Epidemiologische Bedeutung von Hepcidin bei Patienten mit chronischer Nierenerkrankung

Patienten mit chronischer Nierenerkrankung weisen ein erhöhtes Risiko für kardiovaskuläre Erkrankungen auf. Hierbei tragen neben den typischen kardiovaskulären Risikofaktoren insbesondere auch nicht-klassische Risikofaktoren zur Entstehung und Progredienz von Herz- Kreislauferkrankungen bei. Zu diesen Risikofaktoren zählt auch die bei chronisch nierenkranken Menschen mit hoher Prävalenz auftretende Anämie. Rezente Studien beobachteten wiederholt bei mittel- bis hochgradiger chronischer Nierenerkrankung eine höhere Plasmakonzentration von Hepcidin, welches eine Kernrolle im Eisenstoffwechsel hat. Unklar ist allerdings, ob diese Hepcidin Hochregulation zur gehäuften Komorbidität von anämischen, chronisch nierenkranken Menschen beiträgt. Insbesondere wurde bislang in nicht ausreichend großen Kohorten chronisch nierenkranker Menschen untersucht, inwieweit erhöhtes Plasma Hepcidin Prädiktor für kardiovaskuläre Ereignisse ist. Wir überprüften in unserer prospektiven CARE FOR HOMe Studie, inwiefern (1) das Ausmaß der chronischen Nierenerkrankung mit einer fortgeschrittenen chronischen Inflammation und einer höheren Hepcidin Plasmakonzentration assoziiert ist; (2) eine erhöhte Hepcidin Plasmakonzentration mit einer manifesten Eisenmangelanämie assoziiert ist; (3) Hepcidin ein Prädiktor für atherosklerotische kardiovaskuläre Ereignisse ist. Über einen Zeitraum von insgesamt zehn Jahren wurden 599 Patienten mit einer chronischen Nierenerkrankung der Stadien G 2 – G 4 am Universitätsklinikum des Saarlandes in die prospektive CARE FOR HOMe Studie rekrutiert. Dabei erfolgte die Schätzung der glomerulären Filtrationsrate durch die MDRD-Formel. Bei 558 Patienten konnten die Hepcidin Plasmakonzentrationen aus den bei Studienbeginn asservierten Proben bestimmt werden. Im Nachbeobachtungszeitraum von 5,1 ± 2,1 Jahren wurden die Patienten jährlich im Hinblick auf das Auftreten von atherosklerotischen kardiovaskulären und renalen Ereignissen nachverfolgt. Erwartungsgemäß zeigte sich eine signifikante negative Korrelation zwischen der Hepcidin Plasmakonzentration und der glomerulären Filtrationsrate (r = - 0,127; p < 0,001). Allerdings konnte zwischen der Hämoglobinkonzentration und Plasma Hepcidin keine signifikante Korrelation nachgewiesen werden (r = -0,036; p = 0,213). Plasma Hepcidin war weder in univariaten, noch in multivariaten Analysen ein Prädiktor der vordefinierten atherosklerotischen kardiovaskulären und renalen Studienendpunkte. Zusammenfassend wurde in der CARE FOR HOMe Studie nachgewiesen, dass fortgeschrittene Stadien der chronischen Nierenerkrankung mit einer erhöhten Hepcidin Plasmakonzentration assoziiert sind. Entgegen unserer Erwartungen manifestiert sich eine erhöhte Hepcidin Plasmakonzentration allerdings offenbar nicht in einer Anämie. Weiterhin prädiziert Plasma Hepcidin in CARE FOR HOMe nicht das Auftreten von atherosklerotischen kardiovaskulären oder renalen Ereignissen. Nichtsdestotrotz könnte Hepcidin aufgrund seiner zentralen Rolle im Eisenstoffwechsel einen Angriffspunkt für die klinische Therapie der Anämie bei chronisch nierenkranken Patienten darstellen. Vor diesem Hintergrund werden Hepcidin-Antagonisten als potentiell nützliche Therapeutika diskutiert, um eine ausreichende Eisenverfügbarkeit für die im Rahmen der Anämie benötigte gesteigerte Erythropoese zu gewährleisten.Epidemiological significance of hepcidin in patients with chronic kidney disease Patient with chronic kidney disease exhibit an increased risk for cardiovascular diseases. In addition to classical cardiovascular risk factors, non-classical risk factors particularly contribute to the development and progression of cardiovascular diseases. Such non-classical risk factors in chronic kidney disease include a high prevalence of anaemia. Repetitively, recent studies of patients with moderate to severe chronic kidney disease observed high plasma hepcidin, which is a central regulation of iron metabolism. However, it is unclear in how far this hepcidin upregulation may contribute to the cumulative comorbidity of anaemic chronic kidney disease patients. Particularly no sufficiently large cohorts study has analysed if elevated plasma hepcidin predicts cardiovascular events in chronic kidney diseases patients. Therefore we analysed in our prospective CARE FOR HOMe study (1) if the severity of chronic kidney disease is associated with advanced chronic inflammation and higher hepcidin plasma concentrations; (2) if higher plasma hepcidin is associated with manifest iron deficiency anaemia; (3) if hepcidin is a predictor of atherosclerotic cardiovascular events. During a period of ten years, 599 patients with chronic kidney disease stages G 2 – G 4 were recruited into the prospective CARE FORE HOMe study at Saarland University Hospital. For estimating glomerular filtration rate (eGFR), the MDRD formula was applied. Plasma hepcidin could be determined in 558 patients from vials stored at study initiation. Patients have been followed for a mean of 5.1 ± 2.1 years for the occurrence of atherosclerotic cardiovascular event or CKD progression. As expected, plasma hepcidin and the eGFR are negatively correlated (r = - 0.127; p < 0.001). However there was no significant correlation between plasma hemoglobin and plasma hepcidin (r = - 0.036; p = 0.213). Plasma hepcidin predicted atherosclerotic cardiovascular events or CKD progression neither in univariate nor in multivariate analysis. In conclusion, the CARE FORE HOMe study proved that advanced staged of chronic kidney diseases are associated with increased plasma hepcidin. Contrarily to our expectations, plasma hepcidin does apparently not result in anaemia. Furthermore plasma hepcidin is not a predictor for atherosclerotic cardiovascular events or CKD progression in CARE FOR HOMe participants. Our data cannot exclude that hepcidin may nevertheless become a target for the clinical therapy of anaemia in patients with chronic kidney disease, because of its central role in iron metabolism. Against this background hepcidin antagonists are discussed as a novel treatment strategy to allow sufficient iron availability for compensatory erythropoiesis which is needed in anaemia

Evaluation of the prognostic value of electrocardiography parameters and heart rhythm in patients with pulmonary hypertension

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

Myeloproliferative Diseases as Possible Risk Factor for Development of Chronic Thromboembolic Pulmonary Hypertension—A Genetic Study

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

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a clinical consensus statement of the ESC working group on pulmonary circulation and right ventricular function.

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

Endothelial overexpression of TGF-β-induced protein impairs venous thrombus resolution

Endothelial cells play a critical role during venous thrombus remodeling, and unresolved, fibrotic thrombi with irregular vessels obstruct the pulmonary artery in patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study sought to identify endothelial mediators of impaired venous thrombus resolution and to determine their role in the pathogenesis of the vascular obstructions in patients with CTEPH. Endothelial cells outgrown from pulmonary endarterectomy specimens (PEA) were processed for mRNA profiling, and nCounter gene expression and immunohistochemistry analysis of PEA tissue microarrays and immunoassays of plasma were used to validate the expression in CTEPH. Lentiviral overexpression in human pulmonary artery endothelial cells (HPAECs) and exogenous administration of the recombinant protein into C57BL/6J mice after inferior Vena cava ligation were employed to assess their role for venous thrombus resolution. RT2 PCR profiler analysis demonstrated the significant overexpression of factors downstream of transforming growth factor beta (TGFβ), that is TGFβ-Induced Protein (TGFBI or BIGH3) and transgelin (TAGLN), or involved in TGFβ signaling, that is follistatin-like 3 (FSTL3) and stanniocalcin-2 (STC2). Gene expression and immunohistochemistry analysis of tissue microarrays localized potential disease candidates to vessel-rich regions. Lentiviral overexpression of TGFBI in HPAECs increased fibrotic remodeling of human blood clots in vitro, and exogenous administration of recombinant TGFBI in mice delayed venous thrombus resolution. Significantly elevated plasma TGFBI levels were observed in patients with CTEPH and decreased after PEA. Our findings suggest that overexpression of TGFBI in endothelial promotes venous thrombus non-resolution and fibrosis and is causally involved in the pathophysiology of CTEPH

3D Visualization, Skeletonization and Branching Analysis of Blood Vessels in Angiogenesis

Angiogenesis is the process of new blood vessels growing from existing vasculature. Visualizing them as a three-dimensional (3D) model is a challenging, yet relevant, task as it would be of great help to researchers, pathologists, and medical doctors. A branching analysis on the 3D model would further facilitate research and diagnostic purposes. In this paper, a pipeline of vision algorithms is elaborated to visualize and analyze blood vessels in 3D from formalin-fixed paraffin-embedded (FFPE) granulation tissue sections with two different staining methods. First, a U-net neural network is used to segment blood vessels from the tissues. Second, image registration is used to align the consecutive images. Coarse registration using an image-intensity optimization technique, followed by finetuning using a neural network based on Spatial Transformers, results in an excellent alignment of images. Lastly, the corresponding segmented masks depicting the blood vessels are aligned and interpolated using the results of the image registration, resulting in a visualized 3D model. Additionally, a skeletonization algorithm is used to analyze the branching characteristics of the 3D vascular model. In summary, computer vision and deep learning is used to reconstruct, visualize and analyze a 3D vascular model from a set of parallel tissue samples. Our technique opens innovative perspectives in the pathophysiological understanding of vascular morphogenesis under different pathophysiological conditions and its potential diagnostic role

Highlights from the International Chronic Thromboembolic Pulmonary Hypertension Congress 2021

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism. It is caused by persistent obstruction of pulmonary arteries by chronic organised fibrotic clots, despite adequate anticoagulation. The pulmonary hypertension is also caused by concomitant microvasculopathy which may progress without timely treatment. Timely and accurate diagnosis requires the combination of imaging and haemodynamic assessment. Optimal therapy should be individualised to each case and determined by an experienced multidisciplinary CTEPH team with the ability to offer all current treatment modalities. This report summarises current knowledge and presents key messages from the International CTEPH Conference, Bad Nauheim, Germany, 2021. Sessions were dedicated to 1) disease definition; 2) pathophysiology, including the impact of the hypertrophied bronchial circulation, right ventricle (dys)function, genetics and inflammation; 3) diagnosis, early after acute pulmonary embolism, using computed tomography and perfusion techniques, and supporting the selection of appropriate therapies; 4) surgical treatment, pulmonary endarterectomy for proximal and distal disease, and peri-operative management; 5) percutaneous approach or balloon pulmonary angioplasty, techniques and complications; and 6) medical treatment, including anticoagulation and pulmonary hypertension drugs, and in combination with interventional treatments. Chronic thromboembolic pulmonary disease without pulmonary hypertension is also discussed in terms of its diagnostic and therapeutic aspects. Thrombosis and Hemostasi

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension: consensus statement from the ISHLT

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

Eisen in Alumosilicatschmelzen

Das Redox- und das Diffusionsverhalten des polyvalenten Elementes Eisen wurde bei hohen Temperaturen (1000 - 1600 °C) in Schmelzen des Systems Na2O/MgO/CaO/Al2O3/SiO2 mit Hilfe der elektrochemischen Meßmethode Square-Wave Voltammetrie (SWV) untersucht. Die Viskositäten der Schmelzen wurden durch Rotationsviskosimetrie im Temperaturbereich zwischen 1450 - 1150 °C bestimmt. Über die Temperaturabhängigkeit konnten für den Fe3+/Fe2+-Redoxübergang die thermodynamischen Kenngrößen H0 und S0 ermittelt werden. Der Einfluss der Zusammensetzung wurde anhand der Variation des Al2O3-, des MgO- und des Na2O-Gehaltes sowie des [CaO]/[MgO]-Verhältnisses untersucht. Die erhaltenen Ergebnisse wurden bezogen auf ein Strukturmodell zum Einbau der Komponenten in der Schmelze diskutiert