Deposits in the carotid artery, known as plaques, are among the most common causes of stroke. The most dangerous plaques are not necessarily the largest ones that narrow the vessels, but rather those that tear easily. They can trigger a stroke even when the vessel narrowing was not previously particularly noticeable. For those affected, such an event often comes completely unexpectedly.
A research team involving the German Centre for Cardiovascular Research (DZHK), the Technical University of Munich (TUM) and the TUM University Hospital has now investigated, for the first time, the spatial distribution of proteins in different regions of such plaques. The results show why some plaques become unstable and are more prone to rupture. At the same time, the researchers identified PCSK9, a well-known regulator of lipid metabolism, as a possible local marker for particularly dangerous plaques.
Whether a plaque becomes dangerous depends largely on its fibrous cap. This separates the fat-rich core of the plaque from the bloodstream. If this protective layer tears, a blood clot can form within a short time, triggering a stroke. Why the cap becomes unstable in some plaques is, as yet, only partially understood.
The decisive differences lie inside the plaques
For the study, the researchers analysed tissue samples from 112 patients who had undergone surgery due to severe narrowing of the carotid artery. Using a high-resolution method, they examined the necrotic tissue core, the fibrous cap and the vessel wall of each plaque separately. In total, they identified almost 4,900 different proteins and were able to show where these occur within the plaque.
It emerged that unstable plaques differ from more stable ones mainly in the area of the necrotic tissue core and the fibrous cap. There, the researchers found increased evidence of inflammation, changes in lipid metabolism, remodelling of the supporting tissue, and calcification processes. The vessel wall itself showed considerably fewer differences.
"We have known for a long time that it is not the size of a plaque alone that is decisive, but its stability. With our spatial analysis, we can for the first time precisely trace which molecular processes take place in the various regions of a plaque. This opens up new possibilities for better identifying dangerous plaques and treating them more specifically in the long term," says one of the study's two senior authors, Prof. Lars Maegdefessel of TUM University Hospital Munich/DZHK site Munich.
PCSK9 comes into focus as a possible target
The protein PCSK9, already known from lipid metabolism, was particularly conspicuous. It occurred locally more frequently in unstable plaques than in more stable ones. In further experiments, the researchers were able to show that vascular smooth muscle cells produce and release more PCSK9 under inflammatory and oxidative stress. This indicates that PCSK9 not only influences cholesterol metabolism but may also be directly involved in the changes that make plaques unstable.
Original publication:
Sinha A, Sachs N, Kratz E, et al. Proteomics reveals spatial and molecular heterogeneities in advanced atherosclerotic carotid artery plaques. Nat Cardiovasc Res. Published online June 22, 2026. doi:10.1038/s44161-026-00827-1
Scientific contact:
Prof. Dr. Lars Mägdefessel, Institute for Molecular Vascular Medicine, TUM School of Medicine and Health, Technical University of Munich, lars.maegdefessel[at]tum.de
