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The nitric oxide (NO)–soluble guanylate cyclase (sGC)–cyclic guanosine monophosphate (cGMP) pathway plays a key role in the pathogenesis of pulmonary hypertension (PH). Targeted treatments include phosphodiesterase type 5 inhibitors (PDE5i) and sGC stimulators. The sGC stimulator riociguat is approved for the treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). sGC stimulators have a dual mechanism of action, enhancing the sGC response to endogenous NO and directly stimulating sGC, independent of NO. This increase in cGMP production via a dual mechanism differs from PDE5i, which protects cGMP from degradation by PDE5, rather than increasing its production. sGC stimulators may therefore have the potential to increase cGMP levels under conditions of NO depletion that could limit the effectiveness of PDE5i. Such differences in mode of action between sGC stimulators and PDE5i could lead to differences in treatment efficacy between the classes. In addition to vascular effects, sGC stimulators have the potential to reduce inflammation, angiogenesis, fibrosis and right ventricular hypertrophy and remodelling. In this review we describe the evolution of treatments targeting the NO–sGC–cGMP pathway, with a focus on PH. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH. [ABSTRACT FROM AUTHOR]

Background: In the phase 3 STELLAR trial, sotatercept, an investigational first-in-class activin signalling inhibitor, demonstrated beneficial effects on 6-min walk distance and additional efficacy endpoints in pre-treated participants with pulmonary arterial hypertension (PAH)., Methods: This post hoc analysis evaluated data from right heart catheterisation (RHC) and echocardiography (ECHO) obtained from the STELLAR trial. Changes from baseline in RHC and ECHO parameters were assessed at 24 weeks. An analysis of covariance (ANCOVA) model was used to estimate differences in least squares means with treatment and randomisation stratification (mono/double versus triple therapy; World Health Organization functional class II versus III) as fixed factors, and baseline value as covariate., Results: Relative to placebo, treatment with sotatercept led to significant (all p<0.0001 except where noted) improvements from baseline in mean pulmonary artery (PA) pressure (-13.9 mmHg), pulmonary vascular resistance (-254.8 dyn·s·cm -5 ), mean right atrial pressure (-2.7 mmHg), mixed venous oxygen saturation (3.84%), PA elastance (-0.42 mmHg·mL -1 ·beat -1 ), PA compliance (0.58 mL·mmHg -1 ), cardiac efficiency (0.48 mL·beat -1 ·mmHg -1 ), right ventricular (RV) work (-0.85 g·m) and RV power (-32.70 mmHg·L·min -1 ). ECHO showed improvements in tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure ratio (0.12 mm·mmHg -1 ), end-systolic and end-diastolic RV areas (-4.39 cm 2 and -5.31 cm 2 , respectively), tricuspid regurgitation and RV fractional area change (2.04% p<0.050). No significant between-group changes from baseline were seen for TAPSE, heart rate, cardiac output, stroke volume or their indices., Conclusion: In pre-treated patients with PAH, sotatercept demonstrated substantial improvements in PA pressures, PA compliance, PA-RV coupling and right heart function., Competing Interests: Conflict of interest: R. Souza has served as consultant for Acceleron Pharma, Inc., Bayer Healthcare Pharmaceuticals Inc. and Janssen Biotech, Inc. (fees paid to self). D.B. Badesch has received grants/contracts from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA), Altavant and United Therapeutics (all paid to institution, clinical trial), received payment as consultant from Acceleron Pharma, Inc., Merck & Co., Inc. (Rahway, NJ, USA) and Aerovate Inc. (paid through institution), and the author's spouse or partner has stock in Johnson & Johnson Health Care Systems Inc. H.A. Ghofrani has served as consultant for Aerovate, Altavant, Bayer Healthcare, Gossamer Bio, Janssen Diagnostics, LLC, Merck & Co., Inc. (Rahway, NJ, USA) and Pfizer (fees paid to self), and is an employee of Justus Liebig University Giessen, Germany. J.S.R. Gibbs has served a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in data and safety monitoring boards for Actelion Pharmaceuticals, Fundação Bial, GossamerBio and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served in end point review committee for Actelion Pharmaceuticals, Aerovate, Janssen Biotech, Pfizer Pharma GMBH and United Therapeutics Corporation (fees paid to self), and served as Chair of ERN-Lung Functional Committee Patient Reported Outcomes for ERN Lung. M. Gomberg-Maitland has served as a consultant for Acceleron Pharma and Merck & Co., Inc. (Rahway, NJ, USA), Aerami, Bayer HealthCare Pharmaceuticals Inc., Janssen Biotech, Keros and United Therapeutics Corporation (fees paid to self), has received grant/contract from Aerovate, Altavant, Acceleron Pharma and Merck & Co., Inc. (fees paid to institution), and the author's spouse is an employee of Intellia Therapeutics. V.V. McLaughlin has served as a consultant for Aerami, Aerovate, Altavant, Bayer Healthcare, Caremark, Corvista, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics (fees paid to self), received grants/contracts from Aerovate, Altavant, Gossamer Bio, Janssen Biotech, Merck & Co., Inc. (Rahway, NJ, USA) and Sonovie (paid to institution), served as fiduciary officer, board of directors, for Clene (fees paid to self), and is an employee of the University of Michigan. I.R. Preston has served as a steering committee member for Acceleron Pharma, Liquidia and United Therapeutics (fees paid to self), served as scientific advisory board member for Aerovate, Altavant and Gossamer (fees paid to self), served as consultant for Janssen Global Services, LLC and Respira Therapeutics (fees paid to self), and served as principal investigator for Janssen Global Services, LLC and United Therapeutics (fees paid to self). A.B. Waxman has served as consultant for ARIA-CV, Goassamer, Merck & Co., Inc. (Rahway, NJ, USA) and United Therapeutics Corporation (fees paid to self), received grants/contracts from AI Therapeutics, Inc. (fees paid to self), and served on a data and safety monitoring committee for Insmed, Inc. (fees paid to self). E. Grünig has served as consultant for Actelion Pharmaceuticals (fees paid to self), and served as speaker and/or consultant for Bayer Healthcare, Ferrer, GEBRO, GlaxoSmithKline, Janssen Biotech, Merck Sharp & Dohme (MSD) and OMT (fees paid to self). G. Kopeć has served as consultant for Acceleron Pharma, Inc. and Janssen Global Services, LLC, on a scientific advisory board (fees paid to self), served as PI in a clinical study for Acceleron Pharma, Inc., Bayer and Janssen Global Services, LLC (fees paid to self), served as a speaker for Bayer, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self), served as investigator for Janssen Global Services, LLC (fees paid to self), and received travel fees from Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (paid to self). G. Meyer has served as consultant for Bayer Healthcare and Janssen Biotech (fees paid to self), and received grants/contracts from Bayer Healthcare (paid to institution). K.M. Olsson has served as a consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer, Ferrer Pharma, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self). S. Rosenkranz has served as consultant for Abbott Fund, Acceleron Pharma, Inc., Actelion Pharmaceuticals, Aerovate, Altavant, AOP Orphan, AstraZeneca, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Ferrer, Gossamer, Janssen, MSD and United Therapeutics (fees paid to self), and received grants/contracts from Actelion Pharmaceuticals, AstraZeneca, Bayer and Janssen (paid to institution). J. Lin, A.O. Johnson-Levonas and J. de Oliveira Pena are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and own stock/stock shares in Merck & Co., Inc., Rahway, NJ, USA. M. Humbert has served as consultant for Acceleron Pharma, Inc., Aerovate, Altavant, AOP Orphan, Bayer, Chiesi Farmaceutici, Ferrer, Janssen Pharmaceuticals, Merck & Co., Inc. (Rahway, NJ, USA), MorphogenIX and United Therapeutics Corporation (fees paid to self). M.M. Hoeper has served as consultant for Acceleron Pharma, Inc., Actelion Pharmaceuticals, AOP Orphan, Bayer Healthcare, Ferrer, GossamerBio, Janssen Global Services, LLC and Merck & Co., Inc. (Rahway, NJ, USA) (fees paid to self)., (Copyright ©The authors 2023.)

Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered., Competing Interests: Conflict of interest: C.A. Eichstaedt reports lecture fees from MSD, outside the submitted work; and has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued. C. Belge reports consulting fees, participation on advisory boards and lecture honoraria from Janssen and MSD/Bayer; travel support from MSD/Bayer, outside the submitted work. W.K. Chung reports scientific advisory board participation with Regeneron Genetics Center, outside the submitted work. E. Grünig reports grants from Actelion, Bayer, GSK, United Therapeutics, Novartis, Bellerophon, OMT, Pfizer and REATA; lecture fees and consultancy fees from Actelion, Bayer/MSD and GSK; travel support from Janssen; advisory board participation with MSD and Ferrer, outside the submitted work; has a patent “Gene panel specific for pulmonary hypertension and its uses” (European Patent ID: EP3507380) issued; and has also served in leadership roles for ADue and pH e.V., outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck; consulting fees from Acceleron; lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. R.C. Trembath reports lecture fees from Clinical Cases, outside the submitted work. N.W. Morrell reports employment and stock/stock options from Centessa Pharmaceuticals. All other authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Risk stratification plays an essential role in the management of patients with pulmonary arterial hypertension (PAH). The current European guidelines propose a three-stratum model to categorise risk as low, intermediate or high, based on the expected 1-year mortality. However, with this model, most patients are categorised as intermediate risk. We investigated a modified approach based on four risk categories, with intermediate risk subdivided into intermediate-low and intermediate-high risk., Methods: We analysed data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), a European pulmonary hypertension registry, and calculated risk at diagnosis and first follow-up based on World Health Organization functional class, 6-min walk distance (6MWD) and serum levels of brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP), using refined cut-off values. Survival was assessed using Kaplan-Meier analyses, log-rank testing and Cox proportional hazards models., Results: Data from 1655 patients with PAH were analysed. Using the three-stratum model, most patients were classified as intermediate risk (76.0% at baseline and 63.9% at first follow-up). The refined four-stratum risk model yielded a more nuanced separation and predicted long-term survival, especially at follow-up assessment. Changes in risk from baseline to follow-up were observed in 31.1% of the patients with the three-stratum model and in 49.2% with the four-stratum model. These changes, including those between the intermediate-low and intermediate-high strata, were associated with changes in long-term mortality risk., Conclusions: Modified risk stratification using a four-stratum model based on refined cut-off levels for functional class, 6MWD and BNP/NT-proBNP was more sensitive to prognostically relevant changes in risk than the original three-stratum model., Competing Interests: Conflict of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: C. Pausch has nothing to disclose. Conflict of interest: K.M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: D. Huscher has received travel compensation from Shire. Conflict of interest: D. Pittrow has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. Conflict of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GSK, Novartis and Pfizer. Conflict of interest: C.D. Vizza has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. Conflict of interest: O. Distler has/had consultancy relationship and/or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, espeRare foundation, GSK, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm and Sinoxa in the area of potential treatments of scleroderma and its complications including PAH; and has a patent mir-29 for the treatment of systemic sclerosis licensed. Conflict of interest: C. Opitz has nothing to disclose. Conflict of interest: J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: M. Delcroix reports research grants from Actelion/J&J, speaker and consultant fees from Bayer, MSD, Acceleron, AOP and Daiichi Sankyo, outside the submitted work; and is holder of the Janssen Chair for Pulmonary Hypertension at the KU Leuven. Conflict of interest: H.A. Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly and Novartis; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GSK, Actelion, Lilly, Merck, Encysive and Ergonex; has received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE) and the German Ministry for Education and Research (BMBF). Conflict of interest: D-H. Park has nothing to disclose. Conflict of interest: R. Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. Conflict of interest: H. Kaemmerer has received honoraria for lectures and/or consultancy from Actelion, Bristol Myers Squibb and Janssen. Conflict of interest: H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. Conflict of interest: D. Skowasch received fees for lectures and/or consulting and/or research support (paid to institution) from Actelion, Bayer, GSK, Janssen, MSD and Pfizer. Conflict of interest: J. Behr received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/Genzyme. Conflict of interest: K. Milger has received fees from Actelion, AstraZeneca, GSK, Janssen, MSD, Novartis and Sanofi-Aventis. Conflict of interest: M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GSK, Janssen and Novartis. Conflict of interest: H. Wilkens received fees for lectures and/or consultations from Actelion, Bayer, Biotest, Boehringer, GSK, Janssen, Pfizer and Roche. Conflict of interest: H-J. Seyfarth has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen and MSD. Conflict of interest: M. Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. Conflict of interest: D. Dumitrescu declares honoraria for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GSK, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. Conflict of interest: I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GSK, Janssen, MSD, Pfizer and United Therapeutics. Conflict of interest: A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflict of interest: S. Ulrich reports personal fees from Actelion, Janssen and MSD outside the submitted work. Conflict of interest: H. Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GSK, Janssen, MSD, Novartis, Pfizer and United Therapeutics. Conflict of interest: M. Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. Conflict of interest: T.J. Lange has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GSK, Janssen-Cilag, MSD, Pfizer and United Therapeutics. Conflict of interest: S. Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis., (Copyright ©The authors 2022.)

Background: Since 2015, the European pulmonary hypertension guidelines recommend the use of combination therapy in most patients with pulmonary arterial hypertension (PAH). However, it is unclear to what extent this treatment strategy is adopted in clinical practice and if it is associated with improved long-term survival., Methods: We analysed data from COMPERA, a large European pulmonary hypertension registry, to assess temporal trends in the use of combination therapy and survival of patients with newly diagnosed PAH between 2010 and 2019. For survival analyses, we looked at annualised data and at cumulated data comparing the periods 2010-2014 and 2015-2019., Results: A total of 2531 patients were included. The use of early combination therapy (within 3 months after diagnosis) increased from 10.0% in patients diagnosed with PAH in 2010 to 25.0% in patients diagnosed with PAH in 2019. The proportion of patients receiving combination therapy 1 year after diagnosis increased from 27.7% to 46.3%. When comparing the 2010-2014 and 2015-2019 periods, 1-year survival estimates were similar (89.0% (95% CI 87.2-90.9%) and 90.8% (95% CI 89.3-92.4%), respectively), whereas there was a slight but nonsignificant improvement in 3-year survival estimates (67.8% (95% CI 65.0-70.8%) and 70.5% (95% CI 67.8-73.4%), respectively)., Conclusions: The use of combination therapy increased from 2010 to 2019, but most patients still received monotherapy. Survival rates at 1 year after diagnosis did not change over time. Future studies need to determine if the observed trend suggesting improved 3-year survival rates can be confirmed., Competing Interests: Conflicts of interest: M.M. Hoeper has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: C. Pausch has no disclosures. Conflicts of interest: E. Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: G. Staehler has received honoraria for lectures and/or consultancy for Actelion, Bayer, GlaxoSmithKline, Novartis and Pfizer. Conflicts of interest: D. Huscher has received consulting fees from Actelion. Conflicts of interest: D. Pittrow has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, Takeda and Viatris. Conflicts of interest: K.M. Olsson has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: C.D. Vizza has received fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: H. Gall reports personal fees from Actelion, AstraZeneca, Bayer, BMS, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer and United Therapeutics. Conflicts of interest: O. Distler has/had consultancy relationship and/or has received research funding from 4D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, BMS, ChemoAb, EpiPharm, Ergonex, EspeRare Foundation, GlaxoSmithKline, Genentech/Roche, Inventiva, Janssen, Lilly, medac, MedImmune, Mitsubishi Tanabe, Pharmacyclics, Pfizer, Sanofi, Serodapharm and Sinoxa, in the area of potential treatments of scleroderma and its complications including PAH; in addition, the author has a patent “mir-29 for the treatment of systemic sclerosis” licensed. Conflicts of interest: C. Opitz has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Lilly, Novartis and Pfizer. Conflicts of interest: J.S.R. Gibbs has received fees for lectures and/or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: M. Delcroix reports research grants from Actelion/J&J, speaker and consultant fees from Bayer, MSD, Acceleron, AOP and Daiichi Sankyo, outside the submitted work; and is holder of the Janssen Chair for Pulmonary Hypertension at the KU Leuven. Conflicts of interest: H.A. Ghofrani has received honoraria for consultations and/or speaking at conferences from Bayer HealthCare AG, Actelion, Encysive, Pfizer, Ergonex, Lilly and Novartis; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion, Lilly, Merck, Encysive and Ergonex; and has also received governmental grants from the German Research Foundation (DFG), Excellence Cluster Cardiopulmonary Research (ECCPS), State Government of Hessen (LOEWE) and the German Ministry for Education and Research (BMBF). Conflicts of interest: S. Rosenkranz has received fees for lectures and/or consultations from Abbott, Acceleron, Actelion, Bayer, BMS, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics and Vifor; research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis. Conflicts of interest: D-H. Park has nothing to disclose. Conflicts of interest: R. Ewert has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer and United Therapeutics. Conflicts of interest: H. Kaemmerer has received honoraria for lectures and/or consultancy from Actelion, BMS and Janssen. Conflicts of interest: T.J. Lange has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD, Pfizer and United Therapeutics. Conflicts of interest: H-J. Kabitz has received fees from Löwenstein Medical, Weinmann, Philips Respironics, ResMed, Vivisol, Sapio Life and Sanofi-Genzyme. Conflicts of interest: D. Skowasch received fees for lectures and/or consulting and/or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: A. Skride reports no conflicts of interest. Conflicts of interest: M. Claussen reports honoraria for lectures from Boehringer Ingelheim Pharma GmbH and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. Conflicts of interest: J. Behr received grants from Actelion, Bayer, Biogen, Boehringer Ingelheim, Galapagos, Novartis, Roche and Sanofi/Genzyme. Conflicts of interest: K. Milger has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and Sanofi-Aventis. Conflicts of interest: M. Halank has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen and Novartis. Conflicts of interest: H. Wilkens received personal fees from Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. Conflicts of interest: H-J. Seyfarth has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen and MSD. Conflicts of interest: M. Held has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. Conflicts of interest: D. Dumitrescu declares honoraria for lectures and/or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer and Servier. Conflicts of interest: I. Tsangaris has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer and United Therapeutics. Conflicts of interest: A. Vonk-Noordegraaf reports receiving fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. Conflicts of interest: S. Ulrich reports personal fees from Actelion, Janssen and MSD outside the submitted work. Conflicts of interest: H. Klose has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer and United Therapeutics., (Copyright ©The authors 2022.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels <500 µm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions.This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH.It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice., Competing Interests: Conflict of interest: M. Delcroix reports grants and other (investigator, speaker and consultant fees received by the institution) from Actelion/J&J, other (investigator, speaker and consultant fees received by the institution) from Bayer, other (speaker and consultant fees received by the institution) from MSD, other (investigator fees received by the institution) from Reata, other (investigator and consultant fees received by the institution) from Bellarophon, other (consultant fees received by the institution) from Acceleron, outside the submitted work. Conflict of interest: A. Torbicki reports grants and personal fees for lectures and consultancy from Actelion/Janssen, Bayer and MSD, personal fees for lectures from AOP, personal fees for lectures and consultancy from Pfizer, outside the submitted work. Conflict of interest: D. Gopalan reports other (speaker fees) from Actelion/J&J, other (consultancy work and speaker fees) from Bayer, outside the submitted work. Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals and MSD, grants from GlaxoSmithKline, personal fees from Bayer, Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, outside the submitted work. Conflict of interest: F.A. Klok reports research grants from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi-Sankyo, MSD and Actelion, the Dutch Heart Foundation and the Dutch Thrombosis association, outside the submitted work. Conflict of interest: I. Lang reports grants and personal fees from Actelion-Janssen and AOP Orphan Pharma, personal fees from Medtronic, Ferrer and United Therapeutics, outside the submitted work. Conflict of interest: D. Jenkins reports grants from Bayer, personal fees for advisory board work from Actelion, outside the submitted work. Conflict of interest: N.H. Kim reports personal fees for consultancy from Actelion, Bayer and Merck, outside the submitted work. Conflict of interest: M. Humbert reports grants and personal fees from Actelion and Bayer, personal fees from Acceleron, GSK, Merck, Novartis, AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: X. Jais reports personal fees and non-financial support from Actelion and MSD, grants from Bayer, outside the submitted work. Conflict of interest: A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012-08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610), has received speakers’ money from Johnson & Johnson and Ferrer in the past 3 years, and served as a member of the scientific advisory board of Morphogen-XI. Conflict of interest: J. Pepke-Zaba has received speaker fees and honoraria for consultations from Actelion, Merck and Bayer, and her institution received research and educational grants from Actelion and Merck. Conflict of interest: P. Brénot has nothing to disclose. Conflict of interest: P. Dorfmuller has nothing to disclose. Conflict of interest: E. Fadel has nothing to disclose. Conflict of interest: H-A. Ghofrani reports personal fees and other (consultancy fees) from Actelion, Bayer AG, GlaxoSmithKline, Novartis and Pfizer, other (consultancy fees) from Bellerophon Pulse Technologies and MSD, grants from Deutsche Forschungsgemeinschaft (DFG), during the conduct of the study. Conflict of interest: M.M. Hoeper reports personal fees for consultancy and lectures from Bayer AG, MSD, Actelion, Jansen, Acceleron and Pfizer, during the conduct of the study. Conflict of interest: P. Jansa reports other (investigator) from Actelion, personal fees and other (investigator) from Bayer Pharma AG and Reata Pharmaceuticals, personal fees from AOP and MSD, outside the submitted work. Conflict of interest: M. Madani reports personal fees for consultancy from Actelion and Wexler Surgical, outside the submitted work. Conflict of interest: H. Matsubara reports personal fees from Actelion Pharmaceuticals Japan, Ltd, AOP Orphan Pharmaceuticals AG, Bayer Yakuhin, Ltd, Pfizer Japan, Inc., Nippon Shinyaku, Co., Ltd, Kaneka Medix Corporation, GlaxoSmithKline Pharmaceuticals, Ltd and United Therapeutics Corporation, outside the submitted work. Conflict of interest: T. Ogo has nothing to disclose. Conflict of interest: E. Grünig reports fees for lectures and/or consultations from Actelion, Bayer AG, GSK, MSD, United Therapeutics and Pfizer, outside the submitted work. Conflict of interest: A. D'Armini reports personal fees from Actelion Phamaceuticals, Bayer AG and Merck Sharp & Dohme, outside the submitted work. Conflict of interest: N. Galie reports grants and personal fees from Actelion and Janssen, personal fees from Pfizer and Ferrer, outside the submitted work. Conflict of interest: B. Meyer reports personal fees for lectures from Bayer AG, outside the submitted work. Conflict of interest: P. Corkery has nothing to disclose. Conflict of interest: G. Meszaros reports personal fees from Actelion Pharmaceuticals, outside the submitted work. Conflict of interest: E. Mayer reports personal fees for lectures and consultancy from Actelion, Bayer and MSD, during the conduct of the study. Conflict of interest: G. Simonneau reports personal fees and non-financial support from Actelion, Bayer and MSD, outside the submitted work., (Copyright ©ERS 2021. For reproduction rights and permissions contact permissions@ersnet.org.)