Therapeutic silencing Spp1 in cardiac macrophages suppresses atrial fibrillation

Atrial fibrillation (AFib) and the risk of its lethal complications are worsened by atrial fibrosis. A recent study implicates osteopontin (encoded by Spp1) secreted by atrial TREM2+ macrophages in this fibrosis. Here, we show that silencing Spp1 in TREM2+ cardiac macrophages using an antibody-siRNA conjugate (ARC) reduces atrial fibrosis and suppresses AFib, thus offering a new immunotherapy for this common arrhythmia. Single-nucleus RNA sequencing was used to investigate the transcriptomic differences between nuclei isolated from left atrial tissues collected from 3 vehicle- and 3 anti-Trem2-siSpp1-treated HOMER mice.