Leukocytes in atrial fibrillation: mechanisms and therapeutics

Atrial fibrillation (AF) is a highly prevalent arrhythmia and a major cause of morbidity and mortality. Although AF is not a primarily immunologic disorder, increasing clinical, translational, and experimental evidence indicates that leukocytes can modify substrate vulnerability to AF. In this review, we summarize how neutrophils, monocytes, macrophages, B cells, T cells, mast cells, and less-studied leukocyte populations contribute to AF initiation, maintenance, and complications. We first outline core electrophysiologic mechanisms of AF, including focal ectopic activity and re-entry. We then discuss how leukocytes may influence these processes through atrial recruitment, immune-mediated electrical remodeling, neutrophil extracellular trap (NET)-associated thromboinflammation, and fibrosis. We highlight context-specific differences in the role of leukocytes between postoperative AF, cardiometabolic AF models, and persistent AF, and distinguish leukocyte populations with causal in vivo evidence from those supported primarily by associative human data. Finally, we review immune-targeted therapeutic approaches and discuss why clinical translation has been inconsistent, emphasizing timing, patient selection, disease stage, and endpoint heterogeneity.