Publications by authors named "Stefan Wagner"

235 Publications

Data-flow-based adaption of the System-Theoretic Process Analysis for Security (STPA-Sec).

PeerJ Comput Sci 2021 3;7:e362. Epub 2021 Feb 3.

School of Automotive Studies, Tongji University, Shanghai, China.

Security analysis is an essential activity in security engineering to identify potential system vulnerabilities and specify security requirements in the early design phases. Due to the increasing complexity of modern systems, traditional approaches lack the power to identify insecure incidents caused by complex interactions among physical systems, human and social entities. By contrast, the System-Theoretic Process Analysis for Security (STPA-Sec) approach views losses as resulting from interactions, focuses on controlling system vulnerabilities instead of external threats, and is applicable for complex socio-technical systems. However, the STPA-Sec pays less attention to the non-safety but information-security issues (e.g., data confidentiality) and lacks efficient guidance for identifying information security concepts. In this article, we propose a data-flow-based adaption of the STPA-Sec (named STPA-DFSec) to overcome the mentioned limitations and elicit security constraints systematically. We use the STPA-DFSec and STPA-Sec to analyze a vehicle digital key system and investigate the relationship and differences between both approaches, their applicability, and highlights. To conclude, the proposed approach can identify information-related problems more directly from the data processing aspect. As an adaption of the STPA-Sec, it can be used with other STPA-based approaches to co-design systems in multi-disciplines under the unified STPA framework.
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http://dx.doi.org/10.7717/peerj-cs.362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959614PMC
February 2021

A methodology for psycho-biological assessment of stress in software engineering.

PeerJ Comput Sci 2020 10;6:e286. Epub 2020 Aug 10.

Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany.

Stress pervades our everyday life to the point of being considered the scourge of the modern industrial world. The effects of stress on knowledge workers causes, in short term, performance fluctuations, decline of concentration, bad sensorimotor coordination, and an increased error rate, while long term exposure to stress leads to issues such as dissatisfaction, resignation, depression and general psychosomatic ailment and disease. Software developers are known to be stressed workers. Stress has been suggested to have detrimental effects on team morale and motivation, communication and cooperation-dependent work, software quality, maintainability, and requirements management. There is a need to effectively assess, monitor, and reduce stress for software developers. While there is substantial psycho-social and medical research on stress and its measurement, we notice that the transfer of these methods and practices to software engineering has not been fully made. For this reason, we engage in an interdisciplinary endeavor between researchers in software engineering and medical and social sciences towards a better understanding of stress effects while developing software. This article offers two main contributions. First, we provide an overview of supported theories of stress and the many ways to assess stress in individuals. Second, we propose a robust methodology to detect and measure stress in controlled experiments that is tailored to software engineering research. We also evaluate the methodology by implementing it on an experiment, which we first pilot and then replicate in its enhanced form, and report on the results with lessons learned. With this work, we hope to stimulate research on stress in software engineering and inspire future research that is backed up by supported theories and employs psychometrically validated measures.
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http://dx.doi.org/10.7717/peerj-cs.286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7924460PMC
August 2020

Large-area integration of two-dimensional materials and their heterostructures by wafer bonding.

Nat Commun 2021 Feb 10;12(1):917. Epub 2021 Feb 10.

Division of Micro and Nanosystems, School of Electrical Engineering and Computer Science, KTH Royal Institute of Technology, Stockholm, Sweden.

Integrating two-dimensional (2D) materials into semiconductor manufacturing lines is essential to exploit their material properties in a wide range of application areas. However, current approaches are not compatible with high-volume manufacturing on wafer level. Here, we report a generic methodology for large-area integration of 2D materials by adhesive wafer bonding. Our approach avoids manual handling and uses equipment, processes, and materials that are readily available in large-scale semiconductor manufacturing lines. We demonstrate the transfer of CVD graphene from copper foils (100-mm diameter) and molybdenum disulfide (MoS) from SiO/Si chips (centimeter-sized) to silicon wafers (100-mm diameter). Furthermore, we stack graphene with CVD hexagonal boron nitride and MoS layers to heterostructures, and fabricate encapsulated field-effect graphene devices, with high carrier mobilities of up to [Formula: see text]. Thus, our approach is suited for backend of the line integration of 2D materials on top of integrated circuits, with potential to accelerate progress in electronics, photonics, and sensing.
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http://dx.doi.org/10.1038/s41467-021-21136-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876008PMC
February 2021

Imaging temozolomide-induced changes in the myeloid glioma microenvironment.

Theranostics 2021 1;11(5):2020-2033. Epub 2021 Jan 1.

European Institute for Molecular Imaging - EIMI, University of Münster, Münster, Germany.

The heterogeneous nature of gliomas makes the development and application of novel treatments challenging. In particular, infiltrating myeloid cells play a role in tumor progression and therapy resistance. Hence, a detailed understanding of the dynamic interplay of tumor cells and immune cells is necessary. To investigate the complex interaction between tumor progression and therapy-induced changes in the myeloid immune component of the tumor microenvironment, we used a combination of [F]FET (amino acid metabolism) and [F]DPA-714 (TSPO, GAMMs, tumor cells, astrocytes, endothelial cells) PET/MRI together with immune-phenotyping. The aim of the study was to monitor temozolomide (TMZ) treatment response and therapy-induced changes in the inflammatory tumor microenvironment (TME). Eighteen NMRI mice orthotopically implanted with Gli36dEGFR cells underwent MRI and PET/CT scans before and after treatment with TMZ or DMSO (vehicle). Tumor-to-background (striatum) uptake ratios were calculated and areas of unique tracer uptake (FET vs. DPA) were determined using an atlas-based volumetric approach. TMZ therapy significantly modified the spatial distribution and uptake of both tracers. [F]FET uptake was significantly reduced after therapy (-53 ± 84%) accompanied by a significant decrease of tumor volume (-17 ± 6%). In contrast, a significant increase (61 ± 33%) of [F]DPA-714 uptake was detected by TSPO imaging in specific areas of the tumor. Immunohistochemistry (IHC) validated the reduction in tumor volumes and further revealed the presence of reactive TSPO-expressing glioma-associated microglia/macrophages (GAMMs) in the TME. We confirm the efficiency of [F]FET-PET for monitoring TMZ-treatment response and demonstrate that TSPO-PET performed with [F]DPA-714 can be used to identify specific reactive areas of myeloid cell infiltration in the TME.
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http://dx.doi.org/10.7150/thno.47269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797694PMC
January 2021

Synthesis and Pharmacological Evaluation of Fluorinated Quinoxaline-Based κ-Opioid Receptor (KOR) Agonists Designed for PET Studies.

ChemMedChem 2020 Oct 1;15(19):1834-1853. Epub 2020 Sep 1.

Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, 48149, Münster, Germany.

κ-Opioid receptors (KORs) play a predominant role in pain alleviation, itching skin diseases, depression and neurodegenerative disorders such as multiple sclerosis. Therefore, imaging of KOR by a fluorinated PET tracer was envisaged. Two strategies were followed to introduce a F atom into the very potent class of cis,trans-configured perhydroquinoxalines. Whereas the synthesis of fluoroethyltriazole 2 has already been reported, fluoropyrrolidines 14 (1-[2-(3,4-dichlorophenyl)acetyl]-8-[(R)-3-fluoropyrrolidin-1-yl]-perhydroquinoxalines) were prepared by S2 substitution of a cyclic sulfuric acid derivative with hydroxypyrrolidine and subsequent transformation of the OH moiety into a F substituent. Fluoropyrrolidines 14 showed similar low-nanomolar KOR affinity and selectivity to the corresponding pyrrolidines, but the corresponding alcohols were slightly less active. In the cAMP and β-arrestin assay, 14b (proton at the 4-position) exhibited similar KOR agonistic activity as U-50,488. The fluoro derivatives 14b and 14c (COCH at the 4-position) revealed KOR-mediated anti-inflammatory activity as CD11c and the IFN-γ production were reduced significantly in mouse and human dendritic cells. Compounds 14b and 14-c also displayed anti-inflammatory and immunomodulatory activity in mouse and human T cells. The PET tracer [F]-2 was prepared by 1,3-dipolar cycloaddition. In vivo, [F]-2 did not label KOR due to very fast elimination kinetics. Nucleophilic substitution of a mesylate precursor provided [F]-14c. Unfortunately, defluorination of [F]-14c occurred in vivo, which was analyzed in detail by in vitro studies.
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http://dx.doi.org/10.1002/cmdc.202000502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589326PMC
October 2020

Proteomic and functional mapping of cardiac NaV1.5 channel phosphorylation sites.

J Gen Physiol 2021 Feb;153(2)

Université de Nantes, Centre national de la recherche scientifique, Institut National de la Santé et de la Recherche Médicale, l'Institut du thorax, Nantes, France.

Phosphorylation of the voltage-gated Na+ (NaV) channel NaV1.5 regulates cardiac excitability, yet the phosphorylation sites regulating its function and the underlying mechanisms remain largely unknown. Using a systematic, quantitative phosphoproteomic approach, we analyzed NaV1.5 channel complexes purified from nonfailing and failing mouse left ventricles, and we identified 42 phosphorylation sites on NaV1.5. Most sites are clustered, and three of these clusters are highly phosphorylated. Analyses of phosphosilent and phosphomimetic NaV1.5 mutants revealed the roles of three phosphosites in regulating NaV1.5 channel expression and gating. The phosphorylated serines S664 and S667 regulate the voltage dependence of channel activation in a cumulative manner, whereas the nearby S671, the phosphorylation of which is increased in failing hearts, regulates cell surface NaV1.5 expression and peak Na+ current. No additional roles could be assigned to the other clusters of phosphosites. Taken together, our results demonstrate that ventricular NaV1.5 is highly phosphorylated and that the phosphorylation-dependent regulation of NaV1.5 channels is highly complex, site specific, and dynamic.
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http://dx.doi.org/10.1085/jgp.202012646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797897PMC
February 2021

Do fasting or high caloric drinks affect the physiological uptake of fluorine-18 prostate-specific membrane antigen-1007 in liver and bowel?

World J Nucl Med 2020 Jul-Sep;19(3):220-223. Epub 2019 Nov 7.

Department of Nuclear Medicine, University Hospital Münster, Münster, Germany.

Recently introduced fluorine-18 prostate-specific membrane antigen-1007 (F-PSMA-1007) for imaging prostate cancer has an intense physiologic liver uptake and biliary excretion. The aim of the present study was to evaluate the effect of different dietary conditions on this physiological uptake. Forty consecutive prostate cancer patients were scanned with F-PSMA-1007 positron emission tomography/computed tomography at different dietary conditions. In addition to a blinded read scoring, tracer uptake intensities (standardized uptake values [SUVs]) were measured in the liver and small bowel. There was no significant difference in liver and small-bowel uptake between different patient groups. Wilcoxon signed-rank tests revealed no significant difference of the median mean SUV of the liver or maximum SUV of the horizontal part of the duodenum between different dietary conditions groups. A dietary preparation of patients by fasting or the attempt to clear liver activity by high caloric drinks does not have a significant effect on tracer uptake in the liver or in the small bowel.
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http://dx.doi.org/10.4103/wjnm.WJNM_6_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745857PMC
November 2019

A novel mouse model of obstructive sleep apnea by bulking agent-induced tongue enlargement results in left ventricular contractile dysfunction.

PLoS One 2020 10;15(12):e0243844. Epub 2020 Dec 10.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Obstructive sleep apnea (OSA) is a widespread disease with high global socio-economic impact. However, detailed pathomechanisms are still unclear, partly because current animal models of OSA do not simulate spontaneous airway obstruction. We tested whether polytetrafluoroethylene (PTFE) injection into the tongue induces spontaneous obstructive apneas.

Methods And Results: PTFE (100 μl) was injected into the tongue of 31 male C57BL/6 mice and 28 mice were used as control. Spontaneous apneas and inspiratory flow limitations were recorded by whole-body plethysmography and mRNA expression of the hypoxia marker KDM6A was quantified by qPCR. Left ventricular function was assessed by echocardiography and ventricular CaMKII expression was measured by Western blotting. After PTFE injection, mice showed features of OSA such as significantly increased tongue diameters that were associated with significantly and sustained increased frequencies of inspiratory flow limitations and apneas. Decreased KDM6A mRNA levels indicated chronic hypoxemia. 8 weeks after surgery, PTFE-treated mice showed a significantly reduced left ventricular ejection fraction. Moreover, the severity of diastolic dysfunction (measured as E/e') correlated significantly with the frequency of apneas. Accordingly, CaMKII expression was significantly increased in PTFE mice and correlated significantly with the frequency of apneas.

Conclusions: We describe here the first mouse model of spontaneous inspiratory flow limitations, obstructive apneas, and hypoxia by tongue enlargement due to PTFE injection. These mice develop systolic and diastolic dysfunction and increased CaMKII expression. This mouse model offers great opportunities to investigate the effects of obstructive apneas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243844PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728202PMC
February 2021

Decreased GLUT1/NHE1 RNA expression in whole blood predicts disease severity in patients with COVID-19.

ESC Heart Fail 2021 02 20;8(1):309-316. Epub 2020 Nov 20.

Department of Internal Medicine II (Cardiology), University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, 93053, Germany.

Aims: We aimed to assess whether expression of whole-blood RNA of sodium proton exchanger 1 (NHE1) and glucose transporter 1 (GLUT1) is associated with COVID-19 infection and outcome in patients presenting to the emergency department with respiratory infections. Furthermore, we investigated NHE1 and GLUT1 expression in the myocardium of deceased COVID-19 patients.

Methods And Results: Whole-blood quantitative assessment of NHE1 and GLUT1 RNA was performed using quantitative PCR in patients with respiratory infection upon first contact in the emergency department and subsequently stratified by SARS-CoV-2 infection status. Assessment of NHE1 and GLUT1 RNA using PCR was also performed in left ventricular myocardium of deceased COVID-19 patients. NHE1 expression is up-regulated in whole blood of patients with COVID-19 compared with other respiratory infections at first medical contact in the emergency department (control: 0.0021 ± 0.0002, COVID-19: 0.0031 ± 0.0003, P = 0.01). The ratio of GLUT1 to NHE1 is significantly decreased in the blood of COVID-19 patients who are subsequently intubated and/or die (severe disease) compared with patients with moderate disease (moderate disease: 0.497 ± 0.083 vs. severe disease: 0.294 ± 0.0336, P = 0.036). This ratio is even further decreased in the myocardium of patients who deceased from COVID-19 in comparison with the myocardium of non-infected donors.

Conclusions: NHE1 and GLUT1 may be critically involved in the disease progression of SARS-CoV-2 infection. We show here that SARS-CoV-2 infection critically disturbs ion channel expression in the heart. A decreased ratio of GLUT1/NHE1 could potentially serve as a biomarker for disease severity in patients with COVID-19.
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http://dx.doi.org/10.1002/ehf2.13063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835506PMC
February 2021

Development of the First Potential Nonpeptidic Positron Emission Tomography Tracer for the Imaging of CCR2 Receptors.

ChemMedChem 2021 Feb 23;16(4):640-645. Epub 2020 Nov 23.

Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, 48149, Münster, Germany.

Herein we report the design and synthesis of a series of highly selective CCR2 antagonists as F-labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48 different targets. The most potent and selective candidate was applied in vivo in a biodistribution study, demonstrating a promising profile for further preclinical development. This compound represents the first potential nonpeptidic PET tracer for the imaging of CCR2 receptors.
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http://dx.doi.org/10.1002/cmdc.202000728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983900PMC
February 2021

Disease Phenotypes and Mechanisms of iPSC-Derived Cardiomyocytes From Brugada Syndrome Patients With a Loss-of-Function SCN5A Mutation.

Front Cell Dev Biol 2020 22;8:592893. Epub 2020 Oct 22.

Institute of Pharmacology and Toxicology, Technische Universität Dresden, Dresden, Germany.

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of density, a 69.5% reduction of Na1.5 expression, and the impaired localization of Na1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The in BrS-CMs was significantly augmented, and the window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.
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http://dx.doi.org/10.3389/fcell.2020.592893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642519PMC
October 2020

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker treatment and haemodynamic factors are associated with increased cardiac mRNA expression of angiotensin-converting enzyme 2 in patients with cardiovascular disease.

Eur J Heart Fail 2020 12 20;22(12):2248-2257. Epub 2020 Oct 20.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Coronavirus disease 2019 (COVID-19) is a widespread pandemic with an increased morbidity and mortality, especially for patients with cardiovascular diseases. Angiotensin-converting enzyme 2 (ACE2) has been identified as necessary cell entry point for SARS-CoV-2. Previous animal studies have demonstrated an increased ACE2 expression following treatment with either angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) that have led to a massive precariousness regarding the optimal cardiovascular therapy during this pandemic.

Methods And Results: We have measured ACE2 mRNA expression using real-time quantitative polymerase chain reaction in atrial biopsies of 81 patients undergoing coronary artery bypass grafting and we compared 62 patients that received ACEi/ARB vs. 19 patients that were not ACEi/ARB-treated. We found atrial ACE2 mRNA expression to be significantly increased in patients treated with an ACEi or an ARB, independent of potential confounding comorbidities. Interestingly, the cardiac ACE2 mRNA expression correlated significantly with the expression in white blood cells of 22 patients encouraging further evaluation if the latter may be used as a surrogate for the former. Similarly, analysis of 18 ventricular biopsies revealed a significant and independent increase in ACE2 mRNA expression in patients with end-stage heart failure that were treated with ACEi/ARB. On the other hand, cardiac unloading with a left ventricular assist device significantly reduced ventricular ACE2 mRNA expression.

Conclusion: Treatment with ACEi/ARB is independently associated with an increased myocardial ACE2 mRNA expression in patients with coronary artery disease and in patients with end-stage heart failure. Further trials are needed to test whether this association is deleterious for patients with COVID-19, or possibly protective. Nevertheless, haemodynamic factors seem to be equally important for regulation of cardiac ACE2 mRNA expression.
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http://dx.doi.org/10.1002/ejhf.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675329PMC
December 2020

Two-Dimensional Visualization and Quantification of Labile, Inorganic Plant Nutrients and Contaminants in Soil.

J Vis Exp 2020 09 1(163). Epub 2020 Sep 1.

Department General, Analytical and Physical Chemistry, Chair of General and Analytical Chemistry, Montanuniversität Leoben; Department of Crop Sciences, Institute of Agronomy, University of Natural Resources and Life Sciences, Vienna;

We describe a method for two-dimensional (2D) visualization and quantification of the distribution of labile (i.e., reversibly adsorbed) inorganic nutrient (e.g., P, Fe, Mn) and contaminant (e.g., As, Cd, Pb) solute species in the soil adjacent to plant roots (the 'rhizosphere') at sub-millimeter (~100 µm) spatial resolution. The method combines sink-based solute sampling by the diffusive gradients in thin films (DGT) technique with spatially resolved chemical analysis by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS). The DGT technique is based on thin hydrogels with homogeneously distributed analyte-selective binding phases. The variety of available binding phases allows for the preparation of different DGT gel types following simple gel fabrication procedures. For DGT gel deployment in the rhizosphere, plants are grown in flat, transparent growth containers (rhizotrons), which enable minimal invasive access to a soil-grown root system. After a pre-growth period, DGT gels are applied to selected regions of interest for in situ solute sampling in the rhizosphere. Afterwards, DGT gels are retrieved and prepared for subsequent chemical analysis of the bound solutes using LA-ICP-MS line-scan imaging. Application of internal normalization using C and external calibration using matrix-matched gel standards further allows for the quantification of the 2D solute fluxes. This method is unique in its capability to generate quantitative, sub-mm scale 2D images of multi-element solute fluxes in soil-plant environments, exceeding the achievable spatial resolution of other methods for measuring solute gradients in the rhizosphere substantially. We present the application and evaluation of the method for imaging multiple cationic and anionic solute species in the rhizosphere of terrestrial plants and highlight the possibility of combining this method with complementary solute imaging techniques.
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http://dx.doi.org/10.3791/61661DOI Listing
September 2020

Empagliflozin inhibits Na /H exchanger activity in human atrial cardiomyocytes.

ESC Heart Fail 2020 Sep 18. Epub 2020 Sep 18.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Aims: Recent clinical trials have proven gliflozins to be cardioprotective in diabetic and non-diabetic patients. However, the underlying mechanisms are incompletely understood. A potential inhibition of cardiac Na /H exchanger 1 (NHE1) has been suggested in animal models. We investigated the effect of empagliflozin on NHE1 activity in human atrial cardiomyocytes.

Methods And Results: Expression of NHE1 was assessed in human atrial and ventricular tissue via western blotting. NHE activity was measured as the maximal slope of pH recovery after NH pulse in isolated carboxy-seminaphtarhodafluor 1 (SNARF1)-acetoxymethylester-loaded murine ventricular and human atrial cardiomyocytes. NHE1 is abundantly expressed in human atrial and ventricular tissue. Interestingly, compared with patients without heart failure (HF), atrial NHE1 expression was significantly increased in patients with HF with preserved ejection fraction and atrial fibrillation. The largest increase in atrial and ventricular NHE1 expression, however, was observed in patients with end-stage HF undergoing heart transplantation. Importantly, acute exposure to empagliflozin (1 μmol/L, 10 min) significantly inhibited NHE activity to a similar extent in human atrial myocytes and mouse ventricular myocytes. This inhibition was also achieved by incubation with the well-described selective NHE inhibitor cariporide (10 μmol/L, 10 min).

Conclusions: This is the first study systematically analysing NHE1 expression in human atrial and ventricular myocardium of HF patients. We show that empagliflozin inhibits NHE in human cardiomyocytes. The extent of NHE inhibition was comparable with cariporide and may potentially contribute to the improved outcome of patients in clinical trials.
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http://dx.doi.org/10.1002/ehf2.13024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755005PMC
September 2020

CaMKIIδC Drives Early Adaptive Ca Change and Late Eccentric Cardiac Hypertrophy.

Circ Res 2020 Oct 21;127(9):1159-1178. Epub 2020 Aug 21.

Department of Pharmacology, University of California, Davis, CA (S.L.-H., A.W.H., S.M., B.M.W., J.B., D.M.B.).

Rationale: CaMKII (Ca-Calmodulin dependent protein kinase) δC activation is implicated in pathological progression of heart failure (HF) and CaMKIIδC transgenic mice rapidly develop HF and arrhythmias. However, little is known about early spatio-temporal Ca handling and CaMKII activation in hypertrophy and HF.

Objective: To measure time- and location-dependent activation of CaMKIIδC signaling in adult ventricular cardiomyocytes, during transaortic constriction (TAC) and in CaMKIIδC transgenic mice.

Methods And Results: We used human tissue from nonfailing and HF hearts, 4 mouse lines: wild-type, KO (CaMKIIδ-knockout), CaMKIIδC transgenic in wild-type (TG), or KO background, and wild-type mice exposed to TAC. Confocal imaging and biochemistry revealed disproportional CaMKIIδC activation and accumulation in nuclear and perinuclear versus cytosolic regions at 5 days post-TAC. This CaMKIIδ activation caused a compensatory increase in sarcoplasmic reticulum Ca content, Ca transient amplitude, and [Ca] decline rates, with reduced phospholamban expression, all of which were most prominent near and in the nucleus. These early adaptive effects in TAC were entirely mimicked in young CaMKIIδ TG mice (6-8 weeks) where no overt cardiac dysfunction was present. The (peri)nuclear CaMKII accumulation also correlated with enhanced HDAC4 (histone deacetylase) nuclear export, creating a microdomain for transcriptional regulation. At longer times both TAC and TG mice progressed to overt HF (at 45 days and 11-13 weeks, respectively), during which time the compensatory Ca transient effects reversed, but further increases in nuclear and time-averaged [Ca] and CaMKII activation occurred. CaMKIIδ TG mice lacking δB exhibited more severe HF, eccentric myocyte growth, and nuclear changes. Patient HF samples also showed greatly increased CaMKIIδ expression, especially for CaMKIIδC in nuclear fractions.

Conclusions: We conclude that in early TAC perinuclear CaMKIIδC activation promotes adaptive increases in myocyte Ca transients and nuclear transcriptional responses but that chronic progression of this nuclear Ca-CaMKIIδC axis contributes to eccentric hypertrophy and HF.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547876PMC
October 2020

Sub-millimeter distribution of labile trace element fluxes in the rhizosphere explains differential effects of soil liming on cadmium and zinc uptake in maize.

Sci Total Environ 2020 Oct 18;738:140311. Epub 2020 Jun 18.

Department General, Analytical and Physical Chemistry, Montanuniversität Leoben, Franz-Josef-Straße 18, A-8700 Leoben, Austria; University of Natural Resources and Life Sciences, Vienna, Department of Crop Sciences, Institute of Agronomy, Konrad-Lorenz-Straße 24, A-3430 Tulln, Austria.

Trace element concentrations in the rhizosphere were quantified to better understand why soil liming often fails to reduce cadmium (Cd) uptake by plants. Maize seedlings were grown on a soil with natural background levels of Cd and zinc (Zn). Soil liming increased soil pH from 4.9 to 6.5 and lowered the soil solution free ion activities by factor 7 (Cd) and 9 (Zn). In contrast, shoot Cd concentrations were unaffected by liming while shoot Zn concentrations were lowered by factor 1.9. Mapping of labile soil trace elements using diffusive gradients in thin films (DGT) in combination with laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) revealed an almost complete depletion of Cd in the rhizosphere in all soil treatments, showing that Cd uptake is controlled by diffusion. The flux of Cd from soil to the DGT, with direct contact between the soil and the binding gel, was unaffected by liming whereas it decreased by factor 3 for Zn, closely mimicking the contrasting effects of liming on Cd and Zn bioavailability. This evidence, combined with additional flux data of freshly spiked Cd and Zn isotopes in soil and with modelling, suggests that the diffusive transport of Cd in unsaturated soil is more strongly controlled by the labile adsorbed metal concentration than by its concentration in solution. This is less the case for Zn because of its inherently slower desorption compared to Cd.
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http://dx.doi.org/10.1016/j.scitotenv.2020.140311DOI Listing
October 2020

Central Sleep Apnea Predicts Pulmonary Complications After Cardiac Surgery.

Chest 2021 Feb 13;159(2):798-809. Epub 2020 Aug 13.

Department of Internal Medicine II (Cardiology, Pneumology, and Intensive Care), University Medical Center Regensburg, Regensburg, Germany.

Background: Postoperative major pulmonary complications (MPCs) continue to be leading causes of increased morbidity and death after cardiac surgery. Although various risk factors have been identified, reports on the association between sleep-disordered breathing (SDB) and postoperative MPCs remain inconclusive.

Research Question: What is the incidence of the composite end point postoperative MPCs? What are predictors for postoperative MPCs in patients without SDB, with OSA, and with central sleep apnea (CSA) who undergo cardiac surgery?

Study Design And Methods: In this subanalysis of the ongoing prospective observational study "Impact of Sleep-disordered breathing on Atrial Fibrillation and Perioperative complications in Patients undergoing Coronary Artery Bypass grafting Surgery (CONSIDER AF)," preoperative risk factors for postoperative MPCs were examined in 250 patients who underwent cardiac surgery. Postoperative MPCs (including respiratory failure, acute respiratory distress syndrome, pneumonia, or pulmonary embolism) were registered prospectively within the first seven postoperative days. Presence and type of SDB were assessed the night prior to surgery with the use of portable SDB-monitoring.

Results: Patients with SDB experienced significantly more often postoperative MPCs than patients without SDB (24% vs 7%; P < .001). Multivariable logistic regression analysis showed that CSA (OR, 4.68 [95% CI, 1.78-12.26]; P = .002), heart failure (OR, 2.65 [95% CI, 1.11-6.31]; P = .028), and a history of transient ischemic attack or stroke (OR, 2.73 [95% CI, 1.07-6.94]; P = .035) were associated significantly with postoperative MPCs. Compared with patients without MPCs, those with postoperative MPCs had a significantly longer hospital stay (median days, 9 [25th/75th percentile, 7/13] vs 19 [25th/75th percentile, 11/38]; P < .001).

Interpretation: Among established risk factors for postoperative MPCs, CSA, heart failure, and history of transient ischemic attack or stroke were associated significantly with postoperative MPCs. Our findings contribute to the identification of patients who are at high-risk for postoperative MPCs.

Clinical Trial Registration: ClinicalTrials.gov identifier NCT02877745.
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http://dx.doi.org/10.1016/j.chest.2020.07.080DOI Listing
February 2021

Nanoelectromechanical Sensors Based on Suspended 2D Materials.

Research (Wash D C) 2020 20;2020:8748602. Epub 2020 Jul 20.

Department of Precision and Microsystems Engineering, Delft University of Technology, Mekelweg 2, 2628 CD Delft, Netherlands.

The unique properties and atomic thickness of two-dimensional (2D) materials enable smaller and better nanoelectromechanical sensors with novel functionalities. During the last decade, many studies have successfully shown the feasibility of using suspended membranes of 2D materials in pressure sensors, microphones, accelerometers, and mass and gas sensors. In this review, we explain the different sensing concepts and give an overview of the relevant material properties, fabrication routes, and device operation principles. Finally, we discuss sensor readout and integration methods and provide comparisons against the state of the art to show both the challenges and promises of 2D material-based nanoelectromechanical sensing.
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http://dx.doi.org/10.34133/2020/8748602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388062PMC
July 2020

Nanoelectromechanical Sensors Based on Suspended 2D Materials.

Research (Wash D C) 2020 20;2020:8748602. Epub 2020 Jul 20.

Department of Precision and Microsystems Engineering, Delft University of Technology, Mekelweg 2, 2628 CD Delft, Netherlands.

The unique properties and atomic thickness of two-dimensional (2D) materials enable smaller and better nanoelectromechanical sensors with novel functionalities. During the last decade, many studies have successfully shown the feasibility of using suspended membranes of 2D materials in pressure sensors, microphones, accelerometers, and mass and gas sensors. In this review, we explain the different sensing concepts and give an overview of the relevant material properties, fabrication routes, and device operation principles. Finally, we discuss sensor readout and integration methods and provide comparisons against the state of the art to show both the challenges and promises of 2D material-based nanoelectromechanical sensing.
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http://dx.doi.org/10.34133/2020/8748602DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388062PMC
July 2020

The oral Ca/calmodulin-dependent kinase II inhibitor RA608 improves contractile function and prevents arrhythmias in heart failure.

ESC Heart Fail 2020 10 20;7(5):2871-2883. Epub 2020 Jul 20.

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, Regensburg, Germany.

Aims: Excessive activation of Ca/calmodulin-dependent kinase II (CaMKII) is of critical importance in heart failure (HF) and atrial fibrillation. Unfortunately, lack of selectivity, specificity, and bioavailability have slowed down development of inhibitors for clinical use. We investigated a novel CaMKIIδ/CaMKIIɣ-selective, ATP-competitive, orally available CaMKII inhibitor (RA608) on right atrial biopsies of 119 patients undergoing heart surgery. Furthermore, we evaluated its oral efficacy to prevent deterioration of HF in mice after transverse aortic constriction (TAC).

Methods And Results: In human atrial cardiomyocytes and trabeculae, respectively, RA608 significantly reduced sarcoplasmic reticulum Ca leak, reduced diastolic tension, and increased sarcoplasmic reticulum Ca content. Patch-clamp recordings confirmed the safety of RA608 in human cardiomyocytes. C57BL6/J mice were subjected to TAC, and left ventricular function was monitored by echocardiography. Two weeks after TAC, RA608 was administered by oral gavage for 7 days. Oral RA608 treatment prevented deterioration of ejection fraction. At 3 weeks after TAC, ejection fraction was 46.1 ± 3.7% (RA608) vs. 34.9 ± 2.6% (vehicle), n = 9 vs. n = 12, P < 0.05, ANOVA, which correlated with significantly less CaMKII autophosphorylation at threonine 287. Moreover, a single oral dose significantly reduced inducibility of atrial and ventricular arrhythmias in CaMKIIδ transgenic mice 4 h after administration. Atrial fibrillation was induced in 6/6 mice for vehicle vs. 1/7 for RA608, P < 0.05, 'n - 1' χ test. Ventricular tachycardia was induced in 6/7 for vehicle vs. 2/7 for RA608, P < 0.05, 'n - 1' χ test.

Conclusions: RA608 is the first orally administrable CaMKII inhibitor with potent efficacy in human myocytes. Moreover, oral administration potently inhibits arrhythmogenesis and attenuates HF development in mice in vivo.
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http://dx.doi.org/10.1002/ehf2.12895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524064PMC
October 2020

F-Labeled Small-Molecule and Low-Molecular-Weight PET Tracers for the Noninvasive Detection of Cancer.

Recent Results Cancer Res 2020 ;216:283-318

Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, 48149, Münster, Germany.

Noninvasive molecular imaging of cancer by means of the scintigraphic imaging modalities PET, PET/CT, and PET/MRI represents a powerful diagnostic tool in modern nuclear medicine. Radiotracers labeled with the prominent positron emitter fluorine-18 are routinely used to target and visualize discrete biological structures dysregulated in the progression of cancer. Such tracers are therefore capable of detecting oncological pathologies in vivo at the cellular and subcellular level in a timely manner and are thereby used for early detection of cancer as well as monitoring for treatment response. This chapter describes a variety of important F-labeled radiopharmaceuticals that are frequently used in oncological PET imaging. Small-molecule and low-molecular-weight radiotracers for the detection of glucose utilization, amino acid transport, protein synthesis, membrane lipid synthesis, cell proliferation, cell death, hypoxia, estrogen receptor status, prostate-specific membrane antigen (PSMA) expression, and bone mineralization of tumors are introduced. The structural properties, common radiochemical synthesis approaches as well as in vivo metabolism and accumulation mechanisms of the clinically most important F-labeled radiotracers are described.
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http://dx.doi.org/10.1007/978-3-030-42618-7_8DOI Listing
September 2020

Dysferlin links excitation-contraction coupling to structure and maintenance of the cardiac transverse-axial tubule system.

Europace 2020 07;22(7):1119-1131

Department of Child and Adolescent Health, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.

Aims: The multi-C2 domain protein dysferlin localizes to the T-Tubule system of skeletal and heart muscles. In skeletal muscle, dysferlin is known to play a role in membrane repair and in T-tubule biogenesis and maintenance. Dysferlin deficiency manifests as muscular dystrophy of proximal and distal muscles. Cardiomyopathies have been also reported, and some dysferlinopathy mouse models develop cardiac dysfunction under stress. Generally, the role and functional relevance of dysferlin in the heart is not clear. The aim of this study was to analyse the effect of dysferlin deficiency on the transverse-axial tubule system (TATS) structure and on Ca2+ homeostasis in the heart.

Methods And Results: We studied dysferlin localization in rat and mouse cardiomyocytes by immunofluorescence microscopy. In dysferlin-deficient ventricular mouse cardiomyocytes, we analysed the TATS by live staining and assessed Ca2+ handling by patch-clamp experiments and measurement of Ca2+ transients and Ca2+ sparks. We found increasing co-localization of dysferlin with the L-type Ca2+-channel during TATS development and show that dysferlin deficiency leads to pathological loss of transversal and increase in longitudinal elements (axialization). We detected reduced L-type Ca2+-current (ICa,L) in cardiomyocytes from dysferlin-deficient mice and increased frequency of spontaneous sarcoplasmic reticulum Ca2+ release events resulting in pro-arrhythmic contractions. Moreover, cardiomyocytes from dysferlin-deficient mice showed an impaired response to β-adrenergic receptor stimulation.

Conclusions: Dysferlin is required for TATS biogenesis and maintenance in the heart by controlling the ratio of transversal and axial membrane elements. Absence of dysferlin leads to defects in Ca2+ homeostasis which may contribute to contractile heart dysfunction in dysferlinopathy patients.
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http://dx.doi.org/10.1093/europace/euaa093DOI Listing
July 2020

NCX1 represents an ionic Na+ sensing mechanism in macrophages.

PLoS Biol 2020 06 22;18(6):e3000722. Epub 2020 Jun 22.

Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg and University of Regensburg, Regensburg, Germany.

Inflammation and infection can trigger local tissue Na+ accumulation. This Na+-rich environment boosts proinflammatory activation of monocyte/macrophage-like cells (MΦs) and their antimicrobial activity. Enhanced Na+-driven MΦ function requires the osmoprotective transcription factor nuclear factor of activated T cells 5 (NFAT5), which augments nitric oxide (NO) production and contributes to increased autophagy. However, the mechanism of Na+ sensing in MΦs remained unclear. High extracellular Na+ levels (high salt [HS]) trigger a substantial Na+ influx and Ca2+ loss. Here, we show that the Na+/Ca2+ exchanger 1 (NCX1, also known as solute carrier family 8 member A1 [SLC8A1]) plays a critical role in HS-triggered Na+ influx, concomitant Ca2+ efflux, and subsequent augmented NFAT5 accumulation. Moreover, interfering with NCX1 activity impairs HS-boosted inflammatory signaling, infection-triggered autolysosome formation, and subsequent antibacterial activity. Taken together, this demonstrates that NCX1 is able to sense Na+ and is required for amplifying inflammatory and antimicrobial MΦ responses upon HS exposure. Manipulating NCX1 offers a new strategy to regulate MΦ function.
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http://dx.doi.org/10.1371/journal.pbio.3000722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307728PMC
June 2020

Alterations of the renin angiotensin system in human end-stage heart failure before and after mechanical cardiac unloading by LVAD support.

Mol Cell Biochem 2020 Sep 20;472(1-2):79-94. Epub 2020 Jun 20.

Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany.

Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the β-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, β-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, β-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and β-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and β-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.
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http://dx.doi.org/10.1007/s11010-020-03787-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431447PMC
September 2020

Contribution of the neuronal sodium channel Na1.8 to sodium- and calcium-dependent cellular proarrhythmia.

J Mol Cell Cardiol 2020 07 11;144:35-46. Epub 2020 May 11.

Department of Cardiology and Pneumology, University Hospital, Georg-August University Göttingen, and DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany; Department of Internal Medicine II, University Medical Center Regensburg, Regensburg, Germany. Electronic address:

Objective: In myocardial pathology such as heart failure a late sodium current (I) augmentation is known to be involved in conditions of arrhythmogenesis. However, the underlying mechanisms of the I generation are not entirely understood. By now evidence is growing that non-cardiac sodium channel isoforms could also be involved in the I generation. The present study investigates the contribution of the neuronal sodium channel isoform Na1.8 to arrhythmogenesis in a clearly-defined setting of enhanced I by using anemone toxin II (ATX-II) in the absence of structural heart disease.

Methods: Electrophysiological experiments were performed in order to measure I, action potential duration (APD), SR-Ca-leak and cellular proarrhythmic triggers in ATX-II exposed wild-type (WT) and SCN10A mice cardiomyocytes. In addition, WT cardiomyocytes were stimulated with ATX-II in the presence or absence of Na1.8 inhibitors. I was measured by using the whole cell patch clamp method.

Results: In WT cardiomyocytes exposure to ATX-II augmented I prolonged APD, increased SR-Ca-leak and induced proarrhythmic triggers such as early afterdepolarizations (EADs) and Ca-waves. All of them could be significantly reduced by applying Na1.8 blockers PF-01247324 and A-803467. Both blockers had no relevant effects on cellular electrophysiology of SCN10A cardiomyocytes. Moreover, in SCN10A-cardiomyocytes, the ATX-II-dependent increase in I, SR-Ca-leak and APD prolongation was less than in WT and comparable to the results which were obtained with WT cardiomyocytes being exposed to ATX-II and Na1.8 inhibitors in parallel. Moreover, we found a decrease in reverse mode NCX current and reduced CaMKII-dependent RyR2-phosphorylation after application of PF-01247324 as an underlying explanation for the Na-mediated Ca-dependent proarrhythmic triggers.

Conclusion: The current findings demonstrate that Na1.8 is a significant contributor for I-induced arrhythmic triggers. Therefore, Na1.8 inhibition under conditions of an enhanced I constitutes a promising antiarrhythmic strategy which merits further investigation.
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http://dx.doi.org/10.1016/j.yjmcc.2020.05.002DOI Listing
July 2020

Dantrolene reduces CaMKIIδC-mediated atrial arrhythmias.

Europace 2020 07;22(7):1111-1118

Department of Internal Medicine II, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg, Germany.

Aims: In atrial fibrillation (AF), an increased diastolic Ca2+ leak from the sarcoplasmic reticulum (SR) mediated by calcium/calmodulin-dependent-protein-kinaseIIδC (CaMKII) can serve as a substrate for arrhythmia induction and persistence. Dantrolene has been shown to stabilize the cardiac ryanodine-receptor. This study investigated the effects of dantrolene on arrhythmogenesis in human and mouse atria with enhanced CaMKII activity.

Methods And Results: Human atrial cardiomyocytes (CMs) were isolated from patients with AF. To investigate CaMKII-mediated arrhythmogenesis, atrial CMs from mice overexpressing CaMKIIδC (TG) and the respective wildtype (WT) were studied using confocal microscopy (Fluo-4), patch-clamp technique, and in vivo atrial catheter-based burst stimulations. Dantrolene potently reduced Ca2+ spark frequency (CaSpF) and diastolic SR Ca2+ leak in AF CMs. Additional CaMKII inhibition did not further reduce CaSpF or leak compared to dantrolene alone. While the increased SR CaSpF and leak in TG mice were reduced by dantrolene, no effects could be detected in WT. Dantrolene also potently reduced the pathologically enhanced frequency of diastolic SR Ca2+ waves in TG without having effects in WT. As an increased diastolic SR Ca2+ release can induce a depolarizing transient inward current, we could demonstrate that the incidence of afterdepolarizations in TG, but not in WT, mice was significantly diminished in the presence of dantrolene. To translate these findings into an in vivo situation we could show that dantrolene strongly suppressed the inducibility of AF in vivo in TG mice.

Conclusion: Dantrolene reduces CaMKII-mediated atrial arrhythmogenesis and may therefore constitute an interesting antiarrhythmic drug for treating patients with atrial arrhythmias driven by an enhanced CaMKII activity, such as AF.
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http://dx.doi.org/10.1093/europace/euaa079DOI Listing
July 2020

Cooperation Between Hypoxia-Inducible Factor 1α and Activating Transcription Factor 4 in Sleep Apnea-Mediated Myocardial Injury.

Can J Cardiol 2020 06 13;36(6):936-940. Epub 2020 Apr 13.

Laboratoire HP2, Institut National de la Santé et de la Recherche Médicale, Université Grenoble Alpes, Grenoble, France; Institut National de la Santé et de la Recherche Médicale U1042, Grenoble, France. Electronic address:

Chronic intermittent hypoxia (CIH) occurring during sleep apnea amplifies infarct size owing to ischemia-reperfusion. CIH activates hypoxia-inducible factor 1 (HIF-1) and activating transcription factor 4 (ATF4). However, whether HIF-1 and ATF4 interact to promote cardiomyocyte death remains unexplored. For the first time, we observed that in myocardium from apneic patients, CCAAT enhancer-binding protein homologous protein (CHOP) expression is increased and HIF-1α expression is correlated with sleep apnea severity. In mice, single-allele deletion of HIF-1α prevents CIH increase in CHOP expression and infarct size. We uncovered a physical interaction between HIF-1α and ATF4 in CIH that may represent a novel cardiomyocyte death complex.
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http://dx.doi.org/10.1016/j.cjca.2020.04.002DOI Listing
June 2020

Optimizing the Biodistribution of Radiofluorinated Barbiturate Tracers for Matrix Metalloproteinase Imaging by Introduction of Fluorescent Dyes as Pharmacokinetic Modulators.

Bioconjug Chem 2020 04 30;31(4):1117-1132. Epub 2020 Mar 30.

Department of Nuclear Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1, Building A1, D-48149 Münster, Germany.

Dysregulated expression or activation of matrix metalloproteinases (MMPs) is observed in many kinds of life-threatening diseases. Therefore, MMP imaging-for example, with radiolabeled MMP inhibitors (MMPIs)-potentially represents a valuable tool for clinical diagnostics using noninvasive single photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Despite numerous preclinical imaging approaches, translation to a clinical setting has not yet been successful. We introduce and oppose three potential radiofluorinated MMP-targeted imaging probes, modified by the introduction of pentamethine cyanine (Cy5) dyes and therefore containing both radio- as well as fluorescent label with respect to their capability to assess MMP activity by means of scintigraphic (PET) and/or fluorescent (NIRF) imaging. New hybrid MMPI tracer candidates, structurally based on radiofluorinated pyrimidine-2,4,6-triones (barbiturates) from previous approaches, were synthesized by convenient two-step syntheses. In the first step, Cy5 dyes, varying in the number of sulfonate groups ( = 1, 2, or 4) and bearing an additional "clickable" alkyne moiety, were coupled to the barbiturate MMPI by amide formation. In the second step, the [F]fluoride radiolabel was introduced into the resulting Cy5 dye conjugates by "radio-click" chemistry. Biodistribution studies of these hybrid tracer candidates were assessed and compared in C57BL/6 mice by PET as well as fluorescence imaging. MMP activity was imaged in a MMP-positive mouse model of irritant contact dermatitis (ICD) by PET and sequential fluorescence reflectance imaging (FRI), respectively. data were validated by scintillation counting, gelatin zymography, and MMP-histology. Three new potential hybrid MMP imaging probes were prepared, differing essentially in the number of sulfonate groups, introduced by Cy5 dye components. Although the hydrophilicity of these compounds was substantially increased, ( = 1) and ( = 2) were still rapidly eliminated via unfavorable hepatobiliary pathways, as observed in earlier approaches. Only ( = 4) showed delayed clearance and a shift towards higher renal elimination. In the chosen mouse model of ICD, only ( = 4) significantly accumulated in the inflamed mouse ear, which could be precisely visualized by means of PET and FRI.
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http://dx.doi.org/10.1021/acs.bioconjchem.9b00817DOI Listing
April 2020

Reduced store-operated Ca entry impairs mesenteric artery function in response to high external glucose in type 2 diabetic ZDF rats.

Clin Exp Pharmacol Physiol 2020 07 30;47(7):1145-1157. Epub 2020 Mar 30.

Abteilung für Kardiologie, Klinik und Poliklinik für Innere Medizin II, Universitäres Herzzentrum Regensburg, Universitätsklinikum Regensburg, Regensburg, Germany.

Diabetes is a major risk factor for cardiovascular disease, affecting both endothelial and smooth muscle cells. Store-operated Ca channels (SOCCs) have been implicated in many diabetic complications. Vascular dysfunction is common in patients with diabetes, but the role of SOCCs in diabetic vasculopathy is still unclear. Our research aimed to investigate the effects of high glucose (HG) on store-operated Ca entry (SOCE) in small arteries. Small mesenteric arteries from type 2 diabetic Zucker fatty rats (ZDF) versus their non-diabetic controls (Zucker lean, ZL) were examined in a pressurized myograph. Vascular smooth muscle cells (VSMC) were isolated and intracellular Ca was measured (Fura 2-AM). A specific protocol to deplete intracellular Ca stores and thereby open SOCCs, as well as pharmacological SOCE inhibitors (SKF-96365, BTP-2), were used to artificially activate and inhibit SOCE, respectively. High glucose (40 mmol/L) relaxed arteries in a SKF-sensitive manner. Diabetic arteries exhibited reduced HG-induced relaxation, as well as reduced contraction after Ca replenishment. Further, the rise in intracellular Ca on account of SOCE is diminished in diabetic versus non-diabetic VSMCs and was insensitive to HG in diabetic VSMCs. The expression of SOCC proteins was measured, detecting a downregulation of Orai1 in diabetes. In conclusion, diabetes leads to a reduction of SOCE and SOCE-induced contraction, which is unresponsive to HG-mediated inhibition. The reduced expression of Orai1 in diabetic arteries could account for the observed reduction in SOCE.
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http://dx.doi.org/10.1111/1440-1681.13300DOI Listing
July 2020