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BackgroundThe 2022 ESC/ERS guidelines on pulmonary hypertension recommend non-invasive risk assessments based on three non-invasive clinical variables during follow-up in patients with pulmonary arterial hypertension (PAH). We set out to test whether residual risk can be captured from routinely measured non-invasive clinical variables during follow-up in PAH.MethodsWe retrospectively studied 298 incident PAH patients from a German PH centre who underwent routine non-invasive follow-up assessments including exercise testing, echocardiography, electrocardiography, pulmonary function testing and biochemistry. To select variables, we used LASSO-regularized Cox regression models. Outcome was defined as mortality or lung transplant after first follow-up assessment.ResultsTwelve non-invasive variables that were associated with outcomes in a training sub-cohort (n=208) after correction for multiple testing entered LASSO modelling. A model combining 7 variables discriminated 1-year (area under the curve [AUC] 0.83, 95%-confidence interval [95%-CI] 0.68–0.99, p=8.4×10−6) and 3-year (AUC 0.81, 95%-CI 0.70–0.92, p=2.9×10−8) outcome status in a replication sub-cohort (n=90). The model's discriminatory ability was comparable to that of the guideline approach in the replication sub-cohort. From the individual model components, World Health Organisation functional class, 6-min walking distance and the tricuspid annular plane systolic excursion to systolic pulmonary arterial pressure (TAPSE/sPAP) ratio were sensitive to treatment initiation. Addition of TAPSE/sPAP to the guideline approach numerically increased its ability to discriminate outcome status.ConclusionOur real-world data suggests that residual risk can be captured by non-invasive clinical procedures during routine follow-up assessments in patients with PAH and highlights the potential use of echocardiographic imaging to refine risk assessment.

ZusammenfassungDas Angiosarkom ist eine seltene, maligne Erkrankung, die von den Blutgefäßen ausgeht. Das pulmonale Angiosarkom kann sich diagnostisch initial wie eine chronisch thromboembolische pulmonale Hypertonie (CTEPH) darstellen. Die CTEPH ist eine Erhöhung des pulmonal-arteriellen Drucks und Widerstands als Folge einer persistierenden Obstruktion der Lungenstrombahn nach pulmonalen Thromboembolien trotz adäquater Antikoagulation.In unserer Ambulanz für pulmonale Hypertonie stellte sich ein 76-jähriger Patient mit anamnestisch vor 7 Monaten erlittener subakuter, links zentraler Lungenarterienembolie (LAE) vor, die seitdem mit Apixaban therapiert wurde. Bei persistierender Belastungsdyspnoe wurde der Verdacht auf eine CTEPH gestellt und es erfolgte weitere Diagnostik. Passend zur CTEPH zeigte sich spiroergometrisch eine ineffektive Ventilation und echokardiografisch eine Rechtsherzbelastung. Eine Verlaufs-CT des Thorax ergab einen persistierenden und größenkonstanten Füllungsdefekt der linken Pulmonalarterie mit szintigrafischem Nachweis einer primären Perfusionsstörung des gesamten linken Lungenflügels. Mit dem Verdacht auf ein malignes Geschehen veranlassten wir eine PET-CT, in welcher sich die Läsion der Pulmonalarterie stoffwechselaktiv darstellte. Eine unter endobronchialer Ultraschallkontrolle durchgeführte Punktion der Läsion ergab histologisch den Nachweis eines sarkomatoiden Tumors mit Amplifikation des MDM2-Gens. Wir stellten die Diagnose eines Intimasarkoms der linken Pulmonalarterie und führten den Patienten einer Pneumektomie zu.Die Intimasarkome der Pulmonalarterie sind selten und führen durch Wachstum und Thrombusneigung zur Stenose des Gefäßes. Die damit einhergehende klinische und echokardiografische Präsentation kann eine CTEPH imitieren und stellt somit eine wichtige Differenzialdiagnose zu dieser dar. 2015 wurden weniger als 300 Fallberichte beschrieben.Hinweise auf ein pulmonales Angiosarkom: Kontrastmittel aufnehmende, intraluminale Gewebsformation mit Dilatation der Pulmonalarterie und Infiltration der Gefäßwand, erhöhte Stoffwechselaktivität des Befundes in der FDG-PET CT, Größenprogredienz unter Antikoagulation, anamnestisch keine stattgehabte LAE, B-Symptome.Die Diagnosesicherung erfolgt durch Biopsie. Das mediane Überleben wird mit 1,5–17 Monaten beschrieben, welches mit therapeutischen Interventionen um einige Monate mit Symptomreduktion verlängert werden kann. Als therapeutischer Standard gilt die Resektion des Tumors mit ggf. Metastasenentfernung. Der Nutzen von Radio- und Chemotherapie ist Bestandteil aktueller Forschung. Eine Behandlung ist in erfahrenen Zentren anzustreben und es bedarf weiterer Forschung zur Verbesserung von Diagnostik und Therapie.

ZusammenfassungOrganbezogene Folgeerscheinungen nach COVID-19 sind häufig und vielgestaltig. Ab 4 Wochen nach Akutinfektion mit SARS-CoV‑2 werden sie unter dem Begriff „Long-COVID“ zusammengefasst.Nach schweren Akutverläufen treten organbezogene Folgeerscheinungen häufiger auf. Dauer und Intensität variieren jedoch interindividuell stark. Die SARS-CoV-2-Spezifität der Folgeerscheinungen ist ebenfalls weiter unklar. Während sich in der Frühphase nach schweren Verläufen zumeist pulmonale Folgeerscheinungen einstellen, müssen diese nicht auf die Lunge begrenzt bleiben, sondern können prinzipiell jedes Organ betreffen. Die adäquate Diagnostik von COVID-19-Folgeerscheinungen stellt daher eine interdisziplinäre Herausforderung dar. Auch die Therapie richtet sich nach Art, Umfang und Ursache der jeweiligen Folgeerscheinung. Allgemeinmedikamentöse oder zielgerichtete Therapieoptionen gegen Long-COVID bestehen bisher nicht.Im vorliegenden Übersichtsartikel berichten wir über Häufigkeit, Dauer, Spezifität sowie Art und Umfang organspezifischer COVID-19-Folgeerscheinungen und geben einen Überblick über diagnostisches und therapeutisches Vorgehen (mit Datenstand November 2021).

γ-glutamyl transferase (GGT), the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, and the neutrophil-to-lymphocyte ratio (NLR) are prognostic biomarkers in several cardiovascular diseases, but their relevance in pulmonary hypertension (PH) is not fully understood. We aimed to assess their prognostic value in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic PH (CTEPH).We retrospectively analyzed 731 incident patients with idiopathic PAH or CTEPH who entered the Giessen PH registry during 1993-2019. A risk stratification score based on GGT, AST/ALT ratio, and NLR tertiles was compared with a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) risk stratification scheme. Associations with survival were evaluated using Kaplan-Meier and Cox regression analyses. External validation was performed in 311 patients with various types of PAH or CTEPH from a second German center.GGT levels, AST/ALT, and NLR independently predicted mortality at baseline and during follow-up. The scoring system based on these biomarkers predicted mortality at baseline and during follow-up (both log-rank p0.001; hazard ratio [95% confidence interval], high vs low risk: baseline, 7.6 [3.9, 15.0]; follow-up, 13.3 [4.8, 37.1]). Five-year survival of low, intermediate, and high risk groups was 92%, 76%, and 51%, respectively, at baseline and 95%, 78%, and 50%, respectively, during follow-up. Our scoring system showed characteristics comparable to the ESC/ERS scheme, and predicted mortality in the validation cohort.GGT, AST/ALT, and NLR were reliable prognostic biomarkers at baseline and during follow-up, with predictive power comparable to the gold standard for risk stratification.

Pulmonary angiosarcoma is a rare and malignant disease of the blood vessels. Initially, it can be misdiagnosed as chronic thromboembolic hypertension (CTEPH). In CTEPH, there is increased pressure and resistance of the pulmonary arteries following persistent obstruction of pulmonary circulation from (recurrent) thromboembolism despite adequate anticoagulative treatment.A 76-year-old patient was referred to our centre for pulmonary hypertension after a central, left-sided, subacute pulmonary thromboembolism had been observed 7 months earlier. It was treated with apixaban, but the patient described persistent dyspnoea and cough. We observed severely reduced diffusion capacity, ineffective ventilation during cardiopulmonary exercise testing and right heart strain on echocardiograph, signs that are in agreement with suspected CTEPH. Computer tomography of the chest showed a persistent, size-constant obliteration of the left main pulmonary artery, and ventilation perfusion scan confirmed complete interruption of perfusion. We suspected malignancy; PET-CT scan confirmed metabolically active lesions. Histopathological examination of a sample obtained from the lesion by endobronchial ultrasound-guided needle aspiration showed a sarcomatous tumour with amplification of the MDM2-gene. We diagnosed an intimal angiosarcoma of the left pulmonary artery and referred the patient to pneumectomy.Angiosarcoma of the pulmonary arteries is a rare differential diagnosis of persistent thrombotic lesion and suspected CTEPH. In 2015 there were less than 300 cases described.Pulmonary angiosarcoma should be considered if: lesion occupies the entire lumen of pulmonary arteries with dilatation, contrast enhancement and infiltration of the wall in radiological examination, FDG-PET CT reveals metabolically active lesions, no pulmonary thromboembolism was documented in the anamnesis, increase in size is seen despite anticoagulation, patient presents with B symptoms.Diagnosis confirmed by biopsy, resection of tumour and removal of metastases is the therapeutic standard. Median survival remains poor. Further research is needed for improved diagnosis and treatment.Das Angiosarkom ist eine seltene, maligne Erkrankung, die von den Blutgefäßen ausgeht. Das pulmonale Angiosarkom kann sich diagnostisch initial wie eine chronisch thromboembolische pulmonale Hypertonie (CTEPH) darstellen. Die CTEPH ist eine Erhöhung des pulmonal-arteriellen Drucks und Widerstands als Folge einer persistierenden Obstruktion der Lungenstrombahn nach pulmonalen Thromboembolien trotz adäquater Antikoagulation.In unserer Ambulanz für pulmonale Hypertonie stellte sich ein 76-jähriger Patient mit anamnestisch vor 7 Monaten erlittener subakuter, links zentraler Lungenarterienembolie (LAE) vor, die seitdem mit Apixaban therapiert wurde. Bei persistierender Belastungsdyspnoe wurde der Verdacht auf eine CTEPH gestellt und es erfolgte weitere Diagnostik. Passend zur CTEPH zeigte sich spiroergometrisch eine ineffektive Ventilation und echokardiografisch eine Rechtsherzbelastung. Eine Verlaufs-CT des Thorax ergab einen persistierenden und größenkonstanten Füllungsdefekt der linken Pulmonalarterie mit szintigrafischem Nachweis einer primären Perfusionsstörung des gesamten linken Lungenflügels. Mit dem Verdacht auf ein malignes Geschehen veranlassten wir eine PET-CT, in welcher sich die Läsion der Pulmonalarterie stoffwechselaktiv darstellte. Eine unter endobronchialer Ultraschallkontrolle durchgeführte Punktion der Läsion ergab histologisch den Nachweis eines sarkomatoiden Tumors mit Amplifikation des MDM2-Gens. Wir stellten die Diagnose eines Intimasarkoms der linken Pulmonalarterie und führten den Patienten einer Pneumektomie zu.Die Intimasarkome der Pulmonalarterie sind selten und führen durch Wachstum und Thrombusneigung zur Stenose des Gefäßes. Die damit einhergehende klinische und echokardiografische Präsentation kann eine CTEPH imitieren und stellt somit eine wichtige Differenzialdiagnose zu dieser dar. 2015 wurden weniger als 300 Fallberichte beschrieben.Hinweise auf ein pulmonales Angiosarkom: Kontrastmittel aufnehmende, intraluminale Gewebsformation mit Dilatation der Pulmonalarterie und Infiltration der Gefäßwand, erhöhte Stoffwechselaktivität des Befundes in der FDG-PET CT, Größenprogredienz unter Antikoagulation, anamnestisch keine stattgehabte LAE, B-Symptome.Die Diagnosesicherung erfolgt durch Biopsie. Das mediane Überleben wird mit 1,5–17 Monaten beschrieben, welches mit therapeutischen Interventionen um einige Monate mit Symptomreduktion verlängert werden kann. Als therapeutischer Standard gilt die Resektion des Tumors mit ggf. Metastasenentfernung. Der Nutzen von Radio- und Chemotherapie ist Bestandteil aktueller Forschung. Eine Behandlung ist in erfahrenen Zentren anzustreben und es bedarf weiterer Forschung zur Verbesserung von Diagnostik und Therapie.

Rationale: Pulmonary arterial hypertension (PAH) is characterized by structural remodeling of pulmonary arteries and arterioles. Underlying biological processes are likely reflected in a perturbation of circulating proteins. Objectives: To quantify and analyze the plasma proteome of patients with PAH using inherited genetic variation to inform on underlying molecular drivers. Methods: An aptamer-based assay was used to measure plasma proteins in 357 patients with idiopathic or heritable PAH, 103 healthy volunteers, and 23 relatives of patients with PAH. In discovery and replication subgroups, the plasma proteomes of PAH and healthy individuals were compared, and the relationship to transplantation-free survival in PAH was determined. To examine causal relationships to PAH, protein quantitative trait loci (pQTL) that influenced protein levels in the patient population were used as instruments for Mendelian randomization (MR) analysis. Measurements and Main Results: From 4,152 annotated plasma proteins, levels of 208 differed between patients with PAH and healthy subjects, and 49 predicted long-term survival. MR based on cis-pQTL located in proximity to the encoding gene for proteins that were prognostic and distinguished PAH from health estimated an adverse effect for higher levels of netrin-4 (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.08) and a protective effect for higher levels of thrombospondin-2 (OR, 0.83; 95% CI, 0.74-0.94) on PAH. Both proteins tracked the development of PAH in previously healthy relatives and changes in thrombospondin-2 associated with pulmonary arterial pressure at disease onset. Conclusions: Integrated analysis of the plasma proteome and genome implicates two secreted matrix-binding proteins, netrin-4 and thrombospondin-2, in the pathobiology of PAH.

BackgroundInflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.MethodsWe conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels.ResultsWe recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of PAH (OR 0.99, p=0.88).ConclusionAdverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

Purpose Symptoms often persistent for more than 4 weeks after COVID-19—now commonly referred to as ‘Long COVID’. Independent of initial disease severity or pathological pulmonary functions tests, fatigue, exertional intolerance and dyspnea are among the most common COVID-19 sequelae. We hypothesized that respiratory muscle dysfunction might be prevalent in persistently symptomatic patients after COVID-19 with self-reported exercise intolerance. Methods In a small cross-sectional pilot study (n = 67) of mild-to-moderate (nonhospitalized) and moderate-to-critical convalescent (formerly hospitalized) patients presenting to our outpatient clinic approx. 5 months after acute infection, we measured neuroventilatory activity P0.1, inspiratory muscle strength (PImax) and total respiratory muscle strain (P0.1/PImax) in addition to standard pulmonary functions tests, capillary blood gas analysis, 6 min walking tests and functional questionnaires. Results Pathological P0.1/PImax was found in 88% of symptomatic patients. Mean PImax was reduced in hospitalized patients, but reduced PImax was also found in 65% of nonhospitalized patients. Mean P0.1 was pathologically increased in both groups. Increased P0.1 was associated with exercise-induced deoxygenation, impaired exercise tolerance, decreased activity and productivity and worse Post-COVID-19 functional status scale. Pathological changes in P0.1, PImax or P0.1/PImax were not associated with pre-existing conditions. Conclusions Our findings point towards respiratory muscle dysfunction as a novel aspect of COVID-19 sequelae. Thus, we strongly advocate for systematic respiratory muscle testing during the diagnostic workup of persistently symptomatic, convalescent COVID-19 patients.

Pulmonary arterial hypertension is an unmet clinical need. Imatinib, a tyrosine kinase inhibitor, 200 to 400 mg daily reduces pulmonary artery pressure and increases functional capacity in this patient group, but is generally poorly tolerated at the higher dose. We have designed an open-label, single-arm clinical study to investigate whether there is a tolerated dose of imatinib that can be better targeted to patients who will benefit. The study consists of two parts. Part 1 seeks to identify the best tolerated dose of Imatinib in the range from 100 and up to 400 mg using a Bayesian Continuous Reassessment Method. Part 2 will measure efficacy after 24 weeks treatment with the best tolerated dose using a Simon's two-stage design. The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) >1000 dynes �� s �� cm-5, success is defined by an absolute reduction in PVR of ���300 dynes �� s �� cm-5 at 24 weeks. For patients with a baseline PVR ���1000 dynes �� s �� cm-5, success is a 30% reduction in PVR at 24 weeks. PVR will also be evaluated as a continuous variable by genotype as an exploratory analysis. Evaluating the response to that dose by genotype may inform a prospective biomarker-driven study.

Organ-specific sequelae after COVID-19 occur frequently and are highly diverse in their features. Sequelae and symptoms persisting for more than four weeks after COVID-19 define the condition "long COVID."Organ-specific sequelae of COVID-19 generally occur more often after severe disease. Yet, duration and intensity of organ-specific sequelae are highly variable. While pulmonary sequelae typically persist after more severe acute disease, COVID-19 sequelae may also develop weeks after infection and can affect any organ. The degree of SARS-CoV‑2 specificity of COVID-19 sequelae, however, remains unclear. Thus, diagnosis and treatment of COVID-19 sequelae represent an interdisciplinary challenge. Diagnostic and therapeutic approaches are guided by type, extent, and cause of the specific sequelae as targeted therapy options for long COVID are lacking.In the present work, we review current knowledge regarding the prevalence/incidence, duration, specificity, type, and extent of organ-specific COVID-19 sequelae and summarize current diagnostic and therapeutic strategies (as of November 2021).Organbezogene Folgeerscheinungen nach COVID-19 sind häufig und vielgestaltig. Ab 4 Wochen nach Akutinfektion mit SARS-CoV‑2 werden sie unter dem Begriff „Long-COVID“ zusammengefasst.Nach schweren Akutverläufen treten organbezogene Folgeerscheinungen häufiger auf. Dauer und Intensität variieren jedoch interindividuell stark. Die SARS-CoV-2-Spezifität der Folgeerscheinungen ist ebenfalls weiter unklar. Während sich in der Frühphase nach schweren Verläufen zumeist pulmonale Folgeerscheinungen einstellen, müssen diese nicht auf die Lunge begrenzt bleiben, sondern können prinzipiell jedes Organ betreffen. Die adäquate Diagnostik von COVID-19-Folgeerscheinungen stellt daher eine interdisziplinäre Herausforderung dar. Auch die Therapie richtet sich nach Art, Umfang und Ursache der jeweiligen Folgeerscheinung. Allgemeinmedikamentöse oder zielgerichtete Therapieoptionen gegen Long-COVID bestehen bisher nicht.Im vorliegenden Übersichtsartikel berichten wir über Häufigkeit, Dauer, Spezifität sowie Art und Umfang organspezifischer COVID-19-Folgeerscheinungen und geben einen Überblick über diagnostisches und therapeutisches Vorgehen (mit Datenstand November 2021).

In a cross-sectional analysis, we have identified a high prevalence of respiratory muscle dysfunction in persistently symptomatic patients after COVID-19 (‘Long COVID’). Respiratory muscle impairment in these patients was associated with exercise-induced deoxygenation, impaired exercise tolerance, activity and functional outcomes after COVID-19.

Dysfunction of the pulmonary endothelium is associated with most lung diseases. Extracellular nucleotides modulate a plethora of endothelial functions in the lung such as vessel integrity, vasodilatation, inflammatory, and thrombotic responses as well as survival and DNA repair, mostly via Ca2+ signaling pathways. However, a comprehensive analysis of the molecular components of the underlying P2 receptor-mediated Ca2+ signaling pathways in the lung has not been conducted so far. Therefore, our aim was to identify the principal P2 receptor Ca2+ signalosome in the human pulmonary endothelium and investigate potential dysregulation in pulmonary vascular disease. Comparative transcriptomics and quantitative immunohistochemistry were performed on publicly available RNA sequencing and protein datasets to identify the specific expression profile of the P2-receptor Ca2+ signalosome in the healthy human pulmonary endothelium and endothelial cells (EC) dysfunctional due to loss of or defective bone morphogenetic protein receptor (BMPR2). Functional expression of signalosome components was tested by single cell Ca2+ imaging. Comparative transcriptome analysis of 11 endothelial cell subtypes revealed a specific P2 receptor Ca2+ signalosome signature for the pulmonary endothelium. Pulmonary endothelial expression of the most abundantly expressed Ca2+ toolkit genes CALM1, CALM2, VDAC1, and GNAS was confirmed by immunohistochemistry (IHC). P2RX1, P2RX4, P2RY6, and P2YR11 showed strong lung endothelial staining by IHC, P2X5, and P2Y1 were found to a much lesser extent. Very weak or no signals were detected for all other P2 receptors. Stimulation of human pulmonary artery (HPA) EC by purine nucleotides ATP, ADP, and AMP led to robust intracellular Ca2+ signals mediated through both P2X and P2Y receptors. Pyrimidine UTP and UDP-mediated Ca2+ signals were generated almost exclusively by activation of P2Y receptors. HPAEC made dysfunctional by siRNA-mediated BMPR2 depletion showed downregulation of 18 and upregulation of 19 P2 receptor Ca2+ signalosome genes including PLCD4, which was found to be upregulated in iPSC-EC from BMPR2-mutant patients with pulmonary arterial hypertension. In conclusion, the human pulmonary endothelium expresses a distinct functional subset of the P2 receptor Ca2+ signalosome. Composition of the P2 receptor Ca2+ toolkit in the pulmonary endothelium is susceptible to genetic disturbances likely contributing to an unfavorable pulmonary disease phenotype found in pulmonary arterial hypertension.

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.

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO

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

Background Low partial pressure of blood carbon dioxide (PaCO2) is common in patients with pulmonary arterial hypertension (PAH) and may inform on clinical outcomes. We investigated whether PaCO2 measurements could provide prognostic information in addition to standard risk assessment in this group of patients. Methods We conducted a retrospective observational cohort study on patients with newly diagnosed idiopathic, heritable or drug/toxin-induced PAH recruited from two European centres. Arterialised capillary blood gas analyses at diagnosis and follow-up were incorporated into standard risk assessment strategies and related to outcomes, defined as lung transplant or death. C statistics from receiver-operated characteristics and Cox regression models were used to assess the predictive value of models with and without PaCO2 measurements. Unsupervised clustering was applied to assess the relation of PaCO2 to haemodynamic and pulmonary function variables. Results Low PaCO2 measured at diagnosis and follow-up was significantly associated with inferior outcomes in 204 patients with PAH. PaCO2 provided prognostic information independent of established non-invasive variables. Integrating PaCO2 in risk strata improved C statistics of non-invasive and mixed invasive/non-invasive models, and revealed more accurate outcome estimates in regression models. Pairwise correlation and unsupervised cluster analyses supported a link between PaCO2 and haemodynamic variables, particularly with cardiac output, in PAH. Conclusions Measuring PaCO2 at diagnosis and during follow-up in patients with PAH provided independent prognostic information and has the potential to improve current risk assessment strategies.

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early-stage iron deficiency or iron deficiency anaemia. This study investigated whether elevated RDW is causally associated with PAH. A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively. We confirmed the observed association between RDW and PAH (OR 1.90, 95% CI 1.80–2.01) in a multicentre case–control study (cases n=642, disease controls n=15 889). The primary MR analysis was adequately powered to detect a causal effect (odds ratio) between 1.25 and 1.52 or greater based on estimates reported in the RDW genome-wide association study or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal 1.07, 95% CI 0.92–1.24) or the secondary (ORcausal 1.09, 95% CI 0.77–1.54) MR analysis. The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution, as any improvements observed may not be mechanistically linked to the development of PAH., Mendelian randomisation using genetic data from the largest-to-date PAH cohort does not support red cell distribution width or iron deficiency as a cause of PAH, which is important when interpreting iron replacement trials in this condition http://bit.ly/2PPaa88

Rationale: Idiopathic and heritable pulmonary arterial hypertension (PAH) are rare but comprise a genetically heterogeneous patient group. RNA sequencing linked to the underlying genetic architecture can be used to better understand the underlying pathology by identifying key signaling pathways and stratify patients more robustly according to clinical risk. Objectives: To use a three-stage design of RNA discovery, RNA validation and model construction, and model validation to define a set of PAH-associated RNAs and a single summarizing RNA model score. To define genes most likely to be involved in disease development, we performed Mendelian randomization (MR) analysis. Methods: RNA sequencing was performed on whole-blood samples from 359 patients with idiopathic, heritable, and drug-induced PAH and 72 age- and sex-matched healthy volunteers. The score was evaluated against disease severity markers including survival analysis using all-cause mortality from diagnosis. MR used known expression quantitative trait loci and summary statistics from a PAH genome-wide association study. Measurements and Main Results: We identified 507 genes with differential RNA expression in patients with PAH compared with control subjects. A model of 25 RNAs distinguished PAH with 87% accuracy (area under the curve 95% confidence interval: 0.791–0.945) in model validation. The RNA model score was associated with disease severity and long-term survival (P = 4.66 × 10−6) in PAH. MR detected an association between SMAD5 levels and PAH disease susceptibility (odds ratio, 0.317; 95% confidence interval, 0.129–0.776; P = 0.012). Conclusions: A whole-blood RNA signature of PAH, which includes RNAs relevant to disease pathogenesis, associates with disease severity and identifies patients with poor clinical outcomes. Genetic variants associated with lower SMAD5 expression may increase susceptibility to PAH.

Background: Right ventricular dysfunction is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to identify echocardiographic right heart parameters associated with adverse outcome and to develop a non-invasive, echocardiography-based risk score for PAH patients. Methods and Results: In 254 PAH patients we analyzed functional status, laboratory results, and echocardiographic parameters. We included these parameters to estimate all-cause death or lung transplantation using Cox regression models. The analyses included a conventional model using guideline-recommended variables and an extended echocardiographic model. Based on the final model a 12-point risk score was derived, indicating the association with the primary outcome within five years. During a median follow-up time of 4.2 years 74 patients died or underwent lung transplantation. The conventional model resulted in a C-Index of 0.539, whereas the extended echocardiographic model improved the discrimination (C-index 0.639, p-value 0.017). Ultimately, the newly developed risk score included WHO functional class, 6-min walking distance, N-terminal brain natriuretic peptide concentrations, pericardial effusion, right atrial area, tricuspid annular plane systolic excursion, and fractional area change. Conclusion: Integrating right heart function assessed by echocardiography improves prediction of death or lung transplantation in PAH patients. Independent validation of this finding is warranted.

In den vergangenen Jahren hat korperliches Training in der Behandlung von Patienten mit pulmonaler Hypertonie einen grundlegenden Kurswechsel erfahren. Die langjahrige Empfehlung zur Vermeidung von korperlichem Training konnte widerlegt werden. Mehr noch wurde durch eine Vielzahl von Studien gezeigt, dass in spezialisierten Zentren uberwachtes Training bei Patienten mit pulmonaler Hypertonie einen positiven Effekt sowohl auf die Lebensqualitat, die Belastbarkeit als auch auf hamodynamische Parameter ausubt. Neben der Uberwachung der klassischen Parameter wie pulmonaler Hamodynamik im Rechtsherzkatheter, rechtsventrikularer Adaptation in der Echokardiographie und korperlicher Leistungsfahigkeit in der Spiroergometrie konnten auch serologische Biomarker eine Quantifizierung des Trainingseffekts leisten. In Zukunft konnten zudem sog. „smart devices“ zur Fernuberwachung und Selbstkontrolle eine kontinuierliche Uberwachung des Trainings im ambulanten Bereich erreichen. Der aktuelle Stand der Wissenschaft wird im vorliegenden Ubersichtsartikel dargestellt und diskutiert.

Lymph node size affects lymph node retrieval in surgical specimen and is used as criterion for pre-operative radiological estimation of metastatic disease. However, factors determining lymph node size remain to be established. Therefore, the association between lymph node size and presence of metastatic cancer deposits as well as different primary tumor characteristics was analyzed in a prospective cross-sectional study. Visible and palpable nodes were harvested, and conventional histology, immunohistochemistry, and molecular analysis were performed. The study cohort comprised 148 patients (median age 69 years, range 36-92). Lymph node dissection rendered 4167 nodes. Mean lymph node count was 28 (median 26, range 9-67). Metastatic disease was detected in 320 (8%) nodes and was associated with lymph node size (P0.001). Positive nodes measuring ≤2 mm caused upstaging within the N category in one third of cases, but did not identify patients as node-positive as all patients also had positive larger nodes. Large tumor size (P=0.001), right tumor location (P0.001), and deep tumor penetration (P=0.024) were all independently associated with lymph node size, whereas high lymphocytic antitumor reaction just missed statistical significance (P=0.053) in multivariable analysis. Microsatellite instability had no influence on lymph node size when analysis was restricted to right-sided tumors. In conclusion, analysis of small lymph nodes may lead to upstaging within the N category, but they do not identify a patient as node-positive and do therefore not influence clinical decision-making in the adjuvant setting. The majority of enlarged lymph nodes, including those measuring1 cm, are not involved by cancer. Different tumor characteristics, such as large primary tumor size, right tumor location, and deep tumor penetration are independently associated with lymph node size and need to be considered when interpreting enlarged nodes detected by radiological imaging.

Pulmonary arterial hypertension (PAH), at one time a largely overlooked disease, is now the subject of intense study in many academic and biotech groups. The availability of new treatments has increased awareness of the condition. This in turn has driven a change in the demographics of PAH, with an increase in the mean age at diagnosis. The diagnosis of PAH in more elderly patients has highlighted the need for careful phenotyping of patients and for further studies to understand how best to manage pulmonary hypertension associated with, for example, left heart disease. The breadth and depth of expertise focused on unravelling the molecular pathology of PAH has yielded novel insights, including the role of growth factors, inflammation and metabolic remodelling. The description of the genetic architecture of PAH is accelerating in parallel, with novel variants, such as those reported in potassium two-pore domain channel subfamily K member 3 (KCNK3), adding to the list of more established mutations in genes associated with bone morphogenetic protein receptor type 2 (BMPR2) signalling. These insights have supported a paradigm shift in treatment strategies away from simply addressing the imbalance of vasoactive mediators observed in PAH towards tackling more directly the structural remodelling of the pulmonary vasculature. Here, we summarize the changing clinical and molecular landscape of PAH. We highlight novel drug therapies that are in various stages of clinical development, targeting for example cell proliferation, metabolic, inflammatory/immune and BMPR2 dysfunction, and the challenges around developing these treatments. We argue that advances in the treatment of PAH will come through deep molecular phenotyping with the integration of clinical, genomic, transcriptomic, proteomic and metabolomic information in large populations of patients through international collaboration. This approach provides the best opportunity for identifying key signalling pathways, both as potential drug targets and as biomarkers for patient selection. The expectation is that together these will enable the prioritization of potential therapies in development and the evolution of personalized medicine for PAH.

Resumen Introduccion El tratamiento endoscopico de reduccion del volumen pulmonar mediante espirales (RVPE) es una opcion para determinados pacientes con enfisema grave. El estudio se llevo a cabo para determinar la incidencia de complicaciones hemorragicas tras el tratamiento de RVPE, identificar los factores de riesgo y debatir las opciones terapeuticas en los casos sin resolucion espontanea de la hemoptisis. Metodos Estudio observacional retrospectivo efectuado en el Departamento de Medicina Respiratoria del University Medical Center Hamburg-Eppendorf que incluyo a todos los pacientes sometidos a RVPE entre el 1 de abril del 2012 y el 30 de septiembre del 2015. Resultados Durante el periodo de estudio se practicaron 101 procedimientos de RVPE en 62 pacientes. Despues de la intervencion, se observo hemorragia temprana en un 65,3% de los casos. La probabilidad de presentar hemoptisis fue significativamente mayor en los pacientes que recibian acido acetilsalicilico (p = 0,005). La hemoptisis se resolvio espontaneamente en un 98,5% de los casos. En el caso de un paciente (1,5%) que presento hemoptisis persistente, se logro el cese de la hemorragia embolizando la arteria bronquial. La estancia hospitalaria fue significativamente mas prolongada en los pacientes que presentaron hemoptisis (p = 0,01). En cuanto a las exacerbaciones de la enfermedad pulmonar obstructiva cronica, en las 4 semanas siguientes al procedimiento de RVPE no se observaron diferencias significativas entre los pacientes con y sin hemoptisis (p = 0,18). Tres pacientes (3,0%) presentaron complicaciones hemorragicas tardias. Dos de estos se sometieron a embolizacion de la arteria bronquial que puso fin a la hemorragia de manera satisfactoria. Conclusiones La hemorragia de poco volumen y autolimitada es un hallazgo frecuente en los primeros dias despues del tratamiento de RVPE. Sin embargo, tanto en los dias siguientes a la intervencion de RVPE como mas adelante tambien puede aparecer una hemorragia persistente. En estos casos, la embolizacion de la arteria bronquial fue un abordaje viable y satisfactorio para lograr el cese del sangrado.

Introduction Endoscopic lung volume reduction coil (LVRC) treatment is an option for selected patients with severe emphysema. This study was conducted to determine the incidence of bleeding complications after LVRC treatment, to identify risk factors and to discuss treatment options in cases of hemoptysis which does not resolve spontaneously. Methods Retrospective observational study conducted in the Department of Respiratory Medicine at the University Medical Center Hamburg-Eppendorf in all subjects in whom LVRC treatment was performed between April 1, 2012 and September 30, 2015. Results During the study period, 101 LVRC procedures were performed in 62 subjects. Early post-procedural bleeding was encountered in 65.3% of cases. Hemoptysis was significantly more likely to occur in patients receiving acetylsalicylic acid (P=0.005). Hemoptysis resolved spontaneously in 98.5% of cases. In the one case (1.5%) with persistent hemoptysis, bronchial artery embolization was successful in terminating bleeding. Hospital stay was significantly prolonged in subjects with hemoptysis (P=0.01). No significant differences were found between subjects with or without hemoptysis in terms of chronic obstructive pulmonary disease exacerbations within four weeks after LVRC treatment (P=0.18). Late bleeding complications were observed in 3 subjects (3.0%). In 2 of these cases, bronchial artery embolization was performed successfully terminating the bleeding. Conclusions Self-limiting low volume bleeding is a common finding in the first days after LVRC treatment. However, persistent bleeding may occur in the early post-procedural phase and late after LVRC treatment. In these cases, bronchial artery embolization was a feasible and successful approach to terminating bleeding.

Recent genome-wide analyses of rare and common sequence variations have brought greater clarity to the genetic architecture of pulmonary arterial hypertension and implicated novel genes in disease development. Transcriptional signatures have been reported in whole lung tissue, pulmonary vascular cells and peripheral circulating cells. High-throughput platforms for plasma proteomics and metabolomics have identified novel biomarkers associated with clinical outcomes and provided molecular instruments for risk assessment. There are methodological challenges to integrating these datasets, coupled to statistical power limitations inherent to the study of a rare disease, but the expectation is that this approach will reveal novel druggable targets and biomarkers that will open the way to personalized medicine. Here, we review the current state-of-the-art and future promise of 'omics' in the field of translational medicine in pulmonary arterial hypertension. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

Background: Endoscopic lung volume reduction coil (LVRC) treatment is an option for selected patients with severe emphysema. In the advanced stages, emphysema leads to respiratory failure: hypoxemia and eventually chronic hypercapnic respiratory failure. It can be hypothesized that LVRC treatment, a procedure targeting hyperinflation and thereby reducing ventilatory workload, may be especially beneficial in patients with chronic hypercapnic respiratory failure. This study was conducted to gain first insights into the effects and the safety of LVRC treatment in patients with emphysema and chronic hypercapnic respiratory failure. Methods: A retrospective observational study conducted in the Department of Respiratory Medicine at the University Medical Center Hamburg-Eppendorf, Germany on all patients with chronic hypercapnic respiratory failure in whom bilateral LVRC treatment was performed between 1 April 2012 and 30 September 2015. Results: During the study period, bilateral LVRC treatment was performed in 10 patients with chronic hypercapnic respiratory failure. Compared with baseline, bilateral LVRC treatment led to a significant increase in mean forced expiratory volume in one second (FEV1) from 0.5 ± 0.1 l to 0.6 ± 0.2 l ( p = 0.004), a decrease in residual volume (RV) from 6.1 ± 0.9 l to 5.6 ± 1.1 l ( p = 0.02) and a reduction in partial pressure of carbon dioxide in arterial blood (PaCO2) from 53 ± 5 mmHg to 48 ± 4 mmHg ( p = 0.03). One case of hemoptysis requiring readmission to hospital was the only severe adverse event. Conclusions: LVRC treatment was safe and effective in patients with nonsevere chronic hypercapnic respiratory failure. It led not only to an improvement in lung function but also to a significant decrease in PaCO2.

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension (PH) are also valid for Germany. While the guidelines contain detailed recommendations regarding clinical aspects of pulmonary arterial hypertension (PAH) and other forms of PH, they contain only a relatively short paragraph on novel findings on the pathobiology, pathology, and genetics. However, these are of great importance for our understanding of this complex disease both from a clinical and scientific point of view, and they are essential for the development of novel treatment strategies. To this end, a number of current data are relevant, prompting a detailed commentary to the guidelines, and the consideration of new scientific data. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the pathobiology, pathology and genetics of PH. This article summarizes the results and recommendations of this working group.

Tumor grade is a traditional prognostic parameter in colorectal cancer. Remarkably, however, there is still no generally accepted consensus how to perform tumor grading. In this study, we systematically compared the prognostic value of traditional grading based upon histological features, that is, gland formation alone with grading based upon both histological and cytological features, such as nuclear pleomorphism and anaplasia (“alternative grade”). Three hundred eighty-one tumors of randomly selected patients were retrospectively reviewed. Traditional and alternative tumor grades were related to various clinicopathological features and to progression-free and cancer-specific survival applying both univariate and multivariate testing. Traditional and alternative tumor grades were significantly associated with T and N classification, tumor size, lymphovascular invasion, as well as both progression-free and cancer-specific survival. In Cox’s proportional hazards regression models, the alternative grade was superior to the traditional tumor grade and was significantly associated with progression-free survival (hazard ratio 1.57, 95 % confidence interval 1.04–2.35; p = 0.031), independent of patients’ age and gender, T and N classification, and lymphovascular invasion. Likewise, patients with tumors with high alternative grade were more likely to die of disease (hazard ratio 1.30, 95 % confidence interval 0.85–2.00), but this difference was not statistically significant (p = 0.22). Tumor grade based upon both histological and cytological features was superior to grade based upon histological features alone and proved to be an independent prognostic parameter. Thus, tumor grade based upon both histological and cytological features may help to improve prognostic stratification and may thereby affect clinical decision-making and patient management.

Background: Tumour budding is an adverse prognostic indicator in colorectal cancer (CRC). Marked overall peritumoural inflammation has been associated with favourable outcome and may lead to the presence of isolated cancer cells due to destruction of invading cancer cell islets. Methods: We assessed the prognostic significance of tumour budding and peritumoural inflammation in a cohort of 381 patients with CRC applying univariate and multivariate analyses. Results: Patients with high-grade budding and marked inflammation had a significantly better outcome compared with patients with high-grade budding and only mild inflammation. Outcome in these cases, however, was still worse compared with cases with low-grade budding, in which the extent of peritumoural inflammation had no further prognostic effect. Conclusions: Tumour budding proved to be a powerful prognostic variable in patients with CRC. Scattering of invading cancer cell islets by marked overall peritumoural inflammation seems to have a minor role.

Dysfunction of the pulmonary endothelium is associated with most lung diseases. Extracellular nucleotides modulate a plethora of endothelial functions in the lung such as vessel integrity, vasodilatation, inflammatory, and thrombotic responses as well as survival and DNA repair, mostly via Ca(2+) signaling pathways. However, a comprehensive analysis of the molecular components of the underlying P2 receptor-mediated Ca(2+) signaling pathways in the lung has not been conducted so far. Therefore, our aim was to identify the principal P2 receptor Ca(2+) signalosome in the human pulmonary endothelium and investigate potential dysregulation in pulmonary vascular disease. Comparative transcriptomics and quantitative immunohistochemistry were performed on publicly available RNA sequencing and protein datasets to identify the specific expression profile of the P2-receptor Ca(2+) signalosome in the healthy human pulmonary endothelium and endothelial cells (EC) dysfunctional due to loss of or defective bone morphogenetic protein receptor (BMPR2). Functional expression of signalosome components was tested by single cell Ca(2+) imaging. Comparative transcriptome analysis of 11 endothelial cell subtypes revealed a specific P2 receptor Ca(2+) signalosome signature for the pulmonary endothelium. Pulmonary endothelial expression of the most abundantly expressed Ca(2+) toolkit genes CALM1, CALM2, VDAC1, and GNAS was confirmed by immunohistochemistry (IHC). P2RX1, P2RX4, P2RY6, and P2YR11 showed strong lung endothelial staining by IHC, P2X5, and P2Y1 were found to a much lesser extent. Very weak or no signals were detected for all other P2 receptors. Stimulation of human pulmonary artery (HPA) EC by purine nucleotides ATP, ADP, and AMP led to robust intracellular Ca(2+) signals mediated through both P2X and P2Y receptors. Pyrimidine UTP and UDP-mediated Ca(2+) signals were generated almost exclusively by activation of P2Y receptors. HPAEC made dysfunctional by siRNA-mediated BMPR2 depletion showed downregulation of 18 and upregulation of 19 P2 receptor Ca(2+) signalosome genes including PLCD4, which was found to be upregulated in iPSC-EC from BMPR2-mutant patients with pulmonary arterial hypertension. In conclusion, the human pulmonary endothelium expresses a distinct functional subset of the P2 receptor Ca(2+) signalosome. Composition of the P2 receptor Ca(2+) toolkit in the pulmonary endothelium is susceptible to genetic disturbances likely contributing to an unfavorable pulmonary disease phenotype found in pulmonary arterial hypertension. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11302-019-09674-1) contains supplementary material, which is available to authorized users.

The European guidelines, which focus on clinical aspects of pulmonary hypertension (PH), provide only minimal information about the pathophysiological concepts of PH. Here, we review this topic in greater detail, focusing on specific aspects in the pathobiology, pathology and genetics, which include mechanisms of vascular inflammation, the role of transcription factors, ion channels/ion channel diseases, hypoxic pulmonary vasoconstriction, genetics/epigenetics, metabolic dysfunction, and the potential future role of histopathology of PH in the modern era of PH therapy. In addition to new insights in the pathobiology of this disease, this working group of the Cologne Consensus Conference also highlights novel concepts and potential new therapeutic targets to further improve the treatment options in PAH.

Aberrant lipoprotein metabolism has been implicated in experimental pulmonary hypertension, but the relevance to patients with pulmonary arterial hypertension (PAH) is inconclusive.To investigate the relationship between circulating lipoprotein subclasses and survival in patients with PAH.Using nuclear magnetic resonance spectroscopy, 105 discrete lipoproteins were measured in plasma samples from two cohorts of patients with idiopathic or heritable PAH. Data from 1124 plasma proteins were used to identify proteins linked to lipoprotein subclasses. The physical presence of proteins was confirmed in plasma lipoprotein subfractions separated by ultracentrifugation.Plasma levels of three lipoproteins from the small high-density lipoprotein (HDL) subclass, termed HDL-4, were inversely related to survival in both the discovery (n=127) and validation (n=77) cohorts, independent of exercise capacity, comorbidities, treatment, N-terminal probrain natriuretic peptide, C reactive protein and the principal lipoprotein classes. The small HDL subclass rich in apolipoprotein A-2 content (HDL-4-Apo A-2) exhibited the most significant association with survival. None of the other lipoprotein classes, including principal lipoprotein classes HDL and low-density lipoprotein cholesterol, were prognostic. Three out of nine proteins identified to associate with HDL-4-Apo A-2 are involved in the regulation of fibrinolysis, namely, the plasmin regulator, alpha-2-antiplasmin, and two major components of the kallikrein-kinin pathway (coagulation factor XI and prekallikrein), and their physical presence in the HDL-4 subfraction was confirmed.Reduced plasma levels of small HDL particles transporting fibrinolytic proteins are associated with poor outcomes in patients with idiopathic and heritable PAH.

Background: Right ventricular (RV) dysfunction is a major prognostic predictor in pulmonary arterial hypertension (PAH). Objectives: The objective of this study was to assess the prognostic impact of a newly developed index merging haemodynamic parameters into 1 variable. Methods: We retrospectively assessed 2 cohorts of 248 patients (164 from Hamburg and 84 from Heidelberg) with invasively diagnosed PAH. During a median follow-up time of 3.6 years (3.1 and 4.0 years for Hamburg and Heidelberg, respectively), the composite endpoint of all-cause mortality and lung transplantation occurred in 57 patients (53 and 4 patients for Hamburg and Heidelberg, respectively). The RV index was developed in the Hamburg cohort and validated in the Heidelberg cohort: (right atrial pressure × pulmonary vascular resistance)/mixed venous oxygen saturation. Results: Patients with a high RV index had a higher incidence of the combined endpoint in Kaplan-Meier analyses in the Hamburg and Heidelberg cohort (p = 0.017 and p = 0.034, respectively). The calculated RV index cut-off value was 91 and identified patients with a worse outcome in the Hamburg cohort and showed a trend in the Heidelberg cohort (p < 0.001 and p = 0.089, respectively). The RV index in Cox regression hazard models was an independent predictor of outcomes after adjustment for sex and age in both cohorts (Hamburg: hazard ratio [HR] 1.26 [95% CI 1.08, 1.47], p = 0.0027; Heidelberg: HR 2.27 [95% CI 1.46, 3.51], p < 0.001). A nomogram based on these results allowed risk stratification. Conclusion: Merging 3 haemodynamic variables into 1 variable, the RV index increased the prognostic power up to an independent risk factor. The RV index is easy to calculate and allows the construction of a nomogram for an individualized risk assessment.

Die medikamentose Therapie der pulmonal arteriellen Hypertonie (PAH) hat in den vergangenen Jahren eine bemerkenswerte Entwicklung durchlaufen. Neben der „supportiven Therapie“, die Antikoagulation, Diuretika, Sauerstoff, Antiarrhythmika und ggf. Antidepressiva einschliest, ist die sog. gezielte medikamentose Therapie von groster Bedeutung. Hierfur liegt Evidenz aus groseren kontrollierten Studien vor. Die Therapie sollte sich in streng strukturierter Form an definierten Therapiezielen orientieren. Die regelmasige Beurteilung des Ansprechens und der Vertraglichkeit sind erforderlich. Werden die Therapieziele nicht erreicht, kommt einer Kombinationstherapie und der Lungentransplantation eine grose Bedeutung zu. Eine wachsende Anzahl an Substanzen ist fur die gezielte PAH-Therapie zugelassen und neu gewonnene Erkenntnisse verbessern den Einsatz von supportiven Therapien. Die gezielten Medikamente umfassen Kalziumkanalantagonisten (hochdosiert), Endothelinrezeptorantagonisten, Phosphodiesterase-5-Inhibitoren, Guanylatzyklasestimulatoren und Prostanoide. Sie bewirken eine Verbesserung der Symptomatik und Leistungsfahigkeit sowie eine Verzogerung des Eintritts einer klinischen Verschlechterung.

Die pulmonale Hypertonie (PH) gliedert sich nach der 5. Weltkonferenz in Nizza in funf Gruppen. Die pulmonal arterielle Hypertonie (PAH; Gruppe 1) umfasst neben der idiopathischen PAH genetisch und medikamentos bedingte Formen sowie die assoziierte PAH. Bewiesen oder ausgeschlossen werden kann die Diagnose einer PH nur durch die Rechtsherzkatheteruntersuchung. Ohne Diagnosestellung mittels Rechtsherzkatheters sollte keine gezielte Therapie begonnen werden. Neben allgemeinen und supportiven Masnahmen existieren aktuell vier Gruppen von Medikamenten, die fur die gezielte Behandlung der PAH zugelassen sind. Kombinationstherapien, entweder sequenziell oder initial („up-front“), gewinnen an Bedeutung in der Behandlung der PAH. Therapieziele zur Steuerung der Behandlung und Abschatzung des individuellen Patientenrisikos wurden definiert. Trotz aller Innovationen ist ein kurativer Therapieansatz bei der Behandlung der PAH noch in weiter Ferne. Daher stellt nach Ausschopfung der derzeit verfugbaren medikamentosen und supportiven Masnahmen die Lungentransplantation eine wichtige Therapieoption dar.