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Aims: Hepatic T1-time derived from cardiac magnetic resonance imaging (cMRI) reflects venous congestion and may provide a simple alternative to invasive end-diastolic elastance (Eed) for assessment of right ventricular (RV) diastolic function. We investigated the association of native hepatic T1-time with single-beat Eed and the value of hepatic T1-time for longitudinal monitoring in pulmonary hypertension (PH)., Methods and Results: We retrospectively enrolled 85 patients with suspected PH (59% female; 78 with PH diagnosed; 7 with PH excluded) who underwent standard right heart catheterization and cMRI within 24 h between 2015 and 2020. Hepatic T1-time showed moderate to strong correlations (rho >0.3, P ≤ 0.002) with pulmonary vascular resistance, native myocardial T1-time, Eed, RV size and function, brain natriuretic peptide (BNP) level, and 6-min walk distance, and a significant association with functional class (Kruskal-Wallis P < 0.001). Eed, myocardial T1-time, and BNP were independently linked to hepatic T1-time in multivariable regression. Hepatic T1-time > 598 ms predicted elevated Eed with 72.9% sensitivity and 82.1% specificity. Hepatic T1-time was superior to Eed in predicting clinical worsening. In 16 patients with follow-up assessments, those with decreasing hepatic T1-time (7 patients) showed significant hemodynamic improvements, whereas those with increasing hepatic T1-time (9 patients) did not. In a second retrospective cohort of 27 patients with chronic thromboembolic PH undergoing balloon pulmonary angioplasty, hepatic T1-time decreased significantly and hemodynamics improved after the procedure., Conclusions: Hepatic T1-time predicts RV diastolic dysfunction and prognosis, and may be useful for monitoring disease progression and treatment response in PH., Competing Interests: Declaration of competing interest NK has received speaking fees from Janssen outside the submitted work. AY has received personal fees from MSD outside the submitted work. WS has received speaker/consultancy fees from Pfizer and Bayer Pharma AG. CBW has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, and Pfizer. KT has received speaking fees from Actelion, Janssen, and Bayer. All other authors report no relationships that could be construed as a conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, but an important late sequela after acute pulmonary embolism. Therefore, follow-up after at least three months of sufficient anticoagulation is recommended. Patients with suspected CTEPH should be referred to specialized CTEPH centers for further evaluation and treatment.Three treatment modalities are available: pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and pulmonary hypertension-targeted drugs. The indication for surgery depends mainly on the localization of the pulmonary arterial obstructions. Severe comorbidities as well as advanced age need individual evaluation, but do not present strict exclusion criteria. Multimodal treatments are common practice in inoperable CTEPH. However, treatment decision making in an experienced multidisciplinary team is mandatory., Competing Interests: MSDA: Es besteht kein Interessenskonflikt. CBW: Referenten- und/oder Beratertätigkeit für Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD und Pfizer. AJO: Referententätigkeit/Kongressreiseunterstützung: AOP, CSL Behring, Berlin Chemie, Novartis, Pfizer HJS: Es besteht kein Interessenkonflikt. SG: Referenten- und/oder Beratertätigkeit für Actelion/Janssen, Bayer und MSD. HW: Referenten- und/oder Beratertätigkeit für Bayer AG, Biotest, Boehringer Ingelheim, Daiichi Sanchyo, Ferrer, GSK, Janssen, MSD und Roche., (Thieme. All rights reserved.)

Chronic thromboembolic pulmonary disease (CTEPD) is an important late complication of acute pulmonary embolism, in which the thrombi transform into fibrous tissue, become integrated into the vessel wall, and lead to chronic obstructions. CTEPD is differentiated into cases without pulmonary hypertension (PH), characterized by a mean pulmonary arterial pressure up to 20 mmHg and a form with PH. Then, it is still referred to as chronic thromboembolic pulmonary hypertension (CTEPH).When there is suspicion of CTEPH, initial diagnostic tests should include echocardiography and ventilation/perfusion scan to detect perfusion defects. Subsequently, referral to a CTEPH center is recommended, where further imaging diagnostics and right heart catheterization are performed to determine the appropriate treatment.Currently, three treatment modalities are available. The treatment of choice is pulmonary endarterectomy (PEA). For non-operable patients or patients with residual PH after PEA, PH-targeted medical therapy, and the interventional procedure of balloon pulmonary angioplasty (BPA) are available. Increasingly, PEA, BPA, and pharmacological therapy are combined in multimodal concepts.Patients require post-treatment follow-up, preferably at (CTE)PH centers. These centers are required to perform a minimum number of PEA surgeries (50/year) and BPA interventions (100/year)., Competing Interests: S.G. erhielt Redner- und/oder Beraterhonorare von Actelion/Janssen, Bayer, MSD.M. Halank erhielt Honorare für Vorträge von AstraZeneca, Janssen-Cilag und MSD, Honorare für Beratungen im Rahmen von AdBoards von Janssen-Cilag und MSD und finanzielle Unterstützung für die Teilnahme an Kongressen von Janssen-Cilag.M. Held erhielt Redner- und/oder Beraterhonorare von AstraZeneca, Bayer Healthcare, Berlin Chemie, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, MSD, OMT, Pfizer, Santis.L.H. erhielt Redner- und/oder Beraterhonorare von Johnson&Johnson,MSD, INARI und Boston Scientific.S.K. erhielt institutionelle Zuschüsse und Redner- und/oder Beraterhonorare von Bayer AG, Daiichi Sankyo, and Boston Scientific; institutionelle Zuschüsse von Inari Medical; und Redner- und/oder Beraterhonorare von MSD and Bristol Myers Squibb/Pfizer.E.M. erhielt Redner- und/oder Beraterhonorare von Actelion/Janssen, Bayer, MSD.A.O. erhielt Rednerhonorare und Kongressreiseunterstützung von AOP, CSL Behring, Berlin Chemie, Novartis, Pfizer.H.-J. Schäfers hat keinen Interessenkonflikt.H.-J. Seyfarth erhielt Redner- und/oder Beraterhonorare Janssen.H.W. erhielt Redner- und/oder Beraterhonorare von Bayer, Biotest, Boehringer Ingelheim, Daiichi Sanchyo, Ferrer, GSK, Janssen, MSD und Roche.C.B.W. erhielt Redner- und/oder Beraterhonorare von Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD und Pfizer., (Thieme. All rights reserved.)

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

Chronic thromboembolic pulmonary hypertension (CTEPH) is an important late sequela of pulmonary embolism and a common form of pulmonary hypertension. Currently, three specific treatment modalities are available: pulmonary endarterectomy, balloon pulmonary angioplasty, and targeted medical therapy. The treatment decision depends mainly on the exact localization of the underlying pulmonary arterial obstructions. Pulmonary endarterectomy is the gold standard treatment of CTEPH. For inoperable patients, riociguat and treprostinil are approved. In addition, interventional therapy is recommended if appropriate target lesions are proven. Evaluation and treatment of patients with CTEPH in experienced centers are mandatory., (© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by chronic organised fibrotic clots, despite adequate anticoagulation. The pulmonary hypertension is also caused by concomitant microvasculopathy which may progress without timely treatment. Timely and accurate diagnosis requires the combination of imaging and haemodynamic assessment. Optimal therapy should be individualised to each case and determined by an experienced multidisciplinary CTEPH team with the ability to offer all current treatment modalities. This report summarises current knowledge and presents key messages from the International CTEPH Conference, Bad Nauheim, Germany, 2021. Sessions were dedicated to 1) disease definition; 2) pathophysiology, including the impact of the hypertrophied bronchial circulation, right ventricle (dys)function, genetics and inflammation; 3) diagnosis, early after acute pulmonary embolism, using computed tomography and perfusion techniques, and supporting the selection of appropriate therapies; 4) surgical treatment, pulmonary endarterectomy for proximal and distal disease, and peri-operative management; 5) percutaneous approach or balloon pulmonary angioplasty, techniques and complications; and 6) medical treatment, including anticoagulation and pulmonary hypertension drugs, and in combination with interventional treatments. Chronic thromboembolic pulmonary disease without pulmonary hypertension is also discussed in terms of its diagnostic and therapeutic aspects., Competing Interests: Conflict of interest: E. Fadel, G. Martinez, G. Simonneau, K. Salaunkey, N. Screaton and P. Brénot have no conflicts of interest to declare. A. Vonk Noordegraaf is supported by the Netherlands CardioVascular Research Initiative (CVON-2012–08 PHAEDRA, CVON-2017-10 DOLPHIN-GENESIS) and the Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610); his institute received speakers fees from Johnson & Johnson, MSD, Actelion, Bayer and Ferrer in the past 3 years; and he served as a member of the scientific advisory boards of Morphogen-X, Ferrer, Gossamer Bio Services Inc. and Johnson & Johnson. C.B. Wiedenroth has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD and Pfizer. D.P. Jenkins is on the adjudication committees for the SELECT and Maciteph studies (Actelion), and has received fees for lectures on CTEPH from Actelion. E. Mayer has received speaker or consulting fees from Actelion/Janssen, Bayer and MSD. F.A. Klok has received research support from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Leo Pharma, Actelion, the Netherlands Organisation for Health Research and Development, the Dutch Thrombosis Association, the Dutch Heart Foundation and the Horizon Europe Program, unrelated to the current work and paid to his institution. H.A. Ghofrani has received grants/research support from Actelion, Janssen, Bayer, Gossamer, Acceleron; honoraria or consultation fees from Actelion, Janssen, Bayer, Gossamer, Acceleron, Pfizer, Novartis and MSD; and participated in a company sponsored speaker's bureau for Actelion, Janssen, Bayer, Gossamer, Pfizer, Novartis and MSD. H. Matsubara has received honoraria for lectures from Janssen Pharmaceutical KK, Bayer Yakuhin Ltd, Nippon Shinyaku Co Ltd, Mochida Pharmaceutical Co. Ltd and Kaneka Medix Corporation. I.M. Lang has a financial interest with Actelion/Janssen, AOP Orphan, Medtronic, Daiichi Sankyo, Neutrolis, United Therapeutics and Ferrer that could be perceived as a real or apparent conflict of interest in the context of the subject of this article. J. Pepke-Zaba has received speaker or consulting fees from Actelion/Janssen, Bayer, MSD and Ferrer, and a research grant from MSD, all outside submitted work. M.C. McInnis reports honoraria from Bayer and Boehringer Ingelheim, unrelated to the current work. M. Delcroix reports research grants from Actelion/Janssen, speaker and consultant fees from Altavant, Acceleron, AOP, Daiichi Sankyo, Bayer, Ferrer, Gossamer and MSD, outside the submitted work, and all paid to her institution. She is holder of the Janssen Chair for Pulmonary Hypertension at KU Leuven. M.M. Hoeper reports fees for lectures and/or consultations from Acceleron, Actelion, Bayer, GSK, Janssen, MSD and Pfizer. M.M. Madani is a consultant for Actelion. M. Toshner reports grants and personal fees from Bayer, personal fees from MSD, grants and personal fees from Actelion, and personal fees from GSK within the last 5 years. N.H. Kim has served as consultant for Bayer, Janssen, Merck and United Therapeutics. S. Guth has received speaker fees and/or consultant honoraria from Actelion, Bayer, GSK, MSD and Pfizer. X. Jaïs reports grants from the French Ministry of Health and Bayer Healthcare, during the conduct of the study; grants from Acceleron, Janssen and MSD; personal fees from Janssen and MSD; and non-financial support from Janssen., (Copyright ©The authors 2023.)

Background: The combination of riociguat and interventional balloon pulmonary angioplasty (BPA) is currently used to treat patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was to evaluate the impact of this combination therapy on the prognosis of inoperable CTEPH patients by comparing the long-term survival rates of patients undergoing combination therapy with riociguat and BPA with those of inoperable patients from the first international CTEPH registry who did not receive specific treatment., Methods: Between March 2014 and August 2019, 138 technically inoperable patients were included in the present prospective, observational cohort study when they were treated with riociguat and BPA at a single CTEPH referral center. Long-term survival of this cohort was compared using propensity score matching with that of inoperable patients recruited between 2007 and 2009 in the first international CTEPH registry. Kaplan-Meier methods were used to evaluate differences in outcomes., Results: Whereas the survival rate in the historical group was 84.6% in the first year, 76.6% in the second, 68.5% in the third, and 58.5% in the fifth year after diagnosis, implementation of riociguat/BPA led to survival rates of 100%, 96.7%, 92.9%, and 90% in the respective follow-up periods. In a comparison of 83 well-matched pairs from the 2 cohorts, survival was markedly better in the group treated with riociguat and BPA than in the historical cohort (HR = 0.145, 95% CI 0.05, 0.421)., Conclusion: The combination of riociguat and BPA for the treatment of inoperable CTEPH is associated with excellent 5-year survival rates., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: The present study was designed to investigate the dynamics of right atrial pressure (RAP) and mid-regional pro-atrial natriuretic peptide (MR-proANP) during physical exercise in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to determine whether these parameters might serve as a tool to measure exercise-dependent atrial stress as an indicator of right heart failure., Methods: This prospective observational cohort study included 100 CTEPH patients who underwent right heart catheterization during physical exercise (eRHC). Blood samples for MR-proANP measurement were taken prior, during, and after eRHC. MR-proANP levels were correlated to RAP levels at rest, at peak exercise (eRAP), and during recovery. RAP at rest ≤7 mmHg was defined as normal and eRAP >15 mmHg as suggestive of right heart failure., Results: During eRHC mean RAP increased from 6 mmHg (standard deviation, SD 4) to 16 mmHg (SD 7; p < 0.001). MR-proANP levels and dynamics correlated with RAP at rest (r s  = 0.61; p < 0.001) and at peak exercise (r s  = 0.66; p < 0.001). Logistic regression analysis revealed the peak MR-proANP level (B = 0.058; p = 0.004) and the right atrial area (B = 0.389; p < 0.001) to be associated with eRAP dynamics. A peak MR-proANP level ≥139 pmol/L (AUC = 0.81) and recovery level ≥159 pmol/L (AUC = 0.82) predicted an eRAP >15 mmHg. Physical exercise unmasked right heart failure in 39% of patients with normal RAP at rest; these patients were also characterized by a more distinct increase in MR-proANP levels (p = 0.005) and higher peak (p < 0.001) and recovery levels (p < 0.001)., Conclusions: RAP and MR-proANP dynamics unmask manifest and latent right heart failure in CTEPH patients., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: The gold standard treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is pulmonary endarterectomy (PEA). Little is known about the influence of advanced age on surgical outcome. Therefore, the aim of this study was to investigate the impact of patient's age on postoperative morbidity, mortality, and quality of life in a German referral center., Methods: Prospectively collected data from 386 consecutive patients undergoing PEA between 01/2014 and 12/2016 were analyzed. Patients were divided into three groups according to their age: group 1: ≤ 50 years, group 2: > 50 ≤ 70 years, group 3: > 70 years., Results: After PEA, distinct improvements in pulmonary hemodynamics, physical capacity (World Health Organization [WHO] functional class and 6-minute walking distance) and quality of life were found in all groups. There were more complications in elderly patients with longer time of invasive ventilation, intensive care, and in-hospital stay. However, the in-hospital mortality was comparable (0% in group 1, 2.6% in group 2, and 2.1% in group 3 [ p  = 0.326]). Furthermore, the all-cause mortality at 1 year was 1.1% in group 1, 3.2% in group 2, and 6.3% in group 3 ( p  = 0.122)., Conclusions: PEA is an effective treatment for CTEPH patients of all ages accompanied by low perioperative and 1-year mortality. CTEPH patients in advanced age carefully selected by thorough preoperative evaluation should be offered PEA in expert centers to improve quality of life, symptoms, and pulmonary hemodynamics., Competing Interests: CBW has received speaker fees and/or consultant honoraria from Actelion, AOP Orphan Pharmaceuticals AG, Bayer AG, BTG, MSD, and Pfizer.DB has nothing to disclose.KA has nothing to disclose.HAG has reported receiving fees for serving as a board member for Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, and Web MD Global; receiving consultancy fees and fees for serving on a steering committee for Actelion Pharmaceuticals, Bayer, Gilead Sciences, GlaxoSmithKline, Merck, Novartis, and Pfizer; receiving lecture fees from Actelion Pharmaceuticals, Bayer, GlaxoSmithKline, Merck, Novartis, and Pfizer; and receiving grant support from Actelion Pharmaceuticals, Bayer, Novartis, and Pfizer.ML reports consultant and speaker fees from Actelion, Bayer, Thermo Fisher Scientific, Daiichi-Sankyo, MSD and Bristol-Myers Squibb-Pfizer, project funding from Thermo Fisher Scientific and institutional funding from the German Federal Ministry of Education and Research (BMBF 01EO1003 and 01EO1503).CL has received speaker fees from Abbott, Astra Zeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo, Elixir Medical, and Pfizer.DP has received speaker fees from AstraZeneca, and Kerckhoff-Forschungs GmbH, and received grant support from Johnson & Johnson and Medtronic.EM has received speaker fees and/or honoraria for consultations from Actelion, Bayer, GSK, MSD, and Pfizer.SDK has nothing to disclose.SG has received speaker fees from Actelion, Bayer, GSK, MSD and Pfizer., (Thieme. All rights reserved.)

Background: This study analyzed the utility of soluble ST2 (sST2) and GDF-15 as biomarkers of right ventricular (RV) function in patients with pulmonary hypertension (PH). Methods: GDF-15 and sST2 serum concentrations were measured in patients with PH (n = 628), dilated cardiomyopathy (n = 31) and left ventricular hypertrophy (n = 47), and in healthy controls (n = 61). Results: Median sST2 and GDF-15 levels in patients with left ventricular hypertrophy were higher than in patients with PH and dilated cardiomyopathy. In tertile analysis GDF-15 >1363 pg/ml and sST2 >38 ng/ml were associated with higher N-terminal pro-brain natriuretic peptide, RV systolic dysfunction, RV-pulmonary arterial uncoupling and hemodynamic impairment. Conclusion: GDF-15 and sST2 are potential biomarkers of RV dysfunction in patients with PH.

Background: Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) that targets subsegmental branches of the pulmonary artery. As the reported complication rates are high, the aim of the present study was to evaluate the effects of certain complications on the outcome after treatment., Methods: From March 2014 to December 2019, a total of 235 patients with inoperable CTEPH underwent BPA. Of these patients, 140 were included who completed a follow-up examination 6 months after the last intervention; another 2 patients deceased due to complications of BPA., Results: A high baseline pulmonary vascular resistance (PVR) >6.6 WU correlated with a higher rate of complications (mostly pulmonary artery perforations). Wire perforation during BPA did not correlate with worse outcome in terms of PVR reduction. The complication rate per intervention decreased from 21% to 14% during the 5 year period of the study., Conclusions: Complications are frequently observed in BPA, but the mortality rate is very low in expert centers. Importantly, the occurrence of complications does not portend a worse outcome., (Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with pulmonary hypertension (PH) frequently show preserved right ventricular (RV) function at rest. However, volume challenge may uncover pending RV dysfunction. We aimed to assess the physiological and prognostic impact of RV-pulmonary arterial (RV-PA) uncoupling during volume challenge in patients with precapillary PH., Methods: We prospectively assessed 32 patients with PH (pulmonary arterial hypertension, n = 27; inoperable chronic thromboembolic disease, n = 5) and 4 controls using invasive pressure-volume (PV) catheterization. PV loops were recorded during preload reduction (balloon occlusion of inferior vena cava; baseline) and acute volume loading (200 ml saline in 20 s). Contractility (multi-beat end-systolic elastance [Ees]), arterial elastance (Ea), and RV-PA coupling (Ees/Ea) were obtained at baseline and at maximum volume loading (MVL)., Results: Median [interquartile range] time to MVL was 19 [18-22] s. Ees/Ea significantly declined from baseline (0.89 [0.69-1.23]) to MVL (0.16 [0.12-0.34]; p < 0.001) in patients with PH but remained stable in controls (baseline: 1.08 [0.94-1.80]; MVL: 1.01 [0.80-2.49]; p = 0.715). The same pattern was observed for Ees, while Ea remained unchanged. The percent decline of RV-PA coupling (ΔEes/Ea) during fluid challenge was significantly associated with pulmonary resting hemodynamics, RV ejection fraction (RVEF), and RV end-diastolic volume. Kaplan-Meier analysis revealed that patients with PH who had a smaller ΔEes/Ea (<-65%) had a significantly better prognosis (log-rank p = 0.0389). In multivariate Cox regression analysis, clinical worsening was predicted by ΔEes/Ea (hazard ratio: 0.96 [95% confidence interval: 0.93-1.00]) and RVEF (hazard ratio: 0.95 [95% confidence interval: 0.92-0.98])., Conclusions: Assessment of PV loops during fluid challenge uncovers exhausted RV coupling reserve with severely reduced contractility in PH. RV-PA uncoupling during volume challenge can be predicted by pulmonary resting hemodynamics and RVEF. RV-PA uncoupling during fluid challenge and RVEF (as a noninvasive correlate) are predictors of clinical worsening., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03403868 (January 19, 2018)., (Copyright © 2021 International Society for Heart and Lung Transplantation. All rights reserved.)

Purpose: The aim of this study was to assess effects of balloon pulmonary angioplasty (BPA) on right ventricular (RV) mechanical dysfunction in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) via MRI., Method: MRI at 1.5 Tesla and right heart catheterization were performed before and 6 months after BPA in 30 CTEPH patients (mean age 63.4 ± 10.6 years; 17 female). Feature-tracking strain analysis, including global longitudinal (GLS), circumferential (GCS), and radial (GRS) strain, was performed and compared with right ventricular function, myocardial remodelling (assessed by native T1 times), and pulmonary haemodynamics (mean pulmonary arterial pressure and pulmonary vascular resistance)., Results: RVEF (35.9% to 48.4%) increased and mPAP (42.1 mmHg to 33.1 mmHg) and PVR (551.8 to 377.7 dyn∙s/cm 5 ) decreased after BPA (all p < 0.0001). Moreover, RV strain increased (GLS -19.9 to -24.0%, p = 0.0003; GCS -9.4 to -11.0%, p = 0.0022; GRS 38.2 to 50.7%, p = 0.001) and septal native area-adjusted T1 time (AA-T1) decreased (1019.4 to 988.7 ms, p < 0.0001). GLS revealed the best correlations with RVEF (before BPA r = -0.75; after BPA r = -0.54), mPAP (r = 0.36; r = 0.52), PVR (r = 0.49; r = 0.48), and AA-T1 (r = 0.44; 0.19)., Conclusion: RV mechanical dysfunction, pulmonary haemodynamics, and myocardial remodelling are markedly improved by BPA. Moreover, RV strain values showed good correlations with RV function, pulmonary haemodynamics, and myocardial remodelling. Therefore, strain analysis might provide new insights regarding therapy outcome, monitoring, and prognosis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL -1 ) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH., Competing Interests: Conflict of interest: S. Keranov reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study. Conflict of interest: O. Dörr reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study. Conflict of interest: L. Jafari has nothing to disclose. Conflict of interest: C. Troidl has nothing to disclose. Conflict of interest: C. Liebetrau reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study. Conflict of interest: S. Kriechbaum reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study. Conflict of interest: T. Keller has nothing to disclose. Conflict of interest: S. Voss has nothing to disclose. Conflict of interest: T. Bauer has nothing to disclose. Conflict of interest: J. Lorenz has nothing to disclose. Conflict of interest: M.J. Richter has nothing to disclose. Conflict of interest: K. Tello has nothing to disclose. Conflict of interest: H. Gall has nothing to disclose. Conflict of interest: H.A. Ghofrani has nothing to disclose. Conflict of interest: E. Mayer has nothing to disclose. Conflict of interest: C.B. Wiedenroth has nothing to disclose. Conflict of interest: S. Guth has nothing to disclose. Conflict of interest: H. Lörchner has nothing to disclose. Conflict of interest: J. Pöling has nothing to disclose. Conflict of interest: P. Chelladurai has nothing to disclose. Conflict of interest: S.S. Pullamsetti has nothing to disclose. Conflict of interest: T. Braun has nothing to disclose. Conflict of interest: W. Seeger has nothing to disclose. Conflict of interest: C.W. Hamm reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study. Conflict of interest: H. Nef reports grants from German Research Foundation (Project B07, Collaborative Research Center 1213-Pulmonary Hypertension and Cor Pulmonale), during the conduct of the study., (Copyright ©ERS 2021.)

Chronic thromboembolic pulmonary hypertension constitutes a significant late sequela of pulmonary embolism. It is defined by precapillary pulmonary hypertension with mismatched perfusion defects and pulmonary arterial lesions after at least 3 months of effective anticoagulation. Symptomatic patients who do not have pulmonary hypertension yet fulfill all other criteria are diagnosed with chronic thromboembolic disease. The treatment of chronic thromboembolic pulmonary hypertension is based on 3 pillars: pulmonary endarterectomy, pulmonary arterial hypertension-targeted medication, and balloon pulmonary angioplasty. Surgical pulmonary endarterectomy is the standard of care and can be performed in 2/3 of all patients. Targeted medication with or without balloon pulmonary angioplasty is reserved for inoperable patients or those with residual pulmonary hypertension after surgical treatment. Despite the lack of profound evidence, the treatment of chronic thromboembolic disease is similar to that of patients with pulmonary hypertension: pulmonary endarterectomy is offered to operable individuals, whereas balloon pulmonary angioplasty is considered in inoperable patients. Since therapeutic strategies are complex, and diagnostic and therapeutic procedures-demanding, treatment in a specialized, experienced center is mandatory.

Purpose: This study examined sST2, GDF-15, and galectin-3 as indicators of disease severity and therapy response in chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: This study included 57 inoperable CTEPH patients who underwent balloon pulmonary angioplasty and 25 controls without cardiovascular disease. Biomarker levels were examined in relation to advanced hemodynamic impairment [tertile with worst right atrial pressure (RAP) and cardiac index], hemodynamic therapy response [normalized hemodynamics (meanPAP ≤25 mmHg, PVR ≤3 WU and RAP ≤6 mmHg) or a reduction of meanPAP ≥25%; PVR ≥ 35%, RAP ≥25%]., Results: GDF-15 [820 (556-1315) pg/ml vs. 370 (314-516) pg/ml; p  < 0.001] and sST2 [53.7 (45.3-74.1) ng/ml vs. 48.7 (35.5-57.0) ng/ml; p = 0.02] were higher in CTEPH patients than in controls. At baseline, a GDF-15 level ≥1443 pg/ml (AUC 0.88; OR 31.4) and a sST2 level ≥65 ng/ml (AUC 0.80; OR 10.9) were associated with advanced hemodynamic impairment. At follow-up GDF-15 ≤ 958 pg/ml (AUC = 0.74, OR 18) identified patients with optimal hemodynamic therapy response and ≤760 pg/ml (AUC = 0.79, OR 14)., Conclusion: GDF-15 and sST2 levels are higher in CTEPH and identified patients with advanced hemodynamic impairment. Further, decreased GDF-15 levels at follow-up were associated with hemodynamic therapy response. The diagnostic strength was not superior to NT-proBNP.

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.

Introduction: Although a number of risk factors for chronic thromboembolic pulmonary hypertension (CTEPH) have been reported, the exact prevalence is controversial and varies between published cohorts. The aim of the present study was to investigate the prevalence of risk factors in operable CTEPH patients with special emphasis on thyroid disease and function., Material and Methods: Overall, 228 CTEPH patients (47.7% female; median age 63 [IQR 52-72] years) scheduled for pulmonary endarterectomy between 01/2014 and 12/2015 were studied. Prevalence of risk factors was assessed, and patients were classified according to their thyroid function based on laboratory measurements., Results: As many as 86.0% of patients reported a history of pulmonary embolism (PE; of those, 24.5% were diagnosed with "acute" PE less than six months before the diagnosis of CTEPH), 80.7% of patients had a blood group non-0 and 24.1% of patients had known thyroid disease (of those, 78.2% hypothyroidism). Laboratory measurements revealed thyroid dysfunction in 10.5% of patients (of those, 54.8% had no known thyroid disease). Patients with hypothyroid function had higher WHO functional classes, NT-proBNP levels and a lower cardiac index compared to patients with euthyroid function., Conclusions: The prevalence of a history of PE and blood group non-0 was higher than previously reported. However, a relevant proportion of patients might have suffered from pre-existing CTEPH rather than acute PE. Thyroid disease and dysfunction were frequent and hypothyroid function associated with more severe disease., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Extracellular vesicles are released by numerous cell types of the human body under physiological but also under pathophysiological conditions. They are important for cell-cell communication and carry specific signatures of peptides and RNAs. In this study, we aimed to determine whether extracellular vesicles isolated from patients with pulmonary hypertension show a disease specific signature of small non-coding RNAs and thus have the potential to serve as diagnostic and prognostic biomarkers. Extracellular vesicles were isolated from the serum of 23 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and 23 controls using two individual methods: a column-based method or by precipitation. Extracellular vesicle- associated RNAs were analyzed by next-generation sequencing applying molecular barcoding, and differentially expressed small non-coding RNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). We identified 18 microRNAs and 21 P-element induced wimpy testis (PIWI)-interacting RNAs (piRNAs) or piRNA clusters that were differentially expressed in CTEPH patients compared with controls. Bioinformatic analysis predicted a contribution of these piRNAs to the progression of cardiac and vascular remodeling. Expression levels of DQ593039 correlated with clinically meaningful parameters such as mean pulmonary arterial pressure, pulmonary vascular resistance, right ventricular systolic pressure, and levels of N-terminal pro-brain natriuretic peptide. Thus, we identified the extracellular vesicle- derived piRNA, DQ593039, as a potential biomarker for pulmonary hypertension and right heart disease., Competing Interests: C.B.W. has received speaker fees and/or consultant honoraria from Actelion, AOP, Bayer AG, BTG, MSD, and Pfizer. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Background:  Inflammation and incomplete thrombus resolution leading to obstructive fibrotic remodelling are considered critical mechanisms for the development of chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary embolism (PE). Osteopontin (OPN) is involved in a variety of biological processes including inflammation and tissue fibrosis., Methods:  OPN plasma concentrations were measured in 70 CTEPH and 119 PE patients. Tissue material from 6 CTEPH patients removed during pulmonary endarterectomy and murine venous thrombi induced by subtotal ligation of the inferior vena cava in C57BL/6 mice were analysed by (immuno)histochemistry., Results:  CTEPH patients had higher OPN plasma concentrations (median, 106.9 [interquartile range, 75.6-155.9]) compared to PE patients (90.4 [53.3-123.9] ng/mL, p  = 0.001). OPN- and matrix metalloproteinase (MMP)-9-positive cells were predominantly present in myofibroblast-rich and profibrotic areas of CTEPH tissue material. Early stages of murine thrombus resolution were characterised by high numbers of OPN- and MMP-2-positive cells while OPN was almost absent in fresh thrombi of CTEPH tissue material. PE patients with OPN plasma concentrations of < 55 ng/mL had a 15.2-fold (95% confidence interval, 1.7-135.5, p  = 0.015) increased risk for a diagnosis of CTEPH during follow-up., Conclusion:  The results of the present observational translational study point to a possible involvement of OPN in the pathogenesis of CTEPH by affecting early inflammatory and late fibrotic processes., Competing Interests: L.H. reports having received lecture honorary from MSD. C.B.W. reports having received lecture honorary from Actelion, Bayer, BTG, MSD and Pfizer. C.L. reports having received lecture honorary Abbott, AstraZeneca, Bayer, Berlin Chemie, Boehringer-Ingelheim, Daiichi-Sankyo and Pfizer. G.H. reports having received consultancy and lecture honoraria from AstraZeneca, Berlin Chemie, Corvia, Impulse Dynamics, Novartis, Servier and Vifor Pharma; and editor honoraria from Springer International Publishing AG. S.K. reports having received consultancy and lecture honorary from Actelion, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, MSD and Pfizer – Bristol-Myers-Squibb, payment for travel ccommodation/meeting expenses from Bayer and institutional grants from Actelion, Bayer, Boehringer-Ingelheim, Daiichi-Sankyo, and Pfizer – Bristol-Myers-Squibb. E.M. reports having received consultancy and lecture honorary from Actelion, Bayer, GlaxoSmithKline, MSD and Pfizer. S.G. reports having received lecture honorary from Actelion, Bayer, GlaxoSmithKline and Pfizer. M.L. reports having received consultancy and lecture honoraria from Actelion, Bayer, Daiichi-Sankyo, MSD, Pfizer – Bristol-Myers-Squibb and research funding from BRAHMS – Thermo Fisher Scientific. None of the authors reports a conflict of interest related to the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Balloon pulmonary angioplasty (BPA), for chronic thromboembolic pulmonary hypertension, improves pulmonary and systemic hemodynamics. The kidney might benefit from this effect. However, staged BPA therapy comes along with repetitive administration of contrast agent. This study examined the overall effect of BPA therapy on renal function. This study included consecutive patients who underwent BPA treatment and completed a 6-month follow-up between March 2014 and March 2017. Biomarker-based evaluation of renal function was performed at baseline, consecutively prior to and after each BPA and at 6-month follow-up. The 51 patients underwent an average of 5 (±2) BPA sessions. In this course, patients received 133 (±48; 21-300) mL of contrast agent per session and 691 (±24; 240-1410) mL during the whole sequence. Acute kidney injury occurred after 6 (2.3%) procedures. The creatinine [80.1 (IQR 67.8-96.8) µmol/L vs. 77.4 (IQR 66.9-91.5) µmol/L, p = .02] and urea level [13.7 (IQR10.7-16.6) mmol/L vs. 12.5 (IQR 10.0-15.5) mmol/L, p = .02] decreased from baseline to the 6-month follow-up. The estimated glomerular filtration rate (eGFR) [79 (IQR 59-94) mL/min/m 2 vs. 79.6 (IQR 67.1-95.0) mL/min/m 2 , p = .11] did not change. The Chronic kidney disease (CKD) stages at baseline were: G1:15; G2:23; G3a:10; G3b:2; G4:1; G5:0. Among patients with a CKD-stage ≥2, analysis revealed an increase of eGFR, decrease of creatinine and urea from baseline to 6-month follow-up. Among those patients, the baseline-CKD-stage improved in 14 (41.2%) patients. BPA therapy improves pulmonary and systemic hemodynamics, with positive effects on renal function. Repetitive administration of contrast agent seems not to be harmful regarding renal function.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subgroup of pulmonary hypertension that differs from all other forms of PH in terms of its pathophysiology, patient characteristics and treatment. For implementation of the European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension in Germany, the Cologne Consensus Conference 2016 was held and last updated in spring of 2018. One of the working groups was dedicated to CTEPH, practical and controversial issues were commented and updated. In every patient with suspected PH, CTEPH or chronic thromboembolic disease (CTED, i.e. symptomatic residual vasculopathy without pulmonary hypertension) should be excluded. Primary treatment is surgical pulmonary endarterectomy (PEA) in a multidisciplinary CTEPH centre. Inoperable patients or patients with persistent or recurrent CTEPH after PEA are candidates for targeted drug therapy. There is increasing experience with balloon pulmonary angioplasty (BPA) for inoperable patients; this option, like PEA, is reserved for specialised centres with expertise in this treatment method., (Copyright © 2018. Published by Elsevier B.V.)

Background: We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH)., Methods: Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics., Results: We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11-34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11-3.28; p = 0.019; n = 95)., Conclusions: Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed., (Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: Balloon pulmonary angioplasty (BPA) is an interventional treatment modality for inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Therapy monitoring, based on non-invasive biomarkers, is a clinical challenge. This post-hoc study aimed to assess dynamics of high-sensitivity cardiac troponin T (hs-cTnT) as a marker for myocardial damage and its relation to N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels as a marker for cardiac wall stress., Methods and Results: This study included 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between 3/2014 and 3/2017. Biomarker measurement was performed consecutively prior to each BPA and at 6-MFU. In total, the 51 patients underwent an average of 5 BPA procedures. The 6-month survival rate was 96.1%. The baseline (BL) meanPAP (39.5±12.1mmHg) and PVR (515.8±219.2dyn×sec×cm-5) decreased significantly within the 6-MFU (meanPAP: 32.6±12.6mmHg, P<0.001; PVR: 396.9±182.6dyn×sec×cm-5, P<0.001). At BL, the median hs-cTnT level was 11 (IQR 6-16) ng/L and the median NT-proBNP level was 820 (IQR 153-1872) ng/L. The levels of both biomarkers decreased steadily after every BPA, showing the first significant difference after the first procedure. Within the 6-MFU, hs-cTnT levels (7 [IQR 5-12] ng/L; P<0.001) and NT-proBNP levels (159 [IQR 84-464] ng/l; P<0.001) continued to decrease. The hs-cTnT levels correlated with the PVR (rrs = 0.42; p = 0.005), the meanPAP (rrs = 0.32; p = 0.029) and the NT-proBNP (rrs = 0.51; p<0.001) levels at BL., Conclusion: Non-invasive biomarker measurement provides valuable evidence for the decreasing impairment of myocardial function and structure during BPA therapy. Changes in hs-cTNT levels are suggestive for a reduction in ongoing myocardial damage., Competing Interests: CBW received consultant honoraria and/or speaker fees from Actelion, Bayer AG, MSD, Pfizer and BTG; MH received lecture honoraria from Daiichi-Sankyo and Pfizer; TK received speaker fees from Abbott; SG received speaker fees from Actelion, Bayer, GSK and Pfizer; AR received lecture honoraria from Astra Zeneca, Boehringer Ingelheim and Pfizer-Bristol-Myers Squibb; CWH received lecture or consulting honoraria from Astra Zeneca, Bayer, Boehringer Ingelheim, GSK, Daiichi-Sankyo and Pfizer-Bristol-Myers Squibb; EM received lecture or consulting honoraria from Actelion, Bayer, MSD, GSK, Pfizer and MSD; CL received lecture or consulting honoraria from Abbott, Astra Zeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, Daiichi-Sankyo and Pfizer-Bristol-Myers Squibb. AJR received speaker fees from Servier, St. Jude Medical and Actelion, honoraria from Novartis and traveling support by Orion Pharma and Actelion. SDK, JSW, RA, DB, KP, AB, and FCR have nothing to declare. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Symptomatic patients with chronic thromboembolic disease (CTED) without pulmonary hypertension often show an excessive increase in mean pulmonary arterial pressure (MPAP) during exercise.We report on the impact of pulmonary endarterectomy (PEA) on pulmonary haemodynamics in a prospective series of 32 consecutive CTED patients who underwent PEA. All patients had a comprehensive diagnostic work-up including right heart catheterisation at baseline and 12 months after PEA. Furthermore, in 12 patients exercise right heart catheterisation was performed before and after PEA.After PEA, MPAP was lower at rest (20±3 versus 17±3 mmHg; p=0.008) and during maximal exercise (39±8 versus 31±6 mmHg; p=0.016). The mean total pulmonary resistance (TPR) decreased from 3.6±0.8 Wood Units (WU) pre-operatively to 2.7±0.7 WU 1 year after PEA (p=0.004) and the mean slope of the MPAP/cardiac output (CO) relationship decreased from 3.6±1.0 to 2.3±0.8 WU (p=0.002). Peak oxygen uptake increased from 1.2±0.4 to 1.5±0.3 L·min -1 (p=0.014) and ventilatory equivalents of carbon dioxide decreased from 39±2 to 30±2 (p=0.002). There was a significant improvement in quality of life assessed by the Cambridge Pulmonary Hypertension Outcome Review questionnaire.In CTED patients, PEA resulted in haemodynamic and clinical improvements. The means of TPR and MPAP/CO slopes decreased to <3.0 WU., Competing Interests: Conflict of interest: S. Guth reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees from Actelion Pharmaceuticals, Bayer, Pfizer and GSK, outside the submitted work. Conflict of interest: C.B. Wiedenroth reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees from Actelion, Bayer AG, BTG, MSD and Pfizer, outside the submitted work. Conflict of interest: A. Rieth reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees from Actelion Pharmaceuticals, Novartis, Servier and St Jude Medical, and grants from Pfizer, outside the submitted work. Conflict of interest: M.J. Richter reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees and nonfinancial support from Actelion Pharmaceuticals, personal fees from Bayer, Mundipharma, OMT and Roche, outside the submitted work. Conflict of interest: H.A. Ghofrani reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; grants and personal fees from Actelion Pharmaceuticals, Bayer, Pfizer and Novartis, personal fees from Bellerophon Pulse Technologies, Medscape, OMT, UCB Celltech, WebMD Global, Gilead Sciences, GSK and Merck, outside the submitted work. Conflict of interest: C. Liebetrau reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees from Abbott, Bayer, Pfizer, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Daiichi Sankyo and Elixir Medical, outside the submitted work. Conflict of interest: A. Rolf reports personal fees from AstraZeneca, Boehringer Ingelheim and Pfizer-Bristol-Myers Squibb, outside the submitted work. Conflict of interest: C.W. Hamm reports nonfinancial support from the German Center for Lung Research, during the conduct of the study. Conflict of interest: E. Mayer reports nonfinancial support from the German Center for Lung Research, during the conduct of the study; personal fees from Actelion Pharmaceuticals, Bayer, Pfizer, GSK and MSD, outside the submitted work. Conflict of interest: E. Gruenig has received fees for lectures and/or consultations from Actelion Pharmaceuticals, Bayer/MSD, GSK, United Therapeutics and Pfizer., (Copyright ©ERS 2018.)

Background: The incidence of chronic thromboembolic pulmonary hypertension (CTEPH) is unknown. Previous studies from the United Kingdom and Spain have reported incidence rates of 1.75 and 0.9 per million, respectively. These figures, however, may underestimate the true incidence of CTEPH., Methods: We prospectively enrolled patients newly diagnosed with CTEPH within 2016 in Germany. Data were obtained from the three German referral centers and from the German branch of COMPERA, a European pulmonary hypertension registry. The CTEPH incidence was calculated based on German population data, and patient characteristics and treatment patterns were described., Results: A total of 392 patients were newly diagnosed with CTEPH within 2016 in Germany, yielding an incidence of 5.7 new cases per million adults. The (mean ± standard deviation) age was 63.5 ± 15.0 years; males and females were equally affected; 76.3% of the patients had a history of venous thromboembolism. A total of 197 (50.3%) patients underwent pulmonary endarterectomy. Almost all non-operated patients received targeted drug therapy, and 49 patients (25.1% of the non-operated patients) were treated with balloon pulmonary angioplasty., Conclusion: The incidence of CTEPH in Germany 2016 was 5.7 per million adults and thus higher than previously reported from other countries. Half of the patients were operated while the remaining patients received medical or interventional therapies., Clinical Trials Registration: http://www.clinicaltrials.gov NCT02660463 and NCT01347216.

Background: Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success., Methods: In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU., Results: The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm 5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm 5 ; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (r rs = 0.43, p = 0.002) and PVR (r rs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77)., Conclusions: Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring., (Copyright © 2018 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Pulmonary artery (PA) catheters are routinely used for hemodynamic management in patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing pulmonary endarterectomy (PEA). Tip-associated thrombi are frequently detected and might increase the peri-operative risk in these patients. The aim of the study was to investigate the effects of low-dose heparinization before the insertion of the PA catheter on thrombus formation and thrombus weight during PEA surgery. From September 2013 to February 2015, 60 CTEPH patients undergoing PEA were included in the study and randomized into two groups of 30 patients each, including a heparin group (heparin bolus (70 IU per kg body weight) administration before PA catheter insertion) and a control group (pretreatment with placebo). During the PEA procedure the distal part of the PA catheter was drawn out of the PA and thrombus presence and weight were recorded. There were no significant differences in baseline characteristics between the two groups. Twelve patients (20%) had thrombophilic disorders. In the control group, thrombi were detected in 17 patients (57%) with a median thrombus weight of 27 mg (IQR 41). In the heparin group, tip-associated thrombi were found in five patients (17%) with a median weight of 12 mg (IQR 7). There were no bleeding complications in either group. This study demonstrates a high risk of PA catheter-related thrombi in patients with CTEPH. Prophylactic administration of low-dose heparin reduces thrombus formation and thrombus weight without an increased rate of bleeding complications.

Balloon pulmonary angioplasty (BPA) is an emerging treatment for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH).We report on a prospective series of 56 consecutive patients who underwent 266 BPA interventions (median, five per patient) at two German institutions. All patients underwent a comprehensive diagnostic work-up including right heart catheterisation at baseline and 24 weeks after their last intervention.BPA resulted in improvements in WHO functional class, 6 min walk distance (mean change, +33 m), right ventricular function and haemodynamics, including a decline in mean pulmonary artery pressure by 18% and in pulmonary vascular resistance by 26%. Procedure-related adverse events occurred in 9.4% of the interventions. The most common complications were related to pulmonary vascular injury and consecutive pulmonary bleeding. Most of these events were asymptomatic and self-limiting, but one patient died from pulmonary bleeding, resulting in a mortality rate of 1.8%.BPA resulted in haemodynamic and clinical improvements but was also associated with a considerable number of complications, including one fatal pulmonary bleeding. As the effects of BPA on survival are unknown, randomised controlled outcome trials comparing BPA with approved medical therapies in patients with inoperable CTEPH are required to allow for appropriate risk-benefit assessments., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Objectives: The aim of this study was to assess septal and right ventricular insertion point (RVIP) fibrosis in patients with chronic thromboembolic pulmonary hypertension (CTEPH) via native T1 mapping and extracellular volume fraction (ECV) determination and to analyze correlations with functional parameters., Methods: Imaging was performed at 1.5 Tesla in 24 patients diagnosed with CTEPH and 24 controls. T1 values were measured within the septal myocardium, the upper and lower RVIP, and the lateral wall at basal short axis section., Results: The mean septal native T1 values were 1012.8 ms ± 50.5 in the CTEPH group and 956.9 ms ± 24.4 in controls (p < 0.001), upper RIVP 1050.8 ms ± 64.2 vs. 965.3 ms ± 37.1 (p < 0.001), and lower RVIP 1084.4 ms ± 93.1 vs. 959.8 ms ± 40.4 (p < 0.001). The corresponding mean ECV values were also significantly increased in the CTEPH group (p < 0.001). Native septal T1 showed a strong negative correlation with right ventricular ejection fraction (k = -0.92; p = 0.01)., Conclusions: We conclude that native T1 mapping and ECV assessment enable visualization and quantification of septal fibrosis in CTEPH patients. The results also correlate well with right ventricular ejection fraction. Therefore, these parameters might be useful for prognosis and as therapy-monitoring tool in the future., Key Points: • Septal native T1 and ECV values are significantly higher in CTEPH patients. • Native T1 and ECV values are elevated even in absence of LGE. • These techniques therefore enable an improved quantification of septal fibrosis in CTEPH. • Native T1 values also correlate well with right ventricular EF and PA-pressure. • Prognosis and therapy-monitoring might be assessable in the future with these parameters.

The pathomechanisms underlying the development of thrombofibrotic pulmonary artery occlusions in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) are largely unknown. The aim of this study was to allocate distinct cellular processes playing a role in thrombus resolution, such as inflammation, hypoxia, proliferation, apoptosis and angiogenesis, to different stages of thrombofibrotic remodelling. A total of 182 pulmonary endarterectomy (PEA) specimens were collected from 31 CTEPH patients. To facilitate co-localisation, Tissue MicroArrays were prepared and processed for (immuno)-histochemistry and confocal fluorescence microscopy. Murine venous thrombus formation and resolution was examined after inferior vena cava ligation. PEA tissues exhibited five morphologically distinct regions predominantly consisting of either fibrin-, erythrocyte- or extracellular matrix-rich thrombus, myofibroblasts, vessels or fibrotic tissue, and were found to resemble chronological stages of thrombus resolution in mice. Cellularity was highest in vessel-rich regions, and numerous cells were strongly positive for HIF1α or HIF2α as well as markers of activated VEGF signalling, including endothelial nitric oxide synthase. On the other hand, negative regulators of angiogenic growth factor signalling and reactive oxygen species were also highly expressed. Immune cells, primarily macrophages of the M2 subtype and CD117 haematopoietic progenitors were detected and highest in vascularised regions. Our findings demonstrate the simultaneous presence of different stages of thrombus organisation and suggest that hypoxia-induced endothelial, mesenchymal and immune cell activation may contribute to thrombofibrosis in CTEPH. This systematic histological characterisation of the material obstructing pulmonary vessels in CTEPH may provide a valuable basis for further studies aimed at determining causal factors underlying this disease.

Pulmonary endarterectomy is a curative treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH). There is a growing body of evidence suggesting that not only patients with CTEPH but also patients with pulmonary arterial obstructions and mean pulmonary artery pressures < 25 mmHg should be offered surgery. In this review, the recent literature regarding pathophysiology, diagnostic methods, decision making by an expert CTEPH team, and surgical techniques will be summarized. Novel alternative treatment options for inoperable CTEPH patients will be discussed, i.e. targeted medical therapy and balloon pulmonary angioplasty. For the future the major task will be to define a clear selection process for the optimal treatment of the individual CTEPH patient.

Background: Pulmonary endarterectomy (PEA) is a curative treatment option for more than 60% of patients with chronic thromboembolic pulmonary hypertension (CTEPH). For selected inoperable patients, interventional balloon pulmonary angioplasty (BPA) has recently been established in addition to medical treatment. This approach disrupts scar tissue occluding the pulmonary arteries, leading to an improvement in parenchymal perfusion. CTEPH is occasionally heterogeneous, with operable disease on one side but peripheral, inoperable changes on the contralateral side. Performing unilateral PEA (on the operable side only) in these patients may lead to a worse hemodynamic outcome and increased mortality compared with patients who that can be surgically corrected bilaterally. We sought to determine the feasibility, safety, and benefits of BPA applied to the contralateral lung in several patients with predominantly unilateral disease that was amenable to treatment by PEA., Methods: Standard unilateral PEA in deep hypothermic circulatory arrest was performed in 3 CTEPH patients with poor pulmonary hemodynamics, and inoperability of the contralateral pulmonary artery obstructions was confirmed. The inoperable side was treated by BPA. The intervention was performed during the rewarming phase of cardiopulmonary bypass., Results: A dramatic improvement in pulmonary hemodynamics, with a mean reduction in pulmonary vascular resistance of 842 dyne · sec/cm(5), was achieved in all patients. World Health Organization Functional Class was also significantly improved at the midterm follow-up., Conclusions: The combination of surgical PEA and interventional BPA is a new treatment option for highly selected high-risk CTEPH patients. A multidisciplinary CTEPH expert team is a basic pre-requisite for this complex concept., (Copyright © 2016 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Glycosylated hemoglobin A1c (HbA1c) has been proposed as an independent predictor of long-term prognosis in pulmonary arterial hypertension. However, the clinical relevance of HbA1c in patients with operable chronic thromboembolic pulmonary hypertension (CTEPH) remains unknown. The aim of the present study was to investigate the clinical significance of HbA1c as a biomarker in CTEPH., Methods: Prospectively, 102 patients underwent pulmonary endarterectomy (PEA) in our national referral center between March 2013 and March 2014, of which after exclusion 45 patients were analyzed. HbA1c- levels, hemodynamic and exercise parameters were analyzed prior and one-year post-PEA., Results: 45 patients (BMI: 27.3 ± 6.0 kg/m2; age: 62.7 ± 12.3 years) with a mean pulmonary arterial pressure (mPAP) of 43.6 ± 9.4 mmHg, a pulmonary vascular resistance (PVR) of 712.1 ± 520.4 dyn*s/cm5, a cardiac index (CI) of 2.4 ± 0.5 l/min/m2 and a mean HbA1c-level of 39.8 ± 5.6 mmol/mol were included. One-year post-PEA pulmonary hemodynamic and functional status significantly improved in our cohort. Baseline HbA1c-levels were significantly associated with CI, right atrial pressure, peak oxygen uptake and the change of 6-minute walking distance using linear regression analysis. However, using logistic regression analysis baseline HbA1c-levels were not significantly associated with residual post-PEA PH., Conclusions: This is the first prospective study to describe an association of HbA1c-levels with pulmonary hemodynamics and exercise capacity in operable CTEPH patients. Our preliminary results indicate that in these patients impaired glucose metabolism as assessed by HbA1c is of clinical significance. However, HbA1c failed as a predictor of the hemodynamic outcome one-year post-PEA.

Background: Several studies have analyzed arrhythmias in patients with pulmonary hypertension (PH) and increased P-wave duration was identified as a risk factor for development of atrial fibrillation (AF)., Methods: We retrospectively analyzed the incidence of arrhythmias in patients with an initial diagnosis of PH during long-term follow-up and assessed the prognostic value of electrocardiography (ECG) data. Data from 167 patients were analyzed (Dana Point Classification: Group 1: 59 patients, Group 2: 28 patients, Group 3: 39 patients, Group 4: 41 patients). Clinical, 6-min-ute walk distance test, echocardiography and right heart catheterization data were collected, and baseline/follow-up ECGs were analyzed., Results: Baseline ECGs revealed sinus rhythm in 137 patients. Thirteen patients had newly onset AF during follow-up. In 30 patients, baseline ECG showed AF. Patients with baseline AF showed higher atrial diameters and higher right atrial pressure. Patients with P-wave du-ration > 0.11 s had shorter survival. Other ECG parameters (PQ-interval, QRS-width, QT-/ /QTc-interval) were not associated with survival. Mean survival times were 79.4 ± 5.4 months (sinus rhythm), 64.4 ± 12.9 months (baseline AF) and 58.8 ± 8.9 months (newly onset AF during follow-up) (p = 0.565)., Conclusions: Atrial fibrillation predict adverse prognosis in patients with PH and a longer P-wave (> 0.11 s) is associated with shorter survival time.

Background: Pulmonary endarterectomy (PEA) is the treatment of choice in surgically accessible chronic thromboembolic pulmonary hypertension (CTEPH). An important predictor of outcome is postsurgical residual pulmonary hypertension., Objective: We aimed to use the hemodynamic response during exercise before PEA as a measurement for the hemodynamic outcome 1 year after PEA., Methods: Between January 2011 and December 2013, 299 patients underwent PEA in our center. A total of 16 patients who were assessed by means of invasive hemodynamic measurements during exercise both at baseline and 1 year after PEA were retrospectively analyzed., Results: Pre-PEA mean pulmonary arterial pressure (mPAP) increased during exercise from 35.8 ± 7.6 to 53.8 ± 5.1 mm Hg, diastolic pulmonary arterial pressure (dPAP) from 21.5 ± 5.6 to 30.3 ± 9.6 mm Hg, cardiac output (CO) from 4.4 ± 0.8 to 6.5 ± 1.9 l/min and diastolic pulmonary gradient (DPG) from 14.6 ± 4.9 to 20.7 ± 12.7 mm Hg. Post-PEA mPAP increased from 23.7 ± 6.6 at rest to 43.2 ± 7.1 mm Hg, while CO increased to a higher extent from 5.1 ± 0.9 to 8.4 ± 1.9 l/min. There were significant correlations between pre-PEA DPG/CO and dPAP/CO slopes with the pulmonary vascular resistance (Spearman r = 0.578, p = 0.019, and r = 0.547, p = 0.028) and mPAP at rest after PEA (Spearman r = 0.581, p = 0.018, and r = 0.546, p = 0.028)., Conclusions: In CTEPH, the presurgical dynamic DPG/CO and dPAP/CO slopes during submaximal exercise are associated with the hemodynamic outcome 1 year after PEA.