| dc.description.abstract | Inflammation and oxidative stress are linked to the pathogenesis of atrial fibrillation (AF). Reactive dicarbonyls generated by lipid peroxidation represent a major component of oxidative injury, but their role in inflammation-mediated AF is unknown. This dissertation sought to test the hypothesis that lipid dicarbonyls are critical drivers of AF in mice with systemic inflammation due to the deletion of the lymphocyte adaptor protein (Lnk-/-). Therefore, Lnk-/- or wild-type littermate (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger. After 3 months, animals were subjected to morphologic, metabolic, and electrophysiologic characterization with pro-inflammatory cytokines quantified and targeted in vivo. Compared to WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current and increased late Na+ current, as well as reduced peak Na+ current, proarrhythmic effects that were also inhibited by 2-HOBA. Mitochondrial dysfunction, especially for complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodeling in vitro. Inhibition of TNF-α prevented electrical remodeling and AF susceptibility in Lnk-/- mice, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In conclusion, reactive lipid dicarbonyls are critical to the inflammatory AF substrate and mediate the proarrhythmic effects of cytokines, primarily through electrical remodeling. | |
