Abstract 118: NLRP3 Inflammasome Mediates the Obesity-induced Pathogenesis of Atrial Fibrillation

Abstract

Background: Obesity increases the risk of atrial fibrillation (AF), the most common cardiac arrhythmia; but it is unknown what molecular pathway(s) underlying obesity promotes AF pathophysiology. ‘NACHT, LRR & PYD Domains-containing Protein 3’ (NLRP3) inflammasome can activate Caspase-1 (Casp1) and mediate inflammatory response associated with obesity. Prior studies revealed that NLRP3 activity is enhanced in atrial tissues of AF patients, and our preliminary studies demonstrated a positive correlation between obesity and NLRP3 activation. Thus, we hypothesized that diet-induced obesity promotes AF pathogenesis via activation of the NLRP3 inflammasome. Methods and Results: Wildtype (WT) and NLRP3 knockout (KO) mice were fed high fat diet (HFD, 60% kcal) or normal chow (NC, as control) for 10 weeks to establish the obese but non-diabetic phenotype. At 10 weeks, WT+HFD and KO+HFD mice showed a significant increase in body weight, compared to WT+NC and KO+NC mice (P<0.001). Echocardiography showed ventricular function were similar among all groups at 10 weeks. Western blotting revealed increased levels of mature Casp1 in atria of WT+HFD mice (P<0.05 vs WT+NC mice), suggesting activity of NLRP3 is enhanced by HFD. Programmed intracardiac stimulation was performed to assess the inducibility of AF. While only 3 of 14 (21.3%) WT+NC mice showed AF evoked by atrial pacing, 7 of 8 (87.5%) WT+HFD mice developed pacing-induced AF (P<0.05). Atrial effective refractory period (AERP) was reduced in WT+HFD mice (P<0.05 vs WT+NC), suggesting that HFD promotes an electrical remodeling substrate for AF development. In contrast, AF incidence was reduced to 33.3% (3 of 9; P<0.05 vs WT+HFD) and AERP was normalized in KO+HFD mice, suggesting NLRP3 is required for AF development in obese mice. Compared to WT+NC mice, Ca 2+ sparks were increased in atrial myocytes of WT+HFD mice (4.5±0.6 vs 6.4±0.7 sparks/100μm/s, P<0.05), which was normalized in KO+HFD mice (4.4 ±0.4 sparks/100μm/s, P<0.05). Conclusion: Our data suggests that obesity promotes NLRP3 activation and inhibition of NLRP3 can prevent the development of substrate for AF development. Our study potentially establishes a mechanistic link between obesity-induced inflammatory signaling and AF pathogenesis.