Publications by authors named "Johann Wojta"

255 Publications

Circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) are associated with monocyte subsets in patients with stable coronary artery disease.

J Clin Lipidol 2021 Mar 16. Epub 2021 Mar 16.

Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Proprotein convertase subtilisin/kexin type-9 (PCSK9) is an enzyme promoting the degradation of low-density lipoprotein receptors (LDL-R) in hepatocytes. Inhibition of PCSK9 has emerged as a novel target for lipid-lowering therapy. Monocytes are crucially involved in the pathogenesis of atherosclerosis and can be divided into three subsets.

Objective: The aim of this study was to examine whether circulating levels of PCSK9 are associated with monocyte subsets.

Methods: We included 69 patients with stable coronary artery disease. PCSK9 levels were measured and monocyte subsets were assessed by flow cytometry and divided into classical monocytes (CD14++CD16-; CM), intermediate monocytes (CD14++CD16+; IM) and non-classical monocytes (CD14+CD16++; NCM).

Results: Mean age was 64 years and 80% of patients were male. Patients on statin treatment (n = 55) showed higher PCSK9-levels (245.4 (206.0-305.5) ng/mL) as opposed to those without statin treatment (186.1 (162.3-275.4) ng/mL; p = 0.05). In patients on statin treatment, CM correlated with circulating PCSK9 levels (R = 0.29; p = 0.04), while NCM showed an inverse correlation with PCSK9 levels (R = -0.33; p = 0.02). Patients with PCSK9 levels above the median showed a significantly higher proportion of CM as compared to patients with PCSK9 below the median (83.5 IQR 79.2-86.7 vs. 80.4, IQR 76.5-85.2%; p = 0.05). Conversely, PCSK9 levels >median were associated with a significantly lower proportion of NCM as compared to those with PCSK9
Conclusions: We hereby provide a novel link between PCSK9 regulation, innate immunity and atherosclerotic disease in statin-treated patients.
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http://dx.doi.org/10.1016/j.jacl.2021.02.005DOI Listing
March 2021

THE YEAR IN BASIC VASCULAR BIOLOGY RESEARCH: FROM MECHANORECEPTORS AND NETS TO SMARTPHONE DATA AND OMICS.

Cardiovasc Res 2021 Mar 21. Epub 2021 Mar 21.

Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillian-Universität (LMU) München, German Center for Cardiovascular Research (DZHK), partner site Munich Heart Alliance and Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

2020 has been an extraordinary year. The emergence of COVID-19 has driven urgent research in pulmonary and cardiovascular science and other fields. It has also shaped the way that we work with many experimental laboratories shutting down for several months, while bioinformatics approaches and other large data projects have gained prominence. Despite these setbacks, vascular biology research is stronger than ever. On behalf of the European Society of Cardiology Council for Basic Cardiovascular Science (ESC CBCS), here we review some of the vascular biology research highlights for 2020. This review is not exhaustive and there are many outstanding vascular biology publications that we were unable to cite due to page limits. Notwithstanding this, we have provided a snapshot of vascular biology research excellence in 2020 and identify topics that are in the ascendency and likely to gain prominence in coming years.
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http://dx.doi.org/10.1093/cvr/cvab105DOI Listing
March 2021

Mid-regional pro-atrial natriuretic peptide independently predicts short-term mortality in COVID-19.

Eur J Clin Invest 2021 Mar 3:e13531. Epub 2021 Mar 3.

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

Background: Mid-regional pro-atrial natriuretic peptide (MR-proANP) is a strong prognostic marker in several inflammatory, respiratory and cardiovascular conditions, but has not been studied in COVID-19 yet.

Methods: This prospective, observational study of patients with COVID-19 infection was conducted from 6 June to 26 November 2020 in different wards of a tertiary hospital. MR-proANP, N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitive cardiac troponin I levels on admission were collected and tested for their association with disease severity and 28-day mortality.

Results: A total of 213 eligible patients with COVID-19 were included in the final analyses of whom 13.2% (n = 28) died within 28 days. Median levels of MR-proANP at admission were significantly higher in nonsurvivors (307 pmol/L IQR, [161 - 532] vs 75 pmol/L [IQR, 43 - 153], P < .001) compared to survivors and increased with disease severity and level of hypoxaemia. The area under the ROC curve for MR-proANP predicting 28-day mortality was 0.832 (95% CI 0.753 - 0.912, P < .001). An optimal cut-off point of 160 pmol/L yielded a sensitivity of 82.1% and a specificity of 76.2%. MR-proANP was a significant predictor of 28-day mortality independent of clinical confounders, comorbidities and established prognostic markers of COVID-19 (HR 2.77, 95% CI 1.21 - 6.37; P = .016), while NT-proBNP failed to independently predict 28-day mortality and had a numerically lower AUC compared to MR-proANP.

Conclusion: Higher levels of MR-proANP at admission are associated with disease severity of COVID-19 and act as a powerful and independent prognostic marker of 28-day mortality.
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http://dx.doi.org/10.1111/eci.13531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995001PMC
March 2021

The Prognostic Potential of Atrial Natriuretic Peptide on the Development of Postoperative Atrial Fibrillation after Cardiac Surgery.

Thromb Haemost 2021 Feb 25. Epub 2021 Feb 25.

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

Background:  Postoperative atrial fibrillation (POAF) represents a common complication after cardiac surgery associated with major adverse events and poor patient outcome. Tools for risk stratification of this arrhythmia remain scarce. Atrial natriuretic peptide (ANP) represents an easily assessable biomarker picturing atrial function and strain; however, its prognostic potential on the development of POAF has not been investigated so far.

Methods:  Within the present investigation, 314 patients undergoing elective cardiac surgery were prospectively enrolled. Preoperative mid-region proANP (MR-proANP) values were assessed before the surgical intervention. Patients were followed prospectively and continuously screened for the development of arrhythmic events.

Results:  A total of 138 individuals (43.9%) developed POAF. Median concentrations of MR-proANP were significantly higher within the POAF group ( < 0.001). MR-proANP showed a strong association with the development of POAF with a crude odds ratio (OR) of 1.68 per 1 standard deviation (1-SD; 95% confidence interval [CI]: 1.31-2.15;  < 0.001), which remained stable after comprehensive adjustment for confounders with an adjusted OR of 1.74 per 1-SD (95% CI: 1.17-2.58;  = 0.006). The discriminatory power of MR-proANP for the development of POAF was validated by the category-free net reclassification improvement (0.23 [95% CI: 0.0349-0.4193];  = 0.022) and integrated discrimination increment (0.02 [95% CI: 0.0046-0.0397],  = 0.013).

Conclusion:  MR-proANP proved to be a strong and independent predictor of the development of POAF. Considering a personalized diagnostic and prognostic preoperative work-up, a standardized preoperative evaluation of MR-proANP levels might help to identify patients at risk for development of POAF after cardiac surgery.
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http://dx.doi.org/10.1055/a-1400-6096DOI Listing
February 2021

Biomarkers of coagulation and fibrinolysis in acute myocardial infarction: a joint position paper of the Association for Acute CardioVascular Care and the European Society of Cardiology Working Group on Thrombosis.

Eur Heart J Acute Cardiovasc Care 2020 Nov 7. Epub 2020 Nov 7.

Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Blvd. 161, 8200 Aarhus N, Denmark.

The formation of a thrombus in an epicardial artery may result in an acute myocardial infarction (AMI). Despite major advances in acute treatment using network approaches to allocate patients to timely reperfusion and optimal antithrombotic treatment, patients remain at high risk for thrombotic complications. Ongoing activation of the coagulation system as well as thrombin-mediated platelet activation may both play a crucial role in this context. Whether measurement of circulating biomarkers of coagulation and fibrinolysis could be useful for risk stratification in secondary prevention is currently not fully understood. In addition, measurement of such biomarkers could be helpful to identify thrombus formation as the leading mechanism for AMI. The introduction of biomarkers of myocardial injury such as high-sensitivity cardiac troponins made rule-out of AMI even more precise. However, elevated markers of myocardial injury cannot provide proof of a type 1 AMI, let alone thrombus formation. The combined measurement of markers of myocardial injury with biomarkers reflecting ongoing thrombus formation might be helpful for the fast and correct diagnosis of an atherothrombotic type 1 AMI. This position paper gives an overview of the current knowledge and possible role of biomarkers of coagulation and fibrinolysis for the diagnosis of AMI, risk stratification, and individualized treatment strategies in patients with AMI.
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http://dx.doi.org/10.1093/ehjacc/zuaa025DOI Listing
November 2020

Effects of Nicorandil on Inflammation, Apoptosis and Atherosclerotic Plaque Progression.

Biomedicines 2021 Jan 27;9(2). Epub 2021 Jan 27.

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

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap ( = 0.014), a significant reduction in cholesterol clefts ( = 0.045), and enhanced smooth muscle cell content ( = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In HO challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells ( = 0.016) and the ratio of apoptotic to living cells ( = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 ( = 0.034), lower numbers of apoptotic nuclei ( = 0.040), and reduced 8-oxogunanine staining ( = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis.
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http://dx.doi.org/10.3390/biomedicines9020120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912627PMC
January 2021

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

Effect of marathon and ultra-marathon on inflammation and iron homeostasis.

Scand J Med Sci Sports 2021 Mar 17;31(3):542-552. Epub 2020 Nov 17.

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

The physiological response to high-level endurance exercise, such as running a marathon, poses several beneficial but also potentially harmful metabolic changes. The objective of this study was to determine the impact of marathon (M) and ultra-marathon (UM) on inflammation and iron homeostasis in paired samples. Fifteen well-trained, non-professional endurance athletes (14 males, 1 female) performed both a 130 km ultra-marathon and a traditional 42.195 km marathon. We determined markers of inflammation and iron homeostasis before, immediately after, and within 5 days after finishing each run, respectively. Biomarkers of inflammation (leucocytes, neutrophil granulocytes, monocytes, and c-reactive protein [CRP]) increased significantly after both marathon and ultra-marathon with higher levels of CRP after ultra-marathon compared with marathon both immediately after the race (18.15 ± 12.41 vs 5.58 ± 9.65 mg/L, P < .001) and at follow-up (15.67 ± 16.97 vs 7.19 ± 7.75 mg/L, P = .045) Concentrations of ferritin also increased significantly after both races and remained high at follow-up. Higher levels of ferritin immediately after the race (111.5 ± 103.2 vs 84.8 ± 86.3, P = .001) and at follow-up (102.7 ± 79.5 vs 74.6 ± 65.6, P = .001) were found in ultra-marathon finishers. The observed increase of serum iron and transferrin saturation (TSAT) after marathon and the decrease of serum iron and TSAT after ultra-marathon resulted in a significant absolute difference between the two races. The present data suggest a higher degree of inflammation after ultra-marathon compared with marathon. Markers of iron homeostasis also showed different response patterns with regard to running distance.
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http://dx.doi.org/10.1111/sms.13869DOI Listing
March 2021

Monocyte subsets predict mortality after cardiac arrest.

J Leukoc Biol 2020 Oct 5. Epub 2020 Oct 5.

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

After successful cardiopulmonary resuscitation (CPR), many patients show signs of an overactive immune activation. Monocytes are a heterogeneous cell population that can be distinguished into 3 subsets by flow cytometry (classical monocytes [CM: CD14 CD16 ], intermediate monocytes [IM: CD14 CD16 CCR2 ] and non-classical monocytes [NCM: CD14 CD16 CCR2 ]). Fifty-three patients admitted to the medical intensive care unit (ICU) after cardiac arrest were included. Blood was taken on admission and after 72 h. The primary endpoint of this study was survival at 6 months and the secondary endpoint was neurological outcome as determined by cerebral performance category (CPC)-score at 6 months. Median age was 64.5 (49.8-74.3) years and 75.5% were male. Six-month mortality was 50.9% and survival with good neurological outcome was 37.7%. Monocyte subset distribution upon admission to the ICU did not differ according to survival. Seventy-two hours after admission, patients who died within 6 months showed a higher percentage of the pro-inflammatory subset of IM (8.3% [3.8-14.6]% vs. 4.1% [1.5-8.2]%; P = 0.025), and a lower percentage of CM (87.5% [79.9-89.0]% vs. 90.8% [85.9-92.7]%; P = 0.036) as compared to survivors. In addition, IM were predictive of outcome independent of time to ROSC and witnessed cardiac arrest, and correlated with CPC-score at 6 months (R = 0.32; P = 0.043). These findings suggest a possible role of the innate immune system in the pathophysiology of post cardiac arrest syndrome.
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http://dx.doi.org/10.1002/JLB.5A0420-231RRDOI Listing
October 2020

Assessment of a long-term in vitro model to characterize the mechanical behavior and macrophage-mediated degradation of a novel, degradable, electrospun poly-urethane vascular graft.

J Mech Behav Biomed Mater 2020 12 3;112:104077. Epub 2020 Sep 3.

Center for Biomedical Research, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Institute for Cardiovascular Research, Vienna, Austria. Electronic address:

An assessment tool to evaluate the degradation of biodegradable materials in a more physiological environment is still needed. Macrophages are critical players in host response, remodeling and degradation. In this study, a cell culture model using monocyte-derived primary macrophages was established to study the degradation, macro-/micro-mechanical behavior and inflammatory behavior of a new designed, biodegradable thermoplastic polyurethane (TPU) scaffold, over an extended period of time in vitro. For in vivo study, the scaffolds were implanted subcutaneously in a rat model for up to 36 weeks. TPU scaffolds were fabricated via the electrospinning method. This technique provided a fibrous scaffold with an average fiber diameter of 1.39 ± 0.76 μm and an average pore size of 7.5 ± 1.1 μm. The results showed that TPU scaffolds supported the attachment and migration of macrophages throughout the three-dimensional matrix. Scaffold degradation could be detected in localized areas, emphasizing the role of adherent macrophages in scaffold degradation. Weight loss, molecular weight and biomechanical strength reduction were evident in the presence of the primary macrophage cells. TPU favored the switch from initial pro-inflammatory response of macrophages to an anti-inflammatory response over time both in vitro and in vivo. Expression of MMP-2 and MMP-9 (the key enzymes in tissue remodeling based on ECM modifications) was also evident in vitro and in vivo. This study showed that the primary monocyte-derived cell culture model represents a promising tool to characterize the degradation, mechanical behavior as well as biocompatibility of the scaffolds during an extended period of observation.
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http://dx.doi.org/10.1016/j.jmbbm.2020.104077DOI Listing
December 2020

Immature cell fractions after cessation of chronic P2Y-inhibition in patients with coronary artery diseases.

Platelets 2020 Aug 7:1-6. Epub 2020 Aug 7.

Wilhelminenhospital, 3rd Medical Department with Cardiology , Vienna, AT, Austria.

Changes in circulating cell populations may promote ischemic events that occur soon after discontinuation of P2Y-inhibition. The aim of the study was to track the course of thrombopoietic and erythropoietic cells in patients with coronary artery diseases (CAD) after planned and physician-driven cessation of chronic P2Y-inhibition (clopidogrel 75 mg OD, or prasugrel 10 mg OD, or ticagrelor 90 mg BID). Cell fractions were determined in 62 patients at baseline (the last day of P2Y-inhibitor intake), on day-10, day-30, and day-180 thereafter. Immature platelet fraction (IPF), immature reticulocyte fraction (IRF), reticulocyte hemoglobin content (Ret-Hb) and red blood cell count (RBC) significantly increased from baseline to day-180 (IPF: = .003; IRF: = .013; Ret-Hb: < .001; RBC: = .044). Platelet count, leucocyte count and immature granulocyte fraction did not change over time ( = .561, = .869, and = .161, respectively). Fibrinogen levels significantly declined over time ( = .011), thrombopoietin levels increased in a non-significant manner ( = .379). We did not observe any significant interaction with choice of P2Y-inhibitor, therefore suggesting a drug class-effect. Our data shows, that discontinuation of dual antiplatelet therapy is associated with raised thrombopoietic and erythropoietic activity in the bone marrow, without significant upregulation of thrombopoietin. This provides further evidence for a direct stimulation of precursor cells by P2Yinhibitors.
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http://dx.doi.org/10.1080/09537104.2020.1803252DOI Listing
August 2020

Changes in Circulating Extracellular Vesicles in Patients with ST-Elevation Myocardial Infarction and Potential Effects of Remote Ischemic Conditioning-A Randomized Controlled Trial.

Biomedicines 2020 Jul 16;8(7). Epub 2020 Jul 16.

3rd Department of Medicine, Cardiology and Intensive Care Medicine, Wilhelminenhospital, 1160 Vienna, Austria.

(1) Background: Extracellular vesicles (EVs) have been recognized as a cellular communication tool with cardioprotective properties; however, it is unknown whether cardioprotection by remote ischemic conditioning (RIC) involves EVs. (2) Methods: We randomized patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) to additionally receive a protocol of RIC or a sham-intervention. Blood was taken before and immediately, 24 h, four days and one month after PCI. Additionally, we investigated EVs from healthy volunteers undergoing RIC. EVs were characterized by a high-sensitive flow cytometer (Beckman Coulter Cytoflex S, Krefeld, Germany). (3) Results: We analyzed 32 patients (16 RIC, 16 control) and five healthy volunteers. We investigated platelet-, endothelial-, leukocyte-, monocyte- and granulocyte-derived EVs and their pro-thrombotic sub-populations expressing superficial phosphatidylserine (PS). We did not observe a significant effect of RIC on the numbers of circulating EVs, although granulocyte-derived EVs were significantly higher in the RIC group. In line, RIC had not impact on EVs in healthy volunteers. Additionally, we observed changes of PS/PEV, EEVs and PS/CD15 EVs irrespective of RIC with time following STEMI. 4) Conclusion: We provide further insights into the course of different circulating EVs during the acute and sub-acute phases of STEMI. With respect to the investigated EV populations, RIC seems to have no effect, with only minor differences found for granulocyte EVs.
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http://dx.doi.org/10.3390/biomedicines8070218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400268PMC
July 2020

Neutrophil Extracellular Trap Degradation by Differently Polarized Macrophage Subsets.

Arterioscler Thromb Vasc Biol 2020 09 16;40(9):2265-2278. Epub 2020 Jul 16.

From the Division of Cardiology, Department of Medicine II (P. Haider, J.B.K.-P., J.M., M.R., C.K., W.S.S., C.H., J.W., P. Hohensinner), Medical University of Vienna, Austria.

Objective: Macrophages are immune cells, capable to remodel the extracellular matrix, which can harbor extracellular DNA incorporated into neutrophil extracellular traps (NETs). To study the breakdown of NETs we studied the capability of macrophage subsets to degrade these structures in vitro and in vivo in a murine thrombosis model. Furthermore, we analyzed human abdominal aortic aneurysm samples in support of our in vitro and in vivo results. Approach and Results: Macrophages were seeded onto blood clots or isolated NETs and polarized. All macrophages were capable to degrade NETs. For initial breakdown, macrophages relied on extracellular deoxyribonucleases. Proinflammatory polarization enhanced NET degradation. The boost in degradation was because of increased macropinocytosis, as inhibition by imipramine diminished their NET breakdown. Inhibition of macropinocytosis in a murine thrombosis model led to increased NET burden and reduced thrombus resolution in vivo. When analyzing abdominal aortic aneurysm samples, macrophage density furthermore corresponded negatively with the amount of local NETs in the intraluminal thrombi as well as in the vessel wall, as increased macrophage density was associated with a reduction in NET burden.

Conclusions: We provide evidence that macrophages degrade NETs by extracellular predigestion and subsequent uptake. Furthermore, we show that proinflammatory macrophages increase NET degradation through enhanced macropinocytosis, priming them for NET engulfment. Based on our findings, that inhibition of macropinocytosis in mice corresponded to increased NET amounts in thrombi and that local macrophage density in human abdominal aortic aneurysm is negatively associated with surrounding NETs, we hypothesize, that macrophages are able to degrade NETs in vivo.
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http://dx.doi.org/10.1161/ATVBAHA.120.314883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447175PMC
September 2020

Tenascin-C aggravates ventricular dilatation and angiotensin-converting enzyme activity after myocardial infarction in mice.

ESC Heart Fail 2020 10 8;7(5):2113-2122. Epub 2020 Jul 8.

Ludwig Boltzmann Institute for Cardiovascular Research, Medical University of Vienna, Waehringer Guertel 18-20, 1Q, Vienna, 1090, Austria.

Aims: Tenascin-C (TN-C) is suggested to be detrimental in cardiac remodelling after myocardial infarction (MI). The aim of this study is to reveal the effects of TN-C on extracellular matrix organization and its haemodynamic influence in an experimental mouse model of MI and in myocardial cell culture during hypoxic conditions.

Methods And Results: Myocardial infarction was induced in TN-C knockout (TN-C KO) and wild-type mice. Six weeks later, cardiac function was studied by magnetic resonance imaging and under isolated working heart conditions. Myocardial mRNA levels and immunoreactivity of TN-C, TIMP-1, TIMP-3, and matrix metalloproteinase (MMP)-9, as well as serum and tissue activities of angiotensin-converting enzyme (ACE), were determined at 1 and 6 weeks after infarction. Cardiac output and external heart work were higher, while left ventricular wall stress and collagen expression were decreased (P < 0.05) in TN-C KO mice as compared with age-matched controls at 6 weeks after infarction. TIMP-1 expression was down-regulated at 1 and 6 weeks, and TIMP-3 expression was up-regulated at 1 week (P < 0.01) after infarction in knockout mice. MMP-9 level was lower in TN-C KO at 6 weeks after infarction (P < 0.05). TIMP-3/MMP-9 ratio was higher in knockout mice at 1 and 6 weeks after infarction (P < 0.01). ACE activity in the myocardial border zone (i.e. between scar and free wall) was significantly lower in knockout than in wild-type mice 1 week after MI (P < 0.05).

Conclusions: Tenascin-C expression is induced by hypoxia in association with ACE activity and MMP-2 and MMP-9 elevations, thereby promoting left ventricular dilatation after MI.
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http://dx.doi.org/10.1002/ehf2.12794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524253PMC
October 2020

The ISTH DIC score predicts outcome in non-septic patients admitted to a cardiovascular intensive care unit.

Eur J Intern Med 2020 09 1;79:37-42. Epub 2020 Jul 1.

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

Background: The International Society of Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score is widely used to predict mortality in critically ill - typically septic - patients. The objective of this study was to investigate whether the ISTH DIC-2001 and DIC-2018 score can be used to predict the 30-day mortality in non-septic patients in an intensive care unit (ICU).

Methods: In this single-center, prospective observational study we included all patients ≥18 years of age who were admitted to a medical ICU with a focus on cardiovascular diseases between August 2012 and 2013. The DIC-2001 and DIC-2018 scores were calculated on admission (DIC-2001-0h and DIC-2018-0h) and 72 hours thereafter (DIC-2001-72h and DIC-2018-72h) and were classified as overt when ≥ 5 for DIC-2001 and ≥ 4 for DIC-2018.

Results: A total of 233 patients were included in this study. Excluding septic patients and patients after routine surgery/procedures, we calculated the DIC score for 167 patients (32.4% female; median age 64.9 years). Overt DIC-2001-0h, DIC-2018-0h and overt DIC-2001-72h scores were associated with a significantly higher 30-day mortality rate (52.9% vs. 25.0%, 46.2% vs 21.2%, and 57.1% vs. 23.7%; p < 0.04). The DIC-2001 scores and the DIC-2018-0h score significantly predicted the 30-day mortality.

Conclusion: This study suggests that the DIC score may be applied to non-septic ICU populations, and indicates that it is a useful tool for mortality prediction, regardless of the underlying disease.
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http://dx.doi.org/10.1016/j.ejim.2020.06.017DOI Listing
September 2020

CD8+CD28null T Lymphocytes are Associated with the Development of Atrial Fibrillation after Elective Cardiac Surgery.

Thromb Haemost 2020 Aug 28;120(8):1182-1187. Epub 2020 Jun 28.

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

Background:  Postoperative atrial fibrillation (POAF) is assumed as a complex and multifactorial interaction of different pathogenic factors. Data suggests an inflammatory process as the main trigger of this specific type of atrial fibrillation. CD8 T lymphocytes that lack the surface protein CD28 were found to be crucially involved in chronic inflammatory processes within the cardiovascular system. Of utmost interest, these so-called CD8CD28 T cells are known to present with autoaggressive behavior and deleterious cytotoxic effects on human tissue.

Methods:  A total of 129 patients undergoing elective cardiac valve and/or coronary artery bypass graft surgery were enrolled. Fluorescence-activated cell sorting was performed to investigate lymphocyte subsets. Patients were stratified in two subgroups according to patients developing POAF ( = 60) and individuals free of POAF ( = 69).

Results:  Comparing patients developing POAF to individuals free of POAF, the fraction of CD8 lymphocytes was significantly higher in individuals developing POAF (30.5% [POAF] vs. 25.7% [no-POAF];  = 0.021). Interestingly, also the fraction of CD8CD28 T lymphocytes was significantly higher in the POAF subgroup (66.7% [POAF] vs. 61.6% [non-POAF];  = 0.043). Multivariate logistic regression proved that the fraction of CD8CD28 cells is a strong and independent prognosticator for the development of POAF with an adjusted odds ratio per 1 standard deviation of 3.21 (95% confidence interval 1.01-10.18;  = 0.048).

Conclusion:  We found that cytotoxic CD8CD28 T lymphocytes proved to be a strong and independent predictor for the development of POAF after elective cardiac surgery. Our results potentially indicate an autoimmune impact of this preexisting, highly cytotoxic T cell subset in the pathogenesis of POAF.
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http://dx.doi.org/10.1055/s-0040-1713096DOI Listing
August 2020

Epinephrine treatment but not time to ROSC is associated with intestinal injury in patients with cardiac arrest.

Resuscitation 2020 10 6;155:32-38. Epub 2020 Jun 6.

Department of Internal Medicine II - Division of Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address:

Aim: Current guidelines suggest the use of epinephrine in patients with cardiac arrest (CA). However, evidence for increased survival in good neurological condition is lacking. In experimental settings, epinephrine-induced impairment of microvascular flow was shown. The aim of our study was to analyze the association between epinephrine treatment and intestinal injury in patients after CA.

Methods: We have included 52 patients with return of spontaneous circulation (ROSC) after CA admitted to our medical intensive care unit (ICU). Blood was taken on admission and levels of circulating intestinal fatty acid binding protein (iFABP) were analyzed.

Results: Patients were 64 (49.8-73.8) years old and predominantly male (76.9%). After six months, 50% of patients died and 38.5% of patients had a cerebral performance category (CPC)-score of 1-2. iFABP levels were lower in survivors (234 IQR 90-399 pg/mL) as compared to non-survivors (283, IQR 86-11500 pg/mL; p < 0.05). Plasma levels of iFABP were not associated with time to ROSC but correlated with epinephrine-dose (R = 0.32; p < 0.05). 40% of patients receiving ≥3 mg of epinephrine as compared to 10.5% of patients treated with <3 mg (p < 0.05) developed iFABP plasma levels >1500 pg/mL, which was associated with dramatically increased mortality (HR4.87, 95%CI 1.95-12.1; p < 0.001). iFABP levels predicted mortality independent from time to ROSC and the disease severity score SAPS II. In contrast to mortality, iFABP plasma levels were not associated with neurological outcome.

Conclusions: In this small, single centre study, cumulative dose of epinephrine used in cardiac arrest patients was associated with an increase in biomarker indicative of intestinal injury and 6-month mortality.
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http://dx.doi.org/10.1016/j.resuscitation.2020.05.046DOI Listing
October 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

Inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in ACS.

Platelets 2020 Jun 5:1-9. Epub 2020 Jun 5.

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

Inflammation leads to atherosclerosis and acute coronary syndromes (ACS). We performed a prospective, observational study to assess association between the concentrations of inflammatory markers (high sensitivity C-reactive protein, hsCRP; high sensitivity interleukin6, hsIL-6; soluble CD40 ligand, sCD40 L) and platelet reactivity in 338 patients with ACS treated with ticagrelor and prasugrel. We also assessed whether hsCRP, hsIL-6, and sCD40 L are associated with standard inflammatory markers (white blood cell [WBC] and fibrinogen), and whether they differ according to patient diabetic status and pre-treatment with statins. Concentrations of hsCRP and concentrations of hsIL-6 and sCD40 L were assessed using turbidimetric assay and enzyme-linked immunosorbent assay, respectively. Platelet reactivity was measured using multiple electrode aggregometry. There was only a weak inverse correlation between hsIL-6 and platelet reactivity (r≤-0.125). In contrast, concentration of hsIL6 and hsCRP positively correlated with WBC count and fibrinogen (r ≥ 0.199). Insulin-dependent diabetes mellitus (IDDM) was associated with higher concentration of hsIL-6 ( = .014), whereas pre-treatment with statins - with lower concentration of hsIL-6 ( = .035). In conclusion, inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in the acute phase of ACS, confirming the safety and efficacy of potent P2Y12 inhibitors in patients with a high inflammatory burden.
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http://dx.doi.org/10.1080/09537104.2020.1766670DOI Listing
June 2020

The adipokine vaspin is associated with decreased coronary in-stent restenosis in vivo and inhibits migration of human coronary smooth muscle cells in vitro.

PLoS One 2020 11;15(5):e0232483. Epub 2020 May 11.

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

Background: Percutaneous coronary intervention represents the most important treatment modality of coronary artery stenosis. In-stent restenosis (ISR) is still a limitation for the long-term outcome despite the introduction of drug eluting stents. It has been shown that adipokines directly influence vessel wall homeostasis by influencing the function of endothelial cells and arterial smooth muscle cells. Visceral adipose tissue-derived serpin vaspin was recently identified as a member of serine protease inhibitor family and serveral studies could demonstrate a relation to metabolic diseases. The aim of this study was to investigate a role of vaspin in the development of in-stent restenosis in vivo and on migration of smooth muscle cells and endothelial cells in vitro.

Methods: We studied 85 patients with stable coronary artery disease who underwent elective and successful PCI with implatation of drug eluting stents. Blood samples were taken directly before PCI. Vaspin plasma levels were measured by specific ELISA. ISR was evaluated eight months later by coronary angiography. Human coronary artery smooth muscle cells (HCASMC) and human umbilical vein endothelial cells (HUVEC) migration was analyzed by an in-vitro migration assay with different concentrations (0.004ng/mL up to 40ng/mL) of vaspin as well as by an scratch assay. For proliferation an impedance measurement with specialiced E-Plates was performed.

Results: During the follow up period, 14 patients developed ISR. Patients with ISR had significantly lower vaspin plasma levels compared to patients without ISR (0.213 ng/ml vs 0.382 ng/ml; p = 0.001). In patients with plasma vaspin levels above 1.35 ng/ml we could not observe any restenosis. There was also a significant correlation of plasma vaspin levels and late lumen loss in the stented coronary segments. Further we could demonstrate that vaspin nearly abolishes serum induced migration of HCASMC (100% vs. 9%; p<0.001) in a biphasic manner but not migration of HUVEC. Proliferation of HCASMC and HUVEC was not modulated by vaspin treatment.

Conclusion: We were able to show that the adipokine vaspin selectively inhibits human coronary SMC migration in vitro and has no effect on HUVEC migration. Vaspin had no effect on proliferation of HUVEC which is an important process of the healing of the stented vessel. In addition, the occurrence of ISR after PCI with implantation of drug eluting stents was significantly associated with low vaspin plasma levels before intervention. Determination of vaspin plasma levels before PCI might be helpful in the identification of patients with high risk for development of ISR after stent implantation. In addition, the selective effects of vaspin on smooth muscle cell migration could potentially be used to reduce ISR without inhibition of re-endothelialization of the stented segment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232483PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213727PMC
July 2020

Macrophages and Thrombin-Another Link between Inflammation and Coagulation.

Authors:
Johann Wojta

Thromb Haemost 2020 04 14;120(4):537. Epub 2020 Apr 14.

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

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http://dx.doi.org/10.1055/s-0040-1708551DOI Listing
April 2020

Impact of ultra-marathon and marathon on biomarkers of myocyte necrosis and cardiac congestion: a prospective observational study.

Clin Res Cardiol 2020 Nov 8;109(11):1366-1373. Epub 2020 Apr 8.

3rd Medical Department, Cardiology and Intensive Care Medicine, Wilhelminen Hospital, Montleartstrasse 37, 1160, Vienna, Austria.

Background: An elevation of cardiac biomarkers is observed after intense or long-lasting physical activity. However, a recent meta-analysis has suggested that there might be an inverse relationship between duration of exercise and degree of biomarker elevation. The objective of this observational study was to investigate the impact of ultra-marathon (UM) vs. marathon (M) on biomarkers of myocyte necrosis and hemodynamic stress/congestion.

Methods: Well-trained endurance athletes were recruited to participate in a 130-km UM and a M run. Troponin I (TnI), creatine kinase (CK), N-terminal pro-brain natriuretic peptide (NT-proBNP), mid-regional pro-adrenomedullin (MR-proADM), and copeptin were measured after both events, respectively.

Results: Fifteen athletes (14 males, one female) were included. There was no difference in exercise intensity according to the Borg scale (UM 16 [IQR 15-17], M 16 [IQR 14-17]; p = 0.424). Biomarkers of myocyte necrosis both differed significantly with higher levels of TnI (UM 0.056 ng/L [IQR 0.022-0.104), M 0.028 ng/L [IQR 0.022-0.049]; p = 0.016) and CK (UM 6992 U/l [IQR 2886-23038], M 425 U/l [IQR 327-681]; p = 0.001) after UM compared to M. Also, NT-proBNP (UM 723 ng/L [IQR 378-1152], M 132 ng/L [IQR 64-198]; p = 0.001) and MR-proADM (UM 1.012 nmol/L [IQR 0.753-0.975], M 0.877 nmol/L [IQR 0.550-0.985]; p = 0.023) as markers of myocardial congestion were significantly higher after UM. There was a tendency for elevated copeptin levels after M, but did not reach statistical significance (p = 0.078).

Conclusion: Ultra-marathon is associated with higher levels of biomarkers of myocyte necrosis and cardiac congestion compared to marathon, highlighting the impact of exercise duration on the cardiovascular system.
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http://dx.doi.org/10.1007/s00392-020-01634-9DOI Listing
November 2020

The Prognostic Impact of Circulating Regulatory T Lymphocytes on Mortality in Patients with Ischemic Heart Failure with Reduced Ejection Fraction.

Mediators Inflamm 2020 10;2020:6079713. Epub 2020 Feb 10.

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

Background: Heart failure with reduced ejection fraction (HFrEF) constitutes a global health issue. While proinflammatory cytokines proved to have a pivotal role in the development and progression of HFrEF, less attention has been paid to the cellular immunity. Regulatory T lymphocytes (Tregs) seem to have an important role in the induction and maintenance of immune homeostasis. Therefore, we aimed to investigate the impact of Tregs on the outcome in HFrEF.

Methods: We prospectively enrolled 112 patients with HFrEF and performed flow cytometry for cell phenotyping. Individuals were stratified in ischemic (iHFrEF, = 57) and nonischemic etiology (niHFrEF, = 57) and nonischemic etiology (niHFrEF.

Results: Comparing patients with iHFrEF to niHFrEF, we found a significantly lower fraction of Tregs within lymphocytes in the ischemic subgroup (0.42% vs. 0.56%; = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92; = 0.009). After a mean follow-up time of 4.5 years, 32 (28.6%) patients died due to cardiovascular causes. We found that Tregs were significantly associated with cardiovascular survival in the entire study cohort with an adjusted HR per one standard deviation (1-SD) of 0.60 (95% CI: 0.39-0.92.

Conclusion: Our results indicate a potential influence of Tregs in the pathogenesis and progression of iHFrEF, fostering the implication of cellular immunity in iHFrEF pathophysiology and proving Tregs as a predictor for long-term survival among iHFrEF patients. A preview of this study has been presented at a meeting of the European Society of Cardiology earlier this year.
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http://dx.doi.org/10.1155/2020/6079713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035577PMC
November 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

Lipoprotein(a) plasma levels are not associated with survival after acute coronary syndromes: An observational cohort study.

PLoS One 2020 9;15(1):e0227054. Epub 2020 Jan 9.

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

Background: Lipoprotein(a) [Lp(a)] is associated with coronary artery disease in population studies, however studies on its predictive value in patients with cardiovascular disease, in particular after acute coronary syndromes (ACS), are conflicting. The aim of this study was to investigate whether Lp(a) is associated with survival after ACS.

Methods And Results: We analyzed Lp(a) measurement in 1,245 patients who underwent coronary angiography for ACS. The median follow-up for cardiovascular and all-cause mortality was 5.0 (IQR 3.2-8.0) years. 655 (52.6%) presented with ST-segment elevation myocardial infarction (STEMI), 424 (34.1%) with Non-ST-segment elevation myocardial infarction (NSTEMI) and 166 (13.3%) underwent coronary angiography for unstable angina. Cardiovascular mortality was 9.1% and all-cause mortality was 15.7%. Patients were stratified into four groups to their Lp(a) levels. (≤15mg/dL, >15-30mg/dL, >30-60mg/dL, and >60mg/dL). Multivessel disease was significantly more common in patients with Lp(a)>60mg/dL (p<0.05). Increased levels of Lp(a) were not associated with cardiovascular mortality (HR compared with Lp(a) ≤15mg/dL were 1.2, 1.2, and 1.0, respectively; p = 0.69) and not with all-cause mortality (HR compared with Lp(a) ≤15mg/dL were 1.2, 1.2, and 1.2, respectively; p = 0.46).

Conclusions: Lp(a) levels at time of ACS were neither associated with cardiovascular nor with all-cause mortality. Although Lp(a) has been shown to be associated with incidence of coronary artery disease, this study does not support any role of Lp(a) as a risk factor for mortality after ACS. This should be taken into account for development of outcome studies for agents targeting Lp(a) plasma levels.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227054PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952077PMC
April 2020

Long Term Evaluation of Nanofibrous, Bioabsorbable Polycarbonate Urethane Grafts for Small Diameter Vessel Replacement in Rodents.

Eur J Vasc Endovasc Surg 2020 04 23;59(4):643-652. Epub 2019 Dec 23.

Centre for Biomedical Research, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Cardiovascular Research, Medical University of Vienna, Vienna, Austria. Electronic address:

Objective: Biodegradable materials for in situ vascular tissue engineering could meet the increasing clinical demand for sufficient synthetic small diameter vascular substitutes in aortocoronary bypass and peripheral vascular surgery. The aim of this study was to design a new degradable thermoplastic polycarbonate urethane (dPCU) with improved biocompatibility and optimal biomechanical properties. Electrospun conduits made from dPCU were evaluated in short and long term follow up and compared with expanded polytetrafluoroethylene (ePTFE) controls.

Methods: Both conduits were investigated prior to implantation to assess their biocompatibility and inflammatory potential via real time polymerase chain reaction using a macrophage culture. dPCU grafts (n = 28) and ePTFE controls (n = 28) were then implanted into the infrarenal abdominal aorta of Sprague-Dawley rats. After seven days, one, six, and 12 months, grafts were analysed by histology and immunohistochemistry (IHC) and assessed biomechanically.

Results: Anti-inflammatory signalling was upregulated in dPCU conduits and increased significantly over time in vitro. dPCU and ePTFE grafts offered excellent long and short term patency rates (92.9% in both groups at 12 months) in the rat model without dilatation or aneurysm formation. In comparison to ePTFE, dPCU grafts showed transmural ingrowth of vascular specific cells resulting in a structured neovessel formation around the graft. The graft material was slowly reduced, while the compliance of the neovessel increased over time.

Conclusion: The newly designed dPCU grafts have the potential to be safely applied for in situ vascular tissue engineering applications. The degradable substitutes showed good in vivo performance and revealed desirable characteristics such as biomechanical stability, non-thrombogenicity, and minimal inflammatory response after long term implantation.
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http://dx.doi.org/10.1016/j.ejvs.2019.11.004DOI Listing
April 2020

Plasma Levels of snoRNAs are Associated with Platelet Activation in Patients with Peripheral Artery Disease.

Int J Mol Sci 2019 Nov 27;20(23). Epub 2019 Nov 27.

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

In addition to supervised walking therapy, antithrombotic therapy and the management of risk factors, the treatment of peripheral artery disease (PAD) is limited to endovascular and surgical interventions, i.e., angioplasty with stent implantation and bypass surgery, respectively. Both are associated with a high restenosis rate. Furthermore, patients with PAD often suffer atherothrombotic events like myocardial infarction, transient ischemic attacks or stroke. Small ribonucleic acids (RNAs) have proven reliable biomarkers because of their remarkable stability. Small nucleolar RNAs (snoRNAs) guide modifications to small nuclear RNAs and ribosomal RNAs, enabling protein synthesis. In the current study, we measured four snoRNAs in 104 consecutive PAD patients who underwent elective infrainguinal angioplasty with stent implantation. We selected snoRNAs that showed significant overexpression in the plasma of end-stage PAD patients in a previous study. All four snoRNAs are transcribed from the 14q32 locus, which is strongly linked to human cardiovascular disease, including PAD and restenosis. We showed that the four selected 14q32 snoRNAs were abundantly expressed in the plasma of PAD patients. The plasma levels of these snoRNAs were not directly associated with target vessel restenosis, however, levels of SNORD113.2 and SNORD114.1 were strongly linked to platelet activation, which is an important determinant of long-term outcome, in PAD, and in cardiovascular disease in general.
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http://dx.doi.org/10.3390/ijms20235975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929168PMC
November 2019