TY - JOUR A1 - Schneider, Markus P. A1 - Hilgers, Karl F. A1 - Schmid, Matthias A1 - Hübner, Silvia A1 - Nadal, Jennifer A1 - Seitz, David A1 - Busch, Martin A1 - Haller, Hermann A1 - Köttgen, Anna A1 - Kronenberg, Florian A1 - Baid-Agrawal, Seema A1 - Schlieper, Georg A1 - Schultheiss, Ulla A1 - Sitter, Thomas A1 - Sommerer, Claudia A1 - Titze, Stephanie A1 - Meiselbach, Heike A1 - Wanner, Christoph A1 - Eckardt, Kai-Uwe T1 - Blood pressure control in chronic kidney disease: A cross-sectional analysis from the German Chronic Kidney Disease (GCKD) study JF - PLoS ONE N2 - We assessed the prevalence, awareness, treatment and control of hypertension in patients with moderate chronic kidney disease (CKD) under nephrological care in Germany. In the German Chronic Kidney Disease (GCKD) study, 5217 patients under nephrology specialist care were enrolled from 2010 to 2012 in a prospective observational cohort study. Inclusion criteria were an estimated glomerular filtration rate (eGFR) of 30–60 mL/min/1.73 m2 or overt proteinuria in the presence of an eGFR>60 mL/min/1.73 m2. Office blood pressure was measured by trained study personnel in a standardized way and hypertension awareness and medication were assessed during standardized interviews. Blood pressure was considered as controlled if systolic < 140 and diastolic < 90 mmHg. In 5183 patients in whom measurements were available, mean blood pressure was 139.5 ± 20.4 / 79.3 ± 11.8 mmHg; 4985 (96.2%) of the patients were hypertensive. Awareness and treatment rates were > 90%. However, only 2456 (49.3%) of the hypertensive patients had controlled blood pressure. About half (51.0%) of the patients with uncontrolled blood pressure met criteria for resistant hypertension. Factors associated with better odds for controlled blood pressure in multivariate analyses included younger age, female sex, higher income, low or absent proteinuria, and use of certain classes of antihypertensive medication. We conclude that blood pressure control of CKD patients remains challenging even in the setting of nephrology specialist care, despite high rates of awareness and medication use. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231520 VL - 13 ER - TY - JOUR A1 - Mueller, Jonathan Wolf A1 - Vogg, Nora A1 - Lightning, Thomas Alec A1 - Weigand, Isabel A1 - Ronchi, Cristina L A1 - Foster, Paul A A1 - Kroiss, Matthias T1 - Steroid Sulfation in Adrenal Tumors JF - Journal of Clinical Endocrinology & Metabolism N2 - Context The adrenal cortex produces specific steroid hormones including steroid sulfates such as dehydroepiandrosterone sulfate (DHEAS), the most abundant steroid hormone in the human circulation. Steroid sulfation involves a multistep enzyme machinery that may be impaired by inborn errors of steroid metabolism. Emerging data suggest a role of steroid sulfates in the pathophysiology of adrenal tumors and as potential biomarkers. Evidence Acquisition Selective literature search using “steroid,” “sulfat*,” “adrenal,” “transport,” “mass spectrometry” and related terms in different combinations. Evidence Synthesis A recent study highlighted the tissue abundance of estrogen sulfates to be of prognostic impact in adrenocortical carcinoma tissue samples using matrix-assisted laser desorption ionization mass spectrometry imaging. General mechanisms of sulfate uptake, activation, and transfer to substrate steroids are reasonably well understood. Key aspects of this pathway, however, have not been investigated in detail in the adrenal; these include the regulation of substrate specificity and the secretion of sulfated steroids. Both for the adrenal and targeted peripheral tissues, steroid sulfates may have relevant biological actions beyond their cognate nuclear receptors after desulfation. Impaired steroid sulfation such as low DHEAS in Cushing adenomas is of diagnostic utility, but more comprehensive studies are lacking. In bioanalytics, the requirement of deconjugation for gas-chromatography/mass-spectrometry has precluded the study of steroid sulfates for a long time. This limitation may be overcome by liquid chromatography/tandem mass spectrometry. Conclusions A role of steroid sulfation in the pathophysiology of adrenal tumors has been suggested and a diagnostic utility of steroid sulfates as biomarkers is likely. Recent analytical developments may target sulfated steroids specifically. KW - androgens KW - estrogens KW - sex hormones KW - DHEAS KW - DHEA-S KW - steroid disulfate KW - bis-sulfate KW - sulfation KW - sulfurylation KW - sulfonation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-371305 VL - 106 ER - TY - JOUR A1 - Kadowaki, Takashi A1 - Nangaku, Masaomi A1 - Hantel, Stefan A1 - Okamura, Tomoo A1 - von Eynatten, Maximilian A1 - Wanner, Christoph A1 - Koitka-Weber, Audrey T1 - Empagliflozin and kidney outcomes in Asian patients with type 2 diabetes and established cardiovascular disease: Results from the EMPA-REG OUTCOME® trial JF - Journal of Diabetes Investigation N2 - Aims/Introduction In the EMPA-REG OUTCOME® trial, empagliflozin added to standard of care improved clinically relevant kidney outcomes by 39%, slowed progression of chronic kidney disease, and reduced albuminuria in patients with type 2 diabetes and established cardiovascular disease. This exploratory analysis investigated the effects of empagliflozin on the kidneys in Asian patients. Materials and Methods Participants in the EMPA-REG OUTCOME® trial were randomized (1:1:1) to empagliflozin 10 mg, 25 mg or a placebo. In patients of Asian race, we analyzed incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal-replacement therapy or renal death) and its components, estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio changes, and renal safety. Results Of 7,020 treated patients, 1,517 (26.1%) were Asian. In this subgroup, consistent with the overall trial population, empagliflozin reduced the risk of incident or worsening nephropathy (hazard ratio 0.64, 95% confidence interval 0.49–0.83), progression to macroalbuminuria (hazard ratio 0.64, 95% confidence interval 0.49–0.85) and the composite of doubling of serum creatinine, initiation of renal-replacement therapy or renal death (hazard ratio 0.48, 95% confidence interval 0.25–0.92). Furthermore, empagliflozin-treated participants showed slower eGFR decline versus placebo, and showed rapid urine albumin-to-creatinine ratio reduction at week 12, maintained through week 164, with effects most pronounced in those with baseline microalbuminuria or macroalbuminuria. The kidney safety profile of empagliflozin in the Asian subgroup was similar to the overall trial population. Conclusions In Asian patients from the EMPA-REG OUTCOME® trial, empagliflozin improved kidney outcomes, slowed eGFR decline and lowered albuminuria versus placebo, consistent with the overall trial population findings. KW - diabetic kidney disease KW - empagliflozin KW - type 2 diabetes mellitus Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325246 VL - 10 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Brand, Eva A1 - Burlina, Alessandro A1 - Cecchi, Franco A1 - Garman, Scott C. A1 - Kempf, Judy A1 - Laney, Dawn A. A1 - Linhart, Aleš A1 - Maródi, László A1 - Nicholls, Kathy A1 - Ortiz, Alberto A1 - Pieruzzi, Federico A1 - Shankar, Suma P. A1 - Waldek, Stephen A1 - Wanner, Christoph A1 - Jovanovic, Ana T1 - Phenotypic characteristics of the p.Asn215Ser (p.N215S) GLA mutation in male and female patients with Fabry disease: A multicenter Fabry Registry study JF - Molecular Genetics & Genomic Medicine N2 - Background The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. Methods To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. Results In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25–34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55–64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65–74 years), and rarely in females (3%). Conclusion p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males. KW - cardiac variant KW - Fabry disease KW - GLA KW - p.Asn215Ser KW - p.N215S KW - phenotype Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232976 VL - 6 ER - TY - JOUR A1 - Bavendiek, Udo A1 - Berliner, Dominik A1 - Aguirre Dávila, Lukas A1 - Schwab, Johannes A1 - Maier, Lars A1 - Philipp, Sebastian A. A1 - Rieth, Andreas A1 - Westenfeld, Ralf A1 - Piorkowski, Christopher A1 - Weber, Kristina A1 - Hänselmann, Anja A1 - Oldhafer, Maximiliane A1 - Schallhorn, Sven A1 - von der Leyen, Heiko A1 - Schröder, Christoph A1 - Veltmann, Christian A1 - Störk, Stefan A1 - Böhm, Michael A1 - Koch, Armin A1 - Bauersachs, Johann T1 - Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study JF - European Journal of Heart Failure N2 - Aims Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides – although regularly used for HF treatment – remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). Methods Patients with chronic HF, New York Heart Association (NYHA) functional class III–IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8–18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. Conclusion The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment. KW - heart failure KW - cardiac glycosides KW - digitalis KW - digitoxin KW - clinical trial Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-221548 VL - 21 ER - TY - JOUR A1 - Frantz, Stefan A1 - Falcao-Pires, Ines A1 - Balligand, Jean-Luc A1 - Bauersachs, Johann A1 - Brutsaert, Dirk A1 - Ciccarelli, Michele A1 - Dawson, Dana A1 - de Windt, Leon J. A1 - Giacca, Mauro A1 - Hamdani, Nazha A1 - Hilfiker-Kleiner, Denise A1 - Hirsch, Emilio A1 - Leite-Moreira, Adelino A1 - Mayr, Manuel A1 - Thum, Thomas A1 - Tocchetti, Carlo G. A1 - van der Velden, Jolanda A1 - Varricchi, Gilda A1 - Heymans, Stephane T1 - The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC JF - European Journal of Heart Failure N2 - Activation of the immune system in heart failure (HF) has been recognized for over 20 years. Initially, experimental studies demonstrated a maladaptive role of the immune system. However, several phase III trials failed to show beneficial effects in HF with therapies directed against an immune activation. Preclinical studies today describe positive and negative effects of immune activation in HF. These different effects depend on timing and aetiology of HF. Therefore, herein we give a detailed review on immune mechanisms and their importance for the development of HF with a special focus on commonalities and differences between different forms of cardiomyopathies. The role of the immune system in ischaemic, hypertensive, diabetic, toxic, viral, genetic, peripartum, and autoimmune cardiomyopathy is discussed in depth. Overall, initial damage to the heart leads to disease specific activation of the immune system whereas in the chronic phase of HF overlapping mechanisms occur in different aetiologies. KW - immune system KW - macrophage KW - T-cell KW - ischaemic cardiomyopathy KW - hypertensive cardiomyopathy KW - diabetic cardiomyopathy KW - toxic cardiomyopathy KW - viral cardiomyopathy KW - genetic cardiomyopathy KW - peripartum cardiomyopathy KW - autoimmune cardiomyopathy Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229091 VL - 20 ER - TY - JOUR A1 - Nolte, Kathleen A1 - Hermann-Lingen, Christoph A1 - Platschek, Lars A1 - Holzendorf, Volker A1 - Pilz, Stefan A1 - Tomaschitz, Andreas A1 - Düngen, Hans-Dirk A1 - Angermann, Christiane E. A1 - Hasenfuß, Gerd A1 - Pieske, Burkert A1 - Wachter, Rolf A1 - Edelmann, Frank T1 - Vitamin D deficiency in patients with diastolic dysfunction or heart failure with preserved ejection fraction JF - ESC Heart Failure N2 - Aims Vitamin D deficiency is prevalent in heart failure (HF), but its relevance in early stages of heart failure with preserved ejection fraction (HFpEF) is unknown. We tested the association of 25-hydroxyvitamin D [25(OH)D] serum levels with mortality, hospitalizations, cardiovascular risk factors, and echocardiographic parameters in patients with asymptomatic diastolic dysfunction (DD) or newly diagnosed HFpEF. Methods and results We measured 25(OH)D serum levels in outpatients with risk factors for DD or history of HF derived from the DIAST-CHF study. Participants were comprehensively phenotyped including physical examination, echocardiography, and 6 min walk test and were followed up to 5 years. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire. We included 787 patients with available 25(OH)D levels. Median 25(OH)D levels were 13.1 ng/mL, mean E/e′ medial was 13.2, and mean left ventricular ejection fraction was 59.1%. Only 9% (n = 73) showed a left ventricular ejection fraction <50%. Fifteen per cent (n = 119) of the recruited participants had symptomatic HFpEF. At baseline, participants with 25(OH)D levels in the lowest tertile (≤10.9 ng/L; n = 263) were older, more often symptomatic (oedema and fatigue, all P ≤ 0.002) and had worse cardiac [higher N-terminal pro-brain natriuretic peptide (NT-proBNP) and left atrial volume index, both P ≤ 0.023], renal (lower glomerular filtration rate, P = 0.012), metabolic (higher uric acid levels, P < 0.001), and functional (reduced exercise capacity, 6 min walk distance, and SF-36 physical functioning score, all P < 0.001) parameters. Increased NT-proBNP, uric acid, and left atrial volume index and decreased SF-36 physical functioning scores were independently associated with lower 25(OH)D levels. There was a higher risk for lower 25(OH)D levels in association with HF, DD, and atrial fibrillation (all P ≤ 0.004), which remained significant after adjusting for age. Lower 25(OH)D levels (per 10 ng/mL decrease) tended to be associated with higher 5 year mortality, P = 0.05, hazard ratio (HR) 1.55 [1.00; 2.42]. Furthermore, lower 25(OH)D levels (per 10 ng/mL decrease) were related to an increased rate of cardiovascular hospitalizations, P = 0.023, HR = 1.74 [1.08; 2.80], and remained significant after adjusting for age, P = 0.046, HR = 1.63 [1.01; 2.64], baseline NT-proBNP, P = 0.048, HR = 1.62 [1.01; 2.61], and other selected baseline characteristics and co-morbidities, P = 0.043, HR = 3.60 [1.04; 12.43]. Conclusions Lower 25(OH)D levels were associated with reduced functional capacity in patients with DD or HFpEF and were significantly predictive for an increased rate of cardiovascular hospitalizations, also after adjusting for age, NT-proBNP, and selected baseline characteristics and co-morbidities. KW - vitamin D KW - diastolic dysfunction KW - heart failure KW - HFpEF KW - NT-proBNP Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232303 VL - 6 ER - TY - JOUR A1 - Müntze, Jonas A1 - Nordbeck, Peter T1 - Response to “Oral Chaperone Therapy Migalastat for the Treatment of Fabry Disease: Potentials and Pitfalls of Real-World Data” JF - Clinical Pharmacology & Therapeutics N2 - No abstract available Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231600 VL - 106 ER - TY - JOUR A1 - Müntze, Jonas A1 - Gensler, Daniel A1 - Maniuc, Octavian A1 - Liu, Dan A1 - Cairns, Tereza A1 - Oder, Daniel A1 - Hu, Kai A1 - Lorenz, Kristina A1 - Frantz, Stefan A1 - Wanner, Christoph A1 - Nordbeck, Peter T1 - Oral Chaperone Therapy Migalastat for Treating Fabry Disease: Enzymatic Response and Serum Biomarker Changes After 1 Year JF - Clinical Pharmacology & Therapeutics N2 - Long-term effects of migalastat therapy in clinical practice are currently unknown. We evaluated migalastat efficacy and biomarker changes in a prospective, single-center study on 14 patients with Fabry disease (55 ± 14 years; 11 men). After 1 year of open-label migalastat therapy, patients showed significant changes in alpha-galactosidase-A activity (0.06–0.2 nmol/minute/mg protein; P = 0.001), left ventricular myocardial mass index (137–130 g/m2; P = 0.037), and serum creatinine (0.94–1.0 mg/dL; P = 0.021), accounting for deterioration in estimated glomerular filtration rate (87–78 mL/minute/1.73 m2; P = 0.012). The enzymatic increase correlated with myocardial mass reduction (r = −0.546; P = 0.044) but not with renal function (r = −0.086; P = 0.770). Plasma globotriaosylsphingosine was reduced in therapy-naive patients (10.9–6.0 ng/mL; P = 0.021) and stable (9.6–12.1 ng/mL; P = 0.607) in patients switched from prior enzyme-replacement therapy. These first real-world data show that migalastat substantially increases alpha-galactosidase-A activity, stabilizes related serum biomarkers, and improves cardiac integrity in male and female patients with amenable Fabry disease mutations. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-231626 VL - 105 ER - TY - JOUR A1 - Kampf, Thomas A1 - Bauer, Wolfgang Rudolf A1 - Reiter, Theresa T1 - Improved post-processing strategy for MOLLI based tissue characterization allows application in patients with dyspnoe and impaired left ventricular function JF - Zeitschrift für Medizinische Physik N2 - Contrast and non-contrast MRI based characterization of myocardium by T1-mapping will be of paramount importance to obtain biomarkers, e.g. fibrosis, which determines the risk of heart failure patients. T1-mapping by the standard post-processing of the modified look-locker inversion recovery (MOLLI) lacks of accuracy when trying to reduce its duration, which on the other hand, is highly desirable in patients with heart failure. The recently suggested inversion group fitting (IGF) technique, which considers more parameters for fitting, has a superior accuracy for long T1 times despite a shorter duration. However, for short T1 values, the standard method has a superior precision. A conditional fitting routine is proposed which ideally takes advantage of both algorithms. Materials and methods All measurements were performed on a 1.5 T clinical scanner (ACHIEVA, Philips Healthcare, The Netherlands) using a MOLLI 5(n)3(n)3 prototype with n(heart beats) being a variable waiting time between inversion experiments. Phantom experiments covered a broad range of T1 times, waiting times and heart rates. A saturation recovery experiment served as a gold standard for T1 measurement. All data were analyzed with the standard MOLLI, the IGF fit and the conditional fitting routine and the obtained T1 values were compared with the gold standard. In vivo measurements were performed in a healthy volunteer and a total of 34 patients with normal findings, dilative cardiomyopathy and amyloidosis. Results Theoretical analysis and phantom experiments provided a threshold value for an apparent IGF determining processing with IGF post processing for values above, or switching to the standard technique for values below. This was validated in phantoms and patients measurements. A reduction of the waiting time to 1 instead of 3 heart beats between the inversion experiments showed reliable results. The acquisition time was reduced from 17 to 13 heart beats. The in vivo measurements showed ECV values between 25% (18–33%; SD 0.03) in the healthy, 30% (22–40%; SD 0.04) in patients with DCM and 45% (30–60%; SD 0.9) in patients with amyloidosis. Conclusion The adopted post-processing algorithm determines long T1 values with high accuracy and short T1 values while maintaining a high precision. Based on reduction of waiting time, and independence of heart rate, it shortens breath hold duration and allows fast T1-mapping, which is frequently a prerequisite in patients with cardiac diseases. KW - T1-mapping KW - ECV KW - MOLLI KW - post-processing Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325481 VL - 28 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Fomin, Victor V. A1 - Hilz, Max J. A1 - Jovanovic, Ana A1 - Kantola, Ilkka A1 - Linhart, Aleš A1 - Renzo, Mignani A1 - Namdar, Mehdi A1 - Nowak, Albina A1 - Oliveira, João-Paulo A1 - Pieroni, Maurizio A1 - Viana-Baptista, Miguel A1 - Wanner, Christoph A1 - Spada, Marco T1 - The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism Reports N2 - Background Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations. Methods We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients. Results Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes. Conclusions ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment. KW - Fabry disease KW - systematic literature review KW - agalsidase beta KW - agalsidase alfa KW - enzyme replacement therapy KW - adult male patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232987 VL - 19 ER - TY - JOUR A1 - Üçeyler, Nurcan A1 - Urlaub, Daniela A1 - Mayer, Christine A1 - Uehlein, Sabrina A1 - Held, Melissa A1 - Sommer, Claudia T1 - Tumor necrosis factor-α links heat and inflammation with Fabry pain JF - Molecular Genetics and Metabolism N2 - Fabry disease (FD) is an X-linked lysosomal storage disorder associated with pain triggered by heat or febrile infections. We modelled this condition by measuring the cytokine expression of peripheral blood mononuclear cells (PBMC) from FD patients in vitro upon stimulation with heat and lipopolysaccharide (LPS). We enrolled 67 FD patients and 37 healthy controls. We isolated PBMC, assessed their gene expression of selected pro- and anti-inflammatory cytokines, incubated them with heat, LPS, globotriaosylceramide (Gb3), and tumor necrosis factor-α (TNF), and measured TNF secretion in the supernatant and intracellular Gb3 accumulation, respectively. We found increased TNF, interleukin (IL-)1β, and toll-like receptor 4 (TLR4) gene expression in FD men (p < .05 to p < .01). TNF and IL-10 were higher, and IL-4 was lower in the subgroup of FD men with pain compared to controls (p < .05 to p < .01). Hereby, TNF was only increased in FD men with pain and classical mutations (p < .05) compared to those without pain. PBMC from FD patients secreted more TNF upon stimulation with LPS (p < .01) than control PBMC. Incubation with Gb3 and an additional α-galactosidase A inhibitor did not further increase TNF secretion, but incubation with TNF greatly increased the Gb3 load in FD PBMC compared to controls (p < .01). Also, LPS incubation and heat challenge (40 °C) increased Gb3 accumulation in PBMC of patients compared to baseline (p < .05 each), while no alterations were observed in control PBMC. Our data show that TNF holds a crucial role in the pathophysiology of FD associated pain, which may open a novel perspective for analgesic treatment in FD pain. KW - Fabry disease KW - Fabry pain KW - tumor necrosis factor-α KW - peripheral blood mononuclear cells Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229190 VL - 127 ER - TY - JOUR A1 - Germain, Dominique P. A1 - Arad, Michael A1 - Burlina, Alessandro A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Feldt-Rasmussen, Ulla A1 - Hilz, Max J. A1 - Hughes, Derralynn A. A1 - Ortiz, Alberto A1 - Wanner, Christoph A1 - Weidemann, Frank A1 - Spada, Marco T1 - The effect of enzyme replacement therapy on clinical outcomes in female patients with Fabry disease – A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism N2 - Background Heterozygous females with Fabry disease have a wide range of clinical phenotypes depending on the nature of their mutation and their X-chromosome inactivation pattern; it is therefore important to examine outcomes of enzyme replacement therapy (ERT) in the female patient population specifically. This paper presents the findings of a systematic literature review of treatment outcomes with ERT in adult female patients. Methods A comprehensive systematic literature review was conducted through January 2017 to retrieve published papers with original data on ERT in the treatment of Fabry disease. The review included all original articles that presented ERT outcomes data on patients with Fabry disease, irrespective of the study type. Results Clinical evidence for the efficacy of ERT in female patients was available from 67 publications including six clinical trial publications, and indicates significant reductions in plasma and urine globotriaosylceramide (GL-3) accumulation (in female patients with elevated pre-treatment levels) and improvements in cardiac parameters and quality of life (QoL). To date, data are insufficient to conclude on the effects of ERT on the nervous system, gastrointestinal manifestations, and pain in female patients with Fabry disease. Conclusions This review of available literature data demonstrates that ERT in adult female patients with Fabry disease has a beneficial effect on GL-3 levels and cardiac outcomes. The current evidence also suggests that ERT may improve QoL in this patient population, though further studies are needed to examine these results. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - adult female patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232963 VL - 126 ER - TY - JOUR A1 - Spada, Marco A1 - Baron, Ralf A1 - Elliott, Perry M. A1 - Falissard, Bruno A1 - Hilz, Max J. A1 - Monserrat, Lorenzo A1 - Tøndel, Camilla A1 - Tylki-Szymańska, Anna A1 - Wanner, Christoph A1 - Germain, Dominique P. T1 - The effect of enzyme replacement therapy on clinical outcomes in paediatric patients with Fabry disease – A systematic literature review by a European panel of experts JF - Molecular Genetics and Metabolism N2 - Background Fabry disease is caused by a deficiency of the lysosomal enzyme α-galactosidase, resulting in progressive accumulation of globotriaosylceramide (GL-3). The disease can manifest early during childhood and adolescence. Enzyme replacement therapy (ERT) with recombinant human α-galactosidase is the first specific treatment for Fabry disease and has been available in Europe since 2001. This paper presents the findings of a systematic literature review of clinical outcomes with ERT in paediatric patients with Fabry disease. Methods A comprehensive systematic review of published literature on ERT in Fabry disease was conducted in January 2017. The literature analysis included all original articles reporting outcomes of ERT in paediatric patients. Results Treatment-related outcomes in the paediatric population were reported in six publications derived from open-label clinical trials and in 10 publications derived from observational or registry-based studies. ERT was shown to significantly reduce plasma and urine GL-3 levels in paediatric patients with Fabry disease. The effect of ERT on GL-3 clearance from renal podocytes appeared to be agalsidase dose-dependent. ERT relieved pain and improved gastrointestinal symptoms and quality of life. Conclusions Based on the published literature, the use of ERT in paediatric patients can significantly clear GL-3 accumulation, ameliorate the early symptoms of Fabry disease, and improve quality of life. Treatment with ERT in paediatric patients with Fabry disease may be important to prevent further disease progression and overt organ damage. KW - Fabry disease KW - agalsidase alfa KW - agalsidase beta KW - systematic literature review KW - enzyme replacement therapy KW - paediatric patients Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-239287 VL - 126 ER - TY - JOUR A1 - Fazzini, Federica A1 - Lamina, Claudia A1 - Fendt, Liane A1 - Schultheiss, Ulla T. A1 - Kotsis, Fruzsina A1 - Hicks, Andrew A. A1 - Meiselbach, Heike A1 - Weissensteiner, Hansi A1 - Forer, Lukas A1 - Krane, Vera A1 - Eckardt, Kai-Uwe A1 - Köttgen, Anna A1 - Kronenberg, Florian T1 - Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease JF - Kidney International N2 - Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD. KW - chronic kidney disease KW - infections KW - mitochondrial DNA copy number KW - mortality Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227662 VL - 96 ER - TY - JOUR A1 - Storey, Benjamin C. A1 - Staplin, Natalie A1 - Haynes, Richard A1 - Reith, Christina A1 - Emberson, Jonathan A1 - Herrington, William G. A1 - Wheeler, David C. A1 - Walker, Robert A1 - Fellström, Bengt A1 - Wanner, Christoph A1 - Landray, Martin J. A1 - Baigent, Colin T1 - Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation JF - Kidney International N2 - Markers of inflammation, including plasma C-reactive protein (CRP), are associated with an increased risk of cardiovascular disease, and it has been suggested that this association is causal. However, the relationship between inflammation and cardiovascular disease has not been extensively studied in patients with chronic kidney disease. To evaluate this, we used data from the Study of Heart and Renal Protection (SHARP) to assess associations between circulating CRP and LDL cholesterol levels and the risk of vascular and non-vascular outcomes. Major vascular events were defined as nonfatal myocardial infarction, cardiac death, stroke or arterial revascularization, with an expanded outcome of vascular events of any type. Higher baseline CRP was associated with an increased risk of major vascular events (hazard ratio per 3x increase 1.28; 95% confidence interval 1.19-1.38). Higher baseline LDL cholesterol was also associated with an increased risk of major vascular events (hazard ratio per 0.6 mmol/L higher LDL cholesterol; 1.14, 1.06-1.22). Higher baseline CRP was associated with an increased risk of a range of non-vascular events (1.16, 1.12-1.21), but there was a weak inverse association between baseline LDL cholesterol and non-vascular events (0.96, 0.92-0.99). The efficacy of lowering LDL cholesterol with simvastatin/ezetimibe on major vascular events, in the randomized comparison, was similar irrespective of CRP concentration at baseline. Thus, decisions to offer statin-based therapy to patients with chronic kidney disease should continue to be guided by their absolute risk of atherosclerotic events. Estimation of such risk may include plasma biomarkers of inflammation, but there is no evidence that the relative beneficial effects of reducing LDL cholesterol depends on plasma CRP concentration. KW - C-reactive protein KW - inflammation KW - LDL cholesterol KW - randomized trials KW - vascular disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240067 VL - 93 ER - TY - JOUR A1 - Elliot, Perry M. A1 - Germain, Dominique P. A1 - Hilz, Max J. A1 - Spada, Marco A1 - Wanner, Christoph A1 - Falissard, Bruno T1 - Why systematic literature reviews in Fabry disease should include all published evidence JF - European Journal of Medical Genetics N2 - Fabry disease is an X-linked inherited, progressive disorder of lipid metabolism resulting from the deficient activity of the enzyme α-galactosidase. Enzyme replacement therapy (ERT) with recombinant agalsidase, with intravenous infusions of either agalsidase beta or agalsidase alfa, is available and clinical experience now exceeds 15 years. There are very few randomised, placebo-controlled clinical trials evaluating the outcomes of ERT. Data are often derived from observational, registry-based studies and case reports. Pooled analysis of data from different sources may be limited by the heterogeneity of the patient populations, outcomes and treatment. Therefore, comprehensive systematic literature reviews of unpooled data are needed to determine the effects of ERT on disease outcomes. A systematic literature search was conducted in the Embase and PubMed (MEDLINE) databases to retrieve original articles that evaluated outcomes of ERT in patients with Fabry disease; the outcome data were analysed unpooled. The literature analysis included the full range of published literature including observational studies and case series/case reports. Considerable heterogeneity was found among the studies, with differences in sample size, statistical methods, ERT regimens and patient demographic and clinical characteristics. We have demonstrated the value of performing an unpooled systematic literature review of all published evidence of ERT outcomes in Fabry disease, highlighting that in a rare genetic disorder like Fabry disease, which is phenotypically diverse, different patient populations can require different disease management and therapeutic goals depending on age, genotype, and disease severity/level of organ involvement. In addition, these findings are valuable to guide the design and reporting of new clinical studies. KW - Fabry disease KW - enzyme replacement therapy KW - systematic literature review Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226654 VL - 62 ER - TY - JOUR A1 - Eisenhofer, Graeme A1 - Peitzsch, Mirko A1 - Kaden, Denise A1 - Langton, Katharina A1 - Mangelis, Anastasios A1 - Pamporaki, Christina A1 - Masjkur, Jimmy A1 - Geroula, Aikaterini A1 - Kurlbaum, Max A1 - Deutschbein, Timo A1 - Beuschlein, Felix A1 - Prejbisz, Aleksander A1 - Bornstein, Stefan R. A1 - Lenders, Jacques W. M. T1 - Reference intervals for LC-MS/MS measurements of plasma free, urinary free and urinary acid-hydrolyzed deconjugated normetanephrine, metanephrine and methoxytyramine JF - Clinica Chimica Acta N2 - Background Plasma or urinary metanephrines are recommended for screening of pheochromocytomas and paragangliomas (PPGLs). Measurements of urinary free rather than deconjugated metanephrines and additional measurements of methoxytyramine represent other developments. For all measurements there is need for reference intervals. Methods Plasma free, urinary free and urinary deconjugated O-methylated catecholamine metabolites were measured by LC-MS/MS in specimens from 590 hypertensives and normotensives. Reference intervals were optimized using data from 2,056 patients tested for PPGLs. Results Multivariate analyses, correcting for age and body surface area, indicated higher plasma and urinary metanephrine in males than females and sex differences in urinary normetanephrine and free methoxytyramine that largely reflected body size variation. There were positive associations of age with plasma metabolites, but negative relationships with urinary free metanephrine and methoxytyramine. Plasma and urinary normetanephrine were higher in hypertensives than normotensives, but differences were small. Optimization of reference intervals using the data from patients tested for PPGLs indicated that age was the most important consideration for plasma normetanephrine and sex most practical for urinary metabolites. Conclusion This study clarifies impacts of demographic and anthropometric variables on catecholamine metabolites, verifies use of age-specific reference intervals for plasma normetanephrine and establishes sex-specific reference intervals for urinary metabolites. KW - liquid chromatography tandem mass spectrometry (LC-MS/MS) KW - normetanephrine KW - metanephrine KW - methoxytyramine KW - reference intervals KW - age Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226598 VL - 490 ER - TY - THES A1 - Danner, Elisabeth T1 - Systolische Ejektionszeit - Referenzwerte und Einfluss kardiovaskulärer Risikofaktoren in einer populationsbasierten Kohortenstudie T1 - Systolic ejection time - Reference values and impact of cardiovascular risk factors in a population-based cohort study N2 - Die systolische Ejektionszeit (SET) und die prä-Ejektionszeit (pET) sind Zeitintervalle, die sich zuverlässig mittels transthorakaler Echokardiographie erheben lassen und wichtige Aspekte in der kardialen Leistungsdiagnostik abbilden. Gleichwohl gibt es bislang für diese systolischen Zeitintervalle keine Normwerte. Die vorliegende Arbeit analysierte echokardiographische Daten von 4965 ProbandInnen der STAAB-Studie, einer umfänglich phänotypisierten populationsbasierten Kohortenstudie mit dem Ziel der Erstellung von Normwerten für die systolischen Zeitintervalle sowie der Identifizierung und Quantifizierung ihrer Determinanten mittels multivariable Regressionsanalysen. Aufgrund der starken Abhängigkeit der SET von der Herzfrequenz wurde die herzfrequenzkorrigierte SETc eingeführt, die in Anlehnung an die QTc-Zeit nach Fridericia berechnet wurde ("SET" /∛("RR-Intervall" )). Die Normwerte wurden anhand der gesunden Untergruppe (definiert durch Abwesenheit von kardiovaskulären Risikofaktoren oder Erkrankungen; N=966) aus STAAB generiert. Dem starken Einfluss von Geschlecht und Alter wurde dabei Rechnung getragen, indem für SET, SETc und pET alters- und geschlechtsspezifische Referenzwerte berechnet wurden. SETc war stark korreliert mit linksventrikulärer Ejektionsfraktion sowie enddiastolischem Volumen und Schlagvolumen. Zudem zeigte sich ein deutlicher Zusammenhang von SETc mit spezifischen Markern der Nachlast (Ea und Ees). Aus der großen Liste der klinischen Marker, die in STAAB erhoben wurden, ergab sich eine größere Anzahl von Einflussfaktoren. Bedeutsame Determinanten der systolischen Zeitintervalle waren insbesondere das metabolische Syndrom (sowie dessen Komponenten), das Rauchverhalten und die Einnahme von β Blockern. Die Ergebnisse zeigen, dass die systolischen Zeitintervalle, insbesondere SETc, reliable Informationen über das kardiale Kontraktionsverhalten liefern können. Derzeit werden neue Substanzklassen untersucht, die unter anderem über die Modifizierung von SET wirken sollen. Hier zu nennen sind insbesondere Myosin-Aktivatoren bei Herzinsuffizienz mit reduzierter Pumpfunktion wie zum Beispiel Omecamtiv Mecarbil oder Myosin-Inhibitoren bei Hypertropher Obstruktiver Kardiomyopathie. Die hierzu laufenden Studien betrachten auch die Effekte dieser Medikamente auf die systolischen Zeitintervalle als bedeutsame Surrogate der klinischen Effekte und letztlich der Prognose. Die nun vorliegenden Normwerte dieser Zeitintervalle erlauben es, die pathologisch veränderten Werte bei diesen spezifischen Krankheitsbildern und klinischen Studien besser einzuordnen und zu verstehen. N2 - The systolic ejection time (SET) and the pre-ejection time (pET) are time intervals that can be reliably recorded using transthoracic echocardiography and represent important aspects in cardiac performance diagnostics. However, there are currently no standard values for these systolic time intervals. The present research paper analyzed echocardiographic data from 4965 subjects from the STAAB study, a comprehensively characterized population-based cohort study with the aim of establishing standard values for the systolic time intervals and identifying and quantifying their determinants using multivariable regression analyses. Due to the strong dependency of SET on heart rate, the heart rate-corrected SETc was introduced which was calculated based on the QTc-time according to Fridericia ("SET" /∛("RR-Intervall" )). The standard values were generated from the STAAB study based on the healthy subgroup (defined by the absence of cardiovascular risk factors or diseases; N=966). Regarding the strong influence of gender and age, specific reference values for SET, SETc and pET implying gender and age affection were calculated. SETc was strongly correlated with left ventricular ejection fraction as well as end-diastolic volume and stroke volume. In addition, there was a notable correlation between SETc and specific markers of afterload (Ea and Ees). The large list of clinical markers collected in STAAB resulted in a number of affecting factors. Significant determinants of the systolic time intervals were in particular the metabolic syndrome (and its components), smoking behavior and the use of β-blockers. The results show that the systolic time intervals, especially SETc, can provide reliable information about cardiac contraction. New classes of substances are currently being investigated, which are supposed to work, among other things, by modifying SET. In particular, myosin activators in heart failure with reduced ejection fraction such as Omecamtiv Mecarbil or myosin inhibitors in hypertrophic obstructive cardiomyopathy should be mentioned here. The current studies also consider the effects of these drugs on the systolic time intervals as important surrogates of the clinical effects and the prognosis. The standard values for these time intervals enable better classifiying and unterstanding pathologically changed values in these specific disease pattern and clinical studies. KW - Referenzwert KW - Herzinsuffizienz KW - Risikofaktor KW - Systolische Ejektionszeit KW - kardiovaskuläre Risikofaktoren Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-370480 ER - TY - JOUR A1 - Siebert, Claudia A1 - Ciato, Denis A1 - Murakami, Masanori A1 - Frei-Stuber, Ludwig A1 - Perez-Rivas, Luis Gustavo A1 - Monteserin-Garcia, José Luis A1 - Nölting, Svenja A1 - Maurer, Julian A1 - Feuchtinger, Annette A1 - Walch, Axel K. A1 - Haak, Harm R. A1 - Bertherat, Jérôme A1 - Mannelli, Massimo A1 - Fassnacht, Martin A1 - Korpershoek, Esther A1 - Reincke, Martin A1 - Stalla, Günter K. A1 - Hantel, Constanze A1 - Beuschlein, Felix T1 - Heat Shock Protein 90 as a Prognostic Marker and Therapeutic Target for Adrenocortical Carcinoma JF - Frontiers in Endocrinology N2 - Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC. Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines. Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment. Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC. KW - adrenal gland KW - cortisol KW - N-terminal HSP90 inhibitors KW - C-terminal HSP90 inhibitors KW - prognostic marker Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238029 VL - 10 ER -