Gene expression signatures, pathways and networks in carotid atherosclerosis.

BACKGROUND: Embolism from unstable atheromas in the carotid bifurcation is a major cause of stroke. Here, we analysed gene expression in endarterectomies from patients with symptomatic (S) and asymptomatic (AS) carotid stenosis to identify pathways linked to plaque instability. METHODS: Microarrays were prepared from plaques (n = 127) and peripheral blood samples (n = 96) of S and AS patients. Gene set enrichment, pathway mapping and network analyses of differentially expressed genes were performed. RESULTS: These studies revealed upregulation of haemoglobin metabolism (P = 2.20E-05) and bone resorption (P = 9.63E-04) in S patients. Analysis of subgroups of patients indicated enrichment of calcification and osteoblast differentiation in S patients on statins, as well as inflammation and apoptosis in plaques removed >1 month compared to <2 weeks after symptom. By prediction profiling, a panel of 30 genes, mostly transcription factors, discriminated between plaques from S versus AS patients with 78% accuracy. By meta-analysis, common gene networks associated with atherosclerosis mapped to hypoxia, chemokines, calcification, actin cytoskeleton and extracellular matrix. A set of dysregulated genes (LMOD1, SYNPO2, PLIN2 and PPBP) previously not described in atherosclerosis were identified from microarrays and validated by quantitative PCR and immunohistochemistry. CONCLUSIONS: Our findings confirmed a central role for inflammation and proteases in plaque instability, and highlighted haemoglobin metabolism and bone resorption as important pathways. Subgroup analysis suggested prolonged inflammation following the symptoms of plaque instability and calcification as a possible stabilizing mechanism by statins. In addition, transcriptional regulation may play an important role in the determination of plaque phenotype. The results from this study will serve as a basis for further exploration of molecular signatures in carotid atherosclerosis.

Correlations between clinical variables and gene-expression profiles in carotid plaque instability.

OBJECTIVE: Strokes, a major cause of disability, are often caused by embolism from unstable carotid plaques. The aim of this study was to validate a biobank of human carotid endarterectomies as a platform for further exploration of pathways for plaque instability. For this purpose, we investigated the relationship between clinical parameters of plaque instability and expression of genes previously shown to be associated with either plaque instability or healing processes in the vessel wall. METHODS: A database of clinical information and gene-expression microarray data from 106 carotid endarterectomies were used. RESULTS: Expression of matrix metalloproteinase (MMP)-9 and MMP-7 was 100-fold higher in plaques than in normal artery. In general, genes associated with inflammation (such as RANKL and CD68) were overexpressed in symptomatic compared with asymptomatic plaques. Plaques obtained from patients undergoing surgery within 2 weeks after an embolic event showed up-regulation of genes involved in healing reactions in the vessel wall (including elastin and collagen). Statin treatment, as well as echodense lesions, were associated with a more stable phenotype. CONCLUSION: Here, we demonstrate that gene-expression profiles reflect clinical parameters. Our results suggest that microarray technology and clinical variables can be used for the future identification of central molecular pathways in plaque instability.

[Intimal hyperplasia within a vascular anastomosis].

Intimal hyperplasia (IH) appears to rank high amongst plausible causes of reconstructed arteries restenosis. It always occurs in the area of a surgical intervention on a vessel in response to a mechanical lesion. IH is the cause of thrombosis in 15 to 50% of cases following vascular reconstruction during the first year after the operation (with the exception of early thromboses, which are probably caused by an improperly performed interventional technique). Of a wide variety of clinical situations leading to development of IH in the vascular wall, for the purposes of the present review, we singled out the problem concerning the onset and development of this tissue reaction in intervascular anastomoses, which is currently one of the most important issues. Analysing the publications on the problem concerned showed that amongst significantfactors influencing the development of IH in the anastomosis, the investigators single out different parameters of the anastomoses, configuration (either an end-to-end or an end-to-side anastomosis, the use of special inserts and patches within the latter), as well as the use of autologous or synthetic conduits, blanket suture or interrupted suture, peculiarities of local haemodynamics (linear blood flow rate, distribution of parietal fraction forces, zones of stagnation and flow separation), etc. To a certain degree, the published data are rather controversial. There remain many problems, which are either unaddressed as yet, or insufficiently studied, if at all. For instance, while establishing an anastomosis between a bypass graft and an artery, surgeons often resort to endarterectomy. It is not known whether or not this technique would influence the IH pattern in the anastomosis concerned. Neither is it clear whether the high velocity flow exerts a direct damaging action upon the endothelium, whether it promotes the development of IH in the area of the lesion, and if affirmative, then what the mechanisms of this effect really are. Not studied is the role of various types of synthetic fibres and synthetic grafts (except PTFE), various kinds of suture material in the development of IH in the zone of a vascular anastomosis concerned. This of course is far from being a complete list of the challenges requiring further investigation.