Editor’s summary
Atrial fibrillation (AFib), the most common type of heart arrhythmia, is a serious condition that can result in atrial blood clots and thromboembolic stroke. Hulsmans et al. performed single-cell RNA sequencing on atrial tissue from AFib patients and healthy controls to better understand how stromal and immune cells contribute to this disease. They found that recruited CCR2+ SPP1+ macrophages expanded in AFib patients. These cellular and transcriptomic changes were recapitulated in a mouse model of AFib that integrated hypertension, obesity, and mitral valve regurgitation (HOMER). Disrupting Ccr2, which coordinates inflammatory macrophage recruitment to atria, or Spp1, which helps to drive inflammatory fibroblast activation by macrophages, ameliorated disease burden in HOMER mice, suggesting two potential immunotherapy targets for Afib patients. —STS
Abstract
Atrial fibrillation disrupts contraction of the atria, leading to stroke and heart failure. We deciphered how immune and stromal cells contribute to atrial fibrillation. Single-cell transcriptomes from human atria documented inflammatory monocyte and SPP1+ macrophage expansion in atrial fibrillation. Combining hypertension, obesity, and mitral valve regurgitation (HOMER) in mice elicited enlarged, fibrosed, and fibrillation-prone atria. Single-cell transcriptomes from HOMER mouse atria recapitulated cell composition and transcriptome changes observed in patients. Inhibiting monocyte migration reduced arrhythmia in Ccr2−∕− HOMER mice. Cell-cell interaction analysis identified SPP1 as a pleiotropic signal that promotes atrial fibrillation through cross-talk with local immune and stromal cells. Deleting Spp1 reduced atrial fibrillation in HOMER mice. These results identify SPP1+ macrophages as targets for immunotherapy in atrial fibrillation.
