Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration.

Autor:	Polzin A; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital, Düsseldorf, Germany; National Heart and Lung Institute, Imperial College London, London, UK. Electronic address: amin.polzin@med.uni-duesseldorf.de., Benkhoff M; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute of Analytical Chemistry, University of Vienna, Vienna, Austria., Thienel M; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Barcik M; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Mourikis P; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Shchurovska K; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Helten C; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Ehreiser V; Deutsches Herzzentrum der Charité (DHZC) University Hospital Berlin, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Germany; Friede Springer - Centre of Cardiovascular Prevention @ Charité, Charité - University Medicine Berlin, Berlin, Germany., Zhe Z; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., von Wulffen F; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Theiss A; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Peri S; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Cremer S; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Ahlbrecht S; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Zako S; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Wildeis L; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Al-Kassis G; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Metzen D; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Utz A; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Hu H; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Vornholz L; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Pavic G; Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Lüsebrink E; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Strecker J; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany., Tiedt S; Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany., Cramer M; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Gliem M; Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Ruck T; Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Meuth SG; Department of Neurology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany., Zeus T; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany., Mayr C; Helmholtz Munich, Institute of Lung Health and Immunity, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; Institute of Experimental Pneumology, LMU University Hospital, Ludwig-Maximilians University, Munich, Germany., Schiller HB; Helmholtz Munich, Institute of Lung Health and Immunity, Comprehensive Pneumology Center (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Germany; Institute of Experimental Pneumology, LMU University Hospital, Ludwig-Maximilians University, Munich, Germany., Simon L; Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA., Massberg S; Department of Cardiology, LMU University Hospital, LMU Munich, Munich, Germany; DZHK (German Centre for Cardiovascular Research), Munich Heart Alliance, Munich, Germany., Kelm M; Department of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Medical Faculty of the Heinrich Heine University Düsseldorf, Düsseldorf, Germany; CARID, Cardiovascular Research Institute Düsseldorf, Medical Faculty and University Hospital, Düsseldorf, Germany., Petzold T; Deutsches Herzzentrum der Charité (DHZC) University Hospital Berlin, Department of Cardiology, Angiology and Intensive Care Medicine, Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner site Berlin, Germany; Friede Springer - Centre of Cardiovascular Prevention @ Charité, Charité - University Medicine Berlin, Berlin, Germany. Electronic address: tobias.petzold@med.uni-muenchen.de.
Jazyk:	angličtina
Zdroj:	Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2024 Nov 15. Date of Electronic Publication: 2024 Nov 15.
DOI:	10.1016/j.jtha.2024.10.025
Abstrakt:	Background and Aims: Immediate factor Xa (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases. Methods: We evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following acute myocardial infarction (AMI) and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa NOAC and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of AMI patients, we determined CMR based cardiac endpoints under FXa NOAC effects on clinical endpoints in a cohort of AMI patients. Results: Chronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24h after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced NET formation in mice and patient samples. Proteome and RNA expression analysis of FXa-inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet alpha and dense granule release. Subsequent, thromboinflammatory NET density in thrombi isolated from stroke and myocardial infarction patients was reduced. AMI patients treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. Conclusions: Long-term FXa inhibition induces anti-thromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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