title: Induction of atrial fibrillation by neutrophils critically depends on CD11b/CD18 integrins.
abstract: BACKGROUND
  Recent observational clinical and ex-vivo studies suggest that inflammation and in particular leukocyte activation predisposes to atrial fibrillation (AF). However, whether local binding and extravasation of leukocytes into atrial myocardium is an essential prerequisite for the initiation and propagation of AF remains elusive. Here we investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF.
  
  
  RESULTS
  C57bl/6J wildtype (WT) and CD11b/CD18 knock-out (CD11b(-/-)) mice were treated for 14 days with subcutaneous infusion of angiotensin II (Ang II), a known stimulus for PMN activation. Atria of Ang II-treated WT mice were characterized by increased PMN infiltration assessed in immunohistochemically stained sections. In contrast, atrial sections of CD11b(-/-) mice lacked a significant increase in PMN infiltration upon Ang II infusion. PMN infiltration was accompanied by profoundly enhanced atrial fibrosis in Ang II treated WT as compared to CD11b(-/-) mice. Upon in-vivo electrophysiological investigation, Ang II treatment significantly elevated the susceptibility for AF in WT mice if compared to vehicle treated animals given an increased number and increased duration of AF episodes. In contrast, animals deficient of CD11b/CD18 were entirely protected from AF induction. Likewise, epicardial activation mapping revealed decreased electrical conduction velocity in atria of Ang II treated WT mice, which was preserved in CD11b(-/-) mice. In addition, atrial PMN infiltration was enhanced in atrial appendage sections of patients with persistent AF as compared to patients without AF.
  
  
  CONCLUSIONS
  The current data critically link CD11b-integrin mediated atrial PMN infiltration to the formation of fibrosis, which promotes the initiation and propagation of AF. These findings not only reveal a mechanistic role of leukocytes in AF but also point towards a potential novel avenue of treatment in AF.
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Friedrichs
authors.affiliation: Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Matti
authors.initials: M
authors.lastname: Adam
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Remane
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Mollenhauer
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Rudolph
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Tanja K
authors.initials: TK
authors.lastname: Rudolph
authors.affiliation: Department of Medicine-Cardiology, University Hospital of Bonn, Bonn, Germany.
authors.forename: René P
authors.initials: RP
authors.lastname: Andrié
authors.affiliation: Department of Medicine-Cardiology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Stöckigt
authors.affiliation: Department of Medicine-Cardiology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Schrickel
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Thorben
authors.initials: T
authors.lastname: Ravekes
authors.affiliation: Department of General and Interventional Cardiology, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Deuschl
authors.affiliation: Department of Medicine-Cardiology, University Hospital of Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
authors.affiliation: Department of Electrophysiology, University Heart Center Hamburg, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Willems
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Baldus
authors.affiliation: Heart Center, University of Cologne, Cologne, Germany ; Cologne Cardiovascular Research Center, University of Cologne, Cologne, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Klinke
mesh_terms: D000704:Analysis of Variance; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology* / Q000378:metabolism*; D039481:CD11b Antigen / Q000235:genetics / Q000378:metabolism*; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism*; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods; D005455:Fluorescent Antibody Technique; D006325:Heart Atria / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*
chemical_list: D039481:CD11b Antigen; D018821:CD18 Antigens; D000804:Angiotensin II