Abstract 14531: Activation of NLRP3 Inflammasome Promotes Atrial Fibrillation
Introduction: Sterile inflammation is frequently observed in patients with atrial fibrillation (AF), the most common cardiac arrhythmia. However, whether inflammation signaling plays a causative role in AF remains elusive. ‘NACHT, LRR and PYD domains-containing protein 3’ (NLRP3) inflammasome mediates pathologic inflammation by promoting the maturation of caspase-1 and interleukin (IL)-1β. Preliminary results showed an increased activity of NLRP3 inflammasome in atrial tissues of patients with paroxysmal and chronic AF, dogs with atrial tachycardia remodeling, and mice with spontaneous AF (CREM-IbΔC-X Tg mice).
Hypothesis: In this study, we hypothesize that constitutive activation of NLRP3 inflammasome promotes AF development.
Methods: We developed a cardiomyocyte (CM)-specific knockin model, which expresses a gain-of-function mutation of NLRP3 (A350V) in CMs only (αMHC:Nlrp3A350V, KI). Telemetry, programmed intracardiac pacing study (PIS), echocardiography, and Western blotting were performed to evaluate the impact of constitutive activation of NLRP3 inflammasome on the AF development and AF-associated atrial remodeling.
Results: 24hr telemetry ECG recordings showed that 100% of KΙ mice (n=5) developed premature atrial contractions (PACs), whereas only 25% of control mice (n=4, P<0.05) had PACs. PIS revealed that 89% of KΙ mice (n=9) had pacing-induced AF, a much higher incidence than controls (20%, n=5, P<0.05). Meanwhile, the ventricular function in KI mice was comparable to control mice. Protein level of active caspase-1 was increased in atria tissues of KI mice at the age of 2-months, prior to the detectable increase in the level of CD68 (macrophage maker) at the 3-months old animals. We also found an increased level of IL-1β protein and collagen 1a mRNA in the atrial tissues of ΚΙ mice, suggesting an activation of fibroblasts and macrophages in KI mice. Finally, genetic ablation of NLRP3 in CREM-IbΔC-X Tg mice reduced the incidence of spontaneous AF by telemetry, suggesting that NLRP3 is required for AF development.
Conclusion: Our data revealed a causative role of NLRP3 in AF development. Future study will focus on elucidating the NLRP3 inflammasome associated molecular mechanisms contributing to the pathophysiology of AF.
Author Disclosures: C. Yao: Research Grant; Modest; China Scholarship Council (201408130047). L. Scott: None. X. Wehrens: None. D. Dobrev: Consultant/Advisory Board; Modest; OMEICOS Therapeutics GmbH, Berlin: consultancy fees, research grant, XENTION Limited, Cambridge: consultancy fees, research grant. N. Li: Research Grant; Significant; American Heart Association Scientist Development Grant (14SDG20080008).
- © 2016 by American Heart Association, Inc.