Publications by authors named "Walter S Speidl"

75 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

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

Implementation of clinical practices and pathways optimizing ACS patients lipid management: Focus on eight European initiatives.

Atheroscler Suppl 2020 Dec;42:e59-e64

Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Milan; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy. Electronic address:

Post-acute coronary syndrome (ACS) patients are at very high cardiovascular risk. Despite current guidelines strongly recommend to reduce LDL-C levels and initiation of high-intensity statins as early as possible in patients admitted with an ACS, less than half of ACS patients receive a high intensity statin, and a high percentage of has LDL-C well above the goal despite therapy. There are multiple reasons for that, including physician lack of guideline adherence, patient lack of compliance with treatment, and lack of standardized procedures. Furthermore, although the prevalence of familial hypercholesterolemia is higher among patients with ACS, this condition remains poorly estimated. To fill these gaps, some European countries have launched local initiatives for the in-hospital and post-discharge ACS patient lipid management. It appears that ensuring optimal therapy during hospitalization and dedicated follow-up protocols results in a significant improvement of lipid levels in these very high risk patients, which may translate into a reduced risk of recurrent future events.
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http://dx.doi.org/10.1016/j.atherosclerosissup.2021.01.010DOI Listing
December 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

Death is associated to the type of drug-eluting stent in patients with left ventricular dysfunction and elevated natriuretic peptide levels.

Sci Rep 2021 Jan 28;11(1):2443. Epub 2021 Jan 28.

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

As advanced heart failure (HF) with elevated NT-proBNP is characterized by an activated coagulation system, coronary events clinically noticed as sudden or HF death may be more common after treatment with first- compared to newer-generation DES. Our study evaluates (1) if patients with left ventricular dysfunction (LVSD) who underwent percutaneous coronary intervention have a better survival with first- or newer-generation DES, and (2) if the survival benefit is predicted by NT-proBNP. Our observational study evaluated patients with LVSD who were registered in the coronary catheter laboratory database of the Medical University of Vienna. Multivariate Cox regression analyses tested an interaction in the risk of death between those with lower or elevated NT-proBNP levels and the stent-generation. The relative risk of newer- compared to first-generation DES as reference was calculated for patients with low and elevated NT-proBNP levels. In 340 patients (178 newer- and 162 first-generation DES) stent-generation and NT-proBNP were independent predictors of death. When the stent-generation*NTproBNP interaction was forced into a Cox regression model, this term independently predicted death. The relative risk of first- compared to newer-generation DES was similar in patients with lower NT-proBNP (HR 1.02, 95% CI 0.95-1.10, p = 0.560), but was higher in patients with elevated NT-proBNP (HR 1.06, 95% CI 1.01-1.10, p = 0.020). Death is associated to stent-generation. NT-proBNP is a predictor for the stent generation used: elevated levels demonstrated a higher mortality risk when using first- compared to newer-generation DES, while lower levels showed a similar risk when using either DES-generation.
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http://dx.doi.org/10.1038/s41598-021-81569-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844266PMC
January 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

Interdependence of VA-ECMO output, pulmonary congestion and outcome after cardiac surgery.

Eur J Intern Med 2020 11 28;81:67-70. Epub 2020 Jul 28.

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

Background: Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is a life-saving method for patients with low-output failure after cardiac surgery. However, VA-ECMO therapy may increase left ventricular afterload due to retrograde blood flow in the aorta, which may lead to progression of pulmonary congestion. We examined the predictive value of pulmonary congestion in patients that need VA-ECMO support after cardiovascular surgery.

Methods: We enrolled a total of 266 adult patients undergoing VA-ECMO support following cardiovascular surgery at a university-affiliated tertiary care centre into our single-center registry. Pulmonary edema was assessed on bedside chest X rays at day 0, 3, 5 after VA-ECMO implantation.

Results: Median age was 65 (57-72) years, 69% of patients were male and 30-day survival was 63%. At ICU-admission 20% of patients had mild, 54% had moderate and 26% showed severe pulmonary congestion. Pulmonary congestion at day 0 was not associated with outcome (adjusted HR 1.31; 95%-CI 0.89-1.93;P = 0.18), whereas pulmonary congestion at day 3 (adj. HR 2.81; 95%-CI 1.76-4.46;P<0.001) and day 5 (adj. HR 3.01;95%-CI 1.84-4.93;P<0.001) was significantly associated with survival. Linear regression revealed that out of left ventricular function, cardiac output, central venous saturation, maximum dobutamine and norepinephrine dose as well as fluid balance solely ECMO rotation was associated with the evolution of pulmonary congestion (P = 0.007).

Conclusions: Pulmonary edema three and five days after ECMO implantation are associated with poor survival. Interestingly, a high VA-ECMO output was the most important determinant of worsening pulmonary congestion within the first five days.
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http://dx.doi.org/10.1016/j.ejim.2020.07.014DOI Listing
November 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

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

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

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

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

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

Toll-like receptor 2 and 9 expression on circulating neutrophils is associated with increased mortality in critically ill patients.

Shock 2020 07;54(1):35-43

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

Background: Toll-like receptors (TLRs) play an important role in inflammatory processes in critically ill patients by binding to pathogen-associated molecular patterns and danger-associated molecular patterns (DAMPs). Whether neutrophil or monocyte TLR expression patterns are associated with outcome in critical illness is unknown.

Objectives: To answer this question, we conducted a prospective, observational study including 215 consecutive patients admitted to a medical ICU at a tertiary care center.

Methods: Blood was drawn at admission and expression of TLR-2, TLR-4, and TLR-9 on neutrophils and monocytes were analyzed by flow cytometry.

Results: Median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 19, and 30-day mortality was 26%. TLR-2 expression on neutrophils was associated with APACHE II, Simplified Acute Physiology Score II, and Sepsis-related Organ Failure Assessment score. TLR-2 (P < 0.001) and TLR-9 (P < 0.05) expression on neutrophils was significantly higher in nonsurvivors. In contrast, neutrophil TLR-4 expression and monocyte TLR expression were not associated with survival. Neutrophil TLR-2 (odds ratio 3.8; 95% confidence interval 1.4-10.2; P < 0.05) and TLR-9 (odds ratio 4.0; 95% confidence interval 2.0-8.1; P < 0.001) expression in the third tertile predicted mortality independent from APACHE II, serum lactate, serum creatinine, and procalcitonin, respectively.

Conclusion: We provide evidence for prognostic properties of neutrophil TLR-2 and TLR-9 expression regarding 30-day mortality in unselected critically ill patients, independent from baseline clinical characteristics, and laboratory values. These findings suggest that specific TLR-dependent activation of the innate immune system via neutrophils possibly caused by cell damage and release of otherwise intracellular components may play a significant role in the pathophysiology of critical illness.
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http://dx.doi.org/10.1097/SHK.0000000000001467DOI Listing
July 2020

Growth differentiation factor-15 predicts poor survival after cardiac arrest.

Resuscitation 2019 10 5;143:22-28. Epub 2019 Aug 5.

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

Background: Early prognostication in post-cardiac arrest (CA) patients remains challenging and biomarkers have evolved as helpful tools in risk assessment. The stress-response cytokine growth differentiation factor-15 (GDF-15) is dramatically up-regulated during various kinds of tissue injury and predicts outcome in many pathological conditions. We aimed to assess the predictive value of circulating GDF-15 in post-CA patients.

Methods: This prospective observational study included 128 consecutive patients (median age 60.3 years, 75.8% male) with return of spontaneous circulation after in- or out-of-hospital CA who were treated at a tertiary university hospital. GDF-15 serum levels were determined at admission.

Results: A total of 52 patients (40.6%) died during the 6-month follow-up. Median GDF-15 levels were significantly lower in survivors (1601 ng/L (interquartile range: 1114-2983 ng/L) than in non-survivors (3172 ng/L (1927-8340 ng/L); p < 0.001). GDF-15 levels were also significantly lower in patients with favourable neurological 6-month outcome (cerebral performance category (CPC) 1-2) than in those with poor neurological outcome (CPC 3-5; p < 0.001). GDF-15 significantly predicted 6-month mortality in univariate Cox regression analysis (hazard ratio (HR) per 1-standard deviation increase 1.76 [95% confidence interval (CI) 1.35-2.31; p < 0.001] and remained significant after multivariable adjustment (HR 1.57 [95% CI 1.19-2.07; p = 0.001]). Subgroup analysis revealed that the association between GDF-15 and 6-month outcome was present both in patients with in- and out-of-hospital CA.

Conclusions: GDF-15 predicts poor survival and neurological outcome in post-CA patients. GDF-15 may reflect the extent of hypoxic injury to the brain and other organs and might help to improve early risk stratification after CA.
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http://dx.doi.org/10.1016/j.resuscitation.2019.07.028DOI Listing
October 2019

Protease-Activated Receptors 1 and 3 are Differentially Expressed on Human Monocyte Subsets and are Upregulated by Lipopolysaccharide Ex Vivo and In Vivo.

Thromb Haemost 2019 Sep 10;119(9):1394-1402. Epub 2019 Jul 10.

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

Monocytes are activated in inflammatory conditions via a variety of cytokine receptors as well as in a procoagulatory setting through thrombin, acting upon protease-activated receptors (PARs). This study investigated the expression pattern of PAR1 and PAR3 on human monocyte subsets. Furthermore, a possible regulation of the expression of PAR1 and PAR3 in these cells by inflammatory activation were studied. CD16 monocytes showed significantly higher levels of PAR1 and PAR3 as compared with CD16 monocytes. Ex vivo treatment of whole blood with lipopolysaccharide (LPS) increased PAR1 and PAR3 messenger ribonucleic acid (mRNA) in human monocytes. In addition, increase of PAR1 was seen in all three subsets upon LPS treatment, whereas PAR3 increased significantly only in CD16 monocytes and nonclassical CD16 monocytes. Protein levels of PAR1 and PAR3 significantly increased on monocytes in vivo in human endotoxemia 1 hour after LPS infusion. PAR1 increased significantly in CD16 monocytes and nonclassical CD16 monocytes. In this in vivo model, PAR3 was also significantly elevated in CD16 monocytes and increased slightly albeit not significantly in CD16 monocytes. Endotoxemia increased plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression in monocytes in humans. Pretreatment of healthy volunteers with the PAR1 antagonist vorapaxar blocked the increase in PAI-1 but not the increase in TF. We here provide new evidence for a critical role for monocytes as cellular mediators that contribute to the activation of coagulation in diseases characterized by an inflammatory state.
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http://dx.doi.org/10.1055/s-0039-1692219DOI Listing
September 2019

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

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

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

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

Release of mitochondrial DNA is associated with mortality in severe acute heart failure.

Eur Heart J Acute Cardiovasc Care 2020 Aug 11;9(5):419-428. Epub 2019 Jan 11.

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

Background: Inflammation is regarded as an important trigger for disease progression in heart failure. Particularly in severe acute heart failure, tissue hypoxia may lead to cellular damage and the release of intracellular mitochondrial DNA, which acts as an activator of the immune system due to its resemblance to bacterial DNA. It may therefore serve as a mediator of disease progression. The aim of this study was to determine circulating levels of mitochondrial DNA and its association with mortality in patients with heart failure in different presentations.

Methods: Plasma levels of circulating mitochondrial DNA were measured in 90 consecutive patients with severe acute heart failure admitted to our medical intensive care unit as well as 109 consecutive chronic heart failure patients.

Results: In patients admitted to our medical intensive care unit (median age 64 (49-74) years, median NT-pro-brain natriuretic peptide 4986 (1525-23,842) pg/mL, 30-day survival 64.4%), mitochondrial DNA levels were significantly higher in patients who died within 30 days after intensive care unit admission, and patients with plasma levels of mitochondrial DNA in the highest quartile had a 3.4-fold increased risk (=0.002) of dying independent of renal function, vasopressor use and NT-pro-brain natriuretic peptide, troponin T, lactate levels or CardShock and acute physiology and chronic health evaluation II score. However, mitochondrial DNA did not provide incremental prognostic accuracy on top of the current gold standard acute physiology and chronic health evaluation II. Patients with severe acute heart failure showed significantly higher mitochondrial DNA levels (<0.005) as compared to patients with chronic heart failure. In these patients, mitochondrial DNA levels were associated with the New York Heart Association functional class but were not associated with outcome.

Conclusions: The release of mitochondrial DNA into the circulation is associated with mortality in patients with severe acute heart failure but not in patients with chronic heart failure. The release of mitochondrial DNA may therefore play a role within the pathophysiology of acute heart failure, which warrants further research. However, the use of mitochondrial DNA as a biomarker for risk stratification in these patients is of limited utility.
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http://dx.doi.org/10.1177/2048872618823405DOI Listing
August 2020

Prevention is back in the spotlight - Highlights from American Heart Association Scientific Sessions 2018.

Eur J Prev Cardiol 2019 03 22;26(5):502-506. Epub 2018 Dec 22.

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

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http://dx.doi.org/10.1177/2047487318820977DOI Listing
March 2019

Intestinal Fatty Acid Binding Protein is Associated With Mortality in Patients With Acute Heart Failure or Cardiogenic Shock.

Shock 2019 04;51(4):410-415

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

Background: Acute heart failure and cardiogenic shock are associated with an impaired intestinal perfusion, which may lead to a release of cytoplasmatic proteins by hypoxic epithelial injury. Intestinal fatty acid binding protein (iFABP), highly specific for the small bowel enterocyte, may pose a useful novel and very sensitive biomarker for predicting outcome of these patients.The aim of this study was to investigate whether circulating levels of iFABP are associated with mortality in patients with acute heart failure or cardiogenic shock requiring intensive care unit (ICU) admission.

Methods: We included 90 consecutive patients with cardiogenic shock (74.4%) or severe acute heart failure (25.6%) admitted to a cardiac ICU. Blood samples were taken at day 0 and day 3. Median age was 64.7 (49.4-74.3), 76.7% of patients were male and median NT-proBNP levels were 4,986 (1,525-23,842) pg/mL. 30-day survival was 64.4%.

Results: Patients with serum levels of iFABP at day 0 in the highest quartile (iFABP ≥ 588.4 pg/mL) had a 2.5-fold risk (P = 0.02) of dying independent of demographics, NT-proBNP levels, and vasopressor use. Extensively elevated admission levels of iFABP above the 90th percentile (iFABP ≥ 10208.4 pg/mL) were associated with an excessive mortality rate of 88.9%. In contrast, iFABP levels at day 3 were not associated with outcome.

Conclusion: Circulating levels of iFABP at admission predict mortality. This suggests that early inadequate perfusion of the small intestine may be associated with a dramatically decreased survival in patients with cardiogenic shock or severe acute heart failure.
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http://dx.doi.org/10.1097/SHK.0000000000001195DOI Listing
April 2019

Pretreatment With Argon Protects Human Cardiac Myocyte-Like Progenitor Cells from Oxygen Glucose Deprivation-Induced Cell Death by Activation of AKT and Differential Regulation of Mapkinases.

Shock 2018 05;49(5):556-563

Department of Anaesthesia, General Intensive Care and Pain Management, Medical University of Vienna, Vienna, Austria.

Background: The noble gas argon induces cardioprotection in a rabbit model of myocardial ischemia and reperfusion. However, no studies in human primary cells or subjects have been performed so far. We used human cardiac myocyte-like progenitor cells (HCMs) to investigate the protective effect on the cellular level.

Methods: HCMs were pretreated with 30% or 50% argon before oxygen-glucose deprivation (OGD) and reperfusion. We evaluated apoptotic states by flow cytometry and the activation of mitogen-activated protein kinase (MAPKs) members extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38 MAPkinase, and protein kinase B (Akt) by Westernblot analysis and by activity assays of downstream transcription factors. Specific inhibitors were used to proof a significant participation of these pathways in the protection by argon. Beneficial effects were further assessed by TdT-mediated dUTP-biotin nick end labeling (TUNEL) assay, lactate dehydrogenase (LDH), mitochondrial deoxyribonucleic acid (mtDNA), and cytokine release.

Results: Pretreatment with 30% or 50% argon for 90 min before OGD resulted in a significant protection of HCMs against apoptosis. This effect was reversed by the application of MAPK and Akt inhibitors during argon exposure. Argon 30% reduced the release of LDH by 33% and mtDNA by 45%. The release of interleukin 1β was reduced by 44% after OGD and more than 90% during reperfusion.

Conclusions: Pretreatment with argon protects HCMs from apoptosis under ischemic conditions via activation of Akt, Erk, and biphasic regulation of JNK. Argon gas is cheap and easily administrable, and might be a novel therapy to reduce myocardial ischemia-reperfusion injury.
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http://dx.doi.org/10.1097/SHK.0000000000000998DOI Listing
May 2018

N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T exhibit additive prognostic value for the outcome of critically ill patients.

Eur Heart J Acute Cardiovasc Care 2020 Aug 4;9(5):496-503. Epub 2018 Apr 4.

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

Background: Patients treated at medical intensive care units suffer from various pathologies and often present with elevated troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Both markers may reflect different forms of cardiac involvement in critical illness. Therefore, the aim of our study was to examine the synergistic prognostic potential of NT-proBNP and high-sensitivity TnT (hs)TnT in unselected critically ill patients.

Methods: We included all consecutive patients admitted to our intensive care unit within one year, excluding those suffering from acute myocardial infarction or undergoing cardiac surgery and measured NT-proBNP and TnT plasma levels on the day of admission and 72 hours thereafter.

Results: Of the included 148 patients, 52% were male, mean age was of 64.2 ± 16.8 years and 30-day mortality was 33.2%. Non-survivors showed significantly higher NT-proBNP and TnT plasma levels as compared with survivors (<0.01). An elevation of both markers exhibited an additive effect on mortality, as those with both NT-proBNP and TnT levels above the median had a 30-day mortality rate of 51.0%, while those with both markers below the median had a 16.7% mortality rate (hazard ratio 3.7). These findings were independent of demographic and clinical parameters (<0.05).

Conclusions: Our findings regarding the individual predictive properties of NT-proBNP and TnT are in line with literature. However, we were able to highlight that they exhibit additive prognostic potential which exceeds their individual value. This might be attributed to a difference in underlying pathomechanisms and an assessment of synergistic risk factors.
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http://dx.doi.org/10.1177/2048872618768088DOI Listing
August 2020

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

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

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

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

Clopidogrel in Critically Ill Patients.

Clin Pharmacol Ther 2018 02 3;103(2):217-223. Epub 2017 Nov 3.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Only limited data are available regarding the treatment of critically ill patients with clopidogrel. This trial investigated the effects and the drug concentrations of the cytochrome P450 (CYP450) activated prodrug clopidogrel (n = 43) and the half-life of the similarly metabolized pantoprazole (n = 16) in critically ill patients. ADP-induced aggregometry in whole blood classified 74% (95% confidence intervals 59-87%) of critically ill patients as poor responders (n = 43), and 65% (49-79%) responded poorly according to the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Although the plasma levels of clopidogrel active metabolite normally exceed the inactive prodrug ∼30-fold, the parent drug levels even exceeded those of the metabolite 2-fold in critically ill patients. The half-life of pantoprazole was several-fold longer in these patients compared with reference populations. The inverse ratio of prodrug/active metabolite indicates insufficient metabolization of clopidogrel, which is independently confirmed by the ∼5-fold increase in half-life of pantoprazole. Thus, high-risk patients may benefit from treatment with alternative platelet inhibitors.
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http://dx.doi.org/10.1002/cpt.878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5813104PMC
February 2018

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

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

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

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

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

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

Prasugrel in critically ill patients.

Thromb Haemost 2017 08 6;117(8):1582-1587. Epub 2017 Jul 6.

Bernd Jilma, MD, Währinger Gürtel 18-20, 1090 Vienna, Austria, Tel.: +43 1 40400 29810, Fax: +43 1 40400 29980, E-mail:

While prasugrel is indicated for the treatment of myocardial infarction, its effects in the most severely affected patients requiring intensive care is unknown, so that we measured the antiplatelet effects and sparse pharmacokinetics of prasugrel in critically ill patients. Twenty-three patients admitted to medical intensive care units, who were treated with 10 mg prasugrel once daily, were included in this prospective trial. Critically ill patients responded poorly to daily prasugrel treatment: adenosine diphosphate (ADP)-induced aggregation in whole blood classified 65 % (95 % confidence intervals (CI) 43-84 %) of patients as having high on treatment platelet reactivity, platelet function under high shear rates even 74 % (95 %CI 52-90 %). There was only limited additional inhibition provided 2 hours after the next dose of prasugrel. In contrast, insufficient inhibition of the target was only seen in 26 % (95 %CI 10-48 %) of patients as measured by the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Low effective plasma levels of prasugrel active metabolite were measured at trough [0.5 (quartiles 0.5-1.1) ng/ml at baseline], and 2 hours after intake [5.7 (3.8-9.8) ng/ml], but showed coefficients of variation of ~70 %. In sum, inhibition of platelet aggregation by prasugrel is not uniform but highly variable in critically ill patients, similar to clopidogrel in a general population. The pharmacokinetic measurements indicate that poor absorption/metabolism of prasugrel may partly contribute while inflammation induced heightened intrinsic platelet reactivity may also play a role.
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http://dx.doi.org/10.1160/TH17-03-0154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292180PMC
August 2017

Acetylsalicylic acid in critically ill patients: a cross-sectional and a randomized trial.

Eur J Clin Invest 2017 Jul 20;47(7):504-512. Epub 2017 Jun 20.

Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.

Background: Despite decades of clinical use, the pharmacokinetics and the effects of acetylsalicylic acid (ASA) in critically ill patients remain ill-defined. We aimed to investigate the pharmacokinetics and the effects of different ASA formulations during critical illness.

Design: A cross-sectional study and a randomized, parallel-group trial were performed. Critically ill patients under chronic oral ASA treatment (100 mg enteric-coated) were screened for high 'on-treatment' platelet reactivity (HTPR) according to arachidonic acid-induced whole-blood aggregometry. Thirty patients with HTPR were randomized to receive 100 mg ASA intravenously, 100 mg enteric-coated ASA bid (bis in die) or 81 mg chewable ASA (n = 10 per group). Serum thromboxane B2 (TXB2) levels, ASA and salicylic acid levels were quantified.

Results: Of 66 patients, 85% (95% confidence intervals 74-93%) had HTPR. Compared to baseline infusion of 100 mg, ASA significantly reduced platelet aggregation after 24 h to median 80% (Quartiles: 66-84%). Intake of 81 mg chewable ASA significantly reduced platelet aggregation to 75% (54-86%) after four hours, but increased it to 117% after 24 h (81-163%). Treatment with 100 mg enteric-coated ASA bid decreased platelet aggregation after 24 h to median 56% (52-113%). Baseline TXB2 levels were median 0·35 ng/mL (0·07-0·94). Infusion of ASA or intake of 100 mg ASA bid reduced TXB2 levels to 0·07-0·18 ng/mL after 24 h, respectively. Chewable ASA reduced TXB2 levels only transiently. Pharmacokinetic analysis revealed highly variable absorption patterns of oral ASA formulations.

Conclusion: There is a very high prevalence of HTPR in critically ill patients on peroral ASA therapy, caused by an incomplete suppression of TXB2 and/or by impaired absorption of ASA.
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http://dx.doi.org/10.1111/eci.12771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519937PMC
July 2017

Anti-thrombotic and pro-fibrinolytic effects of levosimendan in human endothelial cells in vitro.

Vascul Pharmacol 2017 03 10;90:44-50. Epub 2017 Feb 10.

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

Aims: Levosimendan is an inodilator for the treatment of acute decompensated heart failure (HF). Data from clinical studies suggest that levosimendan is particularly effective in HF due to myocardial infarction. After acute revascularization, no reflow-phenomenon is a common complication that may lead to pump failure and cardiogenic shock. Our aim was to examine whether levosimendan interferes with the pro-thrombotic phenotype of activated endothelial cells in vitro.

Methods: Human heart microvascular endothelial cells (HHMEC) and human umbilical vein endothelial cells (HUVEC) were treated with interleukin-1β (IL-1β) (200U/mL) or thrombin (5U/mL) and co-treated with or without levosimendan (0.1-10μM) for 2-24h. In addition, flow experiments were performed. Effects on plasminogen activator inhibitor-1 (PAI-1) and tissue factor (TF) expression and activity were measured by rt-PCR, specific ELISA and flow cytometry.

Results: Treatment with IL-1β or thrombin significantly increased the expression of PAI-1 and TF in endothelial cells. Co-treatment with levosimendan strongly attenuated the effects of IL-1β and thrombin on PAI-1 and TF mRNA by up to 50% and 45%, in a dose- and time-dependent manner. Similar results were obtained under flow conditions. Furthermore, co-treatment with levosimendan dampened the antigen production of PAI-1 and the surface expression of TF by 35% and 45%, respectively. Additionally, levosimendan diminished both TF and PAI-1 activity.

Conclusion: Levosimendan down-regulates the expression of the pro-thrombotic and anti-fibrinolytic biomolecules TF and PAI-1 in activated human endothelial cells. Our findings may, at least in part, explain some of the beneficial effects of levosimendan after myocardial reperfusion.
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http://dx.doi.org/10.1016/j.vph.2017.02.003DOI Listing
March 2017

Copeptin Predicts Mortality in Critically Ill Patients.

PLoS One 2017 24;12(1):e0170436. Epub 2017 Jan 24.

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

Background: Critically ill patients admitted to a medical intensive care unit exhibit a high mortality rate irrespective of the cause of admission. Besides its role in fluid and electrolyte balance, vasopressin has been described as a stress hormone. Copeptin, the C-terminal portion of provasopressin mirrors vasopressin levels and has been described as a reliable biomarker for the individual's stress level and was associated with outcome in various disease entities. The aim of this study was to analyze whether circulating levels of copeptin at ICU admission are associated with 30-day mortality.

Methods: In this single-center prospective observational study including 225 consecutive patients admitted to a tertiary medical ICU at a university hospital, blood was taken at ICU admission and copeptin levels were measured using a commercially available automated sandwich immunofluorescent assay.

Results: Median acute physiology and chronic health evaluation II score was 20 and 30-day mortality was 25%. Median copeptin admission levels were significantly higher in non-survivors as compared with survivors (77.6 IQR 30.7-179.3 pmol/L versus 45.6 IQR 19.6-109.6 pmol/L; p = 0.025). Patients with serum levels of copeptin in the third tertile at admission had a 2.4-fold (95% CI 1.2-4.6; p = 0.01) increased mortality risk as compared to patients in the first tertile. When analyzing patients according to cause of admission, copeptin was only predictive of 30-day mortality in patients admitted due to medical causes as opposed to those admitted after cardiac surgery, as medical patients with levels of copeptin in the highest tertile had a 3.3-fold (95% CI 1.66.8, p = 0.002) risk of dying independent from APACHE II score, primary diagnosis, vasopressor use and need for mechanical ventilation.

Conclusion: Circulating levels of copeptin at ICU admission independently predict 30-day mortality in patients admitted to a medical ICU.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170436PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5261612PMC
August 2017