B-011-03 sgk1 deficiency is protective in a model of sepsis-related atrial fibrillation
Heart Rhythm(2021)
摘要
Sepsis is associated with new onset atrial fibrillation (AF), and AF in septic patients is associated with worse outcomes. Serum glucocorticoid kinase 1 (SGK1), a serine/threonine kinase in the PI-3 kinase pathway, is involved in cardiac inflammation. Prior work has suggested a potential therapeutic role for SGK1 inhibition in cardiac arrhythmias, which we investigated in a model of bacterial sepsis-induced AF. We sought to determine if 1) CLP, a well established model of polymicrobial sepsis leads to an increased risk of AF, and 2) whether SGK1 inhibition is protective in this model. Cecal ligation and puncture was performed in male wild type C57/Bl6 (WT) and mice with cardiac specific knockdown of SGK1 (SGK1 DN). Approximately 7 (range 7-9) days after sepsis induction, the mice underwent terminal in vivo electrophysiology studies to determine AF inducibility and basic atrial/ventricular tissue parameters. Additional mice were used to perform optical mapping to determine EP properties and flow cytometry to determine cellular composition. CLP-induced sepsis in WT mice led to high AF inducibility (5 out of 7 mice), as well as AF frequency and burden during EP study. As compared with naïve controls, the AF phenotype was associated with significantly slowed right atrial conduction velocity (0.54±0.03 versus 0.62±0.08 m/s) along with a similar trend in the left atrium, as measured by optical mapping. Flow cytometry revealed that sepsis increased fibroblasts, macrophages, and neutrophils in the atrial wall when compared to control mice without CLP. When CLP was performed in WT and SGK1 DN littermates, SGK1 DN mice had significantly (p<0.05 by chi-squared) lower AF inducibility (3 out of 8) than the WT mice (7 out of 8). In addition, there was a significant decrease in AF frequency and a trend towards a decrease in total AF burden during the entirety of the EP study. Bacterial sepsis in mice remodels the atrial cell composition and increases AF inducibility. Genetic SGK1 inhibition protected septic mice against AF. These data motivate further investigation into how inflammatory remodeling of atria contributes to sepsis-induced AF, and the potential of SGK1 inhibitors for treatment of this entity.
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关键词
sgk1 deficiency,atrial fibrillation,sepsis-related
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