Abstract Body: Left and right atria (LA and RA) experience distinct hemodynamic and biochemical environments, yet how these differences shape chamber-specific cardiac microenvironments remains unclear. Here, we combined integrative single-nucleus RNA sequencing and spatial transcriptomics to define cellular heterogeneity and immune specialization across atrial chambers.
Comparative analysis of adult mouse atria revealed transcriptionally distinct stromal and immune states between LA and RA. Stromal populations in the RA, including fibroblasts, endothelial cells, and epicardial cells, shared a convergent transcriptional program enriched for oxidative phosphorylation, protein translation, and stress-response pathways, suggesting a metabolically active microenvironment. Macrophages displayed pronounced chamber specificity: RA macrophages were enriched for monocyte-derived macrophage (MoMP) signatures with elevated basal inflammatory and antigen-presentation programs, whereas LA macrophages preferentially exhibited tissue-resident macrophage (TRMP) signatures associated with anti-inflammatory functions. Human heart datasets confirmed conserved enrichment of MoMP signatures in the RA. Single-cell–resolved spatial transcriptomics further mapped these immune states in situ, revealing preferential localization of MoMP-enriched immune niches within the RA and validating asymmetric macrophage distribution across atrial chambers.
Our findings identify a previously unrecognized and conserved asymmetry in atrial innate immune organization, associated with distinct inflammatory and antigen-presenting activities. This chamber-specific microenvironment may play an important role in maintaining atrial homeostasis, and its dysregulation contributes to the predisposition of atrial pathologies.