## 3 Symptomatic and Asymptomatic Carotid Plaques: From Pathophysiology to Diagnostic Issues  
Atherosclerosis has classically been defined as an immune-inflammatory disease based on the implication of the innate and adaptive immune system and inflammatory cytokines in causing vascular damage, which constitutes the foundation of atherogenesis and plaque formation and perpetuation. Several cytokines have been recognized as critical triggers in the development of atherogenesis. Among these, IL-1 has an essential role in the beginning and progression of atherosclerotic plaque, also representing a marker of risk for atherosclerotic disease severity [25]. In this concern, anti-IL-1 drugs have been proposed as a therapeutic strategy for the treatment of atherosclerotic disease [26; 27]. Other cytokines taking part in the atherogenic processes are IL-18, TNF, and INF-y [28; 29]. With regard to the role of the innate immune system, monocytes are the main cells involved in atherosclerosis development. After migration from peripheral blood to the intima and media layers of the vascular wall, monocytes turn into resident macrophages which are able to secrete proinflammatory cytokines (such as IL-1) responsible for the perpetuation of the local inflammation. The role of monocytes is supported by several studies that have found a correlation between peripheral monocytosis and the risk of atherosclerosis as well as the finding of increased levels of these cells within atherosclerotic plaques [30]. Dendritic cells and neutrophils are also involved in the pathogenesis of atherosclerotic disease, inducing vascular damage through the accumulation of lipid products into the \"foam cells\" and the production of reactive oxygen products and neutrophil extracellular traps recruiting monocytes from peripheral blood [31; 32; 33]. The adaptative immune system participates in the formation of plaque with different roles on the basis of the different cell subtypes. In fact, T-helper 1 cells have a proinflammatory profile promoting atherogenesis [34], while the contribution of T-helper 2 and T-helper 7 is still not well understood [35]. Atherosclerotic plaques show a high accumulation of CD8-T cells, suggesting the possible role of these cells in atherosclerotic disease due to the secretion of proinflammatory cytokines [36]. The role of B cells is still unclear, even though a proatherogenic role has been suggested, given their ability to suppress T cells in lymphoid organs [37]. Moreover, other elements extraneous to the plaque itself are involved in its evolution. Atherosclerotic lesion disruption, in fact, causes the exposition of thrombogenic material to the bloodstream, and this represents the _zero point_ of plaque's progression. In particular, the tissue factor (TF) is considered the primary trigger of the activation of the coagulation cascade in atherosclerotic plaque progression, as also demonstrated by the finding of elevated TF levels in patients with PAD, mainly in early atherosclerotic lesions, suggesting a strong early procoagulant milieu [38; 39]. As confirmation of the interaction between inflammation and coagulation in the pathogenesis of atherosclerosis, high expression of thrombin, factor X, TF (tissue factor), and FXII in atherosclerotic plaques and intima-media thickening has been reported in several studies, suggesting the critical role of coagulation not only in the progression but also in the early development of atherogenesis [40; 41]. Furthermore, clotting factors (in particular TF, factor Xa, and thrombin) induce inflammation through the activation of PAR (protease-activated receptor) pathways, leading to the proliferation of smooth muscle cells, the adhesion of leukocytes on the vessel wall, the activation of proinflammatory signals (NfKb pathway and production of cyclo-oxygenase), and platelet aggregation on the vascular surface [42; 43; 44]. The progression of the atherosclerotic plaques leading to volume increase and vulnerability depends on the cell subtypes infiltrating the arterial wall [45].