TY - JOUR
A1 - Chen, Menjia
A1 - Liu, Dan
A1 - Weidemann, Frank
A1 - Lengenfelder, Björn Daniel
A1 - Ertl, Georg
A1 - Hu, Kai
A1 - Frantz, Stefan
A1 - Nordbeck, Peter
T1 - Echocardiographic risk factors of left ventricular thrombus in patients with acute anterior myocardial infarction
JF - ESC Heart Failure
N2 - Aims
This study aimed to identify echocardiographic determinants of left ventricular thrombus (LVT) formation after acute anterior myocardial infarction (MI).
Methods and results
This case–control study comprised 55 acute anterior MI patients with LVT as cases and 55 acute anterior MI patients without LVT as controls, who were selected from a cohort of consecutive patients with ischemic heart failure in our hospital. The cases and controls were matched for age, sex, and left ventricular ejection fraction. LVT was detected by routine/contrast echocardiography or cardiac magnetic resonance imaging during the first 3 months following MI. Formation of apical aneurysm after MI was independently associated with LVT formation [72.0% vs. 43.5%, odds ratio (OR) = 5.06, 95% confidence interval (CI) 1.65–15.48, P = 0.005]. Echocardiographic risk factors associated with LVT formation included reduced mitral annular plane systolic excursion (<7 mm, OR = 4.69, 95% CI 1.84–11.95, P = 0.001), moderate–severe diastolic dysfunction (OR = 2.71, 95% CI 1.11–6.57, P = 0.028), and right ventricular (RV) dysfunction [reduced tricuspid annular plane systolic excursion < 17 mm (OR = 5.48, 95% CI 2.12–14.13, P < 0.001), reduced RV fractional area change < 0.35 (OR = 3.32, 95% CI 1.20–9.18, P = 0.021), and enlarged RV mid diameter (per 5 mm increase OR = 1.62, 95% CI 1.12–2.34, P = 0.010)]. Reduced tricuspid annular plane systolic excursion (<17 mm) significantly associated with increased risk of LVT in anterior MI patients (OR = 3.84, 95% CI 1.37–10.75, P = 0.010), especially in those patients without apical aneurysm (OR = 5.12, 95% CI 1.45–18.08, P = 0.011), independent of body mass index, hypertension, anaemia, mitral annular plane systolic excursion, and moderate–severe diastolic dysfunction.
Conclusions
Right ventricular dysfunction as determined by reduced TAPSE or RV fractional area change is independently associated with LVT formation in acute anterior MI patients, especially in the setting of MI patients without the formation of an apical aneurysm. This study suggests that besides assessment of left ventricular abnormalities, assessment of concomitant RV dysfunction is of importance on risk stratification of LVT formation in patients with acute anterior MI.
KW - myocardial infarction
KW - aneurysm
KW - left ventricular thrombusv
KW - right ventricular dysfunction
KW - echocardiography
KW - cardiovascular magnetic resonance
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261067
VL - 8
IS - 6
ER -
TY - JOUR
A1 - Kaspar, Mathias
A1 - Fette, Georg
A1 - Hanke, Monika
A1 - Ertl, Maximilian
A1 - Puppe, Frank
A1 - Störk, Stefan
T1 - Automated provision of clinical routine data for a complex clinical follow-up study: A data warehouse solution
JF - Health Informatics Journal
N2 - A deep integration of routine care and research remains challenging in many respects. We aimed to show the feasibility of an automated transformation and transfer process feeding deeply structured data with a high level of granularity collected for a clinical prospective cohort study from our hospital information system to the study's electronic data capture system, while accounting for study-specific data and visits. We developed a system integrating all necessary software and organizational processes then used in the study. The process and key system components are described together with descriptive statistics to show its feasibility in general and to identify individual challenges in particular. Data of 2051 patients enrolled between 2014 and 2020 was transferred. We were able to automate the transfer of approximately 11 million individual data values, representing 95% of all entered study data. These were recorded in n = 314 variables (28% of all variables), with some variables being used multiple times for follow-up visits. Our validation approach allowed for constant good data quality over the course of the study. In conclusion, the automated transfer of multi-dimensional routine medical data from HIS to study databases using specific study data and visit structures is complex, yet viable.
KW - clinical data warehouse
KW - clinical study
KW - electronic data capture
KW - electronic health records
KW - secondary data usage
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260828
VL - 28
IS - 1
ER -
TY - JOUR
A1 - Krieter, Detlef H.
A1 - Jeyaseelan, Jarline
A1 - Rüth, Marieke
A1 - Lemke, Horst-Dieter
A1 - Wanner, Christoph
A1 - Drechsler, Christiane
T1 - Clinical hemocompatibility of double-filtration lipoprotein apheresis comparing polyethersulfone and ethylene-vinyl alcohol copolymer membranes
JF - Artificial Organs
N2 - Activation of the complement system and leukocytes by blood–membrane interactions may further promote arteriosclerosis typically present in patients on lipoprotein apheresis. As clinical data on the hemocompatibility of lipoprotein apheresis are scarce, a controlled clinical study comparing two different types of plasma separation and fractionation membranes used in double-filtration lipoprotein apheresis was urgently needed, as its outcome may influence clinical decision-making. In a prospective, randomized, crossover controlled trial, eight patients on double-filtration lipoprotein apheresis were subjected to one treatment with recent polyethersulfone (PES) plasma separation and fractionation membranes and one control treatment using a set of ethylene-vinyl alcohol copolymer (EVAL) membranes. White blood cell (WBC) and platelet (PC) counts, complement factor C5a and thrombin–antithrombin III (TAT) concentrations were determined in samples drawn at defined times from different sites of the extracorporeal blood and plasma circuit. With a nadir at 25 minutes, WBCs in EVAL decreased to 33.5 ± 10.7% of baseline compared with 63.8 ± 22.0% at 20 minutes in PES (P < .001). The maximum C5a levels in venous blood reentering the patients were measured at 30 minutes, being 30.0 ± 11.2 µg/L with EVAL and 12.3 ± 9.0 µg/L with PES (P < .05). The highest C5a concentrations were found in plasma after the plasma filters (EVAL 56.1 ± 22.0 µg/L at 15 minutes vs PES 23.3 ± 15.2 µg/L at 10 minutes; P < .001). PC did not significantly decrease over time with both membrane types, whereas TAT levels did not rise until the end of the treatment without differences between membranes. Regarding lipoprotein(a) and low-density lipoprotein (LDL) cholesterol removal, both membrane sets performed equally. Compared with EVAL, PES membranes cause less leukocyte and complement system activation, the classical parameters of hemocompatibility of extracorporeal treatment procedures, at identical treatment efficacy. Better hemocompatibility may avoid inflammation-promoting effects through blood–material interactions in patients requiring double-filtration lipoprotein apheresis.
KW - lipoprotein(a)
KW - biocompatibility
KW - fractionation membranev
KW - hypercholesterolemia
KW - LDL cholesterol
KW - lipoprotein apheresis
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258307
VL - 45
IS - 9
ER -
TY - JOUR
A1 - Janz, Anna
A1 - Zink, Miriam
A1 - Cirnu, Alexandra
A1 - Hartleb, Annika
A1 - Albrecht, Christina
A1 - Rost, Simone
A1 - Klopocki, Eva
A1 - Günther, Katharina
A1 - Edenhofer, Frank
A1 - Ergün, Süleyman
A1 - Gerull, Brenda
T1 - CRISPR/Cas9-edited PKP2 knock-out (JMUi001-A-2) and DSG2 knock-out (JMUi001-A-3) iPSC lines as an isogenic human model system for arrhythmogenic cardiomyopathy (ACM)
JF - Stem Cell Research
N2 - Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes.
KW - mutations
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259846
VL - 53
ER -
TY - JOUR
A1 - Winter, Patrick M.
A1 - Andelovic, Kristina
A1 - Kampf, Thomas
A1 - Hansmann, Jan
A1 - Jakob, Peter Michael
A1 - Bauer, Wolfgang Rudolf
A1 - Zernecke, Alma
A1 - Herold, Volker
T1 - Simultaneous measurements of 3D wall shear stress and pulse wave velocity in the murine aortic arch
JF - Journal of Cardiovascular Magnetic Resonance
N2 - Purpose
Wall shear stress (WSS) and pulse wave velocity (PWV) are important parameters to characterize blood flow in the vessel wall. Their quantification with flow-sensitive phase-contrast (PC) cardiovascular magnetic resonance (CMR), however, is time-consuming. Furthermore, the measurement of WSS requires high spatial resolution, whereas high temporal resolution is necessary for PWV measurements. For these reasons, PWV and WSS are challenging to measure in one CMR session, making it difficult to directly compare these parameters. By using a retrospective approach with a flexible reconstruction framework, we here aimed to simultaneously assess both PWV and WSS in the murine aortic arch from the same 4D flow measurement.
Methods
Flow was measured in the aortic arch of 18-week-old wildtype (n = 5) and ApoE\(^{−/−}\) mice (n = 5) with a self-navigated radial 4D-PC-CMR sequence. Retrospective data analysis was used to reconstruct the same dataset either at low spatial and high temporal resolution (PWV analysis) or high spatial and low temporal resolution (WSS analysis). To assess WSS, the aortic lumen was labeled by semi-automatically segmenting the reconstruction with high spatial resolution. WSS was determined from the spatial velocity gradients at the lumen surface. For calculation of the PWV, segmentation data was interpolated along the temporal dimension. Subsequently, PWV was quantified from the through-plane flow data using the multiple-points transit-time method. Reconstructions with varying frame rates and spatial resolutions were performed to investigate the influence of spatiotemporal resolution on the PWV and WSS quantification.
Results
4D flow measurements were conducted in an acquisition time of only 35 min. Increased peak flow and peak WSS values and lower errors in PWV estimation were observed in the reconstructions with high temporal resolution. Aortic PWV was significantly increased in ApoE\(^{−/−}\) mice compared to the control group (1.7 ± 0.2 versus 2.6 ± 0.2 m/s, p < 0.001). Mean WSS magnitude values averaged over the aortic arch were (1.17 ± 0.07) N/m\(^2\) in wildtype mice and (1.27 ± 0.10) N/m\(^2\) in ApoE\(^{−/−}\) mice.
Conclusion
The post processing algorithm using the flexible reconstruction framework developed in this study permitted quantification of global PWV and 3D-WSS in a single acquisition. The possibility to assess both parameters in only 35 min will markedly improve the analyses and information content of in vivo measurements.
KW - 4D flow
KW - pulse wave velocity
KW - wall shear stress
KW - radial
KW - self-navigation
KW - mouse
KW - aortic arch
KW - atherosclerosis
KW - mice
KW - flow
KW - plaque
KW - CMR
KW - quantification
KW - microscopy
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259152
VL - 23
IS - 1
ER -
TY - JOUR
A1 - Augustin, Anne Marie
A1 - Welsch, Stefan
A1 - Bley, Thorsten Alexander
A1 - Lopau, Kai
A1 - Kickuth, Ralph
T1 - Color-coded summation images in the evaluation of renal artery stenosis before and after percutaneous transluminal angioplasty
JF - BMC Medical Imaging
N2 - Background: Endovascular therapy is the gold standard in patients with hemodynamic relevant renal artery stenosis (RAS) resistant to medical therapy. The severity grading of the stenosis as well as the result assessment after endovascular approach is predominantly based on visible estimations of the anatomic appearance. We aim to investigate the application of color-coded DSA parameters to gain hemodynamic information during endovascular renal artery interventions and for the assessment of the procedures technical success.
Methods: We retrospectively evaluated 32 patients who underwent endovascular renal artery revascularization and applied color-coded summation imaging on selected monochromatic DSA images. The differences in time to peak (dTTP) of contrast enhancement in predefined anatomical measuring points were analyzed. Furthermore, differences in systolic blood pressure values (SBP) and serum creatinine were obtained. The value of underlying diabetes mellitus as a predictor for clinical outcome was assessed. Correlation analysis between the patients gender as well as the presence of diabetes mellitus and dTTP was performed.
Results: Endovascular revascularization resulted in statistically significant improvement in 4/7 regions of interest. Highly significant improvement of perfusion in terms of shortened TTP values could be found at the segmental artery level and in the intrastenotical segment (p<0.001), significant improvement prestenotical and in the apical renal parenchyma (p<0.05). In the other anatomic regions, differences revealed not to be significant. Differences between SBP and serum creatinine levels before and after the procedure were significant (p=0.004 and 0.0004). Patients ' gender as well as the presence of diabetes mellitus did not reveal to be predictors for the clinical success of the procedure. Furthermore, diabetes and gender did not show relevant correlation with dTTP in the parenchymal measuring points.
Conclusions: The supplementary use of color-coding DSA and the data gained from parametric images may provide helpful information in the evaluation of the procedures ' technical success. The segmental artery might be a particularly suitable vascular territory for analyzing differences in blood flow characteristics. Further studies with larger cohorts are needed to further confirm the diagnostic value of this technique.
KW - digital subtraction angiography
KW - color-coded
KW - endovascular
KW - renal artery
KW - PTA
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259086
VL - 21
IS - 1
ER -
TY - JOUR
A1 - Morbach, Caroline
A1 - Beyersdorf, Niklas
A1 - Kerkau, Thomas
A1 - Ramos, Gustavo
A1 - Sahiti, Floran
A1 - Albert, Judith
A1 - Jahns, Roland
A1 - Ertl, Georg
A1 - Angermann, Christiane E.
A1 - Frantz, Stefan
A1 - Hofmann, Ulrich
A1 - Störk, Stefan
T1 - Adaptive anti-myocardial immune response following hospitalization for acute heart failure
JF - ESC Heart Failure
N2 - Aims
It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility.
Methods and results
AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49%) female, and 24 (51%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45%) to F6 (n = 36, 77%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88%) compared with patients with reduced ejection fraction (n = 14, 61%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95% confidence interval 1.13–20.21; P = 0.033) compared with patients with persistent or without AMyA at F6.
Conclusions
Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.
KW - adaptive immune response
KW - acute heart failure
KW - anti-myocardial
KW - autoantibody
KW - inflammation
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258907
VL - 8
IS - 4
ER -
TY - JOUR
A1 - Ankenbrand, Markus Johannes
A1 - Lohr, David
A1 - Schlötelburg, Wiebke
A1 - Reiter, Theresa
A1 - Wech, Tobias
A1 - Schreiber, Laura Maria
T1 - Deep learning-based cardiac cine segmentation: Transfer learning application to 7T ultrahigh-field MRI
JF - Magnetic Resonance in Medicine
N2 - Purpose
Artificial neural networks show promising performance in automatic segmentation of cardiac MRI. However, training requires large amounts of annotated data and generalization to different vendors, field strengths, sequence parameters, and pathologies is limited. Transfer learning addresses this challenge, but specific recommendations regarding type and amount of data required is lacking. In this study, we assess data requirements for transfer learning to experimental cardiac MRI at 7T where the segmentation task can be challenging. In addition, we provide guidelines, tools, and annotated data to enable transfer learning approaches by other researchers and clinicians.
Methods
A publicly available segmentation model was used to annotate a publicly available data set. This labeled data set was subsequently used to train a neural network for segmentation of left ventricle and myocardium in cardiac cine MRI. The network is used as starting point for transfer learning to 7T cine data of healthy volunteers (n = 22; 7873 images) by updating the pre-trained weights. Structured and random data subsets of different sizes were used to systematically assess data requirements for successful transfer learning.
Results
Inconsistencies in the publically available data set were corrected, labels created, and a neural network trained. On 7T cardiac cine images the model pre-trained on public imaging data, acquired at 1.5T and 3T, achieved DICE\(_{LV}\) = 0.835 and DICE\(_{MY}\) = 0.670. Transfer learning using 7T cine data and ImageNet weight initialization improved model performance to DICE\(_{LV}\) = 0.900 and DICE\(_{MY}\) = 0.791. Using only end-systolic and end-diastolic images reduced training data by 90%, with no negative impact on segmentation performance (DICE\(_{LV}\) = 0.908, DICE\(_{MY}\) = 0.805).
Conclusions
This work demonstrates and quantifies the benefits of transfer learning for cardiac cine image segmentation. We provide practical guidelines for researchers planning transfer learning projects in cardiac MRI and make data, models, and code publicly available.
KW - 7T
KW - ultrahigh-field
KW - transfer learning
KW - segmentation
KW - neural networks
KW - deep learning
KW - cardiac magnetic resonance
KW - cardiac function
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-257604
VL - 86
IS - 4
ER -
TY - THES
A1 - Hauser, Tobias Gregor
T1 - Mineralocorticoid-receptor antagonism and its metabolic consequences in haemodialysis patients
T1 - Mineralkortikoidrezeptorantagonismus und seine metabolischen Folgen in Hämodialysepatienten
N2 - Patients on haemodialysis are highly susceptible to different forms of heart failure. To date, the benefit of Mineralocorticoid-receptor antagonist (MRA) administration in haemodialysis patients remains subject to discussion. Biomarkers play an important role in therapy guidance and pose a promising tool to detect pathological processes of heart failure in an earlier stage. The randomised-controlled Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease (MiREnDa) trial was set up to investigate the effect of 50 mg of spironolactone once daily on left ventricular mass index in haemodialysis patients and several secondary endpoints. This dissertation reports findings from the MiREnDa trial on (a) the efficacy of spironolactone to influence serum levels of biomarkers of heart failure, fibrosis and inflammation and electrolytes and (b) the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Galectin-3 and soluble source of tumorigenicity 2 (sST2) to reflect left ventricular hypertrophy and diastolic dysfunction assessed by imaging characteristics. Treatment of spironolactone over a 40-week period did not alter serum levels of biomarkers of heart failure, fibrosis and inflammation including NT-proBNP, Galectin-3 and sST2. A small but significant effect on serum sodium but not potassium was observed. NT-proBNP was significantly different in the presence or absence of left ventricular hypertrophy (LVH) (normal vs. LVH (median [IQR]): 2,120 [810; 5,040] vs. 6,340 [2,410; 15,360] pg/ml, p<0.01) or moderate and severe diastolic dysfunction (DD) (normal diastolic function and DD grade I vs. DD grade II and DD grade III: 2,300 [850; 6,050] vs. 12,260 [3,340; 34,830] pg/ml, p=0.02). NT-proBNP further showed a significant correlation at baseline with LVMi (Spearman’s rho=0.41, p<0.001), LAVi (Spearman’s rho=0.55, p<0.001) and septal E/e’ (Spearman’s rho=0.45, p<0.001). No correlation was observed between Galectin-3 and the investigated functional and morphological parameters. sST2 was mildly correlated to LVMi at baseline (Spearman’s rho=0.21, p=0.05) and NT-proBNP at baseline (Spearman’s rho=0.37, p<0.001). In conclusion, spironolactone did not affect the investigated parameters but NT-proBNP proved to be significantly correlated to cardiac imaging measurements.
N2 - Dialysepatienten erkranken häufig an Formen der Herzinsuffizienz. Zugleich ist der Nutzen von Mineralkortikoidrezeptorantagonisten bei Dialysepatienten bis heute umstritten. Biomarkermessungen ermöglichen es, pathologische Prozesse am Herzen in einem möglichst frühen Stadium zu erkennen. In der randomisiert-kontrollierten "Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease" (MiREnDa) Studie wurde der Effekt der täglichen Einnahme von 50 mg Spironolacton auf den linksventrikulären Massenindex bei Dialysepatienten zusammen mit verschiedenen sekundären Endpunkten untersucht. Diese Arbeit beleuchtet Ergebnisse der MiREnDa-Studie zur Wirkung von Spironolacton auf Serumspiegel von Biomarkern für Herzinsuffizienz, Fibrose und Entzündung sowie von Elektrolyten. Darüber hinaus wird der Zusammenhang zwischen N-terminalen natriuretischen Peptid Typ B (NT-proBNP), Galectin-3 und Soluble source of tumorigenicity 2 (sST2) und Veränderungen in den wichtigsten bildgebenden Merkmalen linksventrikulärer Hypertrophie und diastolischer Dysfunktion beschrieben. Die Einnahme von Spironolacton über 40 Wochen hatte keinen Effekt auf Biomarker für Herzinsuffizienz, Fibrose und Entzündung wie NT-proBNP, Galectin-3 und sST2. Lediglich die Natriumspiegel, nicht aber die Kaliumspiegel, wurden signifikant beeinflusst. NT-proBNP unterschied sich signifikant zwischen Patient*innen mit und ohne links-ventrikulärer Hypertrophie (LVH) (normal vs. LVH (Median [IQR]): 2.120 [810; 5.040] vs. 6.340 [2.410; 15.360] pg/ml, p<0,01) beziehungsweise mit und ohne relevanter diastolischer Dysfunktion (DD) (normale diastolische Funktion und DD Grad I vs. DD Grad II und DD Grad III: 2.300 [850; 6.050] vs. 12.260 [3.340; 34.830] pg/ml, p=0,02). NT-proBNP korrelierte außerdem signifikant mit LVMi (Spearman's rho=0,41, p<0,001), LAVi (Spearman's rho=0,55, p<0,001) und E/e' (Spearman's rho=0,45, p<0,001). Galectin-3 war unabhängig von allen untersuchten Parametern. sST2 korrelierte mäßig mit LVMi (Spearman's rho=0,21, p=0,05) und deutlich mit NT-proBNP (Spearman's rho=0,37, p<0,001). Zusammenfassend beeinflusste Spironolacton keinen der untersuchten Parameter relevant und lediglich NT-proBNP wies eine signifikante Korrelation zu kardialen Bildgebungsparameters auf.
KW - Dialyse
KW - Spironolacton
KW - Biomarker
KW - haemodialysis
KW - spironolactone
KW - biomarker
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-259382
ER -
TY - THES
A1 - Gaal, Chiara Claudia
T1 - Cardiac Antigens and T cell Specificity after Experimental Myocardial Infarction in Mice
T1 - Kardiale Antigene und T-Zell Spezifität nach experimentellem Myokardinfarkt in Mäusen
N2 - Cardiovascular diseases (CVD), subsuming atherosclerosis of the coronary arteries and subsequent myocardial infarction, are the leading cause of death in the European Union (over 4 million deaths annually), with devastating individual and economic consequences.
Recent studies revealed that T cells play a crucial role in post-MI inflammation, healing and remodelling processes. Nevertheless, the specificity profile of adaptive immune responses in the infarcted myocardium has not yet been differentiated. The experiments portrayed in this thesis sought to assess whether post-MI CD4+ T cell responses in mice are triggered by heart specific antigens, and eventually identify relevant epitopes.
We were able to create a murine antigen atlas including a list of 206 epitopes for I-Ab and 193 epitopes for I-Ad presented on MHC-II in the context of MI. We sought to consecutively test this panel by in vitro T cell proliferation and antigen recall assays ex vivo. The elispot assay was used as a readout for antigen-specific stimulation by measurement of IL-2 and IFN-γ production, currently the most sensitive approach available to detect even small counts of antigen producing cells. Splenocytes as well as lymphocytes from mediastinal lymph nodes were purified from animals 7 days or 56 days after EMI conducted by ligation of the left anterior descending artery.
We were able to provide evidence that post-MI T cell responses in Balb/c mice are triggered by heart-specific antigens and that MYHCA, especially MYHCA614-628, is relevant for that response. Moreover, a significant specific T cell response after MI in C57BL/6J mice was observed for α actin, cardiac muscle 1 [ACTC1], myosin-binding protein C3 [MYBPC3] and myosin heavy chain α [MYHCA] derived heart specific antigens.
Generally, the epitopes of interest for Balb/c as well as C57BL/6J could be further investigated and may eventually be modulated in the future.
N2 - Herz-Kreislauf-Erkrankungen (CVD) sowie der häufig folgende Myokardinfarkt sind die häufigsten Todesursachen in der Europäischen Union (über 4 Millionen Todesfälle pro Jahr) mit verheerenden individuellen und wirtschaftlichen Folgen.
Aktuelle Studien haben gezeigt, dass T-Zellen eine entscheidende Rolle bei Entzündungs-, Heilungs- und Umbauprozessen nach einem Myokardinfarkt spielen. Das Spezifitätsprofil adaptiver Immunantworten im infarzierten Myokard konnte bisher jedoch noch nicht differenziert werden. Die in dieser Arbeit dargestellten Experimente gingen der Frage nach, ob CD4+ T-Zellantworten nach einem Myokardinfarkt in Mäusen durch herzspezifische Antigene ausgelöst werden und ob hieraus relevante Epitope identifiziert werden können.
Uns gelang es, einen Maus-Antigen-Atlas zu erstellen, der eine Zusammenstellung von 206 Epitopen für I-Ab und 193 Epitope für I-Ad enthält, welche auf MHC-II im Rahmen des Myokardinfarkts präsentiert werden. Dieses Panel wurde nacheinander durch In-vitro-T-Zell-Proliferations- und Antigen-Recall-Assays ex vivo getestet. Der Elispot-Assay wurde als sensitivster verfügbare Ansatz zur Quantifizierung der antigen-spezifischen Stimulation durch Messung der IL-2- und IFN-γ-Produktion verwendet. Splenozyten sowie Lymphozyten aus mediastinalen Lymphknoten der Mäuse wurden 7 Tage bzw. 56 Tage nach einem experimentellen Myokardinfarkt, welcher durch Ligation der RIVA Arterie durchgeführt wurde, aufgereinigt.
Wir konnten nachweisen, dass Post-MI-T-Zellantworten in Balb/c Mäusen durch herzspezifische Antigene ausgelöst werden, und dass MYHCA, insbesondere MYHCA614-628, für diese Antwort relevant ist. Darüber hinaus konnte eine signifikante spezifische T-Zell-Antwort nach Myokardinfarkt in C57BL/6J Mäusen auf aus Alpha-Actin des Herzmuskels 1 [ACTC1], Myosin-bindendes Protein C vom Herztyp [MYBPC3] und der schweren Kette des Myosins α [MYHCA] generierten herzspezifischen Antigenen gezeigt werden.
KW - Regulatorische T-Lymphozyt
KW - Herzinfarkt
KW - Immunreaktion
KW - Myosin
KW - Kardiologie
KW - T-Lymphozyten
KW - T-Lymphocytes
KW - Myocardial infarction
KW - T-Cell Specificity
KW - Cardiac Antigens
KW - Kardinale Antigene
KW - T-Zell Spezifität
KW - Myocardial Healing
KW - Mycardiale Heilung
Y1 - 2022
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260047
ER -
TY - JOUR
A1 - Liu, Dan
A1 - Hu, Kai
A1 - Lau, Kolja
A1 - Kiwitz, Tobias
A1 - Robitzkat, Katharina
A1 - Hammel, Clara
A1 - Lengenfelder, Björn Daniel
A1 - Ertl, Georg
A1 - Frantz, Stefan
A1 - Nordbeck, Peter
T1 - Impact of diastolic dysfunction on outcome in heart failure patients with mid-range or reduced ejection fraction
JF - ESC Heart Failure
N2 - Aims
The role of diastolic dysfunction (DD) in prognostic evaluation in heart failure (HF) patients with impaired systolic function remains unclear. We investigated the impact of echocardiography-defined DD on survival in HF patients with mid-range (HFmrEF, EF 41–49%) and reduced ejection fraction (HFrEF, EF < 40%).
Methods and results
A total of 2018 consecutive hospitalized HF patients were retrospectively included and divided in two groups based on baseline EF: HFmrEF group (n = 951, aged 69 ± 13 years, 74.2% male) and HFrEF group (n = 1067, aged 68 ± 13 years, 76.3% male). Clinical data were collected and analysed. All patients completed ≥1 year clinical follow-up. The primary endpoint was defined as all-cause death (including heart transplantation) and cardiovascular (CV)-related death. All-cause mortality (30.8% vs. 24.9%, P = 0.003) and CV mortality (19.1% vs. 13.5%, P = 0.001) were significantly higher in the HFrEF group than the HFmrEF group during follow-up [median 24 (13–36) months]. All-cause mortality increased in proportion to DD severity (mild, moderate, and severe) in either HFmrEF (17.1%, 25.4%, and 37.0%, P < 0.001) or HFrEF (18.9%, 30.3%, and 39.2%, P < 0.001) patients. The risk of all-cause mortality [hazard ratio (HR) = 1.347, P = 0.015] and CV mortality (HR = 1.508, P = 0.007) was significantly higher in HFrEF patients with severe DD compared with non-severe DD after adjustment for identified clinical and echocardiographic covariates. For HFmrEF patients, severe DD was independently associated with increased all-cause mortality (HR = 1.358, P = 0.046) but not with CV mortality (HR = 1.155, P = 0.469).
Conclusions
Echocardiography-defined severe DD is independently associated with increased all-cause mortality in patients with HFmrEF and HFrEF.
KW - heart failure with mid-range ejection fraction
KW - heart failure with reduced ejection fraction
KW - diastolic dysfunction
KW - echocardiography
KW - prognosis
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258894
VL - 8
IS - 4
ER -
TY - JOUR
A1 - Petri, Nils
A1 - Lengenfelder, Björn
A1 - Voelker, Wolfram
A1 - Nordbeck, Peter
T1 - Interventional closure of aortomitral perforation after TAVR: A case report
JF - Catheterization and Cardiovascular Interventions
N2 - Despite TAVR emerging as the gold standard for a broad spectrum of patients, it is associated with serious complications. In this report we present a case, where a TAVR procedure led to a perforation at the aortomitral continuity, discuss the risk factors for the occurrence of perforations and how we decided to treat the patient.
KW - medicine
KW - closure AV fistula/AVM (CLAV)
KW - transcatheter valveimplantation (TVI)
KW - percutaneous valve therapy (PVT)
KW - aortic valve disease percutaneous intervention (AVDP)
KW - imaging TTE/TEE (ITTE)
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-256625
VL - 98
IS - 3
ER -
TY - JOUR
A1 - Sbiera, Iuliu
A1 - Kircher, Stefan
A1 - Altieri, Barbara
A1 - Lenz, Kerstin
A1 - Hantel, Constanze
A1 - Fassnacht, Martin
A1 - Sbiera, Silviu
A1 - Kroiss, Matthias
T1 - Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications
JF - Frontiers in Endocrinology
N2 - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials.
KW - normal adrenal glands
KW - adrenocortical tumors
KW - FGF-pathway
KW - FGFR
KW - RNA Expression
KW - RNAScope
KW - unsupervised clustering
KW - patient survival
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251953
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - März, Juliane
A1 - Kurlbaum, Max
A1 - Roche-Lancaster, Oisin
A1 - Deutschbein, Timo
A1 - Peitzsch, Mirko
A1 - Prehn, Cornelia
A1 - Weismann, Dirk
A1 - Robledo, Mercedes
A1 - Adamski, Jerzy
A1 - Fassnacht, Martin
A1 - Kunz, Meik
A1 - Kroiss, Matthias
T1 - Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors
JF - Frontiers in Endocrinology
N2 - Context
Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet.
Objective
Evaluation of quantitative metabolomics as a diagnostic tool for PPGL.
Design
Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study.
Patients
Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded.
Results
Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines.
By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling.
Conclusions
The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.
KW - adrenal
KW - pheochromocytoma
KW - paraganglioma
KW - targeted metabolomics
KW - mass spectronomy
KW - catecholamines
KW - machine learning
KW - feature selection
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245710
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Sahiti, Floran
A1 - Morbach, Caroline
A1 - Cejka, Vladimir
A1 - Albert, Judith
A1 - Eichner, Felizitas A.
A1 - Gelbrich, Götz
A1 - Heuschmann, Peter U.
A1 - Störk, Stefan
T1 - Left Ventricular Remodeling and Myocardial Work: Results From the Population-Based STAAB Cohort Study
JF - Frontiers in Cardiovascular Medicine
N2 - Introduction: Left ventricular (LV) dilatation and LV hypertrophy are acknowledged precursors of myocardial dysfunction and ultimately of heart failure, but the implications of abnormal LV geometry on myocardial function are not well-understood. Non-invasive LV myocardial work (MyW) assessment based on echocardiography-derived pressure-strain loops offers the opportunity to study detailed myocardial function in larger cohorts. We aimed to assess the relationship of LV geometry with MyW indices in general population free from heart failure.
Methods and Results: We report cross-sectional baseline data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of the general population of Würzburg, Germany, aged 30–79 years. MyW analysis was performed in 1,926 individuals who were in sinus rhythm and free from valvular disease (49.3% female, 54 ± 12 years). In multivariable regression, higher LV volume was associated with higher global wasted work (GWW) (+0.5 mmHg% per mL/m\(^2\), p < 0.001) and lower global work efficiency (GWE) (−0.02% per mL/m\(^2\), p < 0.01), while higher LV mass was associated with higher GWW (+0.45 mmHg% per g/m\(^2\), p < 0.001) and global constructive work (GCW) (+2.05 mmHg% per g/m\(^2\), p < 0.01) and lower GWE (−0.015% per g/m\(^2\), p < 0.001). This was dominated by the blood pressure level and also observed in participants with normal LV geometry and concomitant hypertension.
Conclusion: Abnormal LV geometric profiles were associated with a higher amount of wasted work, which translated into reduced work efficiency. The pattern of a disproportionate increase in GWW with higher LV mass might be an early sign of hypertensive heart disease.
KW - myocardial work
KW - myocardial work efficiency
KW - left ventricular geometry
KW - left ventricular mass
KW - LV dilatation
KW - left ventricular geometric abnormality
KW - left ventricular remodeling
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240480
SN - 2297-055X
VL - 8
ER -
TY - JOUR
A1 - Lenschow, Christina
A1 - Fuss, Carmina Teresa
A1 - Kircher, Stefan
A1 - Buck, Andreas
A1 - Kickuth, Ralph
A1 - Reibetanz, Joachim
A1 - Wiegering, Armin
A1 - Stenzinger, Albrecht
A1 - Hübschmann, Daniel
A1 - Germer, Christoph Thomas
A1 - Fassnacht, Martin
A1 - Fröhling, Stefan
A1 - Schlegel, Nicolas
A1 - Kroiss, Matthias
T1 - Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management
JF - Frontiers in Endocrinology
N2 - Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.
KW - parathyroid carcinoma
KW - abdominal lymph node metastases
KW - molecular diagnostics
KW - repeated surgery
KW - [18F]FDG-PET-CT
KW - immune check inhibitor
KW - pembrolizumab
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233362
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Delgobo, Murilo
A1 - Heinrichs, Margarete
A1 - Hapke, Nils
A1 - Ashour, DiyaaElDin
A1 - Appel, Marc
A1 - Srivastava, Mugdha
A1 - Heckel, Tobias
A1 - Spyridopoulos, Ioakim
A1 - Hofmann, Ulrich
A1 - Frantz, Stefan
A1 - Ramos, Gustavo Campos
T1 - Terminally Differentiated CD4\(^+\) T Cells Promote Myocardial Inflammaging
JF - Frontiers in Immunology
N2 - The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4\(^+\) T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4\(^+\) T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4\(^+\) T cell compartment was primarily composed of naïve cells defined as CCR7\(^+\)CD45RO\(^-\). However, when transplanted into young lymphocyte-deficient mice, CD4\(^+\) T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7\(^-\) CD45RO\(^+\)) and terminally-differentiated phenotypes (CCR7\(^-\)CD45RO\(^-\)), as typically seen in elderly. Differentiated CD4\(^+\) T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4\(^+\) T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4\(^+\) T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.
KW - CD4+ T-cells
KW - myocardial aging
KW - inflammaging
KW - NSG animals
KW - immunosenescence
KW - lymphocytes
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229612
SN - 1664-3224
VL - 12
ER -
TY - JOUR
A1 - Vetrivel, Sharmilee
A1 - Zhang, Ru
A1 - Engel, Mareen
A1 - Altieri, Barbara
A1 - Braun, Leah
A1 - Osswald, Andrea
A1 - Bidlingmaier, Martin
A1 - Fassnacht, Martin
A1 - Beuschlein, Felix
A1 - Reincke, Martin
A1 - Chen, Alon
A1 - Sbiera, Silviu
A1 - Riester, Anna
T1 - Circulating microRNA Expression in Cushing’s Syndrome
JF - Frontiers in Endocrinology
N2 - Context
Cushing’s syndrome (CS) is a rare disease of endogenous hypercortisolism associated with high morbidity and mortality. Diagnosis and classification of CS is still challenging.
Objective
Circulating microRNAs (miRNAs) are minimally invasive diagnostic markers. Our aim was to characterize the circulating miRNA profiles of CS patients and to identify distinct profiles between the two major CS subtypes.
Methods
We included three groups of patients from the German Cushing’s registry: ACTH-independent CS (Cortisol-Producing-Adenoma; CPA), ACTH-dependent pituitary CS (Cushing’s Disease; CD), and patients in whom CS had been ruled out (controls). Profiling of miRNAs was performed by next-generation-sequencing (NGS) in serum samples of 15 CS patients (each before and after curative surgery) and 10 controls. Significant miRNAs were first validated by qPCR in the discovery cohort and then in an independent validation cohort of 20 CS patients and 11 controls.
Results
NGS identified 411 circulating miRNAs. Differential expression of 14 miRNAs were found in the pre- and postoperative groups. qPCR in the discovery cohort validated 5 of the significant miRNAs from the preoperative group analyses. Only, miR-182-5p was found to be significantly upregulated in the CD group of the validation cohort. Comparing all CS samples as a group with the controls did not reveal any significant differences in expression.
Outcome
In conclusion, our study identified miR-182-5p as a possible biomarker for CD, which has to be validated in a prospective cohort. Furthermore, our results suggest that presence or absence of ACTH might be at least as relevant for miRNA expression as hypercortisolism itself.
KW - cortisol
KW - ACTH
KW - miRNA
KW - biomarker
KW - cortisol-producing adenoma
KW - miR-182-5p
KW - hypercortisolism
KW - miR-183 cluster
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229761
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Herrmann, Johannes
A1 - Adam, Elisabeth Hannah
A1 - Notz, Quirin
A1 - Helmer, Philipp
A1 - Sonntagbauer, Michael
A1 - Ungemach-Papenberg, Peter
A1 - Sanns, Andreas
A1 - Zausig, York
A1 - Steinfeldt, Thorsten
A1 - Torje, Iuliu
A1 - Schmid, Benedikt
A1 - Schlesinger, Tobias
A1 - Rolfes, Caroline
A1 - Reyher, Christian
A1 - Kredel, Markus
A1 - Stumpner, Jan
A1 - Brack, Alexander
A1 - Wurmb, Thomas
A1 - Gill-Schuster, Daniel
A1 - Kranke, Peter
A1 - Weismann, Dirk
A1 - Klinker, Hartwig
A1 - Heuschmann, Peter
A1 - Rücker, Viktoria
A1 - Frantz, Stefan
A1 - Ertl, Georg
A1 - Muellenbach, Ralf Michael
A1 - Mutlak, Haitham
A1 - Meybohm, Patrick
A1 - Zacharowski, Kai
A1 - Lotz, Christopher
T1 - COVID-19 Induced Acute Respiratory Distress Syndrome — A Multicenter Observational Study
JF - Frontiers in Medicine
N2 - Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS).
Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included.
Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay.
Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.
KW - COVID-19
KW - ARDS (acute respiratory distress syndrome)
KW - intensive care medicine
KW - pandemia
KW - Germany
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-219834
SN - 2296-858X
VL - 7
ER -
TY - JOUR
A1 - Andelovic, Kristina
A1 - Winter, Patrick
A1 - Kampf, Thomas
A1 - Xu, Anton
A1 - Jakob, Peter Michael
A1 - Herold, Volker
A1 - Bauer, Wolfgang Rudolf
A1 - Zernecke, Alma
T1 - 2D Projection Maps of WSS and OSI Reveal Distinct Spatiotemporal Changes in Hemodynamics in the Murine Aorta during Ageing and Atherosclerosis
JF - Biomedicines
N2 - Growth, ageing and atherosclerotic plaque development alter the biomechanical forces acting on the vessel wall. However, monitoring the detailed local changes in wall shear stress (WSS) at distinct sites of the murine aortic arch over time has been challenging. Here, we studied the temporal and spatial changes in flow, WSS, oscillatory shear index (OSI) and elastic properties of healthy wildtype (WT, n = 5) and atherosclerotic apolipoprotein E-deficient (Apoe\(^{−/−}\), n = 6) mice during ageing and atherosclerosis using high-resolution 4D flow magnetic resonance imaging (MRI). Spatially resolved 2D projection maps of WSS and OSI of the complete aortic arch were generated, allowing the pixel-wise statistical analysis of inter- and intragroup hemodynamic changes over time and local correlations between WSS, pulse wave velocity (PWV), plaque and vessel wall characteristics. The study revealed converse differences of local hemodynamic profiles in healthy WT and atherosclerotic Apoe\(^{−/−}\) mice, and we identified the circumferential WSS as potential marker of plaque size and composition in advanced atherosclerosis and the radial strain as a potential marker for vascular elasticity. Two-dimensional (2D) projection maps of WSS and OSI, including statistical analysis provide a powerful tool to monitor local aortic hemodynamics during ageing and atherosclerosis. The correlation of spatially resolved hemodynamics and plaque characteristics could significantly improve our understanding of the impact of hemodynamics on atherosclerosis, which may be key to understand plaque progression towards vulnerability.
KW - atherosclerosis
KW - mouse
KW - 4D flow MRI
KW - aortic arch
KW - flow dynamics
KW - WSS
KW - mapping
KW - PWV
KW - plaque characteristics
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-252164
SN - 2227-9059
VL - 9
IS - 12
ER -
TY - JOUR
A1 - Kleinert, Evelyn
A1 - Hillermann, Nele
A1 - Jablonka, Alexandra
A1 - Happle, Christine
A1 - Müller, Frank
A1 - Simmenroth, Anne
T1 - Prescription of antibiotics in the medical care of newly arrived refugees and migrants
JF - Pharmacoepidemiology and Drug Safety
N2 - Purpose
Unnecessary and inappropriate use of antibiotics is a widespread problem in primary care. However, current data on the care of refugees and migrants in initial reception centers is pending. This article provides data on prescription frequencies of various antibiotics and associated diagnoses.
Methods
In this retrospective observational study, patient data of 3255 patients with 6376 medical contacts in two initial reception centers in Germany were analyzed. Patient data, collected by chart review, included sociodemographic characteristics, diagnoses, and prescriptions. Antibiotic prescription behavior and corresponding physician‐coded diagnoses were analyzed.
Results
Nineteen percent of all patients in our study received systemic antibiotics during the observation period, with children below the age of 10 years receiving antibiotics most frequently (24%). The most commonly prescribed antibiotics were penicillins (65%), macrolides (12%), and cephalosporins (7%). The most frequent diagnoses associated with antibiotic prescription were acute tonsillitis (26%), bronchitis (21%), infections of the upper respiratory tract (14%), and urinary tract infections (10%). In case of acute bronchitis 74% of the antibiotic prescriptions were probably not indicated. In addition, we found a significant number of inappropriate prescriptions such as amoxicillin for tonsillitis (67%), and ciprofloxacin and cotrimoxazol for urinary tract infections (49%).
Conclusion
Regarding inappropriate prescription of antibiotics in refugee healthcare, this study shows a rate ranging from 8% for upper respiratory tract infections to 75% for acute bronchitis. Unnecessary use of antibiotics is a global problem contributing to gratuitous costs, side effects, and antimicrobial resistance. This research contributes to the development of stringent antibiotic stewardship regiments in the particularly vulnerable population of migrants and refugees.
KW - antibiotic prescription
KW - antimicrobial resistance
KW - inappropriate prescription
KW - pharmacoepidemiology
KW - primary healthcare
KW - refugee healthcare
KW - viral infection
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244771
VL - 30
IS - 8
SP - 1074
EP - 1083
ER -
TY - JOUR
A1 - Marquardt, André
A1 - Landwehr, Laura-Sophie
A1 - Ronchi, Cristina L.
A1 - di Dalmazi, Guido
A1 - Riester, Anna
A1 - Kollmannsberger, Philip
A1 - Altieri, Barbara
A1 - Fassnacht, Martin
A1 - Sbiera, Silviu
T1 - Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning
JF - Cancers
N2 - Simple Summary
Using a visual-based clustering method on the TCGA RNA sequencing data of a large adrenocortical carcinoma (ACC) cohort, we were able to classify these tumors in two distinct clusters largely overlapping with previously identified ones. As previously shown, the identified clusters also correlated with patient survival. Applying the visual clustering method to a second dataset also including benign adrenocortical samples additionally revealed that one of the ACC clusters is more closely located to the benign samples, providing a possible explanation for the better survival of this ACC cluster. Furthermore, the subsequent use of machine learning identified new possible biomarker genes with prognostic potential for this rare disease, that are significantly differentially expressed in the different survival clusters and should be further evaluated.
Abstract
Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.
KW - adrenocortical carcinoma
KW - in silico analysis
KW - machine learning
KW - bioinformatic clustering
KW - biomarker prediction
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246245
SN - 2072-6694
VL - 13
IS - 18
ER -
TY - JOUR
A1 - Beierle, Felix
A1 - Schobel, Johannes
A1 - Vogel, Carsten
A1 - Allgaier, Johannes
A1 - Mulansky, Lena
A1 - Haug, Fabian
A1 - Haug, Julian
A1 - Schlee, Winfried
A1 - Holfelder, Marc
A1 - Stach, Michael
A1 - Schickler, Marc
A1 - Baumeister, Harald
A1 - Cohrdes, Caroline
A1 - Deckert, Jürgen
A1 - Deserno, Lorenz
A1 - Edler, Johanna-Sophie
A1 - Eichner, Felizitas A.
A1 - Greger, Helmut
A1 - Hein, Grit
A1 - Heuschmann, Peter
A1 - John, Dennis
A1 - Kestler, Hans A.
A1 - Krefting, Dagmar
A1 - Langguth, Berthold
A1 - Meybohm, Patrick
A1 - Probst, Thomas
A1 - Reichert, Manfred
A1 - Romanos, Marcel
A1 - Störk, Stefan
A1 - Terhorst, Yannik
A1 - Weiß, Martin
A1 - Pryss, Rüdiger
T1 - Corona Health — A Study- and Sensor-Based Mobile App Platform Exploring Aspects of the COVID-19 Pandemic
JF - International Journal of Environmental Research and Public Health
N2 - Physical and mental well-being during the COVID-19 pandemic is typically assessed via surveys, which might make it difficult to conduct longitudinal studies and might lead to data suffering from recall bias. Ecological momentary assessment (EMA) driven smartphone apps can help alleviate such issues, allowing for in situ recordings. Implementing such an app is not trivial, necessitates strict regulatory and legal requirements, and requires short development cycles to appropriately react to abrupt changes in the pandemic. Based on an existing app framework, we developed Corona Health, an app that serves as a platform for deploying questionnaire-based studies in combination with recordings of mobile sensors. In this paper, we present the technical details of Corona Health and provide first insights into the collected data. Through collaborative efforts from experts from public health, medicine, psychology, and computer science, we released Corona Health publicly on Google Play and the Apple App Store (in July 2020) in eight languages and attracted 7290 installations so far. Currently, five studies related to physical and mental well-being are deployed and 17,241 questionnaires have been filled out. Corona Health proves to be a viable tool for conducting research related to the COVID-19 pandemic and can serve as a blueprint for future EMA-based studies. The data we collected will substantially improve our knowledge on mental and physical health states, traits and trajectories as well as its risk and protective factors over the course of the COVID-19 pandemic and its diverse prevention measures.
KW - mobile health
KW - ecological momentary assessment
KW - digital phenotyping
KW - longitudinal studies
KW - mobile crowdsensing
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242658
SN - 1660-4601
VL - 18
IS - 14
ER -
TY - JOUR
A1 - Popp, Sandy
A1 - Schmitt-Böhrer, Angelika
A1 - Langer, Simon
A1 - Hofmann, Ulrich
A1 - Hommers, Leif
A1 - Schuh, Kai
A1 - Frantz, Stefan
A1 - Lesch, Klaus-Peter
A1 - Frey, Anna
T1 - 5-HTT Deficiency in Male Mice Affects Healing and Behavior after Myocardial Infarction
JF - Journal of Clinical Medicine
N2 - Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
KW - chronic heart failure
KW - myocardial infarction
KW - serotonin transporter deficient mice
KW - anxiety
KW - depression
KW - behavior
KW - inflammation
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242739
SN - 2077-0383
VL - 10
IS - 14
ER -
TY - JOUR
A1 - Sbiera, Iuliu
A1 - Kircher, Stefan
A1 - Altieri, Barbara
A1 - Fassnacht, Martin
A1 - Kroiss, Matthias
A1 - Sbiera, Silviu
T1 - Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?
JF - Cancers
N2 - A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.
KW - adrenocortical tissues
KW - EMT
KW - epithelial markers
KW - mesenchymal markers
KW - recurrence-free survival
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236486
SN - 2072-6694
VL - 13
IS - 7
ER -
TY - JOUR
A1 - Detomas, Mario
A1 - Altieri, Barbara
A1 - Schlötelburg, Wiebke
A1 - Appenzeller, Silke
A1 - Schlaffer, Sven
A1 - Coras, Roland
A1 - Schirbel, Andreas
A1 - Wild, Vanessa
A1 - Kroiss, Matthias
A1 - Sbiera, Silviu
A1 - Fassnacht, Martin
A1 - Deutschbein, Timo
T1 - Case Report: Consecutive Adrenal Cushing’s Syndrome and Cushing’s Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations
JF - Frontiers in Endocrinology
N2 - The occurrence of different subtypes of endogenous Cushing’s syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing’s disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.
KW - Cushing’s syndrome
KW - Cushing’s disease
KW - hypercortisolism
KW - glucocorticoid excess
KW - USP8
KW - CTNNB1
KW - NR3C1
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244596
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Adam, Pia
A1 - Kircher, Stefan
A1 - Sbiera, Iuliu
A1 - Koehler, Viktoria Florentine
A1 - Berg, Elke
A1 - Knösel, Thomas
A1 - Sandner, Benjamin
A1 - Fenske, Wiebke Kristin
A1 - Bläker, Hendrik
A1 - Smaxwil, Constantin
A1 - Zielke, Andreas
A1 - Sipos, Bence
A1 - Allelein, Stephanie
A1 - Schott, Matthias
A1 - Dierks, Christine
A1 - Spitzweg, Christine
A1 - Fassnacht, Martin
A1 - Kroiss, Matthias
T1 - FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale
JF - Frontiers in Endocrinology
N2 - Background
Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.
Materials and Methods
Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.
Results
PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.
Conclusion
High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.
KW - tyrosine kinase inhibitor (TKI)
KW - immune checkpoint inhibitor (ICI)
KW - immunohistochemistry
KW - immunotherapy
KW - PD-L1
KW - FGFR
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244653
SN - 1664-2392
VL - 12
ER -
TY - JOUR
A1 - Reinecke, Holger
A1 - Jürgensmeyer, Sabine
A1 - Engelbertz, Christiane
A1 - Gerss, Joachim
A1 - Kirchhof, Paulus
A1 - Breithardt, Günter
A1 - Bauersachs, Rupert
A1 - Wanner, Christoph
T1 - Design and rationale of a randomised controlled trial comparing apixaban to phenprocoumon in patients with atrial fibrillation on chronic haemodialysis: the AXADIA-AFNET 8 study
JF - BMJ open
N2 - Introduction Patients with end-stage kidney disease requiring maintenance haemodialysis treatment experience a dramatic cardiovascular morbidity and mortality. Due to the high atherosclerotic and arteriosclerotic burden and profound alterations in haemostasis, they frequently suffer and die from both thromboembolic and bleeding events. This is a particular concern in patients on haemodialysis with atrial fibrillation (AF). Controlled trials on the optimal anticoagulation in patients with AF on haemodialysis are not available. The randomised controlled phase IIIb AXADIA-AFNET 8 trial will evaluate the safety and efficacy of the factor Xa inhibitor apixaban in patients with AF requiring haemodialysis. Methods and analysis A total of 222 patients will be randomised in an open-labelled, 1:1 design to receive either apixaban 2.5mg twice daily or dose-adjusted vitamin K antagonist therapy (target international normalised ratio 2.0-3.0). All patients will be treated and followed up for a minimum of 6 months up to a maximum of 24 months. The primary outcome is major or clinically relevant, non-major bleedings or death of any cause. Secondary outcomes include stroke, cardiovascular death and other thromboembolic events, thus exploring the efficacy of apixaban. The first patient was randomised in June 2017. Ethics and dissemination The study protocol was approved by the Ethical Committee of the Landesaertzekammer, Westfalen-Lippe and the Medical Faculty of the University of Muenster, Muenster, Germany (reference number: 2016-598f-A). Written informed consent will be obtained from all patients prior to study participation, including their consent for long-term follow-up. AXADIA-AFNET 8 is an investigator-initiated trial. Sponsor is AFNET, Muenster, Germany. Study findings will be disseminated to Bristol-Myers Squibb, Munich, Germany, and Pfizer, Berlin, Germany, to the participating centres, at research conferences and in peer-reviewed journals. Trial registration numbers NCT02933697, Pre-results.
KW - arial fibrillation
KW - hemodialysis
KW - cardiovascular morbidity
KW - cardiovascular mortality
KW - anticoagulation
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225156
VL - 8
IS - 9
ER -
TY - JOUR
A1 - Weich, Alexander
A1 - Werner, Rudolf A.
A1 - Buck, Andreas K.
A1 - Hartrampf, Philipp E.
A1 - Serfling, Sebastian E.
A1 - Scheurlen, Michael
A1 - Wester, Hans-Jürgen
A1 - Meining, Alexander
A1 - Kircher, Stefan
A1 - Higuchi, Takahiro
A1 - Pomper, Martin G.
A1 - Rowe, Steven P.
A1 - Lapa, Constantin
A1 - Kircher, Malte
T1 - CXCR4-Directed PET/CT in Patients with Newly Diagnosed Neuroendocrine Carcinomas
JF - Diagnostics
N2 - We aimed to elucidate the diagnostic potential of the C-X-C motif chemokine receptor 4 (CXCR4)-directed positron emission tomography (PET) tracer \(^{68}\)Ga-Pentixafor in patients with poorly differentiated neuroendocrine carcinomas (NEC), relative to the established reference standard \(^{18}\)F-FDG PET/computed tomography (CT). In our database, we retrospectively identified 11 treatment-naïve patients with histologically proven NEC, who underwent \(^{18}\)F-FDG and CXCR4-directed PET/CT for staging and therapy planning. The images were analyzed on a per-patient and per-lesion basis and compared to immunohistochemical staining (IHC) of CXCR4 from PET-guided biopsies. \(^{68}\)Ga-Pentixafor visualized tumor lesions in 10/11 subjects, while \(^{18}\)F-FDG revealed sites of disease in all 11 patients. Although weak to moderate CXCR4 expression could be corroborated by IHC in 10/11 cases, \(^{18}\)F-FDG PET/CT detected significantly more tumor lesions (102 vs. 42; total lesions, n = 107; p < 0.001). Semi-quantitative analysis revealed markedly higher 18F-FDG uptake as compared to \(^{68}\)Ga-Pentixafor (maximum and mean standardized uptake values (SUV) and tumor-to-background ratios (TBR) of cancerous lesions, SUVmax: 12.8 ± 9.8 vs. 5.2 ± 3.7; SUVmean: 7.4 ± 5.4 vs. 3.1 ± 3.2, p < 0.001; and, TBR 7.2 ± 7.9 vs. 3.4 ± 3.0, p < 0.001). Non-invasive imaging of CXCR4 expression in NEC is inferior to the reference standard \(^{18}\)F-FDG PET/CT.
KW - CXCR4
KW - NET
KW - NEC
KW - 68Ga-Pentixafor
KW - 18F-FDG
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234231
SN - 2075-4418
VL - 11
IS - 4
ER -
TY - JOUR
A1 - Andelovic, Kristina
A1 - Winter, Patrick
A1 - Jakob, Peter Michael
A1 - Bauer, Wolfgang Rudolf
A1 - Herold, Volker
A1 - Zernecke, Alma
T1 - Evaluation of plaque characteristics and inflammation using magnetic resonance imaging
JF - Biomedicines
N2 - Atherosclerosis is an inflammatory disease of large and medium-sized arteries, characterized by the growth of atherosclerotic lesions (plaques). These plaques often develop at inner curvatures of arteries, branchpoints, and bifurcations, where the endothelial wall shear stress is low and oscillatory. In conjunction with other processes such as lipid deposition, biomechanical factors lead to local vascular inflammation and plaque growth. There is also evidence that low and oscillatory shear stress contribute to arterial remodeling, entailing a loss in arterial elasticity and, therefore, an increased pulse-wave velocity. Although altered shear stress profiles, elasticity and inflammation are closely intertwined and critical for plaque growth, preclinical and clinical investigations for atherosclerosis mostly focus on the investigation of one of these parameters only due to the experimental limitations. However, cardiovascular magnetic resonance imaging (MRI) has been demonstrated to be a potent tool which can be used to provide insights into a large range of biological parameters in one experimental session. It enables the evaluation of the dynamic process of atherosclerotic lesion formation without the need for harmful radiation. Flow-sensitive MRI provides the assessment of hemodynamic parameters such as wall shear stress and pulse wave velocity which may replace invasive and radiation-based techniques for imaging of the vascular
function and the characterization of early plaque development. In combination with inflammation imaging, the analyses and correlations of these parameters could not only significantly advance basic preclinical investigations of atherosclerotic lesion formation and progression, but also the diagnostic clinical evaluation for early identification of high-risk plaques, which are prone to rupture. In this review, we summarize the key applications of magnetic resonance imaging for the evaluation of plaque characteristics through flow sensitive and morphological measurements. The simultaneous measurements of functional and structural parameters will further preclinical research on atherosclerosis and has the potential to fundamentally improve the detection of inflammation and vulnerable plaques in patients.
KW - atherosclerosis
KW - mouse models
KW - wall shear stress
KW - pulse wave velocity
KW - arterial elasticity
KW - inflammation
KW - magnetic resonance imaging
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228839
SN - 2227-9059
VL - 9
IS - 2
ER -
TY - JOUR
A1 - Rickert, V.
A1 - Wagenhäuser, L.
A1 - Nordbeck, P.
A1 - Wanner, C.
A1 - Sommer, C.
A1 - Rost, S.
A1 - Üçeyler, N.
T1 - Stratification of Fabry mutations in clinical practice: a closer look at α‐galactosidase A‐3D structure
JF - Journal of Internal Medicine
N2 - Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
KW - Fabry disease
KW - Fabry genotype
KW - Fabry phenotype
KW - lyso‐Gb3
KW - α‐GalA 3D‐structure
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218125
VL - 288
IS - 5
SP - 593
EP - 604
ER -
TY - JOUR
A1 - Kraft, Peter
A1 - Drechsler, Christiane
A1 - Gunreben, Ignaz
A1 - Heuschmann, Peter Ulrich
A1 - Kleinschnitz, Christoph
T1 - Regulation of Blood Coagulation Factors XI and XII in Patients with Acute and Chronic Cerebrovascular Disease: A Case-Control Study
JF - Cerebrovascular Diseases
N2 - Background: Animal models have implicated an integral role for coagulation factors XI (FXI) and XII (FXII) in thrombus formation and propagation of ischemic stroke (IS). However, it is unknown if these molecules contribute to IS pathophysiology in humans, and might be of use as biomarkers for IS risk and severity. This study aimed to identify predictors of altered FXI and FXII levels and to determine whether there are differences in the levels of these coagulation factors between acute cerebrovascular events and chronic cerebrovascular disease (CCD). Methods: In this case-control study, 116 patients with acute ischemic stroke (AIS) or transitory ischemic attack (TIA), 117 patients with CCD, and 104 healthy volunteers (HVs) were enrolled between 2010 and 2013 at our University hospital. Blood sampling was undertaken once in the CCD and HV groups and on days 0, 1, and 3 after stroke onset in patients with AIS or TIA. Correlations between serum FXI and FXII levels and demographic and clinical parameters were tested by linear regression and analysis of variance. Results: The mean age of AIS/TIA patients was 70 ± 12. Baseline clinical severity measured with NIHSS and Barthel Index was 4.8 ± 6.0 and 74 ± 30, respectively. More than half of the patients had an AIS (58%). FXI levels were significantly correlated with different leukocyte subsets (p < 0.05). In contrast, FXII serum levels showed no significant correlation (p > 0.1). Neither FXI nor FXII levels correlated with CRP (p > 0.2). FXII levels were significantly higher in patients with CCD compared with those with AIS/TIA (mean ± SD 106 ± 26% vs. 97 ± 24%; univariate analysis: p < 0.05); these differences did not reach significance in multivariate analysis adjusted for sex and age. FXI levels did not differ significantly between study groups. Sex and age were significantly associated with FXI and/or FXII levels in patients with AIS/TIA (p < 0.05). In contrast, no statistical significant influence was found for treatment modality (thrombolysis or not), pre-treatment with platelet inhibitors, and severity of stroke. Conclusions: In this study, there was no differential regulation of FXI and FXII levels between disease subtypes but biomarker levels were associated with patient and clinical characteristics. FXI and FXII levels might be no valid biomarker for predicting stroke risk.
KW - biomarker
KW - factor XI
KW - factor XII
KW - ischemic stroke
KW - chronic cerebrovascular disease
Y1 - 2014
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199076
SN - 1015-9770
SN - 1421-9786
N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL - 38
IS - 5
ER -
TY - JOUR
A1 - Hock, Michael
A1 - Terekhov, Maxim
A1 - Stefanescu, Maria Roxana
A1 - Lohr, David
A1 - Herz, Stefan
A1 - Reiter, Theresa
A1 - Ankenbrand, Markus
A1 - Kosmala, Aleksander
A1 - Gassenmaier, Tobias
A1 - Juchem, Christoph
A1 - Schreiber, Laura Maria
T1 - B\(_{0}\) shimming of the human heart at 7T
JF - Magnetic Resonance in Medicine
N2 - Purpose
Inhomogeneities of the static magnetic B\(_{0}\) field are a major limiting factor in cardiac MRI at ultrahigh field (≥ 7T), as they result in signal loss and image distortions. Different magnetic susceptibilities of the myocardium and surrounding tissue in combination with cardiac motion lead to strong spatio‐temporal B\(_{0}\)‐field inhomogeneities, and their homogenization (B0 shimming) is a prerequisite. Limitations of state‐of‐the‐art shimming are described, regional B\(_{0}\) variations are measured, and a methodology for spherical harmonics shimming of the B\(_{0}\) field within the human myocardium is proposed.
Methods
The spatial B\(_{0}\)‐field distribution in the heart was analyzed as well as temporal B\(_{0}\)‐field variations in the myocardium over the cardiac cycle. Different shim region‐of‐interest selections were compared, and hardware limitations of spherical harmonics B\(_{0}\) shimming were evaluated by calibration‐based B0‐field modeling. The role of third‐order spherical harmonics terms was analyzed as well as potential benefits from cardiac phase–specific shimming.
Results
The strongest B\(_{0}\)‐field inhomogeneities were observed in localized spots within the left‐ventricular and right‐ventricular myocardium and varied between systolic and diastolic cardiac phases. An anatomy‐driven shim region‐of‐interest selection allowed for improved B\(_{0}\)‐field homogeneity compared with a standard shim region‐of‐interest cuboid. Third‐order spherical harmonics terms were demonstrated to be beneficial for shimming of these myocardial B\(_{0}\)‐field inhomogeneities. Initial results from the in vivo implementation of a potential shim strategy were obtained. Simulated cardiac phase–specific shimming was performed, and a shim term‐by‐term analysis revealed periodic variations of required currents.
Conclusion
Challenges in state‐of‐the‐art B\(_{0}\) shimming of the human heart at 7 T were described. Cardiac phase–specific shimming strategies were found to be superior to vendor‐supplied shimming.
KW - 7 T
KW - B
KW - cardiac MRI
KW - shimming
KW - ultrahigh field
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218096
VL - 85
IS - 1
SP - 182
EP - 196
ER -
TY - JOUR
A1 - Schneider, Andreas
A1 - Gutjahr-Lengsfeld, Lena
A1 - Ritz, Eberhard
A1 - Scharnagl, Hubert
A1 - Gelbrich, Götz
A1 - Pilz, Stefan
A1 - Macdougall, Iain C.
A1 - Wanner, Christoph
A1 - Drechsler, Christiane
T1 - Longitudinal Assessments of Erythropoietin-Stimulating Agent Responsiveness and the Association with Specific Clinical Outcomes in Dialysis Patients
JF - Nephron Clinical Practice
N2 - Background: Dose requirements of erythropoietin-stimulating agents (ESAs) can vary considerably over time and may be associated with cardiovascular outcomes. We aimed to longitudinally assess ESA responsiveness over time and to investigate its association with specific clinical end points in a time-dependent approach. Methods: The German Diabetes and Dialysis study (4D study) included 1,255 diabetic dialysis patients, of whom 1,161 were receiving ESA treatment. In those patients, the erythropoietin resistance index (ERI) was assessed every 6 months during a median follow-up of 4 years. The association between the ERI and cardiovascular end points was analyzed by time-dependent Cox regression analyses with repeated ERI measures. Results: Patients had a mean age of 66 ± 8.2 years; 53% were male. During follow-up, a total of 495 patients died, of whom 136 died of sudden death and 102 of infectious death. The adjusted and time-dependent risk for sudden death was increased by 19% per 5-unit increase in the ERI (hazard ratio, HR = 1.19, 95% confidence interval, CI = 1.07-1.33). Similarly, mortality increased by 25% (HR = 1.25, 95% CI = 1.18-1.32) and infectious death increased by 27% (HR = 1.27, 95% CI = 1.13-1.42). Further analysis revealed that lower 25-hydroxyvitamin D levels were associated with lower ESA responsiveness (p = 0.046). Conclusions: In diabetic dialysis patients, we observed that time-varying erythropoietin resistance is associated with sudden death, infectious complications and all-cause mortality. Low 25-hydroxyvitamin D levels may contribute to a lower ESA responsiveness.
KW - dialysis
KW - erythropoietin
KW - diabetes
KW - epidemiology
Y1 - 2014
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196511
SN - 1660-2110
N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL - 128
IS - 1-2
ER -
TY - JOUR
A1 - de Zeeuw, Dick
A1 - Akizawa, Tadao
A1 - Agarwal, Rajiv
A1 - Audhya, Paul
A1 - Bakris, George L.
A1 - Chin, Melanie
A1 - Krauth, Melissa
A1 - Lambers Heerspink, Hiddo J.
A1 - Meyer, Colin J.
A1 - McMurray, John J.
A1 - Parving, Hans-Henrik
A1 - Pergola, Pablo E.
A1 - Remuzzi, Giuseppe
A1 - Toto, Robert D.
A1 - Vaziri, Nosratola D.
A1 - Wanner, Christoph
A1 - Warnock, David G.
A1 - Wittes, Janet
A1 - Chertow, Glenn M.
T1 - Rationale and Trial Design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: The Occurrence of Renal Events (BEACON)
JF - American Journal of Nephrology
N2 - Background: Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Methods: Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. Results: The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. Conclusion: BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD.
KW - clinical trial
KW - diabetes mellitus
KW - glomerular filtration rate
KW - trial design
KW - bardoxolone methyl
KW - Nrf2
KW - end-stage renal disease
KW - cardiovascular death
KW - chronic kidney disease
Y1 - 2013
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196832
SN - 0250-8095
SN - 1421-9670
N1 - This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.
VL - 37
IS - 3
ER -
TY - JOUR
A1 - Eiringhaus, Jörg
A1 - Wünsche, Christoph M.
A1 - Tirilomis, Petros
A1 - Herting, Jonas
A1 - Bork, Nadja
A1 - Nikolaev, Viacheslav O.
A1 - Hasenfuss, Gerd
A1 - Sossalla, Samuel
A1 - Fischer, Thomas H.
T1 - Sacubitrilat reduces pro‐arrhythmogenic sarcoplasmic reticulum Ca\(^{2+}\) leak in human ventricular cardiomyocytes of patients with end‐stage heart failure
JF - ESC Heart Failure
N2 - Aims
Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca\(^{2+}\) cycling remain elusive.
Methods and results
Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca\(^{2+}\) leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca\(^{2+}\) release, SR Ca\(^{2+}\) load, and Ca\(^{2+}\)‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca\(^{2+}\)‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca\(^{2}\) leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca\(^{2+}\) leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca\(^{2+}\) load, and Ca\(^{2+}\)‐transient kinetics including SERCA activity (k\(_{SERCA}\)) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca\(^{2+}\) leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end‐stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3).
Conclusion
This study demonstrates that neprilysin inhibitor Sac directly improves Ca\(^{2+}\) homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca\(^{2+}\) leak without acutely affecting systolic Ca\(^{2+}\) release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial.
KW - heart failure
KW - entresto
KW - Neprilysin inhibition
KW - Ca cycling
KW - SR Ca leak
KW - arrhythmia
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218479
VL - 7
IS - 5
SP - 2992
EP - 3002
ER -
TY - JOUR
A1 - Rogowski-Lehmann, Natalie
A1 - Geroula, Aikaterini
A1 - Prejbisz, Aleksander
A1 - Timmers, Henri J. L. M.
A1 - Megerle, Felix
A1 - Robledo, Mercedes
A1 - Fassnacht, Martin
A1 - Fliedner, Stephanie M. J.
A1 - Reincke, Martin
A1 - Stell, Anthony
A1 - Januszewicz, Andrzej
A1 - Lenders, Jacques W. M.
A1 - Eisenhofer, Graeme
A1 - Beuschlein, Felix
T1 - Missed clinical clues in patients with pheochromocytoma/paraganglioma discovered by imaging
JF - Endocrine Connections
N2 - Background: Pheochromocytomas and paragangliomas (PPGLs) are rare but potentially harmful tumors that can vary in their clinical presentation. Tumors may be found due to signs and symptoms, as part of a hereditary syndrome or following an imaging procedure. Objective: To investigate potential differences in clinical presentation between PPGLs discovered by imaging (iPPGLs), symptomatic cases (sPPGLs) and those diagnosed during follow-up because of earlier disease/known hereditary mutations (fPPGL). Design: Prospective study protocol, which has enrolled patients from six European centers with confirmed PPGLs. Data were analyzed from 235 patients (37 iPPGLs, 36 sPPGLs, 27% fPPGLs) and compared for tumor volume, biochemical profile, mutation status, presence of metastases and self-reported symptoms. iPPGL patients were diagnosed at a significantly higher age than fPPGLs (P<0.001), found to have larger tumors (P=0.003) and higher metanephrine and normetanephrine levels at diagnosis (P=0.021). Significantly lower than in sPPGL, there was a relevant number of self-reported symptoms in iPPGL (2.9 vs 4.3 symptoms, P< 0.001). In 16.2% of iPPGL, mutations in susceptibility genes were detected, although this proportion was lower than that in fPPGL (60.9%) and sPPGL (21.5%). Patients with PPGLs detected by imaging were older, have higher tumor volume and more excessive hormonal secretion in comparison to those found as part of a surveillance program. Presence of typical symptoms indicates that in a relevant proportion of those patients, the PPGL diagnosis had been delayed. Precis: Pheochromocytoma/paraganglioma discovered by imaging are often symptomatic and carry a significant proportion of germline mutations in susceptibility genes.
KW - pheochromocytoma
KW - paraganglioma
KW - imaging
KW - signs and symptoms
KW - prospective
KW - Biochemical-Diagnosis
KW - Plasma
KW - MASS
KW - Normetanephrine
KW - Metanephrine
KW - Paraganglioma
KW - Society
KW - Utility
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226481
VL - 7
IS - 11
ER -
TY - JOUR
A1 - Sailer, Clara Odilia
A1 - Wiedemann, Sophia Julia
A1 - Strauss, Konrad
A1 - Schnyder, Ingeborg
A1 - Fenske, Wiebke Kristin
A1 - Christ-Crain, Mirjam
T1 - Markers of systemic inflammation in response to osmotic stimulus in healthy volunteers
JF - Endocrine Connections
N2 - Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.
KW - TNF-alpha
KW - interleukin-8
KW - interleukin-6
KW - copeptin
KW - hyperosmolality
KW - Hyperosmotic Stress
KW - Interleukin-6
KW - Expression
KW - Protein
KW - Neurons
Y1 - 2019
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227204
VL - 8
IS - 9
ER -
TY - JOUR
A1 - Refardt, Julie
A1 - Sailer, Clara Odilia
A1 - Winzeler, Bettina
A1 - Betz, Matthias Johannes
A1 - Chifu, Irina
A1 - Schnyder, Ingeborg
A1 - Fassnacht, Martin
A1 - Fenske, Wiebke
A1 - Christ-Crain, Mirjam
T1 - FGF-21 levels in polyuria-polydipsia syndrome
JF - Endocrine Connections
N2 - The pathomechanism of primary polydipsia is poorly understood. Recent animal data reported a connection between fibroblast growth factor 21 (FGF-21) and elevated fluid intake independently of hormonal control by the hormone arginine-vasopressin (AVP) and osmotic stimulation. We therefore compared circulating FGF-21 levels in patients with primary polydipsia to patients with AVP deficiency (central diabetes insipidus) and healthy volunteers. In this prospective cohort study, we analyzed FGF-21 levels of 20 patients with primary polydipsia, 20 patients with central diabetes insipidus and 20 healthy volunteers before and after stimulation with hypertonic saline infusion targeting a plasma sodium level >= 150 mmol/L. The primary outcome was the difference in FGF-21 levels between the three groups. Baseline characteristics were similar between the groups except for patients with central diabetes insipidus being heavier. There was no difference in baseline FGF-21 levels between patients with primary polydipsia and healthy volunteers (122 pg/mL (52,277) vs 193 pg/mL (48,301), but higher levels in patients with central diabetes insipidus were observed (306 pg/mL (114,484); P=0.037). However, this was not confirmed in a multivariate linear regression analysis after adjusting for age, sex, BMI and smoking status. Osmotic stimulation did not affect FGF-21 levels in either group (difference to baseline: primary polydipsia -23 pg/mL (-43, 22); central diabetes insipidus 17 pg/mL (-76, 88); healthy volunteers -6 pg/mL (-68, 22); P=0.45). To conclude, FGF-21 levels are not increased in patients with primary polydipsia as compared to central diabetes insipidus or healthy volunteers. FGF-21 therefore does not seem to be causal of elevated fluid intake in these patients.
KW - FGF21
KW - diabetes insipidus
KW - primary polydipsia
KW - osmotic stimulation
KW - copeptin
KW - Fibroblast Growth Factor-21
KW - Klotho-related molecules
KW - Copeptin
KW - Diagnosis
KW - PF-05231023
KW - Resistance
KW - Men
Y1 - 2018
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-225085
VL - 7
IS - 12
ER -
TY - JOUR
A1 - Notz, Quirin
A1 - Lotz, Christopher
A1 - Herrmann, Johannes
A1 - Vogt, Marius
A1 - Schlesinger, Tobias
A1 - Kredel, Markus
A1 - Muellges, Wolfgang
A1 - Weismann, Dirk
A1 - Westermaier, Thomas
A1 - Meybohm, Patrick
A1 - Kranke, Peter
T1 - Severe neurological complications in critically ill COVID‑19 patients
JF - Journal of Neurology
N2 - No abstract available.
KW - COVID-19
KW - neurological complications
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232429
SN - 0340-5354
ER -
TY - JOUR
A1 - Aghai, Fatemeh
A1 - Zimmermann, Sebastian
A1 - Kurlbaum, Max
A1 - Jung, Pius
A1 - Pelzer, Theo
A1 - Klinker, Hartwig
A1 - Isberner, Nora
A1 - Scherf-Clavel, Oliver
T1 - Development and validation of a sensitive liquid chromatography tandem mass spectrometry assay for the simultaneous determination of ten kinase inhibitors in human serum and plasma
JF - Analytical and Bioanalytical Chemistry
N2 - A liquid chromatography tandem mass spectrometry method for the analysis of ten kinase inhibitors (afatinib, axitinib, bosutinib,cabozantinib, dabrafenib, lenvatinib, nilotinib, osimertinib, ruxolitinib, and trametinib) in human serum and plasma for theapplication in daily clinical routine has been developed and validated according to the US Food and Drug Administration andEuropean Medicines Agency validation guidelines for bioanalytical methods. After protein precipitation of plasma samples withacetonitrile, chromatographic separation was performed at ambient temperature using a Waters XBridge® Phenyl 3.5μm(2.1×50 mm) column. The mobile phases consisted of water-methanol (9:1, v/v) with 10 mM ammonium bicarbonate as phase A andmethanol-water (9:1, v/v) with 10 mM ammonium bicarbonate as phase B. Gradient elution was applied at a flow rate of 400μL/min. Analytes were detected and quantified using multiple reaction monitoring in electrospray ionization positive mode. Stableisotopically labeled compounds of each kinase inhibitor were used as internal standards. The acquisition time was 7.0 min perrun. All analytes and internal standards eluted within 3.0 min. The calibration curves were linear over the range of 2–500 ng/mLfor afatinib, axitinib, bosutinib, lenvatinib, ruxolitinib, and trametinib, and 6–1500 ng/mL for cabozantinib, dabrafenib, nilotinib,and osimertinib (coefficients of correlation≥0.99). Validation assays for accuracy and precision, matrix effect, recovery,carryover, and stability were appropriate according to regulatory agencies. The rapid and sensitive assay ensures high throughputand was successfully applied to monitor concentrations of kinase inhibitors in patients.
KW - kinase inhibitors
KW - therapeutic drug monitoring
KW - liquid chromatography tandem mass spectrometry (LC-MS/MS
KW - afatinib
KW - osimertinib
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231925
SN - 1618-2642
VL - 413
ER -
TY - JOUR
A1 - Haring, Bernhard
A1 - Reiner, Alexander P.
A1 - Liu, Jungmin
A1 - Tobias, Deirdre K.
A1 - Whitsel, Eric
A1 - Berger, Jeffrey S.
A1 - Desai, Pinkal
A1 - Wassertheil-Smoller, Sylvia
A1 - LaMonte, Michael J.
A1 - Hayden, Kathleen
A1 - Bick, Alexander G.
A1 - Natarajan, Pradeep
A1 - Weinstock, Joshua S.
A1 - Nguyen, Patricia K.
A1 - Stefanick, Marcia
A1 - Simon, Michael S.
A1 - Eaton, Charles
A1 - Kooperberg, Charles
A1 - Manson, JoAnn E.
T1 - Healthy Lifestyle and Clonal Hematopoiesis of Indeterminate Potential. Results from the Women’s Health Initiative
JF - Journal of the American Heart Association
N2 - Background
Presence of clonal hematopoiesis of indeterminate potential (CHIP) is associated with a higher risk of atherosclerotic cardiovascular disease, cancer, and mortality. The relationship between a healthy lifestyle and CHIP is unknown.
Methods and Results
This analysis included 8709 postmenopausal women (mean age, 66.5 years) enrolled in the WHI (Women's Health Initiative), free of cancer or cardiovascular disease, with deep‐coverage whole genome sequencing data available. Information on lifestyle factors (body mass index, smoking, physical activity, and diet quality) was obtained, and a healthy lifestyle score was created on the basis of healthy criteria met (0 point [least healthy] to 4 points [most healthy]). CHIP was derived on the basis of a prespecified list of leukemogenic driver mutations. The prevalence of CHIP was 8.6%. A higher healthy lifestyle score was not associated with CHIP (multivariable‐adjusted odds ratio [OR] [95% CI], 0.99 [0.80–1.23] and 1.13 [0.93–1.37]) for the upper (3 or 4 points) and middle category (2 points), respectively, versus referent (0 or 1 point). Across score components, a normal and overweight body mass index compared with obese was significantly associated with a lower odds for CHIP (OR, 0.71 [95% CI, 0.57–0.88] and 0.83 [95% CI, 0.68–1.01], respectively; P‐trend 0.0015). Having never smoked compared with being a current smoker tended to be associated with lower odds for CHIP.
Conclusions
A healthy lifestyle, based on a composite score, was not related to CHIP among postmenopausal women. However, across individual lifestyle factors, having a normal body mass index was strongly associated with a lower prevalence of CHIP. These findings support the idea that certain healthy lifestyle factors are associated with a lower frequency of CHIP.
KW - body mass index
KW - clonal hematopoiesis of indeterminate potential
KW - diet
KW - lifestyle
KW - physical activity
KW - smoking
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236146
VL - 10
IS - 5
ER -
TY - JOUR
A1 - Kolokotronis, Konstantinos
A1 - Pluta, Natalie
A1 - Klopocki, Eva
A1 - Kunstmann, Erdmute
A1 - Messroghli, Daniel
A1 - Maack, Christoph
A1 - Tejman-Yarden, Shai
A1 - Arad, Michael
A1 - Rost, Simone
A1 - Gerull, Brenda
T1 - New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis
JF - Journal of Clinical Medicine
N2 - Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.
KW - cardiomyopathy
KW - cardiogenetics
KW - whole exome sequencing
KW - targeted gene panel
KW - candidate genes
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236094
VL - 9
IS - 7
ER -
TY - JOUR
A1 - Frey, Anna
A1 - Gassenmaier, Tobias
A1 - Hofmann, Ulrich
A1 - Schmitt, Dominik
A1 - Fette, Georg
A1 - Marx, Almuth
A1 - Heterich, Sabine
A1 - Boivin-Jahns, Valérie
A1 - Ertl, Georg
A1 - Bley, Thorsten
A1 - Frantz, Stefan
A1 - Jahns, Roland
A1 - Störk, Stefan
T1 - Coagulation factor XIII activity predicts left ventricular remodelling after acute myocardial infarction
JF - ESC Heart Failure
N2 - Aims Acute myocardial infarction (MI) is the major cause of chronic heart failure. The activity of blood coagulation factor XIII (FXIIIa) plays an important role in rodents as a healing factor after MI, whereas its role in healing and remodelling processes in humans remains unclear. We prospectively evaluated the relevance of FXIIIa after acute MI as a potential early prognostic marker for adequate healing.
Methods and results This monocentric prospective cohort study investigated cardiac remodelling in patients with ST-elevation MI and followed them up for 1 year. Serum FXIIIa was serially assessed during the first 9 days after MI and after 2, 6, and 12 months. Cardiac magnetic resonance imaging was performed within 4 days after MI (Scan 1), after 7 to 9 days (Scan 2), and after 12 months (Scan 3). The FXIII valine-to-leucine (V34L) single-nucleotide polymorphism rs5985 was genotyped. One hundred forty-six patients were investigated (mean age 58 ± 11 years, 13% women). Median FXIIIa was 118 % (quartiles, 102–132%) and dropped to a trough on the second day after MI: 109%(98–109%; P < 0.001). FXIIIa recovered slowly over time, reaching the baseline level after 2 to 6 months and surpassed baseline levels only after 12 months: 124 % (110–142%). The development of FXIIIa after MI was independent of the genotype. FXIIIa on Day 2 was strongly and inversely associated with the relative size of MI in Scan 1 (Spearman’s ρ = –0.31; P = 0.01) and Scan 3 (ρ = –0.39; P < 0.01) and positively associated with left ventricular ejection fraction: ρ = 0.32 (P < 0.01) and ρ = 0.24 (P = 0.04), respectively.
Conclusions FXIII activity after MI is highly dynamic, exhibiting a significant decline in the early healing period, with reconstitution 6 months later. Depressed FXIIIa early after MI predicted a greater size of MI and lower left ventricular ejection fraction after 1 year. The clinical relevance of these findings awaits to be tested in a randomized trial.
KW - blood coagulation factor XIII
KW - ST-elevation myocardial infarction
KW - healing and remodelling processes
KW - cardiac magnetic resonance imaging
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236013
VL - 7
IS - 5
ER -
TY - JOUR
A1 - Wanner, Christoph
A1 - Feldt-Rasmussen, Ulla
A1 - Jovanovic, Ana
A1 - Linhart, Aleš
A1 - Yang, Meng
A1 - Ponce, Elvira
A1 - Brand, Eva
A1 - Germain, Dominique P.
A1 - Hughes, Derralynn A.
A1 - Jefferies, John L.
A1 - Martins, Anna Maria
A1 - Nowak, Albina
A1 - Vujkovac, Bojan
A1 - Weidemann, Frank
A1 - West, Michael L.
A1 - Ortiz, Alberto
T1 - Cardiomyopathy and kidney function in agalsidase beta-treated female Fabry patients: a pre-treatment vs. post-treatment analysis
JF - ESC Heart Failure
N2 - Long-term treatment effect studies in large female Fabry patient groups are challenging to design because of phenotype heterogeneity and lack of appropriate comparison groups, and have not been reported. We compared long-term cardiomyopathy and kidney function outcomes after agalsidase beta treatment with preceding treatment-naive outcomes.
Methods and results Self-controlled pretreatment and post-treatment comparison (piecewise mixed linear modelling) included Fabry female patients ≥18 years at treatment initiation who received agalsidase beta (0.9–1.1 mg/kg every other week) for ≥2 years, with ≥2 pretreatment and ≥2 post-treatment outcome measurements during 10-year follow-up. Left ventricular posterior wall thickness (LVPWT)/interventricular septal thickness (IVST) and estimated glomerular filtration rate (eGFR, Chronic Kidney Disease Epidemiology Collaboration creatinine equation) analyses included 42 and 86 patients, respectively, aged 50.0 and 46.3 years at treatment initiation, respectively. LVPWT and IVST increased pretreatment (follow-up 3.5 years) but stabilized during 3.6 years of treatment (LVPWT: n = 38, slope difference [95% confidence interval (CI)] = - 0.41 [ - 0.68, - 0.15] mm/year, P\(_{pre–post difference}\)<0.01; IVST: n = 38, slope difference =-0.32 [-0.67, 0.02] mm/year, P\(_{pre–post difference}\) = 0.07). These findings were not modified by renal involvement or antiproteinuric agent use. Compared with the treatment-naive period (follow-up 3.6 years), eGFR decline remained modest and stabilized within normal ranges during 4.1 years of treatment (slope difference, 95% CI: -0.13 [-1.15, 0.89] mL/min/1.73m\(^2\)/year, P\(_{pre–post difference}\) = 0.80).
Conclusions Cardiac hypertrophy, progressing during pretreatment follow-up, appeared to stabilize during sustained agalsidase beta treatment. eGFR decline remained within normal ranges. This suggests that treatment may prevent further Fabry-related progression of cardiomyopathy in female patients and maintain normal kidney function.
KW - Agalsidase beta
KW - Enzyme replacement therapy
KW - Fabry disease
KW - Cardiomyopathy
KW - Kidney function
KW - Female patients
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235963
VL - 7
IS - 3
ER -
TY - JOUR
A1 - Mitchell, Jonathan S.
A1 - Li, Ni
A1 - Weinhold, Niels
A1 - Försti, Asta
A1 - Ali, Mina
A1 - van Duin, Mark
A1 - Thorleifsson, Gudmar
A1 - Johnson, David C.
A1 - Chen, Bowang
A1 - Halvarsson, Britt-Marie
A1 - Gudbjartsson, Daniel F.
A1 - Kuiper, Rowan
A1 - Stephens, Owen W.
A1 - Bertsch, Uta
A1 - Broderick, Peter
A1 - Campo, Chiara
A1 - Einsele, Hermann
A1 - Gregory, Walter A.
A1 - Gullberg, Urban
A1 - Henrion, Marc
A1 - Hillengass, Jens
A1 - Hoffmann, Per
A1 - Jackson, Graham H.
A1 - Johnsson, Ellinor
A1 - Jöud, Magnus
A1 - Kristinsson, Sigurdur Y.
A1 - Lenhoff, Stig
A1 - Lenive, Oleg
A1 - Mellqvist, Ulf-Henrik
A1 - Migliorini, Gabriele
A1 - Nahi, Hareth
A1 - Nelander, Sven
A1 - Nickel, Jolanta
A1 - Nöthen, Markus M.
A1 - Rafnar, Thorunn
A1 - Ross, Fiona M.
A1 - da Silva Filho, Miguel Inacio
A1 - Swaminathan, Bhairavi
A1 - Thomsen, Hauke
A1 - Turesson, Ingemar
A1 - Vangsted, Annette
A1 - Vogel, Ulla
A1 - Waage, Anders
A1 - Walker, Brian A.
A1 - Wihlborg, Anna-Karin
A1 - Broyl, Annemiek
A1 - Davies, Faith E.
A1 - Thorsteinsdottir, Unnur
A1 - Langer, Christian
A1 - Hansson, Markus
A1 - Kaiser, Martin
A1 - Sonneveld, Pieter
A1 - Stefansson, Kari
A1 - Morgan, Gareth J.
A1 - Goldschmidt, Hartmut
A1 - Hemminki, Kari
A1 - Nilsson, Björn
A1 - Houlston, Richard S.
T1 - Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
JF - Nature Communications
N2 - Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10−8), 6q21 (rs9372120, P=9.09 × 10−15), 7q36.1 (rs7781265, P=9.71 × 10−9), 8q24.21 (rs1948915, P=4.20 × 10−11), 9p21.3 (rs2811710, P=1.72 × 10−13), 10p12.1 (rs2790457, P=1.77 × 10−8), 16q23.1 (rs7193541, P=5.00 × 10−12) and 20q13.13 (rs6066835, P=1.36 × 10−13), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
KW - Cancer genetics
KW - Genome-wide association studies
KW - Myeloma
Y1 - 2016
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165983
VL - 7
ER -
TY - JOUR
A1 - Landwehr, Laura-Sophie
A1 - Altieri, Barbara
A1 - Schreiner, Jochen
A1 - Sbiera, Iuliu
A1 - Weigand, Isabel
A1 - Kroiss, Matthias
A1 - Fassnacht, Martin
A1 - Sbiera, Silviu
T1 - Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma
JF - Journal for ImmunoTherapy of Cancer
N2 - Background
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy.
Methods
We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess).
Results
86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess).
Conclusion
Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies.
KW - immunity
KW - immunotherapy
KW - lymphocytes
KW - tumor-infiltrating
KW - t-lymphocytes
KW - tumor microenvironment
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229893
VL - 8
ER -
TY - JOUR
A1 - Grebe, Sören Jendrik
A1 - Malzahn, Uwe
A1 - Donhauser, Julian
A1 - Liu, Dan
A1 - Wanner, Christoph
A1 - Krane, Vera
A1 - Hammer, Fabian
T1 - Quantification of left ventricular mass by echocardiography compared to cardiac magnet resonance imaging in hemodialysis patients
JF - Cardiovascular Ultrasound
N2 - Background: Left ventricular hypertrophy (LVH), defined by the left ventricular mass index (LVMI), is highly prevalent in hemodialysis patients and a strong independent predictor of cardiovascular events. Compared to cardiac magnetic resonance imaging (CMR), echocardiography tends to overestimate the LVMI. Here, we evaluate the diagnostic performance of transthoracic echocardiography (TTE) compared to CMR regarding the assessment of LVMI in hemodialysis patients.
Methods: TTR and CMR data for 95 hemodialysis patients who participated in the MiREnDa trial were analyzed. The LVMI was calculated by two-dimensional (2D) TTE-guided M-mode measurements employing the American Society of Echocardiography (ASE) and Teichholz (Th) formulas, which were compared to the reference method, CMR.
Results: LVH was present in 44% of patients based on LVMI measured by CMR. LVMI measured by echocardiography correlated moderately with CMR, ASE: r = 0.44 (0.34-0.62); Th: r = 0.44 (0.32-0.62). Compared to CMR, both echocardiographic formulas overestimated LVMI (mean increment LVMI (ASE-CMR): 19.5 +/- 19.48 g/m(2),p < 0.001; mean increment LVMI (Th-CMR): 15.9 +/- 15.89 g/m(2),p < 0.001). We found greater LVMI overestimation in patients with LVH using the ASE formula compared to the Th formula. Stratification of patients into CMR LVMI quartiles showed a continuous decrease in increment LVMI with increasing CMR LVMI quartiles for the Th formula (p < 0.001) but not for the ASE formula (p = 0.772). Bland-Altman analysis showed that the Th formula had a constant bias independent of LVMI. Both methods had good discrimination ability for the detection of LVH (ROC-AUC: 0.819 (0.737-0.901) and 0.808 (0.723-0.892) for Th and ASE, respectively).
Conclusions: The ASE and Th formulas overestimate LVMI in hemodialysis patients. However, the overestimation is less with the Th formula, particularly with increasing LVMI. The results suggest that the Th formula should be preferred for measurement of LVMI in chronic hemodialysis patients.
KW - Teichholz formula
KW - ASE formula
KW - echocardiography
KW - left ventricular hypertrophy
KW - left ventricular mass index
KW - hemodialysis
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229282
VL - 18
ER -
TY - JOUR
A1 - Albert, Judith
A1 - Lezius, Susanne
A1 - Störk, Stefan
A1 - Morbach, Caroline
A1 - Güder, Gülmisal
A1 - Frantz, Stefan
A1 - Wegscheider, Karl
A1 - Ertl, Georg
A1 - Angermann, Christiane E.
T1 - Trajectories of Left Ventricular Ejection Fraction After Acute Decompensation for Systolic Heart Failure: Concomitant Echocardiographic and Systemic Changes, Predictors, and Impact on Clinical Outcomes
JF - Journal of the American Heart Association
N2 - Prospective longitudinal follow‐up of left ventricular ejection fraction (LVEF) trajectories after acute cardiac decompensation of heart failure is lacking. We investigated changes in LVEF and covariates at 6‐months' follow‐up in patients with a predischarge LVEF ≤40%, and determined predictors and prognostic implications of LVEF changes through 18‐months' follow‐up.
Methods and Results
Interdisciplinary Network Heart Failure program participants (n=633) were categorized into subgroups based on LVEF at 6‐months' follow‐up: normalized LVEF (>50%; heart failure with normalized ejection fraction, n=147); midrange LVEF (41%–50%; heart failure with midrange ejection fraction, n=195), or persistently reduced LVEF (≤40%; heart failure with persistently reduced LVEF , n=291). All received guideline‐directed medical therapies. At 6‐months' follow‐up, compared with patients with heart failure with persistently reduced LVEF, heart failure with normalized LVEF or heart failure with midrange LVEF subgroups showed greater reductions in LV end‐diastolic/end‐systolic diameters (both P<0.001), and left atrial systolic diameter (P=0.002), more increased septal/posterior end‐diastolic wall‐thickness (both P<0.001), and significantly greater improvement in diastolic function, biomarkers, symptoms, and health status. Heart failure duration <1 year, female sex, higher predischarge blood pressure, and baseline LVEF were independent predictors of LVEF improvement. Mortality and event‐free survival rates were lower in patients with heart failure with normalized LVEF (P=0.002). Overall, LVEF increased further at 18‐months' follow‐up (P<0.001), while LV end‐diastolic diameter decreased (P=0.048). However, LVEF worsened (P=0.002) and LV end‐diastolic diameter increased (P=0.047) in patients with heart failure with normalized LVEF hospitalized between 6‐months' follow‐up and 18‐months' follow‐up.
Conclusions
Six‐month survivors of acute cardiac decompensation for systolic heart failure showed variable LVEF trajectories, with >50% showing improvements by ≥1 LVEF category. LVEF changes correlated with various parameters, suggesting multilevel reverse remodeling, were predictable from several baseline characteristics, and were associated with clinical outcomes at 18‐months' follow‐up. Repeat hospitalizations were associated with attenuation of reverse remodeling."
KW - acute heart failure
KW - left ventricular ejection fraction
KW - morbidity
KW - mortality
KW - natriuretic peptide
KW - recovery
Y1 - 2021
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230210
VL - 10
ER -
TY - JOUR
A1 - Riedl, Katharina A.
A1 - Kampf, Thomas
A1 - Herold, Volker
A1 - Behr, Volker C.
A1 - Bauer, Wolfgang R.
T1 - Wall shear stress analysis using 17.6 Tesla MRI: A longitudinal study in ApoE\(^{-/-}\)mice with histological analysis
JF - PLoS One
N2 - This longitudinal study was performed to evaluate the feasibility of detecting the interaction between wall shear stress (WSS) and plaque development. 20 ApoE\(^{-/-}\)mice were separated in 12 mice with Western Diet and 8 mice with Chow Diet. Magnetic resonance (MR) scans at 17.6 Tesla and histological analysis were performed after one week, eight and twelve weeks. Allin vivoMR measurements were acquired using a flow sensitive phase contrast method for determining vectorial flow. Histological sections were stained with Hematoxylin and Eosin, Elastica van Gieson and CD68 staining. Data analysis was performed using Ensight and a Matlab-based "Flow Tool". The body weight of ApoE\(^{-/-}\)mice increased significantly over 12 weeks. WSS values increased in the Western Diet group over the time period; in contrast, in the Chow Diet group the values decreased from the first to the second measurement point. Western Diet mice showed small plaque formations with elastin fragmentations after 8 weeks and big plaque formations after 12 weeks; Chow Diet mice showed a few elastin fragmentations after 8 weeks and small plaque formations after 12 weeks. Favored by high-fat diet, plaque formation results in higher values of WSS. With wall shear stress being a known predictor for atherosclerotic plaque development, ultra highfield MRI can serve as a tool for studying the causes and beginnings of atherosclerosis.
KW - phase-contrast MRI
KW - flow patterns
KW - blood flow
KW - apolipoprotein-E
KW - atheriosclerosis
KW - mouse
KW - mice
KW - quantification
KW - association
KW - lesions
Y1 - 2020
U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229318
VL - 15
IS - 8
ER -