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Carotid atherosclerotic plaques stabilize after stroke:

insights into the natural process of atherosclerotic plaque stabilization - an interview with the senior author, Prof. Pasterkamp.

Early after stroke and TIA, plaques revealed an unstable phenotype. After stroke, the content of macrophages decreased significantly with time (P=0.02), whereas SMC content tended to increase. At protein level, IL-6, IL-8 expression levels and caspase activity strongly decreased after stroke or TIA.



INTERVIEW:

Q: Dr. Pasterkamp, this year began with the publication of a very exciting study of yours in Arteriosclerosis Thrombosis and Vascular Biology. It points out the natural history of carotid artery plaques after an acute cerebral ischemia event providing support for current concepts as well as new aspects. What would point out as the key findings of the study?

A: For our research group there are several key findings. First, it confirms the outcome of previous studies and concepts that plaque remodeling can go in two directions. The mechanism of plaque destabilization has always been the main research domain for many cardiovascular investigators. But this study strengthens the idea that unstable plaques also stabilize after an event, which, in fact, is a normal response after an injury (like a rupture of cap). Secondly, it shows that cytokine expression in plaques can rapidly change over time independent of the amount of inflammatory cells. Many researchers use a limited number of human atherosclerotic samples to show that a specific expression pattern is associated with a plaque phenotype or any risk factor. This study clearly shows that for expression studies you cannot ignore the baseline characteristics. Expression of many genes and proteins in plaques vary strongly with age, gender, medication use, time after an event, vascular territory etc. In my opinion, larger study samples are needed to reliably show co-expression of any gene or protein so that one can correct for confounding.  

Q: Reviewing the histological data, is the macrophage the “embodiment” of the biological activity of the atherosclerosis plaque? If this were to be the case, could we define plaque vulnerability simply as a function of plaque macrophage content?

A:  This study shows that just the presence of staining for a macrophage marker (like CD68) is not the embodiment for biological activity. Interleukin expressions were fluctuating independent of macrophage content. There are different macrophage subtypes in atherosclerotic lesions. The identification of these subtypes is an interesting field of research which may point to a subtype that could be considered the embodiment of activity. We should not forget, however, that smooth muscle cells outnumber the macrophages. These synthetic smooth muscle cells also have the biological machinery to generate a strong pro-inflammatory stimulus.

 

Q: It is striking that the plaques of the statin-treated patients did not behave “differently”. Does this imply we have to look for therapies that would modulate macrophage content and/or activity beyond statins?

A: I think this has to do with the fact that these are patients already suffering from atherosclerotic disease. Many of them already were on statin treatment. Due to the retrospective nature, we cannot draw conclusions with regard to statin use.

Q: As a final question, where do you think this study takes us beyond the points addressed above?

A:  The samples were obtained from the Athero-Express biobank study. This study has a unique study design in that all patients in this plaque biobank undergo follow up. Even if plaques are dissected, they hold a strong biomarker portfolio that predict outcome in the entire vascular system. This is beyond the scope of this paper, but publications related to this issue are expected soon.

Conclusion:

Symptomatic carotid lesions remodel into more stable plaques over time after stroke. Changes in IL-6 and IL-8 and caspase preceded the decrease of macrophages. These temporal phenotypic plaque alterations should be taken into account for biomarker and therapeutic target validation studies using human atherosclerotic plaques.

References


Arterioscler Thromb Vasc Biol. 2009;29:128-33.

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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