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 of the atherogenic process the selective recruitment of a specific subtype of CD4+ cells play a major role determining the future development of the lesion. Th1 cells secreting proiflammatory cytokines, such as IFNγ promote macrophage activation, inflammation, and atherosclerosis, whereas Th2 cells (cytokine pattern IL‐4, IL‐5 and IL‐10) mediate antibody production and generally have anti‐inflammatory and antiatherogenic effects [92]. Therefore, the switch to a selective recruitment of Th1 lymphocyte represents a key point toward plaque vulnerability/disruption. T cells in the plaque may encounter antigens such as oxLDL. Moreover T cell response can be triggered by heat shock proteins of endogenous or microbial origins [93]. The mechanisms of why the initial inflammatory response becomes a chronic inflammatory condition remains unclear. However, when the plaque microenvironment triggers the selective recruitment and activation of Th1 cells they in turn determine a potent inflammatory cascade.
The combination of IFNγ and TNFα upregulates the expression of fractalkine (CX3CL1) [94]. Interleukin 1 and TNFα‐activated endothelium express also fractalkine (membrane bound form) that directly mediates the capture and adhesion of CX3CR1 expressing leukocytes providing a further pathway for leukocyte activation [95]. This cytokine network promotes the development of the Th‐1 pathway which is strongly pro‐inflammatory and induces macrophage activation, superoxide production and protease activity.
Plaque erosions
Improvement in anti‐atherosclerotic therapy reduces the risk of plaque rupture [7]. Atherosclerotic plaques have become less inflamed and more fibrous, minimising the risk of rupture due to fissure of the fibrous cap [96]. Plaque erosions tend to have a rich extracellular matrix without a thin, friable fibrous cap, with less foam cells and lipid accumulation [97]. It typically shows endothelial denudation with intact internal and external elastic laminas and a well‐developed media with contractile SMCs unlike ruptured plaque where internal lamina is disrupted and the underlying media is thin and disorganised [98]. Interestingly, plaque erosions sometimes found in up‐ or downstream of a plaque rupture with a fatal superimposed thrombus, which might suggest that loss of endothelium can occur secondarily to thrombus formation assuming that the ruptured plaque nearby is the sole precipitating cause.
Neoatherosclerosis
The neointimal tissue inside the stents is subject to similar atherogenic forces as the native vessels [99, 100]. Neoatherosclerosis is the development of atherosclerosis within this neointima following bare metal stent (BMS) and drug eluting stent (DES). See Figure 1.1. Histologically it is recognized by the presence of clusters of lipid‐laden foamy macrophages within the neointima with or without necrotic core formation [100,101]. Although the exact pathogenesis of this phenomenon is yet to be proven, inflammation and endothelial dysfunction have been shown to play a fundamental role [100–102]. It has been reported in autopsy and in‐vivo imaging studies that neoatherosclerosis occurs at an earlier stage and with higher frequency in DES than BMS [100,103], suggesting that mechanisms of failure after BMS and DES implantation are quite different. Indeed, in general, patients with BMS are likely to develop in‐stent restenosis (ISR) early due to neointima hyperplasia, whereas patients with DES are likely to develop less neointima in the early period, leading to less frequency of target lesion revascularization (TLR) after one year follow‐up compared to BMS. However, patients with DES are likely to develop neoatherosclerosis later, which possibly related to the late catch‐up phenomenon and very late stent thrombosis (VLST) [99,101,104].
Insights from coronary imaging
Technological advances enable us to visualise the extent and composition of atherosclerotic plaques in the coronary artery non‐invasively and invasively. Intravascular imaging modalities including intravascular ultrasound (IVUS), backscattered radio‐frequency (RF) IVUS, optical coherence tomography (OCT) and near‐infrared spectroscopy (NIRS) have been currently available for assessing coronary atherosclerotic plaque morphology and composition. The great advantage of intravascular imaging is that it is based on a device that is practical for use in the clinical setting, and it generates a real‐time assessment of plaque morphology. In addition, serial intravascular imaging enables us to evaluate the natural history progression of coronary atherosclerosis, which has also been used for assessing the pharmaceutical effects on coronary atherosclerosis. A number of studies have employed these techniques for detecting the factors contributing to cardiovascular events and assessing the efficacy of therapies targeting cardiovascular risk factors. These high‐risk or vulnerable atherosclerotic plaques which are defined as precursors to lesions that rupture have specific characteristics, such as large plaque burden, expansive arterial remodelling, thin cap fibroatheroma (TCFA), lipid pools, necrotic core, inflammatory cell accumulation and neovascularisation [105]. These markers of vulnerability provide potential targets for high‐risk plaque imaging. However, each intravascular imaging device has specific individual advantages and disadvantages in regards to evaluating plaque morphology and plaque compositions, shown in Table 1.1.
Figure 1.1 OCT illustration of Neoatherosclerosis. (a) Neo‐intimal hyperplasia inside the stent. A uniform layer of neo‐intima is seen covering the stent struts (white arrows) from 12 to 4 o’clock. Remainder of the stent circumference is covered by an irregular, very thick tissue layer containing dark, signal poor core consistent with lipid pool and signal rich, thick fibrous cap. (b) Lipid/ necrotic core in the neo‐atherosclerotic plaque has been highlighted in yellow.
Table 1.1 Comparison of plaque characteristics evaluation.
| IVUS | VH‐IVUS | OCT | NIRS | |
|---|---|---|---|---|
| Imaging technology | Ultrasound | Ultrasound | Infrared | Near‐infrared |
| Resolution (m) |
|
