Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Although sterile inflammation has been implicated as a possible etiologic factor in AF and has been linked to atrial fibrosis, the cellular mechanisms underlying this association have been poorly delineated. A multiprotein complex known as `NACHT, LRR and PYD domains-containing protein 3' (NLRP3) inflammasome plays an important role in inflammation signaling pathway. Our preliminary studies have revealed the increased activity of the NRLP3 inflammasome in paroxysmal and chronic AF patients and also in a canine model of AF induced by atrial tachycardia pacing. Particularly pertinent to this proposal, the inflammasome has been invoked in a mouse model of AF induced by angiotensin II infusion. In addition, NLRP3 heterozygous knockout mice showed a reduced susceptibility to pacing-induced AF after angiotensin II infusion. These data suggest that inflammasome activation promotes both initiation and maintenance of AF and have led to the proposed studies that seek to characterize the cellular events associated with this inflammasome-mediated process. Both the cardiomyocyte (CM) and cardiac fibroblast (CF) contain inflammasomes. While inflammasomes have been most completely characterized in macrophages (initially) and fibroblasts, our recent data suggest that the inflammasome in the cardiac cells may have important pathological significance. Preliminary studies showed that mice with either CM-specific or CF-specific knockin of a gain-of-function NLRP3 mutation exhibit enhanced susceptibility to AF development. The respective contributions of CM and CF inflammasomes to AF pathogenesis need further elucidation, which are detailed in our proposal. Overall, our preliminary results suggest that the effects of inflammasome activation can spreads from cell to cell, promoting 1) focal ectopic firing via increased spontaneous sarcoplasmic reticulum Ca2+ releases and 2) AF-maintaining reentry via action potential shortening. We will test the overall hypothesis that enhanced activation of the NLRP3 inflammasome promotes AF by pyroptotic and fibrotic remodeling. The novelty of the current proposal includes 1) to establish the mechanistic link between inflammation signaling and AF pathophysiology, 2) to characterize the role of the inflammasome in the two principal cell types associated with AF and the mechanisms by which it induces AF, and 3) most importantly, to examine a potential therapeutic target in AF intervention.
Atrial Fibrillation (AF) is the most prevalent arrhythmia with an increasing prevalence and associated with pronounced morbidity, mortality, and socioeconomic burden. Although sterile inflammation is frequently associated with patient with AF, the molecular mechanism underlying enhanced inflammatory response and the arrhythmic mechanisms downstream of inflammation signaling have never been clearly understood. This proposal will investigate the molecular and cellular mechanisms of inflammation signaling in the pathophysiology of AF, and evaluate the potential of targeting the inflammasome as a novel therapy in AF intervention.