Interventional Cardiology. Группа авторов

Seven isoforms of the catalytic, membrane‐spanning NADPH oxidase subunit NOX exist, each encoded by a separate gene, i.e. NOX1–5 and Duox1 and Duox2 [47]. They differ in molecular composition, subcellular localisation, tissue distribution, and expression [48]. Endothelial cells mainly express NOX2 and NOX4, and vascular smooth muscle cells mainly express NOX4 [49]. In vascular smooth muscle cells of resistance arteries, NOX2 expression is relatively high [50], and cardiomyocytes mainly express NOX2 and NOX4 [51], NOX activity contributes to the oxidised LDL production in macrophages [52], overexpression of endothelial adhesion molecules, monocyte infiltration, and VSMC proliferation [53]. Coupled eNOS (the physiological condition) generates NO, which induces vascular smooth muscle relaxation and inhibits platelet aggregation and adhesion [54]. However, under conditions of oxidative stress, eNOS becomes uncoupled, dysfunctional, and generates superoxide instead of NO. Subsequently, low NO bioavailability can up‐regulate VCAM‐1 in the endothelial cell layer that binds monocytes and lymphocytes in the first step of invasion of the vascular wall, via induction of NFkB expression [55]. Furthermore, NO inhibits leukocyte adhesion [56] and NO reduction results in induction of monocyte chemotactic protein‐1 (MCP‐1) expression which recruits monocytes [57]. NO is in a sensitive balance with endothelin1 (ET‐1) regulating vascular tone [58]. Plasma ET‐1 concentrations are increased in patients with advanced atherosclerosis and correlate with the severity of the disease [59,60]. In addition to its vasoconstrictor activity, ET‐1 also promotes leukocyte adhesion [61] and thrombus formation [62]. The deficiency of eNOS cofactor tetrahydrobiopterin (BH4), or eNOS substrate ι‐arginine, or eNOS S‐glutathionylation were found to be the culprit of the eNOS uncoupling [6].3 Endothelial NOS‐dependent ROS production has been shown as one of significant contributor in patients with atherosclerosis [64], hypertension [65], hypercholesterolemia [66], diabetes mellitus [67], and chronic smoker [68].

Mitochondrial is a crucial element in physiology vascular cell growth and function; however, mitochondrial dysfunction can result in excessive ROS production. Mitochondrial oxidative stress also found to be associated with atherosclerosis which can occur under pathological situation because of over ROS production or failure of antioxidant mechanisms [69]. Mitochondrial dysfunction also associated with plaque ruptures, which accelerate the progression of hemodynamically significant atherosclerotic lesions [69], XO is found both in plasma and endothelial cells and generates superoxide anions and hydrogen peroxide by using molecular oxygen as an electron acceptor [70]. The expression and activity of endothelial XO are enhanced in human atherosclerotic plaque [71]. XO stimulates SRs expression on the macrophages and VSMC, namely LOX‐1 and CD 36, resulting in ROS production and subsequently causing transformation of macrophages and VSMC into foam cells [52].

Progression of atherosclerotic plaque

      Stable plaque

      Once established, atherosclerosis develops progressively through continuous accumulation of cholesterol‐rich lipids and the accompanying inflammatory response, which can vary considerably among individuals [4]. Early fibroatheroma involves numerous foam cells, extracellular proteoglycans, accumulation of extracellular lipid which progressively distorts the normal architecture of the intima [4]. The extracellular matrix contains collagen, elastin, proteoglycans, and glycosaminoglycans, entrap lipoproteins and promote lipid accumulation which subsequently causes cell necrosis that dominate the central part of the intima, ultimately occupying up to half the volume of the arterial wall and can lead to the formation of flow‐limiting lesions [4,7]. Gradually, the loose fibro cellular tissue is replaced and expanded by collagen‐rich fibrous tissue, with tissues that lie in between a necrotic core and the luminal surface of the plaque (fibrous cap) are fibrous with a high content of type I collagen [72,73]. Macrophages colony stimulating factor (M‐CSF) acts as the main stimulator in this process, next to granulocyte‐macrophage stimulating factor (MG‐CSF) and IL‐2 for lymphocytes [74]. Lymphocytes enter the intima by binding adhesion molecules (VCAM‐1, P‐selectin, ICAM‐1 MCP‐1(CCL2), IL‐8 (CxCL8) [26]. T cells have been proven as a critical driver in the pathogenesis of atherosclerosis, with different T cells subset can serve as a pro‐atherogenic or anti‐atherogenic [75]. CD4+ T helper 1 (TH1) cells and natural killer T cells have pro‐atherogenic roles, on the contrary, regulatory T (Treg) cells have anti‐atherogenic properties [75]. Fernandez et al. [76] showed that the majority of CD4+ T cells in the atherosclerotic plaque are TH1 and TH2, and more TH1 cells are found in plaque compared with peripheral blood. Initially, antigen‐presenting cells (APCs) process oxidised LDL, and present peptides from apolipoprotein B (ApoB) on major histocompatibility complex (MHC) class II molecules to the naïve T cells, which recognise this complex through their specific T cell receptors (TCRs). This process induces T cells to express various transcription factors that favour the differentiation into distinct TH phenotypes and subsequently will differentiate to the complete phenotype of the effector (Teff) or Treg [76]. Even the pro‐atherogenic role for TH1 cells and the anti‐atherogenic role of Treg cells have been well established, the role of the other TH cells subtypes, such as TH2, TH9, TH17, TH22 and follicular helper T (TFH) is still controversial and warrant further investigations [75].

The vulnerable plaque

      The different pathologic characterization of atherosclerotic lesions largely depends on the thickness of the fibrous cap and its grade of inflammatory infiltrate, which is in turn largely constituted by macrophages and activated T lymphocytes. Typically, the accumulating plaque burden is initially accommodated by an adaptive positive remodelling with expansion of the vessel external elastic lamina and minimal changes in lumen size [77,78]. The plaque contains monocyte‐derived macrophages, smooth muscle cells, and T cells. Interaction between these cells types and the connective tissue appears to determine the development and progression of the plaque itself, including important complications, such as thrombosis and rupture. Atherosclerotic lesions expand outward radially, in the direction away from the lumen to preserve the lumen calibre [7]. Plaque with limited lipid accumulation and thicker fibrous caps are referred as “stable plaques” [7]. On the other hand, thin‐cap fibroatheromas (TCFAs) or “vulnerable plaques” are likely the precursors of plaque ruptures, usually in the proximal segments of the major coronary arteries, where most plaque ruptures and thrombi are seen [79–81]. Burke et al. identified a cut‐off value for cap thickness of 65 microns to define a vulnerable coronary plaque [80]. Rupture occurs where the cap is thinnest and most infiltrated by foam cells.72 Despite the predominant hypothesis focusing on the responsibility of a specific vulnerable atherosclerotic plaque rupture [82,83] for acute coronary syndromes, some pathophysiologic, clinical and angiographic observations seem to suggest the possibility that the principal cause of coronary instability is not to be found in the vulnerability of a single atherosclerotic plaque, but in the presence of multiple vulnerable plaques in the entire coronary tree, correlated with the presence of a diffuse inflammatory process [84–87]. The gradual loss of SMCs from the fibrous cap and infiltrating macrophages degrade the collagen‐rich cap matrix lead to TCFAs formation, as ruptured caps contain less collagen and SMCs with numerous foam cells compared with intact caps [88–90]. Emotional or physical stress, such as anger, anxiety, work stress, earthquakes, war, sexual activity, hyperthermia, infections, and cocaine use, is known to cause plaque rupture [91]. Plaque rupture exposes the contents of the plaque to the blood compartment, where thrombogenic material in the plaque core produced by macrophages and smooth muscle cells can trigger thrombosis, the most dreaded complication of atherosclerosis, resulting in acute coronary syndrome or stroke [7].

      Vulnerable plaque: a shift towards Th1 pattern

Immunoinflammation drives the formation, progression, and rupture of atherosclerotic plaques. Early phases of the plaque development are characterized by an acute innate immune response against exogenous (infectious) and endogenous non‐infectious stimuli. Specific antigens activate adaptive immune system leading to proliferation of T and B cells. A first burst of activation might occur in regional lymph nodes by dendritic cells (DCs) trafficking from the plaque to lymph node. Subsequent cycle of activation can be sustained by interaction of activated /memory T cells re‐entering in the plaque by selective binding to endothelial cell surface adhesion molecules with plaque macrophages expressing MHC class II molecules. In this phase