Masahiro Yamazoe, Kenneth Ting, I‐Hsiu Lee, Aneesh Bapat, Andrew Lewis, Ling Xiao, Fadi E. Pulous, Kyle I. Mentkowski, Alexandre Paccalet, Noor Momin, Hana Seung, Theresa Dolejsi, Nina Kumowski, Maximilian J. Schloss, Yoshiko Iwamoto, Gustavo Ramos, Kenneth Chan, Charalambos Antoniades, Barbara Casadei, Filip K. Świrski, Patrick T. Ellinor, Kamila Naxerova, Steffen Pabel, Maarten Hulsmans, Matthias Nahrendorf
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 Mb1cre/+ Prdm1fl/fl 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. Yamazoe et al. show that B cell-derived autoantibodies contribute to the development of atrial fibrillation, suggesting that targeting the humoral immune response may represent a viable therapeutic approach.