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BACKGROUND: Clonal hematopoiesis of indeterminate potential (CHIP), a common age-associated phenomenon, associates with increased risk of both hematological malignancy and cardiovascular disease. Although CHIP is known to increase the risk of myocardial infarction and heart failure, the influence of CHIP in cardiac arrhythmias, such as atrial fibrillation (AF), is less explored.METHODS: CHIP prevalence was determined in the UK Biobank, and incident AF analysis was stratified by CHIP status and clone size using Cox proportional hazard models. Lethally irradiated mice were transplanted with hematopoietic-specific loss of , hematopoietic-specific loss of and , or wild-type control and fed a Western diet, compounded with or without NLRP3 (NLR [NACHT, LRR {leucine rich repeat}] family pyrin domain containing protein 3) inhibitor, NP3-361, for 6 to 9 weeks. Mice underwent in vivo invasive electrophysiology studies and ex vivo optical mapping. Cardiomyocytes from mice with hematopoietic-specific loss of or wild-type control and fed a Western diet were isolated to evaluate calcium signaling dynamics and analysis. Cocultures of pluripotent stem cell-derived atrial cardiomyocytes were incubated with -deficient bone marrow-derived macrophages, wild-type control, or cytokines IL-1β (interleukin 1β) or IL-6 (interleukin 6).RESULTS: Analysis of the UK Biobank showed individuals with CHIP, in particular CHIP, have increased incident AF. Hematopoietic-specific inactivation of increases AF propensity in atherogenic and nonatherogenic mouse models and is associated with increased Nlrp3 expression and CaMKII (Ca2+/calmodulin-dependent protein kinase II) activation, with AF susceptibility prevented by inactivation of . Cardiomyocytes isolated from mice with hematopoietic inactivation of and fed a Western diet have impaired calcium release from the sarcoplasmic reticulum into the cytosol, contributing to atria arrhythmogenesis. Abnormal sarcoplasmic reticulum calcium release was recapitulated in cocultures of cardiomyocytes with the addition of -deficient macrophages or cytokines IL-1β or IL-6.CONCLUSIONS: We identified a modest association between CHIP, particularly CHIP, and incident AF in the UK Biobank population. In a mouse model of AF resulting from hematopoietic-specific inactivation of , we propose altered calcium handling as an arrhythmogenic mechanism, dependent on inflammasome activation. Our data are in keeping with previous studies of CHIP in cardiovascular disease, and further studies into the therapeutic potential of NLRP3 inhibition for individuals with CHIP may be warranted.