Publications by authors named "Andreas Mangold"

27 Publications

  • Page 1 of 1

Culprit site extracellular DNA and microvascular obstruction in ST-elevation myocardial infarction.

Cardiovasc Res 2021 Jun 26. Epub 2021 Jun 26.

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

Aims: Extracellular chromatin and deoxyribonuclease (DNase) have been identified as important players of thrombosis, inflammation and homeostasis in a murine model. We previously demonstrated that activated neutrophils release neutrophil extracellular traps (NETs) at the culprit site in ST elevation myocardial infarction (STEMI), which significantly contribute to extracellular chromatin burden, and are associated with larger infarcts. To understand the correlation between neutrophil activation, extracellular chromatin and infarct size (IS), we investigated these parameters in a porcine myocardial infarction model, and at different time points and sites in a prospective STEMI trial with cardiac magnetic resonance (CMR) endpoints.

Methods And Results: In a prospective STEMI trial (NCT01777750), 101 STEMI patients were included and blood samples were obtained from first medical contact until 6 months after primary percutaneous coronary intervention (pPCI) including direct sampling from the culprit site. CMR was performed 4 ± 2 days and 6 months after pPCI. Neutrophil counts, markers of extracellular chromatin and inflammation were measured. Double-stranded DNA (dsDNA), citrullinated histone 3, nucleosomes, myeloperoxidase, neutrophil elastase and interleukin (IL)-6 were significantly increased, while DNase activity was significantly decreased at the culprit site in STEMI patients. High neutrophil counts and dsDNA levels at the culprit site correlated with high microvascular obstruction (MVO) and low ejection fraction (EF). High DNase activity at the culprit site correlated with low MVO and high EF.In correspondence, dsDNA correlated with IS in the porcine myocardial infarction model. In porcine infarcts, neutrophils and extracellular chromatin were detected in congested small arteries corresponding with MVO. Markers of neutrophil activation, extracellular chromatin, DNase activity and CMR measurements correlated with markers of systemic inflammation C-reactive protein and IL-6 in patients.

Conclusions: NETs and extracellular chromatin are important determinants of MVO in STEMI. Rapid degradation of extracellular chromatin by DNases appears to be crucial for microvascular patency and outcome.

Translational Perspective: We show that NETs and extracellular DNA obstruct microvessels in the porcine myocardial infarction model and is connected to increased infarct size. We are able to prove this observation in human STEMI patients. DNase is capable to counteract these effects. Extracellular DNA could be a new treatment target in STEMI.
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http://dx.doi.org/10.1093/cvr/cvab217DOI Listing
June 2021

Exploratory echocardiographic strain parameters for the estimation of myocardial infarct size in ST-elevation myocardial infarction.

Clin Cardiol 2021 Jul 12;44(7):925-931. Epub 2021 Jun 12.

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

Background: Outcome after ST-elevation myocardial infarction (STEMI) can be most reliably estimated by cardiac magnetic resonance (CMR) imaging. However, CMR is expensive, laborious, and has only limited availability. In comparison, transthoracic echocardiography (TTE) is widely available and cost-efficient.

Hypothesis: TTE strain parameters can be used as surrogate markers for CMR-measured parameters after STEMI.

Methods: TTE strain analysis was performed of patients included in a controlled, prospective STEMI trial (NCT01777750) 4 ± 2 days after the event. Longitudinal peak strain (LPS), post-systolic shortening, early systolic lengthening, early systolic lengthening time, and time to peak shortening were measured, and index parameters were computed. Global longitudinal strain (GLS) and ejection fraction (EF) were compiled. Parameters were correlated with CMR-measured variables 4 ± 2 days after STEMI.

Results: In 70 STEMI patients, high quality CMR and TTE data were available. Highest correlation with CMR-measured infarct size was observed with GLS (r = 0.577, p < 0.0001), LPS (r = 0.571, p < 0.0001), and EF (r = -0.533, p < 0.0001). Highest correlation with CMR-measured area at risk was observed with GLS (r = 0.666, p < 0.0001), LPS (0.661, p < 0.0001) and early systolic lengthening index (r = 0.540, p < 0.0001). Receiver operating characteristics for the detection of large infarcts (quartile with highest infarct size) showed the highest area under the curve for LPS, GLS, EF, and myocardial dysfunction index. Multiple linear regression displayed the best association between GLS and infarct size.

Conclusion: Exploratory strain parameters significantly correlate with CMR-measured area at risk and infarct size and are of potential interest as endpoint variables in clinical trials.
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http://dx.doi.org/10.1002/clc.23608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259148PMC
July 2021

Deoxyribonuclease is prognostic in patients undergoing transcatheter aortic valve replacement.

Eur J Clin Invest 2021 Jun 8:e13595. Epub 2021 Jun 8.

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

Degenerative aortic valve stenosis is an inflammatory process that resembles atherosclerosis. Neutrophils release their DNA upon activation and form neutrophil extracellular traps (NETs), which are present on degenerated aortic valves. NETs correlate with pressure gradients in severe aortic stenosis. Transcatheter aortic valve replacement (TAVR) is an established treatment option for aortic valve stenosis. Bioprosthetic valve deterioration promoted by inflammatory, fibrotic and thrombotic processes limits outcome. Deoxyribonuclease is a natural counter mechanism to degrade DNA in circulation. In the present observational study, we investigated plasma levels of double-stranded DNA, deoxyribonuclease activity and outcome after TAVR. 345 consecutive patients undergoing TAVR and 100 healthy reference controls were studied. Double-stranded DNA was measured by fluorescence assays in plasma obtained at baseline and after TAVR. Deoxyribonuclease activity was measured at baseline using single radial enzyme diffusion assays. Follow-up was performed at 12 months, and mean aortic pressure gradient and survival were evaluated. Receiver operating characteristic, Kaplan-Meier curves and Cox regression models were calculated. Baseline double-stranded DNA in plasma was significantly higher compared to healthy controls, was increased at 3 and 7 days after TAVR, and declined thereafter. Baseline deoxyribonuclease activity was decreased compared to healthy controls. Interestingly, low deoxyribonuclease activity correlated with higher C-reactive protein and higher mean transaortic gradient after 12 months. Finally, deoxyribonuclease activity was a strong independent predictor of outcome 12 months after TAVR. Deoxyribonuclease activity is a potential biomarker for risk stratification after TAVR. Pathomechanisms of bioprosthetic valve deterioration involving extracellular DNA and deoxyribonuclease merit investigation.
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http://dx.doi.org/10.1111/eci.13595DOI Listing
June 2021

Deoxyribonuclease 1 Q222R single nucleotide polymorphism and long-term mortality after acute myocardial infarction.

Basic Res Cardiol 2021 04 23;116(1):29. Epub 2021 Apr 23.

Department of Cardiology, Division of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Upon activation, neutrophils release neutrophil extracellular traps (NETs), which contribute to circulating DNA burden and thrombosis, including ST-segment elevation myocardial infarction (STEMI). Deoxyribonuclease (DNase) 1 degrades circulating DNA and NETs. Lower DNase activity correlates with NET burden and infarct size. The DNase 1 Q222R single nucleotide polymorphism (SNP), impairing DNase 1 function, is linked with myocardial infarction. We assessed whether the Q222R SNP is connected to increased NET burden in STEMI and influences long-term outcomes. We enrolled 711 STEMI patients undergoing primary percutaneous coronary intervention (pPCI), and 1422 controls. Genotyping was performed for DNase 1 Q222R SNP. DNase activity, double-stranded (ds)DNA and citrullinated histone H3 were determined in culprit site and peripheral plasma during pPCI. The association of the Q222R variant on cardiovascular and all-cause mortality was assessed by multivariable Cox regression adjusted for cardiovascular risk factors. Homozygous Q222R DNase 1 variant was present in 64 (9.0%) STEMI patients, at the same frequency as in controls. Patients homozygous for Q222R displayed less DNase activity and increased circulating DNA burden. In overall patients, median survival was 60 months. Homozygous Q222R variant was independently associated with cardiovascular and all-cause mortality after STEMI. dsDNA/DNase ratio independently predicted cardiovascular and all-cause mortality. These findings highlight that the Q222R DNase 1 SNP is associated with increased NET burden and decreased compensatory DNase activity, and may serve as an independent risk factor for poor outcome after STEMI.
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http://dx.doi.org/10.1007/s00395-021-00864-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064981PMC
April 2021

Neutrophil extracellular traps promote fibrous vascular occlusions in chronic thrombosis.

Blood 2021 02;137(8):1104-1116

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

Acute pulmonary embolism generally resolves within 6 months. However, if the thrombus is infected, venous thrombi transform into fibrotic vascular obstructions leading to chronic deep vein thrombosis and/or chronic thromboembolic pulmonary hypertension (CTEPH), but precise mechanisms remain unclear. Neutrophils are crucial in sequestering pathogens; therefore, we investigated the role of neutrophil extracellular traps (NETs) in chronic thrombosis. Because chronic pulmonary thrombotic obstructions are biologically identical to chronic deep venous thrombi, the murine inferior vena cava ligation model was used to study the transformation of acute to chronic thrombus. Mice with staphylococcal infection presented with larger thrombi containing more neutrophils and NETs but less resolution. Targeting NETs with DNase1 diminished fibrosis and promoted thrombus resolution. For translational studies in humans, we focused on patients with CTEPH, a severe type of deep venous and pulmonary artery fibrotic obstruction after thrombosis. Neutrophils, markers of neutrophil activation, and NET formation were increased in CTEPH patients. NETs promoted the differentiation of monocytes to activated fibroblasts with the same cellular phenotype as fibroblasts from CTEPH vascular occlusions. RNA sequencing of fibroblasts isolated from thrombo-endarterectomy specimens and pulmonary artery biopsies revealed transforming growth factor-β (TGF-β) as the central regulator, a phenotype which was replicated in mice with fibroblast-specific TGF-β overactivity. Our findings uncover a role of neutrophil-mediated inflammation to enhance TGF-β signaling, which leads to fibrotic thrombus remodeling. Targeting thrombus NETs with DNases may serve as a new therapeutic concept to treat thrombosis and prevent its sequelae.
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http://dx.doi.org/10.1182/blood.2020005861DOI Listing
February 2021

Neutrophil Extracellular Traps Induce MCP-1 at the Culprit Site in ST-Segment Elevation Myocardial Infarction.

Front Cell Dev Biol 2020 9;8:564169. Epub 2020 Nov 9.

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

Background: Leukocyte-mediated inflammation is crucial in ST-segment elevation myocardial infarction (STEMI). We recently observed that neutrophil extracellular traps (NETs) are increased at the culprit site, promoting activation and differentiation of fibrocytes, cells with mesenchymal and leukocytic properties. Fibrocyte migration is mediated by monocyte chemoattractant protein (MCP)-1 and C-C chemokine receptor type 2 (CCR2). We investigated the interplay between NETs, fibrocyte function, and MCP-1 in STEMI.

Methods: Culprit site and peripheral blood samples of STEMI patients were drawn during primary percutaneous coronary intervention. MCP-1 and the NET marker citrullinated histone H3 (citH3) were measured by ELISA while double-stranded DNA was stained with a fluorescent dye. The influence of MCP-1 on NET formation was assessed using isolated healthy donor neutrophils. Human coronary artery endothelial cells (hCAECs) were stimulated with isolated NETs, and MCP-1 gene expression was measured by ELISA and qPCR. CCR2 expression of culprit site and peripheral blood fibrocytes was characterized by flow cytometry. Healthy donor fibrocyte receptor expression and chemotaxis were investigated in response to stimulation with MCP-1 and NETs

Results: NETs and concentrations of MCP-1 were increased at the culprit site of 50 consecutive STEMI patients. NET stimulation of hCAECs induced transcription of ICAM-1, IL-6, and MCP-1, and secretion of MCP-1. MCP-1 promoted NET formation of healthy donor neutrophils . An increasing MCP-1 gradient correlated with fibrocyte accumulation at the culprit site. Locally increased MCP-1 levels were negatively correlated with CCR2 expression on fibrocytes. MCP-1 and NETs induced CCR2 downregulation on fibrocytes . NETs did not function as a chemotactic stimulus for fibrocytes or monocytes and could block migration in response to MCP-1 for both cell populations.

Conclusion: NETs function as signaling scaffolds at the culprit site of STEMI. NETs assist MCP-1 and ICAM-1 release from culprit site coronary artery endothelial cells. MCP-1 facilitates further NETosis. Monocytes enter the culprit site along an MCP-1 gradient, to transdifferentiate into fibrocytes in the presence of NETs.
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http://dx.doi.org/10.3389/fcell.2020.564169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680894PMC
November 2020

Monocyte subsets predict mortality after cardiac arrest.

J Leukoc Biol 2021 Jun 5;109(6):1139-1146. 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247267PMC
June 2021

Neutrophil Extracellular Trap Formation Correlates with Favorable Overall Survival in High Grade Ovarian Cancer.

Cancers (Basel) 2020 Feb 21;12(2). Epub 2020 Feb 21.

Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria.

It is still a question of debate whether neutrophils, often found in the tumor microenvironment, mediate tumor-promoting or rather tumor-inhibiting activities. The present study focuses on the involvement of neutrophils in high grade serous ovarian cancer (HGSOC). Macroscopic features classify two types of peritoneal tumor spread in HGSOC. Widespread and millet sized lesions characterize the miliary type, while non-miliary metastases are larger and associated with better prognosis. Multi-omics and FACS data were generated from ascites samples. Integrated data analysis demonstrates a significant increase of neutrophil extracellular trap (NET)-associated molecules in non-miliary ascites samples. A co-association network analysis performed with the ascites data further revealed a striking correlation between NETosis-associated metabolites and several eicosanoids. The congruence of data generated from primary neutrophils with ascites analyses indicates the predominance of NADPH oxidase 2 (NOX)-independent NETosis. NETosis is associated with protein S100A8/A9 release. An increase of the S100A8/CRP abundance ratio was found to correlate with favorable survival of HGSOC patients. The analysis of additional five independent proteome studies with regard to S100A8/CRP ratios confirmed this observation. In conclusion, NET formation seems to relate with better cancer patient outcome.
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http://dx.doi.org/10.3390/cancers12020505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072166PMC
February 2020

Neutrophil extracellular traps and monocyte subsets at the culprit lesion site of myocardial infarction patients.

Sci Rep 2019 11 8;9(1):16304. Epub 2019 Nov 8.

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

Neutrophils release their chromatin into the extracellular space upon activation. These web-like structures are called neutrophil extracellular traps (NETs) and have potent prothrombotic and proinflammatory properties. In ST-elevation myocardial infarction (STEMI), NETs correlate with increased infarct size. The interplay of neutrophils and monocytes impacts cardiac remodeling. Monocyte subsets are classified as classical, intermediate and non-classical monocytes. In the present study, in vitro stimulation with NETs led to an increase of intermediate monocytes and reduced expression of CX3CR1 in all subsets. Intermediate monocytes have been associated with poor outcome, while non-classical CX3CR1-positive monocytes could have reparative function after STEMI. We characterized monocyte subsets and NET markers at the culprit lesion site of STEMI patients (n = 91). NET surrogate markers were increased and correlated with larger infarct size and with fewer non-classical monocytes. Intermediate and especially non-classical monocytes were increased at the culprit site compared to the femoral site. Low CX3CR1 expression of monocytes correlated with high NET markers and increased infarct size. In this translational system, causality cannot be proven. However, our data suggest that NETs interfere with monocytic differentiation and receptor expression, presumably promoting a subset shift at the culprit lesion site. Reduced monocyte CX3CR1 expression may compromise myocardial salvage.
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http://dx.doi.org/10.1038/s41598-019-52671-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841683PMC
November 2019

Neutrophil extracellular traps and fibrocytes in ST-segment elevation myocardial infarction.

Basic Res Cardiol 2019 07 16;114(5):33. Epub 2019 Jul 16.

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

Leukocyte-mediated inflammation is central in atherothrombosis and ST-segment elevation myocardial infarction (STEMI). Neutrophil extracellular traps (NETs) have been shown to enhance atherothrombosis and stimulate fibroblast function. We analyzed the effects of NETs on cardiac remodeling after STEMI. We measured double-stranded (ds)DNA and citrullinated histone H3 (citH3) as NET surrogate markers in human culprit site and femoral blood collected during primary percutaneous coronary intervention (n = 50). Fibrocytes were characterized in whole blood by flow cytometry, and in culprit site thrombi and myocardium by immunofluorescence. To investigate mechanisms of fibrocyte activation, isolated NETs were used to induce fibrocyte responses in vitro. Enzymatic infarct size was assessed using creatine-phosphokinase isoform MB area under the curve. Left ventricular function was measured by transthoracic echocardiography. NET surrogate markers were increased at the culprit site compared to the femoral site and were positively correlated with infarct size and left ventricular dysfunction at follow-up. In vitro, NETs promoted fibrocyte differentiation from monocytes and induced fibrocyte activation. Highly activated fibrocytes accumulated at the culprit site and in the infarct transition zone. Our data suggest that NETs might be important mediators of fibrotic remodeling after STEMI, possibly by stimulating fibrocytes.
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http://dx.doi.org/10.1007/s00395-019-0740-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647191PMC
July 2019

Out-of-hospital initiation of hypothermia in ST-segment elevation myocardial infarction: a randomised trial.

Heart 2019 04 25;105(7):531-537. Epub 2018 Oct 25.

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

Objective: To evaluate the effect of prereperfusion hypothermia initiated in the out-of-hospital setting in awake patients with ST-segment elevation myocardial infarction (STEMI) on myocardial salvage measured by cardiac MRI (CMR).

Methods: Hypothermia was initiated within 6 hours of symptom onset by the emergency medical service with surface cooling pads and cold saline, and continued in the cath lab with endovascular cooling (target temperature: ≤35°C at time of reperfusion). Myocardial salvage index (using CMR) was compared in a randomised, controlled, open-label, endpoint blinded trial to a not-cooled group of patients at day 4±2 after the event.

Results: After postrandomisation exclusion of 19 patients a total of 101 patients were included in the intention-to-treat analysis (control group: n=54; hypothermia group: n=47). Target temperature was reached in 38/47 patients (81%) in the intervention group. Study-related interventions resulted in a delay in time from first medical contact to reperfusion of 14 min (control group 89±24 min; hypothermia group 103±21 min; p<0.01). Myocardial salvage index was 0.37 (±0.26) in the control group and 0.43 (±0.27) in the hypothermia group (p=0.27). No differences in cardiac biomarkers or clinical outcomes were found. In a CMR follow-up 6 months after the initial event no significant differences were detected.

Conclusion: Out-of-hospital induced therapeutic hypothermia as an adjunct to primary percutaneous coronary intervention did not improve myocardial salvage in patients with STEMI.

Trial Registration Number: NCT01777750.
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http://dx.doi.org/10.1136/heartjnl-2018-313705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580740PMC
April 2019

Liver transplantation reverses hypergammaglobulinemia in patients with chronic hepatic failure.

Biochem Med (Zagreb) 2015 5;25(2):252-61. Epub 2015 Jun 5.

Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria ; RAIC Laboratory 13C1, Medical University of Vienna, Vienna, Austria.

Introduction: Sparse data are available about the effect of therapy methods on antibody levels in patients with liver failure. The aim of this study was to determine serum immunoglobulin concentrations in patients with chronic hepatic failure (CHF), acute- (ALF), or acute-on-chronic liver failure (ACLF) and to evaluate the impact of MARS treatment or liver transplantation (LT) on antibody levels.

Materials And Methods: We followed ten patients with ALF, twelve with ACLF and 18 with CHF. Eight patients with ALF and seven with ACLF underwent MARS therapy, whereas the rest received LT. 13 healthy volunteers served as controls. Serum antibody concentrations were measured using ELISA-technique.

Results: Median serum levels of IgA, IgG and IgM were significantly increased in patients with CHF compared to ALF or controls (P<0.02, P<0.01, and P<0.01). IgM and IgG concentrations were also significantly elevated in patients with CHF compared to ACLF (IgM, 3.7 vs. 1 g/L, P<0.001; IgG, 8.7 vs. 3.1 g/L, P=0.004). Immediately after LT a significant decrease of IgA (6.9 vs. 3.1 g/L, P=0.004), IgG (8.7 vs. 5.1 g/L, P=0.02) and IgM (3.7 vs. 1.8 g/L, P=0.001) was detected in patients with CHF and antibody levels further decreased the days after LT reaching levels comparable to healthy individuals. MARS treatment had no apparent effect on the immunoglobulin profile in patients with ALF or ACLF.

Conclusion: We provide evidence that LT reverses hypergammaglobulinemia in patients suffering from CHF within one day, which could be explained to a reconstituted hepatic antibody clearance, whereas MARS treatment has no immediate effect on immunoglobulin levels.
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http://dx.doi.org/10.11613/BM.2015.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470094PMC
August 2015

Pro-oxidant HDL predicts poor outcome in patients with ST-elevation acute coronary syndrome.

Thromb Haemost 2015 Jul 2;114(1):133-8. Epub 2015 Apr 2.

Irene Lang, MD, Medical University of Vienna, Department of Internal Medicine II, Division of Cardiology, Waehringer Guertel 18-20, A-1090 Vienna, Austria, Tel.: +43 1 40400 46140, Fax: +43 1 40400 42160, E-mail:

Oxidative stress affects clinical outcome in patients with ST-elevation acute coronary syndrome (STE-ACS). Although high-density lipoprotein (HDL) particles are generally considered protective, deleterious properties of HDL have been observed in patients with acute myocardial infarction. Here, we analysed the association between pro-oxidant HDL and all-cause mortality in STE-ACS patients. We determined the antioxidant function of HDL in 247 prospectively enrolled patients undergoing primary percutaneous coronary intervention for STE-ACS. Patients were stratified as by a pro-oxidant serum HDL oxidant index (HOI≥ 1) or with an antioxidant serum HOI (HOL< 1) capacity. Multivariate regression analysis was used to relate HOI to survival. The median follow-up time was 23 months (IQR 14.4-40.0 months). Pro-oxidant HDL was observed in 44.1 % of STE-ACS patients and was independently associated with all-cause mortality with a hazard ratio of 3.30(95 %CI 1.50-7.27, p = 0.003). Mortality rates were higher in patients with baseline pro-oxidant HDL compared to patients with preserved HDL function at 30 days (11.9 % vs 2.2 %, p=0.002), and at 4 years (22.9 % vs 8.7 %, p=0.002). Elevated neutrophil counts were a strong and independent predictor for pro-oxidant HDL with an odds ratio per standard deviation of 1.50 (95 %CI 1.11-2.03, p=0.008), as was history of prior acute myocardial infarction, elevated triglycerides levels and reduced glomerular filtration rate. In conclusion, pro-oxidant HDL represents a strong and independent predictor of long-term as well as short-term all-cause mortality in STE-ACS patients. Elevated neutrophil counts predicted the presence of serum pro-oxidant HDL. The maintenance of HDL functions might be a promising therapeutic target in STE-ACS patients.
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http://dx.doi.org/10.1160/TH14-10-0834DOI Listing
July 2015

Coronary neutrophil extracellular trap burden and deoxyribonuclease activity in ST-elevation acute coronary syndrome are predictors of ST-segment resolution and infarct size.

Circ Res 2015 03 29;116(7):1182-92. Epub 2014 Dec 29.

From the Division of Cardiology, Department of Internal Medicine II (A.M., S.A., T.S., T.H., J.J., A.P., D.S., A.K., J.M., M.-P.W., K.D., C.A., I.M.L.), Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology (D.L., C.B.), Vienna General Hospital, Medical University of Vienna, Austria; and Institute for Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany (K.T.P.).

Rationale: Mechanisms of coronary occlusion in ST-elevation acute coronary syndrome are poorly understood. We have previously reported that neutrophil (polymorphonuclear cells [PMNs]) accumulation in culprit lesion site (CLS) thrombus is a predictor of cardiovascular outcomes.

Objective: The goal of this study was to characterize PMN activation at the CLS. We examined the relationships between CLS neutrophil extracellular traps (NETs), bacterial components as triggers of NETosis, activity of endogenous deoxyribonuclease, ST-segment resolution, and infarct size.

Methods And Results: We analyzed coronary thrombectomies from 111 patients with ST-elevation acute coronary syndrome undergoing primary percutaneous coronary intervention. Thrombi were characterized by immunostaining, flow cytometry, bacterial profiling, and immunometric and enzymatic assays. Compared with femoral PMNs, CLS PMNs were highly activated and formed aggregates with platelets. Nucleosomes, double-stranded DNA, neutrophil elastase, myeloperoxidase, and myeloid-related protein 8/14 were increased in CLS plasma, and NETs contributed to the scaffolds of particulate coronary thrombi. Copy numbers of Streptococcus species correlated positively with dsDNA. Thrombus NET burden correlated positively with infarct size and negatively with ST-segment resolution, whereas CLS deoxyribonuclease activity correlated negatively with infarct size and positively with ST-segment resolution. Recombinant deoxyribonuclease accelerated the lysis of coronary thrombi ex vivo.

Conclusions: PMNs are highly activated in ST-elevation acute coronary syndrome and undergo NETosis at the CLS. Coronary NET burden and deoxyribonuclease activity are predictors of ST-segment resolution and myocardial infarct size.
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http://dx.doi.org/10.1161/CIRCRESAHA.116.304944DOI Listing
March 2015

Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies.

J Lipid Res 2015 Feb 18;56(2):440-8. Epub 2014 Dec 18.

Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria Christian Doppler Laboratory for Innovative Therapy Approaches in Sepsis, Krems, Austria.

Oxidation-specific epitopes (OSEs) present on apoptotic cells and oxidized low density lipoprotein (OxLDL) represent danger-associated molecular patterns that are recognized by different arcs of innate immunity, including natural IgM antibodies. Here, we investigated whether circulating microparticles (MPs), which are small membrane vesicles released by apoptotic or activated cells, are physiological carriers of OSEs. OSEs on circulating MPs isolated from healthy donors and patients with ST-segment elevation myocardial infarction (STE-MI) were characterized by flow cytometry using a panel of OSE-specific monoclonal antibodies. We found that a subset of MPs carry OSEs on their surface, predominantly malondialdehyde (MDA) epitopes. Consistent with this, a majority of IgM antibodies bound on the surface of circulating MPs were found to have specificity for MDA-modified LDL. Moreover, we show that MPs can stimulate THP-1 (human acute monocytic leukemia cell line) and human primary monocytes to produce interleukin 8, which can be inhibited by a monoclonal IgM with specificity for MDA epitopes. Finally, we show that MDA(+) MPs are elevated at the culprit lesion site of patients with STE-MI. Our results identify a subset of OSE(+) MPs that are bound by OxLDL-specific IgM. These findings demonstrate a novel mechanism by which anti-OxLDL IgM antibodies could mediate protective functions in CVD.
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http://dx.doi.org/10.1194/jlr.P054569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306697PMC
February 2015

Myocardial infarct size measurement using geometric angle calculation.

Eur J Clin Invest 2014 Feb 19;44(2):160-7. Epub 2013 Dec 19.

Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, Jena, Germany; Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Vienna, Austria.

Background: In basic cardiovascular research focusing on animal models of myocardial infarction (MI), the measurement of infarct size is performed by planimetry of histological sections of the heart. However, in the setting of chronic MI with ongoing changes in ventricular geometry caused by wall thinning and hypertrophy, the scar area tends to become smaller.

Materials And Methods: Here, in this study we compared infarct measurements in tissue sections (of rat and porcine hearts) based on three different calculation approaches, that is, infarct area, infarct lengths and infarct angles utilizing the centroid of the left ventricle using a newly developed calculation approach.

Results: Infarct sizes from all three measurement approaches showed significant correlation with parameters of cardiac function. However, results derived from area measurements were significantly smaller than those obtained using the other two measurement approaches due to scar thinning (infarct size area: 14·81% ± 1·27 SEM, length: 23·94% ± 2·04 SEM, angle: 24·75% ± 2·13 SEM, P < 0·0001, n = 30). Moreover, results from angle measurements evidenced a much better correlation with parameters of cardiac function in a small animal model of chronic MI (e.g. ejection fraction, angle: r = -0·73; length: r = -0·64; area: r = -0·59, n = 30) as well as in a large animal model of acute MI (angle: r = -0·82; area: r = -0·67, n = 10).

Conclusions: We concluded that area-, length- and angle-based measurements can be used to determine the relative infarct size in acute MI models, although an area-based measurement might be less accurate in the setting of chronic MI. Our new method of infarct angle measurement is a reliable and simple way to calculate infarct size compared with conventional measurement approaches.
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http://dx.doi.org/10.1111/eci.12202DOI Listing
February 2014

Prognostic value of culprit site neutrophils in acute coronary syndrome.

Eur J Clin Invest 2014 20;44(3):257-65. Epub 2014 Jan 20.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria; Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA.

Background: Recent data suggest that acute coronary syndromes (ACS) and acute myocardial infarction (AMI) are characterized by an inflammatory subset of thrombosis. We have previously described the accumulation of neutrophils at the coronary culprit lesion site. In this work, we assessed the prognostic value of culprit site (CS) neutrophil accumulation on long-term mortality in patients with AMI.

Materials And Methods: In this prospective study, 417 AMI patients were enrolled after thrombectomy during primary percutaneous coronary intervention. The optimal cut-off for CS neutrophil accumulation for predicting 4-year all-cause mortality was calculated using time-dependent receiver operator characteristic curve analyses.

Results: The median follow-up time was 39 months interquartile range (IQR 21·4-54·6 months) corresponding to 1217 patient years of follow-up. The cut-off for CS neutrophil accumulation (difference between culprit neutrophil counts and systemic neutrophil counts) was 0·25 Giga/l. CS neutrophil accumulation occurred in 195 patients (47%) and was independently associated with mortality (hazard ratio 1·88 (95%CI 1·02-3·41, P = 0·043)). In patients with CS neutrophil accumulation, 1-year mortality (10·8% vs. 7·2%) and 4-year mortality (19·8% vs. 10·4%) were markedly increased compared with patients without local neutrophil accumulation. Concordance index for CS neutrophil accumulation and mortality was 0·64 (95% CI 0·51-0·77; P = 0·035). Patients with CS neutrophil accumulation had significantly more often nonobstructive lesions compared with patients without neutrophil accumulation (32·6% vs. 22·4%; P = 0·024).

Conclusions: Neutrophil accumulation at the coronary culprit lesion site is a strong and independent predictor of mortality in patients with ACS/AMI.
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http://dx.doi.org/10.1111/eci.12228DOI Listing
October 2014

Defective angiogenesis delays thrombus resolution: a potential pathogenetic mechanism underlying chronic thromboembolic pulmonary hypertension.

Arterioscler Thromb Vasc Biol 2014 Apr 13;34(4):810-819. Epub 2014 Feb 13.

Department of Cardiology, Medical University of Vienna, Vienna, Austria.

Objective: Restoration of patency is a natural target of vascular remodeling after venous thrombosis that involves vascular endothelial cells and smooth muscle cells, as well as leukocytes. Acute pulmonary emboli usually resolve <6 months. However, in some instances, thrombi transform into fibrous vascular obstructions, resulting in occlusion of the deep veins, or in chronic thromboembolic pulmonary hypertension (CTEPH). We proposed that dysregulated thrombus angiogenesis may contribute to thrombus persistence.

Approach And Results: Mice with an endothelial cell-specific conditional deletion of vascular endothelial growth factor receptor 2/kinase insert domain protein receptor were used in a model of stagnant flow venous thrombosis closely resembling human deep vein thrombosis. Biochemical and functional analyses were performed on pulmonary endarterectomy specimens from patients with CTEPH, a human model of nonresolving venous thromboembolism. Endothelial cell-specific deletion of kinase insert domain protein receptor and subsequent ablation of thrombus vascularization delayed thrombus resolution. In accordance with these findings, organized human CTEPH thrombi were largely devoid of vascular structures. Several vessel-specific genes, such as kinase insert domain protein receptor, vascular endothelial cadherin, and podoplanin, were expressed at lower levels in white CTEPH thrombi than in organizing deep vein thrombi and organizing thrombi from aortic aneurysms. In addition, red CTEPH thrombi attenuated the angiogenic response induced by vascular endothelial growth factor.

Conclusions: In the present work, we propose a mechanism of thrombus nonresolution demonstrating that endothelial cell-specific deletion of kinase insert domain protein receptor abates thrombus vessel formation, misguiding thrombus resolution. Medical conditions associated with the development of CTEPH may be compromising early thrombus angiogenesis.
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http://dx.doi.org/10.1161/ATVBAHA.113.302991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728746PMC
April 2014

Reviewing α-Gal in valve immunology.

Eur J Cardiothorac Surg 2012 May 21;41(5):1214-5 author reply 1215-6. Epub 2011 Dec 21.

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http://dx.doi.org/10.1093/ejcts/ezr175DOI Listing
May 2012

Anti-alpha-Gal antibody titres remain unaffected by the consumption of fermented milk containing Lactobacillus casei in healthy adults.

Int J Food Sci Nutr 2012 May 4;63(3):278-82. Epub 2011 Oct 4.

Christian Doppler Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Austria.

Alpha-Gal is a glycoconjugate present on cell membranes of non-primate mammals and bacteria, but not in humans, who display anti-Gal antibodies (ABs) in high titres. Probiotics contain bacterial strains which colonize the intestinal tract. In the present study, we investigated whether intake of fermented milk containing Lactobacillus casei (FML) affects anti-Gal AB titres. Serum was drawn from healthy probands (n = 19) for 6 weeks. After the second week, the probands consumed 125 ml of FML per day. Anti-Gal ABs of all isotypes and cytokines were measured. Bacterial cultures were bred from FML and bacteria were stained for alpha-Gal. Concentration of bacteria in FML was manifold higher than in conventional yoghurt (2 × 10(5)/g yoghurt vs. 1.1 × 10(7)/g FML). Both stained highly positive for Alpha-Gal. Alpha-Gal-specific ABs and cytokines remained unaffected by FML intake. Our results indicated that the consumption of FML does not elicit a humoral immune response in healthy adults.
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http://dx.doi.org/10.3109/09637486.2011.622741DOI Listing
May 2012

Vein of Galen aneurysmal malformation: combined transvenous and transarterial method using a "kissing microcatheter technique".

Neuroradiology 2012 Jan 1;54(1):51-9. Epub 2011 Apr 1.

Department of Radiology and Neuroradiology, Klinikum Duisburg, Zu den Rehwiesen 9, 47055, Duisburg, Germany.

Introduction: Vein of Galen aneurysmal malformation (VGAM) is a severe pediatric neurovascular disease. Children often present with congestive heart failure in the neonatal period. In the last decades, endovascular treatment became the first therapeutic option. The purpose of this study is to report our results in the treatment of VGAM with a combined transvenous and transarterial method in the last ten years.

Methods: In our cohort of 28 patients with VGAM, 22 patients were treated endovascularly between 1992 and 2010. In the last 10 years, a consecutive series of 14 children were treated with a combined transvenous and transarterial method. The therapeutic goal was immediate shunt reduction of the arteriovenous malformation, especially in the neonatal period. Closure of the fistulous connections was achieved by coiling using a combined transvenous and transarterial approach, called "kissing microcatheter technique".

Results: Eight of 14 children presented in the neonatal period with severe congestive heart failure. The other six patients presented between the age of 2 and 17 months. One patient died due to a non-procedural complication in another hospital 2 years after the last treatment. Complete or >90% of angiographically confirmed closure of the malformation was documented in 11 of 14 patients. Normal or near-normal outcome was achieved in 9 of 13 surviving children, a non-favorable outcome was observed in four children. Control of heart failure was achieved in all patients.

Conclusion: Endovascular treatment of VGAM using a combined transvenous and transarterial method is a safe procedure with a low complication rate. The overall outcome can be improved, especially in the high-risk neonatal group with congestive heart failure.
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http://dx.doi.org/10.1007/s00234-011-0860-4DOI Listing
January 2012

Up-regulation of interleukin 33 and soluble ST2 serum levels in liver failure.

J Surg Res 2010 Oct 19;163(2):e79-83. Epub 2010 Jun 19.

Department of Anesthesiology, General Intensive Care and Pain Medicine, Medical University of Vienna, Vienna, Austria.

Background: IL-33, a member of the IL-1 family, induces the production of pro-inflammatory and Th2-associated cytokines and may also serve as an 'alarmin' similar to HMGB1. Soluble ST2 has been implicated as a decoy receptor, to attenuate Th2 inflammatory responses. The relevance of both molecules in hepatic failure is unknown.

Materials And Methods: The trial was a prospective preliminary study in a university hospital surgical ICU; 11 patients with acute liver failure (ALF) and 12 patients with acute-on-chronic liver failure (ACLF), who were admitted to the ICU; 14 patients with chronic hepatic failure (CHF) awaiting liver transplantation; 13 healthy individuals served as controls. IL-33 and soluble ST2 concentrations were determined by enzyme linked immunosorbent assay (ELISA).

Results: The concentration of IL-33 and soluble ST2 was significantly higher in ALF, ACLF, and CHF patients compared with the controls. Soluble ST2 serum concentration was significantly elevated in ALF and ACLF compared with CHF; moreover, soluble ST2 was significantly higher in CHF compared with healthy controls. IL-33 and soluble ST2 serum levels correlated significantly (r = 0.6117, P < 0.0001). Moreover, there was a correlation between IL-33 serum levels and alanine aminotransferase (ALT) activity in CHF, ALF, and ACLF patients (r = 0.4321, P = 0.0171).

Conclusion: Our data provide evidence for elevated levels of IL-33 and soluble ST2 in liver failure, which could a sign of immune hyperactivation, and/or a mechanism to down-regulate inflammation. Especially, soluble ST2 maybe useful to discern acute from chronic hepatic failure or to monitor the course and the severity of the disease.
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http://dx.doi.org/10.1016/j.jss.2010.04.004DOI Listing
October 2010

Questionable model choice in valve calcification research addressing alpha-Gal.

J Heart Lung Transplant 2010 Aug 8;29(8):911-2; discussion 912-3. Epub 2010 Jun 8.

Department of Thoracic Surgery, Medical University of Vienna, Wien, Austria.

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http://dx.doi.org/10.1016/j.healun.2010.03.018DOI Listing
August 2010

Increased soluble serum markers caspase-cleaved cytokeratin-18, histones, and ST2 indicate apoptotic turnover and chronic immune response in COPD.

J Clin Lab Anal 2009 ;23(6):372-9

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

Introduction: Chronic obstructive pulmonary disease (COPD) is a worldwide burden and a major cause of death. The disease is accompanied by chronic inflammation and increased cellular turnover that is partly due to an overwhelming induction of apoptosis. In this study, we hypothesized that systemic markers of apoptosis are altered in patients with mild-to-severe COPD.

Materials And Methods: A total number of 64 patients and controls were enrolled in the study. Lung function parameters of all groups (nonsmoker, healthy smoker, COPD GOLD I&II, COPD GOLD III&IV) were evaluated at the time of inclusion. Enzyme-linked immunosorbent assays were used to quantify protein levels in serum samples.

Results: Serum contents of apoptotic end-products caspase-cleaved cytokeratin-18 and histone-associated-DNA-fragments were increased in patients with COPD, whereas anti-inflammatory soluble ST2 showed a peak in patients with COPD I&II (P=0.031) compared to healthy smokers. Levels of pro-inflammatory caspase-1/ ICE correlated significantly with the number of pack years (R=0.337; P=0.007).

Discussion: Our results indicate a systemic release of apoptosis-specific proteins as markers for increased cellular turnover accompanied by progression of COPD. Furthermore, soluble ST2 seems to have a critical role in the anti-inflammatory regulatory mechanism at early stages of the disease.
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http://dx.doi.org/10.1002/jcla.20348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649135PMC
March 2010

Elevated HSP27, HSP70 and HSP90 alpha in chronic obstructive pulmonary disease: markers for immune activation and tissue destruction.

Clin Lab 2009 ;55(1-2):31-40

Department of Surgery, Medical University of Vienna, Austria.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death. Although the underlying pathomechanism remains poorly understood, COPD is accompanied by increased cellular stress and inflammation. We investigated serum contents of heat shock proteins (HSP 27, 60, 70, 90 alpha), 20S proteasomes, C-reactive protein (CRP), and interleukin-6 (IL-6) in patients with mild or severe COPD, healthy smokers and nonsmokers. HSP27, HSP70 and HSP90 alpha were significantly altered in patients suffering from COPD as compared to controls. HSP27 and HSP70 are potential novel serum markers for the diagnosis of COPD in the smoking population. This is the first study to demonstrate elevated serum levels of the described heat shock proteins in patients with COPD. We showed sensitivity and specificity of serum HSP27 and HSP70 as diagnostic markers for COPD.
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April 2009

Heat shock proteins 27, 60, 70, 90alpha, and 20S proteasome in on-pump versus off-pump coronary artery bypass graft patients.

Ann Thorac Surg 2008 Jan;85(1):80-7

Department of Cardiac Surgery, University of Debrecen, Debrecen, Hungary.

Background: The secretion of heat shock protein (HSP) 27, HSP60, HSP70, HSP90alpha, 20S proteasome, and their correlations to proinflammatory cytokine interleukin-6 is unknown in patients undergoing on-pump versus off-pump coronary artery bypass graft (CABG) operation.

Methods: Forty patients were included in this explorative study (on- versus off-pump CABG, each n = 20). Serum samples were obtained before and 30 minutes, 60 minutes, and 24 hours after CABG operation. Enzyme-linked immunosorbent assay technique was utilized to determine soluble HSP27, 60, 70, and 90alpha, 20S proteasome, and levels of interleukin-6.

Results: Serum levels of HSP are increased in patients undergoing on-pump CABG operation as compared with off-pump CABG technique. These differences were highly significant for HSP27, 70, and 90alpha at 60 minutes after initiation of cardiopulmonary bypass (all, p < 0.001). Concentrations of soluble 20S proteasome were increased 24 hours after operation in on- and off-pump CABG patients (p < 0.001) and correlated significantly with the serum content of HSP 27, 70, and 90alpha at 60 minutes after initiation of cardiopulmonary bypass (p < 0.001). No correlation was found when comparing interleukin-6 levels with intravascular leakage of HSP and 20S proteasome after CABG operation.

Conclusions: We conclude from our data that the innate immune system is activated owing to spillage of known immune modulatory and apoptosis-associated proteins after CABG operation.
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http://dx.doi.org/10.1016/j.athoracsur.2007.06.049DOI Listing
January 2008

Otogenic cerebellar abscess due to purulent labyrinthitis and defect of the superior semicircular canal and its propagation through the endolymphatic sac.

Eur Arch Otorhinolaryngol 2007 Aug 20;264(8):955-8. Epub 2007 Mar 20.

Department of Otorhinolaryngology, Medical University of Hannover, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany.

The otogenic cerebellar abscess still is one of the most dangerous complications of otitis media and implicates a high risk of mortality. Early diagnosis and therapy are decisive factors for the chances of rehabilitation. Radiologic imaging (CT/MRI) plays an important role. A broad-spectrum antibiotic according to antibiogram is indispensable. The type of surgical intervention depends on the cause and localization of the abscess. In this case the cerebellar abscess was a complication resulting from labyrinthitis, which was propagated through the endolymphatic duct and sac to the posterior fossa dura. Consequently, it could be cured ultimately only after petrosectomy and abscess drainage toward the mastoid cavity. It is mandatory to completely sanitize the infection surgically in order to avoid lethal complication especially in case of a delayed clinical course or recurrent symptoms of labyrinth involvement. Close interdisciplinary collaboration between ORL, neurosurgery and neuroradiology is desirable for successful therapy.
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http://dx.doi.org/10.1007/s00405-007-0287-zDOI Listing
August 2007
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