Search

Stem cells are undifferentiated cells that are defined by their ability to both self-renew and to differentiate in order to produce mature progeny cells, including both non-renewing progenitors and terminally differentiated effector cells. Human mesenchymal stem cells can potentially be used in therapy in a variety of conditions on the basis of their demonstrated efficiency in animal models of human diseases, varying from Parkinson's disease to neoplasia. Given that ionizing radiation is a crucial and widespread diagnostic and therapeutic tool in oncology, it is important to investigate further the factors and mechanisms that underlie stem cell radiosensitivity. The study uses human mesenchymal stem cells, characterized using monoclonal antibodies and cultured in complex osteogenic medium after being irradiated at 0.5 Gy, 1 Gy, 2 Gy and 4 Gy using a 60Co source. Genetic alterations and DNA repair were evaluated using the Alkaline comet assay. Osteogenic differentiation was confirmed by histology stainings (Alizarin Red S, Alcian Blue and von Kossa) and cell proliferation assesed using the MTT based proliferation assay. Our research team challenges current knowledge by investigating the effects of ionizing radiation on stem cells in culture, focusing on the importance of DNA damage and stem cell kinetics in oncology and radiotherapy. [ABSTRACT FROM AUTHOR]

Background: Echocardiographic tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary arterial pressure (sPAP) ratio is a noninvasive surrogate for right ventricle (RV)-pulmonary arterial (PA) coupling. It has been related to outcome in patients with moderate to severe pulmonary hypertension (PH)., Research Question: Is RV-PA coupling of prognostic relevance in patients with suspected PH, but only normal or mildly elevated mean pulmonary arterial pressure (mPAP), and is it associated with impaired exercise capacity and exercise hemodynamics?., Study Design and Methods: Patients with mPAP of < 25 mm Hg who underwent echocardiography and exercise right heart catheterization in our PH clinic were analyzed retrospectively. Mild PH was defined as mPAP of 21 to 24 mm Hg and exercise PH (EPH) was defined as an mPAP to cardiac output (CO) slope of > 3 mm Hg/L/min. Multivariate analysis was performed to identify independent predictors for clinical worsening (CW), defined by disease-related hospitalization, transplantation, or death., Results: Two hundred thirty-seven patients (155 female with median age, 64 years [interquartile range (IQR), 54-73 years]; no PH: n = 147; mild PH: n = 90; EPH: n = 202) were included. During the observation time of 63 months (IQR, 29-104 months), 36 patients died and 126 CW events occurred. TAPSE to sPAP ratio was an age- and sex-independent predictor of mortality (hazard ratio [HR], 0.09; 95% CI, 0.01-0.62; P = .014) and CW (HR, 0.05; 95% CI, 0.35-0.78; P = .002). TAPSE to sPAP ratio also was correlated significantly to 6-minute walk distance (6MWD; r = 0.33; P < .001) and exercise hemodynamics (mPAP to CO slope: r ρ  = -0.56; P < .001). The best multivariate predictive model for CW in this population consisted of TAPSE to sPAP ratio (HR, 0.71; 95% CI, 0.53-0.95; P = .021), NT-proBNP (HR, 1.15; 95% CI, 0.99-1.34; P = .065), and 6MWD (HR, 0.998; 95% CI, 0.995-1.00; P = .042)., Interpretation: In patients with suspected PH, but normal or only mildly elevated resting mPAP, TAPSE to sPAP ratio is an independent predictor of outcome. In addition, it is associated significantly with exercise capacity and exercise hemodynamics and may be a helpful tool in the prediction of future CW of this patient population., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Pulmonary fibrosis (PF) can be a fatal disease characterized by progressive lung scarring. It is still poorly understood how the pulmonary endothelium is involved in the disease pathogenesis. Differences of the pulmonary vasculature between patients and donors were analyzed using transmission electron microscopy, immunohistochemistry, and single-cell RNA sequencing. Vascular barrier resistance, endothelial-immune cell adhesion, and sensitivity to an inflammatory milieu were studied in vitro . Integrity and activation markers were measured by ELISA in human plasma. Transmission electron microscopy demonstrated abnormally swollen endothelial cells (ECs) in fibrotic lungs compared with donors. A more intense CD31 and von Willebrand Factor (vWF) and patchy vascular endothelial (VE)-Cadherin staining in fibrotic lungs supported the presence of a dysregulated endothelium. Integrity markers CD31, VE-Cadherin, Thrombomodulin, and VEGFR-2 (vascular endothelial growth factor receptor-2) and activation marker vWF gene expression was increased in different endothelial subpopulations (e.g., arterial, venous, general capillary, aerocytes) in PF. This was associated with a heightened sensitivity of fibrotic ECs to TNF-α or IFN-γ and elevated immune cell adhesion. The barrier strength was overall reduced in ECs from fibrotic lungs. vWF and IL-8 were increased in the plasma of patients, whereas VE-Cadherin, Thrombomodulin, and VEGFR-2 were decreased. VE-Cadherin staining was also patchy in biopsy tissue and was decreased in plasma samples of patients with PF 6 months after the initial diagnosis. Our data demonstrate highly abnormal ECs in PF. The vascular compartment is characterized by hyperactivation and increased immune cell adhesion, as well as dysfunctional endothelial barrier function. Reestablishing EC homeostasis and function might represent a new therapeutic option for fibrotic lung diseases.

Purpose of Review: In this review, we provide an overview of the prognostic implications of exPH in patients with various common cardiac and pulmonary diseases., Recent Findings: Exercise pulmonary hypertension (exPH) has been recently re-introduced in the current European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. Accordingly, exPH is defined as a mean pulmonary arterial pressure (mPAP)/cardiac output ( CO ) slope greater than 3 mmHg/l/min. Key considerations for this re-introduction included increasing understanding on normal pulmonary hemodynamics during exercise and the broadly available evidence on the association of an abnormal mPAP/ CO slope with poor survival in the general population and in different disease entities., Summary: Exercise (patho-)physiology has opened a new field for clinical research facilitating recognition of cardiovascular and pulmonary vascular diseases in an early stage. Such early recognition with significant prognostic and possibly therapeutic relevance, but being undetectable at rest, makes exercise pulmonary hemodynamics particularly interesting for common diseases, such as valvular heart disease, left heart disease, and chronic pulmonary disease., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodeling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, whereas the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant decorin (DCN). Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs in patients with IPAH and PH-PF. We demonstrated that transforming growth factor-beta (TGF-β) regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes. NEW & NOTEWORTHY Idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries (PAs) displayed the greatest proteoglycan (PG) changes, with PH associated with pulmonary fibrosis (PH-PF) and PH associated with chronic obstructive pulmonary disease (PH-COPD) following. Agrin, an endothelial cell-specific PG, was solely upregulated in IPAH. Among all cells, neo-intima-forming smooth muscle cells (SMCs) displayed the most significant PG increase. Increased levels of circulating decorin, lumican, and versican, mainly derived from SMCs, and adventitial fibroblasts, may serve as systemic indicators of pulmonary remodeling, reflecting perivascular fibrosis and neointima formation.

Background: In patients with end-stage chronic obstructive pulmonary disease (COPD), severe pulmonary hypertension (PH) is frequently associated with less severe airway obstruction as compared to mild or no PH. However, the histologic correlate of this finding is not clear. We aimed to quantify remodeling of pulmonary arteries, airways, and parenchyma in random samples of explanted end-stage COPD lungs., Methods: We quantified remodeling of small pulmonary arteries, small airways, and the degree of emphysema (mean interseptal distance [MID]) with dedicated software. As primary objective, we compared COPD patients with severe PH (SevPH-COPD) with age- and sex-matched MildPH-COPD. For comparison, we also investigated COPD lungs with no PH (NoPH-COPD), idiopathic PAH (IPAH), and healthy donors., Results: We included n = 17 SevPH-COPD (mPAP = 43 [39-45]mm Hg), n = 17 MildPH-COPD (mPAP = 28 [24-31]mm Hg), n = 5 NoPH-COPD (mPAP = 18 [16-19]mm Hg), n = 10 IPAH (mPAP = 72 [65-91]mm Hg), and n = 10 healthy donor lungs. SevPH-COPD versus MildPH-COPD was characterized by better preserved forced vital capacity (51% vs 40% predicted, p < 0.05), less emphysema (MID 169 µm vs 279 µm, p < 0.001), and less PAS-positive and CD45-positive mucosa cells (15% vs 22%, p = 0.063% and 5% vs 7%, p = 0.058) suggesting less airway inflammation. In COPD patients, intimal and medial thickening were strongly correlated with mPAP (r = 0.676, p < 0.001 and r = 0.595, p < 0.001). MID was negatively correlated with mPAP (r = -0.556, p < 0.001) and was highest in NoPH-COPD (mean 281 µm), suggesting that emphysema per se is not associated with PH., Conclusions: End-stage COPD with severe PH is characterized by pronounced pulmonary vascular remodeling, less inflammation of small airways, and less emphysema as compared to COPD with mild PH or no PH, suggesting that COPD with severe PH may represent a unique phenotype of COPD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Extensive research has been dedicated to the solution-processable white organic light-emitting diodes (WOLEDs), which can potentially influence future solid-state lighting and full-color flat-panel displays. The proposed strategy based on WOLEDs involves blending two or more emitting polymers or copolymerizing two or more emitting chromophores with different doping concentrations to produce white light emission from a single layer. Toward this direction, the development of blends was conducted using commercial blue poly(9,9-di-n-octylfluorenyl2,7-diyl) (PFO), green poly(9,9-dioctylfluorenealt-benzothiadiazole) (F8BT), and red spiro-copolymer (SPR) light-emitting materials, whereas the synthesized copolymers were based on different chromophores, namely distyryllanthracene, distyrylcarbazole, and distyrylbenzothiadiazole, as yellow, blue, and orange-red emitters, respectively. A comparative study between the two approaches was carried out to examine the main challenge for these doping systems, which is ensuring the proper balance of emissions from all the units to span the entire visible range. The emission characteristics of fabricated WOLEDs will be explored in terms of controlling the emission from each emitter, which depends on two possible mechanisms: energy transfer and carrier trapping. The aim of this work is to achieve pure white emission through the color mixing from different emitters based on different doping concentrations, as well as color stability during the device operation. According to these aspects, the WOLED devices based on the copolymers of two chromophores exhibit the most encouraging results regarding white color emission coordinates (0.28, 0.31) with a CRI value of 82.

Deposition of basement membrane components, such as collagen IVα5, is associated with altered endothelial cell function in pulmonary hypertension. Collagen IVα5 harbors a functionally active fragment within its C-terminal noncollageneous (NC1) domain, called pentastatin, whose role in pulmonary endothelial cell behavior remains unknown. Here, we demonstrate that pentastatin serves as a mediator of pulmonary endothelial cell dysfunction, contributing to pulmonary hypertension. In vitro, treatment with pentastatin induced transcription of immediate early genes and proinflammatory cytokines and led to a functional loss of endothelial barrier integrity in pulmonary arterial endothelial cells. Mechanistically, pentastatin leads to β1-integrin subunit clustering and Rho/ROCK activation. Blockage of the β1-integrin subunit or the Rho/ROCK pathway partially attenuated the pentastatin-induced endothelial barrier disruption. Although pentastatin reduced the viability of endothelial cells, smooth muscle cell proliferation was induced. These effects on the pulmonary vascular cells were recapitulated ex vivo in the isolated-perfused lung model, where treatment with pentastatin-induced swelling of the endothelium accompanied by occasional endothelial cell apoptosis. This was reflected by increased vascular permeability and elevated pulmonary arterial pressure induced by pentastatin. This study identifies pentastatin as a mediator of endothelial cell dysfunction, which thus might contribute to the pathogenesis of pulmonary vascular disorders such as pulmonary hypertension. NEW & NOTEWORTHY This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the β1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.

The recently published new European guidelines for diagnosis and treatment of pulmonary hypertension now offer the so far most extensive description of genetic testing and counselling for pulmonary arterial hypertension patients. In addition, the importance of a clinical screening of healthy mutation carriers is highlighted as well as the genetic testing of patients with a suspicion of pulmonary veno-occlusive disease. We frame the respective parts of the guidelines on genetic testing and counselling in the context of recent data and provide comments. Finally, we give an outlook on novel molecular approaches starting from Sotatercept, addressing ion channels and novel therapeutic developments., Competing Interests: C.A.E. und K.H. sind Erfinderinnen des europäischen Patentens (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. CAE hat von MSD Vortragshonorare erhalten, unabhängig von dieser Arbeit.N.S. hat Berater- und Vortragstätigkeiten für MSD und Janssen.R.T.S. erhielt Forschungsförderung von Gossamer.S.S.P. erhielt Forschungsgelder und Honorare von Gossamer Bio, Inc.N.W. ist Besitzer des Patentes: L-NIL als Inhibitor zur Regeneration der Lunge von an COPD leidenden Patienten (EP2591777B1).L.H. erhielt Vortragshonorare von Janssen-Cilag und AOP Health sowie Forschungsmittel von MSD.C.T. erhielt finanzielle Förderung für Forschung von der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin e. V., Bayer HealthCare, Boehringer Ingelheim, und für Vorträge und Beratungstätigkeit von Actelion Pharmaceuticals, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, GlaxoSmithKline, und nicht-finanzielle Förderung von Actelion, ALK-Abelló, Bayer HealthCare, Boehringer Ingelheim und GlaxoSmithKline.M.W. erhielt Vortragshonorare von Janssen.V.F. erhielt Reisekosten und Vortragstätigkeiten von Boehringer Ingelheim, BMS, Chiesi, Janssen, MSD, alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.A.O. ist Erfinderin des Patentes (WO2017153472A1 priority date 09.03.2016, erteilt in US, KR, JP, pending in CA, EP, AU) “Biomarker for the diagnosis of pulmonary hypertension (PH)”, ohne daraus persönlichen Gewinn zu erhalten. A.O. hat Honorare für Präsentationen und Reiseförderung von MSD erhalten, unabhängig von dieser Arbeit.O.B., W.M.K., G.K. haben keinen Interessenkonflikt., (Thieme. All rights reserved.)

Lung diseases and hypoventilation syndromes are often associated with pulmonary hypertension (PH). In most cases, PH is not severe. This is defined hemodynamically by a mean pulmonary arterial pressure (PAPm) > 20 mmHg, a pulmonary arterial wedge pressure (PAWP) ≤ 15 mmHg and a pulmonary vascular resistance of ≤ 5 Wood units (WU). Both the non-severe (PVR ≤ 5 WU) and much more the severe PH (PVR > 5 WU) have an unfavorable prognosis.If PH is suspected, it is recommended to primarily check whether risk factors for pulmonary arterial hypertension (PAH, group 1 PH) or chronic thromboembolic pulmonary hypertension (CTEPH, group 4 PH) are present. If risk factors are present or there is a suspicion of severe PH in lung patients, it is recommended that the patient should be presented to a PH outpatient clinic promptly.For patients with severe PH associated with lung diseases, personalized, individual therapy is recommended - if possible within the framework of therapy studies. Currently, a therapy attempt with PH specific drugs should only be considered in COPD patients if the associated PH is severe and a "pulmonary vascular" phenotype (severe precapillary PH, but typically only mild to moderate airway obstruction, no or mild hypercapnia and DLCO < 45 % of predicted value) is present. In patients with severe PH associated with interstitial lung disease phosphodiesterase-5-inhibitors may be considered in individual cases. Inhaled treprostinil may be considered also in non-severe PH in this patient population., Competing Interests: M.H.: Honorare für Vortrags- und Beratertätigkeiten von AstraZeneca, Janssen und MSD. Reisekosten von Janssen. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.K.E.Z.: Reisekosten und Vortragstätigkeiten von Fa. MSD, Janssen und Ferrer. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.N.S.: Honorare für Berater- und Vortragstätigkeiten von MSD und Janssen. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.S.U.: Forschungsgelder vom Schweizerischen Nationalfond, der Lungenliga Schweiz, der Lunge Zürich, der Emdo Foundation, von Janssen SA, Orpha Swiss. Reisekosten und Vortragstätigkeiten von Janssen SA, Orpha Swiss, MSD und Novartis, alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.M.H.: Beratungshonorare: Actelion, Bayer Healthcare, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, MSD, Pfizer. Honorare für Vorträge von: Actelion, AstraZeneca, Bayer HealthCare, Berlin Chemie, Boehringer Ingelheim, Bristol Myers Squibb, Daichi Sankyo, Janssen, MSD, Pfizer, Santis.T.K.: Honorare für Vortragstätigkeiten und Reisekostenübernahme von AstraZeneca, Berlin Chemie, Janssen und MSD. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.V.F.: Honorare für Vortragstätigkeiten und Reisekostenübernahme von Boehringer Ingelheim, BMS, Chiesi, Janssen, MSD, alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.M.H.: keineC.N.: Honorare für Vortrags- und Beratertätigkeiten von AstraZeneca, Janssen und MSD. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.J.R.: keineS.H.: Zuwendungen von Janssen, Bayer und MSD, die in keinem Zusammenhang mit dieser Arbeit stehen.D.S.: Vortrags- und Beratungshonorare und/oder Forschungsunterstützung von AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, GSK, Janssen, MSD, Sanofi, DFG, BMBF. Alle nicht im Zusammenhang mit der aktuellen Übersichtsarbeit.N.K.: erhielt finanzielle Zuwendungen von Janssen, Ferrer, Bayer und MSD, die in keinem Zusammenhang mit dieser Arbeit stehen.J.B.: Honorare für Vorträge und Beratertätigkeit von AstraZeneca, Biogen, Boehringer-Ingelheim, BMS, Ferrer, Novartis, Roche, and Sanofi-Genzyme. Für Tätigkeiten im Rahmen von Data Monitoring and Safety Boards erhielt er Honorare von Actelion und Galapagos. Es besteht kein Zusammenhang mit der vorliegenden Publikation., (Thieme. All rights reserved.)

Objectives: Pathways contributing to endothelial dysfunction in patients with limited cutaneous systemic sclerosis (lcSSc) are largely unknown. The aim of this study was to investigate potential associations of amino acids and parameters of bone metabolism with endothelial dysfunction and vasculopathy-related changes in patients with lcSSc and early-stage vasculopathy., Methods: Amino acids, calciotropic parameters, including 25-hydroxyvitamin D and parathyroid hormone (PTH), and bone turnover parameters, including osteocalcin and N-terminal peptide of procollagen-3 (P3NP), were measured in 38 lcSSc patients and 38 controls. Endothelial dysfunction was assessed by biochemical parameters, pulse-wave analysis, flow-mediated and nitroglycerine-mediated dilation. Additionally, vasculopathy-related and SSc-specific clinical changes including capillaroscopic, skin, renal, pulmonary, gastrointestinal and periodontal parameters were recorded., Results: No significant differences in amino acids, calciotropic and bone turnover parameters were observed between lcSSc patients and controls. In patients with lcSSc, several significant correlations were found between selected amino acids, parameters of endothelial dysfunction, vasculopathy-related and SSc-specific clinical changes (all with p  < 0.05). In addition, significant correlations were observed between PTH and 25-hydroxyvitamin D with homoarginine, and between osteocalcin, PTH and P3NP with modified Rodnan skin score and selected periodontal parameters (all with p  < 0.05). Vitamin D deficiency defined as 25-hydroxyvitamin D < 20 ng/ml was associated with the presence of puffy finger ( p  = 0.046) and early pattern ( p  = 0.040)., Conclusion: Selected amino acids may affect endothelial function and may be associated to vasculopathy-related and clinical changes in lcSSc patients, while the association with parameters of bone metabolism seems to be minor., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jud, Meinitzer, Strohmaier, Arefnia, Wimmer, Obermayer-Pietsch, Foris, Kovacs, Odler, Moazedi-Fürst, Brodmann and Hafner.)

COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelial Hif-2 α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular "switch" between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidases via iron- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets., Competing Interests: Conflicts of interest: The authors have no conflicts of interest to disclose., (Copyright ©The authors 2023.)

Background: NT-proBNP and GDF-15 are established blood-derived biomarkers for risk assessment in pulmonary hypertension (PH), despite limited sensitivity and specificity. Apelin has a crucial function in endothelial homeostasis, thus it might represent a new biomarker for PH. However, there are numerous circulating apelin isoforms, and their potential role in this setting is unknown. This study evaluated different apelin isoforms in PH patients and prospectively evaluated the role of apelin-17 in comparison with NT-proBNP and GDF-15 as diagnostic marker in idiopathic pulmonary arterial hypertension (IPAH). Methods: Based on our pilot study, we performed a power calculation for apelin-13, apelin-17, apelin-36, as predictor of IPAH vs healthy controls. Apelin-17 provided the best discriminatory power, and accordingly, we enrolled n = 31 patients with IPAH and n = 31 matched healthy controls in a prospective study. NT-proBNP and GDF-15 was determined in all patients. ROC curve analysis was performed to assess the diagnostic value of the markers and their combinations. Results: Apelin-17, NT-proBNP, and GDF-15 were significantly elevated in IPAH patients as compared to controls ( p < .001). Apelin-17 detected IPAH with a sensitivity of 68% and a specificity of 93% at a cut-off value of >1,480 pg/ml (AUC 0.86, 95%CI:0.76-0.95) as compared to GDF-15 (sensitivity 86%; specificity 72%, AUC 0.81 (95%CI:0.7-0.92)) and NT-proBNP (sensitivity 86%; specificity 72% (AUC 0.85, 95%CI:0.75-0.95)). Combinations of these markers could be used to increase either specificity or sensitivity. Conclusion: Apelin-17 appears to be suitable blood derived diagnostic marker for idiopathic pulmonary arterial hypertension., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Foris, Kovacs, Avian, Bálint, Douschan, Ghanim, Klepetko, Olschewski and Olschewski.)

Background: Pulmonary hypertension (PH) is a frequent complication in COPD and it is associated with decreased exercise capacity and poor prognosis. We hypothesized that even in COPD patients without significant PH at rest, abnormal pulmonary hemodynamics during exercise affect exercise capacity., Methods: Consecutive COPD patients with clinically indicated right heart catheterization and resting mean pulmonary arterial pressure (mPAP) < 25 mmHg and age- and sex-matched controls with the same limits of pulmonary hemodynamics but no chronic lung disease who underwent clinical work-up including invasive hemodynamic assessment during exercise, were retrospectively analyzed. Chi-square tests were used to evaluate differences between groups for categorical data and Fisher's exact test or Mann-Whitney-U-tests for continuous variables. Associations were analyzed with Spearman rank correlation tests., Results: We included n = 26 COPD patients (female/male: 16/10, 66 ± 11 yr, FEV 1 : 56 ± 25%predicted) and n = 26 matched controls (FEV 1 : 96 ± 22%predicted). At rest, COPD patients presented with slightly increased mPAP (21 (18-23) vs. 17 (14-20) mmHg, p = 0.022), and pulmonary vascular resistance (PVR) [2.5 (1.9-3.0) vs. 1.9 (1.5-2.4) WU, p = 0.020] as compared to controls. During exercise, COPD patients reached significantly higher mPAP [47 (40-52) vs. 38 (32-44) mmHg, p = 0.015] and PVR [3.1 (2.2-3.7) vs. 1.7 (1.1-2.9) WU, p = 0.028] values despite lower peak exercise level [50 (50-75) vs. 100 (75-125) Watt, p = 0.002]. The mPAP/cardiac output slope was increased in COPD vs. controls [6.9 (5.5-10.9) vs. 3.7 (2.4-7.4) mmHg/L/min, p = 0.007] and negatively correlated with both peak oxygen uptake (r = - 0.46, p = 0.007) and 6-min walk distance (r = - 0.46, p = 0.001)., Conclusion: Even in the absence of significant PH at rest, COPD patients reveal characteristic abnormalities in pulmonary hemodynamics during exercise, which may represent an important exercise-limiting factor., (© 2022. The Author(s).)