Carotid atherosclerosis is a risk factor for ischemic stroke, the third cause of death in developed countries. Degree of stenosis, evaluated by imaging techniques, is used to predict the risk of future cerebrovascular events. However, it has been observed that a subset of patients, particularly women, with lesions at an early stage of development undergoes sudden death. Therefore, there is the need of more sensitive tools that in addition to imaging techniques permit to identify plaques at high risk of clinical events. Sex differences have been observed in plaque composition and in stroke incidence. Women have higher rates of stable plaques, whereas unstable lesions are more frequent in men. Nevertheless, in women the risk for stroke roughly doubles during the 10 years after menopause. Data exist indicating that oestrogens may have a role in plaque composition and in ischemic stroke occurrence. Vascular and immune cells are oestrogen targets because they express oestrogen receptors (ER). Increased expression of the ER gene has been shown to protect against atherosclerosis. Methylation of the ER gene can reduce ER expression leading to a higher risk for cardiovascular disease. Recently, microRNAs have been found to regulate DNA methyltransferases and thus control methylation status in several genes. A previous experimental study demonstrated that pro-atherosclerotic conditions decrease microRNA-152 expression thus determining the hypermethylation of the ER gene and the decrease of ER level. The aim of this project is to evaluate whether the determination of circulating levels of microRNA-152 in patients with carotid atherosclerosis could provide a useful adjunctive criterion to ensure a better risk stratification and to identify, in combination with imaging techniques, high risk- plaques eligible for endarterectomy. Gender differences will be taken into account to determine the role of microRNA-152 as a suitable biomarker of plaque vulnerability.
The large majority of clinical studies focused on the association between biomarkers and subclinical atherosclerosis that is carotid intima-media thickening, which represents an earlier stage of the disease. Furthermore, even though some data exist on the association between circulating molecules and the risk of clinical events, until now no definitive results on biomarkers able to identify patients with CVD at high risk of clinical fatal events are available. The innovation of our proposal is that it is aimed to investigate if circulating miRNA-152 levels are associated with a higher atherosclerotic burden and with features of carotid plaque vulnerability in patients at an advanced stage of disease as evaluated by carotid intima-media thickening and the presence of clinical symptoms. Furthermore, the monitoring of plaque development requires information obtained with different diagnostic tools. Studies on the associations of ultrasonographic features with multiple biomarkers in the blood are strongly encouraged to increase our knowledge of the complex pathophysiologic phenomena of carotid plaques and to aid the clinicians to identify patients eligible for CEA. The combination of degree of stenosis with innovative circulating biomarkers may provide a better insight into the development of atherosclerotic vascular disease, and will aid the surgeons to identify vulnerable plaques eligible for CEA but also the clinicians to evaluate the response to pharmacological therapy. Ideally, the association of plaque activity evaluated by circulating biomarkers with plaque characteristics evaluated by ultrasound will enhance the value of echogenicity indices for an accurate morphologic characterization of vulnerable plaques and will accelerate incorporation of echogenicity as a non-invasive tool in individualized patient management.