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Atrial fibrillation, the most frequent cardiac arrhythmia, causes heart failure and stroke. Here we describe that combining the typical risk factors of atrial fibrillation (hypertension, obesity and mitral valve regurgitation (HOMER)) activates adaptive immunity in wild-type mice, ultimately causing electrical remodeling of cardiomyocytes. In HOMER mice, dendritic cells expanded in the left atria and heart-draining lymph nodes, where we detected cardiomyocyte-derived proteins. Systemically expanding B cells, while exposed to interferon-α, produced autoantibodies that disrupted calcium handling in cardiomyocytes. Depleting B cells by using μMT HOMER mice or plasma cells by using Mb1 Prdm1 HOMER mice reduced atrial fibrillation while mitigating the prolonged action potential duration we observed in the left atria of HOMER mice. CD20 antibody B cell depletion, a clinical tool in treating lymphoma and autoimmune disease, reduced atrial fibrillation fivefold in HOMER mice. Targeting humoral immunity may provide therapeutic avenues for patients with autoantibody-induced atrial fibrillation.