Publications by authors named "Daniel Duerschmied"

157 Publications

Platelets in Myocardial Ischemia/Reperfusion Injury.

Hamostaseologie 2022 Jul 29. Epub 2022 Jul 29.

Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.

Coronary artery disease, including myocardial infarction (MI), remains a leading cause of global mortality. Rapid reperfusion therapy is key to the improvement of patient outcome but contributes substantially to the final cardiac damage. This phenomenon is called "ischemia/reperfusion injury (IRI)." The underlying mechanisms of IRI are complex and not fully understood. Contributing cellular and molecular mechanisms involve the formation of microthrombi, alterations in ion concentrations, pH shifts, dysregulation of osmolality, and, importantly, inflammation. Beyond their known action as drivers of the development of coronary plaques leading to MI, platelets have been identified as important mediators in myocardial IRI. Circulating platelets are activated by the IRI-provoked damages in the vascular endothelium. This leads to platelet adherence to the reperfused endothelium, aggregation, and the formation of microthrombi. Furthermore, activated platelets release vasoconstrictive substances, act via surface molecules, and enhance leukocyte infiltration into post-IR tissue, that is, via platelet-leukocyte complexes. A better understanding of platelet contributions to myocardial IRI, including their interaction with other lesion-associated cells, is necessary to develop effective treatment strategies to prevent IRI and further improve the condition of the reperfused myocardium. In this review, we briefly summarize platelet properties that modulate IRI. We also describe the beneficial impacts of antiplatelet agents as well as their mechanisms of action in IRI beyond classic effects.
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http://dx.doi.org/10.1055/a-1739-9351DOI Listing
July 2022

Thrombelastography Compared with Multiple Impedance Aggregometry to Assess High On-Clopidogrel Reactivity in Patients with Atrial Fibrillation Undergoing Percutaneous Coronary Intervention.

J Clin Med 2022 Jul 21;11(14). Epub 2022 Jul 21.

Department of Cardiology and Angiology, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Background: High on-clopidogrel platelet reactivity (HPR) following percutaneous coronary intervention (PCI) is associated with increased ischemic risk. It is unclear whether conventional definitions of HPR apply to patients with concomitant oral anticoagulation (OAC). This study aimed to compare the performance of multiple platelet aggregometry (MEA) and thrombelastography (TEG) to detect HPR in patients with atrial fibrillation (AF) and indication for an OAC.

Methods: In this observational single-center cohort study, MEA and TEG were performed in patients with AF with an indication for OAC on day 1 to 3 after PCI. The primary outcome was HPR as assessed by MEA (ADP area under the curve ≥ 46 units [U]) or TEG (MA ≥ 47 mm), respectively. The secondary exploratory outcomes were a composite of all-cause death, myocardial infarction (MI) or stroke and bleeding, as defined by the International Society on Thrombosis and Hemostasis, at 6 months.

Results: Platelet function of 39 patients was analyzed. The median age was 78 (interquartile range [IQR] was 72-82) years. 25 (64%) patients were male, and 19 (49%) presented with acute coronary syndrome. All patients received acetylsalicylic acid and clopidogrel prior to PCI. Median (IQR) ADP-induced aggregation, MA, TRAP-induced aggregation, and MA were 9 (6-15) U, 50 (43-60) mm, 54 (35-77) U and 65 (60-67) mm, respectively. The rate of HPR was significantly higher if assessed by TEG compared with MEA (25 [64%] vs. 1 [3%]; < 0.001). Within 6 months, four (10%) deaths, one (3%) MI and nine (23%) bleeding events occurred.

Conclusion: In patients with AF undergoing PCI, the rates of HPR detected by TEG were significantly higher compared with MEA. Conventional cut-off values for HPR as proposed by consensus documents may need to be re-evaluated for this population at high ischemic and bleeding risk. Further studies are needed to assess the association with outcomes.
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http://dx.doi.org/10.3390/jcm11144237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320091PMC
July 2022

Survival of Patients Treated with Extracorporeal Hemoadsorption and Extracorporeal Membrane Oxygenation: Results from a Nation-Wide Registry.

ASAIO J 2022 Aug 3. Epub 2022 Aug 3.

From the Interdisciplinary Medical Intensive Care, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Extracorporeal hemoadsorption with the CytoSorb adsorber is increasingly being used during the past years. The use in combination with extracorporeal membrane oxygenation (ECMO) is feasible, but frequency of its use and outcomes have not been assessed in larger cohorts. We analyzed all patients treated with veno-venous (VV) ECMO either with or without CytoSorb in Germany from 2017 to 2019. Data were retrieved from a nationwide claim dataset collected by the Research Data Center of the Federal Bureau of Statistics. During this three-year episode, 7,699 patients were treated with VV ECMO. Among these, the number of CytoSorb-treated patients constantly increased from 156 (6.6%) in 2017 to 299 (11.8%) in 2019. In this large cohort hemoadsorption with the CytoSorb adsorber was associated with higher mortality and increased treatment costs. Due to limited information in the dataset about the severity of disease comparison of outcomes of patients treated with and without CytoSorb has to be interpreted with caution. Further studies have to examine if this finding is due to a negative effect of hemoadsorption with the CytoSorb device or is rather to be attributed to disease severity.
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http://dx.doi.org/10.1097/MAT.0000000000001788DOI Listing
August 2022

Enoxaparin for primary thromboprophylaxis in symptomatic outpatients with COVID-19 (OVID): a randomised, open-label, parallel-group, multicentre, phase 3 trial.

Lancet Haematol 2022 Aug 30;9(8):e585-e593. Epub 2022 Jun 30.

Department of Angiology, University Hospital Zurich, Zurich, Switzerland; University of Zurich, Zurich, Switzerland.

Background: COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.

Methods: OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50-70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.

Findings: At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53-62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37-2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Interpretation: These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.

Funding: SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.
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http://dx.doi.org/10.1016/S2352-3026(22)00175-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9243568PMC
August 2022

Diagnostic value of sST2, VCAM-1 and adiponectin in patients with breast cancer to predict anti-tumor treatment-related cardiac events: A pilot study.

Oncol Res Treat 2022 Jun 28. Epub 2022 Jun 28.

Aim The present exploratory study investigated the diagnostic value of inflammatory markers in patients with breast cancer to predict anti-tumour treatment-related cardiac events. Methods Twenty-one patients with breast cancer were enrolled in this prospective observational study and followed over 6 months. Transthoracic echocardiography and measurement of cardiac (N terminal prohormone of brain natriuretic peptide (NT proBNP), Troponin I (TnI)) and inflammatory biomarkers (vascular adhesion molecule 1 (VCAM-1), soluble suppression of tumorigenesis-2 (sST2), adiponectin) was performed at 3-month intervals (baseline, follow-up, final visit). Cardiac events were defined as decrease in left ventricular ejection fraction (LVEF, decrease by 10 % or < 50 %) or increase in global longitudinal strain (GLS, increase by 15 % or > 16 %), as a more sensitive marker of LV function. Results Cardiac deterioration was observed in nine out of 21 patients (event group). While LVEF did not differ significantly between the two groups (event vs no event) at any visit, GLS was significantly higher during follow-up (follow-up: event -16 ± 3.3 % vs no event -18 ± 1.6 %, p = 0.04, final visit: event -16 ± 2.1 % vs no event -19 ± 1.9 %, p = 0.003). NT-proBNP was numerically higher in patients with a cardiac event during all visits, with NT-proBNP negatively correlated with LVEF and MAPSE (both r = -0.33, p = 0.02), whereas GLS (r = 0.40, p = 0.006), TnI (r = 0.44, p = 0.001), and VCAM-1 (r = 0.48, p = 0.003) showed a positive association with NT-proBNP. In comparison, higher VCAM 1 and sST2 concentrations were detected in the event group at both baseline and the final visit, with a significant difference for baseline (VCAM-1: p = 0.02; sST2: p = 0.03). Adiponectin was also lower in patients with a treatment-related event. Thresholds for VCAM 1 > 762 ng/ml and sST2 > 18.7 ng/ml, as detected by ROC analysis, correlated best with the primary endpoint. Conclusion Cardiac events during anti-tumour treatment in patients with breast cancer are relatively common. Inflammatory markers such as VCAM-1 or sST2 were associated with an increased likelihood for occurrence of a treatment-related event, which may therefore hold the promise to better identify patients at high risk.
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http://dx.doi.org/10.1159/000525683DOI Listing
June 2022

Adverse Cardiovascular Effects of Anti-tumor Therapies in Patients With Breast Cancer: A Single-center Cross-sectional Analysis.

Anticancer Res 2022 Jun;42(6):3075-3084

Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Centre Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;

Background/aim: Cardiotoxicity due to antitumor therapy is a dreaded complication and could thus impact the prognosis of patients with breast cancer. This study sought to analyze the occurrence of adverse cardiovascular events and to identify potential risk factors.

Patients And Methods: A total of 136 patients with breast cancer were divided into two groups based on the occurrence of treatment-related cardiovascular toxicity [event 47 (35%) vs. no event 89 (65%)]. Patients were followed over a median of 45 months (range=37-83 months).

Results: Most common events were thromboembolic complications (26%), followed by heart failure (15%) and acute toxic cardiomyopathy (5%), with a reduced left ventricular ejection fraction [LVEF (%), no event 59±5.0 vs. event 55±11, p=0.01 ]. Patients with leftsided breast cancer and an advanced stage disease had a higher risk of developing adverse cardiovascular events. The highest risk was found for patients with a high number of cardiovascular risk factors. In addition to LVEF, mitral annular plane systolic excursion was also significantly reduced in the event group, while there was a trend for higher global longitudinal strain. During follow-up, 26 patients (19.1%) deceased, whereof 12 had a treatment-related cardiovascular event, but without statistical difference.

Conclusion: Treatment-related cardiovascular events are relatively common in about one third of patients with breast cancer. Women with a cardiovascular risk profile or an advanced stage disease had a higher risk for adverse events. Despite the treatment-related cardiac deterioration, no difference in mortality was observed during follow up.
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http://dx.doi.org/10.21873/anticanres.15795DOI Listing
June 2022

Clinical analysis on diagnostic accuracy of Bosch Vivalytic SARS-CoV-2 point-of-care test and evaluation of cycle threshold at admission for COVID-19 risk assessment.

BMC Infect Dis 2022 May 23;22(1):486. Epub 2022 May 23.

Department of Cardiology and Medical Intensive Care, Augustinerinnen Hospital, Academic Teaching Hospital University of Cologne, Cologne, Germany.

Background: Point-of-care (POC) polymerase chain reaction (PCR) tests have the ability to improve testing efficiency in the Coronavirus disease 2019 (COVID-19) pandemic. However, real-world data on POC tests is scarce.

Objective: To evaluate the efficiency of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) POC test in a clinical setting and examine the prognostic value of cycle threshold (CT) on admission on the length of hospital stay (LOS) in COVID-19 patients.

Methods: Patients hospitalised between January and May 2021 were included in this prospective cohort study. Patients' nasopharyngeal swabs were tested for SARS-CoV-2 with Allplex™2019-nCoV (Seegene Inc.) real-time (RT) PCR assay as gold standard as well as a novel POC test (Bosch Vivalytic SARS-CoV-2 [Bosch]) and the SARS-CoV-2 Rapid Antigen Test (Roche) accordingly. Clinical sensitivity and specificity as well as inter- and intra-assay variability were analyzed.

Results: 120 patients met the inclusion criteria with 46 (38%) having a definite COVID-19 diagnosis by RT-PCR. Bosch Vivalytic SARS-CoV-2 POC had a sensitivity of 88% and specificity of 96%. The inter- and intra- assay variability was below 15%. The CT value at baseline was lower in patients with LOS ≥ 10 days when compared to patients with LOS < 10 days (27.82 (± 4.648) vs. 36.2 (25.9-39.18); p = 0.0191). There was a negative correlation of CT at admission and LOS (r[44] = - 0.31; p = 0.038) but only age was associated with the probability of an increased LOS in a multiple logistic regression analysis (OR 1.105 [95% CI, 1.03-1.19]; p = 0.006).

Conclusion: Our data indicate that POC testing with Bosch Vivalytic SARS-CoV-2 is a valid strategy to identify COVID-19 patients and decrease turnaround time to definite COVID-19 diagnosis. Also, our data suggest that age at admission possibly with CT value as a combined parameter could be a promising tool for risk assessment of increased length of hospital stay and severity of disease in COVID-19 patients.
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http://dx.doi.org/10.1186/s12879-022-07447-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9125343PMC
May 2022

Case Report: Transient Increase of CMR T1 Mapping Indices in a Patient With COVID-19 mRNA Vaccine Induced Acute Myocarditis.

Front Cardiovasc Med 2022 27;9:880717. Epub 2022 Apr 27.

First Department of Medicine, Faculty of Medicine Mannheim, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.

Background: Acute myocarditis is commonly associated with viral infections, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Myocarditis following mRNA COVID-19 vaccination has also been reported, however this is rare and usually resolves within days or weeks. We present a case of acute myocarditis reported after vaccination with mRNA-1273 COVID-19 vaccine (Moderna) diagnosed using cardiac magnetic resonance imaging (CMR). This report describes the utility of CMR in the diagnosis and follow-up of such patients using parameters which could suggest the clinical course of myocarditis.

Case Summary: A 23-year-old male presented in the emergency department with complaints of chest pain radiating to the left arm following vaccination with the second dose of COVID-19 mRNA-1273 vaccine (Moderna). Patient's history revealed an incidence of myocarditis in the past. CMR showed a mid-range left ventricular ejection fraction (38%) and subepicardial late gadolinium enhancement (LGE) in the inferolateral and apical myocardial segments with diffuse elevation of native T1 mapping relaxation times in all myocardial segments. The patient was admitted briefly in the intensive care unit and after a favorable clinical course was discharged from the hospital in stable condition. A follow-up CMR after 3 months revealed normalization of LVEF (57%) and native T1- times in most segments. Scarred myocardium reflecting chronic myocarditis continued to show elevated T1 times.

Conclusions: Our patient presenting with acute myocarditis after recent COVID-19 mRNA vaccination reported a favorable clinical course. CMR revealed increased T1 mapping relaxation times diffusely spread across the myocardium and an impairment of the left ventricular function (LVEF) during the acute phase. However, the LVEF as well as the T1 times normalized at follow-up in all segments except for myocardium affected by chronic myocarditis.
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http://dx.doi.org/10.3389/fcvm.2022.880717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9091656PMC
April 2022

Early and Rapid Identification of COVID-19 Patients with Neutralizing Type I Interferon Auto-antibodies.

J Clin Immunol 2022 May 5. Epub 2022 May 5.

Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Freiburgstrasse, CH-3010, Bern, Switzerland.

Purpose: Six to 19% of critically ill COVID-19 patients display circulating auto-antibodies against type I interferons (IFN-AABs). Here, we establish a clinically applicable strategy for early identification of IFN-AAB-positive patients for potential subsequent clinical interventions.

Methods: We analyzed sera of 430 COVID-19 patients from four hospitals for presence of IFN-AABs by ELISA. Binding specificity and neutralizing activity were evaluated via competition assay and virus-infection-based neutralization assay. We defined clinical parameters associated with IFN-AAB positivity. In a subgroup of critically ill patients, we analyzed effects of therapeutic plasma exchange (TPE) on the levels of IFN-AABs, SARS-CoV-2 antibodies and clinical outcome.

Results: The prevalence of neutralizing AABs to IFN-α and IFN-ω in COVID-19 patients from all cohorts was 4.2% (18/430), while being undetectable in an uninfected control cohort. Neutralizing IFN-AABs were detectable exclusively in critically affected (max. WHO score 6-8), predominantly male (83%) patients (7.6%, 18/237 for IFN-α-AABs and 4.6%, 11/237 for IFN-ω-AABs in 237 patients with critical COVID-19). IFN-AABs were present early post-symptom onset and at the peak of disease. Fever and oxygen requirement at hospital admission co-presented with neutralizing IFN-AAB positivity. IFN-AABs were associated with lower probability of survival (7.7% versus 80.9% in patients without IFN-AABs). TPE reduced levels of IFN-AABs in three of five patients and may increase survival of IFN-AAB-positive patients compared to those not undergoing TPE.

Conclusion: IFN-AABs may serve as early biomarker for the development of severe COVID-19. We propose to implement routine screening of hospitalized COVID-19 patients for rapid identification of patients with IFN-AABs who most likely benefit from specific therapies.
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http://dx.doi.org/10.1007/s10875-022-01252-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9069123PMC
May 2022

Platelet Subtypes in Inflammatory Settings.

Front Cardiovasc Med 2022 7;9:823549. Epub 2022 Apr 7.

Department of Cardiology and Angiology I, Heart Center, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.

In addition to their essential role in hemostasis and thrombosis, platelets also modulate inflammatory reactions and immune responses. This is achieved by specialized surface receptors as well as secretory products including inflammatory mediators and cytokines. Platelets can support and facilitate the recruitment of leukocytes into inflamed tissue. The various properties of platelet function make it less surprising that circulating platelets are different within one individual. Platelets have different physical properties leading to distinct subtypes of platelets based either on their function (procoagulant, aggregatory, secretory) or their age (reticulated/immature, non-reticulated/mature). To understand the significance of platelet phenotypic variation, qualitatively distinguishable platelet phenotypes should be studied in a variety of physiological and pathological circumstances. The advancement in proteomics instrumentation and tools (such as mass spectrometry-driven approaches) improved the ability to perform studies beyond that of foundational work. Despite the wealth of knowledge around molecular processes in platelets, knowledge gaps in understanding platelet phenotypes in health and disease exist. In this review, we report an overview of the role of platelet subpopulations in inflammation and a selection of tools for investigating the role of platelet subpopulations in inflammation.
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http://dx.doi.org/10.3389/fcvm.2022.823549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021412PMC
April 2022

P2Y-dependent activation of hematopoietic stem and progenitor cells promotes emergency hematopoiesis after myocardial infarction.

Basic Res Cardiol 2022 03 30;117(1):16. Epub 2022 Mar 30.

Department of Cardiology and Angiology I, University Heart Center Freiburg - Bad Krozingen, Medical Faculty, University of Freiburg, Hugstetterstr. 55, 79106, Freiburg, Germany.

Emergency hematopoiesis is the driving force of the inflammatory response to myocardial infarction (MI). Increased proliferation of hematopoietic stem and progenitor cells (LSK) after MI enhances cell production in the bone marrow (BM) and replenishes leukocyte supply for local cell recruitment to the infarct. Decoding the regulation of the inflammatory cascade after MI may provide new avenues to improve post-MI remodeling. In this study, we describe the influence of adenosine diphosphate (ADP)-dependent P2Y-mediated signaling on emergency hematopoiesis and cardiac remodeling after MI. Permanent coronary ligation was performed to induce MI in a murine model. BM activation, inflammatory cell composition and cardiac function were assessed using global and platelet-specific gene knockout and pharmacological inhibition models for P2Y. Complementary in vitro studies allowed for investigation of ADP-dependent effects on LSK cells. We found that ADP acts as a danger signal for the hematopoietic BM and fosters emergency hematopoiesis by promoting Akt phosphorylation and cell cycle progression. We were able to detect P2Y in LSK, implicating a direct effect of ADP on LSK via P2Y signaling. P2Y knockout and P2Y inhibitor treatment with prasugrel reduced emergency hematopoiesis and the excessive inflammatory response to MI, translating to lower numbers of downstream progeny and inflammatory cells in the blood and infarct. Ultimately, P2Y inhibition preserved cardiac function and reduced chronic adverse cardiac remodeling after MI. P2Y-dependent signaling is involved in emergency hematopoiesis after MI and fuels post-ischemic inflammation, proposing a novel, non-canonical value for P2Y antagonists beyond inhibition of platelet-mediated atherothrombosis.
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http://dx.doi.org/10.1007/s00395-022-00927-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967792PMC
March 2022

P2X deficiency reduces atherosclerosis and plaque inflammation in mice.

Sci Rep 2022 02 18;12(1):2801. Epub 2022 Feb 18.

Department of Cardiology and Angiology I, University Heart Center Freiburg, Medical Faculty, University of Freiburg, Hugstetter Straße 55, 79106, Freiburg, Germany.

Extracellular adenosine-5'-triphosphate (ATP) acts as an import signaling molecule mediating inflammation via purinergic P2 receptors. ATP binds to the purinergic receptor P2X and promotes inflammation via increased expression of pro-inflammatory cytokines. Because of the central role of inflammation, we assumed a functional contribution of the ATP-P2X-axis in atherosclerosis. Expression of P2X was increased in atherosclerotic aortic arches from low-density lipoprotein receptor-deficient mice being fed a high cholesterol diet as assessed by real-time polymerase chain reaction and immunohistochemistry. To investigate the functional role of P2X in atherosclerosis, P2X-deficient mice were crossed with low-density lipoprotein receptor-deficient mice and fed high cholesterol diet. After 16 weeks, P2X-deficient mice developed smaller atherosclerotic lesions compared to P2X-competent mice. Furthermore, intravital microscopy showed reduced ATP-induced leukocyte rolling at the vessel wall in P2X-deficient mice. Mechanistically, we found a reduced RNA expression of CC chemokine ligand 2 (CCL-2), C-X-C motif chemokine-1 (CXCL-1), C-X-C motif chemokine-2 (CXCL-2), Interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) as well as a decreased nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3)-inflammasome priming in atherosclerotic plaques from P2X-deficient mice. Moreover, bone marrow derived macrophages isolated from P2X-deficient mice revealed a reduced ATP-mediated release of CCL-2, CC chemokine ligand 5 (CCL-5), Interleukin-1β (IL-1β) and IL-6. Additionally, P2X-deficient mice shared a lower proportion of pro-inflammatory Ly6C monocytes and a higher proportion of anti-inflammatory Ly6C monocytes, and expressend less endothelial VCAM-1. Finally, increased P2X expression in human atherosclerotic lesions from carotid endarterectomy was found, indicating the importance of potential implementations of this study's findings for human atherosclerosis. Collectively, P2X deficiency reduced experimental atherosclerosis, plaque inflammation and inflammasome priming, pointing to P2X as a potential therapeutic target in the fight against atherosclerosis.
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http://dx.doi.org/10.1038/s41598-022-06706-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857235PMC
February 2022

Cytokine adsorption in patients with post-cardiac arrest syndrome after extracorporeal cardiopulmonary resuscitation (CYTER) - A single-centre, open-label, randomised, controlled trial.

Resuscitation 2022 04 7;173:169-178. Epub 2022 Feb 7.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Germany.

Aim: To investigate the effect of cytokine adsorption in patients receiving extracorporeal cardiopulmonary resuscitation (ECPR) after cardiac arrest.

Methods: CYTER was a single-centre, open-label, randomised, controlled trial. Patients selected for ECPR at the University Medical Center Freiburg (Freiburg, Germany) were assigned to extracorporeal membrane oxygenation (ECMO) support with or without cytokine adsorption (1:1) using the CytoSorb adsorber, incorporated into the ECMO, replaced every 24 hours, and removed after 72 hours. The primary endpoint was serum interleukin (IL)-6 concentration at 72 hours (intention-to-treat analysis). Secondary endpoints included 30-day survival, vasopressor support and biomarkers of end-organ injury.

Results: Of 50 patients enrolled in the trial, 26 (52%) were treated with cytokine adsorption and 24 (48%) without. Nine patients were excluded (informed consent could not be obtained); 41 patients were therefore included in the primary analysis. Median IL-6 levels (IQR) decreased from 408.0(93.4-906.5) to 324.0 (134.3-4617.3) pg/mL and increased from 133.0 (56.2-528.5) to 241.0 (132.8-718.0) pg/mL in the cytokine adsorption and control group, respectively (linear regression for treatment [cytokine adsorption vs control]: p = 0.48). Three (14%) of 22 patients treated with cytokine adsorption and 8 (42%) of 19 patients treated without cytokine adsorption survived to day 30 (HR = 1.85, 95% CI 0.86-4.01; p = 0.10). Vasopressor support and NSE, S100b, troponin T, CRP and PCT levels were similar between groups.

Conclusion: Cytokine adsorption in patients receiving ECPR did not reduce serum IL-6 and had no significant effect on survival, vasopressor support, or biomarkers of injury.

Clinical Trial Registration: ClinicalTrials.gov: NCT03685383.
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http://dx.doi.org/10.1016/j.resuscitation.2022.02.001DOI Listing
April 2022

On the Use of Hemadsorption with CytoSorb in Patients with Septic Shock. Comment on Kogelmann et al. First Evaluation of a New Dynamic Scoring System Intended to Support Prescription of Adjuvant CytoSorb Hemoadsorption Therapy in Patients with Septic Shock. 2021, , 2939.

J Clin Med 2022 Jan 11;11(2). Epub 2022 Jan 11.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, 79106 Freiburg, Germany.

With great interest we read the article by Klaus Kogelmann and co-authors on the "First Evaluation of a New Dynamic Scoring System Intended to Support Prescription of Adjuvant CytoSorb Hemoadsorption Therapy in Patients with Septic Shock" [...].
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http://dx.doi.org/10.3390/jcm11020334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8781718PMC
January 2022

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Nat Rev Cardiol 2022 07 13;19(7):475-495. Epub 2022 Jan 13.

Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and D-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.
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http://dx.doi.org/10.1038/s41569-021-00665-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8757397PMC
July 2022

P2Y Inhibition in Murine Myocarditis Results in Reduced Platelet Infiltration and Preserved Ejection Fraction.

Cells 2021 12 4;10(12). Epub 2021 Dec 4.

Heart Center Freiburg University, Department of Cardiology and Angiology I, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.

Previous mouse studies have shown the increased presence of platelets in the myocardium during early stages of myocarditis and their selective detection by MRI. Here, we aimed to depict early myocarditis using molecular contrast-enhanced ultrasound of activated platelets, and to evaluate the impact of a P2Y receptor platelet inhibition. Experimental autoimmune myocarditis was induced in BALB/c mice by subcutaneous injection of porcine cardiac myosin and complete Freund adjuvant (CFA). Activated platelets were targeted with microbubbles (MB) coupled to a single-chain antibody that binds to the "ligand-induced binding sites" of the GPIIb/IIIa-receptor (=LIBS-MB). Alongside myocarditis induction, a group of mice received a daily dose of 100 g prasugrel for 1 month. Mice injected with myosin and CFA had a significantly deteriorated ejection fraction and histological inflammation on day 28 compared to mice only injected with myosin. Platelets infiltrated the myocardium before reduction in ejection fraction could be detected by echocardiography. No selective binding of the LIBS-MB contrast agent could be detected by either ultrasound or histology. Prasugrel therapy preserved ejection fraction and significantly reduced platelet aggregates in the myocardium compared to mice without prasugrel therapy. Therefore, P2Y inhibition could be a promising early therapeutic target in myocarditis, requiring further investigation.
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http://dx.doi.org/10.3390/cells10123414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699761PMC
December 2021

Thromboinflammation as a Driver of Venous Thromboembolism.

Hamostaseologie 2021 Dec 23;41(6):428-432. Epub 2021 Dec 23.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Thrombus formation has been identified as an integral part in innate immunity, termed immunothrombosis. Activation of host defense systems is known to result in a procoagulant environment. In this system, cellular players as well as soluble mediators interact with each other and their dysregulation can lead to the pathological process of thromboinflammation. These mechanisms have been under intensified investigation during the COVID-19 pandemic. In this review, we focus on the underlying mechanisms leading to thromboinflammation as one trigger of venous thromboembolism.
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http://dx.doi.org/10.1055/a-1661-0257DOI Listing
December 2021

Complement system component dysregulation is a distinctive feature of COVID-19 disease: a prospective and comparative analysis of patients admitted to the emergency department for suspected COVID-19 disease.

J Thromb Thrombolysis 2022 May 14;53(4):788-797. Epub 2021 Dec 14.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

The complement system (CS) plays a pivotal role in Coronavirus disease 2019 (COVID-19) pathophysiology. The objective of this study was to provide a comparative, prospective data analysis of CS components in an all-comers cohort and COVID-19 patients. Patients with suspected COVID-19 infection admitted to the Emergency department were grouped for definite diagnosis of COVID-19 and no COVID-19 accordingly. Clinical presentation, routine laboratory and von Willebrand factor (vWF) antigen as well as CS components 3, 4 and activated 5 (C5a) were assessed. Also, total complement activity via the classical pathway (CH50) was determined. Levels of calprotectin in serum were measured using an automated quantitative lateral flow assay. We included 80 patients in this prospective trial. Of those 19 (23.7%) were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with COVID-19 had higher levels of CS components 5a and 4 (54.79 [24.14-88.79] ng/ml vs. 35 [23.15-46.1] ng/ml; p = 0.0433 and 0.3772 [± 0.1056] g/L vs. 0.286 [0.2375-0.3748] g/L; p = 0.0168). COVID-19 patients had significantly higher levels of vWF antigen when compared to the control group (288.3 [± 80.26] % vs. 212 [151-320] %; p = 0.0469). There was a significant correlation between CS C3 and 5a with vWF antigen (r = 0.5957 [p = 0.0131] and r = 0.5015 [p = 0.042]) in COVID-19 patients. There was no difference in calprotectin plasma levels (4.786 [± 2.397] µg/ml vs. 4.233 [± 2.142] µg/ml; p = 0.4175) between both groups. This prospective data from a single centre all-comers cohort accentuates altered levels of CS components as a distinct feature of COVID-19 disease. Deregulation of CS component 3 and C5a are associated with increased vWF antigen possibly linking vascular damage to alternative CS activation in COVID-19.
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http://dx.doi.org/10.1007/s11239-021-02617-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8668393PMC
May 2022

Coronary angiography following out-of-hospital cardiac arrest (OHCA): a review of outcomes and clinical considerations.

Expert Rev Cardiovasc Ther 2021 Dec 15;19(12):1045-1051. Epub 2021 Dec 15.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Introduction: In patients suffering a sudden out-of-hospital cardiac arrest (OHCA), the prevalence of a coronary artery lesion as the underlying cause is relatively high, but many other causes have been described. For this reason, identifying patients who would benefit from an emergency coronary angiography is important.

Areas Covered: In the present manuscript, we reviewed the literature covering some relevant studies regarding the role of coronary angiography in patients with OHCA, including our local algorithm for the management of patients with OHCA. We particularly focused on the selection of patients who would benefit from an emergency coronary angiography, the time period until the performance of the angiography, the role of extracorporeal cardiopulmonary resuscitation (ECPR), the identification of a coronary artery lesion as the underlying cause of cardiac arrest and clinical outcomes.

Expert Opinion: In summary, a local standard algorithm for the management of patients with OHCA appears favorable. An emergency coronary angiography should be advised in patients with a presumed cardiac cause and without obvious non-cardiac cause. A shockable initial rhythm, ST elevation in the post-resuscitation ECG, a previously known coronary artery disease, and ECPR are important predictors of cardiac cause of OHCA.
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http://dx.doi.org/10.1080/14779072.2021.2013815DOI Listing
December 2021

Long-term survival and health-related quality of life in patients with severe acute respiratory distress syndrome and veno-venous extracorporeal membrane oxygenation support.

Crit Care 2021 Nov 29;25(1):410. Epub 2021 Nov 29.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: There is limited information about the long-term outcome of patients suffering from acute respiratory distress syndrome (ARDS) supported with veno-venous extracorporeal membrane oxygenation (VV ECMO). Most studies focused on short- to mid-term follow-up. We aimed to investigate long-term survival and health-related quality of life (HRQL) in these patients.

Methods: We report retrospective data from a single-centre registry of patients with severe ARDS treated with VV ECMO at the Interdisciplinary Medical Intensive Care Unit at the Medical Centre, University of Freiburg, Germany, between 10/2010 and 06/2019. Follow-up data of all patients that survived the index hospitalisation were collected by telephone interviews from 02/2020 till 09/2020. Long-term survival, HRQL (Short-Form Health Survey-36 (SF-36), St. Georges Respiratory Questionnaire (SGRQ), Hospital Anxiety and Depression Scale (HADS)) and the return to work rate were documented.

Results: In total, 289 patients were treated with VV ECMO during the study period (median age 55 years, 67% males, hospital survival 45%). After a median duration of 3.9 years, follow-up assessment was complete in 94 of 129 hospital survivors (73%). Fifty-three patients completed the HRQL assessment. Hospital survivors showed a high 6- and 12-month survival rate (89% and 85%, respectively). Estimated survival rate of those discharged alive from ICU was 68.5% (95%-CI 56.9-80.1%) after 9.7 years. These patients reported high levels of HRQL (median SF-36 total score 73) and only few pulmonary (median SGRQ total score 19) and mental limitations (median HAD-D score 2 and HAD-A score 3). In total, 80% of the patients were able to resume employment.

Conclusion: This analysis of VV ECMO patients showed favourable long-term survival and high levels of HRQL suggesting promising prospects for VV ECMO survivors.
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http://dx.doi.org/10.1186/s13054-021-03821-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8628468PMC
November 2021

Advantages of score-based delirium detection compared to a clinical delirium assessment-a retrospective, monocentric cohort study.

PLoS One 2021 29;16(11):e0259841. Epub 2021 Nov 29.

Faculty of Medicine, Department of Cardiology and Angiology I, Heart Center Freiburg University, University of Freiburg, Freiburg, Germany.

Purpose: Delirium is an underdiagnosed complication on intensive care units (ICU). We hypothesized that a score-based delirium detection using the Nudesc score identifies more patients compared to a traditional diagnosis of delirium by ICU physicians.

Methods: In this retrospective study, all patients treated on a general medical ICU with 30 beds in a university hospital in 2019 were analyzed. Primary outcome was a documented physician diagnosis of delirium, or a delirium score ≥2 using the Nudesc.

Results: In 205/943 included patients (21.7%), delirium was diagnosed by ICU physicians compared to 438/943 (46.4%; ratio 2.1) by Nudesc≥2. Both assessments were independent predictors of ICU stay (p<0.01). The physician diagnosis however was no independent predictor of mortality (OR 0.98 (0.57-1.72); p = 0.989), in contrast to the score-based diagnosis (OR 2.31 (1.30-4.10); p = 0.004). Subgroup analysis showed that physicians underdiagnosed delirium in case of hypoactive delirium and delirium in patients with female gender and in patients with an age below 60 years.

Conclusion: Delirium in patients with hypoactive delirium, female patients and those below 60 years was underdiagnosed by physicians. The score-based delirium diagnosis detected delirium more frequently and correlated with ICU mortality and stay.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0259841PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8629257PMC
January 2022

Extracellular Vesicles Are Associated With Outcome in Veno-Arterial Extracorporeal Membrane Oxygenation and Myocardial Infarction.

Front Cardiovasc Med 2021 4;8:747453. Epub 2021 Nov 4.

Department of Cardiology and Angiology I, University Heart Center Freiburg - Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is being increasingly applied in patients with circulatory failure, but mortality remains high. An inflammatory response syndrome initiated by activation of blood components in the extracorporeal circuit may be an important contributing factor. Patients with ST-elevation myocardial infarction (STEMI) may also experience a systemic inflammatory response syndrome and are at risk of developing cardiogenic shock and cardiac arrest, both indications for VA-ECMO. Extracellular vesicles (EV) are released by activated cells as mediators of intercellular communication and may serve as prognostic biomarkers. Cardiomyocyte EV, released upon myocardial ischemia, hold strong potential for this purpose. The aim of this study was to assess the EV-profile in VA-ECMO and STEMI patients and the association with outcome. In this prospective observational study, blood was sampled on day 1 after VA-ECMO initiation or myocardial reperfusion (STEMI patients). EV were isolated by differential centrifugation. Leukocyte, platelet, endothelial, erythrocyte and cardiomyocyte (caveolin-3) Annexin V EV were identified by flow cytometry. EV were assessed in survivors vs. non-survivors of VA-ECMO and in STEMI patients with normal-lightly vs. moderately-severely reduced left ventricular function. Logistic regression was conducted to determine the predictive accuracy of EV. Pearson correlation analysis of EV with clinical parameters was performed. Eighteen VA-ECMO and 19 STEMI patients were recruited. Total Annexin V, cardiomyocyte and erythrocyte EV concentrations were lower ( ≤ 0.005) while the percentage of platelet EV was increased in VA-ECMO compared to STEMI patients ( = 0.002). Total Annexin V EV were increased in non-survivors of VA-ECMO ( = 0.01), and higher levels were predictive of mortality (AUC = 0.79, = 0.05). Cardiomyocyte EV were increased in STEMI patients with moderately-severely reduced left ventricular function ( = 0.03), correlated with CK-MB ( = 0.57, = 0.02) and time from reperfusion to blood sampling ( = 0.58, = 0.01). Leukocyte EV correlated with the number of coronary stents placed ( = 0.60, = 0.02). Elevated total Annexin V EV on day 1 of VA-ECMO are predictive of mortality. Increased cardiomyocyte EV on day 1 after STEMI correlate with infarct size and are associated with poor outcome. These EV may aid in the early identification of patients at risk of poor outcome, helping to guide clinical management.
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http://dx.doi.org/10.3389/fcvm.2021.747453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600355PMC
November 2021

Severe dysbiosis and specific Haemophilus and Neisseria signatures as hallmarks of the oropharyngeal microbiome in critically ill COVID-19 patients.

Clin Infect Dis 2021 Oct 25. Epub 2021 Oct 25.

Department of Medicine II, Section of Hepatology, University Medical Center Mannheim, University of Heidelberg, Mannheim, and Center for Preventive Medicine and Digital Health Baden-Württemberg, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Background: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with Coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict COVID-19 illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders.

Methods: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multi-center, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate and severe COVID-19 (n=322 participants).

Results: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features.

Conclusion: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.
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http://dx.doi.org/10.1093/cid/ciab902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586732PMC
October 2021

Medical history of coronary artery disease and time to electrocardiogram in the emergency department: a real-life, single-center, retrospective analysis.

BMC Cardiovasc Disord 2021 10 7;21(1):480. Epub 2021 Oct 7.

Department of Cardiology and Medical Intensive Care, Augustinerinnen Hospital, Academic Teaching Hospital University of Cologne, Cologne, Germany.

Background: Timely acquisition of 12-lead Electrocardiogram (ECG) in the emergency department (ED) is crucial and recommended by current guidelines.

Objectives: To evaluate the association of medical history of coronary artery disease (hCAD) on door-to-ECG time in the ED.

Methods: In this single center, retrospective cohort study, patients admitted to ED for cardiac evaluation were grouped according to hCAD and no hCAD. The primary outcome was door-to-ECG time. A multivariate analysis adjusted for the cofounders sex, age, type of referral and shift was performed to evaluate the association of hCAD with door-to-ECG time.

Results: 1101 patients were included in this analysis. 362 patients (33%) had hCAD. Patients with hCAD had shorter door-to-ECG time (20 min. [Inter Quartile Range [IQR] 13-30] vs. 22 min. [IQR 14-37]; p < 0.001) when compared to patients with no hCAD. In a multivariable regression analysis hCAD was significantly associated with a shorter door-to-ECG time (- 3 min [p = 0.007; 95% confidence Interval [CI] - 5.16 to - 0.84 min]).

Conclusion: In this single center registry, hCAD was associated with shorter door-to-ECG time. In patients presenting in ED for cardiac evaluation, timely ECG diagnostic should be facilitated irrespective of hCAD.
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http://dx.doi.org/10.1186/s12872-021-02274-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8496093PMC
October 2021

Peripheral serotonin lacks effects on endothelial adhesion molecule expression in acute inflammation.

J Thromb Haemost 2022 01 8;20(1):222-229. Epub 2021 Oct 8.

Department of Cardiology and Angiology I, Heart Center, University of Freiburg, Freiburg, Germany.

Background: Peripheral, non-neuronal serotonin promotes the recruitment of neutrophils to sites of acute inflammation and tissue damage. Direct effects of serotonin on neutrophil function were shown to be involved. However, the influence of serotonin on the endothelial counterpart is unknown.

Objectives: To investigate whether serotonin alters the function of endothelial cells in leukocyte recruitment during acute inflammation.

Methods: We used two murine models of acute inflammation: intraperitoneal lipopolysaccharide (LPS) injection and mesenteric ischemia/reperfusion injury (I/R). To study effects of peripheral serotonin, leukocyte recruitment and endothelial adhesion molecule expression were compared in wild type (WT) and tryptophan hydroxylase 1 deficient (Tph1 ) mice, which are unable to synthesize peripheral serotonin.

Results: As expected, neutrophil transmigration into the peritoneal cavity following LPS injection was impaired in Tph1 mice. Abdominal blood vessels, however, showed no difference in adhesion molecule expression. In the early reperfusion phase after mesenteric I/R, the number of rolling leukocytes was significantly lower in Tph1 compared to WT. In line with the LPS model, endothelial adhesion molecule expression was independent of serotonin. In vitro experiments using human umbilical vein endothelial cells (HUVECs) confirmed that serotonin does not affect endothelial adhesion molecules.

Conclusions: The inflammatory release of peripheral serotonin is dispensable for the regulation of endothelial adhesion molecules.
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http://dx.doi.org/10.1111/jth.15541DOI Listing
January 2022

Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial.

Thromb Haemost 2022 May 24;122(5):857-866. Epub 2021 Sep 24.

AP-HP, hôpital européen Georges-Pompidou, Service de Pneumologie et de Soins Intensifs, APHP.Centre - Université de Paris, Paris, France.

Intermediate-high-risk pulmonary embolism (PE) is characterized by right ventricular (RV) dysfunction and elevated circulating cardiac troponin levels despite apparent hemodynamic stability at presentation. In these patients, full-dose systemic thrombolysis reduced the risk of hemodynamic decompensation or death but increased the risk of life-threatening bleeding. Reduced-dose thrombolysis may be capable of improving safety while maintaining reperfusion efficacy. The Pulmonary Embolism International THrOmbolysis (PEITHO)-3 study (ClinicalTrials.gov Identifier: NCT04430569) is a randomized, placebo-controlled, double-blind, multicenter, multinational trial with long-term follow-up. We will compare the efficacy and safety of a reduced-dose alteplase regimen with standard heparin anticoagulation. Patients with intermediate-high-risk PE will also fulfill at least one clinical criterion of severity: systolic blood pressure ≤110 mm Hg, respiratory rate >20 breaths/min, or history of heart failure. The primary efficacy outcome is the composite of all-cause death, hemodynamic decompensation, or PE recurrence within 30 days of randomization. Key secondary outcomes, to be included in hierarchical analysis, are fatal or GUSTO severe or life-threatening bleeding; net clinical benefit (primary efficacy outcome plus severe or life-threatening bleeding); and all-cause death, all within 30 days. All outcomes will be adjudicated by an independent committee. Further outcomes include PE-related death, hemodynamic decompensation, or stroke within 30 days; dyspnea, functional limitation, or RV dysfunction at 6 months and 2 years; and utilization of health care resources within 30 days and 2 years. The study is planned to enroll 650 patients. The results are expected to have a major impact on risk-adjusted treatment of acute PE and inform guideline recommendations.
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http://dx.doi.org/10.1055/a-1653-4699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9197594PMC
May 2022

Pre-medication with oral anticoagulants is associated with better outcomes in a large multinational COVID-19 cohort with cardiovascular comorbidities.

Clin Res Cardiol 2022 Mar 21;111(3):322-332. Epub 2021 Sep 21.

Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Aims: Coagulopathy and venous thromboembolism are common findings in coronavirus disease 2019 (COVID-19) and are associated with poor outcome. Timely initiation of anticoagulation after hospital admission was shown to be beneficial. In this study we aim to examine the association of pre-existing oral anticoagulation (OAC) with outcome among a cohort of SARS-CoV-2 infected patients.

Methods And Results: We analysed the data from the large multi-national Lean European Open Survey on SARS-CoV-2 infected patients (LEOSS) from March to August 2020. Patients with SARS-CoV-2 infection were eligible for inclusion. We retrospectively analysed the association of pre-existing OAC with all-cause mortality. Secondary outcome measures included COVID-19-related mortality, recovery and composite endpoints combining death and/or thrombotic event and death and/or bleeding event. We restricted bleeding events to intracerebral bleeding in this analysis to ensure clinical relevance and to limit reporting errors. A total of 1 433 SARS-CoV-2 infected patients were analysed, while 334 patients (23.3%) had an existing premedication with OAC and 1 099 patients (79.7%) had no OAC. After risk adjustment for comorbidities, pre-existing OAC showed a protective influence on the endpoint death (OR 0.62, P = 0.013) as well as the secondary endpoints COVID-19-related death (OR 0.64, P = 0.023) and non-recovery (OR 0.66, P = 0.014). The combined endpoint death or thrombotic event tended to be less frequent in patients on OAC (OR 0.71, P = 0.056).

Conclusions: Pre-existing OAC is protective in COVID-19, irrespective of anticoagulation regime during hospital stay and independent of the stage and course of disease.
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http://dx.doi.org/10.1007/s00392-021-01939-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453472PMC
March 2022

Coronary artery bypass grafting versus stent implantation in patients with chronic coronary syndrome and left main disease: insights from a register throughout Germany.

Clin Res Cardiol 2022 Jul 28;111(7):742-749. Epub 2021 Aug 28.

Department of Cardiology and Angiology I, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Background: Recent randomized controlled trials have sparked debate about the optimal treatment of patients suffering from left main coronary artery disease. The present study analyzes outcomes of left main stenting versus coronary bypass grafting (CABG) in a nationwide registry in patients with chronic coronary syndrome (CCS).

Methods: All cases suffering from CCS and left main coronary artery disease treated either with CABG or stent, were identified within the database of the German bureau of statistics. Logistic or linear regression models were used with 20 baseline patient characteristics as potential confounders to compare both regimens.

Results: In 2018, 1318 cases with left main stenosis were treated with CABG and 8,920 with stent. Patients assigned for stenting were older (72.58 ± 9.87 vs. 68.63 ± 9.40, p < 0.001) and at higher operative risk, as assessed by logistic EuroSCORE (8.77 ± 8.45 vs. 4.85 ± 4.65, p < 0.001). After risk adjustment, no marked differences in outcomes were found for in-hospital mortality and stroke (risk adjusted odds ratio (aOR) for stent instead of CABG: aOR mortality: 1.08 [95% CI 0.66; 1.78], p = 0.748; aOR stroke: 0.59 [0.27; 1.32], p = 0.199). Stent implantation was associated with a reduced risk of relevant bleeding (aOR 0.38 [0.24; 0.61], p < 0.001), reduced prolonged ventilation time (aOR 0.54 [0.37 0.79], p = 0.002), and postoperative delirium (aOR 0.16 [0.11; 0.22], p < 0.001). Furthermore, stent implantation was associated with shorter hospital stay (- 6.78 days [- 5.86; - 7.71], p < 0.001) and lower costs (- €10,035 [- €11,500; - €8570], p < 0.001).

Conclusion: Left main stenting is a safe and effective treatment option for CCS-patients suffering from left main coronary artery disease at reasonable economic cost. Coronary artery bypass grafting versus stent implantation in patients with chronic coronary syndrome and left main disease: insights from a register throughout Germany. All cases with chronic coronary syndrome and left main stenosis treated in 2018 in Germany either with left main stenting or coronary bypass grafting were extracted from a nation-wide database. In-hospital outcomes were compared after logistic regression analysis.
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http://dx.doi.org/10.1007/s00392-021-01931-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397600PMC
July 2022

Incidence and predictors of delirium on the intensive care unit in patients with acute kidney injury, insight from a retrospective registry.

Sci Rep 2021 08 26;11(1):17260. Epub 2021 Aug 26.

Department of Cardiology and Angiology I, Faculty of Medicine, Heart Center Freiburg University, University of Freiburg, Hugstetter Strasse 55, 79106, Freiburg, Germany.

Acute kidney injury (AKI) and delirium are common complications on the intensive care unit (ICU). Few is known about the association of AKI and delirium, as well as about incidence and predictors of delirium in patients with AKI. In this retrospective study, all patients with AKI, as defined by the KDIGO (kidney disease improving global outcome) guideline, treated for more than 24 h on the ICU in an university hospital in 2019 were included and analyzed. Delirium was defined by a NuDesc (Nursing Delirium screening scale) ≥ 2, which is evaluated three times a day in every patient on our ICU as part of daily routine. A total of 383/919 (41.7%) patients developed an AKI during the ICU stay. Delirium was detected in 230/383 (60.1%) patients with AKI. Independent predictors of delirium were: age, psychiatric disease, alcohol abuse, mechanical ventilation, severe shock, and AKI stage II/III (all p < 0.05). The primary cause of illness had no influence on the onset of delirium. Among patients with AKI, the duration of the ICU stay correlated with higher stages of AKI and the presence of delirium (stage I/no delirium: median 1.9 (interquartile range (25th-75th) 1.3-2.9) days; stage II/III/no delirium: 2.6 (1.6-5.5) days; stage I/delirium: 4.1 (2.5-14.3) days; stage II/III/delirium: 6.8 (3.5-11.9) days; all p < 0.01). Delirium, defined as NuDesc ≥ 2 is frequent in patients with AKI on an ICU and independently predicted by higher stages of AKI.
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http://dx.doi.org/10.1038/s41598-021-96839-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390667PMC
August 2021
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