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Kleber M.E.,Medical Clinic V Nephrology | Koller L.,Medical University of Vienna | Goliasch G.,Medical University of Vienna | Sulzgruber P.,Medical University of Vienna | And 9 more authors.
Circulation: Heart Failure | Year: 2015

Background-Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. Methods and Results-Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.261.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal proB-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEFrelated comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.051.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWFNT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). Conclusions-vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients. © 2015 American Heart Association, Inc.


Leistner D.M.,Goethe University Frankfurt | Klotsche J.,TU Dresden | Pieper L.,TU Dresden | Stalla G.K.,Max Planck Institute of Psychiatry | And 7 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Measuring circulating cardiac troponin using novel sensitive assays has revealed that even minute elevations are associated with increased mortality in patients with coronary artery disease or even in the general population. Less well defined, however, is the incremental value of measuring circulating cardiac troponin I (cTnI) by a sensitive assay for risk assessment in primary prevention. METHODS: We measured circulating concentrations of cTnI, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hsCRP) in 5388 individuals free of known cardiovascular disease recruited into the DETECT study, a prospective longitudinal population-based cohort study. We determined the prognostic implications for incident major adverse cardiovascular events (MACE) during 5 years of follow-up. RESULTS: Circulating cTnI was detectable in 19% of the subjects. Increased cTnI concentrations were associated with established risk factors for atherosclerosis and demonstrated a graded relationship with all-cause mortality and incident MACE during 5-year follow-up. A single measurement of cTnI significantly improved risk prediction over established risk factors, and also added prognostic information, when adjusted for serum concentrations of NT-proBNP and hsCRP. CONCLUSIONS: Minute increases in cTnI are associated with increased mortality and incident MACE in a large primary prevention cohort and, thus, identify contributors to cardiovascular risk not fully captured by traditional risk factor assessment. © 2011 American Association for Clinical Chemistry.


Kniepeiss D.,Medical University of Graz | Wagner D.,Medical University of Graz | Wasler A.,Medical University of Graz | Tscheliessnigg K.-H.,Medical University of Graz | Renner W.,Clinical Institute of Medical and Chemical Laboratory Diagnostics
Wiener Klinische Wochenschrift | Year: 2013

Summary: Everolimus is an immunosuppressive drug metabolized by enzymes of the CYP family. A common variant of the CYP2C8 gene, CYP2C8*3, results in strongly decreased CYP2C8 activity, but its role for the pharmacogenetics of everolimus remains unclear. Aim of the present study was to examine the role of CYP2C8 variants in everolimus dose and drug levels after heart transplantation. The present study comprised 30 patients with everolimus based maintenance therapy after heart transplantation. CYP2C8 genotypes were determined and correlated with clinical data. In all, 21 subjects carried the CYP2C8*1/*1 genotype and 9 subjects carried the CYP2C8*1/ *3 genotype. Neither everolimus dose nor everolimus levels were associated with CYP2C8 genotype at any point of time (p < 0.05). During follow-up, graft rejection reactions were observed in two patients and infections were observed in seven patients. In one patient, type 2 diabetes was diagnosed during follow-up. None of these adverse events were significantly associated with CYP2C8 genotypes. We conclude that in adult patients after heart transplantation, CYP2C8 genotypes are not associated with dose requirements or levels of everolimus. © 2013 Springer-Verlag Wien.


Almer G.,Clinical Institute of Medical and Chemical Laboratory Diagnostics
International journal of nanomedicine | Year: 2011

Atherosclerosis is a leading cause of mortality in the Western world, and plaque diagnosis is still a challenge in cardiovascular medicine. The main focus of this study was to make atherosclerotic plaques visible using targeted nanoparticles for improved imaging. Today various biomarkers are known to be involved in the pathophysiologic scenario of atherosclerotic plaques. One promising new candidate is the globular domain of the adipocytokine adiponectin (gAd), which was used as a targeting sequence in this study. gAd was coupled to two different types of nanoparticles, namely protamine-oligonucleotide nanoparticles, known as proticles, and sterically stabilized liposomes. Both gAd-targeted nanoparticles were investigated for their potency to characterize critical scenarios within early and advanced atherosclerotic plaque lesions using an atherosclerotic mouse model. Aortic tissue from wild type and apolipoprotein E-deficient mice, both fed a high-fat diet, were stained with either fluorescent-labeled gAd or gAd-coupled nanoparticles. Ex vivo imaging was performed using confocal laser scanning microscopy. gAd-targeted sterically stabilized liposomes generated a strong signal by accumulating at the surface of atherosclerotic plaques, while gAd-targeted proticles became internalized and showed more spotted plaque staining. Our results offer a promising perspective for enhanced in vivo imaging using gAd-targeted nanoparticles. By means of nanoparticles, a higher payload of signal emitting molecules could be transported to atherosclerotic plaques. Additionally, the opportunity is opened up to visualize different regions in the plaque scenario, depending on the nature of the nanoparticle used.


Wonisch W.,Clinical Institute of Medical and Chemical Laboratory Diagnostics | Wonisch W.,Medical University of Graz | Falk A.,Institute for Nutrition and Metabolic Diseases | Sundl I.,University of Graz | And 2 more authors.
Aging Male | Year: 2012

Oxidative stress is a risk factor for chronic diseases and was previously shown to be independently associated with obesity. The authors investigated the relationship between body mass index (BMI), age and oxidative stress on 2190 subjects undergoing a health care examination. Total antioxidant status (TAS), total peroxides (TOC) and autoantibodies against oxidized LDL (oLAb) were used as oxidative stress biomarkers in addition to serum lipoproteins, bilirubin and uric acid. Gender-specific differences were observed for age, BMI, serum concentrations of bilirubin, low-density lipoprotein (LDL), uric acid and TAS, all of which were higher in males (p < 0.001), while high-density lipoprotein (HDL), HDL/LDL ratio and TOC were higher in females (p < 0.001). Total cholesterol (p < 0.05) and LDL were increased (p < 0.05), while HDL was decreased (p < 0.05) in overweight and obese subjects. This was accompanied by increased uric acid and TAS concentrations. Lowest oLAb titers were detected in obese subjects. In extremely obese subjects, increased TOC and decreased TAS were observed in spite of high uric acid levels. These results demonstrate that oxidative stress increases with increasing BMI and age, as a sequel to an impaired antioxidant status, the consumption of oLAbs, an increase of peroxides and uric acid and a disadvantaged lipid profile. © 2012 Informa UK, Ltd.


Baranyi A.,Medical University of Graz | Meinitzer A.,Clinical Institute of Medical and Chemical Laboratory Diagnostics | Stepan A.,Medical University of Graz | Putz-Bankuti C.,Medical University of Graz | And 4 more authors.
Psychotherapy and Psychosomatics | Year: 2013

Background: The aim of this prospective study was to gain a more comprehensive picture of the biopsychosocial effects of interferon (IFN) treatment of patients with chronic hepatitis C (HCV). The predictors of depressive development and changes in health-related quality of life, life satisfaction and cognitive ability were measured with the inclusion of the social context. Furthermore, the effects of IFN treatment on indoleamine 2,3-dioxygenase, the level of tryptophan supply in the brain, the development of neurotoxic kynurenine metabolites and the thyroid glands were investigated. Therefore, for the first time the conditions for the development of depressive episodes in HCV patients treated with IFN were examined over the entire period of treatment as well as 3 months later, applying a holistic biopsychosocial model. Method: Psychiatric and biological assessments were carried out at 6 different times: before, during (at 1, 3, 6 and 9 months) and after the end of IFN treatment. Results: During IFN treatment 22 (53.7%) of 41 patients fulfilled the criteria for a treatment-related depressive disorder at least once during treatment. Contributing factors are tryptophan depletion (tryptophan to competing amino acids quotient), increased neurotoxic challenge (kynurenine to kynurenic acid quotient), less social support, female gender, preexisting psychiatric vulnerability, means of transmission, low financial security, impaired sexual satisfaction, small circle of friends, impaired physical role, strong body pain, low general health and vitality, reduced social functioning, impaired mental health and impaired emotional role. Conclusions: The awareness of relevant risk factors of IFN treatment-induced depression is essential to develop preventative treatment strategies. © 2013 S. Karger AG, Basel.


PubMed | University of Hamburg, Paracelsus Medical University, Medical University of Graz, Institute for Medical Informatics and 3 more.
Type: Clinical Trial | Journal: The Journal of infectious diseases | Year: 2015

The interplay between Candida species and pattern recognition receptors, interleukins, kynurenine, and T cells has been studied in murine and ex vivo human studies, but data are lacking from patients with invasive fungal infections. Interleukin 17A (IL-17A) is considered an important component in host defense against Candida infections and is modulated by Candida-induced impairment of tryptophan-kynurenine metabolism.Dectin-1, Toll-like receptor 2, and Toll-like receptor 4 expression; regulatory T cell (Treg) percentages; and interleukin 6, interleukin 10, IL-17A, interleukin 22, interleukin 23, interferon , kynurenine, and tryptophan levels were determined in candidemic patients and compared to levels in noncandidemic patients who are in the intensive care unit (ICU) and receiving antibiotic therapy and those in healthy controls, both with and without Candida colonization.Candidemic patients had significantly higher IL-17A and kynurenine levels, compared with noncandidemic patients, including Candida-colonized ICU patients and healthy controls. Within candidemic patients, time-dependent elevation of IL-17A and kynurenine levels was detected. IL-17A areas under the curve for differentiation between patients with early candidemia and those without candidemia (ICU patients, including Candida-colonized patients, and healthy controls) were between 0.94 (95% confidence interval [CI], .89-.99) and 0.99 (95% CI, .99-1).Candidemic patients had significantly higher IL-17A and kynurenine levels, compared with noncandidemic patients. The statistically significant association between IL-17A and kynurenine levels and candidemia suggests their potential as biomarkers for anticipation of invasive candidiasis.NCT00786903.


PubMed | Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, University of Toronto, Innsbruck Medical University and Institute of Pathophysiology and Immunology
Type: | Journal: Journal of affective disorders | Year: 2016

Oxidative and nitrosative stress are implicated in the pathogenesis of uni- and bipolar disorder. Herein we primarily sought to characterize markers of oxidative/nitrosative stress during euthymia in adults with bipolar disorder (BD). Oxidative markers were further evaluated in this BD sample in synopsis with excess overweight or obesity and/or comorbid metabolic syndrome (MetS).Peripheral markers of oxidative stress [i.e. thiobarbituric acid reactive substance, (TBARS), malondialdehyde (MDA), and carbonyl proteins] and antioxidant markers [e.g. total antioxidative capacity (TAC), superoxide dismutase (SOD), glutathione S-transferase (GST)] were obtained in a cohort of euthymic adults with BD (N=113) and compared to healthy controls (CG) (N=78). Additionally, anthropometric measures included the body mass index (BMI) [kg/m(2)], waist and hip circumference [cm], waist-to-hip-ratio (WHR), waist to height ratio (WtHR) as well as the IDF-defined MetS.The major finding was a significantly decreased TAC in BD compared to the CG (p<0.01; BD: M 1.18, SD 0.47; CG: M 1.39, SD 0.49). MDA was significantly and TBARS by trend higher in the CG compared to the euthymic bipolar test persons (MDA: p<0.01, BD: M 0.70, SD 0.18; CG: M 0.81, SD 0.25; TBARS: p<0.1, BD: M 0.78, SD 0.28; CG: M 0.76, SD 0.30). The antioxidative enzyme GST was significantly elevated in both patients and controls (BD: M 298.24, SD 133.02; CG: M 307.27 SD 118.18). Subgroup analysis revealed that the CG with concurrent MetS and obesity had significantly elevated TAC when compared to CG without concurrent MetS (p<0.05, no MetS: M 1.33, SD 0.50; MetS: M 1.67, SD 0.32), as well as persons with BD with or without current MetS (no MetS: M 1.18, SD 0.44; MetS: M 1.15, SD 0.49). Significant correlations between GST and anthropometric variables were found in male study participants. Multivariate analysis indicated a significant gender effect concerning TBARS values in all patients and CG (p<0.01, females: M 0.73, SD 0.29; males: M 0.83, SD 0.28).Euthymic bipolar adults exhibit peripheral evidence of a disturbed biosignature of oxidative stress and antioxidative defense. Male test persons showed significantly higher peripheral markers of oxidative stress than women- female sex may exert protective effects. Furthermore, the biosignature of oxidative stress obtained herein was more pronounced in males with concurrent metabolic disorders. Our results further extend knowledge by introducing the moderating influence of gender and obesity on oxidative stress and BD.


PubMed | Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz and Center for Cardiovascular Rehabilitation
Type: Journal Article | Journal: Trials | Year: 2016

Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35% suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters. Therefore, the aim of this study is to investigate the effects of linagliptin in CAD patients with early T2DM on various cardiovascular surrogate measurements including mechanical and biochemical endothelial function assessments.Forty-two subjects with early diabetes and CAD are included in this investigator-driven, randomized, placebo-controlled, double-blind, phase IV, single-center study. Participants will be randomized to receive either linagliptin (5mg) administered once daily per os or placebo for 12weeks. Before and after the intervention, evaluation of endothelial function (flow-mediated dilatation and biochemical biomarkers) and a Meal Tolerance Test are performed.Cardiovascular surrogate parameters, such as endothelial function, are able to provide insights into the potential mechanisms of the cardiovascular effects of antihyperglycemic agents. Currently ongoing trials do not specifically focus on early diabetes as a target of intervention and we therefore believe that our study will contribute to a better understanding of the cardiovascular effects of dipeptidylpeptidase-4 (DPP-4) inhibitors in early diabetes.NCT02350478 . Registered 26 January 2015. Protocol date/version 24 October 2014/version 2.4 EudraCT number: 2013-000330-35.


PubMed | Clinical Institute of Medical and Chemical Laboratory Diagnostics
Type: | Journal: International journal of nanomedicine | Year: 2011

Atherosclerosis is a leading cause of mortality in the Western world, and plaque diagnosis is still a challenge in cardiovascular medicine. The main focus of this study was to make atherosclerotic plaques visible using targeted nanoparticles for improved imaging. Today various biomarkers are known to be involved in the pathophysiologic scenario of atherosclerotic plaques. One promising new candidate is the globular domain of the adipocytokine adiponectin (gAd), which was used as a targeting sequence in this study.gAd was coupled to two different types of nanoparticles, namely protamine-oligonucleotide nanoparticles, known as proticles, and sterically stabilized liposomes. Both gAd-targeted nanoparticles were investigated for their potency to characterize critical scenarios within early and advanced atherosclerotic plaque lesions using an atherosclerotic mouse model. Aortic tissue from wild type and apolipoprotein E-deficient mice, both fed a high-fat diet, were stained with either fluorescent-labeled gAd or gAd-coupled nanoparticles. Ex vivo imaging was performed using confocal laser scanning microscopy.gAd-targeted sterically stabilized liposomes generated a strong signal by accumulating at the surface of atherosclerotic plaques, while gAd-targeted proticles became internalized and showed more spotted plaque staining.Our results offer a promising perspective for enhanced in vivo imaging using gAd-targeted nanoparticles. By means of nanoparticles, a higher payload of signal emitting molecules could be transported to atherosclerotic plaques. Additionally, the opportunity is opened up to visualize different regions in the plaque scenario, depending on the nature of the nanoparticle used.

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