Article Impact Level: HIGH Data Quality: STRONG Summary of JCI Insight, 10(10), e188281. https://doi.org/10.1172/jci.insight.188281 Dr. Lasse Bach Steffensen et al.
Points
- Whole-exome sequencing identified somatic mutations in 12 of 13 atherosclerotic plaques investigated, while no mutations were found in 11 healthy non-atherosclerotic arteries from control patients.
- These mutated clones were found to be substantial within the tissue, frequently constituting more than 10 percent of the total cellular population in the analyzed plaque samples.
- Further genetic analysis of the mutational landscape revealed a specific enrichment for mutations occurring in genes that are directly associated with the cellular contractile apparatus of the vessel wall.
- In patients with clonal hematopoiesis of indeterminate potential, hematopoietic clones originating from the circulation were found to have infiltrated the plaque tissue alongside the locally expanded cellular clones.
- The study concludes that plaques exhibit a pattern of multiple coexisting, large, mutated clones, introducing a new paradigm that links atherosclerosis pathophysiology with processes similar to those found in tumor biology.
Summary
A recent study investigated the role of somatic mutations and clonal expansion in the pathophysiology of human atherosclerosis. Utilizing whole-exome sequencing, researchers analyzed tissue from 13 carotid plaques and 11 non-atherosclerotic arteries. Somatic mutations were identified in 12 of the 13 (92.3%) investigated plaques, a stark contrast to the 11 non-atherosclerotic control arteries, where no mutations were detected. This establishes somatic mutation as a standard feature of advanced atherosclerotic lesions, suggesting a proliferative cellular process previously undemonstrated in the disease.
The study demonstrated that these mutated clones were not rare events within the tissue; they frequently constituted over 10% of the total cellular population in a given sample. Analysis of the mutational landscape revealed an enrichment for mutations in genes associated with the contractile apparatus. Furthermore, in patients with pre-existing clonal hematopoiesis of indeterminate potential (CHIP), the study confirmed that hematopoietic clones had infiltrated the plaque tissue. These CHIP-derived clones coexisted with locally expanded clones, forming substantial fractions of the plaque’s cellularity together.
The authors concluded that while their data do not support plaque monoclonality in the manner of a typical tumor, they do reveal a pattern of coexisting, large, mutated clones spanning different regions of the plaques. These findings suggest an interplay between genetic alterations and extensive cell division, introducing a new paradigm for understanding atherosclerosis beyond traditional risk factors, such as inflammation and lipid deposition. The identification of somatic mutations provides a novel tool for future studies to uncover pathological processes and may ultimately lead to new therapeutic targets targeting the vessel wall itself.
Link to the article: https://insight.jci.org/articles/view/188281
References Steffensen, L. B., Kavan, S., Jensen, P. S., Pedersen, M. K., Bøttger, S. M., Larsen, M. J., Dembic, M., Bergman, O., Matic, L., Hedin, U., Andersen, L. V. B., Lindholt, J. S., Houlind, K. C., Riber, L. P., Thomassen, M., & Rasmussen, L. M. (2025). Mutational landscape of atherosclerotic plaques reveals large clonal cell populations. JCI Insight, 10(10), e188281. https://doi.org/10.1172/jci.insight.188281
