Friedrichs, Kai, Adam, Matti ORCID: 0000-0002-6990-8135, Remane, Lisa, Mollenhauer, Martin, Rudolph, Volker, Rudolph, Tanja K., Andrie, Rene P., Stoeckigt, Florian, Schrickel, Jan W., Ravekes, Thorben, Deuschl, Florian, Nickenig, Georg, Willems, Stephan, Baldus, Stephan and Klinke, Anna (2014). Induction of Atrial Fibrillation by Neutrophils Critically Depends on CD11b/CD18 Integrins. PLoS One, 9 (2). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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. Methods and 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Friedrichs, KaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adam, MattiUNSPECIFIEDorcid.org/0000-0002-6990-8135UNSPECIFIED
Remane, LisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mollenhauer, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rudolph, Tanja K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andrie, Rene P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoeckigt, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrickel, Jan W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ravekes, ThorbenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deuschl, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nickenig, GeorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willems, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-445831
DOI: 10.1371/journal.pone.0089307
Journal or Publication Title: PLoS One
Volume: 9
Number: 2
Date: 2014
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
C-REACTIVE PROTEIN; CATHETER ABLATION; MAC-1 CD11B/CD18; INFLAMMATION; MYELOPEROXIDASE; MARKERS; OVEREXPRESSION; INTERLEUKIN-6; ARRHYTHMIAS; RECURRENCEMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44583

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