Publications by authors named "Svitlana Demyanets"

44 Publications

Circulating MicroRNAs and Monocyte-Platelet Aggregate Formation in Acute Coronary Syndrome.

Thromb Haemost 2021 Jan 14. Epub 2021 Jan 14.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Background:  Monocyte-platelet aggregates (MPAs) are a sensitive marker of in vivo platelet activation in acute coronary syndrome (ACS) and associated with clinical outcomes. MicroRNAs (miRs) play an important role in the regulation of platelet activation, and may influence MPA formation. Both, miRs and MPA, could be influenced by the type of P2Y12 inhibitor.

Aim:  To study the association of platelet-related miRs with MPA formation in ACS patients on dual antiplatelet therapy (DAPT), and to compare miRs and MPA levels between prasugrel- and ticagrelor-treated patients.

Methods And Results:  We analyzed 10 circulating platelet-related miRs in 160 consecutive ACS patients on DAPT with low-dose aspirin and either prasugrel ( = 80) or ticagrelor ( = 80). MPA formation was measured by flow cytometry without addition of platelet agonists and after simulation with the toll-like receptor (TLR)-1/2 agonist Pam3CSK4, adenosine diphosphate (ADP), or arachidonic acid (AA). In multivariate regression analyses, we identified miR-21 (β = 9.50, 95% confidence interval [CI]: 1.60-17.40,  = 0.019) and miR-126 (β = 7.50, 95% CI: 0.55-14.44,  = 0.035) as independent predictors of increased MPA formation in vivo and after TLR-1/2 stimulation. In contrast, none of the investigated miRs was independently associated with MPA formation after stimulation with ADP or AA. Platelet-related miR expression and MPA formation did not differ significantly between prasugrel- and ticagrelor-treated patients.

Conclusion:  Platelet-related miR-21 and miR-126 are associated with MPA formation in ACS patients on DAPT. miRs and MPA levels were similar in prasugrel- and ticagrelor-treated patients.
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http://dx.doi.org/10.1055/s-0040-1722226DOI Listing
January 2021

Association of Soluble Suppression of Tumorigenesis 2 (sST2) With Platelet Activation, Monocyte Tissue Factor and Ischemic Outcomes Following Angioplasty and Stenting.

Front Cardiovasc Med 2020 22;7:605669. Epub 2020 Dec 22.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Peripheral artery disease (PAD) patients undergoing infrainguinal angioplasty with stenting suffer high rates of target lesion restenosis and ischemic events. Blood-based prognostic markers in these patients are currently limited. The IL-33/ST2-system is involved in atherothrombosis. Soluble ST2 has been proposed as a biomarker in patients with cardiovascular disease. To investigate the association of sST2 with platelet activation and monocyte tissue factor (TF) in 316 patients undergoing elective angioplasty and stenting for cardiovascular disease, and its predictive value for ischemic outcomes following infrainguinal angioplasty with stent implantation in 104 PAD patients within this cohort. Circulating levels of sST2, platelet surface P-selectin, monocyte TF expression as well as soluble P-selectin were determined in 316 consecutive patients on dual antiplatelet therapy following angioplasty and stenting. sST2 was independently associated with soluble P-selectin (B = 6.4, 95% CI 2.0-10.7, = 0.004) and TF expression (B = 0.56, 95% CI 0.02-1.1, = 0.041) but not with platelet surface P-selectin (B = 0.1, 95% CI -0.1-0.3, = 0.307) after adjustment for age, sex, clinical risk factors and inflammatory parameters. During the follow-up of 24 months, the primary endpoint occurred in 41 of 104 PAD patients (39.4%). However, circulating levels of sST2 did not predict the primary endpoint in PAD patients (HR 1.1, 95% CI 0.76-1.71, = 0.527). sST2 is associated with soluble P-selectin and monocyte TF expression in atherosclerosis but not with ischemic outcomes following infrainguinal angioplasty with stent implantation for PAD.
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http://dx.doi.org/10.3389/fcvm.2020.605669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782352PMC
December 2020

Polymorphisms in the IL-6 and TNF-α gene are associated with an increased risk of abdominal aortic aneurysm.

Int J Cardiol 2021 Apr 6;329:192-197. Epub 2021 Jan 6.

Department of Surgery, Division of Vascular Surgery, Medical University of Vienna, Vienna, Austria.

Background: An abdominal aortic aneurysm (AAA) is a complex disease of the aging population that is associated with inflammation and the cellular immune response. To investigate the influence of interleukin (IL)-6 and tumor necrosis factor (TNF)-α single nucleotide polymorphisms (SNPs) on the risk of AAA formation and progression, the frequency of AAA and its associated risk factors were determined.

Method: Four SNPs in the IL-6 (-174G/C, rs1800795; -572G/C, rs1800796) and TNF-α (-238G/A, rs361525; -308G/A, rs1800629) genes were studied by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in patients with AAA and healthy volunteers. The mRNA expression and plasma IL-6 and TNF-α levels were also determined.

Results: A mutation detected in at least one allele of the IL-6 -174G/C SNP was associated with a 2-fold increased risk of AAA occurrence (OR: 2.08; 95% CI: 1.15-3.76; p = 0.014, in the dominant model). An increased risk of AAA incidence among heterozygous carriers of the TNF-α - 308G/A genotype was observed (OR: 2.06; 95% CI: 1.17-3.62; p = 0.011, in the overdominant model). The wild-type genotypes of the IL-6 -174G/C and the TNF-α -308G/A SNPs coexisted more frequently in healthy subjects than in AAA patients and was associated with decreased risk of AAA (p < 0.001). Moreover, elevated levels of IL-6 and TNF-α were associated with an increased risk of hypertension (p < 0.001 and p = 0.022, respectively).

Conclusions: The IL-6 -174G/C and the TNF-α -238G/A gene polymorphisms are associated with an increased risk of abdominal aortic aneurysm development.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.051DOI Listing
April 2021

Biological properties of bone marrow plasma cells influence their recovery in aspirate specimens: impact on classification of plasma cell disorders and potential bias to evaluation of treatment response.

Ann Hematol 2020 Nov 15;99(11):2599-2609. Epub 2020 Sep 15.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Methods to estimate bone marrow plasma cells (BMPC) basically include histopathology, cytomorphology, and flow cytometry. The present study compares the outcomes of these methods with special focus on the impact of BMPC-specific characteristics on their recovery by either method. Laboratory reports of diagnostic samples from 238 consecutive patients with suspected or known plasma cell disease were retrospectively analyzed. The median (IQR) proportion of BMPC was 30.0% (15.0-70.0%) by histological review (hBMPC), 7.0% (2.0-16.0%) by smear review (sBMPC), and 3.0% (0.8-10.0%) by flow cytometry (fBMPC). The disparity of results between core biopsy and aspirate smear was enhanced in case of poor quality of the smear, increased BM fiber content, higher grade cell atypia, expression of CD56 (all P < 0.0001), the number of cytogenetic aberrations (P = 0.0002), and abnormalities of the MYC gene (P = 0.0002). Conversely, expression of CD19 and a non-clonal plasma cell phenotype were associated with a lower difference between hBMPC and sBMPC (both P < 0.0001). The disparity between the percentages of sBMPC and fBMPC was associated with the quality of the smear (P = 0.0007) and expression of CD56 (P < 0.0001). Our results suggest that the recovery of BMPC in aspirate specimens not only is a matter of sampling quality but also depends on biological cell properties. Aspiration failure due to malignant type features of BMPC may lead to misclassification of plasma cell disorders and represent a bias for the detection of minimal residual disease after therapy.
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http://dx.doi.org/10.1007/s00277-020-04249-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7536141PMC
November 2020

Elevated plasma levels of asymmetric dimethylarginine and the risk for arrhythmic death in ischemic and non-ischemic, dilated cardiomyopathy - A prospective, controlled long-term study.

Clin Biochem 2020 Sep 4;83:37-42. Epub 2020 Jun 4.

Medical University of Vienna, Department of Medicine II, Division of Cardiology, Austria.

Introduction: Elevated plasma levels of asymmetric dimethylarginine (ADMA), an inhibitor of NO synthase, are associated with adverse outcome. There is no data available, whether ADMA levels are associated with arrhythmic death (AD) in patients with ischemic cardiomyopathy (ICM) or non-ischemic, dilated cardiomyopathy (DCM).

Methods And Results: A total of 110 ICM, 52 DCM and 30 control patients were included. Primary outcome parameter of this prospective study was arrhythmic death (AD) or resuscitated cardiac arrest (RCA). Plasma levels of ADMA were significantly higher in ICM (p < 0.001) and in DCM (p < 0.001) patients compared to controls. During a median follow-up of 7.0 years, 62 (32.3%) patients died. AD occurred in 26 patients and RCA was observed in 22 patients. Plasma levels of ADMA were not associated with a significantly increased risk of AD or RCA in ICM (hazard ratio (HR) = 1.37, p = 0.109) or in DCM (HR = 1.06, p = 0.848) patients. No significant association was found with overall mortality in ICM (HR = 1.39, p = 0.079) or DCM (HR = 1.10, p = 0.666) patients. Stratified Kaplan-Meier curves for ADMA levels in the upper tertile (>0.715 µmol/l) or the two lower tertiles (≤0.715 µmol/l) did not show a higher risk for AD or RCA (p = 0.221) or overall mortality (p = 0.548). In patients with left ventricular ejection fraction ≤ 35%, ADMA was not associated with AD or RCA (HR = 1.35, p = 0.084) or with overall mortality (HR = 1.24, p = 0.162).

Conclusions: Plasma levels of ADMA were elevated in patients with ICM or DCM as compared to controls, but were not significantly predictive for overall mortality or the risk for arrhythmic death.
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http://dx.doi.org/10.1016/j.clinbiochem.2020.05.016DOI Listing
September 2020

Insight into the expression of toll-like receptors 2 and 4 in patients with abdominal aortic aneurysm.

Mol Biol Rep 2020 Apr 7;47(4):2685-2692. Epub 2020 Mar 7.

Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna General Hospital, Vienna, Austria.

An abdominal aortic aneurysm (AAA) is a relatively common, life-threatening disease prevalent in persons over the age of 65. In recent years, an increasing number of studies have suggested that pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs), may serve as important regulators in the development of AAAs. In this study, we evaluated the TLR2 and TLR4 expression in the aortic wall and blood of patients with AAA. The TLR2 and TLR4 mRNA expression were significantly higher in the blood of patients with AAA than in the blood of healthy volunteers (p = 0.009 and p = 0.010, respectively). The expression of TLR2 and TLR4 transcripts was also higher in the blood compared with the aortic wall tissue of AAA patients (p = 0.001 for both). Higher TLR2 protein expression was observed in the aortic wall of AAA patients compared with the blood (p = 0.026). A significantly higher concentration of TNF-α and IL-4 in patients with AAA than in healthy volunteers (p < 0.001 for both) was noticed. This study suggests that TLR2 may play a role in the inflammatory response in the aorta, both locally and systemically, in patients with AAA.
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http://dx.doi.org/10.1007/s11033-020-05366-xDOI Listing
April 2020

The pro-inflammatory marker soluble suppression of tumorigenicity-2 (ST2) is reduced especially in diabetic morbidly obese patients undergoing bariatric surgery.

Cardiovasc Diabetol 2020 02 26;19(1):26. Epub 2020 Feb 26.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Background: High soluble suppression of tumorigenicity-2 (sST2) is a marker of poor prognosis in chronic inflammatory conditions. ST2 and its ligand interleukin (IL)-33 are elevated in adipose tissue of obese individuals. We aimed to evaluate circulating sST2 and IL-33 as possible markers of metabolic benefit in morbidly overweight patients after Roux-en-Y gastric bypass (RYGB) bariatric surgery.

Methods: sST2, IL-33, high sensitive IL-6, high sensitive C-reactive protein (hsCRP), leptin, cholesterol metabolism and liver parameters were measured in 80 morbidly obese individuals before and 1 year after bariatric surgery.

Results: sST2 was higher (P = 0.03) in diabetics as compared to individuals without diabetes. Baseline sST2 was also higher in males than in females (P= 0.0002). One year after bariatric surgery, sST2 levels were decreased (median 120, IQR 59-176 pg/mL) as compared to sST2 before surgery (median 141, IQR 111-181, P = 0.0024), and the diabetic group showed most pronounced reduction in sST2 (P = 0.0016). An association was found between sST2 and liver function parameters before and after bariatric surgery, and between baseline sST2 and total cholesterol, triglyceride, total low density lipoprotein (LDL), small dense LDL, Apolipoprotein B as well as with small dense high density lipoproteins (HDL). In the subgroup of diabetic patients positive correlation between IL-33 and sST2 (r = 0.44, P = 0.05) was noticed.

Conclusions: Circulating sST2 is associated with markers of liver functions and lipid metabolism in severely obese patients and a reduction of sST2 was shown after successful bariatric surgery, most prominently in diabetic patients.
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http://dx.doi.org/10.1186/s12933-020-01001-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7045735PMC
February 2020

Surrogate Markers of Neutrophil Extracellular Trap Formation are Associated with Ischemic Outcomes and Platelet Activation after Peripheral Angioplasty and Stenting.

J Clin Med 2020 Jan 22;9(2). Epub 2020 Jan 22.

Department of Internal Medicine II, Medical University of Vienna, Waehringer-Guertel 18-20, 1090 Vienna, Austria.

Neutrophil extracellular traps (NETs) are supposed to play a central role in atherothrombosis. We measured circulating citrullinated histone H3 (H3Cit) and cell-free DNA (cfDNA), which serve as surrogate markers of NET formation, in 79 patients with peripheral artery disease (PAD) following infrainguinal angioplasty with stent implantation. Analysis of cfDNA and H3Cit was performed using Quant-iT™ PicoGreen dsDNA Assay Kit or an ELISA, respectively. Within two years of follow-up, the primary endpoint defined as nonfatal myocardial infarction, stroke or transient ischemic attack, cardiovascular death, and >80% target vessel restenosis occurred in 34 patients (43%). Both H3Cit (HR per 1-SD: 2.72; 95% CI: 1.2-6.3; = 0.019) and cfDNA (HR per 1-SD: 2.15; 95% CI: 1.1-4.2; = 0.028) were associated with the primary endpoint in a univariate Cox regression analysis. Multivariate linear regression analyses showed associations between cfDNA and platelet surface expression of P-selectin ( = 0.006) and activated glycoprotein IIb/IIIa ( < 0.001) in response to arachidonic acid (AA) after adjustment for age, sex, clinical risk factors, and inflammatory markers. H3Cit was also associated with P-selectin expression in response to thrombin-receptor activating peptide ( = 0.048) and AA ( = 0.032). Circulating H3Cit and cfDNA predict ischemic outcomes after peripheral angioplasty with stent implantation, and are associated with on-treatment platelet activation in stable PAD.
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http://dx.doi.org/10.3390/jcm9020304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073960PMC
January 2020

Alternative activation of human macrophages enhances tissue factor expression and production of extracellular vesicles.

Haematologica 2021 Feb 1;106(2):454-463. Epub 2021 Feb 1.

Medical University of Vienna.

Macrophages are versatile cells that can be polarized by the tissue environment to fulfill required needs. Proinflammatory polarization is associated with increased tissue degradation and propagation of inflammation whereas alternative polarization within a Th2 cytokine environment is associated with wound healing and angiogenesis. To understand if polarization of macrophages can lead to a procoagulant macrophage subset we polarized human monocyte derived macrophages to a proinflammatory and an alternative activation state. Alternative polarization with interleukin-4 and IL-13 led to a macrophage phenotype characterized by increased tissue factor (TF) production and release and by an increase in extracellular vesicle production. In addition, also TF activity was enhanced in extracellular vesicles of alternatively polarized macrophages. This TF induction was dependent on signal transducer and activator of transcription-6 signaling and poly ADP ribose polymerase activity. In contrast to monocytes, human macrophages did not show increased tissue factor expression upon stimulation with lipopolysaccharide and interferon-γ. Previous polarization to either a proinflammatory or an alternative activation subset does not change the subsequent stimulation of TF. The inability of proinflammatory activated macrophages to respond to lipopolysaccharide and interferon-γ with an increase in TF production seems to be due to an increase in TF promoter methylation and was reversible when treating these macrophages with a demethylation agent. In conclusion, we provide evidence that proinflammatory polarization of macrophages does not lead to enhanced procoagulatory function, whereas alternative polarization of macrophages leads to an increased expression of TF and increased production of TF bearing extracellular vesicles by these cells suggesting a procoagulatory phenotype of alternatively polarized macrophages.
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http://dx.doi.org/10.3324/haematol.2019.220210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849567PMC
February 2021

Reproducibility of GMP-compliant production of therapeutic stressed peripheral blood mononuclear cell-derived secretomes, a novel class of biological medicinal products.

Stem Cell Res Ther 2020 01 3;11(1). Epub 2020 Jan 3.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

Background: The recent concept of secretome-based tissue regeneration has profoundly altered the field of regenerative medicine and offers promising novel therapeutic options. In contrast to medicinal products with a single active substance, cell-derived secretomes comprise pleiotropic bioactive ingredients, representing a major obstacle for reproducible drug product efficacy and warranting patient safety. Good manufacturing practice (GMP)-compliant production guarantees high batch-to-batch consistency and reproducible efficacy of biological medicinal products, but different batches of cellular secretomes produced under GMP have not been compared yet, and suitable quality control parameters have not been established. To this end, we analyzed diverse biological and functional parameters of different batches produced under GMP of the secretome obtained from γ-irradiated peripheral blood mononuclear cells with proven tissue regenerative properties in infarcted myocardium, stroke, spinal cord injury, and skin wounds.

Methods: We quantified key secretome ingredients, including cytokines, lipids, and extracellular vesicles, and functionally assessed potency in tube formation assay, ex vivo aortic ring sprouting assay, and cell-based protein and reporter gene assays. Furthermore, we determined secretome stability in different batches after 6 months of storage at various ambient temperatures.

Results: We observed that inter-batch differences in the bioactive components and secretome properties were small despite considerable differences in protein concentrations and potencies between individual donor secretomes. Stability tests showed that the analytical and functional properties of the secretomes remained stable when lyophilisates were stored at temperatures up to + 5 °C for 6 months.

Conclusions: We are the first to demonstrate the consistent production of cell-derived, yet cell-free secretome as a biological medicinal product. The results from this study provide the basis for selecting appropriate quality control parameters for GMP-compliant production of therapeutic cell secretomes and pave the way for future clinical trials employing secretomes in tissue regenerative medicine.
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http://dx.doi.org/10.1186/s13287-019-1524-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942406PMC
January 2020

Differential expression of Plg-R and its effects on migration of proinflammatory monocyte and macrophage subsets.

Blood 2019 08 20;134(6):561-567. Epub 2019 Jun 20.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Membrane-bound plasmin is used by immune cells to degrade extracellular matrices, which facilitates migration. The plasminogen receptor Plg-R is expressed by immune cells, including monocytes and macrophages. Among monocytes and macrophages, distinct subsets can be distinguished based on cell surface markers and pathophysiological function. We investigated expression of Plg-R by monocyte and macrophage subsets and whether potential differential expression might have functional consequences for cell migration. Proinflammatory CD14CD16 human monocytes and Ly6C mouse monocytes expressed the highest levels of Plg-R and bound significantly more plasminogen compared with the other respective subsets. Proinflammatory human macrophages, generated by polarization with lipopolysaccharide and interferon-γ, showed significantly higher expression of Plg-R compared with alternatively activated macrophages, polarized with interleukin-4 and interleukin-13. Directional migration of proinflammatory monocytes was plasmin dependent and was abolished by anti-Plg-R monoclonal antibody, ε-amino-caproic acid, aprotinin, and the aminoterminal fragment of urokinase-type plasminogen activator. In an in vivo peritonitis model, significantly less Ly6C monocyte recruitment was observed in Plg-R compared with Plg-R mice. Immunohistochemical analysis of human carotid plaques and adipose tissue showed that proinflammatory macrophages also exhibited high levels of Plg-R in vivo. Our data demonstrate higher expression of Plg-R on proinflammatory monocyte and macrophage subsets that impacts their migratory capacity.
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http://dx.doi.org/10.1182/blood.2018850420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6688429PMC
August 2019

Neutrophil Gelatinase Associated Lipocalin (NGAL) for Identification of Unstable Plaques in Patients with Asymptomatic Carotid Stenosis.

Eur J Vasc Endovasc Surg 2019 Jun 1;57(6):768-777. Epub 2019 Jun 1.

Department of Surgery, Division of Vascular Surgery, Medical University of Vienna, Austria. Electronic address:

Objective: Neutrophil gelatinase associated lipocalin (NGAL) and matrix metalloproteinase (MMP)-9/NGAL complex were investigated in asymptomatic patients with carotid artery stenosis including gender specific differences aiming at vulnerable plaques prone to embolisation.

Methods: Serum NGAL and MMP-9/NGAL levels were analysed in 83 patients with asymptomatic carotid artery stenosis. Pre-operative ultrasound and post-endarterectomy histology of carotid atherosclerotic lesions were evaluated.

Results: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of the American Heart Association), displayed the highest levels of NGAL and MMP-9/NGAL complex (p = .0003 and p = .0078, respectively). Grade VI plaques were primarily detected in patients with "soft" plaques (12 type VI plaques in 25 patients), but also in patients with mixed (four of 19) and calcified (three of 39) plaques according to ultrasound. Higher grade carotid artery stenosis (≥90%) was not associated with elevated NGAL levels. The receiver operating characteristic curve analysis detecting grade VI lesions yields an area under the curve (AUC) = 0.85, with respect to soft plaque on ultrasound the AUC = 0.86. There were no gender specific differences in levels of NGAL 80.9 (37.7) ng/mL in women vs. 76.7 (36.3) ng/mL in men, p = .607) nor of MMP-9/NGAL 33.0 (18.2-55.5) ng/mL in women vs. 36.7 (20.2-54.0) ng/mL in men, p = .969. Likewise, there were no gender associated differences in vulnerable plaque characteristics: either for grade VI plaques (17.9% vs. 27.3%, p = .582) or for the presence of soft plaques as evaluated by ultrasound (35.9% vs. 25%, p = .503).

Conclusion: Circulating NGAL and MMP-9/NGAL are significantly increased in asymptomatic patients with vulnerable carotid atherosclerotic plaques independent of gender. Accordingly, serum NGAL may be proposed as a valuable biomarker for the detection of unstable carotid plaques in asymptomatic patients, who can then be selected for early carotid endarterectomy or stenting.
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http://dx.doi.org/10.1016/j.ejvs.2018.12.029DOI Listing
June 2019

Changes of Circulating Extracellular Vesicles from the Liver after Roux-en-Y Bariatric Surgery.

Int J Mol Sci 2019 Apr 30;20(9). Epub 2019 Apr 30.

Department of Internal Medicine II, Medical University of Vienna, A-1090 Vienna, Austria.

Circulating extracellular vesicles are small particles enclosed by a phospholipid bilayer. Vesicles deriving directly from the cellular membrane by an active budding process retain cell origin specific proteins and RNA. These vesicles carry pathophysiological information from their parental cell and hold the potential to allow analysis of organs without the need for a biopsy. We included in our study 27 patients undergoing bariatric surgery. Hepatic extracellular vesicles were determined by flow cytometry. mRNA specific for hepatic cellular origin was determined in the extracellular vesicle fraction using qPCR. Surgery led to a massive reduction of weight and overall hepatic stress as determined by alanine transaminase (ALT), aspartate transaminase (AST) and γ-glutamyltransferase (GGT). Total extracellular vesicle numbers were reduced after bariatric surgery. Liver specific vesicles identified by HepPar1 or asialoglycoprotein receptor (ASGPR) were significantly reduced after bariatric surgery in both AnnexinV and AnnexinV subgroups. When analyzing circulating liver-specific mRNAs, we found reduced levels of these mRNAs after surgery even though total circulating RNA remained unchanged. We conclude that circulating hepatic extracellular vesicles are detectable in samples from patients undergoing gastric bypass surgery. These vesicles are reduced after a reduction of hepatic stress also observed with classic liver enzyme measurements. We conclude that ASGPR or HepPar positive vesicles hold the potential to serve as liver specific vesicle markers.
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http://dx.doi.org/10.3390/ijms20092153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539504PMC
April 2019

Toxicological testing of allogeneic secretome derived from peripheral mononuclear cells (APOSEC): a novel cell-free therapeutic agent in skin disease.

Sci Rep 2019 04 3;9(1):5598. Epub 2019 Apr 3.

Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria.

A cell-free approach using secretomes derived from stem cells or peripheral blood mononuclear cells is an active area of regenerative medicine that holds promise for therapies. Regulatory authorities classify these secretomes as biological medicinal products, and non- clinical safety assessment thus falls under the scope of ICH S6. A secretome of stressed peripheral blood mononuclear cells (APOSEC) was successfully tested in a toxicology program, supporting clinical use of the new drug candidate. Here, to allow for topical, dermal treatment of patients with diabetic foot ulcer, several non-clinical safety studies were performed. Acute toxicity (single dose) and neuropharmacological screening were tested intravenously in a rat model. Risk for skin sensitisation was tested in mice. A 4-week intravenous toxicity study in mice and a 4-week subcutaneous toxicity study in minipigs were conducted to cover the clinical setting and application in a rodent and a non-rodent model. Acute and repeated-dose toxicity studies show that APOSEC administered intravenously and subcutaneously does not involve major toxicities or signs of local intolerance at levels above the intended total human maximal dose of 3.3 U/kg/treatment, 200 U/wound/treatment, and 100 U/cm/treatment. The non-clinical data support the safe topical use of APOSEC in skin diseases related to deficient wound healing.
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http://dx.doi.org/10.1038/s41598-019-42057-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6447581PMC
April 2019

Plasma levels of interleukin-33 and soluble suppression of tumorigenicity 2 in patients with advanced pancreatic ductal adenocarcinoma undergoing systemic chemotherapy.

Med Oncol 2018 Nov 13;36(1). Epub 2018 Nov 13.

Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.

Interleukin-33 (IL-33) and its "decoy" receptor soluble ST2 (sST2) are involved in the development of chronic inflammation and cancer. We explored IL-33 and sST2 as a potential prognostic marker in patients with metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). IL-33 and sST2 plasma levels were assessed in 20 patients with advanced PDAC before start of systemic chemotherapy and were analyzed in relation to clinical outcome. Kaplan Meier and multivariable Cox proportional hazards model analysis revealed a significant association between sST2 plasma levels and survival (HR 2.10, 95% CI 1.33-3.41, p = 0.002) and link high sST2 plasma levels to inferior survival in patients with advanced PDAC undergoing chemotherapy.
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http://dx.doi.org/10.1007/s12032-018-1223-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244890PMC
November 2018

Cardioprotective cytokine interleukin-33 is up-regulated by statins in human cardiac tissue.

J Cell Mol Med 2018 12 14;22(12):6122-6133. Epub 2018 Sep 14.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

Interleukin (IL)-33 is a member of the IL-1 family and is able to act cardioprotective. The aim of this study was to investigate the regulation of IL-33 by 3-hydroxy-3-methylglutaryl-coenzyme-A (HMG-CoA) reductase inhibitors (statins) and bisphosphonates (BPs) in human cardiac tissue. The lipophilic fluvastatin, simvastatin, atorvastatin, and lovastatin as well as the nitrogenous BPs alendronate and ibandronate, but not hydrophilic pravastatin increased IL-33 mRNA and intracellular IL-33 protein levels in both human adult cardiac myocytes (HACM) and fibroblasts (HACF). Additionally, fluvastatin reduced soluble ST2 secretion from HACM. IL-33 was also up-regulated by the general inhibitor of prenylation perillic acid, a RhoA kinase inhibitor Y-27632, and by latrunculin B, but statin-induced IL-33 expression was inhibited by mevalonate, geranylgeranyl pyrophosphate (GGPP) and RhoA activator U-46619. The IL-33 promoter was 2.3-fold more accessible in statin-treated HACM compared to untreated cells (P = 0.037). In explanted hearts of statin-treated patients IL-33 protein was up-regulated as compared with the hearts of non-statin-treated patients (P = 0.048). As IL-33 was previously shown to exert cardioprotective effects, one could speculate that such up-regulation of IL-33 expression in human cardiac cells, which might happen mainly through protein geranylgeranylation, could be a novel mechanism contributing to known cardioprotective effects of statins and BPs.
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http://dx.doi.org/10.1111/jcmm.13891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237563PMC
December 2018

GDF-15 is a better complimentary marker for risk stratification of arrhythmic death in non-ischaemic, dilated cardiomyopathy than soluble ST2.

J Cell Mol Med 2018 04 4;22(4):2422-2429. Epub 2018 Feb 4.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria.

Growth differentiation factor (GDF)-15 and soluble ST2 (sST2) are established prognostic markers in acute and chronic heart failure. Assessment of these biomarkers might improve arrhythmic risk stratification of patients with non-ischaemic, dilated cardiomyopathy (DCM) based on left ventricular ejection fraction (LVEF). We studied the prognostic value of GDF-15 and sST2 for prediction of arrhythmic death (AD) and all-cause mortality in patients with DCM. We prospectively enrolled 52 patients with DCM and LVEF ≤ 50%. Primary end-points were time to AD or resuscitated cardiac arrest (RCA), and secondary end-point was all-cause mortality. The median follow-up time was 7 years. A cardiac death was observed in 20 patients, where 10 patients had an AD and 2 patients had a RCA. One patient died a non-cardiac death. GDF-15, but not sST2, was associated with increased risk of the AD/RCA with a hazard ratio (HR) of 2.1 (95% CI = 1.1-4.3; P = .031). GDF-15 remained an independent predictor of AD/RCA after adjustment for LVEF with adjusted HR of 2.2 (95% CI = 1.1-4.5; P = .028). Both GDF-15 and sST2 were independent predictors of all-cause mortality (adjusted HR = 2.4; 95% CI = 1.4-4.2; P = .003 vs HR = 1.6; 95% CI = 1.05-2.7; P = .030). In a model including GDF-15, sST2, LVEF and NYHA functional class, only GDF-15 was significantly associated with the secondary end-point (adjusted HR = 2.2; 95% CI = 1.05-5.2; P = .038). GDF-15 is superior to sST2 in prediction of fatal arrhythmic events and all-cause mortality in DCM. Assessment of GDF-15 could provide additional information on top of LVEF and help identifying patients at risk of arrhythmic death.
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http://dx.doi.org/10.1111/jcmm.13540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867130PMC
April 2018

Predictive value of low interleukin-33 in critically ill patients.

Cytokine 2018 03 30;103:109-113. Epub 2017 Sep 30.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Waehringer-Guertel 18-20, A-1090 Vienna, Austria.

Patients admitted to a medical intensive care unit (ICU) are characterized by an activated immune system and exhibit a high mortality rate irrespective of the underlying cause of admission. Interleukin (IL)-33 has been shown to be protective in experimental sepsis models and it has been demonstrated that circulating levels of its "decoy" receptor soluble ST2 (sST2) are associated with outcome in critically ill patients. The aim of the present study was to investigate whether circulating IL-33 is associated with 30-day mortality in patients admitted to a medical ICU. In this prospective, observational study, both IL-33 and sST2 levels were assessed in 223 consecutive patients at ICU admission using specific enzyme-linked immunosorbent assays (ELISAs). During the 30-day follow-up, 58 patients (26%) died. Circulating IL-33 was detectable in 166 patients and in 57 patients, serum IL-33 was below the detection limit. Both detectable IL-33 and sST2 below the median were strong predictors of survival in critically ill patients independent of acute physiology and chronic health evaluation II (APACHE II) score. IL-33 and sST2 predicted risk independent from each other. Patients with both, non-detectable levels of IL-33 and sST2 levels above the median, showed a dramatically increased mortality risk (HR 6.9 95% CI 3.0-16.2; p<0.001). Low levels of IL-33 and increased levels of sST2 predict mortality risk in critically ill patients independent from each other and APACHE II score. Both together showed additive predictive value suggesting a pathogenic role of the IL-33/ST2 system in critically ill patients.
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http://dx.doi.org/10.1016/j.cyto.2017.09.017DOI Listing
March 2018

PAI-1 (Plasminogen Activator Inhibitor-1) Expression Renders Alternatively Activated Human Macrophages Proteolytically Quiescent.

Arterioscler Thromb Vasc Biol 2017 10 17;37(10):1913-1922. Epub 2017 Aug 17.

From the Department of Internal Medicine II, Division of Cardiology (P.J.H., J.B., B.E., B.T., K.D., S.S., S.D., W.S.S., J.W.), Center for Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research (J.B.K.-P., P.U., G.S.), Department of Laboratory Medicine (S.D.), Clinic for Blood Group Serology and Transfusion Medicine (M.B.F.), and Core Facilities (J.W.), Medical University of Vienna, Austria; Department for Health Science and Biomedicine, Danube University Krems, Austria (M.B.F.); 3rd Medical Department, Wilhelminenspital, Vienna, Austria (K.H.); and Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria (K.H., J.W.).

Objective: Macrophages are versatile immune cells capable of polarizing into functional subsets depending on environmental stimulation. In atherosclerotic lesions, proinflammatory polarized macrophages are associated with symptomatic plaques, whereas Th2 (T-helper cell type 2) cytokine-polarized macrophages are inversely related with disease progression. To establish a functional cause for these observations, we analyzed extracellular matrix degradation phenotypes in polarized macrophages.

Approach And Results: We provide evidence that proinflammatory polarized macrophages rely on membrane-bound proteases including MMP-14 (matrix metalloproteinase-14) and the serine protease uPA (urokinase plasminogen activator) together with its receptor uPAR for extracellular matrix degradation. In contrast, Th2 cytokine alternatively primed macrophages do not show different proteolytic activity in comparison to unpolarized macrophages and lack increased localization of MMP-14 and uPA receptor to the cell membrane. Nonetheless, they express the highest amount of the serine protease uPA. However, uPA activity is blocked by similarly increased expression of its inhibitor PAI-1 (plasminogen activator inhibitor 1). When inhibiting PAI-1 or when analyzing macrophages deficient in PAI-1, Th2 cytokine-polarized macrophages display the same matrix degradation capability as proinflammatory-primed macrophages. Within atherosclerotic lesions, macrophages positive for the alternative activation marker CD206 express high levels of PAI-1. In addition, to test changed tissue remodeling capacities of alternatively activated macrophages, we used a bleomycin lung injury model in mice reconstituted with PAI-1 bone marrow. These results supported an enhanced remodeling phenotype displayed by increased fibrosis and elevated MMP activity in the lung after PAI-1 loss.

Conclusions: We were able to demonstrate matrix degradation dependent on membrane-bound proteases in proinflammatory stimulated macrophages and a forced proteolytical quiescence in alternatively polarized macrophages by the expression of PAI-1.
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http://dx.doi.org/10.1161/ATVBAHA.117.309383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5627534PMC
October 2017

NGAL and MMP-9/NGAL as biomarkers of plaque vulnerability and targets of statins in patients with carotid atherosclerosis.

Clin Chem Lab Med 2017 Nov;56(1):147-156

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Background: Neutrophil gelatinase associated lipocalin (NGAL) is expressed in atherosclerotic lesions and was recently implicated in the pathogenesis of cardiovascular pathologies. Statins are known to exert stabilizing effects on atherosclerotic plaque. The aims of our study were (1) to investigate the association of serum NGAL and metalloproteinase (MMP)-9/NGAL complex with the vulnerability of the atherosclerotic plaque, and (2) to reveal the effects of statin treatment on circulating NGAL and MMP-9/NGAL levels in patients with carotid artery stenosis.

Methods: We examined the levels of NGAL and MMP-9/NGAL in blood samples from 136 patients with carotid artery stenosis by specific enzyme-linked immunosorbent assays.

Results: Patients with vulnerable plaques, as determined by ultrasound (plaques with decreased echogenicity) and histological analysis (type VI according to the classification of American Heart Association [AHA]), displayed the highest levels of NGAL (both p<0.0001) and MMP-9/NGAL complex (p=0.0004 and p=0.004, respectively). Moreover, patients with symptomatic carotid atherosclerosis had significantly higher NGAL levels compared to asymptomatic patients (p=0.0007). The statin-treated group (n=108) demonstrated lower NGAL (73.9 vs. 128.0 μg/L, p<0.0001) and MMP-9/NGAL (28.9 vs. 40.6 μg/L, p=0.046) as compared to the non-statin group (n=28). Furthermore, in multivariate regression analysis NGAL, but not MMP-9/NGAL levels, were independently associated with symptomatic carotid artery stenosis. In addition, statin treatment was independently associated with lower NGAL levels.

Conclusions: Circulating NGAL and MMP-9/NGAL are associated with plaque vulnerability in patients with carotid artery stenosis. Statin treatment could contribute to plaque stabilization by reducing circulating NGAL and MMP-9/NGAL levels.
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http://dx.doi.org/10.1515/cclm-2017-0156DOI Listing
November 2017

IL-33 stimulates the release of procoagulant microvesicles from human monocytes and differentially increases tissue factor in human monocyte subsets.

Thromb Haemost 2017 06 11;117(7):1379-1390. Epub 2017 May 11.

Johann Wojta, Department of Internal Medicine II and Core Facilities, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Telephone: +43 1 40400/73500, Fax: +43 1 40400/73587, E-mail: or, Agneta Siegbahn, Department of Medical Sciences, Clinical Chemistry and Science for Life Laboratory, University Hospital and Uppsala University, SE 751 85 Uppsala, Sweden, Tel.: +46 18 611 4251, Fax: +46 18 552562, E-mail:

Monocytes and monocyte-derived microvesicles (MVs) are the main source of circulating tissue factor (TF). Increased monocyte TF expression and increased circulating levels of procoagulant MVs contribute to the formation of a prothrombotic state in patients with cardiovascular disease. Interleukin (IL)-33 is a pro-inflammatory cytokine involved in atherosclerosis and other inflammatory diseases, but its role in regulating thrombosis is still unclear. The aim of the present study was to investigate the effects of IL-33 on the procoagulant properties of human monocytes and monocyte-derived MVs. IL-33 induced a time- and concentration-dependent increase of monocyte TF mRNA and protein levels via binding to the ST2-receptor and activation of the NF-κB-pathway. The IL-33 treated monocytes also released CD14+TF+ MVs and IL-33 was found to increase the TF activity of both the isolated monocytes and monocyte-derived MVs. The monocytes were classified into subsets according to their CD14 and CD16 expression. Intermediate monocytes (IM) showed the highest ST2 receptor expression, followed by non-classical monocytes (NCM), and classical monocytes (CM). IL-33 induced a significant increase of TF only in the IM (p<0.01), with a tendency in NCM (p=0.06), but no increase was observed in CM. Finally, plasma levels of IL-33 were positively correlated with CD14+TF+ MVs in patients undergoing carotid endarterectomy (r=0.480; p=0.032; n=20). We hereby provide novel evidence that the proinflammatory cytokine IL-33 induces differential TF expression and activity in monocyte subsets, as well as the release of procoagulant MVs. In this manner, IL-33 may contribute to the formation of a prothrombotic state characteristic for cardiovascular disease.
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http://dx.doi.org/10.1160/TH16-10-0784DOI Listing
June 2017

The JAK2 blocker TG101209 is a potent inhibitor of clonogenic progenitor cell growth in patients with chronic myeloid leukaemia.

Br J Haematol 2018 04 21;181(1):137-139. Epub 2017 Feb 21.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.

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http://dx.doi.org/10.1111/bjh.14508DOI Listing
April 2018

Diagnostic performance and reference values of novel biomarkers of paediatric heart failure.

Heart 2016 10 24;102(20):1633-9. Epub 2016 May 24.

Department of Paediatrics and Adolescent Medicine, Division of Paediatric Cardiology, Medical University of Vienna, Vienna, Austria.

Objective: Biomarkers play a pivotal role in heart failure (HF) management. Reference values and insights from studies in adults cannot be extrapolated to the paediatric population due to important differences in pathophysiology and compensatory reserve. We assessed the diagnostic utility of four novel biomarkers in paediatric HF.

Methods: Midregional (MR) pro-atrial natriuretic peptide (proANP), soluble ST2 (sST2), growth differentiation factor-15 (GDF-15), MR-pro-adrenomedullin (proADM) and N-terminal pro-B natriuretic peptide (NT-proBNP) were measured in 114 patients and 89 controls. HF was defined as the presence of HF symptoms and/or abnormal systolic ventricular function. Receiver-operating characteristics were plotted, and the area under the curve (AUC) was measured. This was repeated for subgroups with cardiomyopathy and congenital heart disease (CHD). Ventricular systolic function was measured by magnetic resonance or echocardiography. Reference values were calculated according to the current guidelines.

Results: The AUC for diagnosing HF was 0.76 for MR-proANP (CI 0.70 to 0.84) and 0.82 for NT-proBNP (CI 0.75 to 0.88). These parameters performed similarly in the subgroups with CHD and cardiomyopathy. By contrast, MR-proADM, GDF-15 and sST2 performed poorly. When used in conjunction with NT-proBNP, no parameter added significantly to its diagnostic accuracy. NT-proBNP, MR-proANP, GDF-15 and sST2 could accurately discriminate between patients with preserved and patients with poor functional status. In a subset of patients with dilated cardiomyopathy, NT-proBNP, MR-proANP, MR-proADM and GDF-15 were associated with poor LV function.

Conclusions: MR-proANP could accurately detect HF in children and adolescents. Its diagnostic performance was comparable with that of NT-proBNP, regardless of the underlying condition. Reference values are presented.
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http://dx.doi.org/10.1136/heartjnl-2016-309460DOI Listing
October 2016

Interleukin-33 stimulates GM-CSF and M-CSF production by human endothelial cells.

Thromb Haemost 2016 08 12;116(2):317-27. Epub 2016 May 12.

Svitlana Demyanets, MD, PhD, Department of Laboratory Medicine, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Tel.: +43 1 40400 73516, Fax: +43 1 40400 73587, E-mail:

Interleukin (IL)-33, a member of the IL-1 family of cytokines, is involved in various inflammatory conditions targeting amongst other cells the endothelium. Besides regulating the maturation and functions of myeloid cells, granulocyte macrophage-colony stimulating factor (GM-CSF) and macrophage-CSF (M-CSF) have been shown to play a role in such pathologies too. It was the aim of our study to investigate a possible influence of IL-33 on GM-CSF and M-CSF production by human endothelial cells. IL-33, but not IL-18 or IL-37, stimulated GM-CSF and M-CSF mRNA expression and protein production by human umbilical vein endothelial cells (HUVECs) and human coronary artery ECs (HCAECs) through the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway in an IL-1-independent way. This effect was inhibited by the soluble form of ST2 (sST2), which is known to act as a decoy receptor for IL-33. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor fluvastatin could also be shown to moderately reduce the IL-33-mediated effect on M-CSF, but not on GM-CSF expression. In addition, IL-33, IL-1β, GM-CSF and M-CSF were detected in endothelial cells of human carotid atherosclerotic plaques using immunofluorescence. Upregulation of GM-CSF and M-CSF production by human endothelial cells, an effect that appears to be mediated by NF-κB and to be independent of IL-1, may be an additional mechanism through which IL-33 contributes to inflammatory activation of the vessel wall.
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http://dx.doi.org/10.1160/TH15-12-0917DOI Listing
August 2016

Tissue factor is induced by interleukin-33 in human endothelial cells: a new link between coagulation and inflammation.

Sci Rep 2016 05 4;6:25171. Epub 2016 May 4.

Department of Internal Medicine II, Medical University of Vienna, Austria.

Tissue factor (TF) is the primary trigger of coagulation. Elevated levels of TF are found in atherosclerotic plaques, and TF leads to thrombus formation when released upon plaque rupture. Interleukin (IL)-33 was previously shown to induce angiogenesis and inflammatory activation of endothelial cells (ECs). Here, we investigated the impact of IL-33 on TF in human ECs, as a possible new link between inflammation and coagulation. IL-33 induced TF mRNA and protein in human umbilical vein ECs and coronary artery ECs. IL-33-induced TF expression was ST2- and NF-κB-dependent, but IL-1-independent. IL-33 also increased cell surface TF activity in ECs and TF activity in ECs-derived microparticles. IL-33-treated ECs reduced coagulation time of whole blood and plasma but not of factor VII-deficient plasma. In human carotid atherosclerotic plaques (n = 57), TF mRNA positively correlated with IL-33 mRNA expression (r = 0.691, p < 0.001). In this tissue, IL-33 and TF protein was detected in ECs and smooth muscle cells by immunofluorescence. Furthermore, IL-33 and TF protein co-localized at the site of clot formation within microvessels in plaques of patients with symptomatic carotid stenosis. Through induction of TF in ECs, IL-33 could enhance their thrombotic capacity and thereby might impact on thrombus formation in the setting of atherosclerosis.
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http://dx.doi.org/10.1038/srep25171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855148PMC
May 2016

Premature myocardial infarction is strongly associated with increased levels of remnant cholesterol.

J Clin Lipidol 2015 Nov-Dec;9(6):801-806.e1. Epub 2015 Aug 29.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.

Background: Remnant cholesterol has been defined as the cholesterol present in triglyceride-rich remnant lipoproteins. Elevated levels of remnant cholesterol have been associated with increased cardiovascular risk. Acute myocardial infarction (AMI) in very young individuals (≤40 years) represents a rare disease with a typical risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins.

Objective: The aim of this study was to investigate the role of remnant cholesterol in premature AMI.

Methods: We prospectively enrolled 302 patients into our multicenter case-control study comprising 102 consecutive myocardial infarction survivors (≤40 years) and 200 hospital controls. Myocardial infarction patients were frequency matched for age, gender, and center. Remnant cholesterol was calculated from standard lipid parameters.

Results: Remnant cholesterol was 1.7-fold higher in premature AMI patients compared with controls (61.1 ± 36.8 vs 35.8 ± 16.8 mg/dL; P < .001). Remnant cholesterol was the lipid fraction most strongly associated with premature myocardial infarction (odds ratio 3.87; 95% confidence interval 2.26-6.64; P < .001) for an increase of 1-standard deviation. This observation was independent from clinical risk factors and plasma lipid levels.

Conclusions: Remnant cholesterol is strongly associated with premature myocardial infarction, can be easily calculated, and might serve as a new potent risk marker in this young patient population.
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http://dx.doi.org/10.1016/j.jacl.2015.08.009DOI Listing
September 2016

G-CSF Predicts Cardiovascular Events in Patients with Stable Coronary Artery Disease.

PLoS One 2015 10;10(11):e0142532. Epub 2015 Nov 10.

3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminenhospital, Vienna, Austria.

Granulocyte-colony-stimulating-factor (G-CSF) induces mobilization of progenitor cells but may also exert pro-inflammatory and pro-thrombotic effects. Treatment with recombinant G-CSF after acute myocardial infarction is currently under examination and has been associated with in-stent restenosis. However, it is not known whether plasma levels of endogenous G-CSF are also associated with an increased cardiovascular risk. Therefore we included 280 patients with angiographically proven stable coronary artery disease. G-CSF was measured by specific ELISA and patients were followed for a median of 30 months for the occurrence of major adverse cardiovascular events (MACE: death, myocardial infarction, re-hospitalization). Those with cardiac events during follow-up showed significant higher G-CSF levels (32.3 pg/mL IQR 21.4-40.5 pg/mL vs. 24.6 pg/mL IQR 16.4-34.9 pg/mL; p<0.05) at baseline. Patients with G-CSF plasma levels above the median had a 2-fold increased risk for MACE (p<0.05). This was independent from established cardiovascular risk factors. In addition, G-CSF above the median was a predictor of clinical in-stent restenosis after implantation of bare-metal stents (6.6% vs. 19.4%; p<0.05) but not of drug-eluting stents (7.7% vs. 7.6%; p = 0.98). This data suggests that endogenous plasma levels of G-CSF predict cardiovascular events independently from established cardiac risk factors and are associated with increased in-stent restenosis rates after implantation of bare metal stents.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142532PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640870PMC
June 2016

Levosimendan exerts anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro.

Thromb Haemost 2015 Feb 2;113(2):350-62. Epub 2014 Oct 2.

Johann Wojta, PhD, Department of Internal Medicine II, Medical University of Vienna, Austria, Tel.: +43 1 4040073500, Fax: +43 1 4040073586, E-mail:

Levosimendan is a positive inotropic drug for the treatment of acute decompensated heart failure (HF). Clinical trials showed that levosimendan was particularly effective in HF due to myocardial infarction. Myocardial necrosis induces a strong inflammatory response, involving chemoattractants guiding polymorphonuclear neutrophils (PMN) into the infarcted myocardial tissue. Our aim was to examine whether levosimendan exhibits anti-inflammatory effects on human adult cardiac myocytes (HACM) and human heart microvascular endothelial cells (HHMEC). Cardiac myocytes and endothelial cells were stimulated with interleukin-1β (IL)-1β (200 U/ml) and treated with levosimendan (0.1-10 µM) for 2-48 hours. IL-1β strongly induced expression of IL-6 and IL-8 in HACM and E-selectin and intercellular adhesion molecule-1 (ICAM-1) in HHMEC and human umbilical vein endothelial cells (HUVEC). Treatment with levosimendan strongly attenuated IL-1β-induced expression of IL-6 and IL-8 in HACM as well as E-selectin and ICAM-1 in ECs. Levosimendan treatment further reduced adhesion of PMN to activated endothelial cells under both static and flow conditions by approximately 50 %. Incubation with 5-hydroxydecanoic acid, a selective blocker of mitochondrial ATP-dependent potassium channels, partly abolished the above seen anti-inflammatory effects. Additionally, levosimendan strongly diminished IL-1β-induced reactive oxygen species and nuclear factor-κB (NF-κB) activity through inhibition of S536 phosphorylation. In conclusion, levosimendan exhibits anti-inflammatory effects on cardiac myocytes and endothelial cells in vitro. These findings could explain, at least in part, the beneficial effects of levosimendan after myocardial infarction.
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http://dx.doi.org/10.1160/TH14-06-0549DOI Listing
February 2015

Soluble ST2 and interleukin-33 levels in coronary artery disease: relation to disease activity and adverse outcome.

PLoS One 2014 21;9(4):e95055. Epub 2014 Apr 21.

Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria; Core Facilities, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Cardiovascular Research, Vienna, Austria.

Objectives: ST2 is a receptor for interleukin (IL)-33. We investigated an association of soluble ST2 (sST2) and IL-33 serum levels with different clinical stages of coronary artery disease. We assessed the predictive value of sST2 and IL-33 in patients with stable angina, non-ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI).

Methods: We included 373 patients of whom 178 had stable angina, 97 had NSTEMI, and 98 had STEMI. Patients were followed for a mean of 43 months. The control group consisted of 65 individuals without significant stenosis on coronary angiography. Serum levels of sST2 and IL-33 were measured by ELISAs.

Results: sST2 levels were significantly increased in patients with STEMI as compared to patients with NSTEMI and stable angina as well as with controls. IL-33 levels did not differ between the four groups. During follow-up, 37 (10%) patients died and the combined endpoint (all cause death, MI and rehospitalisation for cardiac causes) occurred in 66 (17.6%) patients. sST2 serum levels significantly predicted mortality in the total cohort. When patients were stratified according to their clinical presentation, the highest quintile of sST2 significantly predicted mortality in patients with STEMI, but not with NSTEMI or stable coronary artery disease. sST2 was a significant predictor for the combined endpoint in STEMI patients and in patients with stable angina. Serum levels of IL-33 were not associated with clinical outcome in the total cohort, but the highest quintile of IL-33 predicted mortality in patients with STEMI.

Conclusions: Serum levels of sST2 are increased in patients with acute coronary syndromes as compared to levels in patients with stable coronary artery disease and in individuals without coronary artery disease. sST2 and IL-33 were associated with mortality in patients with STEMI but not in patients with NSTEMI or stable angina.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095055PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994012PMC
January 2015