Abstract
BackgroundRecent 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 ResultsC57bl/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.ConclusionsThe 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.
Highlights
Atrial fibrillation (AF) stands out as the most prevalent human rhythm disorder
The current data critically link CD11b-integrin mediated atrial polymorphonuclear neutrophils (PMN) infiltration to the formation of fibrosis, which promotes the initiation and propagation of atrial fibrillation (AF). These findings reveal a mechanistic role of leukocytes in AF and point towards a potential novel avenue of treatment in AF
Immunohistochemical analysis of atrial sections revealed increased atrial infiltration of PMN in WT mice (n = 13) as compared to vehicle treated animals (n = 6; p,0.05). This angiotensin II (Ang II)-dependent increase in PMN extravasation proved to be CD11b-dependent, since mice devoid of the integrin did not demonstrate any significant increase in extravascular deposition of PMN in the atria (Ang II: n = 15, vehicle: n = 7; p = 0.09) (Fig. 1A, B)
Summary
Atrial fibrillation (AF) stands out as the most prevalent human rhythm disorder. Atrial fibrillation is associated with an increased long-term risk of heart failure, remains a principal and common cause of stroke and doubles mortality [1,2,3,4]. Inflammation appears to be a critical confounder for structural remodeling of the atria and for the genesis of atrial fibrillation [10,11]. Clinical studies support this view by revealing a predictive role of biomarkers such as Creactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-a with respect to AF occurrence, persistence, recurrence and left atrial dimensions. Clinical observations revealed leukocytes to be of critical significance for this disease in humans: Leukocytes were identified in atrial tissue of AF patients even without an underlying structural heart disease [11], and postoperative atrial leukocyte infiltration independently predicted postsurgery AF [23,24]. We investigated the role of atrial CD11b/CD18 mediated infiltration of polymorphonuclear neutrophils (PMN) for the susceptibility to AF
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