Abstract 14785: The Reactive Lipid Mediators Isolevuglandins Promote Atrial Fibrillation Mediated by Inflammation

Abstract

Introduction: Inflammation and oxidative stress are linked to multiple risk factors for atrial fibrillation (AF), and to AF itself in the setting of sterile injury (e.g. after catheter ablation or cardiac surgery). However, anti-inflammatory therapies and conventional antioxidants cause adverse effects or are ineffective to prevent AF. Highly reactive mediators of lipid peroxidation such as isolevuglandins (IsoLGs) have been identified as a major component of oxidative stress-related injury. We hypothesized that during AF promoted by cardiac inflammation, a scavenger of IsoLG will decrease AF susceptibility. Methods: We studied mice with a systemic inflammatory phenotype due to deficiency in the lymphocyte adaptor protein ( Lnk -/- ), a negative regulator of cytokine signaling. At weaning, Lnk -/- mice and their wild-type (WT) littermates received either vehicle or a potent IsoLG scavenger, 2-hydroxybenzylamine (2-HOBA), by oral administration. At age 14 weeks, animals underwent transesophageal burst pacing, echocardiography, and tissue harvest or flow cytometry to measure atrial inflammation and IsoLG-adducts. Results: Cardiac histology and echocardiography revealed no major histologic or structural abnormalities in Lnk -/- mice. Nevertheless, Lnk -/- mice demonstrated a significant increase in AF burden compared to WT controls (124.8±43.3 vs 6.8±3 sec, respectively [mean±SEM, n=28, 12; P<0.05]), as well as increased sustained AF (> 30 sec; 48.1% vs 0%; P<0.01]). Leukocyte infiltration was present in the atria of Lnk -/- mice, with a significant increase in CD3, CD19, NK1.1, and CD11b/MHCII positive cells, compared to atria from WT control mice. Furthermore, there was a 2 to 4-fold increase in IsoLG-adducts for Lnk -/- atrial immune cells positive for CD3, CD19, NK1.1 and CD11b/MHCII, compared to cells from WT atria. Lnk -/- mice treated with 2-HOBA had significantly reduced AF burden (4.7±4.5 sec, n=7; P<0.05) with a trend towards reduction in sustained AF (0%, n=7; P=0.057). Conclusions: IsoLGs play a critical role in the pathogenesis of inflammation-mediated AF, and 2-HOBA, a scavenger of IsoLGs, represents a potentially novel therapeutic strategy for AF in this clinical setting.