A Single-Cell Analysis Reveals Macrophage Heterogeneity Driving Plaque Vulnerability in Coronary and Carotid Arteries

Acute coronary syndrome (ACS) and ischemic stroke are major life-threatening conditions caused by atherosclerosis. Although the mechanisms of atherosclerosis appear to be broadly similar across different vascular beds, growing evidence suggests that there are morphological and histological differences between coronary and carotid atherosclerosis. To identify disease-specific therapeutic strategies, we aimed to compare ACS and chronic coronary syndrome (CCS) in coronary artery disease, and symptomatic and asymptomatic carotid artery disease.

We analyzed our own single-cell RNA sequencing dataset for coronary artery disease (GSE184073) and a publicly available dataset for carotid artery disease (GSE253903). Myeloid cells were extracted from these datasets and comparative analyses were performed using metabolic profiling and an RNA velocity analysis.

By integrating multiple velocity-inference approaches, including the original and dynamic RNA velocity models, TFvelo using transcription factor regulatory information, and CellRank, we consistently identified a differentiation trajectory toward interleukin-1B (IL1B)^＋ inflammatory macrophages marked by high expression of matrix metalloproteinase 19 (MMP19). This trajectory was accompanied by the activation of the glycolytic and glycosaminoglycan degradation pathways. A similar directional flow toward IL1B^＋ inflammatory macrophages was also observed in symptomatic carotid artery plaques. However, unlike coronary lesions, carotid lesions activated the glycolytic pathway in SPP1^＋ foamy macrophages expressing MMP19.

Our findings revealed a shared differentiation trajectory into IL1B^＋ inflammatory macrophages in carotid and coronary artery diseases, which is associated with plaque vulnerability. Notably, the distinct activation of the glycolytic pathway in a separate macrophage subset suggests that tailored therapeutic strategies may be necessary to effectively address plaque vulnerability in each vascular bed.