Histopathological studies have revealed key processes of atherosclerotic plaque thrombosis. However, the diversity and complexity of lesion types highlight the need for improved subphenotyping. Here, we analyzed the gene expression profiles of 654 advanced human carotid plaques. The unsupervised, transcriptome-driven clustering revealed five dominant plaque types. These plaque phenotypes were associated with clinical presentation and showed differences in cellular compositions. Validation in coronary segments showed that the molecular signature of these plaques was linked to coronary ischemia. One of the plaque types with the most severe clinical symptoms pointed to both inflammatory and fibrotic cell lineages. Furthermore, we did a preliminary analysis of potential circulating biomarkers that mark the different plaque phenotypes. In conclusion, the definition of the plaque at risk for a thrombotic event can be fine-tuned by in-depth transcriptomic-based phenotyping. These differential plaque phenotypes prove clinically relevant for both carotid and coronary artery plaques and point to distinct underlying biology of symptomatic lesions.
Mokry et al. performed bulk RNA sequencing of 654 advanced human carotid plaques from the Athero-Express biobank and 162 coronary samples, and they show that unsupervised clustering defines plaque types corresponding to different cell compositions and clinical presentations. Circulating biomarkers can be potentially used to mark the different transcriptomic-defined plaque phenotypes.