Cardiac fibroblast inflammasome and atrial myopathy

PROJECT SUMMARY Atrial fibrillation (AF) is the most frequent arrhythmia. Atrial myopathy is a key determinant of the development of AF. The molecular mechanisms underlying the evolution of AF-promoting atrial myopathy are complex and poorly understood. Innate inflammatory signaling including the ‘NLR family pyrin domain containing 3’ (NLRP3) inflammasome pathway can modulate cardiac function and atrial arrhythmogenesis. Our preliminary study revealed that NLRP3 inflammasome activity is enhanced in atrial cardiac fibroblasts (CFs) of persistent AF patients compared with sinus rhythm controls. The CF-specific activation of NLRP3 in mice promotes the development of atrial fibrosis, enlarged left atrium, reduced atrial contractility, abnormal impulse conduction, sinus node dysfunction, and increased AF susceptibility, phenocopying atrial myopathy associated with AF development. In this proposal, we will test the hypothesis that activation of CF inflammasomes enhances atrial arrhythmogenesis by promoting atrial myopathy. Additionally, the therapeutic potential of enhancing the resolution of inflammation to combat atrial myopathy and atrial arrhythmogenesis deserves evaluation. In this proposal, we will also evaluate whether an inducer of inflammation resolution can prevent the inflammasome- induced atrial myopathy, thereby reducing atrial arrhythmogenesis. This proposal addresses several understudied areas in AF pathogenesis. The outcome of this study will provide novel insights into the development of atrial myopathy and sinus node dysfunction, as well as provide rationale for using the pro- resolution molecule in AF prevention.