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Background: Among patients meeting diagnostic criteria for idiopathic pulmonary arterial hypertension (IPAH), there is an emerging lung phenotype characterised by a low diffusion capacity for carbon monoxide (DLCO) and a smoking history. The present study aimed at a detailed characterisation of these patients., Methods: We analysed data from two European pulmonary hypertension registries, COMPERA (launched in 2007) and ASPIRE (from 2001 onwards), to identify patients diagnosed with IPAH and a lung phenotype defined by a DLCO of less than 45% predicted and a smoking history. We compared patient characteristics, response to therapy, and survival of these patients to patients with classical IPAH (defined by the absence of cardiopulmonary comorbidities and a DLCO of 45% or more predicted) and patients with pulmonary hypertension due to lung disease (group 3 pulmonary hypertension)., Findings: The analysis included 128 (COMPERA) and 185 (ASPIRE) patients with classical IPAH, 268 (COMPERA) and 139 (ASPIRE) patients with IPAH and a lung phenotype, and 910 (COMPERA) and 375 (ASPIRE) patients with pulmonary hypertension due to lung disease. Most patients with IPAH and a lung phenotype had normal or near normal spirometry, a severe reduction in DLCO, with the majority having no or a mild degree of parenchymal lung involvement on chest computed tomography. Patients with IPAH and a lung phenotype (median age, 72 years [IQR 65-78] in COMPERA and 71 years [65-76] in ASPIRE) and patients with group 3 pulmonary hypertension (median age 71 years [65-77] in COMPERA and 69 years [63-74] in ASPIRE) were older than those with classical IPAH (median age, 45 years [32-60] in COMPERA and 52 years [38-64] in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries). While 99 (77%) patients in COMPERA and 133 (72%) patients in ASPIRE with classical IPAH were female, there was a lower proportion of female patients in the IPAH and a lung phenotype cohort (95 [35%] COMPERA; 75 [54%] ASPIRE), which was similar to group 3 pulmonary hypertension (336 [37%] COMPERA; 148 [39%] ASPIRE]). Response to pulmonary arterial hypertension therapies at first follow-up was available from COMPERA. Improvements in WHO functional class were observed in 54% of patients with classical IPAH, 26% of patients with IPAH with a lung phenotype, and 22% of patients with group 3 pulmonary hypertension (p<0·0001 for classical IPAH vs IPAH and a lung phenotype, and p=0·194 for IPAH and a lung phenotype vs group 3 pulmonary hypertension); median improvements in 6 min walking distance were 63 m, 25 m, and 23 m for these cohorts respectively (p=0·0015 for classical IPAH vs IPAH and a lung phenotype, and p=0·64 for IPAH and a lung phenotype vs group 3 pulmonary hypertension), and median reductions in N-terminal-pro-brain-natriuretic-peptide were 58%, 27%, and 16% respectively (p=0·0043 for classical IPAH vs IPAH and a lung phenotype, and p=0·14 for IPAH and a lung phenotype vs group 3 pulmonary hypertension). In both registries, survival of patients with IPAH and a lung phenotype (1 year, 89% in COMPERA and 79% in ASPIRE; 5 years, 31% in COMPERA and 21% in ASPIRE) and group 3 pulmonary hypertension (1 year, 78% in COMPERA and 64% in ASPIRE; 5 years, 26% in COMPERA and 18% in ASPIRE) was worse than survival of patients with classical IPAH (1 year, 95% in COMPERA and 98% in ASPIRE; 5 years, 84% in COMPERA and 80% in ASPIRE; p<0·0001 for IPAH with a lung phenotype vs classical IPAH in both registries)., Interpretation: A cohort of patients meeting diagnostic criteria for IPAH with a distinct, presumably smoking-related form of pulmonary hypertension accompanied by a low DLCO, resemble patients with pulmonary hypertension due to lung disease rather than classical IPAH. These observations have pathogenetic, diagnostic, and therapeutic implications, which require further exploration., Funding: COMPERA is funded by unrestricted grants from Acceleron, Bayer, GlaxoSmithKline, Janssen, and OMT. The ASPIRE Registry is supported by Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK., Competing Interests: Declaration of interests MMH received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, and Pfizer. KD has received research funding from Janssen Pharmaceuticals, National Institute of Health Research (NIHR), UK and The Wellcome Trust, UK. RAL has received honoraria and research grants from Janssen Pharmaceuticals. KMO has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. DH has received travel compensation from Shire. DP has received fees for consultations from Actelion, Amgen, Aspen, Bayer, Biogen, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Sanofi-Genzyme, Takeda and Viatris. EG has received fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. GS has received honoraria for lectures or consultancy for Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. CDV has received fees for lectures or consultations from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. HG reports personal fees from Actelion, AstraZeneca, Bayer, Bristol Myers Squib, GlaxoSmithKline, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. OD has or has had a consultancy relationship or has received research funding from 4 D Science, Actelion, Active Biotec, Bayer, Biogen Idec, Boehringer Ingelheim Pharma, Bristol Myers Squib, 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; and reports a patent mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143). JSRG has received fees for lectures or consultations from Acceleron, Actelion, Aerovate, Bayer, Complexia, Janssen, MSD, Pfizer, and United Therapeutics. MD reports research grants from Actelion/J&J; speaker and consultant fees from Bayer, MSD, Acceleron, AOP, Daiichi Sankyo, outside of the submitted work; and being a holder of the Janssen Chair for Pulmonary Hypertension at the Katholieke Universiteit Leuven, Leuven, Belgium. D-HP has received lecture fees from Janssen Pharmaceuticals. HAG has received honorariums for consultations or speaking at conferences from Bayer HealthCare, Actelion, Pfizer, Janssen, Merck/MSD, and Gossamer; is member of advisory boards for Acceleron, Bayer HealthCare AG, Pfizer, GlaxoSmithKline, Actelion, Merck/MSD, Janssen, and Gossamer; and has received public grants from the German Research Foundation, Excellence Cluster Cardiopulmonary Institute, State Government of Hessen, and the German Ministry for Education and Research. RE has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, and United Therapeutics. HKa has received honoraria for lectures or consultancy from Actelion, Bristol Myers Squibb, and Janssen. H-JK has received fees from Actelion, Anamed, AstraZeneca, Berlin Chemie/Menarini, Boehringer Ingelheim, Chiesi, Daiichi-Sankyo, Dräger, Fisher & Paykel Healthcare, GlaxoSmithKline, Heinen + Löwenstein, Lilly, MSD, Novartis, Pfizer, Weinmann, Philips Healthcare, Pulmonx, ResMed, Roche, Sanofi-Genzyme, Sapio Life, Weinmann. DS received fees for lectures, consulting, or research support to institution from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. JB received grants from Actelion, Boehringer Ingelheim and Roche; and honoraria from Bayer, Biogen, Boehringer-Ingelheim, Galapagos, Novartis, Roche, and Sanofi/Genzyme. KM has received fees from Actelion, AstraZeneca, GlaxoSmithKline, Janssen, MSD, Novartis and Sanofi-Aventis. TJL has received speaker fees and honoraria for consultation from Acceleron, Actelion, Bayer, GlaxoSmithKline, Janssen-Cilag, MSD, Pfizer, and United Therapeutics. HW received fees for lectures or consultations from Actelion, Bayer, Biotest, Boehringer, GlaxoSmithKline, Janssen, Pfizer and Roche. H-JS has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, and MSD. MHe has received speaker fees and honoraria for consultations from Actelion, Bayer, Boehringer Ingelheim Pharma, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Nycomed, Roche and Servier. DD declares honoraria for lectures or consultancy from Actelion, AstraZeneca, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, Servier and Vifor. IT has received fees from Actelion, Bayer, ELPEN, GlaxoSmithKline, Janssen, MSD, Pfizer, and United Therapeutics. AV-N reports receiving fees for lectures or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD and Pfizer. SU reports personal fees from Actelion, Janssen, MSD, and Orpha-Swiss outside of the submitted work. HKl has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, and United Therapeutics. MC reports honoraria for lectures from Boehringer Ingelheim Pharma and Roche Pharma, and for serving on advisory boards from Boehringer Ingelheim. SE has received honoraria for lectures or consultations from Actelion, MSD, Bayer, Acceleron, Gilead, AstraZeneca, Pulmox, Boston Scientific, and Boehringer Ingelheim. K-HS has received fees for lectures and educational events from Abbott, Janssen, and MSD. AJS has received research grants from GlaxoSmithKline, Janssen Pharmaceuticals, Wellcome Trust, and NIHR; has undertaken consultancy work and received honoraria for lectures from Janssen Pharmaceuticals; and has undertaken consultancy work for General Electric. AART is supported by a British Heart Foundation Intermediate Clinical Fellowship (FS/18/13/33281) and has received research grants to their institution from Janssen Pharmaceuticals and GlaxoSmithKline. CAE has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen and MSD. SR has received fees for lectures or consultations from Abbott, Acceleron, Actelion, Bayer, Bristol Myers Squib, Gilead, GlaxoSmithKline, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; and research grants to institution from AstraZeneca, Actelion, Bayer Janssen and Novartis. RC has received honoraria for lectures or consultations from Actelion, GlaxoSmithKline, Janssen, and MSD. DGK has received honoraria for lectures or consultations from Acceleron, Actelion, Ferrer, GlaxoSmithKline, Janssen Pharmaceuticals, and MSD; and research grants to institution from Actelion, GlaxoSmithKline and Janssen Pharmaceuticals. MHa has received speaker fees and honoraria for consultations from Acceleron, Actelion, AstraZeneca, Bayer, BerlinChemie, GlaxoSmithKline, Janssen, and Novartis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aims: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria., Methods and Results: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI., Conclusion: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care., Competing Interests: Conflict of interest: A.C.M. was supported by a research grant from the German Academic Exchange Service (DAAD; 57440918). S.B. reports grants or contracts from Bayer, INARI, Boston Scientific, Medtronic, Bard, SANOFI, and Concept Medical; consulting fees from INARI; payment or honoraria from INARI, Boston Scientific, and Concept Medical; and support for attending meetings and/or travel from Bayer and Daiichi Sankyo. R.E. reports consulting fees from Actelion Germany, Boehringer Ingelheim, Janssen, AstraZeneca, OMT, and LungPacer; payment or honoraria from Janssen, Boehringer Ingelheim, AstraZeneca, OMT, Berlin Chemie, and Novartis; support for attending meetings and/or travel from Janssen, Boehringer Ingelheim, AstraZeneca, OMT, Berlin Chemie, and Novartis; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen, Boehringer Ingelheim, AstraZeneca, and Berlin Chemie. M.F. reports payment or honoraria and support for attending meetings and/or travel from Janssen. F.G. reports grants or contracts from Janssen, Bayer; consulting fees from Bayer & Janssen and AstraZeneca; payment or honoraria from Bayer, Janssen, AstraZeneca, and MSD; payment for expert testimony from Janssen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Janssen. H.-A.G. reports grants or contracts from Actelion/Janssen and Bayer; consulting fees from Actelion/Janssen, Bayer, MSD, Accelleron, MorphogenIX, and Gossamer Bio; payment or honoraria from Actelion/Janssen, Bayer, MSD, and Gossamer Bio; and support for attending meetings and/or travel from Actelion/Janssen, Bayer, and MSD. A.G. reports payment or honoraria from Bayer Vital, Roche, MSD, and Boehringer-Ingelheim; and support for attending meetings and/or travel from Bayer Vital. E.G. reports consulting fees from Actelion, Bayer/MSD, GSK, United Therapeutics, Novartis, REATA, OMT, and Pfizer; payment or honoraria from Actelion, Bayer/MSD, and GSK; participation on a Data Safety Monitoring Board or Advisory Board for MSD, Janssen and Bayer; and leadership or fiduciary role for Actelion/Janssen. M.Ha. reports consulting fees from MSD; payment or honoraria from Actelion, AstraZeneca, Bayer, Berlin Chemie, Janssen-Cilag, and MSD; support for attending meetings and/or travel from Actelion; and participation on a Data Safety Monitoring Board or Advisory Board for Acceleron, Actelion, GSK, Janssen-Cilag, and MSD. M.He. reports consulting fees from Actelion, Bayer, Berlin Chemie, BMS, Boehringer Ingelheim, Janssen, MSD, and Pfizer; payment or honoraria from Actelion, AstraZeneca, Bayer, BMS, Berlin Chemie, Boehringer Ingelheim, Daiichi Sankyo, Janssen, MSD, and Pfuter Santis; and support for attending meetings and/or travel from Boehringer Ingelheim and Janssen. L.H. reports payment or honoraria from Actelion and MSD. M.M.H. reports consulting fees from Acceleron, Actelion, Bayer, GSK, Janssen, MSD, and Pfizer; and payment or honoraria from Actelion, Bayer, GSK, Janssen, MSD, and Pfizer. F.A.K. reports grants or contracts from Bayer, BMS, Boehringer Ingelheim, MSD, Daiichi Sankyo, Actelion. M.L. reports grants or contracts from Thermo Fisher Scientific, payment or honoraria from Actelion/Johnson & Johnson, Bayer, Daiichi Sankyo, MSD, Pfizer, and Georg Thieme Verlag Stuttgart Germany; support for attending meetings and/or travel from Actelion/Johnson & Johnson and Bayer; participation on a Data Safety Monitoring Board or Advisory Board for Thermo Fisher Scientific. H.H.L. reports travel fees for the study by Bayer, Germany, consulting fees, payment or honoraria, and payment for expert testimony from MSD, Germany; and participation on a Data Safety Monitoring Board or Advisory Board for MSD, Germany. E.M. reports payment or honoraria from Actelion/Janssen, MSD, and Bayer; support for attending meetings and/or travel from Actelion/Janssen, MSD, and Bayer; and participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen. H.-J.S. reports payment or honoraria from Janssen/Actelion, Bayer, GSK, and MSD; and participation on a Data Safety Monitoring Board or Advisory Board for Janssen. R.W. reports grants or contracts from Boehringer Ingelheim and Medtronic; and payment or honoraria from Abbott, AstraZeneca, Bayer, BMS, CVRx, Daichii Sankyo, Novartis, Pfizer, Pharmacosmos, Sanofi, Servier, and SOBI. H.W. reports payment or honoraria from Actelion/Janssen, Bayer, Biotest, Boehringer Ingelheim, MSD, Pfizer, and Roche; support for attending meetings and/or travel from Actelion and Boehringer Ingelheim; and participation on a Data Safety Monitoring Board or Advisory Board for Actelion/Janssen, Boehringer Ingelheim, and MSD. P.S.W. reports study grants from Bayer AG, grants or contracts from Boehringer Ingelheim, DiaSorin, Sanofi-Aventis, AstraZeneca, Bayer Health Care, Bayer Vital, Daiichy Sankyo Europe, and Novartis Pharma; payment or honoraria from Bayer Health Care, Pfizer Pharma, and Bristol Myers Squibb; and other non-financial support from Philips Medical Systems, DiaSorin, and IEM. S.V.K. reports grants or contracts from Bayer AG; consulting fees from Bayer AG, Daiichi Sankyo, and Boston Scientific; and payment or honoraria from Bayer AG, INARI Medical, MSD, Pfizer, and Bristol-Myers Squibb. S.R. reports grants or contracts from Actelion, AstraZeneca, Bayer, Janssen, and Novartis; consulting fees from Abbott, Acceleron, Actelion, Bayer, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor; payment or honoraria from Actelion, Bayer, BMS, Ferrer, GSK, Janssen, MSD, Novartis, Pfizer, United Therapeutics, and Vifor. The remaining authors (A.C.M., C.A., D.B., L.B., D.F., N.M., F.J.M., C.N., C.O., and K.-H.S.) declare no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Aims: The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFpEF). To date, neither established heart failure therapies nor pulmonary vasodilators proved beneficial. This study investigated the efficacy of chronic treatment with the oral soluble guanylate cyclase stimulator riociguat in patients with PH-HFpEF., Methods and Results: The phase IIb, randomized, double-blind, placebo-controlled, parallel-group, multicentre DYNAMIC trial assessed riociguat in PH-HFpEF. Patients were recruited at five hospitals across Austria and Germany. Key eligibility criteria were mean pulmonary artery pressure ≥25 mmHg, pulmonary arterial wedge pressure >15 mmHg, and left ventricular ejection fraction ≥50%. Patients were randomized to oral treatment with riociguat or placebo (1:1). Patients started at 0.5 mg three times daily (TID) and were up-titrated to 1.5 mg TID. The primary efficacy endpoint was change from baseline to week 26 in cardiac output (CO) at rest, measured by right heart catheterization. Primary efficacy analyses were performed on the full analysis set. Fifty-eight patients received riociguat and 56 patients placebo. After 26 weeks, CO increased by 0.37 ± 1.263 L/min in the riociguat group and decreased by -0.11 ± 0.921 L/min in the placebo group (least-squares mean difference: 0.54 L/min, 95% confidence interval 0.112, 0.971; P = 0.0142). Five patients dropped out due to riociguat-related adverse events but no riociguat-related serious adverse event or death occurred., Conclusion: The vasodilator riociguat improved haemodynamics in PH-HFpEF. Riociguat was safe in most patients but led to more dropouts as compared to placebo and did not change clinical symptoms within the study period., Competing Interests: Conflict of interest: E.G. received grants/contracts from Bayer, MSD, United Therapeutics and OMT; consulting fees from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics; payments/honoraria from Bayer, Janssen and MSD; support for attending meetings and/or travel from Bayer, GlaxoSmithKline, Janssen, MSD, Merck, Sharp & Dohme, and United Therapeutics. E.G. participated on data monitoring/advisory boards for Janssen, United Therapeutics, and Acceleron. I.P. has received honoraria for lectures from Orion, AOP Orphan and Amomed. D.B. received financial support for the present manuscript in form of an unrestricted research grant by Bayer (all payments were made to the Medical University of Vienna); research grants by Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi (all payments were made to the Medical University of Vienna); and payments/honoraria from Bayer AG, Pfizer, Alnylam, Ionis, SOBI, Novartis, Sanofi, Astra Zeneca, Boehringer Ingelheim, Zoll, Janssen, AOP Orphan, and MSD. All other authors declare that there is no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology.)

Objectives: To assess diagnostic accuracy of automated 3D volumetry of cardiac chambers based on computed tomography pulmonary angiography (CTPA) for the differentiation of pulmonary hypertension due to left heart disease (group 2 PH) from non-group 2 PH compared to manual diameter measurements., Methods: Patients with confirmed PH undergoing right heart catheterisation and CTPA within 100 days for diagnostic workup of PH between August 2013 and February 2016 were included in this retrospective, single-centre study. Automated 3D segmentation of left atrium, left ventricle, right atrium and right ventricle (LA/LV/RA/RV) was performed by two independent and blinded radiologists using commercial software. For comparison, axial diameters were manually measured. The ability to differentiate group 2 PH from non-group 2 PH was assessed by means of logistic regression., Results: Ninety-one patients (median 67.5 years, 44 women) were included, thereof 19 patients (20.9%) classified as group 2 PH. After adjustment for age, sex and mean pulmonary arterial pressure, group 2 PH was significantly associated with larger LA volume (p < 0.001), larger LV volume (p = 0.001), lower RV/LV volume ratio (p = 0.04) and lower RV/LA volume ratio (p = 0.003). LA volume demonstrated the highest discriminatory ability to identify group 2 PH (AUC, 0.908; 95% confidence interval, 0.835-0.981) and was significantly superior to LA diameter (p = 0.009). Intraobserver and interobserver agreements were excellent for all volume measurements (intraclass correlation coefficients 0.926-0.999, all p < 0.001)., Conclusions: LA volume quantified by automated, CTPA-based 3D volumetry can differentiate group 2 PH from other PH groups with good diagnostic accuracy and yields significantly higher diagnostic accuracy than left atrial diameter., Key Points: • Automated cardiac chamber volumetry using non-gated CT pulmonary angiography can differentiate pulmonary hypertension due to left heart disease from other causes with good diagnostic accuracy. • Left atrial volume yields significantly higher diagnostic accuracy than left atrial axial diameter for identification of pulmonary hypertension due to left heart disease without time-consuming manual processing., (© 2022. The Author(s).)

Background: The objective of this study was to investigate the prognostic impact of right ventricular (RV) function at rest and during exercise in patients with systemic sclerosis (SSc) presenting for a screening for pulmonary hypertension (PH)., Methods: In this study, data from SSc patients who underwent routinely performed examinations for PH screening including echocardiography and right heart catheterization at rest and during exercise were analysed. Uni- and multivariable analyses were performed to identify prognostic parameters., Results: Out of 280 SSc patients screened for PH, 225 were included in the analysis (81.3% female, mean age 58.1±13.0 years, 68% limited cutaneous SSc, WHO-FC II-III 74%, 24 manifest PH). During the observation period of 3.2±2.7 (median 2.6) years 35 patients died. Tricuspid annular plane systolic excursion (TAPSE) at rest <18 mm (p=0.001), RV output reserve as increase of cardiac index (CI) during exercise <2 l/min (p<0.0001), RV pulmonary vascular reserve (Δ mean pulmonary artery pressure/Δ cardiac output) ≥3 mmHg/l/min (p<0.0001), peak CI <5.5 l/min/m 2 (p=0.001), pulmonary arterial compliance <2 ml/mmHg (p=0.002), TAPSE/systolic pulmonary arterial pressure (sPAP) ratio ≤0.6 ml/mmHg (p<0.0001) and echocardiographic qualitative RV function at rest (p<0.0001) significantly predicted worse survival. In the multivariable analysis TAPSE/sPAP ratio and diffusion capacity for carbon monoxide ≤65% were identified as independent prognostic predictors and had 75% sensitivity and 69% specificity to predict future development of pulmonary vascular disease (PVD) during follow-up., Conclusions: This study demonstrates that assessment of RV function at rest and during exercise may provide crucial information to identify SSc patients who are at a high risk of poor outcome and for the development of PH and/or PVD., (© 2022. The Author(s).)

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: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated., Methods: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses., Results: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools., Conclusion: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

BACKGROUND. Noninvasive tests for pulmonary hypertension (PH) are needed to help select patients for diagnostic right heart catheterization (RHC). CT pulmonary angiography (CTPA) is commonly performed for suspected PH. OBJECTIVE. The purpose of this study was to assess the utility of CTPA-based cardiac chamber volumetric measurements for the diagnosis of PH in comparison with echocardiographic and conventional CTPA parameters, with the 2018 updated hemodynamic definition used as reference. METHODS. This retrospective study included 109 patients (72 women and 37 men; median age, 68 years) who underwent nongated CTPA, transthoracic echocardiography, and RHC for the workup of suspected PH between August 2013 and February 2016. Two radiologists independently used automated 3D segmentation software to determine the volumes of the right ventricle (RV), right atrium (RA), left ventricle (LV), and left atrium (LA) and also measured the axial diameters of the cardiac chambers, main pulmonary artery, and ascending aorta. Interobserver agreement was assessed, and mean values were obtained; one observer repeated volumetric measurements to assess intraobserver agreement. ROC analysis was used to assess diagnostic performance for the detection of PH. A multivariable binary logistic regression model was established. RESULTS. A total of 60 of 109 patients had PH. Intra- and interobserver agreements were excellent for all volume measurements (intraclass correlation coefficients, 0.935-0.999). In patients with PH versus those without PH, RV volume was 172.6 versus 118.1 mL, and RA volume was 130.2 versus 77.0 mL (both p < .05). Cardiac chamber measurements with the highest AUC for PH were the RV/LV volume ratio and RA volume (both 0.791). Significant predictors of PH 20 (as defined using the 2018 hemodynamic definition from the Sixth World Symposium on Pulmonary Hypertension) after adjustment for age, sex, and body surface area included RV volume per 10 mL (odds ratio [OR], 1.21), RA volume per 10 mL (OR, 1.27), RV/LV volume ratio (OR, 2.91), and RA/LA volume ratio (OR, 11.22). Regression analysis yielded a predictive model for PH that contained two independent predictors: echocardiographic pulmonary arterial systolic pressure and CTPA-based RA volume; the model had an AUC of 0.898, sensitivity of 83.3%, and specificity of 85.7%. CONCLUSION. Automated cardiac chamber volumetry using nongated CTPA, particularly of the RA, provides incremental utility relative to echocardiographic and conventional CTPA parameters for diagnosis of PH. CLINICAL IMPACT. Automated volumetry of cardiac chambers based on nongated CTPA may facilitate early noninvasive detection of PH, identifying patients who warrant further evaluation by RHC.

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.)

Pulmonary hypertension (PH) often complicates chronic left-sided heart failure, with a remarkable impact on quality of life, exercise capacity, and survival. PH in chronic left-sided heart failure (PH-LHD) is not only caused by backward transmission of pressures but also involves impairment of atrial function, inflammation, and vasoconstriction. Once the left atrium loses its reservoir capacity, usually pulmonary vascular resistances increase. Right atrial dilation commonly represents the first sign of PH-LHD, before right ventricle dilatation and systolic dysfunction develop, leading to right heart insufficiency, and ultimately, right heart failure., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (BMPR2). While BMPR2 protein expression levels are known to be reduced in the lung tissue of heritable PAH (HPAH) patients, a systematic study evaluating expression in more easily accessible blood samples and its clinical relevance is lacking. Thus, we analyzed the BMPR2 mRNA expression in idiopathic/HPAH patients and healthy controls in blood by quantitative polymerase chain reaction and protein expression by enzyme-linked immunosorbent assay. Clinical parameters included right heart catherization, echocardiography, six-minute walking test and laboratory tests. BMPR2 variant-carriers (n = 23) showed significantly lower BMPR2 mRNA expression in comparison to non-carriers (n = 56) and healthy controls (n = 30; p < 0.0001). No difference in BMPR2 protein expression was detected. Lower BMPR2 mRNA expression correlated significantly with greater systolic pulmonary artery pressure and pulmonary vascular resistance. Higher BMPR2 mRNA expression correlated with greater glomerular filtration rate, cardiac index and six-minute walking distance. We demonstrated the feasibility to assess BMPR2 expression in blood and, for the first time, that BMPR2 mRNA expression levels are significantly reduced in variant carriers and correlated with clinical parameters. Further studies may evaluate the usefulness of BMPR2 mRNA expression in blood as a new marker for disease severity.

Although major breakthroughs in the field of pediatric cardiology, cardiac surgery, intervention, and overall care improved the outlook of congenital heart disease, Eisenmenger syndrome (ES) is still encountered and remains a complex clinical entity with multisystem involvement, including secondary erythrocytosis, increased thrombotic and bleeding diathesis, high arrhythmogenic risk, progressive heart failure, and premature death. Clearly, care for ES is best delivered in multidisciplinary expert centers. In this review, we discuss the considerable recent progress in understanding the complex pathophysiology of ES, means of prognostication, and improvement in clinical outcomes achieved with pulmonary arterial hypertension-targeted therapies. Additionally, we delineate areas of uncertainty in various aspects of care, discuss gaps in current evidence, and review current status in less privileged countries and propose initiatives to reduce disease burden. Finally, we propose the application of emerging technologies to enhance the delivery and quality of health care related to ES and beyond., Competing Interests: Funding Support and Author Disclosures Dr Arvanitaki is the recipient of the International Training and Research Fellowship EMAH Stiftung Karla Voellm. Dr Gatzoulis has received unrestricted educational grants from Actelion, Pfizer, and GlaxoSmithKline. Dr Opotowsky has received funding from Actelion, Janssen, and Johnson and Johnson, not directly related to the current work; and has received funding by the Heart Institute Research Core (HIRC) supporting research in the Cincinnati Children’s Heart Institute. Dr Khairy is supported by the André Chagnon Research Chair in Electrophysiology and Congenital Heart Disease. Dr Diller has received funding from Actelion, Daiichi-Sankyo, and Bayer, unrelated to the current work; and has received funding by the Karla Völlm Foundation, supporting research in the Department. Dr Giannakoulas has receiving honoraria and consultancy fees from Actelion Pharmaceuticals Hellas, Bayer, ELPEN, Galenica-Ferrer, GlaxoSmithKline, Pfizer, Lilly, Merck Sharp & Dohme, and United Therapeutics, not directly related to this work. Dr Grünig has received fees for lectures and/or consultations from Actelion, Bayer, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Pfizer, and United Therapeutics. Dr D’Alto has received funding from Actelion-Janssen, Merck Sharp & Dohme, GlaxoSmithKline, and Dompé, not directly related to the current work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: A genetic predisposition can lead to the rare disease pulmonary arterial hypertension (PAH). Most mutations have been identified in the gene BMPR2 in heritable PAH. However, as of today 15 further PAH genes have been described. The exact prevalence across these genes particularly in other PAH forms remains uncertain. We present the distribution of mutations across PAH genes identified at the largest German referral centre for genetic diagnostics in PAH over a course of > 3 years., Methods: Our PAH-specific gene diagnostics panel was used to sequence 325 consecutive PAH patients from March 2017 to October 2020. For the first year the panel contained thirteen PAH genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. These were extended by the three genes ATP13A3, AQP1 and SOX17 from March 2018 onwards following the genes' discovery., Results: A total of 79 mutations were identified in 74 patients (23%). Of the variants 51 (65%) were located in the gene BMPR2 while the other 28 variants were found in ten further PAH genes. We identified disease-causing variants in the genes AQP1, KCNK3 and SOX17 in families with at least two PAH patients. Mutations were not only detected in patients with heritable and idiopathic but also with associated PAH., Conclusions: Genetic defects were identified in 23% of the patients in a total of 11 PAH genes. This illustrates the benefit of the specific gene panel containing all known PAH genes., (© 2022. The Author(s).)

Preclinical and early clinical studies suggest that angiotensin-converting enzyme type 2 activity may be impaired in patients with pulmonary arterial hypertension (PAH); therefore, administration of exogenous angiotensin-converting enzyme type 2 (ACE2) may be beneficial. This Phase IIa, multi-center, open-label, exploratory, single-dose, dose-escalation study (NCT03177603) assessed the potential vasodilatory effects of single doses of GSK2586881 (a recombinant human ACE2) on acute cardiopulmonary hemodynamics in hemodynamically stable adults with documented PAH who were receiving background PAH therapy. Successive cohorts of participants were administered a single intravenous dose of GSK2586881 of 0.1, 0.2, 0.4, or 0.8 mg/kg. Dose escalation occurred after four or more participants per cohort were dosed and a review of safety, tolerability, pharmacokinetics, and hemodynamic data up to 24 h postdose was undertaken. The primary endpoint was a change in cardiopulmonary hemodynamics (pulmonary vascular resistance, cardiac index, and mean pulmonary artery pressure) from baseline. Secondary/exploratory objectives included safety and tolerability, effect on renin-angiotensin system peptides, and pharmacokinetics. GSK2586881 demonstrated no consistent or sustained effect on acute cardiopulmonary hemodynamics in participants with PAH receiving background PAH therapy ( N  = 23). All doses of GSK2586881 were well tolerated. GSK2586881 was quantifiable in plasma for up to 4 h poststart of infusion in all participants and caused a consistent and sustained reduction in angiotensin II and a corresponding increase in angiotensin (1-7) and angiotensin (1-5). While there does not appear to be a consistent acute vasodilatory response to single doses of GSK2586881 in participants with PAH, the potential benefits in terms of chronic vascular remodeling remain to be determined., Competing Interests: Marc A. Simon: Consultancy for Acceleron, Actelion, Altavant Sciences, Bial—Portela C S.A., and United Therapeutics. Research grants from Novartis. Hemodynamic core lab work for Aadi. Supported by NIH grants R01AG058659 and P01HL103455. Fernando Torres: Personal fees from Actelion, Bayer, Reata, and Arena and grants from Gilead, United Therapeutics, Medtronic, Eiger, and Bellerophon. Ekkehard Grünig: Research grants and lecture fees from Actelion/Janssen and Bayer/MSD, research grants from GSK, United Therapeutics, and Novartis, and lecture fees from SCOPE, OrPha Swiss GmbH, and Zurich Heart House. Pilar Escribano‐Subias: Consultancy and/or lectures for Acceleron, Actelion, Janssen, MSD United Therapeutics, Ferrer, and Abbott. Research grants to institutions from Janssen and Ferrer. Manuel López Meseguer: Remunerations for consultancy and/or lectures from Janssen, MSD, and GSK. Michael Halank: Wages for consultancy and/or lectures from Acceleron, Actelion, AstraZenca, Bayer, BerlinChemie, GSK, Janssen, MSD, and Novartis. Christian Opitz: Institution has received speaker fees and honoraria for consultations from Actelion, Bayer, GlaxoSmithKline, Novartis, and Pfizer. Stephan Rosenkranz: Remunerations for consultancy and/or lectures from Abbott, Acceleron, Actelion, AstraZeneca, Bayer, BMS, Janssen, MSD, Novartis, Pfizer, United Therapeutics. Research grants to institution from Actelion, AstraZeneca, Bayer, Novartis; Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and Else‐Kröner‐Fresenius‐Stiftung (EKFS). Kate Hanrott, David A. Hall, Deborah Hewens, William M. Powley, David C. Budd, Sarah Siederer, Aili L. Lazaar, and Anthony Cahn are employees and stock/shareholders of GlaxoSmithKline plc., (© 2021 The Authors. Pulmonary Circulation published by Wiley Periodicals LLC on behalf of the Pulmonary Vascular Research Institute.)

Background: Persistent symptoms after acute coronavirus-disease-2019 (COVID-19) are common, and there is no significant correlation with the severity of the acute disease. In long-COVID (persistent symptoms >4 weeks after acute COVID-19), respiratory symptoms are frequent, but lung function testing shows only mild changes that do not explain the symptoms. Although COVID-19 may lead to an impairment of the peripheral nervous system and skeletal muscles, respiratory muscle function has not been examined in this setting., Methods: In this study, we assessed the severity of dyspnea (NYHA-function class) in long-COVID patients and analyzed its association with body mass index (BMI), FEV1, forced vital capacity, other parameters of body plethysmography, diffusing capacity for carbon monoxide (DLCO), arterial blood gases, and inspiratory muscle function, assessed by airway occlusion pressure (P0.1) and maximal inspiratory pressure (PImax) in two respiratory clinics in Germany between Oct 2020 and Aug 2021., Results: A total of 116 patients were included in the study. The mean age was 50.2 ± 14.5 years; BMI, 26.7 ± 5.87 kg/m2; NYHA class I, 19%; II, 27%; III, 41%; and IV, 14%. While lung function values and computed tomography or conventional X-ray of the chest were in the normal range, inspiratory muscle function was markedly impaired. P01 was elevated to 154 ± 83%predicted and PImax was reduced to 41 ± 25%predicted. PImax reduction was strongly associated with the severity of dyspnea but independent of BMI, time after acute COVID-19 and most of the other parameters., Conclusions: This study shows that in long-COVID patients, respiratory symptoms may be mainly caused by reduced inspiratory muscle strength. Assessment of PImax and P0.1 might better explain dyspnea than classical lung function tests and DLCO. A prospective study is needed to confirm these results., (© 2022 S. Karger AG, Basel.)

Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data., Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD., Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described., Conclusions: Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients., Trial Registration: www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

The present study analyzes age-specific changes in RV function and RV-PA coupling in a large cohort of apparently healthy subjects with a wide age-range, to identify reference values and to study the influence of clinical and echocardiographic cofactors. 1899 Consecutive healthy subjects underwent a standardized transthoracic echocardiographic examination. Tricuspid annular plane systolic excursion (TAPSE) and systolic pulmonary artery pressure (SPAP) were measured. Ventriculo-arterial coupling was then inferred from the TAPSE/SPAP ratio. A quantile regression analysis was used to estimate quantiles 0.05, 0.10, 0.50 (median), 0.90, and 0.95 of TAPSE, SPAP and TAPSE/SPAP. The association between age and each of these values was determined. The mean age of the group was 45.2 ± 18.5 years (range 1 to 102 years), 971 were males. SPAP increased with age, whereas TAPSE and TAPSE/SPAP ratio decreased. Upon multivariate modeling, the most significant positive associations for TAPSE were body surface area (BSA) driven by the pediatric group, stroke volume (SV), E/A and negatively heart rate and E/e' ratio. SPAP was positively associated with increasing age, SV, E/A, E/e' and negatively with BSA. TAPSE/SPAP ratio was negatively associated with age, female sex, and E/e' and positively with BSA. A preserved relationship between TAPSE and SPAP was found across the different age groups. TAPSE, SPAP and TAPSE/SPAP demonstrate important trends and associations with advancing age, impaired diastolic function, affected by female sex and BSA However the relationship between TAPSE and SPAP is relatively well preserved across the age spectrum., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Iron deficiency affects up to 50% of patients with pulmonary arterial hypertension (PAH) but iron markers such as ferritin and serum iron are confounded by several non-disease related factors like acute inflammation and diet. The aim of this study was to identify a new marker for iron deficiency and clinical outcome in PAH patients., Methods: In this single-center, retrospective study we assessed indicators of iron status and clinical parameters specifying the time to clinical worsening (TTCW) and survival in PAH patients at time of initial diagnosis and at 1-year follow-up using univariable and multivariable analysis., Results: In total, 150 patients were included with an invasively confirmed PAH and complete data on iron metabolism. The proportion of hypochromic erythrocytes > 2% at initial diagnosis was identified as an independent predictor for a shorter TTCW (p = 0.0001) and worse survival (p = 0.002) at initial diagnosis as well as worse survival (p = 0.016) at 1-year follow-up. Only a subset of these patients (64%) suffered from iron deficiency. Low ferritin or low serum iron neither correlated with TTCW nor survival. Severe hemoglobin deficiency at baseline was significantly associated with a shorter TTCW (p = 0.001)., Conclusions: The presence of hypochromic erythrocytes > 2% was a strong and independent predictor of mortality and shorter TTCW in this cohort of PAH patients. Thus, it can serve as a valuable indicator of iron homeostasis and prognosis even in patients without iron deficiency or anemia. Further studies are needed to confirm the results and to investigate therapeutic implications., (© 2021. The Author(s).)

Background: In pulmonary arterial hypertension (PAH), there are no data comparing initial triple oral therapy with initial double oral therapy., Objectives: TRITON (The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension; NCT02558231), a multicenter, double-blind, randomized phase 3b study, evaluated initial triple (macitentan, tadalafil, and selexipag) versus initial double (macitentan, tadalafil, and placebo) oral therapy in newly diagnosed, treatment-naive patients with PAH., Methods: Efficacy was assessed until the last patient randomized completed week 26 (end of main observation period). The primary endpoint was change in pulmonary vascular resistance (PVR) at week 26., Results: Patients were assigned to initial triple (n = 123) or initial double therapy (n = 124). At week 26, both treatment strategies reduced PVR compared with baseline (by 54% and 52%), with no significant difference between groups (ratio of geometric means: 0.96; 95% confidence interval: 0.86-1.07; P = 0.42). Six-minute walk distance and N-terminal pro-brain natriuretic peptide improved by week 26, with no difference between groups. Risk for disease progression (to end of main observation period) was reduced with initial triple versus initial double therapy (hazard ratio: 0.59; 95% confidence interval: 0.32-1.09). Most common adverse events with initial triple therapy included headache, diarrhea, and nausea. By the end of the main observation period, 2 patients in the initial triple and 9 in the initial double therapy groups had died., Conclusions: In patients with newly diagnosed PAH, both treatment strategies markedly reduced PVR by week 26, with no significant difference between groups (primary endpoint not met). Exploratory analyses suggested a possible signal for improved long-term outcomes with initial triple versus initial double oral therapy., Competing Interests: Funding Support and Author Disclosures This study was funded by Actelion Pharmaceuticals, a Janssen Pharmaceutical Company of Johnson & Johnson. Dr Chin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson, the National Institutes of Health, Ironwood Pharmaceuticals, and SoniVie; has served on advisory boards for Bayer Healthcare (through the University of California, San Diego) and Flowonix; has served as an adjudication committee member for Arena Pharmaceuticals; is an associate editor of Circulation for the American Heart Association; and has received consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Sitbon has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; and has served as an advisory board member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. Dr Doelberg is an employee of Actelion Pharmaceuticals. Dr Feldman has received speaker and consultancy fees from Bayer and United Therapeutics; and has received consultancy fees from Gilead, Gossamer, Acceleron, Altavant, Janssen Pharmaceutical Companies of Johnson & Johnson, and Bellerophon. Dr Gibbs has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson, Complexa, and Acceleron; has received consultancy fees from Arena; has received speaker fees from GlaxoSmithKline and Merck Sharp & Dohme; has served as a clinical endpoints committee member for Pfizer, Bayer, Bellerophon, Janssen Pharmaceutical Companies of Johnson & Johnson, and United Therapeutics; and has served as a data and safety monitoring board member for Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Grünig has received grants and personal fees from Bayer, Janssen Pharmaceutical Companies of Johnson & Johnson, Merck Sharp & Dohme, and GlaxoSmithKline; and has received grants from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer/Merck Sharp & Dohme, GlaxoSmithKline, and United Therapeutics. Prof Hoeper has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer; and has received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson. Mr Martin is an employee of Actelion Pharmaceuticals. Dr Mathai has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; and has served as a consultant for Arena, Liquidia, and United Therapeutics. Prof McLaughlin has served as a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grants, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; has received grants from Eiger and SoniVie; and has received personal fees from United Therapeutics, Arena, Caremark, Medtronic, and Merck Sharp & Dohme. Dr Perchenet is an employee of Actelion Pharmaceuticals; has previously held stock and stock options with Actelion Pharmaceuticals; and currently holds stock and stock options in the parent company Johnson & Johnson. Dr Poch has received speaker and consultancy fees from Bayer Healthcare. Dr Saggar has received consultancy fees and research funding from United Therapeutics and Janssen Pharmaceutical Companies of Johnson & Johnson. Prof Simonneau has served as a steering committee member for and received research grants from Janssen Pharmaceutical Companies of Johnson & Johnson and Bayer; and has received speaker and consultancy fees from Janssen Pharmaceutical Companies of Johnson & Johnson, Bayer, GlaxoSmithKline, Merck Sharp & Dohme, and Pfizer. Prof Galiè is a steering committee member for Janssen Pharmaceutical Companies of Johnson & Johnson; has received grant support, personal fees, and nonfinancial support from Janssen Pharmaceutical Companies of Johnson & Johnson; and has received grant support and personal fees from Bayer Healthcare, Pfizer, and GlaxoSmithKline., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429)., Methods: This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed., Results: In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05)., Conclusion: This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition., Research Question: Which factors determine the outcome of PH in COPD?, Study Design and Methods: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH)., Results: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes., Interpretation: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further., Trial Registry: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.gov., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Exercise Doppler echocardiography (EDE) is a well-validated tool in ischemic and valvular heart diseases. However, its use in the assessment of the right heart and pulmonary circulation unit (RH-PCU) is limited. The aim of this study is to assess the semi-recumbent bicycle EDE feasibility for the evaluation of RH-PCU in a large multi-center population, from healthy individuals and elite athletes to patients with overt or at risk of developing pulmonary hypertension (PH). From January 2019 to July 2019, 954 subjects [mean age 54.2 ± 16.4 years, range 16-96, 430 women] underwent standardized semi-recumbent bicycle EDE with an incremental workload of 25 watts every 2 min, were prospectively enrolled among 7 centers participating to the RIGHT Heart International NETwork (RIGHT-NET). EDE parameters of right heart structure, function and pressures were obtained according to current recommendations. Right ventricular (RV) function at peak exercise was feasible in 903/940 (96%) by tricuspid annular plane systolic excursion (TAPSE), 667/751 (89%) by tissue Doppler-derived tricuspid lateral annular systolic velocity (S') and 445/672 (66.2%) by right ventricular fractional area change (RVFAC). RV-right atrial pressure gradient [RV-RA gradient = 4 × tricuspid regurgitation velocity 2 (TRV)] was feasible in 894/954 patients (93.7%) at rest and in 816/954 (85.5%) at peak exercise. The feasibility rate in estimating pulmonary artery pressure improved to more than 95%, if both TRV and/or right ventricular outflow tract acceleration time (RVOT AcT) were considered. In high specialized echocardiography laboratories semi-recumbent bicycle EDE is a feasible tool for the assessment of the RH-PCU pressure and function., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

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.)

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: Few data are available on the long-term course and predictors of quality of life (QoL) following acute pulmonary embolism (PE)., Research Question: What are the kinetics and determinants of disease-specific and generic health-related QoL 3 and 12 months following an acute PE?, Study Design and Methods: The Follow-up after Acute Pulmonary Embolism (FOCUS) study prospectively followed up consecutive adult patients with objectively diagnosed PE. Patients were considered for study who completed the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire at predefined visits 3 and 12 months following PE. The course of disease-specific QoL as assessed using the PEmb-QoL and the impact of baseline characteristics using multivariable mixed effects linear regression were studied; also assessed was the course of generic QoL as evaluated by using the EuroQoL Group 5-Dimension 5-Level utility index and the EuroQoL Visual Analog Scale., Results: In 620 patients (44% women; median age, 62 years), overall disease-specific QoL improved from 3 to 12 months, with a decrease in the median PEmb-QoL score from 19.4% to 13.0% and a mean individual change of -4.3% (95% CI, -3.2 to -5.5). Female sex, cardiopulmonary disease, and higher BMI were associated with worse QoL at both 3 and 12 months. Over time, the association with BMI became weaker, whereas older age and previous VTE were associated with worsening QoL. Generic QoL also improved: the mean ± SD EuroQoL Group 5-Dimension 5-Level utility index increased from 0.85 ± 0.22 to 0.87 ± 0.20 and the visual analog scale from 72.9 ± 18.8 to 74.4 ± 19.1., Interpretation: In a large cohort of survivors of acute PE, the change of QoL was quantified between months 3 and 12 following diagnosis, and factors independently associated with lower QoL and slower recovery of QoL were identified. This information may facilitate the planning and interpretation of clinical trials assessing QoL and help guide patient management., Clinical Trial Registration: German Clinical Trials Registry (Deutsches Register Klinischer Studien: www.drks.de); No.: DRKS00005939., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although cardiovascular rehabilitation (CR) is well accepted in general, CR-attendance and delivery still considerably vary between the European countries. Moreover, clinical and prognostic effects of CR are not well established for a variety of cardiovascular diseases., Methods: The guidelines address all aspects of CR including indications, contents and delivery. By processing the guidelines, every step was externally supervised and moderated by independent members of the " Association of the Scientific Medical Societies in Germany" (AWMF). Four meta-analyses were performed to evaluate the prognostic effect of CR after acute coronary syndrome (ACS), after coronary bypass grafting (CABG), in patients with severe chronic systolic heart failure (HFrEF), and to define the effect of psychological interventions during CR. All other indications for CR-delivery were based on a predefined semi-structured literature search and recommendations were established by a formal consenting process including all medical societies involved in guideline generation., Results: Multidisciplinary CR is associated with a significant reduction in all-cause mortality in patients after ACS and after CABG, whereas HFrEF-patients (left ventricular ejection fraction <40%) especially benefit in terms of exercise capacity and health-related quality of life. Patients with other cardiovascular diseases also benefit from CR-participation, but the scientific evidence is less clear. There is increasing evidence that the beneficial effect of CR strongly depends on "treatment intensity" including medical supervision, treatment of cardiovascular risk factors, information and education, and a minimum of individually adapted exercise volume. Additional psychologic interventions should be performed on the basis of individual needs., Conclusions: These guidelines reinforce the substantial benefit of CR in specific clinical indications, but also describe remaining deficits in CR-delivery in clinical practice as well as in CR-science with respect to methodology and presentation.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice., Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms., Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2])., Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice., Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms., Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years., Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: This study was a quality-control study of resting and exercise Doppler echocardiography (EDE) variables measured by 19 echocardiography laboratories with proven experience participating in the RIGHT Heart International NETwork., Methods: All participating investigators reported the requested variables from ten randomly selected exercise stress tests. Intraclass correlation coefficients (ICC) were calculated to evaluate the inter-observer agreement with the core laboratory. Inter-observer variability of resting and peak exercise tricuspid regurgitation velocity (TRV), right ventricular outflow tract acceleration time (RVOT Act), tricuspid annular plane systolic excursion (TAPSE), tissue Doppler tricuspid lateral annular systolic velocity (S'), right ventricular fractional area change (RV FAC), left ventricular outflow tract velocity time integral (LVOT VTI), mitral inflow pulsed wave Doppler velocity (E), diastolic mitral annular velocity by TDI (e') and left ventricular ejection fraction (LVEF) were measured., Results: The accuracy of 19 investigators for all variables ranged from 99.7 to 100%. ICC was > 0.90 for all observers. Inter-observer variability for resting and exercise variables was for TRV = 3.8 to 2.4%, E = 5.7 to 8.3%, e' = 6 to 6.5%, RVOT Act = 9.7 to 12, LVOT VTI = 7.4 to 9.6%, S' = 2.9 to 2.9% and TAPSE = 5.3 to 8%. Moderate inter-observer variability was found for resting and peak exercise RV FAC (15 to 16%). LVEF revealed lower resting and peak exercise variability of 7.6 and 9%., Conclusions: When performed in expert centers EDE is a reproducible tool for the assessment of the right heart and the pulmonary circulation.

To improve acceptance and use of physical training by patients with chronic lung diseases, recommendations for performing lung exercises on an outpatient basis in a group setting are given by experts in physical training, sports therapists and pulmonologists. The evidence-based positive effects of physical training were analyzed for asthma , COPD, interstitial lung diseases, cystic fibrosis, lung carcinoma, and pulmonary hypertension. The requirements for lung exercises in outpatient groups as well as compensation by care providers were given on the basis of legal regulations. Furthermore, the main items of the training units as well as supervision by specially trained group leaders in relation to the severity of the underlying lung disease are described. Finally, aspects of safety of the participating patients are discussed, including the prevention of infection with corona-2-virus., Competing Interests: H. Worth sieht keine Interessenkonflikte zum Inhalt der Empfehlung. Er erhielt Honorare für Beratungen und Vorträge von: AstraZeneca, Berlin Chemie, Chiesi, GSK, Klosterfrau, MSD, Novartis und Omron., (Thieme. All rights reserved.)

Background: Pulmonary hypertension (PH) is a severe progressive disease, associated with reduced exercise capacity and poor quality of life. Although scientific evidence supports the incorporation of specialized training in the treatment of PH, it is only available in a few countries., Objectives and Methods: This article aims to share the experience of implementing a PH rehabilitation program, to summarize the barriers and prerequisites for launching this service, and to assess its early effect. We retrospectively analyzed our pathway in organizing this program, by singling out essential steps., Results: The preparation phase took about 14 months. Establishing and running of a PH rehabilitation program required dedicated rehabilitation specialists to join the multidisciplinary PH expert team. Team members needed to gain special knowledge on exercise training in severely compromised patients; thus, supervision and education by experienced consultants was crucial. The main eligibility criteria for patients were stable status, optimal medical treatment, and motivation to undergo the training. The first results evaluating the effect of a specialized PH training program in 9 patients are promising. Seven of them improved their functional capacity over the period of 15 weeks., Conclusions: Despite a number of challenges and barriers, the implementation of a specialized rehabilitation program should be encouraged in a few dedicated PH expert centers per country, who are capable to fulfill all prerequisites and organizational aspects. Local PH experts, supervision by an experienced center, in-patient rehabilitation facilities, dedicated personnel, equipment, and patient motivation are essential., (© 2021 S. Karger AG, Basel.)

Background: Pulmonary arterial compliance (PAC) is a prognostic parameter in pulmonary arterial hypertension (PAH) reflecting the elasticity of the pulmonary vessels., Objectives: The objective of this post hoc analysis of a prospective randomized controlled trial (RCT) was to assess the effect of exercise training on PAC and stroke volume (SV) in patients with PAH and persistent/inoperable chronic thromboembolic pulmonary hypertension (CTEPH)., Method: From the previous RCT, 43 out of 87 patients with severe PAH (n = 29) and CTEPH (n = 14) had complete haemodynamic examinations at baseline and after 15 weeks by right heart catheterization and were analysed (53% female, 79% World Health Organization functional class III/IV, 58% combination therapy, 42% on supplemental oxygen therapy, training group n = 24, and control group n = 19). Medication remained unchanged for all patients., Results: Low-dose exercise training at 4-7 days/week significantly improved PAC (training group 0.33 ± 0.65 mL/mm Hg vs. control group -0.06 ± 1.10 mL/mm Hg; mean difference 0.39 mL/mm Hg, 95% confidence interval [CI] 0.15-0.94 mL/mm Hg; p = 0.004) and SV (training group 9.9 ± 13.4 mL/min vs. control group -4.2 ± 11.0 mL/min; mean difference 14.2 mL, 95% CI 6.5-21.8 mL; p < 0.001) in the training versus control group. Furthermore, exercise training significantly improved cardiac output and pulmonary vascular resistance at rest, peak oxygen consumption, and oxygen pulse., Conclusions: Our findings suggest that supervised exercise training may improve right ventricular function and PAC at the same time. Further prospective studies are needed to evaluate these findings., (© 2021 S. Karger AG, Basel.)

Various parameters reflecting right heart size, right ventricular function and capacitance have been shown to be prognostically important in patients with pulmonary hypertension (PH). In the advanced disease, patients suffer from right heart failure, which is a main reason for an impaired prognosis. Right heart size has shown to be associated with right ventricular function and reserve and is correlated with prognosis in patients with PH. Right ventricular reserve, defined as the ability of the ventricle to adjust to exercise or pharmacologic stress, is expressed by various parameters, which may be determined invasively by right heart catheterization or by stress-Doppler-echocardiography as a noninvasive approach. As the term "right ventricular contractile reserve" may be misleading, "right ventricular output reserve" seems desirable as a preferred term of increase in cardiac output during exercise. Both right heart size and right ventricular reserve have been shown to be of prognostic importance and may therefore be useful for risk assessment in patients with pulmonary hypertension. In this article we aim to display different aspects of right heart size and right ventricular reserve and their prognostic role in PH.

Background - Approximately 25% of patients with pulmonary arterial hypertension (PAH) have been found to harbor rare mutations in disease-causing genes. To identify missing heritability in PAH we integrated deep phenotyping with whole-genome sequencing data using Bayesian statistics. Methods - We analyzed 13,037 participants enrolled in the NIHR BioResource - Rare Diseases (NBR) study, of which 1,148 were recruited to the PAH domain. To test for genetic associations between genes and selected phenotypes of pulmonary hypertension (PH), we used the Bayesian rare-variant association method BeviMed. Results - Heterozygous, high impact, likely loss-of-function variants in the Kinase Insert Domain Receptor ( KDR ) gene were strongly associated with significantly reduced transfer coefficient for carbon monoxide (KCO, posterior probability (PP)=0.989) and older age at diagnosis (PP=0.912). We also provide evidence for familial segregation of a rare nonsense KDR variant with these phenotypes. On computed tomographic imaging of the lungs, a range of parenchymal abnormalities were observed in the five patients harboring these predicted deleterious variants in KDR . Four additional PAH cases with rare likely loss-of-function variants in KDR were independently identified in the US PAH Biobank cohort with similar phenotypic characteristics. Conclusions - The Bayesian inference approach allowed us to independently validate KDR , which encodes for the Vascular Endothelial Growth Factor Receptor 2 (VEGFR2), as a novel PAH candidate gene. Furthermore, this approach specifically associated high impact likely loss-of-function variants in the genetically constrained gene with distinct phenotypes. These findings provide evidence for KDR being a clinically actionable PAH gene and further support the central role of the vascular endothelium in the pathobiology of PAH.

The goal of treatment in patients with pulmonary arterial hypertension is to achieve a low risk status, indicating a favorable long-term outcome. The REPLACE study investigated the efficacy of switching to riociguat in patients with pulmonary arterial hypertension and an insufficient response to phosphodiesterase-5 inhibitors. In this post hoc analysis, we applied the REPLACE composite endpoint of clinical improvement to the placebo-controlled PATENT-1 study of riociguat in pulmonary arterial hypertension and its long-term extension, PATENT-2. Clinical improvement was defined as ≥2 of the following in patients who completed the study without clinical worsening: ≥10% or ≥30 m improvement in 6-minute walking distance; World Health Organization functional class I or II; ≥30% decrease in N -terminal prohormone of brain natriuretic peptide. At PATENT-1 Week 12, patients treated with riociguat were more likely to achieve the composite endpoint vs. placebo ( P  < 0.0001), with similar results in pretreated ( P  = 0.0189) and treatment-naïve ( P  < 0.0001) patients. Achievement of the composite endpoint at Week 12 was associated with a 45% reduction in relative risk of death and a 19% reduction in relative risk of clinical worsening in PATENT-2. Overall, these data suggest that use of the REPLACE composite endpoint in patients with pulmonary arterial hypertension is a valid assessment of response to treatment., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: GS reports grants, personal fees, and non-financial support from Actelion, Bayer, GSK, and Merck. H-AG reports non-financial support, grants, and personal fees from Actelion; grants and personal fees from Bayer, Novartis Corporation, and Pfizer; and personal fees from Gilead Sciences, GSK, and Merck. PAC reports grants and personal fees from Actelion and Bayer, and personal fees from MSD. SR reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics, and research support from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. EG reports grants and personal fees from Actelion and Bayer/MSD; grants from GSK, Novartis, and United Therapeutics, and personal fees from OrPha Swiss GmbH, SCOPE, and Zurich Heart House. JW reports no conflicts of interest. VVM reports grants, personal fees, and non-financial support from Actelion and Bayer; grants from Eiger and SoniVie; and personal fees from Arena, Caremark, Medtronic, MSD, and United Therapeutics. DL reports grants, personal fees, and non-financial support from Actelion and Bayer, personal fees from Merck and United Therapeutics; and grants from Northern Therapeutics. CM and FK are employees of Bayer AG. DB was an employee of Chrestos Concept GmbH & Co., KG, Essen, Germany at the time of the study and manuscript development. RLB reports grants from Actelion, Bayer AG, Eiger, Gilead, and United Therapeutics paid to his institution, and honoraria from Actelion, Bayer AG and Gilead., (© The Author(s) 2020.)

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward's minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background We investigated changes in right atrial pressure (RAP) during exercise and their prognostic significance in patients assessed for pulmonary hypertension (PH). Methods and Results Consecutive right heart catheterization data, including RAP recorded during supine, stepwise cycle exercise in 270 patients evaluated for PH, were analyzed retrospectively and compared among groups of patients with PH (mean pulmonary artery pressure [mPAP] ≥25 mm Hg), exercise-induced PH (exPH; resting mPAP <25 mm Hg, exercise mPAP >30 mm Hg, and mPAP/cardiac output >3 Wood Units (WU)), and without PH (noPH). We investigated RAP changes during exercise and survival over a median (quartiles) observation period of 3.7 (2.8-5.6) years. In 152 patients with PH, 58 with exPH, and 60 with noPH, median (quartiles) resting RAP was 8 (6-11), 6 (4-8), and 6 (4-8) mm Hg ( P <0.005 for noPH and exPH versus PH). Corresponding peak changes (95% CI) in RAP during exercise were 5 (4-6), 3 (2-4), and -1 (-2 to 0) mm Hg (noPH versus PH P <0.001, noPH versus exPH P =0.027). RAP increase during exercise correlated with mPAP/cardiac output increase ( r =0.528, P <0.001). The risk of death or lung transplantation was higher in patients with exercise-induced RAP increase (hazard ratio, 4.24; 95% CI, 1.69-10.64; P =0.002) compared with patients with unaltered or decreasing RAP during exercise. Conclusions In patients evaluated for PH, RAP during exercise should not be assumed as constant. RAP increase during exercise, as observed in exPH and PH, reflects hemodynamic impairment and poor prognosis. Therefore, our data suggest that changes in RAP during exercise right heart catheterization are clinically important indexes of the cardiovascular function.

Pathogenic variants have been identified in 85% of heritable pulmonary arterial hypertension (PAH) patients. These variants were mainly located in the bone morphogenetic protein receptor 2 ( BMPR2 ) gene. However, the penetrance of BMPR2 variants was reduced leading to a disease manifestation in only 30% of carriers. In these PAH patients, further modifiers such as additional pathogenic BMPR2 promoter variants could contribute to disease manifestation. Therefore, the aim of this study was to identify BMPR2 promoter variants in PAH patients and to analyze their transcriptional effect on gene expression and disease manifestation. BMPR2 promoter variants were identified in PAH patients and cloned into plasmids. These were transfected into human pulmonary artery smooth muscle cells to determine their respective transcriptional activity. Nine different BMPR2 promoter variants were identified in seven PAH families and three idiopathic PAH patients. Seven of the variants (c.-575A>T, c.-586dupT, c.-910C>T, c.-930&#95;-928dupGGC, c.-933&#95;-928dupGGCGGC, c.-930&#95;-928delGGC and c.-1141C>T) led to a significantly decreased transcriptional activity. This study identified novel BMPR2 promoter variants which may affect BMPR2 gene expression in PAH patients. They could contribute to disease manifestations at least in some families. Further studies are needed to investigate the frequency of BMPR2 promoter variants and their impact on penetrance and disease manifestation.

Pulmonary hypertension is frequently underdiagnosed, and referral is delayed with subsequent impact on outcomes. During the SARS-CoV-2 pandemic, restrictions on daily life and changes in hospitals' daily routine care were introduced in Germany. This multi-centre study provides evidence for a negative influence of these restrictions on patient care in pulmonary hypertension expert referral centres., (© The Author(s) 2020.)

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum ( N  = 131 pretreated patients) and placebo ( N  = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies., (© The Author(s) 2020.)

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and death worldwide. Peroxynitrite, formed from nitric oxide, which is derived from inducible nitric oxide synthase, and superoxide, has been implicated in the development of emphysema, but the source of the superoxide was hitherto not characterized. Here, we identify the non-phagocytic NADPH oxidase organizer 1 (NOXO1) as the superoxide source and an essential driver of smoke-induced emphysema and pulmonary hypertension development in mice. NOXO1 is consistently upregulated in two models of lung emphysema, Cybb (also known as NADPH oxidase 2, Nox2)-knockout mice and wild-type mice with tobacco-smoke-induced emphysema, and in human COPD. Noxo1-knockout mice are protected against tobacco-smoke-induced pulmonary hypertension and emphysema. Quantification of superoxide, nitrotyrosine and multiple NOXO1-dependent signalling pathways confirm that peroxynitrite formation from nitric oxide and superoxide is a driver of lung emphysema. Our results suggest that NOXO1 may have potential as a therapeutic target in emphysema.

Background: The objective of this study was to analyze prognostic factors and risk stratification in patients with pulmonary arterial hypertension (PAH) and comorbidities., Methods: Patients with invasively diagnosed PAH were included in the analysis. Comorbidities were clinically diagnosed as proposed in the 6th World Symposium of pulmonary hypertension. Uni- and multivariate analysis were employed for identification of factors predicting survival and time to first clinical worsening (TTCW). Risk stratification was based on parameters from ESC/ERS-guidelines 2015., Results: In total 142 patients were enrolled in the study, 90 of them were diagnosed as PAH without and 52 with comorbidities. All patients received targeted PAH therapy and were followed for 3.3 ± 2.4 years. In PAH patients without comorbidities survival and TTCW were significantly associated with reduced 6-min walking distance (6MWD), elevated N-terminal pro brain natriuretic peptide (NT-proBNP), WHO-functional class (WHO-FC) and right atrial (RA) area. In the multivariate analysis, 6MWD was an independent predictor for survival (p = 0.002) and WHO-FC for TTCW (p = 0.001). In patients with PAH and comorbidities these parameters had no significant association with survival and TTCW. Average risk score was significantly associated with survival (p = 0.001) and TTCW (p = 0.013) in PAH but not in PAH with comorbidities (both p > 0.05; figure 1)., Conclusion: Risk stratification based on ESC/ERS-guidelines could only be confirmed in patients without comorbidities, but not in patients with PAH and comorbidities. The data of this study suggest, that a different risk stratification needs to be applied to PAH patients with comorbidities. Further studies are needed to confirm these results., Trial Registration: Not applicable, retrospective registry.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension., Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data., Methods and Results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients´ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy ( n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status., Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy., Competing Interests: COMPERA is supported by an educational grant from Bayer, GSK, OMT and Actelion. The authors declare no conflicts of interest in relation to the study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G>T p.Val617Phe) in the Janus kinase 2 ( JAK2 ) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected ( p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients.

Heritable pulmonary arterial hypertension (PAH) is an autosomal dominantly inherited disease caused by mutations in the bone morphogenetic protein receptor 2 ( BMPR2 ) gene and/or genes of its signaling pathway in ~85% of patients. A genetic predisposition to high-altitude pulmonary edema (HAPE) has long been suspected because of familial HAPE cases, but very few possibly disease-causing mutations have been identified to date. This minireview provides an overview of genetic analyses investigating common polymorphisms in HAPE-susceptible patients and the directed identification of disease-causing mutations in PAH patients. Increased pulmonary artery pressure is highlighted as an overlapping clinical feature of the two diseases. Moreover, studies showing increased pulmonary artery pressures in HAPE-susceptible patients during exercise or hypoxia as well as in healthy BMPR2 mutation carriers are illustrated. Finally, high-altitude pulmonary hypertension is introduced and future research perspectives outlined.

The diagnostic strategy for chronic thromboembolic pulmonary hypertension (CTEPH) is composed of two components required for a diagnosis of CTEPH: the presence of chronic pulmonary embolism and an elevated pulmonary artery pressure. The current guidelines require that ventilation-perfusion single-photon emission computed tomography (VQ-SPECT) is used for the first step diagnosis of chronic pulmonary embolism. However, VQ-SPECT exposes patients to ionizing radiation in a radiation sensitive population. The prospective, multicenter, comparative phase III diagnostic trial C TEP H di agn osis E urope - MRI (CHANGE-MRI, ClinicalTrials.gov identifier NCT02791282 ) aims to demonstrate whether functional lung MRI can serve as an equal rights alternative to VQ-SPECT in a diagnostic strategy for patients with suspected CTEPH. Positive findings are verified with catheter pulmonary angiography or computed tomography pulmonary angiography (gold standard). For comparing the imaging methods, a co-primary endpoint is used. (i) the proportion of patients with positive MRI in the group of patients who have a positive SPECT and gold standard diagnosis for chronic pulmonary embolism and (ii) the proportion of patients with positive MRI in the group of patients with negative SPECT and gold standard. The CHANGE-MRI trial will also investigate the performance of functional lung MRI without i.v. contrast agent as an index test and identify cardiac, hemodynamic, and pulmonary MRI-derived parameters to estimate pulmonary artery pressures and predict 6-12 month survival. Ultimately, this study will provide the necessary evidence for the discussion about changes in the recommendations on the diagnostic approach to CTEPH., (Copyright © 2020 Lasch, Karch, Koch, Derlin, Voskrebenzev, Alsady, Hoeper, Gall, Roller, Harth, Steiner, Krombach, Ghofrani, Rengier, Heußel, Grünig, Beitzke, Hacker, Lang, Behr, Bartenstein, Dinkel, Schmidt, Kreitner, Frauenfelder, Ulrich, Hamer, Pfeifer, Johns, Kiely, Swift, Wild and Vogel-Claussen.)

Rationale: Oral treprostinil improves exercise capacity in patients with pulmonary arterial hypertension (PAH), but the effect on clinical outcomes was unknown. Objectives: To evaluate the effect of oral treprostinil compared with placebo on time to first adjudicated clinical worsening event in participants with PAH who recently began approved oral monotherapy. Methods: In this event-driven, double-blind study, we randomly allocated 690 participants (1:1 ratio) with PAH to receive placebo or oral treprostinil extended-release tablets three times daily. Eligible participants were using approved oral monotherapy for over 30 days before randomization and had a 6-minute-walk distance 150 m or greater. The primary endpoint was the time to first adjudicated clinical worsening event: death; hospitalization due to worsening PAH; initiation of inhaled or parenteral prostacyclin therapy; disease progression; or unsatisfactory long-term clinical response. Measurements and Main Results: Clinical worsening occurred in 26% of the oral treprostinil group compared with 36% of placebo participants (hazard ratio, 0.74; 95% confidence interval, 0.56-0.97; P  = 0.028). Key measures of disease status, including functional class, Borg dyspnea score, and N-terminal pro-brain natriuretic peptide, all favored oral treprostinil treatment at Week 24 and beyond. A noninvasive risk stratification analysis demonstrated that oral treprostinil-assigned participants had a substantially higher mortality risk at baseline but achieved a lower risk profile from Study Weeks 12-60. The most common adverse events in the oral treprostinil group were headache, diarrhea, flushing, nausea, and vomiting. Conclusions: In participants with PAH, addition of oral treprostinil to approved oral monotherapy reduced the risk of clinical worsening.Clinical trial registered with www.clinicaltrials.gov (NCT01560624).