TY  - JOUR
A1  - Lippert, Juliane
A1  - Fassnacht, Martin
A1  - Ronchi, Cristina L.
T1  - The role of molecular profiling in adrenocortical carcinoma
JF  - Clinical Endocrinology
N2  - Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.
KW  - adrenocortical cancer
KW  - biomarkers
KW  - precision medicine
KW  - prognosis
KW  - targeted treatment
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258382
VL  - 97
IS  - 4
ER  - 
TY  - JOUR
A1  - Basile, Vittoria
A1  - Puglisi, Soraya
A1  - Altieri, Barbara
A1  - Canu, Letizia
A1  - Libè, Rossella
A1  - Ceccato, Filippo
A1  - Beuschlein, Felix
A1  - Quinkler, Marcus
A1  - Calabrese, Anna
A1  - Perotti, Paola
A1  - Berchialla, Paola
A1  - Dischinger, Ulrich
A1  - Megerle, Felix
A1  - Baudin, Eric
A1  - Bourdeau, Isabelle
A1  - Lacroix, André
A1  - Loli, Paola
A1  - Berruti, Alfredo
A1  - Kastelan, Darko
A1  - Haak, Harm R.
A1  - Fassnacht, Martin
A1  - Terzolo, Massimo
T1  - What is the optimal duration of adjuvant mitotane therapy in adrenocortical carcinoma? An unanswered question
JF  - Journal of Personalized Medicine
N2  - A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.
KW  - mitotane
KW  - adjuvant treatment
KW  - adrenocortical cancer
KW  - recurrence
KW  - recurrence free survival
KW  - timing
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236507
SN  - 2075-4426
VL  - 11
IS  - 4
ER  - 
TY  - JOUR
A1  - Traub, Jan
A1  - Husseini, Leila
A1  - Weber, Martin S.
T1  - B cells and antibodies as targets of therapeutic intervention in neuromyelitis optica spectrum disorders
JF  - Pharmaceuticals
N2  - The first description of neuromyelitis optica by Eugène Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.
KW  - neuromyelitis optica spectrum disorders
KW  - B cells
KW  - antibodies
KW  - eculizumab
KW  - ravulizumab
KW  - inebilizumab
KW  - tocilizumab
KW  - satralizumab
KW  - ublituximab
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222957
SN  - 1424-8247
VL  - 14
IS  - 1
ER  - 
TY  - JOUR
A1  - Altieri, Barbara
A1  - Di Dato, Carla
A1  - Modica, Roberta
A1  - Bottiglieri, Filomena
A1  - Di Sarno, Antonella
A1  - Pittaway, James F.H.
A1  - Martini, Chiara
A1  - Faggiano, Antongiulio
A1  - Colao, Annamaria
T1  - Bone metabolism and vitamin D implication in gastroenteropancreatic neuroendocrine tumors
JF  - Nutrients
N2  - Patients affected by gastroenteropancreatic–neuroendocrine tumors (GEP–NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP–NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP–NET, focusing on vitamin D and its role in GEP–NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.
KW  - bone
KW  - vitamin D
KW  - neuroendocrine tumor
KW  - osteoporosis
KW  - mineral bone density
KW  - cortisol
KW  - serotonin
KW  - miRNA
KW  - MEN1
KW  - therapy
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203823
SN  - 2072-6643
VL  - 12
IS  - 4
ER  - 
TY  - JOUR
A1  - Hankir, Mohammed K.
A1  - Rotzinger, Laura
A1  - Nordbeck, Arno
A1  - Corteville, Caroline
A1  - Dischinger, Ulrich
A1  - Knop, Juna-Lisa
A1  - Hoffmann, Annett
A1  - Otto, Christoph
A1  - Seyfried, Florian
T1  - Leptin receptors are not required for Roux-en-Y gastric bypass surgery to normalize energy and glucose homeostasis in rats
JF  - Nutrients
N2  - Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.
KW  - Roux-en-Y gastric bypass surgery
KW  - energy homeostasis
KW  - glucose homeostasis
KW  - fatty liver
KW  - leptin system
KW  - Zucker fatty fa/fa rats
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239550
SN  - 2072-6643
VL  - 13
IS  - 5
ER  - 
TY  - JOUR
A1  - Sahiti, Floran
A1  - Morbach, Caroline
A1  - Cejka, Vladimir
A1  - Tiffe, Theresa
A1  - Wagner, Martin
A1  - Eichner, Felizitas A.
A1  - Gelbrich, Götz
A1  - Heuschmann, Peter U.
A1  - Störk, Stefan
T1  - Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study
JF  - Journal of Human Hypertension
N2  - Myocardial work is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops, and has been validated against invasively derived pressure-volume measurements. Myocardial work is described by its components (global constructive work [GCW], global wasted work [GWW]) and indices (global work index [GWI], global work efficiency [GWE]). Applying this innovative concept, we characterized the prevalence and severity of subclinical left ventricular compromise in the general population and estimated its association with cardiovascular (CV) risk factors. Within the Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study we comprehensively phenotyped a representative sample of the population of Würzburg, Germany, aged 30-79 years. Indices of myocardial work were determined in 1929 individuals (49.3% female, mean age 54 ± 12 years). In multivariable analysis, hypertension was associated with a mild increase in GCW, but a profound increase in GWW, resulting in higher GWI and lower GWE. All other CV risk factors were associated with lower GCW and GWI, but not with GWW. The association of hypertension and obesity with GWI was stronger in women. We conclude that traditional CV risk factors impact selectively and gender-specifically on left ventricular myocardial performance, independent of systolic blood pressure. Quantifying active systolic and diastolic compromise by derivation of myocardial work advances our understanding of pathophysiological processes in health and cardiac disease.
KW  - myocardial work
KW  - left ventricular performance
KW  - cardiovascular risk factors
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271770
SN  - 1476-5527
VL  - 36
IS  - 3
ER  - 
TY  - JOUR
A1  - Hauser, T.
A1  - Dornberger, V.
A1  - Malzahn, U.
A1  - Grebe, S. J.
A1  - Liu, D.
A1  - Störk, S.
A1  - Nauck, M.
A1  - Friedrich, N.
A1  - Dörr, M.
A1  - Wanner, C.
A1  - Krane, V.
A1  - Hammer, F.
T1  - The effect of spironolactone on diastolic function in haemodialysis patients
JF  - The International Journal of Cardiovascular Imaging
N2  - Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5% female) with preserved left ventricular ejection fraction (LVEF > 50%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m\(^{2}\) vs. 1.7 ± 14.1 ml/m\(^{2}\), p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m\(^{2}\) vs. + 2.7 ± 15.9 g/m\(^{2}\); p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.
KW  - HFpEF
KW  - diastolic function
KW  - echocardiography
KW  - E/e’
KW  - haemodialysis
KW  - spironolactone
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-269033
SN  - 1573-0743
VL  - 37
IS  - 6
ER  - 
TY  - JOUR
A1  - Gram, Maximilian
A1  - Gensler, Daniel
A1  - Winter, Patrick
A1  - Seethaler, Michael
A1  - Arias-Loza, Paula Anahi
A1  - Oberberger, Johannes
A1  - Jakob, Peter Michael
A1  - Nordbeck, Peter
T1  - Fast myocardial T\(_{1P}\) mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern
JF  - Magnetic Resonance Materials in Physics, Biology and Medicine
N2  - Purpose
T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals.
Methods
A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal.
Results
The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56%) and precision (+ 49%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz.
Conclusion
This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization.
KW  - TT\(_{1rho}\) mapping
KW  - small animal
KW  - KWIC
KW  - radial
KW  - cardiac
KW  - mice
KW  - spin lock
KW  - T\(_{1P}\) dispersion
KW  - T\(_{1P}\) mapping
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-268903
SN  - 1352-8661
VL  - 35
IS  - 2
ER  - 
TY  - JOUR
A1  - Güder, Gülmisal
A1  - Wilkesmann, Joana
A1  - Scholz, Nina
A1  - Leppich, Robert
A1  - Düking, Peter
A1  - Sperlich, Billy
A1  - Rost, Christian
A1  - Frantz, Stefan
A1  - Morbach, Caroline
A1  - Sahiti, Floran
A1  - Stefenelli, Ulrich
A1  - Breunig, Margret
A1  - Störk, Stefan
T1  - Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study
JF  - Clinical Research in Cardiology
N2  - Background
Exercise training in heart failure (HF) is recommended but not routinely offered, because of logistic and safety-related reasons. In 2020, the German Society for Prevention&Rehabilitation and the German Society for Cardiology requested establishing dedicated ""HF training groups."" Here, we aimed to implement and evaluate the feasibility and safety of one of the first HF training groups in Germany.
Methods
Twelve patients (three women) with symptomatic HF (NYHA class II/III) and an ejection fraction ≤ 45% participated and were offered weekly, physician-supervised exercise training for 1 year. Patients received a wrist-worn pedometer (M430 Polar) and underwent the following assessments at baseline and after 4, 8 and 12 months: cardiopulmonary exercise test, 6-min walk test, echocardiography (blinded reading), and quality of life assessment (Kansas City Cardiomyopathy Questionnaire, KCCQ).
Results
All patients (median age [quartiles] 64 [49; 64] years) completed the study and participated in 76% of the offered 36 training sessions. The pedometer was worn ≥ 1000 min per day over 86% of the time. No cardiovascular events occurred during training. Across 12 months, NT-proBNP dropped from 986 pg/ml [455; 1937] to 483 pg/ml [247; 2322], and LVEF increased from 36% [29;41] to 41% [32;46]%, (p for trend = 0.01). We observed no changes in exercise capacity except for a subtle increase in peak VO2% predicted, from 66.5 [49; 77] to 67 [52; 78]; p for trend = 0.03. The physical function and social limitation domains of the KCCQ improved from 60 [54; 82] to 71 [58; 95, and from 63 [39; 83] to 78 [64; 92]; p for trend = 0.04 and = 0.01, respectively. Positive trends were further seen for the clinical and overall summary scores.
Conclusion
This pilot study showed that the implementation of a supervised HF-exercise program is feasible, safe, and has the potential to improve both quality of life and surrogate markers of HF severity. This first exercise experiment should facilitate the design of risk-adopted training programs for patients with HF.
KW  - m exercise training
KW  - heart failure
KW  - cardiac training group
KW  - heart failure training group
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266678
SN  - 1861-0692
VL  - 111
ER  - 
TY  - JOUR
A1  - Doghman-Bouguerra, Mabrouka
A1  - Finetti, Pascal
A1  - Durand, Nelly
A1  - Parise, Ivy Zortéa S.
A1  - Sbiera, Silviu
A1  - Cantini, Giulia
A1  - Canu, Letizia
A1  - Hescot, Ségolène
A1  - Figueiredo, Mirna M. O.
A1  - Komechen, Heloisa
A1  - Sbiera, Iuliu
A1  - Nesi, Gabriella
A1  - Paci, Angelo
A1  - Al Ghuzlan, Abir
A1  - Birnbaum, Daniel
A1  - Baudin, Eric
A1  - Luconi, Michaela
A1  - Fassnacht, Martin
A1  - Figueiredo, Bonald C.
A1  - Bertucci, François
A1  - Lalli, Enzo
T1  - Cancer-testis antigen FATE1 expression in adrenocortical tumors is associated with a pervasive autoimmune response and is a marker of malignancy in adult, but not children, ACC
JF  - Cancers
N2  - The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.
KW  - adrenocortical carcinoma
KW  - cancer-testis antigens
KW  - autoantibodies
KW  - immune response
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203211
SN  - 2072-6694
VL  - 12
IS  - 3
ER  - 
TY  - JOUR
A1  - Oreglia, Maurine
A1  - Sbiera, Silviu
A1  - Fassnacht, Martin
A1  - Guyon, Laurent
A1  - Denis, Josiane
A1  - Cristante, Justine
A1  - Chabre, Olivier
A1  - Cherradi, Nadia
T1  - Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer
JF  - Cancers
N2  - We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5% sensitivity (CI 31.6–86.1) and 100% specificity (CI 71.5–100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.
KW  - adrenocortical carcinoma
KW  - biomarker
KW  - circulating microRNA
KW  - miR-483-5p
KW  - early prognosis
KW  - recurrence
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203227
SN  - 2072-6694
VL  - 12
IS  - 3
ER  - 
TY  - JOUR
A1  - Lacombe, Amanda Meneses Ferreira
A1  - Soares, Iberê Cauduro
A1  - Mariani, Beatriz Marinho de Paula
A1  - Nishi, Mirian Yumie
A1  - Bezerra-Neto, João Evangelista
A1  - Charchar, Helaine da Silva
A1  - Brondani, Vania Balderrama
A1  - Tanno, Fabio
A1  - Srougi, Victor
A1  - Chambo, José Luiz
A1  - Costa de Freitas, Ricardo Miguel
A1  - Mendonca, Berenice Bilharinho
A1  - Hoff, Ana O.
A1  - Almeida, Madson Q.
A1  - Weigand, Isabel
A1  - Kroiss, Matthias
A1  - Zerbini, Maria Claudia Nogueira
A1  - Fragoso, Maria Candida Barisson Villares
T1  - Sterol O-acyl transferase 1 as a prognostic marker of adrenocortical carcinoma
JF  - Cancers
N2  - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0–4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95% 1.26–3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95% 1.09–4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.
KW  - adrenocortical carcinoma
KW  - prognostic factors
KW  - SOAT1
KW  - target therapies
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200857
SN  - 2072-6694
VL  - 12
IS  - 1
ER  - 
TY  - JOUR
A1  - Weigand, Isabel
A1  - Ronchi, Cristina L.
A1  - Vanselow, Jens T.
A1  - Bathon, Kerstin
A1  - Lenz, Kerstin
A1  - Herterich, Sabine
A1  - Schlosser, Andreas
A1  - Kroiss, Matthias
A1  - Fassnacht, Martin
A1  - Calebiro, Davide
A1  - Sbiera, Silviu
T1  - PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser\(^{114}\) phosphorylation
JF  - Science Advances
N2  - Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing’s syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser\(^{114}\) phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing’s syndrome.
KW  - mutation triggers
KW  - phosphorylation
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270445
VL  - 7
IS  - 8
ER  - 
TY  - JOUR
A1  - Yurdadogan, Tino
A1  - Malsch, Carolin
A1  - Kotseva, Kornelia
A1  - Wood, David
A1  - Leyh, Rainer
A1  - Ertl, Georg
A1  - Karmann, Wolfgang
A1  - Müller-Scholden, Lara
A1  - Morbach, Caroline
A1  - Breuning, Margret
A1  - Wagner, Martin
A1  - Gelbrich, Götz
A1  - Bots, Michiel L.
A1  - Heuschmann, Peter U.
A1  - Störk, Stefan
T1  - Functional versus morphological assessment of vascular age in patients with coronary heart disease
JF  - Scientific Reports
N2  - Communicating cardiovascular risk based on individual vascular age (VA) is a well acknowledged concept in patient education and disease prevention. VA may be derived functionally, e.g. by measurement of pulse wave velocity (PWV), or morphologically, e.g. by assessment of carotid intima-media thickness (cIMT). The purpose of this study was to investigate whether both approaches produce similar results. Within the context of the German subset of the EUROASPIRE IV survey, 501 patients with coronary heart disease underwent (a) oscillometric PWV measurement at the aortic, carotid-femoral and brachial-ankle site (PWVao, PWVcf, PWVba) and derivation of the aortic augmentation index (AIao); (b) bilateral cIMT assessment by high-resolution ultrasound at three sites (common, bulb, internal). Respective VA was calculated using published equations. According to VA derived from PWV, most patients exhibited values below chronological age indicating a counterintuitive healthier-than-anticipated vascular status: for VA(PWVao) in 68% of patients; for VA\(_{AIao}\) in 52% of patients. By contrast, VA derived from cIMT delivered opposite results: e.g. according to VA\(_{total-cIMT}\) accelerated vascular aging in 75% of patients. To strengthen the concept of VA, further efforts are needed to better standardise the current approaches to estimate VA and, thereby, to improve comparability and clinical utility.
KW  - arterial stiffening
KW  - atherosclerosis
KW  - calcification
KW  - carotid artery disease
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265810
VL  - 11
IS  - 1
ER  - 
TY  - JOUR
A1  - Henneges, Carsten
A1  - Morbach, Caroline
A1  - Sahiti, Floran
A1  - Scholz, Nina
A1  - Frantz, Stefan
A1  - Ertl, Georg
A1  - Angermann, Christiane E.
A1  - Störk, Stefan
T1  - Sex-specific bimodal clustering of left ventricular ejection fraction in patients with acute heart failure
JF  - ESH Heart Failure
N2  - Aims
There is an ongoing discussion whether the categorization of patients with heart failure according to left ventricular ejection fraction (LVEF) is scientifically justified and clinically relevant. Major efforts are directed towards the identification of appropriate cut-off values to correctly allocate heart failure-specific pharmacotherapy. Alternatively, an LVEF continuum without definite subgroups is discussed. This study aimed to evaluate the natural distribution of LVEF in patients presenting with acutely decompensated heart failure and to identify potential subgroups of LVEF in male and female patients.

Methods and results
We identified 470 patients (mean age 75 ± 11 years, n = 137 female) hospitalized for acute heart failure in whom LVEF could be quantified by Simpson's method in an in-hospital echocardiogram. Non-parametric modelling revealed a bimodal shape of the LVEF distribution. Parametric modelling identified two clusters suggesting two LVEF peaks with mean (variance) of 61% (9%) and 31% (10%), respectively. Sub-differentiation by sex revealed a sex-specific bimodal clustering of LVEF. The respective threshold differentiating between ‘high’ and ‘low’ LVEF was 45% in men and 52% in women.

Conclusions
In patients presenting with acute heart failure, LVEF clustered in two subgroups and exhibited profound sex-specific distributional differences. These findings might enrich the scientific process to identify distinct subgroups of heart failure patients, which might each benefit from respectively tailored (pharmaco)therapies.
KW  - heart failure
KW  - left ventricular ejection fraction
KW  - sex differences
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265839
VL  - 9
IS  - 1
ER  - 
TY  - JOUR
A1  - Brodehl, Andreas
A1  - Pour Hakimi, Seyed Ahmad
A1  - Stanasiuk, Caroline
A1  - Ratnavadivel, Sandra
A1  - Hendig, Doris
A1  - Gaertner, Anna
A1  - Gerull, Brenda
A1  - Gummert, Jan
A1  - Paluszkiewicz, Lech
A1  - Milting, Hendrik
T1  - Restrictive cardiomyopathy is caused by a novel homozygous desmin (DES) mutation p.Y122H leading to a severe filament assembly defect
JF  - Genes
N2  - Here, we present a small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block. Genetic analysis revealed a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H), which is absent in human population databases. The mutation is localized in the highly conserved coil-1 desmin subdomain. In silico, prediction tools indicate a deleterious effect of the desmin (DES) mutation p.Y122H. Consequently, we generated an expression plasmid encoding the mutant and wildtype desmin formed, and analyzed the filament formation in vitro in cardiomyocytes derived from induced pluripotent stem cells and HT-1080 cells. Confocal microscopy revealed a severe filament assembly defect of mutant desmin supporting the pathogenicity of the DES mutation, p.Y122H, whereas the wildtype desmin formed regular intermediate filaments. According to the guidelines of the American College of Medical Genetics and Genomics, we classified this mutation, therefore, as a novel pathogenic mutation. Our report could point to a recessive inheritance of the DES mutation, p.Y122H, which is important for the genetic counseling of similar families with restrictive cardiomyopathy caused by DES mutations.
KW  - cardiovascular genetics
KW  - restrictive cardiomyopathy
KW  - desmin
KW  - intermediate filaments
KW  - desmin-related myopathy
KW  - cardiomyopathy
KW  - desminopathy
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193121
SN  - 2073-4425
VL  - 10
IS  - 11
ER  - 
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  - 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  - <sup>68</sup>Ga-Pentixafor
KW  - <sup>18</sup>F-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  - 
TY  - JOUR
A1  - Assfalg, Volker
A1  - Selig, Katharina
A1  - Tolksdorf, Johanna
A1  - van Meel, Marieke
A1  - de Vries, Erwin
A1  - Ramsoebhag, Anne‐Marie
A1  - Rahmel, Axel
A1  - Renders, Lutz
A1  - Novotny, Alexander
A1  - Matevossian, Edouard
A1  - Schneeberger, Stefan
A1  - Rosenkranz, Alexander R.
A1  - Berlakovich, Gabriela
A1  - Ysebaert, Dirk
A1  - Knops, Noël
A1  - Kuypers, Dirk
A1  - Weekers, Laurent
A1  - Muehlfeld, Anja
A1  - Rump, Lars‐Christian
A1  - Hauser, Ingeborg
A1  - Pisarski, Przemyslaw
A1  - Weimer, Rolf
A1  - Fornara, Paolo
A1  - Fischer, Lutz
A1  - Kliem, Volker
A1  - Sester, Urban
A1  - Stippel, Dirk
A1  - Arns, Wolfgang
A1  - Hau, Hans‐Michael
A1  - Nitschke, Martin
A1  - Hoyer, Joachim
A1  - Thorban, Stefan
A1  - Weinmann‐Menke, Julia
A1  - Heller, Katharina
A1  - Banas, Bernhard
A1  - Schwenger, Vedat
A1  - Nadalin, Silvio
A1  - Lopau, Kai
A1  - Hüser, Norbert
A1  - Heemann, Uwe
T1  - Repeated kidney re‐transplantation—the Eurotransplant experience: a retrospective multicenter outcome analysis
JF  - Transplant International
N2  - In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re‐transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15‐year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re‐DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re‐DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re‐DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.
KW  - allocation
KW  - child
KW  - fourth
KW  - graft
KW  - kidney
KW  - loss
KW  - repeated
KW  - re‐transplantation
KW  - survival
KW  - third
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214161
VL  - 33
IS  - 6
SP  - 617
EP  - 631
ER  - 
TY  - JOUR
A1  - Kirschmer, Nadine
A1  - Bandleon, Sandra
A1  - von Ehrlich-Treuenstätt, Viktor
A1  - Hartmann, Sonja
A1  - Schaaf, Alice
A1  - Lamprecht, Anna-Karina
A1  - Miranda-Laferte, Erick
A1  - Langsenlehner, Tanja
A1  - Ritter, Oliver
A1  - Eder, Petra
T1  - TRPC4α and TRPC4β Similarly Affect Neonatal Cardiomyocyte Survival during Chronic GPCR Stimulation
JF  - PLoS ONE
N2  - The Transient Receptor Potential Channel Subunit 4 (TRPC4) has been considered as a crucial Ca\(^{2+}\) component in cardiomyocytes promoting structural and functional remodeling in the course of pathological cardiac hypertrophy. TRPC4 assembles as homo or hetero-tetramer in the plasma membrane, allowing a non-selective Na\(^{+}\) and Ca\(^{2+}\) influx. Gαq protein-coupled receptor (GPCR) stimulation is known to increase TRPC4 channel activity and a TRPC4-mediated Ca\(^{2+}\) influx which has been regarded as ideal Ca\(^{2+}\) source for calcineurin and subsequent nuclear factor of activated T-cells (NFAT) activation. Functional properties of TRPC4 are also based on the expression of the TRPC4 splice variants TRPC4α and TRPC4β. Aim of the present study was to analyze cytosolic Ca\(^{2+}\) signals, signaling, hypertrophy and vitality of cardiomyocytes in dependence on the expression level of either TRPC4α or TRPC4β. The analysis of Ca\(^{2+}\) transients in neonatal rat cardiomyocytes (NRCs) showed that TRPC4α and TRPC4β affected Ca\(^{2+}\) cycling in beating cardiomyocytes with both splice variants inducing an elevation of the Ca\(^{2+}\) transient amplitude at baseline and TRPC4β increasing the Ca\(^{2+}\) peak during angiotensin II (Ang II) stimulation. NRCs infected with TRPC4β (Ad-C4β) also responded with a sustained Ca\(^{2+}\) influx when treated with Ang II under non-pacing conditions. Consistent with the Ca\(^{2+}\) data, NRCs infected with TRPC4α (Ad-C4α) showed an elevated calcineurin/NFAT activity and a baseline hypertrophic phenotype but did not further develop hypertrophy during chronic Ang II/phenylephrine stimulation. Down-regulation of endogenous TRPC4α reversed these effects, resulting in less hypertrophy of NRCs at baseline but a markedly increased hypertrophic enlargement after chronic agonist stimulation. Ad-C4β NRCs did not exhibit baseline calcineurin/NFAT activity or hypertrophy but responded with an increased calcineurin/NFAT activity after GPCR stimulation. However, this effect was not translated into an increased propensity towards hypertrophy but rather less hypertrophy during GPCR stimulation. Further analyses revealed that, although hypertrophy was preserved in Ad-C4α NRCs and even attenuated in Ad-C4β NRCs, cardiomyocytes had an increased apoptosis rate and thus were less viable after chronic GPCR stimulation. These findings suggest that TRPC4α and TRPC4β differentially affect Ca\(^{2+}\) signals, calcineurin/NFAT signaling and hypertrophy but similarly impair cardiomyocyte viability during GPCR stimulation.
KW  - Apoptosis
KW  - calcineurin signaling cascade
KW  - small interfering RNAs
KW  - G protein coupled receptors
KW  - hyperexpression techniques
KW  - heart
KW  - adenoviruses
KW  - cardiac pacing
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178539
VL  - 11
IS  - 12
ER  - 
TY  - JOUR
A1  - Eisele, Marion
A1  - Boczor, Sigrid
A1  - Rakebrandt, Anja
A1  - Blozik, Eva
A1  - Trader, Jens-Martin
A1  - Stork, Stefan
A1  - Herrmann-Lingen, Christoph
A1  - Scherer, Martin
T1  - General practitioners' awareness of depressive symptomatology is not associated with quality of life in heart failure patients - cross-sectional results of the observational RECODE-HF Study
JF  - BMC Family Practice
N2  - Background
Depression is a common comorbidity in patients with chronic heart failure (HF) and linked to a wider range of symptoms which, in turn, are linked to a decreased health-related quality of life (HRQOL). Treatment of depression might improve HRQOL but detecting depression is difficult due to the symptom overlap between HF and depression. Therefore, clinical guidelines recommend to routinely screen for depression in HF patients. No studies have so far investigated the treatment after getting aware of a depressive symptomatology and its correlation with HRQOL in primary care HF patients. Therefore, we examined the factors linked to depression treatment and those linked to HRQOL in HF patients. We hypothesized that GPs’ awareness of depressive symptomatology was associated with depression treatment and HRQOL in HF patients.

Methods
For this observational study, HF patients were recruited in primary care practices and filled out a questionnaire including PHQ-9 and HADS. A total of 574 patients screened positive for depressive symptomatology. Their GPs were interviewed by phone regarding the patients’ comorbidities and potential depression treatment. Descriptive and regression analysis were performed.

Results
GPs reported various types of depression treatments (including dialogue/counselling by the GP him/herself in 31.8% of the patients). The reported rates differed considerably between GP-reported initiated treatment and patient-reported utilised treatment regarding psychotherapy (16.4% vs. 9.5%) and pharmacotherapy (61.2% vs. 30.3%). The GPs' awareness of depressive symptomatology was significantly associated with the likelihood of receiving pharmacotherapy (OR 2.8; p < 0.001) but not psychotherapy. The patient’s HRQOL was not significantly associated with the GPs' awareness of depression.

Conclusion
GPs should be aware of the gap between GP-initiated and patient-utilised depression treatments in patients with chronic HF, which might lead to an undersupply of depression treatment. It remains to be investigated why GPs’ awareness of depressive symptomatology is not linked to patients’ HRQOL. We hypothesize that GPs are aware of cases with reduced HRQOL (which improves under depression treatment) and unaware of cases whose depression do not significantly impair HRQOL, resulting in comparable levels of HRQOL in both groups. This hypothesis needs to be further investigated.
KW  - Medicine
KW  - Depression
KW  - Heart failure
KW  - Recognition of depression
KW  - Quality of life
KW  - Depression treatment
KW  - Observational study
KW  - Primary care
KW  - Healthcare research
KW  - Depressive symptomatology
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-172445
VL  - 18
ER  - 
TY  - JOUR
A1  - Lapa, Constantin
A1  - Reiter, Theresa
A1  - Kircher, Malte
A1  - Schirbel, Andreas
A1  - Werner, Rudolf A.
A1  - Pelzer, Theo
A1  - Pizarro, Carmen
A1  - Skowasch, Dirk
A1  - Thomas, Lena
A1  - Schlesinger-Irsch, Ulrike
A1  - Thomas, Daniel
A1  - Bundschuh, Ralph A.
A1  - Bauer, Wolfgang R.
A1  - Gartner, Florian C.
T1  - Somatostatin receptor based PET/CT in patients with the suspicion of cardiac sarcoidosis: an initial comparison to cardiac MRI
JF  - Oncotarget
N2  - Diagnosis of cardiac sarcoidosis is often challenging. Whereas cardiac magnetic resonance imaging (CMR) and positron emission tomography/computed tomography (PET/CT) with \(^{18}\)F-fluorodeoxyglucose (FDG) are most commonly used to evaluate patients, PET/CT using radiolabeled somatostatin receptor (SSTR) ligands for visualization of inflammation might represent a more specific alternative. This study aimed to investigate the feasibility of SSTR–PET/CT for detecting cardiac sarcoidosis in comparison to CMR.

15 patients (6 males, 9 females) with sarcoidosis and suspicion on cardiac involvement underwent SSTR-PET/CT imaging and CMR. Images were visually scored. The AHA 17-segment model of the left myocardium was used for localization and comparison of inflamed myocardium for both imaging modalities. In semi-quantitative analysis, mean (SUV\(_{mean}\)) and maximum standardized uptake values (SUV\(_{max}\)) of affected myocardium were calculated and compared with both remote myocardium and left ventricular (LV) cavity.

SSTR-PET was positive in 7/15, CMR in 10/15 patients. Of the 3 CMR+/PET- subjects, one patient with minor involvement (<25% of wall thickness in CMR) was missed by PET. The remaining two CMR+/PET- patients displayed no adverse cardiac events during follow-up.

In the 17-segment model, PET/CT yielded 27 and CMR 29 positive segments. Overall concordance of the 2 modalities was 96.1% (245/255 segments analyzed). SUV\(_{mean}\) and SUV\(_{max}\) in inflamed areas were 2.0±1.2 and 2.6±1.2, respectively. The lesion-to-remote myocardium and lesion-to-LV cavity ratios were 1.8±0.2 and 1.9±0.2 for SUV\(_{mean}\) and 2.0±0.3 and 1.7±0.3 for SUV\(_{max}\), respectively.

Detection of cardiac sarcoidosis by SSTR-PET/CT is feasible. Our data warrant further analysis in larger prospective series.
KW  - sarcoidosis
KW  - PET
KW  - SSTR
KW  - somatostatin receptor
KW  - DOTATOC
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175423
VL  - 7
IS  - 47
ER  - 
TY  - JOUR
A1  - Stritt, Simon
A1  - Nurden, Paquita
A1  - Favier, Remi
A1  - Favier, Marie
A1  - Ferioli, Silvia
A1  - Gotru, Sanjeev K.
A1  - van Eeuwijk, Judith M.M.
A1  - Schulze, Harald
A1  - Nurden, Alan T.
A1  - Lambert, Michele P.
A1  - Turro, Ernest
A1  - Burger-Stritt, Stephanie
A1  - Matsushita, Masayuki
A1  - Mittermeier, Lorenz
A1  - Ballerini, Paola
A1  - Zierler, Susanna
A1  - Laffan, Michael A.
A1  - Chubanov, Vladimir
A1  - Gudermann, Thomas
A1  - Nieswandt, Bernhard
A1  - Braun, Attila
T1  - Defects in TRPM7 channel function deregulate thrombopoiesis through altered cellular Mg\(^{2+}\) homeostasis and cytoskeletal architecture
JF  - Nature Communications
N2  - Mg\(^{2+}\) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg\(^{2+}\)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic α-kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7\(^{fl/fl-Pf4Cre}\)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7\(^{fl/fl-Pf4Cre}\) MKs, which is rescued by Mg\(^{2+}\) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.
KW  - Cytoskeleton
KW  - homeostasisIon channels
KW  - thrombopoiesis
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173843
VL  - 7
ER  - 
TY  - JOUR
A1  - Dischinger, Ulrich
A1  - Hasinger, Julia
A1  - Königsrainer, Malina
A1  - Corteville, Carolin
A1  - Otto, Christoph
A1  - Fassnacht, Martin
A1  - Hankir, Mohamed
A1  - Seyfried, Florian Johannes David
T1  - Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats
JF  - Frontiers in Endocrinology
N2  - Background
Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting.


Methods
High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed.


Results
RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM.


Conclusions
Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB.
KW  - obesity
KW  - rygb
KW  - liraglutide
KW  - peptide tyrosine tyrosine (PYY)
KW  - treatment
KW  - gastric bypass
KW  - peptide tyrosine tyrosine 3-36 (PYY3-36)
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223113
SN  - 1664-2392
VL  - 11
ER  - 
TY  - JOUR
A1  - Burek, Malgorzata
A1  - Burmester, Sandra
A1  - Salvador, Ellaine
A1  - Möller-Ehrlich, Kerstin
A1  - Schneider, Reinhard
A1  - Roewer, Norbert
A1  - Nagai, Michiaki
A1  - Förster, Carola Y.
T1  - Kidney Ischemia/Reperfusion Injury Induces Changes in the Drug Transporter Expression at the Blood–Brain Barrier in vivo and in vitro
JF  - Frontiers in Physiology
N2  - Ischemia/reperfusion injury is a major cause of acute kidney injury (AKI). AKI is characterized by a sudden decrease in kidney function, systemic inflammation, oxidative stress, and dysregulation of the sodium, potassium, and water channels. While AKI leads to uremic encephalopathy, epidemiological studies have shown that AKI is associated with a subsequent risk for developing stroke and dementia. To get more insights into kidney–brain crosstalk, we have created an in vitro co-culture model based on human kidney cells of the proximal tubule (HK-2) and brain microvascular endothelial cells (BMEC). The HK-2 cell line was grown to confluence on 6-well plates and exposed to oxygen/glucose deprivation (OGD) for 4 h. Control HK-2 cells were grown under normal conditions. The BMEC cell line cerebED was grown to confluence on transwells with 0.4 μm pores. The transwell filters seeded and grown to confluence with cereEND were inserted into the plates with HK-2 cells with or without OGD treatment. In addition, cerebEND were left untreated or treated with uremic toxins, indole-3-acetic acid (IAA) and indoxyl sulfate (IS). The protein and mRNA expression of selected BBB-typical influx transporters, efflux transporters, cellular receptors, and tight junction proteins was measured in BMECs. To validate this in vitro model of kidney–brain interaction, we isolated brain capillaries from mice exposed to bilateral renal ischemia (30 min)/reperfusion injury (24 h) and measured mRNA and protein expression as described above. Both in vitro and in vivo systems showed similar changes in the expression of drug transporters, cellular receptors, and tight junction proteins. Efflux pumps, in particular Abcb1b, Abcc1, and Abcg2, have shown increased expression in our model. Thus, our in vitro co-culture system can be used to study the cellular mechanism of kidney and brain crosstalk in renal ischemia/reperfusion injury.
KW  - kidney ischemia/reperfusion injury
KW  - brain pathology
KW  - blood–brain barrier
KW  - drug transporter
KW  - tight junctions
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216413
SN  - 1664-042X
VL  - 11
ER  - 
TY  - JOUR
A1  - Chifu, Irina
A1  - Heinze, Britta
A1  - Fuss, Carmina T.
A1  - Lang, Katharina
A1  - Kroiss, Matthias
A1  - Kircher, Stefan
A1  - Ronchi, Cristina L.
A1  - Altieri, Barbara
A1  - Schirbel, Andreas
A1  - Fassnacht, Martin
A1  - Hahner, Stefanie
T1  - Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma
JF  - Frontiers in Endocrinology
N2  - Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=−0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.
KW  - chemokine receptor
KW  - prognosis
KW  - adrenocortical carcinoma
KW  - CXCR4
KW  - CXCR7
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216494
SN  - 1664-2392
VL  - 11
ER  - 
TY  - JOUR
A1  - Notz, Quirin
A1  - Schmalzing, Marc
A1  - Wedekink, Florian
A1  - Schlesinger, Tobias
A1  - Gernert, Michael
A1  - Herrmann, Johannes
A1  - Sorger, Lena
A1  - Weismann, Dirk
A1  - Schmid, Benedikt
A1  - Sitter, Magdalena
A1  - Schlegel, Nicolas
A1  - Kranke, Peter
A1  - Wischhusen, Jörg
A1  - Meybohm, Patrick
A1  - Lotz, Christopher
T1  - Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome—An Observational Pilot Study
JF  - Frontiers in Immunology
N2  - Objectives
The severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS).


Methods
This was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed.


Results
All patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment.


Conclusions
Massively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.
KW  - Coronavirus Disease 2019
KW  - acute respiratory distress syndrome
KW  - Severe Acute Respiratory Syndrome Coronavirus 2
KW  - cytokines
KW  - inflammation
KW  - growth differentiation factor 15
KW  - immune response
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-212815
SN  - 1664-3224
VL  - 11
ER  - 
TY  - JOUR
A1  - Bauer, Wolfgang Rudolf
T1  - Impact of Interparticle Interaction on Thermodynamics of Nano-Channel Transport of Two Species
JF  - Entropy
N2  - Understanding the function and control of channel transport is of paramount importance for cell physiology and nanotechnology. In particular, if several species are involved, the mechanisms of selectivity, competition, cooperation, pumping, and its modulation need to be understood. What lacks is a rigorous mathematical approach within the framework of stochastic thermodynamics, which explains the impact of interparticle in-channel interactions on the transport properties of the respective species. To achieve this, stochastic channel transport of two species is considered in a model, which different from mean field approaches, explicitly conserves the spatial correlation of the species within the channel by analysis of the stochastic dynamics within a state space, the elements of which are the channel’s spatial occupation states. The interparticle interactions determine the stochastic transitions between these states. Local flow and entropy production in this state space reveal the respective particle flows through the channel and the intensity of the Brownian ratchet like rectifying forces, which these species exert mutually on each other, together with its thermodynamic effectiveness and costs. Perfect coupling of transport of the two species is realized by an attractive empty channel and strong repulsive forces between particles of the same species. This confines the state space to a subspace with circular topology, in which the concentration gradients as thermodynamic driving forces act in series, and channel flow of both species becomes equivalent. For opposing concentration gradients, this makes the species with the stronger gradient the driving, positive entropy producing one; the other is driven and produces negative entropy. Gradients equal in magnitude make all flows vanish, and thermodynamic equilibrium occurs. A differential interparticle interaction with less repulsive forces within particles of one species but maintenance of this interaction for the other species adds a bypass path to this circular subspace. On this path, which is not involved in coupling of the two species, a leak flow of the species with less repulsive interparticle interaction emerges, which is directed parallel to its concentration gradient and, hence, produces positive entropy here. Different from the situation with perfect coupling, appropriate strong opposing concentration gradients may simultaneously parallelize the flow of their respective species, which makes each species produce positive entropy. The rectifying potential of the species with the bypass option is diminished. This implies the existence of a gradient of the other species, above which its flow and gradient are parallel for any gradient of the less coupled species. The opposite holds for the less coupled species. Its flow may always be rectified and turned anti-parallel to its gradient by a sufficiently strong opposing gradient of the other one.
KW  - channel transport
KW  - entropy production
KW  - thermodynamics
KW  - non-equilibrium thermodynamics
KW  - statistical mechanics
KW  - free energy
KW  - state space
KW  - Brownian ratchet
KW  - interparticle interaction
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203240
SN  - 1099-4300
VL  - 22
IS  - 4
ER  - 
TY  - JOUR
A1  - Gaudron, Philipp Daniel
A1  - Liu, Dan
A1  - Scholz, Friederike
A1  - Hu, Kai
A1  - Florescu, Christiane
A1  - Herrmann, Sebastian
A1  - Bijnens, Bart
A1  - Ertl, Georg
A1  - Störk, Stefan
A1  - Weidemann, Frank
T1  - The septal bulge - an early echocardiographic sign in hypertensive heart disease
JF  - Journal of the American Society of Hypertension
N2  - Patients in the early stage of hypertensive heart disease tend to have normal echocardiographic findings. The aim of this study was to investigate whether pathology-specific echocardiographic morphologic and functional parameters can help to detect subclinical hypertensive heart disease. One hundred ten consecutive patients without a history and medication for arterial hypertension (AH) or other cardiac diseases were enrolled. Standard echocardiography and two-dimensional speckle tracking -imaging analysis were performed. Resting blood pressure (BP) measurement, cycle ergometer test (CET), and 24-hour ambulatory BP monitoring (ABPM) were conducted. Patients were referred to "septal bulge (SB)" group (basal-septal wall thickness >= 2 mm thicker than mid-septal wall thickness) or "no-SB" group. Echocardiographic SB was found in 48 (43.6%) of 110 patients. In this SB group, 38 (79.2%) patients showed AH either by CET or ABPM. In contrast, in the no-SB group (n = 62), 59 (95.2%) patients had no positive test for AH by CET or ABPM. When AH was solely defined by resting BP, SB was a reasonable predictive sign for AH (sensitivity 73%, specificity 76%). However, when AH was confirmed by CET or ABPM the echocardiographic SB strongly predicted clinical AH (sensitivity 93%, specificity 86%). In addition, regional myocardial deformation of the basal-septum in SB group was significantly lower than in no-SB group (14 +/- 4% vs. 17 +/- 4%; P < .001). In conclusion, SB is a morphologic echocardiographic sign for early hypertensive heart disease. Sophisticated BP evaluation including resting BP, ABPM, and CET should be performed in all patients with an accidental finding of a SB in echocardiography.
KW  - Septal bulge
KW  - hypertension
KW  - blood pressure monitoring
KW  - echocardiography
KW  - heart disease
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191433
VL  - 10
IS  - 1
ER  - 
TY  - JOUR
A1  - Macdougall, Iain C.
A1  - Bircher, Andreas J.
A1  - Eckhardt, Kai-Uwe
A1  - Obrador, Gregorio T.
A1  - Pollock, Carol A.
A1  - Stenvinkel, Peter
A1  - Swinkels, Dorine W.
A1  - Wanner, Christoph
A1  - Weiss, Günter
A1  - Chertow, Glenn M.
T1  - Iron management in chronic kidney disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference
JF  - Kidney International
N2  - Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.
KW  - chronic kidney disease
KW  - hypersensitivity
KW  - infections
KW  - iron
KW  - overload
KW  - oxidative stress
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-191467
VL  - 89
IS  - 1
ER  - 
TY  - JOUR
A1  - Altieri, Barbara
A1  - Sbiera, Silviu
A1  - Della Casa, Silvia
A1  - Weigand, Isabel
A1  - Wild, Vanessa
A1  - Steinhauer, Sonja
A1  - Fadda, Guido
A1  - Kocot, Arkadius
A1  - Bekteshi, Michaela
A1  - Mambretti, Egle M.
A1  - Rosenwald, Andreas
A1  - Pontecorvi, Alfredo
A1  - Fassnacht, Martin
A1  - Ronchi, Cristina L.
T1  - Livin/BIRC7 expression as malignancy marker in adrenocortical tumors
JF  - Oncotarget
N2  - Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R.
The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression.
Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability.
In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy.
KW  - cancer
KW  - livin
KW  - BIRC7
KW  - adrenocortical cancer
KW  - adrenal tumor
KW  - caspase-3
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171887
VL  - 8
IS  - 6
ER  - 
TY  - JOUR
A1  - Gotschy, Alexander
A1  - Bauer, Wolfgang R.
A1  - Winter, Patrick
A1  - Nordbeck, Peter
A1  - Rommel, Eberhard
A1  - Jakob, Peter M.
A1  - Herold, Volker
T1  - Local versus global aortic pulse wave velocity in early atherosclerosis: An animal study in ApoE\(^{-/-}\) mice using ultrahigh field MRI
JF  - PLoS ONE
N2  - Increased aortic stiffness is known to be associated with atherosclerosis and has a predictive value for cardiovascular events. This study aims to investigate the local distribution of early arterial stiffening due to initial atherosclerotic lesions. Therefore, global and local pulse wave velocity (PWV) were measured in ApoE\(^{-/-}\) and wild type (WT) mice using ultrahigh field MRI. For quantification of global aortic stiffness, a new multi-point transit-time (TT) method was implemented and validated to determine the global PWV in the murine aorta. Local aortic stiffness was measured by assessing the local PWV in the upper abdominal aorta, using the flow/area (QA) method. Significant differences between age matched ApoE\(^{-/-}\) and WT mice were determined for global and local PWV measurements (global PWV: ApoE\(^{-/-}\): 2.7 ±0.2m/s vs WT: 2.1±0.2m/s, P<0.03; local PWV: ApoE\(^{-/-}\): 2.9±0.2m/s vs WT: 2.2±0.2m/s, P<0.03). Within the WT mouse group, the global PWV correlated well with the local PWV in the upper abdominal aorta (R\(^2\) = 0.75, P<0.01), implying a widely uniform arterial elasticity.
In ApoE\(^{-/-}\) animals, however, no significant correlation between individual local and global PWV was present (R\(^2\) = 0.07, P = 0.53), implying a heterogeneous distribution of vascular stiffening in early atherosclerosis. The assessment of global PWV using the new multi-point TT measurement technique was validated against a pressure wire measurement in a vessel
phantom and showed excellent agreement. The experimental results demonstrate that vascular stiffening caused by early atherosclerosis is unequally distributed over the length of large vessels. This finding implies that assessing heterogeneity of arterial stiffness by multiple local measurements of PWV might be more sensitive than global PWV to identify early atherosclerotic lesions.
KW  - MRI
KW  - Atherosclerosis
KW  - Aorta
KW  - Stiffness
KW  - Measurement
KW  - Time measurement
KW  - Magnetic resonance imaging
KW  - Mouse models
KW  - Systole
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171824
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Bornstein, Stefan R.
A1  - Allolio, Bruno
A1  - Arlt, Wiebke
A1  - Barthel, Andreas
A1  - Don-Wauchope, Andrew
A1  - Hammer, Gary D.
A1  - Husebye, Eystein S.
A1  - Merke, Deborah P.
A1  - Murad, M. Hassan
A1  - Stratakis, Constantine A.
A1  - Torpy, David J.
T1  - Diagnosis and treatment of primary adrenal insufficiency: an Endocrine Society Clinical Practice Guideline
JF  - Journal of Clinical Endocrinology & Metabolism
N2  - Objective: This clinical practice guideline addresses the diagnosis and treatment of primary adrenal insufficiency. Participants: The Task Force included a chair, selected by The Clinical Guidelines Subcommittee of the Endocrine Society, eight additional clinicians experienced with the disease, a methodologist, and a medical writer. The co-sponsoring associations (European Society of Endocrinology and the American Association for Clinical Chemistry) had participating members. The Task Force received no corporate funding or remuneration in connection with this review. Evidence: This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to determine the strength of recommendations and the quality of evidence. 
Consensus Process: The evidence used to formulate recommendations was derived from two commissioned systematic reviews as well as other published systematic reviews and studies identified by the Task Force. The guideline was reviewed and approved sequentially by the Endocrine Society's Clinical Guidelines Subcommittee and Clinical Affairs Core Committee, members responding to a web posting, and the Endocrine Society Council. At each stage, the Task Force incorporated changes in response to written comments. 
Conclusions: We recommend diagnostic tests for the exclusion of primary adrenal insufficiency in all patients with indicative clinical symptoms or signs. In particular, we suggest a low diagnostic (and therapeutic) threshold in acutely ill patients, as well as in patients with predisposing factors. This is also recommended for pregnant women with unexplained persistent nausea, fatigue, and hypotension. We recommend a short corticotropin test (250 mu g) as the "gold standard" diagnostic tool to establish the diagnosis. If a short corticotropin test is not possible in the first instance, we recommend an initial screening procedure comprising the measurement of morning plasma ACTH and cortisol levels. Diagnosis of the underlying cause should include a validated assay of autoantibodies against 21-hydroxylase. In autoantibody-negative individuals, other causes should be sought. We recommend once-daily fludrocortisone (median, 0.1 mg) and hydrocortisone (15-25 mg/d) or cortisone acetate replacement (20-35 mg/d) applied in two to three daily doses in adults. In children, hydrocortisone (similar to 8 mg/m\(^2\)/d) is recommended. Patients should be educated about stress dosing and equipped with a steroid card and glucocorticoid preparation for parenteral emergency administration. Follow-up should aim at monitoring appropriate dosing of corticosteroids and associated autoimmune diseases, particularly autoimmune thyroid disease.
KW  - glucocorticoid replacement therapy
KW  - Addison's disease
KW  - short Synacthen test
KW  - insulin tolerance test
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190893
VL  - 101
IS  - 2
ER  - 
TY  - JOUR
A1  - Rothe, Hansjörg
A1  - Brandenburg, Vincent
A1  - Haun, Margot
A1  - Kollerits, Barbara
A1  - Kronenberg, Florian
A1  - Ketteler, Markus
A1  - Wanner, Christoph
T1  - Ecto-5 ' -Nucleotidase CD73 (NT5E), vitamin D receptor and FGF23 gene polymorphisms may play a role in the development of calcific uremic arteriolopathy in dialysis patients - Data from the German Calciphylaxis Registry
JF  - PLoS One
N2  - Introduction: Calciphylaxis/calcific uremic arteriolopathy affects mainly end-stage kidney disease patients but is also associated with malignant disorders such as myeloma, melanoma and breast cancer. Genetic risk factors of calciphylaxis have never been studied before.

Methods: We investigated 10 target genes using a tagging SNP approach: the genes encoding CD73/ ecto-5'-nucleotidase (purinergic pathway), Matrix Gla protein, Fetuin A, Bone Gla protein, VKORC1 (all related to intrinsic calcification inhibition), calcium-sensing receptor, FGF23, Klotho, vitamin D receptor, stanniocalcin 1 (all related to CKD-MBD). 144 dialysis patients from the German calciphylaxis registry were compared with 370 dialysis patients without history of CUA. Genotyping was performed using iPLEX Gold MassARRAY(Sequenom, San Diego, USA), KASP genotyping chemistry (LGC, Teddington, Middlesex, UK) or sequencing. Statistical analysis comprised logistic regression analysis with adjustment for age and sex.

Results: 165 SNPs were finally analyzed and 6 SNPs were associated with higher probability for calciphylaxis (OR>1) in our cohort. Nine SNPs of three genes (CD73, FGF23 and Vitamin D receptor) reached nominal significance (p< 0.05), but did not reach statistical significance after correction for multiple testing. Of the CD73 gene, rs4431401 (OR = 1.71, 95%CI 1.08-2.17, p = 0.023) and rs9444348 (OR = 1.48, 95% CI 1.11-1.97, p = 0.008) were associated with a higher probability for CUA. Of the FGF23 and VDR genes, rs7310492, rs11063118, rs13312747 and rs17882106 were associated with a higher probability for CUA.

Conclusion: Polymorphisms in the genes encoding CD73, vitamin D receptor and FGF23 may play a role in calciphylaxis development. Although our study is the largest genetic study on calciphylaxis, it is limited by the low sample sizes. It therefore requires replication in other cohorts if available.
KW  - single nucleotide polymorphisms
KW  - calcification
KW  - medical dialysis
KW  - genotyping
KW  - cancer risk factors
KW  - vitamin D
KW  - chronic kidney disease
KW  - melanoma
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171817
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Üçeyler, Nurcan
A1  - Schröter, Nils
A1  - Kafke, Waldemar
A1  - Kramer, Daniela
A1  - Wanner, Christoph
A1  - Weidemann, Frank
A1  - Sommer, Claudia
T1  - Skin Globotriaosylceramide 3 Load Is Increased in Men with Advanced Fabry Disease
JF  - PLoS ONE
N2  - Background
The X-chromosomally linked life-limiting Fabry disease (FD) is associated with deposits of the sphingolipid globotriaosylceramide 3 (Gb3) in various tissues. Skin is easily accessible and may be used as an additional diagnostic and follow-up medium. Our aims were to visualize skin Gb3 deposits in FD patients applying immunofluorescence and to determine if cutaneous Gb3 load correlates with disease severity.

Methods
At our Fabry Center for Interdisciplinary Therapy we enrolled 84 patients with FD and 27 healthy controls. All subjects underwent 5-mm skin punch biopsy at the lateral lower leg and the back. Skin samples were processed for immunohistochemistry using antibodies against CD77 (i.e. Gb3). Cutaneous Gb3 deposition was quantified in a blinded manner and correlated to clinical data.

Results
We found that Gb3 load was higher in distal skin of male FD patients compared to healthy controls (p<0.05). Men (p<0.01) and women (p<0.05) with a classic FD phenotype had higher distal skin Gb3 load than healthy controls. Men with advanced disease as reflected by impaired renal function, and men and women with small fiber neuropathy had more Gb3 deposits in distal skin samples than males with normal renal function (p<0.05) and without small fiber neuropathy. Gb3 deposits were not different between patients with and without enzyme replacement therapy.

Conclusions
Immunofluorescence on minimally invasive skin punch biopsies may be useful as a tool for assessment and follow-up in FD patients.
KW  - biopsy
KW  - neuropathy
KW  - Fabry disease
KW  - renal system
KW  - immunofluorescence
KW  - enzyme replacement therapy
KW  - skin diseases
KW  - nerve fibers
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-178856
VL  - 11
IS  - 11
ER  - 
TY  - JOUR
A1  - Gerull, Brenda
A1  - Brodehl, Andreas
T1  - Genetic Animal Models for Arrhythmogenic Cardiomyopathy
JF  - Frontiers in Physiology
N2  - Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.
KW  - arrhythmogenic cardiomyopathy
KW  - desmosomes
KW  - animal models of human disease
KW  - sudden death
KW  - genetics
KW  - mouse
KW  - zebrafish
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206903
SN  - 1664-042X
VL  - 11
IS  - 264
ER  - 
TY  - JOUR
A1  - Salman Haider, Malik
A1  - Schreiner, Jochen
A1  - Kendl, Sabine
A1  - Kroiss, Matthias
A1  - Luxenhofer, Robert
T1  - A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models
JF  - Macromolecular Bioscience
N2  - Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
KW  - adrenocortical carcinoma
KW  - amphiphilic block copolymer
KW  - NCI-H295R
KW  - poly(2-oxazoline)
KW  - solubility enhancement
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206224
VL  - 20
IS  - 1
ER  - 
TY  - JOUR
A1  - Altieri, Barbara
A1  - Sbiera, Silviu
A1  - Herterich, Sabine
A1  - De Francia, Silvia
A1  - Della Casa, Silvia
A1  - Calabrese, Anna
A1  - Pontecorvi, Alfredo
A1  - Quinkler, Marcus
A1  - Kienitz, Tina
A1  - Mannelli, Massimo
A1  - Canu, Letizia
A1  - Angelousi, Anna
A1  - Chortis, Vasileios
A1  - Kroiss, Matthias
A1  - Terzolo, Massimo
A1  - Fassnacht, Martin
A1  - Ronchi, Cristina L.
T1  - Effects of Germline CYP2W1*6 and CYP2B6*6 Single Nucleotide Polymorphisms on Mitotane Treatment in Adrenocortical Carcinoma: A Multicenter ENSAT Study
JF  - Cancers
N2  - Mitotane is the only approved drug for advanced adrenocortical carcinoma (ACC) and no biomarkers are available to predict attainment of therapeutic plasma concentrations and clinical response. Aim of the study was to evaluate the suitability of cytochrome P450(CYP)2W1 and CYP2B6 single nucleotide polymorphisms (SNPs) as biomarkers. A multicenter cohort study including 182 ACC patients (F/M = 121/61) treated with mitotane monotherapy after radical resection (group A, n = 103) or in not completely resectable, recurrent or advanced disease (group B, n = 79) was performed. CYP2W1*2, CYP2W1*6, CYP2B6*6 and CYP2B6 rs4803419 were genotyped in germline DNA. Mitotane blood levels were measured regularly. Response to therapy was evaluated as time to progression (TTP) and disease control rate (DCR). Among investigated SNPs, CYP2W1*6 and CYP2B6*6 correlated with mitotane treatment only in group B. Patients with CYP2W1*6 (n = 21) achieved less frequently therapeutic mitotane levels (>14 mg/L) than those with wild type (WT) allele (76.2% vs 51.7%, p = 0.051) and experienced shorter TTP (HR = 2.10, p = 0.019) and lower DCR (chi-square = 6.948, p = 0.008). By contrast, 55% of patients with CYP2B6*6 vs. 28.2% WT (p = 0.016) achieved therapeutic range. Combined, a higher rate of patients with CYP2W1*6WT+CYP2B6*6 (60.6%) achieved mitotane therapeutic range (p = 0.034). In not completely resectable, recurrent or advanced ACC, CYP2W1*6 SNP was associated with a reduced probability to reach mitotane therapeutic range and lower response rates, whereas CYP2B6*6 correlated with higher mitotane levels. The association of these SNPs may predict individual response to mitotane.
KW  - adrenocortical carcinoma
KW  - mitotane
KW  - CYP2W1
KW  - CYP2B6
KW  - SNP
KW  - biomarker
KW  - predictive marker
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200565
SN  - 2072-6694
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Dinnes, Jacqueline
A1  - Bancos, Irina
A1  - di Ruffano, Lavinia Ferrante
A1  - Chortis, Vasileios
A1  - Davenport, Clare
A1  - Bayliss, Susan
A1  - Sahdev, Anju
A1  - Guest, Peter
A1  - Fassnacht, Martin
A1  - Deeks, Jonathan J
A1  - Arlt, Wiebke
T1  - Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis
JF  - European Journal of Endocrinology
N2  - Objective: 
Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses. Design: A systematic review and meta-analysis was conducted. 

Methods: 
We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or F-18-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard. 

Results: 
We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n = 16), MRI (n = 15), and FDG-PET (n = 9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10 HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with <= 10 HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers. 

Conclusions: 
Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis.
KW  - Positron-emission-tomography
KW  - Cell lung canger
KW  - Adrenocortial carcinomas
KW  - Disease prevalence
KW  - Spin echo
KW  - Contrast-enhanced CT
KW  - Test accuracy
KW  - Methodological quality
KW  - F-18-FDG PET/CT
KW  - MR
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188086
VL  - 175
IS  - 2
ER  - 
TY  - JOUR
A1  - Ortiz, Alberto
A1  - Abiose, Ademola
A1  - Bichet, Daniel G.
A1  - Cabrera, Gustavo
A1  - Charrow, Joel
A1  - Germain, Dominique P.
A1  - Hopkin, Robert J.
A1  - Jovanovic, Ana
A1  - Linhart, Aleš
A1  - Maruti, Sonia S.
A1  - Mauer, Michael
A1  - Oliveira, João P.
A1  - Patel, Manesh R.
A1  - Politei, Juan
A1  - Waldek, Stephen
A1  - Wanner, Christoph
A1  - Yoo, Han-Wook
A1  - Warnock, David G.
T1  - Time to treatment benefit for adult patients with Fabry disease receiving agalsidase beta: data from the Fabry Registry
JF  - Journal of Medical Genetics
N2  - Background 
Agalsidase beta is a form of enzyme replacement therapy for Fabry disease, a genetic disorder characterised by low alpha-galactosidase A activity, accumulation of glycosphingolipids and life-threatening cardiovascular, renal and cerebrovascular events. In clinical trials, agalsidase beta cleared glycolipid deposits from endothelial cells within 6 months; clearance from other cell types required sustained treatment. We hypothesised that there might be a 'lag time' to clinical benefit after initiating agalsidase beta treatment, and analysed the incidence of severe clinical events over time in patients receiving agalsidase beta. 

Methods 
The incidence of severe clinical events (renal failure, cardiac events, stroke, death) was studied in 1044 adult patients (641 men, 403 women) enrolled in the Fabry Registry who received agalsidase beta (average dose 1 mg/kg every 2 weeks) for up to 5 years. 

Results 
The incidence of all severe clinical events was 111 per 1000 person-years (95% CI 84 to 145) during the first 6 months. After 6 months, the incidence decreased and remained stable within the range of 40-58 events per 1000 patient-years. The largest decrease in incidence rates was among male patients and those aged >= 40 years when agalsidase beta was initiated. 

Conclusions 
Contrary to the expected increased incidence of severe clinical events with time, adult patients with Fabry disease had decreased incidence of severe clinical events after 6 months treatment with agalsidase beta 1 mg/kg every 2 weeks.
KW  - Enzyme replacement therapy
KW  - Natural-history data
KW  - Racial differences
KW  - Outcome survey
KW  - Galactosidase-A gene
KW  - Alpha-Galactosidase
KW  - Kidney function
KW  - Lag time
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188241
VL  - 53
IS  - 7
ER  - 
TY  - JOUR
A1  - Seydelmann, Nora
A1  - Liu, Dan
A1  - Krämer, Johannes
A1  - Drechsler, Christiane
A1  - Hu, Kai
A1  - Nordbeck, Peter
A1  - Schneider, Andreas
A1  - Störk, Stefan
A1  - Bijnens, Bart
A1  - Ertl, Georg
A1  - Wanner, Christoph
A1  - Weidemann, Frank
T1  - High-Sensitivity Troponin: A Clinical Blood Biomarker for Staging Cardiomyopathy in Fabry Disease
JF  - Journal of the American Heart Association
N2  - Background
High‐sensitivity troponin (hs‐TNT), a biomarker of myocardial damage, might be useful for assessing fibrosis in Fabry cardiomyopathy. We performed a prospective analysis of hs‐TNT as a biomarker for myocardial changes in Fabry patients and a retrospective longitudinal follow‐up study to assess longitudinal hs‐TNT changes relative to fibrosis and cardiomyopathy progression.

Methods and Results
For the prospective analysis, hs‐TNT from 75 consecutive patients with genetically confirmed Fabry disease was analyzed relative to typical Fabry‐associated echocardiographic findings and total myocardial fibrosis as measured by late gadolinium enhancement (LE) on magnetic resonance imaging. Longitudinal data (3.9±2.0 years), including hs‐TNT, LE, and echocardiographic findings from 58 Fabry patients, were retrospectively collected. Hs‐TNT level positively correlated with LE (linear correlation coefficient, 0.72; odds ratio, 32.81 [95% CI, 3.56–302.59]; P=0.002); patients with elevated baseline hs‐TNT (>14 ng/L) showed significantly increased LE (median: baseline, 1.9 [1.1–3.3] %; follow‐up, 3.2 [2.3–4.9] %; P<0.001) and slightly elevated hs‐TNT (baseline, 44.7 [30.1–65.3] ng/L; follow‐up, 49.1 [27.6–69.5] ng/L; P=0.116) during follow‐up. Left ventricular wall thickness and EF of patients with elevated hs‐TNT were decreased during follow‐up, indicating potential cardiomyopathy progression.

Conclusions
hs‐TNT is an accurate, easily accessible clinical blood biomarker for detecting replacement fibrosis in patients with Fabry disease and a qualified predictor of cardiomyopathy progression. Thus, hs‐TNT could be helpful for staging and follow‐up of Fabry patients.
KW  - biomarker
KW  - cardiomyopathy
KW  - fabry disease
KW  - myocardial fibrosis
KW  - troponin T
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-165682
VL  - 5
IS  - e002839
ER  - 
TY  - JOUR
A1  - Perkovic, Vlado
A1  - Agarwal, Rajiv
A1  - Fioretto, Paola
A1  - Hemmelgarn, Brenda R.
A1  - Levin, Adeera
A1  - Thomas, Merlin C.
A1  - Wanner, Christoph
A1  - Kasiske, Bertram L.
A1  - Wheeler, David C.
A1  - Groop, Per-Henrik
T1  - Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) controversies conference
JF  - Kidney International
N2  - The prevalence of diabetes around the world has reached epidemic proportions and is projected to increase to 642 million people by 2040. Diabetes is already the leading cause of end-stage kidney disease (ESKD) in most developed countries, and the growth in the number of people with ESKD around the world parallels the increase in diabetes. The presence of kidney disease is associated with a markedly elevated risk of cardiovascular disease and death in people with diabetes. Several new therapies and novel investigational agents targeting chronic kidney disease patients with diabetes are now under development. This conference was convened to assess our current state of knowledge regarding optimal glycemic control, current antidiabetic agents and their safety, and new therapies being developed to improve kidney function and cardiovascular outcomes for this vulnerable population.
KW  - stage renal-disease
KW  - converting enzyme-inhibition
KW  - dietary sodium restriction
KW  - intensive glucose control
KW  - albumin excretion rate
KW  - blood pressure
KW  - cardiovascular outcomes
KW  - randomized trial
KW  - glycemic control
KW  - receptor
KW  - antidiabetic agents
KW  - cardiovascular disease
KW  - chronic kidney disease
KW  - diabetes
KW  - renoprotection
KW  - antagonist
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186599
VL  - 90
IS  - 6
ER  - 
TY  - JOUR
A1  - Dietrich, Georg
A1  - Krebs, Jonathan
A1  - Liman, Leon
A1  - Fette, Georg
A1  - Ertl, Maximilian
A1  - Kaspar, Mathias
A1  - Störk, Stefan
A1  - Puppe, Frank
T1  - Replicating medication trend studies using ad hoc information extraction in a clinical data warehouse
JF  - BMC Medical Informatics and Decision Making
N2  - Background
Medication trend studies show the changes of medication over the years and may be replicated using a clinical Data Warehouse (CDW). Even nowadays, a lot of the patient information, like medication data, in the EHR is stored in the format of free text. As the conventional approach of information extraction (IE) demands a high developmental effort, we used ad hoc IE instead. This technique queries information and extracts it on the fly from texts contained in the CDW.

Methods
We present a generalizable approach of ad hoc IE for pharmacotherapy (medications and their daily dosage) presented in hospital discharge letters. We added import and query features to the CDW system, like error tolerant queries to deal with misspellings and proximity search for the extraction of the daily dosage. During the data integration process in the CDW, negated, historical and non-patient context data are filtered. For the replication studies, we used a drug list grouped by ATC (Anatomical Therapeutic Chemical Classification System) codes as input for queries to the CDW.

Results
We achieve an F1 score of 0.983 (precision 0.997, recall 0.970) for extracting medication from discharge letters and an F1 score of 0.974 (precision 0.977, recall 0.972) for extracting the dosage. We replicated three published medical trend studies for hypertension, atrial fibrillation and chronic kidney disease. Overall, 93% of the main findings could be replicated, 68% of sub-findings, and 75% of all findings. One study could be completely replicated with all main and sub-findings.

Conclusion
A novel approach for ad hoc IE is presented. It is very suitable for basic medical texts like discharge letters and finding reports. Ad hoc IE is by definition more limited than conventional IE and does not claim to replace it, but it substantially exceeds the search capabilities of many CDWs and it is convenient to conduct replication studies fast and with high quality.
KW  - data warehouse
KW  - medication extraction
KW  - information extraction
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200409
VL  - 19
ER  - 
TY  - JOUR
A1  - Maniuc, Octavian
A1  - Salinger, Tim
A1  - Anders, Fabian
A1  - Müntze, Jonas
A1  - Liu, Dan
A1  - Hu, Kai
A1  - Ertl, Georg
A1  - Frantz, Stefan
A1  - Nordbeck, Peter
T1  - Impella CP use in patients with non‐ischaemic cardiogenic shock
JF  - ESC Heart Failure
N2  - Aims
From the various mechanical cardiac assist devices and indications available, the use of the percutaneous intraventricular Impella CP pump is usually restricted to acute ischaemic shock or prophylactic indications in high‐risk interventions. In the present study, we investigated clinical usefulness of the Impella CP device in patients with non‐ischaemic cardiogenic shock as compared with acute ischaemia.

Methods and results
In this retrospective single‐centre analysis, patients who received an Impella CP at the University Hospital Würzburg between 2013 and 2017 due to non‐ischaemic cardiogenic shock were age‐matched 2:1 with patients receiving the device due to ischaemic cardiogenic shock. Inclusion criteria were therapy refractory haemodynamic instability with severe left ventricular systolic dysfunction and serum lactate >2.0 mmol/L at implantation. Basic clinical data, indications for mechanical ventricular support, and outcome were obtained in all patients with non‐ischaemic as well as ischaemic shock and compared between both groups. Continuous variables are expressed as mean ± standard deviation or median (quartiles). Categorical variables are presented as count and per cent. Twenty‐five patients had cardiogenic shock due to non‐ischaemic reasons and were compared with 50 patients with cardiogenic shock due to acute myocardial infarction. Resuscitation rates before implantation of Impella CP were high (32 vs. 42%; P = 0.402). At implantation, patients with non‐ischaemic cardiogenic shock had lower levels of high‐sensitive troponin T (110.65 [57.87–322.1] vs. 1610 [450.8–3861.5] pg/mL; P = 0.001) and lactate dehydrogenase (377 [279–608] vs. 616 [371.3–1109] U/L; P = 0.007), while age (59 ± 16 vs. 61.7 ± 11; P = 0.401), glomerular filtration rate (43.5 [33.2–59.7] vs. 48 [35.75–69] mL/min; P = 0.290), C‐reactive protein (5.17 [3.27–10.26] vs. 10.97 [3.23–17.2] mg/dL; P = 0.195), catecholamine index (30.6 [10.6–116.9] vs. 47.6 [11.7–90] μg/kg/min; P = 0.663), and serum lactate (2.6 [2.2–5.8] vs. 2.9 [1.3–6.6] mmol/L; P = 0.424) were comparable between both groups. There was a trend for longer duration of Impella support in the non‐ischaemic groups (5 [2–7.5] vs. 3 [2–5.25] days, P = 0.211). Rates of haemodialysis (52 vs. 47%; P = 0.680) and transition to extracorporeal membrane oxygenation (13.6 vs. 22.2%; P = 0.521) were comparable. No significant difference was found regarding both 30 day survival (48 vs. 30%; P = 0.126) and in‐hospital mortality (66.7 vs. 74%; P = 0.512), although there was a trend for better survival in the non‐ischaemic group.

Conclusions
These data suggest that temporary use of the Impella CP device might be a useful therapeutic option for bridge to recovery not only in ischaemic but also in non‐ischaemic cardiogenic shock.
KW  - Impella
KW  - Non‐ischaemic cardiogenic shock
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-202794
VL  - 6
IS  - 4
ER  - 
TY  - JOUR
A1  - Müller-Scholden, Lara
A1  - Kirchhof, Jan
A1  - Morbach, Caroline
A1  - Breunig, Margret
A1  - Meijer, Rudy
A1  - Rücker, Viktoria
A1  - Tiffe, Theresa
A1  - Yurdadogan, Tino
A1  - Wagner, Martin
A1  - Gelbrich, Götz
A1  - Bots, Michiel L.
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
T1  - Segment-specific association of carotid-intima-media thickness with cardiovascular risk factors – findings from the STAAB cohort study
JF  - BMC Cardiovascular Disorders
N2  - Background
The guideline recommendation to not measure carotid intima-media thickness (CIMT) for cardiovascular risk prediction is based on the assessment of just one single carotid segment. We evaluated whether there is a segment-specific association between different measurement locations of CIMT and cardiovascular risk factors.

Methods
Subjects from the population-based STAAB cohort study comprising subjects aged 30 to 79 years of the general population from Würzburg, Germany, were investigated. CIMT was measured on the far wall of both sides in three different predefined locations: common carotid artery (CCA), bulb, and internal carotid artery (ICA). Diabetes, dyslipidemia, hypertension, smoking, and obesity were considered as risk factors. In multivariable logistic regression analysis, odds ratios of risk factors per location were estimated for the endpoint of individual age- and sex-adjusted 75th percentile of CIMT.

Results
2492 subjects were included in the analysis. Segment-specific CIMT was highest in the bulb, followed by CCA, and lowest in the ICA. Dyslipidemia, hypertension, and smoking were associated with CIMT, but not diabetes and obesity. We observed no relevant segment-specific association between the three different locations and risk factors, except for a possible interaction between smoking and ICA.

Conclusions
As no segment-specific association between cardiovascular risk factors and CIMT became evident, one simple measurement of one location may suffice to assess the cardiovascular risk of an individual.
KW  - Carotid intima-media thickness (CIMT)
KW  - Carotid segment
KW  - Carotid ultrasound
KW  - Cardiovascular risk factors
KW  - Cardiovascular risk prediction
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200720
VL  - 19
IS  - 84
ER  - 
TY  - JOUR
A1  - Heidenreich, Julius F.
A1  - Weng, Andreas M.
A1  - Donhauser, Julian
A1  - Greiser, Andreas
A1  - Chow, Kelvin
A1  - Nordbeck, Peter
A1  - Bley, Thorsten A.
A1  - Köstler, Herbert
T1  - T1- and ECV-mapping in clinical routine at 3 T: differences between MOLLI, ShMOLLI and SASHA
JF  - BMC Medical Imaging
N2  - Background
T1 mapping sequences such as MOLLI, ShMOLLI and SASHA make use of different technical approaches, bearing strengths and weaknesses. It is well known that obtained T1 relaxation times differ between the sequence techniques as well as between different hardware. Yet, T1 quantification is a promising tool for myocardial tissue characterization, disregarding the absence of established reference values. The purpose of this study was to evaluate the feasibility of native and post-contrast T1 mapping methods as well as ECV maps and its diagnostic benefits in a clinical environment when scanning patients with various cardiac diseases at 3 T.

Methods
Native and post-contrast T1 mapping data acquired on a 3 T full-body scanner using the three pulse sequences 5(3)3 MOLLI, ShMOLLI and SASHA in 19 patients with clinical indication for contrast enhanced MRI were compared. We analyzed global and segmental T1 relaxation times as well as respective extracellular volumes and compared the emerged differences between the used pulse sequences.

Results
T1 times acquired with MOLLI and ShMOLLI exhibited systematic T1 deviation compared to SASHA. Myocardial MOLLI T1 times were 19% lower and ShMOLLI T1 times 25% lower compared to SASHA. Native blood T1 times from MOLLI were 13% lower than SASHA, while post-contrast MOLLI T1-times were only 5% lower. ECV values exhibited comparably biased estimation with MOLLI and ShMOLLI compared to SASHA in good agreement with results reported in literature. Pathology-suspect segments were clearly differentiated from remote myocardium with all three sequences.

Conclusion
Myocardial T1 mapping yields systematically biased pre- and post-contrast T1 times depending on the applied pulse sequence. Additionally calculating ECV attenuates this bias, making MOLLI, ShMOLLI and SASHA better comparable. Therefore, myocardial T1 mapping is a powerful clinical tool for classification of soft tissue abnormalities in spite of the absence of established reference values.
KW  - T1 mapping
KW  - MOLLI
KW  - ShMOLLI
KW  - SASHA
KW  - Extracellular volume
KW  - 3 T
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201999
VL  - 19
ER  - 
TY  - JOUR
A1  - Haring, Bernhard
A1  - Crandall, Carolyn J
A1  - Carbone, Laura
A1  - Liu, Simin
A1  - Li, Wenjun
A1  - Johnson, Karen C
A1  - Wactawski-Wende, Jean
A1  - Shadyab, Aladdin H
A1  - Gass, Margery L
A1  - Kamensky, Victor
A1  - Cauley, Jane A
A1  - Wassertheil-Smoller, Sylvia
T1  - Lipoprotein(a) plasma levels, bone mineral density and risk of hip fracture: a post hoc analysis of the Women’s Health Initiative, USA
JF  - BMJ Open
N2  - Objectives 
Elevated Lipoprotein(a) (Lp[a]) is a well-known risk factor for cardiovascular disease. However, its roles in bone metabolism and fracture risk are unclear. We therefore investigated whether plasma Lp(a) levels were associated with bone mineral density (BMD) and incident hip fractures in a large cohort of postmenopausal women.

Design 
Post hoc analysis of data from the Women’s Health Initiative (WHI), USA.

Setting 
40 clinical centres in the USA.

Participants 
The current analytical cohort consisted of 9698 white, postmenopausal women enrolled in the WHI, a national prospective study investigating determinants of chronic diseases including heart disease, breast and colorectal cancers and osteoporotic fractures among postmenopausal women. Recruitment for WHI took place from 1 October 1993 to 31 December 1998.

Exposures 
Plasma Lp(a) levels were measured at baseline.

Outcome measures 
Incident hip fractures were ascertained annually and confirmed by medical records with follow-up through 29 August 2014. BMD at the femoral neck was measured by dual X-ray absorptiometry in a subset of participants at baseline.

Statistical analyses 
Cox proportional hazards and logistic regression models were used to evaluate associations of quartiles of plasma Lp(a) levels with hip fracture events and hip BMD T-score, respectively.

Results 
During a mean follow-up of 13.8 years, 454 incident cases of hip fracture were observed. In analyses adjusting for confounding variables including age, body mass index, history of hysterectomy, smoking, physical activity, diabetes mellitus, general health status, cardiovascular disease, use of menopausal hormone therapy, use of bisphosphonates, calcitonin or selective-oestrogen receptor modulators, baseline dietary and supplemental calcium and vitamin D intake and history of fracture, no significant association of plasma Lp(a) levels with low hip BMD T-score or hip fracture risk was detected.

Conclusions 
These findings suggest that plasma Lp(a) levels are not related to hip BMD T-score or hip fracture events in postmenopausal women.
KW  - hip fracture
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201139
VL  - 9
ER  - 
TY  - JOUR
A1  - Blümel, Rabea
A1  - Zink, Miriam
A1  - Klopocki, Eva
A1  - Liedtke, Daniel
T1  - On the traces of tcf12: Investigation of the gene expression pattern during development and cranial suture patterning in zebrafish (Danio rerio)
JF  - PLoS ONE
N2  - The transcription factor 12 (tcf12) is a basic Helix-Loop-Helix protein (bHLH) of the E-protein family, proven to play an important role in developmental processes like neurogenesis, mesoderm formation, and cranial vault development. In humans, mutations in TCF12 lead to craniosynostosis, a congenital birth disorder characterized by the premature fusion of one or several of the cranial sutures. Current research has been primarily focused on functional studies of TCF12, hence the cellular expression profile of this gene during embryonic development and early stages of ossification remains poorly understood. Here we present the establishment and detailed analysis of two transgenic tcf12:EGFP fluorescent zebrafish (Danio rerio) reporter lines. Using these transgenic lines, we analyzed the general spatiotemporal expression pattern of tcf12 during different developmental stages and put emphasis on skeletal development and cranial suture patterning. We identified robust tcf12 promoter-driven EGFP expression in the central nervous system (CNS), the heart, the pronephros, and the somites of zebrafish embryos. Additionally, expression was observed inside the muscles and bones of the viscerocranium in juvenile and adult fish. During cranial vault development, the transgenic fish show a high amount of tcf12 expressing cells at the growth fronts of the ossifying frontal and parietal bones and inside the emerging cranial sutures. Subsequently, we tested the transcriptional activity of three evolutionary conserved non-coding elements (CNEs) located in the tcf12 locus by transient transgenic assays and compared their in vivo activity to the expression pattern determined in the transgenic tcf12:EGFP lines. We could validate two of them as tcf12 enhancer elements driving specific gene expression in the CNS during embryogenesis. Our newly established transgenic lines enhance the understanding of tcf12 gene regulation and open up the possibilities for further functional investigation of these novel tcf12 enhancer elements in zebrafish.
KW  - Zebrafish
KW  - Neurons
KW  - Skull
KW  - Enhancer elements
KW  - Hindbrain
KW  - Cranial sutures
KW  - Embryos
KW  - Somites
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201428
VL  - 14
IS  - 6
ER  - 
TY  - JOUR
A1  - Winter, Patrick
A1  - Andelovic, Kristina
A1  - Kampf, Thomas
A1  - Gutjahr, Fabian Tobias
A1  - Heidenreich, Julius
A1  - Zernecke, Alma
A1  - Bauer, Wolfgang Rudolf
A1  - Jakob, Peter Michael
A1  - Herold, Volker
T1  - Fast self-navigated wall shear stress measurements in the murine aortic archusing radial 4D-phase contrast cardiovascular magnetic resonance at 17.6 T
JF  - Journal of Cardiovascular Magnetic Resonance
N2  - Purpose
4D flow cardiovascular magnetic resonance (CMR) and the assessment of wall shear stress (WSS) are non-invasive tools to study cardiovascular risks in vivo. Major limitations of conventional triggered methods are the long measurement times needed for high-resolution data sets and the necessity of stable electrocardiographic (ECG) triggering. In this work an ECG-free retrospectively synchronized method is presented that enables accelerated high-resolution measurements of 4D flow and WSS in the aortic arch of mice.

Methods
4D flow and WSS were measured in the aortic arch of 12-week-old wildtype C57BL/6 J mice (n = 7) with a radial 4D-phase-contrast (PC)-CMR sequence, which was validated in a flow phantom. Cardiac and respiratory motion signals were extracted from the radial CMR signal and were used for the reconstruction of 4D-flow data. Rigid motion correction and a first order B0 correction was used to improve the robustness of magnitude and velocity data.

The aortic lumen was segmented semi-automatically. Temporally averaged and time-resolved WSS and oscillatory shear index (OSI) were calculated from the spatial velocity gradients at the lumen surface at 14 locations along the aortic arch. Reproducibility was tested in 3 animals and the influence of subsampling was investigated.

Results
Volume flow, cross-sectional areas, WSS and the OSI were determined in a measurement time of only 32 min. Longitudinal and circumferential WSS and radial stress were assessed at 14 analysis planes along the aortic arch. The average longitudinal, circumferential and radial stress values were 1.52 ± 0.29 N/m2, 0.28 ± 0.24 N/m2 and − 0.21 ± 0.19 N/m2, respectively. Good reproducibility of WSS values was observed.

Conclusion
This work presents a robust measurement of 4D flow and WSS in mice without the need of ECG trigger signals. The retrospective approach provides fast flow quantification within 35 min and a flexible reconstruction framework.
KW  - 4D flow
KW  - WSS
KW  - OSI
KW  - Self-navigation
KW  - Mouse
KW  - Aortic arch
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201120
VL  - 21
ER  - 
TY  - JOUR
A1  - Tiffe, Theresa
A1  - Morbach, Caroline
A1  - Rücker, Viktoria
A1  - Gelbrich, Götz
A1  - Wagner, Martin
A1  - Faller, Hermann
A1  - Störk, Stefan
A1  - Heuschmann, Peter U.
T1  - Impact of patient beliefs on blood pressure control in the general population: findings from the population-based STAAB cohort study
JF  - International Journal of Hypertension
N2  - Background. 
Effective antihypertensive treatment depends on patient compliance regarding prescribed medications. We assessed the impact of beliefs related towards antihypertensive medication on blood pressure control in a population-based sample treated for hypertension. 

Methods. 
We used data from the Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) study investigating 5000 inhabitants aged 30 to 79 years from the general population of Würzburg, Germany. The Beliefs about Medicines Questionnaire German Version (BMQ-D) was provided in a subsample without established cardiovascular diseases (CVD) treated for hypertension. We evaluated the association between inadequately controlled hypertension (systolic RR >140/90 mmHg; >140/85 mmHg in diabetics) and reported concerns about and necessity of antihypertensive medication. 

Results. 
Data from 293 participants (49.5% women, median age 64 years [quartiles 56.0; 69.0]) entered the analysis. Despite medication, half of the participants (49.8%) were above the recommended blood pressure target. Stratified for sex, inadequately controlled hypertension was less frequent in women reporting higher levels of concerns (OR 0.36; 95%CI 0.17-0.74), whereas no such association was apparent in men. We found no association for specific-necessity in any model.
 
Conclusion. 
Beliefs regarding the necessity of prescribed medication did not affect hypertension control. An inverse association between concerns about medication and inappropriately controlled hypertension was found for women only. Our findings highlight that medication-related beliefs constitute a serious barrier of successful implementation of treatment guidelines and underline the role of educational interventions taking into account sex-related differences.
KW  - hypertension
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200992
VL  - 2019
ER  - 
TY  - JOUR
A1  - Marzocco, Stefania
A1  - Fazeli, Gholamreza
A1  - Di Micco, Lucia
A1  - Autore, Giuseppina
A1  - Adesso, Simona
A1  - Dal Piaz, Fabrizio
A1  - Heidland, August
A1  - Di Iorio, Biagio
T1  - Supplementation of short-chain fatty acid, sodium propionate, in patients on maintenance hemodialysis: beneficial effects on inflammatory parameters and gut-derived uremic toxins, a pilot study (PLAN Study)
JF  - Journal of Clinical Medicine
N2  - Background: In end-stage renal disease (ESRD), gut-derived uremic toxins play a crucial role in the systemic inflammation and oxidative stress promoting the excess morbidity and mortality. The biochemical derangement is in part a consequence of an insufficient generation of short-chain fatty acids (SCFA) due to the dysbiosis of the gut and an insufficient consumption of the fermentable complex carbohydrates. Aim of the study: The primary end-point was to evaluate the potential efficacy of SCFA (specifically, sodium propionate (SP)) for patients on maintenance hemodialysis (MHD) on systemic inflammation. Secondary end-points included potential attenuation of oxidative stress markers, insulin resistance and production of gut-derived uremic toxins indoxyl sulfate and p-cresol sulfate, as well as health status after SP supplementation. Study design: We performed a single-center non-randomized pilot study in 20 MHD patients. They received the food additive SP with a daily intake of 2 × 500 mg in the form of capsules for 12 weeks. Pre-dialysis blood samples were taken at the beginning, after six weeks and at the end of the administration period, as well as four weeks after withdrawal of the treatment. Results: The subjects revealed a significant decline of inflammatory parameters C-reactive protein (−46%), interleukin IL-2 (−27%) and IL-17 (−15%). The inflammatory parameters IL-6 and IFN-gamma showed a mild non-significant reduction and the anti-inflammatory cytokine IL-10 increased significantly (+71%). While the concentration of bacterial endotoxins and TNF-α remained unchanged, the gut-derived uremic toxins, indoxyl sulfate (−30%) and p-cresyl sulfate (−50%), revealed a significant decline. The SP supplementation reduced the parameters of oxidative stress malondialdehyde (−32%) and glutathione peroxidase activity (−28%). The serum insulin levels dropped by 30% and the HOMA-index by 32%. The reduction of inflammatory parameters was associated with a lowering of ferritin and a significant increase in transferrin saturation (TSAT). Four weeks after the end of the treatment phase, all improved parameters deteriorated again. Evaluation of the psycho-physical performance with the short form 36 (SF-36) questionnaire showed an enhancement in the self-reported physical functioning, general health, vitality and mental health. The SP supplementation was well tolerated and without important side effects. No patient had left the study due to intolerance to the medication. The SP supplementation in MHD patients reduced pro-inflammatory parameters and oxidative stress and improved insulin resistance and iron metabolism. Furthermore, SP effectively lowered the important gut-derived uremic toxins indoxyl and p-cresol sulfate. These improvements were associated with a better quality of life. Further controlled studies are required in a larger cohort to evaluate the clinical outcome.
KW  - propionic acid
KW  - chronic kidney disease
KW  - hemodialysis
KW  - gut microbiome
KW  - systemic micro-inflammation oxidative stress
KW  - indoxyl sulfate
KW  - p-cresyl sulfate
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197626
SN  - 2077-0383
VL  - 7
IS  - 10
ER  - 
TY  - JOUR
A1  - Krieter, Detlef H.
A1  - Kerwagen, Simon
A1  - Rüth, Marieke
A1  - Lemke, Horst-Dieter
A1  - Wanner, Christoph
T1  - Differences in dialysis efficacy have limited effects on protein-bound uremic toxins plasma levels over time
JF  - Toxins
N2  - The protein-bound uremic toxins para-cresyl sulfate (pCS) and indoxyl sulfate (IS) are associated with cardiovascular disease in chronic renal failure, but the effect of different dialysis procedures on their plasma levels over time is poorly studied. The present prospective, randomized, cross-over trial tested dialysis efficacy and monitored pre-treatment pCS and IS concentrations in 15 patients on low-flux and high-flux hemodialysis and high-convective volume postdilution hemodiafiltration over six weeks each. Although hemodiafiltration achieved by far the highest toxin removal, only the mean total IS level was decreased at week three (16.6 ± 12.1 mg/L) compared to baseline (18.9 ± 13.0 mg/L, p = 0.027) and to low-flux dialysis (20.0 ± 12.7 mg/L, p = 0.021). At week six, the total IS concentration in hemodiafiltration reached the initial values again. Concentrations of free IS and free and total pCS remained unaltered. Highest beta2-microglobulin elimination in hemodiafiltration (p < 0.001) led to a persistent decrease of the plasma levels at week three and six (each p < 0.001). In contrast, absent removal in low-flux dialysis resulted in rising beta2-microglobulin concentrations (p < 0.001). In conclusion, this trial demonstrated that even large differences in instantaneous protein-bound toxin removal by current extracorporeal dialysis techniques may have only limited impact on IS and pCS plasma levels in the longer term.
KW  - protein-bound uremic toxins
KW  - end-stage renal disease
KW  - hemodialysis
KW  - hemodiafiltration
KW  - dialysis adequacy
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201770
VL  - 11
IS  - 4
ER  - 
TY  - JOUR
A1  - Seidlmayer, Lea K.
A1  - Mages, Christine
A1  - Berbner, Annette
A1  - Eder-Negrin, Petra
A1  - Arias-Loza, Paula Anahi
A1  - Kaspar, Mathias
A1  - Song, Moshi
A1  - Dorn, Gerald W.
A1  - Kohlhaas, Michael
A1  - Frantz, Stefan
A1  - Maack, Christoph
A1  - Gerull, Brenda
A1  - Dedkova, Elena N.
T1  - Mitofusin 2 is essential for IP3-mediated SR/Mitochondria metabolic feedback in ventricular myocytes
JF  - Frontiers in Physiology
N2  - Aim: Endothelin-1 (ET-1) and angiotensin II (Ang II) are multifunctional peptide hormones that regulate the function of the cardiovascular and renal systems. Both hormones increase the intracellular production of inositol-1,4,5-trisphosphate (IP\(_3\)) by activating their membrane-bound receptors. We have previously demonstrated that IP\(_3\)-mediated sarcoplasmic reticulum (SR) Ca\(^{2+}\) release results in mitochondrial Ca\(^{2+}\) uptake and activation of ATP production. In this study, we tested the hypothesis that intact SR/mitochondria microdomains are required for metabolic IP\(_3\)-mediated SR/mitochondrial feedback in ventricular myocytes.
Methods: As a model for disrupted mitochondrial/SR microdomains, cardio-specific tamoxifen-inducible mitofusin 2 (Mfn2) knock out (KO) mice were used. Mitochondrial Ca\(^{2+}\) uptake, membrane potential, redox state, and ATP generation were monitored in freshly isolated ventricular myocytes from Mfn2 KO mice and their control wild-type (WT) littermates.
Results: Stimulation of ET-1 receptors in healthy control myocytes increases mitochondrial Ca\(^{2+}\) uptake, maintains mitochondrial membrane potential and redox balance leading to the enhanced ATP generation. Mitochondrial Ca\(^{2+}\) uptake upon ET-1 stimulation was significantly higher in interfibrillar (IFM) and perinuclear (PNM) mitochondria compared to subsarcolemmal mitochondria (SSM) in WT myocytes. Mfn2 KO completely abolished mitochondrial Ca\(^{2+}\) uptake in IFM and PNM mitochondria but not in SSM. However, mitochondrial Ca2+ uptake induced by beta-adrenergic receptors activation with isoproterenol (ISO) was highest in SSM, intermediate in IFM, and smallest in PNM regions. Furthermore, Mfn2 KO did not affect ISO-induced mitochondrial Ca\(^{2+}\) uptake in SSM and IFM mitochondria; however, enhanced mitochondrial Ca\(^{2+}\) uptake in PNM. In contrast to ET-1, ISO induced a decrease in ATP levels in WT myocytes. Mfn2 KO abolished ATP generation upon ET-1 stimulation but increased ATP levels upon ISO application with highest levels observed in PNM regions.
Conclusion: When the physical link between SR and mitochondria by Mfn2 was disrupted, the SR/mitochondrial metabolic feedback mechanism was impaired resulting in the inability of the IP\(_3\)-mediated SR Ca\(^{2+}\) release to induce ATP production in ventricular myocytes from Mfn2 KO mice. Furthermore, we revealed the difference in Mfn2-mediated SR-mitochondrial communication depending on mitochondrial location and type of communication (IP\(_3\)R-mRyR1 vs. ryanodine receptor type 2-mitochondrial calcium uniporter).
KW  - mitofusin 2
KW  - IP3
KW  - SR/mitochondria metabolic feedback
KW  - mitochondrial mRyR1
KW  - ATP generation
KW  - endothelin-1
KW  - Mfn2 KO mice
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199141
SN  - 1664-042X
VL  - 10
IS  - 733
ER  - 
TY  - JOUR
A1  - Sbiera, Silviu
A1  - Kunz, Meik
A1  - Weigand, Isabel
A1  - Deutschbein, Timo
A1  - Dandekar, Thomas
A1  - Fassnacht, Martin
T1  - The new genetic landscape of Cushing’s disease: deubiquitinases in the spotlight
JF  - Cancers
N2  - Cushing’s disease (CD) is a rare condition caused by adrenocorticotropic hormone (ACTH)-producing adenomas of the pituitary, which lead to hypercortisolism that is associated with high morbidity and mortality. Treatment options in case of persistent or recurrent disease are limited, but new insights into the pathogenesis of CD are raising hope for new therapeutic avenues. Here, we have performed a meta-analysis of the available sequencing data in CD to create a comprehensive picture of CD’s genetics. Our analyses clearly indicate that somatic mutations in the deubiquitinases are the key drivers in CD, namely USP8 (36.5%) and USP48 (13.3%). While in USP48 only Met415 is affected by mutations, in USP8 there are 26 different mutations described. However, these different mutations are clustering in the same hotspot region (affecting in 94.5% of cases Ser718 and Pro720). In contrast, pathogenic variants classically associated with tumorigenesis in genes like TP53 and BRAF are also present in CD but with low incidence (12.5% and 7%). Importantly, several of these mutations might have therapeutic potential as there are drugs already investigated in preclinical and clinical setting for other diseases. Furthermore, network and pathway analyses of all somatic mutations in CD suggest a rather unified picture hinting towards converging oncogenic pathways.
KW  - Cushing’s disease
KW  - pathogenesis
KW  - somatic mutations
KW  - deubiquitinases
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-193194
SN  - 2072-6694
VL  - 11
IS  - 11
ER  -