Publications by authors named "Lutz Binder"

48 Publications

The diagnostic and prognostic value of galectin-3 in patients at risk for heart failure with preserved ejection fraction: results from the DIAST-CHF study.

ESC Heart Fail 2021 Apr 10;8(2):829-841. Epub 2021 Feb 10.

Department of Internal Medicine and Cardiology, Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, Augustenburger Platz 1, Berlin, 13353, Germany.

Aims: Galectin-3 (Gal-3) predicts long-term outcome among patients with heart failure (HF) with preserved ejection fraction (HFpEF). The ability of Gal-3 to diagnose and predict incident HFpEF in a cohort at risk for HFpEF is of particular interest. We aimed to determine the association between Gal-3 and clinical manifestations of HFpEF, the relationship between Gal-3 and all-cause mortality, or the composite of cardiovascular hospitalization and death.

Methods And Results: The observational Diast-CHF study included patients aged 50 to 85 years with ≥1 risk factor for HF (e.g. hypertension, diabetes mellitus, and atherosclerotic disease) or previously suspected HF. Patients were followed for 10 years. The association between Gal-3, evidence of diastolic dysfunction, and Framingham criteria for HF was examined. All deaths and hospitalizations were adjudicated as cardiovascular or non-cardiovascular. The analysis population was composed of 1386 subjects (67 years old, 50.9% female). The area under the receiver operating characteristic curve to diagnose HFpEF was 0.71. At a cut-off value of 13.57 ng/mL, sensitivity was 0.61 and specificity was 0.73 for Gal-3, and the diagnostic power to detect HFpEF was superior to N-terminal pro-brain natriuretic peptide (area under the receiver operating characteristic curve 0.59, P > 0.001). Baseline Gal-3 was associated with risk factors for HF (P < 0.001). Higher levels of Gal-3 predicted incident HFpEF (P < 0.05), adjusted all-cause mortality (P < 0.001), and the adjusted composite of cardiovascular hospitalization and death (P < 0.001), both independent from N-terminal pro-brain natriuretic peptide.

Conclusions: Gal-3 differentiated patients with HFpEF from an overall cohort of well-characterized patients with risk factors for HFpEF. Independent of other factors, baseline Gal-3 levels were associated with a higher risk for incident HFpEF, mortality, or the composite of cardiovascular hospitalization and death over 10 year follow-up. In conjunction with clinical parameters, Gal-3 adds a statistically significant value for the diagnosis of HFpEF within this study, yet the clinical relevance remains debatable.
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http://dx.doi.org/10.1002/ehf2.13174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006663PMC
April 2021

Higher galectin-3 levels are independently associated with lower anxiety in patients with risk factors for heart failure.

Biopsychosoc Med 2020 2;14:24. Epub 2020 Oct 2.

Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen Medical Center, Göttingen, Germany.

Background: Galectin-3 promotes the proliferation of neural progenitor cells and is engaged in cell-cell adhesion, cell-matrix interactions, and macrophage activation. In addition, in patients with heart failure this carbohydrate-binding protein is a known prognostic marker for cardiovascular mortality. However, its association with psychological variables has not been investigated so far.

Methods: Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) trial, we studied in participants with cardiovascular risk factors ( = 1260, age 66.7 ± 8.0 years, males 51%, left ventricular ejection fraction 60.0 ± 8.1%) the relationship between serum concentrations of galectin-3 and anxiety. Galectin-3 levels were measured by means of a sandwich enzyme-linked immunosorbent assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS).

Results: In univariate analysis, there was a weak but significant inverse correlation between galectin-3 and HADS anxiety (rho = - 0.076;  = 0.008). Linear regression models adjusted for sex, age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-min walking distance, the 36-item Short-Form Health Survey (SF-36) subscale physical functioning, and known biomarkers for heart failure confirmed that serum galectin-3 significantly and independently predicted self-rated anxiety (B = -2.413; 95%CI = -2.413--4.422;  = 0.019).

Conclusion: In patients with cardiovascular risk factors, serum concentrations of galectin-3 showed an inverse association with anxiety, which was independent of both the severity of physical impairment and established risk factors for the progression of heart failure.
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http://dx.doi.org/10.1186/s13030-020-00195-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531142PMC
October 2020

Outcome assessment using estimation of left ventricular filling pressure in asymptomatic patients at risk for heart failure with preserved ejection fraction.

Int J Cardiol Heart Vasc 2020 Jun 7;28:100525. Epub 2020 May 7.

Charité Universitätsmedizin Berlin, Department of Cardiology Internal Medicine and Cardiology, Berlin, Germany.

Aims: High prevalence and lack of pharmacological treatment are making heart failure with preserved ejection fraction (HFpEF) a growing public health problem. No algorithm for the screening of asymptomatic patients with risk for HFpEF exists to date. We assessed whether HFA/ESC 2007 diagnostic criteria for HFpEF are helpful to investigate the cardiovascular outcome in asymptomatic patients.

Methods And Results: We performed an analysis of the Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that recruited patients with cardiovascular risk factors. All patients underwent a comprehensive diagnostic workup at baseline. Asymptomatic patients with preserved LVEF (>50%) were selected and classified according to HFA/ESC surrogate criteria for left ventricular elevated filling pressure (mean E/e' >15 or E/e' >8 and presence of either NT-proBNP > 220 ng/l, BNP > 200 ng/l or atrial fibrillation) into elevated filling pressure (FPe) or controls. Cardiovascular hospitalizations and all-cause death were assessed for both groups over a 10-year-follow-up.851 asymptomatic patients (age 65.5 ± 7.6 years, 44% female) were included in the analysis. FPe-patients were significantly older (p < 0.001), more often female (p = 0.003) and more often had a history of coronary artery disease, atrial fibrillation and renal dysfunction (p < 0.001, respectively) compared to controls. Incidence of death was significantly higher in the FPe group after a 10-year follow-up (p < 0.001), whereas cardiovascular hospitalization did not differ between groups.

Conclusion: Asymptomatic patients that fulfill HFA/ESC diagnostic criteria for HFpEF are at higher risk of symptomatic HFpEF and have a worse 10-year-outcome than those who do not fulfill criteria.
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http://dx.doi.org/10.1016/j.ijcha.2020.100525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218096PMC
June 2020

Brain Natriuretic Peptide and Discovery of Atrial Fibrillation After Stroke: A Subanalysis of the Find-AF Trial.

Stroke 2020 02 9;51(2):395-401. Epub 2019 Dec 9.

Clinic for Cardiology and Pneumology (M.W.-K., R.W.), University of Göttingen, Germany.

Background and Purpose- Diagnosing paroxysmal atrial fibrillation (pAF) can be challenging after acute ischemic stroke. Enhanced and prolonged Holter-ECG monitoring (EPM) improves the detection rate but is not feasible for all patients. We hypothesized that brain natriuretic peptide (BNP) may help to identify patients with stroke at high risk for pAF to select patients for EPM more effectively. Methods- Patients with acute cerebral ischemia ≥60 years presenting in sinus rhythm and without history of AF were included into a prospective, randomized multicenter study to receive either EPM (3× 10-day Holter-ECG) or usual stroke care diagnostic work-up. BNP plasma levels were measured on randomization and 3 months thereafter. Levels were compared between patients with and without pAF detected by means of EPM or usual care. Furthermore, the number needed to screen for EPM depending on BNP cut offs was calculated. Results- A total of 398 patients were analyzed. In 373 patients (93.7%), BNP was measured at baseline and in 275 patients (69.1%) after 3 months. pAF was found in 27 patients by means of EPM and in 9 patients by means of usual care (=0.002). Median BNP was higher in patients with pAF as compared to patients without AF in both study arms at baseline (57.8 versus 28.3 pg/mL in the EPM arm, =0.0003; 46.2 versus 27.7 pg/mL, =0.28 in the control arm) and after 3 months (74.9 versus 31.3 pg/mL, =0.012 in the EPM arm, 99.3 versus 26.3 pg/mL, =0.02 in the control arm). Applying a cut off of 100 pg/mL, the number needed to screen was reduced from 18 by usual care to 3 by EPM. Conclusions- BNP measured early after ischemic stroke identifies a subgroup of patients with stroke at increased risk for AF, in whom EPM is particularly efficacious. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01855035.
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http://dx.doi.org/10.1161/STROKEAHA.119.026496DOI Listing
February 2020

Longitudinal relationship between B-type natriuretic peptide and anxiety in coronary heart disease patients with depression.

J Psychosom Res 2019 08 21;123:109728. Epub 2019 May 21.

Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen Medical Center, Von-Siebold-Str. 5, 37075 Göttingen, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany. Electronic address:

Objective: Patients with coronary heart disease (CHD) suffer from physical limitations, but also from psychological distress. Natriuretic peptides may be involved in the neurobiological processes that modulate psychological adaptation, as they are increased in heart disease and seem to have an anxiolytic-like function. Longitudinal data on this association are scarce.

Methods: To assess the relationship between NT-proBNP and anxiety (Hospital Anxiety and Depression Scale (HADS)), we used secondary data from a multicenter trial from baseline to 24 months. Patients (N = 308, 80.8% male, mean age 60.1 years) had stable CHD and moderate levels of depression (HADS ≥8).

Results: Multiple linear regression adjusted for age, sex, BMI, and physical functioning revealed NT-proBNP as a significant predictor for anxiety at baseline, 1, 6, 12, 18, and 24 months (all p < .05). Linear mixed model analysis with the six anxiety measures as level-1 variable and NT-proBNP as fixed factor revealed a significant time*NT-proBNP interaction (t(1535.99) = -2.669, p = .01) as well as a significant time*NT-proBNP*sex interaction (t(1535.99) = 3.277, p = .001), when NT-proBNP was dichotomized into lowest vs. the three highest quartiles.

Conclusion: Our results indicate a stable negative association of baseline NT-proBNP with anxiety over two years. In men and women, different pathways modulating this relationship appear to be in effect. Female patients with very low NT-proBNP levels, despite their cardiac disease, show persistently higher levels of anxiety compared to women with higher levels of NT-proBNP and compared to men. Trial name: A Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD).

Trial Registration: www.clinicaltrials.govNCT00705965; www.isrctn.com ISRCTN76240576.
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http://dx.doi.org/10.1016/j.jpsychores.2019.05.006DOI Listing
August 2019

Assessing the role of extracellular signal-regulated kinases 1 and 2 in volume overload-induced cardiac remodelling.

ESC Heart Fail 2019 10 19;6(5):1015-1026. Epub 2019 Jul 19.

Department of Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany.

Aims: Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal-regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen-activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO-induced cardiac remodelling as this was unknown.

Methods And Results: Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr-Glu-Tyr) motif (-28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte-specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6-fold, P < 0.05) and protein level (3.1-fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice.

Conclusions: VO-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte-specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
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http://dx.doi.org/10.1002/ehf2.12497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6816056PMC
October 2019

Higher plasma levels of CT-proAVP are linked to less anxiety in men but not women with cardiovascular risk factors: Results from the observational Diast-CHF study.

Psychoneuroendocrinology 2019 03 20;101:272-277. Epub 2018 Dec 20.

Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen Medical Center, Göttingen, Germany; German Center for Cardiovascular Research (DZHK), partner site Göttingen, Germany.

Aim: Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, this post-hoc analysis aimed at assessing the association between serum concentrations of C-terminal pro-arginine vasopressin (CT-proAVP) and anxiety in patients with cardiovascular risk factors.

Background: Animal studies have demonstrated that centrally released AVP is involved in the development of anxiety-like behaviors, however, it is unknown whether, also in humans, CT-proAVP used as a proxy for the co-secreted AVP is associated with self-reported anxiety.

Methods: In 1463 study participants with cardiovascular risk factors (mean age 66.7 ± 8.1 years, 51.3% males, mean left ventricular ejection fraction 59.8 ± 8.3%), serum concentrations of CT-proAVP were measured by means of an ELISA assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS).

Results: Data showed that there was a significant and inverse correlation between HADS anxiety and CT-proAVP (rho = -0.074; p = 0.005). Serum CT-proAVP and the HADS anxiety differed between the two sexes: men displayed lower anxiety (4.7 ± 3.5 versus 5.5 ± 3.7) and had higher CT-proAVP levels (5.8 pmol/L, interquartile range 3.5-9.9 pmol/L versus 3.0 pmol/L, interquartile range 2.0-4.7) than women (both, p < 0.001). Using univariate ANOVA adjusted for age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-minute walking distance, SF-36 physical functioning, and the natriuretic peptides NT-proBNP and MR-proANP, the interaction term sex*CT-proAVP was significantly associated with anxiety (p = 0.006). Further analysis showed that CT-proAVP was inversely related to anxiety only in men (B = -0.991; 95%CI = -1.650 to -0.331; p = 0.003), but not in women (p = 0.335).

Conclusion: In male study participants with cardiovascular risk factors, serum concentrations of CT-proAVP showed an inverse association with anxiety, which was independent from the severity of physical impairment.
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http://dx.doi.org/10.1016/j.psyneuen.2018.12.230DOI Listing
March 2019

Macro-CK type 2 in metastatic prostate cancer.

Diagnosis (Berl) 2019 08;6(3):307-309

Institute for Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany.

The isoenzyme creatine kinase muscle/brain (CK-MB) still plays an important role for the differential diagnosis of CK elevations and the clarification of their origin from heart or skeletal muscle. Therefore, it is necessary to know the diagnostic pitfalls in interpreting CK-MB results. We demonstrate a case of macro-CK type 2 in a 75-year-old patient with metastatic castration-resistant prostate cancer and its identification by isoenzyme electrophoresis, which can be typical for cancer diseases.
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http://dx.doi.org/10.1515/dx-2018-0039DOI Listing
August 2019

Differences in procalcitonin measurements between three BRAHMS-partnered immunoassays (Liaison, Elecsys and Architect).

Clin Chem Lab Med 2019 08;57(9):e207-e210

Institute for Clinical Chemistry, University Medical Center Goettingen, Goettingen, Germany.

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http://dx.doi.org/10.1515/cclm-2018-0916DOI Listing
August 2019

Associations of NT-proBNP and parameters of mental health in depressed coronary artery disease patients.

Psychoneuroendocrinology 2018 10 4;96:188-194. Epub 2018 Jun 4.

Department of Psychosomatic Medicine and Psychotherapy, University of Göttingen Medical Center, von-Siebold-Str. 5, 37075 Göttingen, Germany and German Center for Cardiovascular Research (DZHK), partner site Göttingen.

Natriuretic peptides (NP) are involved in the regulation of blood pressure and blood volume, and are elevated in patients with coronary artery disease (CAD). They are used as markers for illness severity, but their role in mental health is not well understood. Recently, A-type NP (ANP) has been associated with reduced anxiety in studies on cardiac patients; however, this study is the first to assess this effect for B-type NP (BNP) and for further dimensions of well-being and mental health. Depression, anxiety, and distress are more common in CAD patients than in the general population and are most likely not only influenced by psychological adaptation but also by neurobiological processes. We used baseline N-terminal proBNP (NT-proBNP) samples and psychometric assessments of 529 at least mildly depressed (Hospital Anxiety and Depression Scale, depression score ≥ 8) CAD patients from the multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial. Psychosocial status was assessed using standardized self-rating questionnaires on anxiety, depression, coping with illness, vital exhaustion, type D personality, and quality of life. Separate linear regression models for each psychometric scale revealed significant negative correlations of NT-proBNP with anxiety, depression, vital exhaustion, depressive coping, and negative affectivity. Moreover, patients with higher levels of NT-proBNP experienced less bodily pain and had a better self-rated mental health, despite worse physical functioning. Linear regression adjusted for age, sex, and physical functioning (Short Form Health Survey [SF-36]) revealed NT-proBNP to be a significant predictor for all tested measures of the patients' psychosocial status. These results indicate that NT-proBNP is not only positively associated with greater disease severity in mildly to moderately depressed CAD patients but also with better psychosocial status and mental well-being. Possible mechanisms of this effect are discussed.
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http://dx.doi.org/10.1016/j.psyneuen.2018.06.001DOI Listing
October 2018

Systematic forensic toxicological analysis by liquid-chromatography-quadrupole-time-of-flight mass spectrometry in serum and comparison to gas chromatography-mass spectrometry.

Forensic Sci Int 2018 Jun 3;287:63-73. Epub 2018 Apr 3.

Institute for Clinical Chemistry/UMG-Laboratories, University Medical Center Göttingen, Georg-August-University, 37075 Göttingen, Germany.

Comprehensive screening procedures for psychoactive agents in body fluids are an essential task in clinical and forensic toxicology. With the continuous emergence and adaption of new psychoactive substances (NPS) keeping a screening method up to date is challenging. To meet these demands, hyphenated high-resolution mass spectrometry has gained interest as extensive and expandable screening approach. Here we present a comprehensive method for systematic toxicological analysis of serum by liquid chromatography-quadrupole-time-of-flight mass spectrometry (LC-QTOF-MS) with data independent acquisition. The potential of this method was demonstrated by analysis of 247 authentic serum- and 12 post-mortem femoral blood samples. Thus 950 compounds, comprising 185 different drugs and metabolites could be identified. For the detected substances, including pharmaceutical substances, illicit drugs as well as NPS, serum concentrations were confirmed ranging from traces to toxic values indicating the capability for forensic toxicological requirements. Positive identification of drugs was achieved by accurate mass measurement (±5ppm for [M+H]; ±10ppm for [M-H]), retention time (±0.35min), isotopic pattern match (less than 10 m/z RMS [ppm]), isotope match intensity (less than 20% RMS) and the presence of at least two fragment ions. The LC-QTOF-MS procedure was shown to be superior to serum screening by GC-MS, since 240% (335 versus 141) more drugs were identified in serum samples compared to GC-MS.
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http://dx.doi.org/10.1016/j.forsciint.2018.03.039DOI Listing
June 2018

MPA Modulates Tight Junctions' Permeability via Midkine/PI3K Pathway in Caco-2 Cells: A Possible Mechanism of Leak-Flux Diarrhea in Organ Transplanted Patients.

Front Physiol 2017 26;8:438. Epub 2017 Jun 26.

Institute for Clinical Chemistry/UMG-Laboratories, University Medical CenterGoettingen, Germany.

Mycophenolic acid (MPA) is prescribed to prevent allograft rejection in organ transplanted patients. However, its use is sporadically linked to leak flux diarrhea and other gastrointestinal (GI) disturbances in around 75% of patients through yet unknown mechanisms. Recently, we identified Midkine as a modulator of tight junctions (TJs) permeability in MPA treated Caco-2 monolayer. In the present study, we investigated the possible involvement of Midkine dependent PI3K pathway in alteration of TJs under MPA treatment. Caco-2 cells were grown as monolayer to develop TJs and were treated for 72 h with DMSO (control) or MPA in presence and absence of Midkine inhibitor (iMDK) or PI3K inhibitors (LY/AMG). Caco-2 monolayer integrity was assessed by transepithelial electrical resistance (TEER) and FITC-dextran assays. Our functional assays showed that PI3K inhibitors (LY/AMG) can significantly inhibit the compromised TJs integrity of MPA-treated Caco-2 cells monolayer. Chromatin immunoprecipitation analyses showed a significant epigenetic activation of M, and genes and epigenetic repression of gene after MPA treatment. The MPA-induced epigenetic alterations were further confirmed by mRNA and protein expression analysis. Collectively, our data shows that PI3K pathway as the downstream target of Midkine which in turn modulates p38MAPK and pAKT signaling to alter TJs permeability in Caco-2 cell monolayers treated with MPA. These results highlight the possible use of either Midkine or PI3K inhibitors as therapeutic agents to prevent MPA induced GI disturbances.
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http://dx.doi.org/10.3389/fphys.2017.00438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483464PMC
June 2017

Active and Repressive Chromatin-Associated Proteome after MPA Treatment and the Role of Midkine in Epithelial Monolayer Permeability.

Int J Mol Sci 2016 Apr 20;17(4). Epub 2016 Apr 20.

Institute for Clinical Chemistry/UMG-Laboratories, University Medical Center, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

Unlabelled: Mycophenolic acid (MPA) is prescribed to maintain allografts in organ-transplanted patients. However, gastrointestinal (GI) complications, particularly diarrhea, are frequently observed as a side effect following MPA therapy. We recently reported that MPA altered the tight junction (TJ)-mediated barrier function in a Caco-2 cell monolayer model system. This study investigates whether MPA induces epigenetic changes which lead to GI complications, especially diarrhea.

Methods: We employed a Chromatin Immunoprecipitation-O-Proteomics (ChIP-O-Proteomics) approach to identify proteins associated with active (H3K4me3) as well as repressive (H3K27me3) chromatin histone modifications in MPA-treated cells, and further characterized the role of midkine, a H3K4me3-associated protein, in the context of epithelial monolayer permeability.

Results: We identified a total of 333 and 306 proteins associated with active and repressive histone modification marks, respectively. Among them, 241 proteins were common both in active and repressive chromatin, 92 proteins were associated exclusively with the active histone modification mark, while 65 proteins remained specific to repressive chromatin. Our results show that 45 proteins which bind to the active and seven proteins which bind to the repressive chromatin region exhibited significantly altered abundance in MPA-treated cells as compared to DMSO control cells. A number of novel proteins whose function is not known in bowel barrier regulation were among the identified proteins, including midkine. Our functional integrity assays on the Caco-2 cell monolayer showed that the inhibition of midkine expression prior to MPA treatment could completely block the MPA-mediated increase in barrier permeability.

Conclusions: The ChIP-O-Proteomics approach delivered a number of novel proteins with potential implications in MPA toxicity. Consequently, it can be proposed that midkine inhibition could be a potent therapeutic approach to prevent the MPA-mediated increase in TJ permeability and leak flux diarrhea in organ transplant patients.
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http://dx.doi.org/10.3390/ijms17040597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849051PMC
April 2016

Immunosuppressant MPA Modulates Tight Junction through Epigenetic Activation of MLCK/MLC-2 Pathway via p38MAPK.

Front Physiol 2015 22;6:381. Epub 2015 Dec 22.

Proteomics Group, Institute for Clinical Chemistry/UMG-Laboratories, University Medical Centre Goettingen, Germany.

Background: Mycophenolic acid (MPA) is an important immunosuppressive drug (ISD) prescribed to prevent graft rejection in the organ transplanted patients, however, its use is also associated with adverse side effects like sporadic gastrointestinal (GI) disturbances. Recently, we reported the MPA induced tight junctions (TJs) deregulation which involves MLCK/MLC-2 pathway. Here, we investigated the global histone acetylation as well as gene-specific chromatin signature of several genes associated with TJs regulation in Caco-2 cells after MPA treatment.

Results: The epigenetic analysis shows that MPA treatment increases the global histone acetylation levels as well as the enrichment for transcriptional active histone modification mark (H3K4me3) at promoter regions of p38MAPK, ATF-2, MLCK, and MLC-2. In contrast, the promoter region of occludin was enriched for transcriptional repressive histone modification mark (H3K27me3) after MPA treatment. In line with the chromatin status, MPA treatment increased the expression of p38MAPK, ATF-2, MLCK, and MLC-2 both at transcriptional and translational level, while occludin expression was negatively influenced. Interestingly, the MPA induced gene expression changes and functional properties of Caco-2 cells could be blocked by the inhibition of p38MAPK using a chemical inhibitor (SB203580).

Conclusions: Collectively, our results highlight that MPA disrupts the structure of TJs via p38MAPK-dependent activation of MLCK/MLC-2 pathway that results in decreased integrity of Caco-2 monolayer. These results led us to suggest that p38MAPK-mediated lose integrity of epithelial monolayer could be the possible cause of GI disturbance (barrier dysfunction) in the intestine, leading to leaky style diarrhea observed in the organ-transplanted patients treated with MPA.
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http://dx.doi.org/10.3389/fphys.2015.00381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687409PMC
January 2016

The brain as immunoprecipitator of serum autoantibodies against N-Methyl-D-aspartate receptor subunit NR1.

Ann Neurol 2016 Jan 2;79(1):144-51. Epub 2015 Dec 2.

Department of Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen.

Autoantibodies (AB) against N-methyl-D-aspartate receptor subunit NR1 (NMDAR1) are highly seroprevalent in health and disease. Symptomatic relevance may arise upon compromised blood-brain barrier (BBB). However, it remained unknown whether circulating NMDAR1 AB appear in the cerebrospinal fluid (CSF). Of n = 271 subjects with CSF-serum pairs, 26 were NMDAR1 AB seropositive, but only 1 was CSF positive. Contrariwise, tetanus AB (non-brain-binding) were present in serum and CSF of all subjects, with CSF levels higher upon BBB dysfunction. Translational mouse experiments proved the hypothesis that the brain acts as an 'immunoprecipitator'; simultaneous injection of NMDAR1 AB and the non-brain-binding green fluorescent protein AB resulted in high detectability of the former in brain and the latter in CSF.
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http://dx.doi.org/10.1002/ana.24545DOI Listing
January 2016

Natriuretic peptides for the detection of paroxysmal atrial fibrillation.

Open Heart 2015;2(1):e000182. Epub 2015 Aug 3.

Department of Cardiology and Pneumology , University of Göttingen , Göttingen , Germany ; German Cardiovascular Research Center (DZHK) , Göttingen , Germany.

Background And Purpose: Silent atrial fibrillation (AF) and tachycardia (AT) are considered precursors of ischaemic stroke. Therefore, detection of paroxysmal atrial rhythm disorders is highly relevant, but is clinically challenging. We aimed to evaluate the diagnostic value of natriuretic peptide levels in the detection of paroxysmal AT/AF in a pilot study.

Methods: Natriuretic peptide levels were analysed in two independent patient cohorts (162 patients with arterial hypertension or other cardiovascular risk factors and 82 patients with retinal vessel disease). N-terminal-pro-brain natriuretic peptide (NT-proBNP) and BNP were measured before the start of a 7-day Holter monitoring period carefully screened for AT/AF.

Results: 244 patients were included; 16 had paroxysmal AT/AF. After excluding patients with a history of AT/AF (n=5), 14 patients had newly diagnosed AT/AF (5.8%) NT-proBNP and BNP levels were higher in patients with paroxysmal AT/AF in both cohorts: (1) 154.4 (IQR 41.7; 303.6) versus 52.8 (30.4; 178.0) pg/mL and 70.0 (31.9; 142.4) versus 43.9 (16.3; 95.2) and (2) 216.9 (201.4; 277.1) versus 90.8 (42.3-141.7) and 96.0 (54.7; 108.2) versus 29.1 (12.0; 58.1). For the detection of AT/AF episodes, NT-proBNP and BNP had an area under the curve in receiver operating characteristic analysis of 0.76 (95% CI, 0.64 to 0.88; p=0.002) and 0.75 (0.61 to 0.89; p=0.004), respectively.

Conclusions: NT-proBNP and BNP levels are elevated in patients with silent AT/AF as compared with sinus rhythm. Thus, screening for undiagnosed paroxysmal AF using natriuretic peptide level initiated Holter monitoring may be a useful strategy in prevention of stroke or systemic embolism.
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http://dx.doi.org/10.1136/openhrt-2014-000182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533200PMC
August 2015

Determinants of submaximal exercise capacity in patients at risk for heart failure with preserved ejection fraction-results from the DIAST-CHF study.

ESC Heart Fail 2015 Jun 27;2(2):76-84. Epub 2015 Apr 27.

Department of Cardiology and Pneumology, Göttingen University Medical Center, Göttingen, Germany.

Objectives And Background: The aim of this study was to identify determinants of submaximal exercise capacity as measured by 6 min walking distance in patients at risk for heart failure with preserved ejection fraction (HFpEF).

Methods: A cross-sectional analysis from the prospective cohort programme Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) that included a total of 1937 patients (age, 50-85 years) with >1 risk factor (hypertension, atherosclerotic disease, diabetes mellitus, and obstructive sleep apnoea) was carried out. Besides comprehensive clinical phenotyping, standardized 6 min walk test and state-of-the-art echocardiography were performed, and blood samples for biomarker assessment were obtained. Patients with an ejection fraction <50% or without evaluable exercise test were excluded from this analysis.

Results: One thousand three hundred eighty-seven patients fulfilled all criteria for this analysis. In the univariate analysis, 6 min walk distance was inversely related to E/e' values (P < 0.001). In the multivariate analysis, 6 min walk distance decreased significantly with age, female sex, increasing body mass index, diabetes, chronic obstructive lung disease, and peripheral artery disease. However, the association of 6 min walk distance with resting parameters of diastolic function was significantly attenuated with multivariate regression. In contrast, mid-regional pro-adrenomedullin, mid-regional pro-atrial natriuretic peptide, and N-terminal pro-B-type natriuretic peptide were independently associated with submaximal exercise capacity when added to the base model (all P < 0.001).

Conclusions: Classical risk factors for heart failure and neuroendocrine activation are independently associated with sub-maximal exercise capacity, while diastolic function parameters obtained at rest were not. This observation substantiates the role of co-morbidities as relevant contributors to the clinical picture of HFpEF and the limitation of resting indices of diastolic function for diagnosing HFpEF.
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http://dx.doi.org/10.1002/ehf2.12034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6410539PMC
June 2015

Preexisting Serum Autoantibodies Against the NMDAR Subunit NR1 Modulate Evolution of Lesion Size in Acute Ischemic Stroke.

Stroke 2015 May 12;46(5):1180-6. Epub 2015 Mar 12.

From the Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany (M.Z., C.O., E.D., I.H., L.D., H.E.); Department of Neurology, Hannover Medical School, Hannover, Germany (K.W., H.W., A.B.T.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Göttingen, Germany (J.W.); Institute of Clinical Chemistry, University Medical Center, Göttingen, Germany (A.R.A., L.B.); Institute for Experimental Immunology, affiliated to Euroimmun, Lübeck, Germany (K.R., W.S.); Department of Psychiatry, University of Magdeburg, Magdeburg, Germany (J.S.); Department of Psychiatry and Psychotherapy, University of Göttingen, Germany (J.W.); and Department of Neurosurgery, University of Würzburg, Germany (A.-L.S.).

Background And Purpose: Recently, we reported high seroprevalence (age-dependent up to >19%) of N-methyl-d-aspartate-receptor subunit NR1 (NMDAR1) autoantibodies in both healthy and neuropsychiatrically ill subjects (N=4236). Neuropsychiatric syndrome relevance was restricted to individuals with compromised blood-brain barrier, for example, apolipoprotein E4 (APOE4) carrier status, both clinically and experimentally. We now hypothesized that these autoantibodies may upon stroke be protective in individuals with hitherto intact blood-brain barrier, but harmful for subjects with chronically compromised blood-brain barrier.

Methods: Of 464 patients admitted with acute ischemic stroke in the middle cerebral artery territory, blood for NMDAR1 autoantibody measurements and APOE4 carrier status as indicator of a preexisting leaky blood-brain barrier was collected within 3 to 5 hours after stroke. Evolution of lesion size (delta day 7-1) in diffusion-weighted magnetic resonance imaging was primary outcome parameter. In subgroups, NMDAR1 autoantibody measurements were repeated on days 2 and 7.

Results: Of all 464 patients, 21.6% were NMDAR1 autoantibody-positive (immunoglobulin M, A, or G) and 21% were APOE4 carriers. Patients with magnetic resonance imaging data available on days 1 and 7 (N=384) were divided into 4 groups according to NMDAR1 autoantibody and APOE4 status. Groups were comparable in all stroke-relevant presenting characteristics. The autoantibody+/APOE4- group had a smaller mean delta lesion size compared with the autoantibody-/APOE4- group, suggesting a protective effect of circulating NMDAR1 autoantibodies. In contrast, the autoantibody+/APOE4+ group had the largest mean delta lesion area. NMDAR1 autoantibody serum titers dropped on day 2 and remounted by day 7.

Conclusions: Dependent on blood-brain barrier integrity before an acute ischemic brain injury, preexisting NMDAR1 autoantibodies seem to be beneficial or detrimental.
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http://dx.doi.org/10.1161/STROKEAHA.114.008323DOI Listing
May 2015

Higher plasma levels of MR-pro-atrial natriuretic peptide are linked to less anxiety: results from the observational DIAST-CHF study.

Clin Res Cardiol 2015 Jul 10;104(7):574-81. Epub 2015 Feb 10.

Department of Psychosomatic Medicine and Psychotherapy, German Centre for Cardiovascular Research, University of Göttingen, Göttingen, Germany,

Aims: Growing evidence suggests that natriuretic peptides play a role in the neurobiology of anxiety. In the present study, we investigated whether in patients with cardiovascular risk factors higher plasma levels of natriuretic peptides are linked to reduced anxiety.

Methods: A total of 1,360 patients from the observational DIAST-CHF study (mean age 65.9 ± 8.2 years, 48.7 % males, mean left ventricular ejection fraction 60.0 ± 8.2 %) with risk factors for diastolic heart failure were included. Study participants underwent physical examination, echocardiography, and assessment of anxiety using the Hospital Anxiety and Depression Scale (HADS). In addition, plasma concentrations of natriuretic peptides were measured.

Results: Among the total study population, there were n = 117 patients (8.6 %) with HADS anxiety scores above the cut-off (≥11) suggestive of clinically relevant anxiety. In bivariate analyses, we found a significant inverse association between elevated HADS anxiety and log-transformed mid-regional pro-atrial natriuretic peptide (MR-proANP) (p < 0.001) and amino-terminal pro-brain natriuretic peptide (NT-proBNP) (p = 0.008). Logistic regression models adjusted for sex, age, body mass index, and Framingham score confirmed that plasma MR-proANP (exp(β) = 0.35, 95 % confidence interval [95 % CI] 0.14-0.92, p = 0.032) concentrations were significantly and inversely associated with clinically relevant anxiety, while NT-proBNP (exp(β) = 0.67, 95 % CI 0.41-1.07, p = 0.094) failed to reach the significance level in independently predicting anxiety.

Conclusions: In our study population of outpatients with cardiovascular risk factors, plasma concentrations of MR-proANP were negatively and independently related to clinically relevant anxiety. Further investigations are required to search for possible anxiolytic effects of this circulating natriuretic peptide in medical outpatients with cardiovascular risk factors for diastolic dysfunction.
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http://dx.doi.org/10.1007/s00392-015-0820-9DOI Listing
July 2015

Advances in endothelial shear stress proteomics.

Expert Rev Proteomics 2014 Oct 12;11(5):611-9. Epub 2014 Jul 12.

Institute of Clinical Chemistry UMG-Laboratories, Robert-Koch Str. 40, 37075 Goettingen, Germany.

The vascular endothelium lining the luminal surface of all blood vessels is constantly exposed to shear stress exerted by the flowing blood. Blood flow with high laminar shear stress confers protection by activation of antiatherogenic, antithrombotic and anti-inflammatory proteins, whereas low or oscillatory shear stress may promote endothelial dysfunction, thereby contributing to cardiovascular disease. Despite the usefulness of proteomic techniques in medical research, however, there are relatively few reports on proteome analysis of cultured vascular endothelial cells employing conditions that mimic in vivo shear stress attributes. This review focuses on the proteome studies that have utilized cultured endothelial cells to identify molecular mediators of shear stress and the roles they play in the regulation of endothelial function, and their ensuing effect on vascular function in general. It provides an overview on current strategies in shear stress-related proteomics and the key proteins mediating its effects which have been characterized so far.
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http://dx.doi.org/10.1586/14789450.2014.933673DOI Listing
October 2014

NT-proANP and NT-proBNP as prognostic markers in patients with acute decompensated heart failure of different etiologies.

Clin Biochem 2013 Aug 28;46(12):1013-1019. Epub 2013 Mar 28.

Department of Cardiology, University of Graz, Austria.

Background And Purpose: Peak NT-proANP and NT-proBNP plasma levels after hospital admission may be of additional prognostic value in patients with acute decompensation of heart failure. The time-course of natriuretic plasma levels after hospital admission, and a possible influence of the underlying etiology on the time-course have not been sufficiently investigated.

Methods And Results: Natriuretic peptide plasma levels of 85 patients with decompensated heart failure from ischemic and non-ischemic origins were measured at baseline and at 12h after hospital admission. NT-proBNP plasma levels on admission were lower compared to 12-hour-plasma levels, whereas NT-proANP plasma levels on admission were higher compared to 12-hour-plasma levels. Twenty-six patients (31%) died within the first 30 days. In patients who died within the first 30 days after admission NT-proANP and NT-proBNP plasma levels on admission and 12h later were significantly higher compared to survivors. Irrespective of different etiologies NT-proANP on admission and NT-proBNP 12h after admission were highest and demonstrated superior impact with respect to the prediction of 30-day-mortality.

Conclusions: NT-proANP and NT-proBNP are powerful markers of 30-day-mortality in patients with acute heart failure of ischemic and non-ischemic origins. With respect to the prediction of 30-day-mortality, NT-proBNP plasma levels at 12h after admission are comparable with NT-proANP plasma levels on admission. These data underline the fact that with regard to etiology-dependent hemodynamic changes and plasma half-time, the determination of peak plasma levels is of highest importance for the estimation of the impact of natriuretic peptides on the prognosis of patients with decompensated heart failure.
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http://dx.doi.org/10.1016/j.clinbiochem.2013.03.014DOI Listing
August 2013

Pharmacokinetics of meropenem in critically ill patients with severe infections.

Ther Drug Monit 2013 Feb;35(1):63-70

Department of Clinical Chemistry, University Medical Center Göttingen, Göttingen, Germany.

Background: Meropenem is an effective β-lactam antibiotic that is frequently used to treat serious infections in both intensive care unit (ICU) and febrile neutropenic hematology/oncology (Hem/Onc) patients. Studies suggest that to be effective, meropenem concentrations must be maintained above the inhibitory concentrations for the majority of a dosing interval. However, the pharmacokinetics (PK) of meropenem seem to differ in critically ill patients compared with healthy or less ill subjects used to select labeled dosing regimens.

Objectives: This study was designed to investigate meropenem PK in critically ill patients and to see how often standard dosing regimens produced adequate plasma concentrations. A secondary objective was to investigate how achieved concentrations were related to outcomes (morbidity and mortality) in these patients.

Methods: Meropenem plasma concentrations over time were measured using a high pressure liquid chromatography assay in febrile Hem/Onc and ICU patients who were treated with standard meropenem dosing schedules. Outcomes such as fever control and survival were assessed in these patients and compared with individual meropenem PK data and with recommended target concentrations.

Results: A total of 25 subjects including 10 febrile Hem/Onc and 15 ICU patients with a variety of serious illnesses and baseline renal function were studied. Mean peak concentrations were less variable than were pre-dose concentrations. Post peak and trough concentrations were often below recommended minimum inhibitory concentrations. Both clearance and volumes of distribution were greater than reported in less ill subjects, only in part explained by increased renal clearance. Therefore, serum concentrations often did not exceed recommended concentration targets even for moderately sensitive organisms. Inadequate concentrations were especially common in the mostly ill, febrile neutropenic Hem/Onc subjects and seemed to explain at least some therapeutic failures. Conversely, drug accumulation occurred in ICU subjects with decreased renal function.

Conclusions: Standard meropenem dosing regimens were inadequate in many critically ill febrile, neutropenic Hem/Onc, and septic ICU patients. These data suggest a role for meropenem concentration monitoring in such patients.
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http://dx.doi.org/10.1097/FTD.0b013e31827d496cDOI Listing
February 2013

Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study.

J Am Coll Cardiol 2011 Oct;58(17):1780-91

Department of Cardiology, University of Göttingen, Göttingen, Germany.

Objectives: We sought to determine whether structured exercise training (ET) improves maximal exercise capacity, left ventricular diastolic function, and quality of life (QoL) in patients with heart failure with preserved ejection fraction (HFpEF).

Background: Nearly one-half of patients with heart failure experience HFpEF, but effective therapeutic strategies are sparse.

Methods: A total of 64 patients (age 65 ± 7 years, 56% female) with HFpEF were prospectively randomized (2:1) to supervised endurance/resistance training in addition to usual care (ET, n = 44) or to usual care alone (UC) (n = 20). The primary endpoint was the change in peak Vo(2) after 3 months. Secondary endpoints included effects on cardiac structure, diastolic function, and QoL.

Results: Peak Vo(2) increased (16.1 ± 4.9 ml/min/kg to 18.7 ± 5.4 ml/min/kg; p < 0.001) with ET and remained unchanged (16.7 ± 4.7 ml/min/kg to 16.0 ± 6.0 ml/min/kg; p = NS) with UC. The mean benefit of ET was 3.3 ml/min/kg (95% confidence interval [CI]: 1.8 to 4.8, p < 0.001). E/e' (mean difference of changes: -3.2, 95% CI: -4.3 to -2.1, p < 0.001) and left atrial volume index (milliliters per square meter) decreased with ET and remained unchanged with UC (-4.0, 95% CI: -5.9 to -2.2, p < 0.001). The physical functioning score (36-Item Short-Form Health Survey) improved with ET and remained unchanged with UC (15, 95% CI: 7 to 24, p < 0.001). The ET-induced decrease of E/e' was associated with 38% gain in peak Vo(2) and 50% of the improvement in physical functioning score.

Conclusions: Exercise training improves exercise capacity and physical dimensions of QoL in HFpEF. This benefit is associated with atrial reverse remodeling and improved left ventricular diastolic function. (Exercise Training in Diastolic Heart Failure-Pilot Study: A Prospective, Randomised, Controlled Study to Determine the Effects of Physical Training on Exercise Capacity and Quality of Life [Ex-DHF-P]; ISRCTN42524037).
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http://dx.doi.org/10.1016/j.jacc.2011.06.054DOI Listing
October 2011

Use of total and unbound imatinib and metabolite LC-MS/MS assay to understand individual responses in CML and GIST patients.

Ther Drug Monit 2011 Oct;33(5):632-43

Central Laboratory, Department of Clinical Chemistry, University Medical Center, George-August-University, Goettingen, Germany.

Objectives: Trough total imatinib (t-IM) concentrations have been reported to be associated with therapeutic and toxic responses in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Little is known about the relationships between effects and concentrations of either unbound imatinib (f-IM) or imatinib's major metabolite, N-desmethyl imatinib (NDI). In part, this is because of the lack of a single, validated, well-described clinically useful assay for these measurements. The authors report the development and application of such an assay.

Materials And Methods: A single liquid-chromatography tandem-mass-spectrometry assay was used to monitor t-IM, f-IM, and t-NDI concentrations in CML and GIST patients treated at a tertiary German teaching hospital. The assay was also validated for measuring other kinase inhibitors, including t-nilotinib, sunitinib, and erlotinib. Ultrafiltration assays were validated and used to measure f-IM and to compare free fractions to plasma α1-acid glycoprotein concentrations (AGP).

Results: The assays were linear over a working range (in micrograms per liter) of 8.4-8370, 8.3-4165, and 1.0-250 and had within- and between-run coefficient of variance of <7%, <12%, and <9% for t-IM, t-NDI, and f-IM, respectively. The f-IM assay was reproducible despite high (25.2%-31.6%) but concentration-independent binding to ultrafiltration devices. Clinically relevant results, such as nondetectable (ND) t-IM (<8.4 μg/L) in non-responders and >1500 μg/L in patients with major toxicity, were found. Of 156 total samples from 68 adult CML patients and 127 total samples from 42 adult GIST, only 48 samples from 22 CML patients and 40 samples from 20 GIST patients were trough samples with adequate dosing and collection information. More than half (27 of 48 CML and 24 of 40 GIST) had t-IM concentrations ≥10% below recommended target concentrations (1002 μg/L for CML and 1100 μg/L for GIST). Concentrations >50% over targets were also found in 6 of 48 CML and 4 of 40 GIST samples. Wide variations in concentrations of t-IM (range, ND to 2973 μg/L), t-NDI (range, ND to 659 μg/L), f-IM (range, 8.3-262 μg/L), and t-IM:f-IM ratios (range, 2.6%-14%) were found both between and within patients. A statistically significant association (Spearman correlation coefficient and P value for all samples, r = 0.290 and P = 0.023; for trough only, r = -0.585 and P = 0.028) was found between AGP and f-IM concentrations but wide interpatient and intrapatient variations made individual predictions unreliable.

Conclusions: The liquid-chromatography tandem-mass-spectrometry methods developed provided information useful to understand individual responses to therapy even though necessary sampling and dosing information was often not available. Wide unpredictable variations in t-IM, t-NDI, and f-IM were found. Clinical outcome trials are needed to examine whether f-IM or NDI monitoring can improve the ability to predict individual responses.
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http://dx.doi.org/10.1097/FTD.0b013e3182263ac4DOI Listing
October 2011

Serum levels of interleukin-6 and interleukin-10 in relation to depression scores in patients with cardiovascular risk factors.

Behav Med 2011 Jul;37(3):105-12

University of Göttingen, Germany.

It is currently unknown whether elevated cytokine levels in depression are confined to any specific subgroup of depressive patients. In this study, medical out-patients presenting with cardiovascular risk factors (N = 356) were assessed for both cognitive-affective and physical symptoms of depression using the Hospital Anxiety and Depression Scale (HADS) and the Maastricht questionnaire (MQ), respectively. In study participants assigned to the highest (≥21) and lowest (≤5) quartile for the MQ score, serum levels of cytokines were measured. We found highly significant associations between cognitive-affective symptoms of depression and elevated serum levels of interleukin-6 (IL-6; ρ = .231; p = .002) and interleukin-10 (IL-10; ρ = .370; p < .001), respectively. In multiple regression models elevated IL-10 serum concentration was independently related to cognitive-affective symptoms of depression (ρ = .165; p = .002). When all cytokines were included in one model, elevated IL-10 serum concentrations remained a significant predictor for depressive mood (ρ = .157; p = .009). In patients with cardiovascular risk factors and extreme scores for vital exhaustion, elevated serum IL-6 and even more IL-10 concentrations are linked to the presence of depressive mood. Future studies will have to test whether the so far unreported association of IL-10 with depressive mood represents a causal pathway involved in the pathogenesis or in the prognostic effect of depressive mood in cardiac patients.
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http://dx.doi.org/10.1080/08964289.2011.609192DOI Listing
July 2011

Serum aldosterone and its relationship to left ventricular structure and geometry in patients with preserved left ventricular ejection fraction.

Eur Heart J 2012 Jan 19;33(2):203-12. Epub 2011 Aug 19.

Department of Cardiology and Pneumology, University of Goettingen, Germany.

Aims: Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results.

Methods And Results: We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass (P= 0.001), LV mass index (P= 0.001), relative wall thickness (P= 0.011), and LV posterior wall thickness (P< 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31-2.68; P= 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling.

Conclusion: Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.
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http://dx.doi.org/10.1093/eurheartj/ehr292DOI Listing
January 2012

Growth differentiation factor 15: an additional diagnostic tool for the risk stratification of developing heart failure in patients with operated congenital heart defects?

Am Heart J 2011 Jul;162(1):131-5

Division of Paediatric Cardiology, Department of Paediatrics, London Health Sciences Centre, University of Western Ontario, Canada.

Background: Many young adults who have congenital heart defects develop heart failure despite corrective surgeries. Growth differentiation factor 15 (GDF-15) has an established role as a marker for risk stratification and mortality both in patients after acute myocardial infarction and in patients with heart failure. Our aim was to establish a role for GDF-15 for monitoring heart failure in operated congenital heart defects (ACHD). This potential biomarker was validated through comparison with maximal oxygen uptake (VO(2max)) and to another biomarker, N-terminal pro-brain natriuretic peptide (NT-proBNP).

Methods: A total of 317 ACHD patients (129 females) with an average age of 26.5 ± 8.5 years (mean ± SD) enrolled in the study. We studied the relation between GDF-15 and NT-proBNP and VO(2max%) (percent predicted for age and gender). The cutoffs for the groups were as follows: NT-proBNP <100, 100 to 300, and >300 pg/mL; VO(2max%) <65%, 65% to 85%, and >85% of predicted normal.

Results: Significant differences in mean GDF-15 levels were found between the NT-proBNP <100 and NT-proBNP >300 groups, as well as between the 100 to 300 and the >300 groups. For VO(2max%), significant differences were found in GDF-15 levels between <65% and >85% and between <65% and 65% to 85%, respectively. The lowest mean GDF-15 was found in groups with NT-proBNP <100 pg/mL and VO(2max%) >85%. The highest mean GDF-15 was found in the groups with NT-proBNP >300 pg/mL and VO(2max%) <65%. A subgroup analysis, including 82 patients with operated tetralogy of Fallot, showed that patients in the New York Heart Association I class have significantly lower NT-proBNP and GDF-15 level and markedly higher VO(2max) compared with the patients in higher New York Heart Association class.

Conclusion: Growth differentiation factor 15 might be used as a surrogate marker for latent heart failure and could help to identify patients with ACHD who are at risk for developing heart failure, even if they are clinically asymptomatic.
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http://dx.doi.org/10.1016/j.ahj.2011.03.036DOI Listing
July 2011

Impaired physical quality of life in patients with diastolic dysfunction associates more strongly with neurohumoral activation than with echocardiographic parameters: quality of life in diastolic dysfunction.

Am Heart J 2011 Apr;161(4):797-804

Department of Cardiology and Pneumology, University of Göttingen, Germany.

Background: Quality of life (QoL) is impaired in diastolic heart failure. Little is known about QoL in diastolic dysfunction (DD) without heart failure.

Methods: In the DIAST-CHF observational study, outpatients with risk factors for or a history of heart failure were included. In a cross-sectional analysis, we classified patients with preserved systolic function as having normal diastolic function (N, n = 264) or DD without (DD-, n = 957) or with (DD+, n = 321) elevated filling pressures according to echocardiography. Quality of life was evaluated by the Short Form 36 (SF-36) questionnaire.

Results: Short Form 36 physical function (SF-36-PF) was worse in DD+ (mean ± SD 67.2 ± 25.6) than in DD- (76.2 ± 22.7, P < .05) than in N (mean ± SD 81.1 ± 23.5, P < .01). Other physical dimensions and the physical component score were also lower in DD, whereas the mental component score did not differ. The SF-36-PF correlated weakly with echocardiographic indicators of diastolic function. In multivariate linear regression controlling for age, sex, body mass index, depressiveness as assessed by Patient Health Questionnaire 9, N-terminal probrain-type natriuretic peptide, and midregional proadrenomedullin (MR-proADM), individual echocardiographic parameters or grade of DD was not independently associated with SF-36-PF, whereas the presence of DD+ was. Both N-terminal probrain-type natriuretic peptide and MR-proADM were independently associated with SF-36-PF, with MR-proADM showing the stronger association.

Conclusions: Physical dimensions of QoL are reduced in DD. Impaired SF-36-PF is only weakly associated with DD per se but rather seems to be contingent on the presence of elevated filling pressures. Biomarkers are more strongly and independently associated with SF-36-PF and may be more adequate surrogate markers of QoL in DD than echocardiographic measurements.
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http://dx.doi.org/10.1016/j.ahj.2011.01.003DOI Listing
April 2011

Multicenter evaluation of a new automated electrochemiluminescence immunoassay for the quantification of testosterone compared to liquid chromatography tandem mass spectrometry.

Clin Biochem 2011 Feb 12;44(2-3):264-7. Epub 2010 Oct 12.

Department of Clinical Chemistry, University Medical Center Goettingen, Germany.

Objectives: A new electrochemiluminescence testosterone immunoassay (Elecsys® Testo II) was evaluated.

Design And Methods: Within-run precision, total precision, and method comparisons to the former immunoassay and LC-MS/MS were investigated. Reference intervals were established for adults and children.

Results: Imprecision ranged from 0.9% to 8.5%. Method comparisons revealed slopes from 0.68 to 1.32 and coefficients of correlation from 0.893 to 0.991.

Conclusions: Improved agreement with LC-MS/MS was demonstrated, especially for female patients. The assay may be a suitable alternative for laboratories with no access to MS techniques.
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http://dx.doi.org/10.1016/j.clinbiochem.2010.09.024DOI Listing
February 2011

[Importance of surfactant proteins B and D for the differential diagnosis of acute dyspnea].

Med Klin (Munich) 2010 Sep 28;105(9):611-8. Epub 2010 Sep 28.

Abteilung Innere Medizin - Kardiologie, Philipps-Universität Marburg, Marburg, Germany.

Background And Purpose: The basis for an optimal therapy of cardiopulmonary diseases is the assessment of an early diagnosis. This implies an evaluation of possible differential diagnoses of acute dyspnea. In numerous studies, natriuretic peptides were characterized as additional, meaningful parameters for the assessment of left ventricular function. Current studies could demonstrate that surfactant proteins B (SP-B) and D (SP-D) are of importance for the differentiation of patients with acute dyspnea. The aim of this study was to compare the values of NT-proBNP (N-terminal brain natriuretic peptide) and surfactant proteins for the assessment of a final diagnosis in patients with acute dyspnea.

Patients And Methods: NT-proBNP, SP-B and SP-D were measured in 81 patients with acute dyspnea in the emergency room and were correlated with clinical and echocardiographic parameters with respect to the final diagnosis. For this, patients were classified with respect to clinical and echocardiographic parameters in different subgroups concerning the final diagnosis of acute dyspnea.

Results: In patients with a cardiac origin of acute dyspnea, plasma levels of NT-proBNP were significantly higher as compared to patients with a noncardiac diagnosis (p = 0.04). SP-D was highest in patients with a cardiac origin of acute dyspnea, but after performing regression analysis it seems to be of less importance for the differential diagnosis of acute dyspnea as compared to NT-proBNP. SP-B plasma levels were not different between the four subgroups.

Conclusion: NT-proBNP is of importance for the differential diagnosis of acute dyspnea. Although SP-D shows similar changes of plasma levels between the four subgroups, it seems to be of less importance for the differential diagnosis of acute dysnea. SP-B occurs to be of no relevance for the differentiation between cardiac and noncardiac origin of acute dyspnea.
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http://dx.doi.org/10.1007/s00063-010-1100-0DOI Listing
September 2010