title: Ticagrelor, but not clopidogrel active metabolite, displays antithrombotic properties in the left atrial endocardium.
abstract: OBJECTIVE
  Oral anticoagulation is considered standard therapy for stroke prevention in atrial fibrillation (AF). Endocardial activation triggers expression of pro-thrombotic mediators including tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1), and contributes to thrombus formation in the left atrial appendage (LAA) of AF patients. Recently, pleiotropic effects of specific P2Y12 receptor antagonists were demonstrated; however, whether these drugs possess antithrombotic effects on LAA endocardial cells currently remains unknown.
  
  
  RESULTS
  LAA were obtained from 14 patients with known AF undergoing elective cardiac surgery including LAA removal at the University Hospital Zurich. LAA endocardial cells were isolated and pre-incubated with ticagrelor (10-7, 10-6, 10-5M) or clopidogrel active metabolite (CAM) (1.5 × 10-8, 1.5 × 10-7, 1.5 × 10-6 M) before stimulation with tumour necrosis factor-alpha (TNF-α) (10 ng/mL). Finally, TF and PAI-1 expression and activity were analysed. Ticagrelor, unlike CAM, concentration dependently decreased TNF-α-induced TF expression and TF activity in LAA endocardial cells. Further, ticagrelor, but not CAM reduced PAI-1 expression and enzyme activity in TNF-α-stimulated LAA endocardial cells. In contrast, TF pathway inhibitor (TFPI) remained unaffected by both dugs.
  
  
  CONCLUSIONS
  Ticagrelor, but not CAM, reduces expression and activity of TF and PAI-1 in LAA endocardial cells isolated from patients with AF, indicating possible local antithrombotic effects. Such pleiotropic properties of ticagrelor may contribute to a reduction in thromboembolic complications in patients with AF.
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Center for Integrative Human Physiology (ZHIP), University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.|Departement of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Reiner
authors.affiliation: Departement of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.|Department of Electrophysiology, St. Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Breitenstein
authors.affiliation: Departement of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Holy
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Glanzmann
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Amstalden
authors.affiliation: Departement of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Simon F
authors.initials: SF
authors.lastname: Stämpfli
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Departement of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Bonetti
authors.affiliation: Departement of Cardiovascular Surgery, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Falk
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Keller
authors.affiliation: Division of Cardiology, Department of Medicine, Karolinska Institute, Solna (MedS), K2, Z5:00, 171 76 Stockholm, Sweden.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Savarese
authors.affiliation: Departement of Cardiovascular Surgery, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Benussi
authors.affiliation: Departement of Cardiovascular Surgery, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Maisano
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Departement of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Departement of Internal Medicine, Cantonal Hospital Baden, Im Ergel 1, 5404 Baden, Switzerland.
authors.forename: Jürg H
authors.initials: JH
authors.lastname: Beer
authors.affiliation: Departement of Cardiology, University Heart Center, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Jan
authors.initials: J
authors.lastname: Steffel
authors.affiliation: Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.|Center for Integrative Human Physiology (ZHIP), University of Zurich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000991:Antithrombins / Q000494:pharmacology*; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D000077144:Clopidogrel; D004699:Endocardium / Q000378:metabolism; D006325:Heart Atria; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000187:drug effects / Q000378:metabolism; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D013925:Thromboplastin / Q000037:antagonists & inhibitors; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000991:Antithrombins; D017395:Plasminogen Activator Inhibitor 1; D058921:Purinergic P2Y Receptor Antagonists; D014409:Tumor Necrosis Factor-alpha; D013925:Thromboplastin; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: Atrial fibrillation; Clopidogrel; Endothelial activation; Thrombosis; Ticagrelor