESV and EDV) using cardiac magnetic resonance imaging and RV pressures during right heart catheterization in 140 incident PAH patients and 22 controls. A maximum RV pressure (Pmax) was calculated from the nonlinear extrapolations of early and late systolic portions of the RV pressure curve. The gold standard measure of RV function adaptation to afterload, or RV-arterial coupling (Ees/Ea) was estimated by the stroke volume (SV)/ESV ratio (volume method) or as Pmax/mean pulmonary artery pressure (mPAP) minus 1 (pressure method) (n=84). RV function was also assessed by ejection fraction (EF), right atrial pressure (RAP) and SV., Results: Higher Ea and RAP, and lower compliance, SV and EF predicted outcome at univariate analysis. Ees/Ea estimated by the pressure method did not predict outcome but Ees/Ea estimated by the volume method (SV/ESV) did. At multivariate analysis, only SV/ESV and EF were independent predictors of outcome. Survival was poorer in patients with a fall in EF or SV/ESV during follow-up (n=44, p=0.008)., Conclusion: RV function to predict outcome in PAH is best evaluated by imaging derived SV/ESV or EF. In this study, there was no added value of invasive measurements or simplified pressure-derived estimates of RV-arterial coupling., Competing Interests: Dr Bellofiore, Dr Vanderpool, Dr Chesler and Professor Naeije report no relationships that could be construed as a conflict of interest., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Noninvasive imaging of the heart plays an important role in the diagnosis and management of pulmonary hypertension (PH), and several well-established techniques are available for assessing performance of the right ventricle, the key determinant of patient survival. While right heart catheterisation is mandatory for establishing a diagnosis of PH, echocardiography is the most important screening tool for early detection of PH. Cardiac magnetic resonance imaging (CMRI) is also a reliable and practical tool that can be used as part of the diagnostic work-up. Echocardiography can measure a range of haemodynamic and anatomical variables (e.g. pericardial effusion and pulmonary artery pressure), whereas CMRI provides complementary information to echocardiography via high-resolution, three-dimensional imaging. Together with echocardiography and CMRI, techniques such as high-resolution computed tomography and positron emission tomography may also be valuable for screening, monitoring and follow-up assessments of patients with PH, but their clinical relevance has yet to be established. Technological advances have produced new variants of echocardiography, CMRI and positron emission tomography, and these permit closer examination of myocardial architecture, motion and deformation. Integrating these new tools into clinical practice in the future may lead to more precise noninvasive determination of diagnosis, risk and prognosis for PH., (Copyright ©ERS 2015.)

Pulmonary hypertension (PH) due to lung disease (World Health Organization (WHO) group 3) is common, but severe PH, arbitrarily defined as mean pulmonary artery pressure ≥35 mmHg is reported in only a small proportion. Whether these should be treated as patients in WHO group 1 (i.e. pulmonary arterial hypertension) with PH-targeted therapies is unknown. We compared the phenotypic characteristics and outcomes of 118 incident patients with severe PH and lung disease with 74 idiopathic pulmonary arterial hypertension (IPAH) patients, all treated with pulmonary vasodilators. Lung disease patients were older, more hypoxaemic, and had lower gas transfer, worse New York Heart Association functional class and lower 6-min walking distance (6MWD) than IPAH patients. Poorer survival in those with lung disease was driven by the interstitial lung disease (ILD) cohort. In contrast to IPAH, where significant improvements in 6MWD and N-terminal pro-brain natruiretic peptide (NT-proBNP) occurred, PH therapy in severe PH lung disease did not lead to improvement in 6MWD or functional class, but neither was deterioration seen. NT-proBNP decreased from 2200 to 1596 pg·mL(-1) (p=0.015). Response varied by lung disease phenotype, with poorer outcomes in patients with ILD and emphysema with preserved forced expiratory volume in 1 s. Further study is required to investigate whether vasodilator therapy may delay disease progression in severe PH with lung disease., (Copyright ©ERS 2015.)