Abstract 59: Inflammasome Activation Promotes the Arrhythmogenesis of Atrial Fibrillation

Abstract

Background: Inflammation is a known risk factor of atrial fibrillation (AF), the most common arrhythmia; however, the mechanistic link between the inflammatory signaling and the pathophysiology of AF has not been established. ‘NACHT, LRR and PYD domains-containing protein 3’ (NLRP3) inflammasome is a signaling platform that is responsible for the activation of caspase-1 and interleukin (IL)-1b release. The activity of NLRP3 inflammasome is enhanced in atrial tissues of paroxysmal or long-lasting persistent AF patients. Thus, we tested the hypothesis that activation of NLRP3 inflammasome promotes the development of AF. Results: To elucidate the role of NLRP3 inflammasome in cardiomyocytes (CMs) and AF development, a CM-specific knockin murine model expressing a constitutive active NLRP3 (aMHC:NLRP3 A350V/+ , CKI) was developed. At 3-month old, telemetry recordings showed that 100% of CKΙ mice (n=5) developed premature atrial contractions (PACs), whereas only 25% of control mice (n=4, P<0.05) had PACs. Rapid atrial pacing induced AF in 89% of CKI mice (n=9), a much higher incidence than control mice (20%, n=5, P<0.05). Level of the active caspase-1 was increased in atrial tissues of 3-month old CKI mice, prior to a detectable increase in the level of macrophage marker at 7-month old, suggesting that the onset of PACs and AF vulnerability is not associated with the activated macrophages. Compared to the control mice, 3-month old CKI mice exhibited atrial hypertrophy, abnormal Ca 2+ release via RyR2, and shortening of atrial effective refractory period, which were associated with the upregulation of Mef2c , Ryr2 , Kcna5 (encoding Kv1.5), Kcnj 3 (encoding Kir3.1) and Kcnj5 (encoding Kir3.4) mRNA. Lastly, inflammasome inhibitor MCC950 (i.p., 10mg/kg, 10 days) reduced the AF inducibility in CKI mice (0%, n=3, P<0.05 vs vehicle-treated CKI). Conclusion: Activation of NLRP3 inflammasome promotes structural and electrical remodeling, permissive to the AF development. In addition to its canonical function, NLRP3 inflammasome may exhibit alternative function in regulating gene transcription. Our study establishes a mechanistic link between the inflammatory signaling and the pathogenesis of AF, and the inhibition of NLRP3 may become a novel anti-AF therapy.