Search

ZusammenfassungDieser Artikel stellt die gezielte Therapie der pulmonalarteriellen Hypertonie (PAH) vor. Die medikamentöse Therapie der PAH hat sich in den letzten Jahren entscheidend verbessert und ermöglicht heute vielen Patienten eine deutliche Verbesserung der körperlichen Belastbarkeit, Lebensqualität und des Langzeitüberlebens. Die neuen ESC/ERS-Leitlinien zur pulmonalen Hypertonie haben die aus vielen neuen Studien entstandenen Evidenzen zusammengetragen, bewertet und den therapeutischen Algorithmus und die Therapieempfehlungen entsprechend angepasst. In dem folgenden Artikel werden die neuen Empfehlungen zur medikamentösen Therapie der PAH zusammengefasst und eingeordnet. Die PAH-Therapie wird wie bisher am Schweregrad der Erkrankung orientiert, der bei Diagnose nach einem 3-Risikostufen-Modell abgeschätzt wird. Neu ist die Anwendung eines 4-stufigen Risikomodells bei der Therapieanpassung im Krankheitsverlauf. In den neuen Leitlinien werden erstmals auch Therapieempfehlungen für Patienten mit PAH und Komorbiditäten gegeben.

Hintergrund: Anhaltende Symptome nach akuter Coronavirus-Krankheit-2019 (COVID-19) sind häufig und es besteht kein signifikanter Zusammenhang mit der Schwere der akuten Erkrankung. Bei Long COVID (anhaltende Symptome > 4 Wochen nach akuter COVID-19) treten häufig respiratorische Symptome auf, aber Lungenfunktionstests zeigen nur leichte Veränderungen, die die Symptome nicht erklären. Obwohl COVID-19 zu einer Beeinträchtigung des peripheren Nervensystems und der Skelettmuskulatur führen kann, wurde die Funktion der Atemmuskulatur in diesem Zusammenhang nicht untersucht. Methoden: In dieser Studie haben wir den Schweregrad der Dyspnoe (NYHA-Funktionsklasse) bei Long-COVID-Patienten untersucht und analysierten dessen Zusammenhang mit dem Body-Mass-Index (BMI), der Einsekundenkapazität (FEV1), der forcierten Vitalkapazität, anderen Parametern der Bodyplethysmographie, der Diffusionskapazität für Kohlenmonoxid (DLCO), den arteriellen Blutgasen und der Funktion der Atemmuskulatur, die anhand des Atemwegsokklusionsdrucks (P0,1) und des maximalen Inspirationsdrucks (PImax) in 2 Atemwegskliniken in Deutschland zwischen Oktober 2020 und August 2021 gemessen wurde. Ergebnisse: Insgesamt wurden 116 Patienten in die Studie aufgenommen. Das Durchschnittsalter betrug 50,2 ± 14,5 Jahre, BMI 26,7 ± 5,87 kg/m2, NYHA-Klasse I 19%, II 27%, III 41% und IV 14%. Während die Lungenfunktionswerte und die Computertomografie oder die konventionelle Röntgenaufnahme des Brustkorbs im normalen Bereich lagen, war die Funktion der Atemmuskulatur deutlich beeinträchtigt. Der P0,1 war auf 154 ± 83% des Sollwerts erhöht und der PImax war auf 41 ± 25% des Sollwerts reduziert. Die PImax-Reduktion war stark mit dem Schweregrad der Dyspnoe verbunden, aber nicht abhängig vom BMI, der Zeit nach der akuten COVID-19 und den meisten anderen Parametern. Schlussfolgerungen: Diese Studie zeigt, dass die Atemwegssymptome bei Patienten mit Long COVID hauptsächlich durch eine verminderte Inspirationsmuskelkraft verursacht sein können. Die Bewertung von PImax und P0,1 könnte eine Dyspnoe besser erklären als klassische Lungenfunktionstests und die DLCO. Eine prospektive Studie ist erforderlich, um diese Ergebnisse zu bestätigen.

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.

Oxygenated hemoglobin (OxyHem) in arterial blood may reflect disease severity in patients with systemic sclerosis (SSc). The aim of this study was to analyze the predictive value of OxyHem in SSc patients screened for pulmonary hypertension (PH). OxyHem (g/dl) was measured by multiplying the concentration of hemoglobin with fractional oxygen saturation in arterialized capillary blood. Prognostic power was compared with known prognostic parameters in SSc using uni- and multivariable analysis. A total of 280 SSc patients were screened, 267 were included in the analysis. No signs of pulmonary vascular disease were found in 126 patients, while 141 patients presented with mean pulmonary arterial pressure ≥ 21 mmHg. Interstitial lung disease (ILD) was identified in 70 patients. Low OxyHem ≤ 12.5 g/dl at baseline was significantly associated with worse survival (P = 0.046). In the multivariable analysis presence of ILD, age ≥ 60 years and diffusion capacity for carbon monoxide (DLCO) ≤ 65% were negatively associated with survival. The combination of low DLCO and low OxyHem at baseline could predict PH at baseline (sensitivity 76.1%). This study detected for the first time OxyHem ≤ 12.5 g/dl as a prognostic predictor in SSc patients. Further studies are needed to confirm these results.

Pulmonary arterial hypertension (PAH) can be caused by pathogenic variants in the gene bone morphogenetic protein receptor 2 (

The impact of exercise training and physiotherapy on heart function and pulmonary circulation parameters in heart failure with preserved ejection fraction (HFpEF) patients is uncertain. Hence, we performed a systematic review of published trials studying physical training in HFpEF population, with a focus on exercise and physiotherapy effect on left ventricular (LV), right ventricular (RV) morphological, functional, and pulmonary circulation parameters. We searched Cochrane Library and MEDLINE/PubMed for trials that evaluated the effect of exercise training and/or physiotherapy in adult HFpEF patients (defined as LVEF ≥ 45%), including publications until March 2021. Our systematic review identified eighteen articles (n = 418 trained subjects, 4 to 52 weeks of training) and covered heterogeneous trials with various populations, designs, methodologies, and interventions. Five of twelve trials revealed a significant reduction of mitral E/e’ ratio after the training (− 1.2 to − 4.9). Seven studies examined left atrial volume index; three of them showed its decrease (− 3.7 to − 8 ml/m2). Findings were inconsistent regarding improvement of cardiac output, E/A ratio, and E wave DecT and uncertain for RV function and pulmonary hypertension parameters. For now, no reliable evidence about rehabilitation effect on HFpEF cardiac mechanisms is available. There are some hypotheses generating findings on potential positive effects to parameters of LV filling pressure (E/e’), left atrium size, cardiac output, and RV function. This encourages a broader and more complex assessment of parameters reflecting cardiac function in future HFpEF exercise training studies.

Genes 13(5), 759 (2022). doi:10.3390/genes13050759, Published by MDPI, Basel

BackgroundIn this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc).MethodsIn SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses.ResultsThe final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21–24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21–24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (pConclusionThe data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.

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.

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.

Objective This prospective study was undertaken to evaluate right ventricular function and pulmonary arterial compliance (PAC; ratio of stroke volume to pulse pressure) at rest and during exercise in patients with systemic sclerosis (SSc) with normal mean pulmonary artery pressure (PAP), patients with SSc with mildly elevated mean PAP, and patients with SSc with manifest pulmonary hypertension (PH). Methods Patients with SSc (n = 112) underwent clinical assessment and right-sided heart catheterization at rest and during exercise and were divided into 3 groups according to their resting mean PAP values: normal mean PAP (≤20 mm Hg), mildly elevated mean PAP (21-24 mm Hg), and PH (mean PAP ≥25 mm Hg). Results were compared between groups by analysis of variance followed by post hoc Student's t-test. Results Compared to patients with normal mean PAP, patients with mildly elevated mean PAP had a lower 6-minute walking distance (P = 0.008), lower cardiac index (P = 0.027) and higher pulmonary vascular resistance (P = 0.0002) during exercise, and lower PAC at rest (P = 0.016) and different stages of exercise (P = 0.033 for 25W and P = 0.024 for 75W). Conclusion The results of this study suggest that impaired 6-minute walking distance in SSc patients with mildly elevated mean PAP might be caused by reduced PAC during exercise and reduced right ventricular output reserve, presumably due to impaired coupling between the right ventricle and the pulmonary vasculature. These findings provide further evidence of the clinical relevance of mildly elevated mean PAP in patients with SSc.

To assess the diagnostic accuracy of automated 3D volumetry of central pulmonary arteries using computed tomography pulmonary angiography (CTPA) for suspected pulmonary hypertension alone and in combination with echocardiography.This retrospective diagnostic accuracy study included 70 patients (mean age 66.7, 48 female) assessed for pulmonary hypertension by CTPA and transthoracic echocardiography with estimation of the pulmonary arterial systolic pressure (PASP). Gold standard right heart catheterisation with measurement of the invasive mean pulmonary arterial pressure (invasive mPAP) served as the reference. Volumes of the main, right and left pulmonary arteries (MPA, RPA and LPA) were computed using automated 3D segmentation. For comparison, axial dimensions were manually measured. A linear regression model was established for prediction of mPAP (predicted mPAP).MPA, RPA and LPA volumes were significantly increased in patients with vs. without pulmonary hypertension (all p 0.001). Of all measures, MPA volume demonstrated the strongest correlation with invasive mPAP (r = 0.76, p 0.001). Predicted mPAP using MPA volume and echocardiographic PASP as covariates showed excellent correlation with invasive mPAP (r = 0.89, p 0.001). Area under the curves for predicting pulmonary hypertension were 0.94 for predicted mPAP, compared to 0.90 for MPA volume and 0.92 for echocardiographic PASP alone. A predicted mPAP 25.8 mmHg identified pulmonary hypertension with sensitivity, specificity, positive and negative predictive values of 86%, 93%, 95% and 81%, respectively.Automated 3D volumetry of central pulmonary arteries based on CTPA may be used in conjunction with echocardiographic pressure estimates to noninvasively predict mPAP and pulmonary hypertension as confirmed by gold standard right heart catheterisation with higher diagnostic accuracy than either test alone.• This diagnostic accuracy study derived a regression model for noninvasive prediction of invasively measured mean pulmonary arterial pressure as assessed by gold standard right heart catheterisation. • This regression model using automated 3D volumetry of the central pulmonary arteries based on CT pulmonary angiography in conjunction with the echocardiographic pressure estimate predicted pulmonary arterial pressure and the presence of pulmonary hypertension with good diagnostic accuracy. • The combination of automated 3D volumetry and echocardiographic pressure estimate in the regression model provided superior diagnostic accuracy compared to each parameter alone.

GATA2 deficiency is characterized by monocytopenia, deficiency of dendritic cells, and a variable degree of lymphocytopenia affecting B cells and NK cells, leading to an enhanced risk of mycobacterial, viral, and fungal infections. Here we present a patient with a heterozygous intronic GATA2 mutation who acquired a fatal disseminated mycosis due to the black yeast-like fungus Arthrocladium fulminans following an infection with Mycobacterium sherrisii. This case illustrates that in patients with severe uncommon infections, immunodeficiency syndromes must be ruled out.

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.

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. © 2020 The Authors Eli Lilly and Company; Pfizer; Bayer; GlaxoSmithKline; Merck; Actelion Pharmaceuticals; Meso Scale Diagnostics; United Therapeutics Corporation; Novartis Pharma; Merck Sharp and Dohme; GlaxoSmithKline Australia; Deutsche Forschungsgemeinschaft; Grupo Ferrer Internacional, S.A The EXPERT registry was funded by Bayer AG (Berlin, Germany) and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co. Inc., Kenilworth, NJ, USA. The authors acknowledge the database administration by Torsten Tille, Dresden, and the project administration of Mrs Romy Hoppenz and Mrs Linda Kottke at GWT-TUD GmbH, Dresden. Medical writing services provided by Richard Murphy PhD of Adelphi Communications Ltd, Macclesfield, UK were funded by Bayer AG in accordance with Good Publication Practice (GPP3) guidelines. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof Marius M. Hoeper reports personal fees from Bayer AG, during the conduct of the study; personal fees from Actelion, personal fees from Acceleron, personal fees from MSD, personal fees from Jansen, personal fees from Pfizer, outside the submitted work. Dr Hans Klose reports speaker and consultancy fees from Actelion, Bayer AG, GSK, Novartis, Pfizer, and United Therapeutics and research support from Actelion, Bayer AG, GSK, Pfizer, and MSD. Dr Michael Halank reports personal fees and non-financial support from Actelion, AstraZeneca, Bayer AG, Berlin-Chemie, GSK, OMT, MSD, and Novartis. Dr George Giannakoulas reports speaker and consultancy fees from Actelion, Bayer, ELPEN Pharmaceuticals, GSK, Pfizer, Lilly, and United Therapeutics, and research support from GSK, ELPEN Pharmaceuticals, and Galenica. Dr Henning Gall has received honoraria and/or other support from Actelion, AstraZeneca, Bayer, BMS, GSK, Janssen-Cilag, Lilly, MSD, Novartis, OMT, Pfizer, and United Therapeutics. Dr Pavel Jansa reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Prof Ekkehard Grünig reports research grants and speaker honoraria/consultancy fees from Actelion and Bayer/MSD, research grants from GSK, United Therapeutics, Bellerophon, OMT GmbH, Pfizer, Reata, and Novartis, and speaker honoraria from Bial, Medscape, and OrPha Swiss GmbH. Prof David Pittrow reports personal fees from Actelion, Bayer AG, Aspen, Boehringer Ingelheim, Sanofi, Biogen, Shire, and MSD outside the submitted work. Silvia Ulrich reports research grants and personal fees from Actelion, Bayer, MSD, and Orpha Swiss. Tobias J. Lange has received personal fees from Actelion, MSD, Pfizer, and OMT orphan. Dr Iraklis Tsangaris reports speaker and consultancy fees from Actelion, Bayer AG, ELPEN, GSK, MSD, Pfizer, and United Therapeutics. Stephan Rosenkranz reports remunerations for lectures and/or consultancy from Abbott, Actelion, Arena, Bayer, Ferrer, GSK, MSD, Novartis, Pfizer, and United Therapeutics; and research support to his institution from Actelion, Bayer, Novartis, Pfizer, and United Therapeutics. Repke J. Snijder reports grants from Pfizer and Actelion Pharmaceuticals. Prof Iveta Šimková reports consultancy and speaker fees from MSD, AOP Orphan, and Actelion. Dr Marc Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, and United Therapeutics. Marion Delcroix has received investigator, speaker, consultant, and steering committee member fees from Actelion, Bayer AG, Bellerophon, Eli Lilly, GlaxoSmithKline, MSD, Pfizer, and Reata, and research grants from Actelion. Joan A. Barberà reports receipt of honoraria for consultation or speaker fees from Actelion and Merck; and research support through his institution from Actelion, Merck, GlaxoSmithKline, and Ferrer. Joanna Pepke-Zaba reports research grants and speaker honoraria/consultancy fees from Actelion, Bayer/MSD, and GSK. Jean-Luc Vachiéry reports ongoing consultancies to Actelion, Sonnivie, Arena Pharma, Bial Portela, and Respira Therapeutics, past consultancies to AstraZeneca, BayerShering, CardioMEMS, GlaxoSmithKline, Pfizer, Merck, and United Therapeutics, and current membership of an advisory board or similar group for Actelion and GlaxoSmithKline. Jean-Luc Vachiéry's institution receives funding from Actelion Pharmaceuticals for performing clinical studies. Regina Steringer-Mascherbauer, Jens Klotsche, and Miguel-Angel Gomez Sanchez have no conflicts of interest relevant to the EXPERT study. Hossein-Ardeschir Ghofrani reports personal fees for advisory board work, and payment for lectures including service on speaker bureaus, from Actelion, Bayer, GSK, Novartis, and Pfizer; consultancy fees from Actelion, Bayer, Bellerophon Pulse Technologies, GSK, MSD, Novartis, and Pfizer; and grants from Deutsche Forschungsgemeinschaft (DFG). Pilar Escribano Subias reports personal fees from Actelion, Bayer AG, GlaxoSmithKline, and Merck Sharp & Dohme, and grants from Actelion, Bayer AG, GlaxoSmithKline, and Ferrer, outside the submitted work. Gérald Simonneau reports personal fees and non-financial support from Actelion, personal fees and non-financial support from Bayer, personal fees and non-financial support from MSD, outside the submitted work. Douglas S. Helmersen reports industry-sponsored research with Bayer AG, United Therapeutics, and Gilead Sciences, Inc., and advisory board/speaker fees from Bayer AG and Actelion. David Langleben reports honoraria, consultation fees, research support, and/or travel expenses from Actelion, Arena, Bayer AG, Northern Therapeutics, PhaseBio, Acceleron, Janssen, and United Therapeutics. Anco Boonstra reports consultancy fees from Pfizer BV and hospitality from Teva Nederland. Lisa M. Mielniczuk reports speaker fees and honoraria from Bayer AG, and speaker fees, consultancy fees, and travel fees from Actelion. Evgenia Williams and Christian Meier are employees of Bayer AG.

Background: Safety, feasibility and effect of combined supervised inpatient rehabilitation as early follow-up treatment after pulmonary endarterectomy (PEA) has not yet been prospectively investigated in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods: Forty-five patients with CTEPH (49% female, 57.6 ± 12.4years, 60% WHO functional class III pre-PEA) started a 19-week rehabilitation program (3 weeks inpatient and continued at home for another 16 weeks) with supervised exercise training as follow-up treatment shortly after PEA. Haemodynamics were assessed by right heart catheterization before PEA and 22 weeks post PEA. Non-invasive assessments as transthoracic echocardiography and 6-minute walking test (6MWD) were performed before PEA and after 3 (= beginning of rehabilitation), 6- and 22-weeks post PEA. Adverse events were recorded throughout the study. Results: Rehabilitation was started 3.3 ± 0.9 weeks after PEA. Exercise training was well tolerated in all patients without severe side effects. Haemodynamics measured by right heart catheterization significantly improved from pre PEA to 22 weeks post PEA in cardiac output (+1.2 ± 1.5 l/min, equals 33.4%, p=0.001) and mean pulmonary arterial pressure (-19 ± 13 mmHg, equals -39.6%, p Conclusions: Supervised exercise training was feasible and safe as early follow-up treatment after PEA.

Background: A genetic predisposition has been identified in different forms of pulmonary arterial hypertension (PAH). Most pathogenic variants have been identified in BMPR2 in hereditary PAH. However, many further PAH genes have been described. Objective: The aim of this study was to screen for all known PAH genes in a large cohort of patients with PAH and other forms of PH who have been referred for genetic testing. Methods: DNA from 244 patients was extracted and sequenced using a PAH specific gene diagnostics panel for the genes: ACVRL1, BMPR1B, BMPR2, CAV1, EIF2AK4, ENG, GDF2, KCNA5, KCNK3, KLF2, SMAD4, SMAD9 and TBX4. Of these, 180 samples were also sequenced for ATP13A3, AQP1 and SOX17. Results: Of the 244 patients about 50% were classified as IPAH and 17% as HPAH. Further patients with associated PAH such as congenital heart disease or connective tissue disease patients, pulmonary veno-occlusive disease (PVOD) and patients with sarcoidosis associated PH were included. A total of 70 pathogenic variants were identified in 66 patients. The majority of the variants (56%) was located in the gene BMPR2 but the others were found across 10 other PAH genes. Most HPAH patients had pathogenic variants in BMPR2 but also in AQP1, KCNK3, SMAD9 and SOX17. Two sarcoidosis associated PH patients carried pathogenic variants in the genes GDF2 and SOX17. Conclusion: Pathogenic variants were located in BMPR2 and in further PAH genes. Genetic predisposition was not restricted to HPAH, IPAH and PVOD but could also be identified PH with sarcoidosis and other forms of associated PAH. Thus, genetic diagnostics might be useful in a larger patient cohort than currently recommended.

Background: Data on exercise training in chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA) as well as data on clinical and haemodynamic changes shortly after PEA are lacking. Objective: The objective of this prospective study was to analyse the safety, feasibility, and the effectiveness of combined supervised inpatient rehabilitation in patients with CTEPH directly after PEA. Methods: CTEPH patients started a 19-week rehabilitation program (3 weeks as inpatients and continued at home for another 16 weeks) with supervised exercise training as follow-up treatment shortly after PEA. Haemodynamics were assessed by right heart catheterisation before PEA and 22 weeks after PEA. Non-invasive assessments as transthoracic echocardiography and 6-min walking distance (6MWD) were performed before PEA and after 3 (that is, beginning of rehabilitation), 6, and 22 weeks following PEA. Adverse events were recorded throughout the study. Results: Forty-five CTEPH patients were included (49% female, 57.6 ± 12.4 years old, 60% WHO functional class III). Rehabilitation was started 3.3 ± 0.9 weeks after PEA. Exercise training was well tolerated in all patients without severe side effects. Haemodynamics measured by right heart catheterisation significantly improved from pre-PEA to 22 weeks post-PEA in cardiac output (+1.2 ± 1.5 L/min, 33.4%, p = 0.001) and mean pulmonary arterial pressure (–19 ± 13 mm Hg, –39.6%, p < 0.0001). Right heart size measured by echocardiography, 6MWD, quality of life, and oxygen saturation significantly improved not only within the first 3 weeks after PEA but also during the following 19 weeks of exercise training. Conclusions: Supervised exercise training was feasible as early follow-up treatment after PEA. Further controlled studies are needed to discriminate the effects of PEA and early follow-up rehabilitation. Trial Registration: The study was registered at clinicaltrials.gov (NCT01393327) on July 13, 2011. The study start date was January 2010, and completion date was December 2013.

In their correspondence Iudici et al 1 highlight three important aspects which are to consider in the interpretation of survival data when introducing new thresholds of an early stage of disease.2 They point out, that lead-time bias, length-time bias as well as increasing numbers of patients have to be considered for the new haemodynamic definition of pulmonary arterial hypertension (PAH). In studies investigating the effect of systematic PAH screening programmes on survival in patients with systemic sclerosis, part of the effect of an increased survival may be attributed to lead-time bias and length-time bias.3 4 We agree with Iudici et al that lead-time bias is an important aspect when introducing a new definition of a disease, which includes patients at a less severe stage. This becomes especially important for screening programmes, as survival of screened patients who are diagnosed at early disease stages may implicitly be better compared with patients with a more severe disease. In our study we analysed the frequency of PAH in patients with systemic sclerosis when applying the new PAH definition according to the suggestion from the World Symposium on pulmonary hypertension in Nice 2018. According to a large meta-analysis of haemodynamic data of healthy people, a pulmonary vascular resistance (PVR) >2 Wood Units (WU) …

Background: Combination therapy with the phosphodiesterase type 5 inhibitors (PDE-5i) sildenafil or tadalafil and the endothelin receptor antagonists (ERA) bosentan, ambrisentan, or macitentan may cause mutual pharmacokinetic interactions in patients with pulmonary arterial hypertension (PAH). Objective: The objective of this study was to analyze plasma drug concentrations in PAH patients receiving different combination treatments. Methods: PAH patients receiving a stable combination treatment with ERA and PDE-5i with targeted dosage for at least 1 month were routinely assessed, including clinical parameters and plasma drug concentrations. Concentrations were normalized considering dose and time from last medication intake and presented as multiples of the expected mean (MoM) of the respective monotherapies. Results: A total of 125 PAH patients (84 female, 41 male, 57% idiopathic/heritable) were included. Sildenafil and tadalafil concentrations were lowest in combination with bosentan (MoM 0.44 ± 0.42, 95% confidence interval [CI] 0.30-0.57, and MoM 0.89 ± 0.53, 95% CI 0.50-1.28, respectively) compared to the combination with ambrisentan (MoM 1.3 ± 0.97, 95% CI 0.86-1.73, and MoM 1.67 ± 0.63, 95% CI 1.40-1.94, respectively) and macitentan (MoM 1.16 ± 0.87, 95% CI 0.86-1.46, and MoM 1.59 ± 0.99, 95% CI 0.80-2.38, respectively). The combination of sildenafil and bosentan led to more than twice the expected bosentan concentrations in 53.8%. Patients switching from sildenafil-bosentan to macitentan showed a significant increase in sildenafil concentrations (p < 0.001). Conclusions: Only the combination with macitentan or ambrisentan led to targeted mean PDE-5i plasma concentrations and should therefore be preferred to combination with bosentan. Sildenafil-bosentan showed the strongest interaction, with low sildenafil and high bosentan concentrations. The study was not powered to analyze whether lower PDE-5i concentrations cause unsatisfying clinical response. However, plasma concentrations within a targeted range are desirable and may become of increasing importance.

Background Patients with systemic sclerosis (SSc) are at high risk of developing concomitant pulmonary hypertension (PH) which has a crucial impact on the patients' symptoms, quality of life and prognosis. Purpose The aim of this study was to analyse the impact of the new hemodynamic definition of precapillary PH as proposed at the 2018 World Symposium on PH in Nice in patients with SSc. Although recent data suggest that PVR >2 WU could be considered as abnormal in the new definition a conservative cut-off value of PVR ≥3 WU has been used. Methods SSc-patients were screened for PH using clinical assessments as WHO-functional class, 6 minute walking distance and right heart catheterisation. Patients were divided into hemodynamic subgroups according to their mean pulmonary arterial pressure (mPAP) values with mPAP ≤20 mmHg, 21–24 mmHg and ≥25 mmHg. These subgroups were further divided according to their pulmonary vascular resistance (PVR) with PVR Results One-hundred-twenty-two patients (79% female, age 57.6±12.7 years, 6MWD 439.5±98.1 meters, 70% diffuse cutaneous SSc, 30% limited cutaneous SSc, 53% WHO-FC II, 25% WHO-FC III) who were prospectively screened for PH were included in the analysis (Figure 1). Among them 26 had a symptomatic manifest PH using the cut-off value of mPAP ≥25 mmHg. Only half of this group presented with PVR ≥3 WU, the others had PVR Overview of systemic sclerosis patients Conclusions The new definition of precapillary pulmonary hypertension may on the one hand allow detecting an additional 10% of PH patients with mild elevated mPAP. On the other hand, eight of 13 patients (62%), who met the former definition of pulmonary arterial hypertension, would be classified as “normal” due to a lack of increase in PVR according to the new definition. The data of this study suggest that for SSc-patients the cut-off value of mPAP >20 mmHg is useful, but the criteria of PVR ≥3 WU may be too strict. Further studies with larger sample sizes will be needed to better characterise these hemodynamic subgroups and to define the extent of pulmonary vascular disease and treatability.

Background: Prostacyclins (PCs) are used as targeted treatment for pulmonary arterial hypertension (PAH). Data regarding safety and long-term outcomes of s.c. and/or i.v. treprostinil (T) administered via s.c. Corno and the implantable LENUS Pro pump in patients with PAH are lacking. Methods: Thirty-seven PAH patients (20 females, 51±15 y.o., mean pulmonary arterial pressure 62.3±14.4 mmHg, cardiac index 2.4±0.7 L/min/m2, 6 WHO functional class II, 26 III, 5 IV) on triple targeted PAH medication (ERA, PDE5 inhibitors and treprostinil s.c.) were clinically assessed every 3 months. Survival rate was analysed using Kaplan Mayer estimation. Results: Patients showed a significant improvement of 6-minute walking distance after 3 (p=0.021), 6 (p=0.033) and 12 months (p=0.042) of s.c. treprostinil treatment. Furthermore, tricuspid annular plane systolic excursion, right atrial and right ventricular area improved after 3 and 6 months s.c. treatment (all p Conclusion: Subcutaneous T as add-on to double combination treatment significantly improved right heart size and function in this patient cohort. In most patients T could be continued i.v. by implanted Lenus Pro pump with a good overall-survival.

Background: Patients with systemic sclerosis (SSc) are at high risk of developing pulmonary hypertension (PH) which crucially affects patients’ symptoms, quality of life and prognosis. The aim of this study was to analyse the impact of the new hemodynamic definition of precapillary PH as proposed at the 2018 World Symposium on PH in SSc-patients. Methods: SSc-patients were screened for PH using clinical assessments as WHO-functional class, 6 minute walking distance (6MWD) and right heart catheterisation. Patients were divided into hemodynamic subgroups according to their mean pulmonary arterial pressure (mPAP) values with mPAP ≤20mmHg, 21-24mmHg and ≥25mmHg and their pulmonary vascular resistance (PVR) with PVR Results: The analysis included 158 patients (81% female, age 57±13years, 6MWD 438±101meters, 76% WHO-FC II or III) who were prospectively screened for PH. Among them, 40 had a manifest PH with an mPAP ≥25mmHg. Half of them presented with PVR ≥3WU. Thirteen presented with PH due to left heart disease. Out of 30 patients with mPAP 21-24mmHg, 4 (13%) met the new definition criteria of PH. Out of 88 patients with mPAP Conclusions: The new definition of precapillary PH may allow detecting an additional ~10% of PH patients with mPAP 21-24mmHg. On the other hand, 11/27 patients (40.7%), would be classified as “normal” due to PVR 20mmHg presented as useful, while the criterium of PVR ≥3WU seemed too strict. Further studies will be needed to characterise thee hemodynamic subgroups and to define the extent of pulmonary vascular disease and treatability.

Objective The objective of this randomized, placebo-controlled, double-blind, parallel group, trial was to assess the effect of ambrisentan on mean pulmonary arterial pressure (mPAP) in patients with systemic sclerosis (SSc) and mildly elevated pulmonary hypertension (PH). Methods Thirty-eight SSc patients with mildly elevated mPAP at rest between 21 and 24 mmHg and/or > 30 mmHg during low-dose exercise were randomly assigned to treatment with either ambrisentan 5–10 mg/day or placebo. Right heart catheterization and further clinical parameters were assessed at baseline and after 6 months. The primary endpoint was the difference of mPAP change at rest between groups. Results After 6 months, the two groups did not differ in the primary endpoint (ambrisentan mPAP − 1 ± 6.4 mmHg vs. placebo − 0.73 ± 3.59 mmHg at rest, p = 0.884). However, three patients from the placebo group but none of the ambrisentan group progressed to SSc-associated pulmonary arterial hypertension. Furthermore, ambrisentan treatment showed significant improvements in the secondary endpoints cardiac index (CI) and pulmonary vascular resistance (PVR) at rest (CI 0.36 ± 0.66 l/min/m2 vs. − 0.31 ± 0.71 l/min/m2, p = 0.010; PVR − 0.70 ± 0.78 WU vs. 0.01 ± 0.71 WU, p = 0.012) and during exercise (CI 0.7 ± 0.81 l/min/m2 vs. − 0.45 ± 1.36 l/min/m2, p = 0.015; PVR − 0.84 ± 0.48 WU vs. − 0.0032 ± 0.34 WU, p Conclusion This is the first randomized, double-blind, placebo-controlled study testing the effect of ambrisentan in patients with mildly elevated mPAP and/or exercise PH. The primary endpoint change in mPAP did only tendentially improve in the ambrisentan group, but the significant improvement of other hemodynamic parameters points to a possible benefit of ambrisentan and will be helpful to design future trials. Trial registration www.ClinicalTrials.gov, unique identifier NCT: NCT02290613, registered 14th of November 2014.

Background The objective of this study was to assess, whether right atrial (RA) and ventricular (RV) size is related to RV pump function at rest and during exercise in patients with pulmonary arterial hypertension (PAH). Methods We included 54 patients with invasively diagnosed PAH that had been stable on targeted medication. All patients underwent clinical assessments including right heart catheterization and echocardiography at rest and during exercise. RV output reserve was defined as increase of cardiac index (CI) from rest to peak exercise (∆CIexercise). Patients were classified according to the median of RA and RV-area. RV pump function and further clinical parameters were compared between groups by student’s t-test. Uni- and multivariate Pearson correlation analyses were performed. Results Patients with larger RA and/or RV-areas (above a median of 16 and 20cm2, respectively) showed significantly lower ∆CIexercise , higher mean pulmonary arterial pressure, pulmonary vascular resistance at rest and NT-proBNP levels. Furthermore, patients with higher RV-areas presented with a significantly lower RV stroke volume and pulmonary arterial compliance at peak exercise than patients with smaller RV-size. RV area was identified as the only independent predictor of RV output reserve. Conclusion RV and RA areas represent valuable and easily accessible indicators of RV pump function at rest and during exercise. Cardiac output reserve should be considered as an important clinical parameter. Prospective studies are needed for further evaluation.