the effect of atorvastatin therapy on fibrous cap thickness in coronary atherosclerotic plaque assessed by optical coherence tomography (EASY‐FIT) trial compared the efficacy of 20 mg and 5 mg atorvastatin on plaque microstructures acquired from OCT in 70 patients with unstable angina pectoris. The increase in fibrous cap thickness was significantly greater with the higher dose of atorvastatin (69% vs 17%, p<0.001), along with more favourable changes in lipid arc (–27% vs –8%, p<0.001) and macrophage grade (–38% vs –24%, p<0.001) [147].
Macrophage infiltration
Pathophysiologically, macrophages play a very important role in the development of atherosclerosis and are the predominant inflammatory cell population within the fibrous cap of vulnerable plaques [79]. TCFA manifested by the infiltration of macrophages (average size 20 to 50 μm) has been recognized as contributing to weakening structural integrity of the cap [148–150] and predispose plaques to rupture. They are more frequently found in coronary artery specimens obtained from patients with ACS compared to stable CAD.150 The high contrast and resolution of OCT enables the quantification of macrophages within fibrous caps. OCT visualizes macrophages as signal‐rich, distinct or confluent punctuate regions with heterogeneous backward shadows (Figure 1.5,). Tearney, et al. demonstrated that the OCT‐derived macrophage density of plaque fibrous caps correlated strongly (r=0.84, p<0.0001) with macrophage density quantified histolomorphometrically by CD68 immunoperoxidase staining in the corresponding histological samples [151]. They also showed that macrophage density in the fibrous caps correlated with the circulating white blood cell count, which is used in clinical practice as a marker of systemic inflammation and has been shown to be an independent predictor of cardiovascular events, and presence of TCFA [152]. Thus, OCT has been employed to identify and quantify macrophage infiltration.
Cholesterol crystal (CCs)
CCs are formed very early in the process of atherogenesis and activate the proinflammatory cytokines interleukin‐1‐beta (IL‐1β) and IL‐18 via activating inflammasomes in neutrophils and monocytes/macrophages [153], which has been postulated to contribute to CC‐mediated plaque destabilization. These findings are supported by the fact that demonstrated CCs are often seen abundantly within atheromatous plaques and at sites of plaque disruption [154]. Cholesterol crystallization in plaque is an important trigger for core expansion, leading to intimal injury [155]. Therefore, CCs have been thought to be one of the factors leading to disruption of the plaque cap and overlying intima. With OCT, cholesterol crystals (CCs) are defined as linear, highly backscattering structures within the plaque (Figure 1.5). Preliminary, Kataoka, et al. demonstrated that plaques containing CCs exhibited distinct OCT‐derived microstructures associated with plaque vulnerability [156]. Recently, in a study that investigated the relationship between CCs and culprit lesion vulnerability in patients with ACS, the frequency of CCs was significantly higher in patients with STEMI compared to NSTEMI (50.8% vs 34.7%, p=0.032). Moreover, culprit lesions with CCs had higher prevalence of macrophage accumulation (77.8% vs 40.0%, p<0.001), microchannels (67.9% vs 24.8%, p<0.001), plaque rupture (58.0% vs 36.0%, p=0.001), thrombosis (66.7% vs 49.6%, p=0.016) and spotty calcification (35.8% vs 10.4%, p<0.001), suggesting that CCs may increase plaque vulnerability and trigger plaque rupture in patients with ACS [157].
Neovascularization
In atherosclerotic plaques, neovascularization proliferates from the adventitia into the arterial wall in order to supply nutrition and inflammatory cell accumulation to the lesion. Also, micro‐vessels play a role in plaque haemorrhage associated with lipid core expansion through the accumulation of free cholesterol from erythrocyte membranes [89]. Therefore, pathological neovascularization of the artery wall is a consistent feature of atherosclerotic plaque development and progression of disease. In addition, it has also been recognized as a common feature of plaque vulnerability [89]. Some previous reports showed that micro‐vessels are increased in coronary lesions from patients with acute myocardial infarction [158, 159]. Micro‐channels are characterized using OCT as black holes with a diameter of 50–300 μm within plaque that are present on at least three consecutive frames (Figure 1.5). According to a study that examined 63 patients with CAD, micro‐channels detected by OCT evaluation were associated with a higher incidence of concomitant TCFAs and increased high‐sensitivity C‐reactive protein levels, which indicates the importance of intraplaque micro‐channels as a marker for plaque vulnerability [160].
Neoatherosclerosis
It is seen as diffusely bordered, signal‐poor regions with overlying signal‐rich bands, while calcific neointima shows well‐delineated, signal‐poor regions with sharp borders (Figure 1.1).
Near infrared spectroscopy (NIRS)
Advances in catheter‐based spectroscopy enables generation of a chemical fingerprint of atherosclerotic plaque. Near infrared spectroscopy (NIRS) is a technique that has been used for decades in the physical sciences to characterize chemical composition for substances [161]. This method could be ideal for identification of lipid‐rich and potentially vulnerable atherosclerotic plaques. The initial catheter‐based system was LipiscanTM (InfraRedx Inc., Burlington, MA, USA). Subsequently, since NIRS imaging did not provide any volumetric data of plaques, the NIRS/intravascular ultrasound (IVUS) catheter (TVC Imaging SystemTM, InfraRedx Inc., Burlington, MA, USA) was developed. NIRS generates a color map that displays the lipid content of the arterial wall as a “chemogram”. Every pixel represents the probability of lipid presence at the given location on a colour scale in which low probabilities of lipids are depicted as red, and high probabilities of lipids are shown as yellow (Figure 1.6). The “block chemogram” is a semiquantitative summary of the results for each 2 mm segment of the imaged artery. The lipid core burden index (LCBI) is the quantification of lipid present in the scanned region and is defined as the fraction of yellow pixels on the chemogram multiplied by 1000. The maximal lipid core burden index (max LCBI) per 4 mm describes the region with the highest lipid burden. ex vivo validation studies support the feasibility of NIRS imaging with reasonable sensitivity and specificity for evaluating the extent of lipidic materials [162, 163]. Signal loss behind calcium due to acoustic shadowing is an important limitation for conventional IVUS, whereas NIRS penetrates effectively through calcium and stents, not affected by lower intensity due to attenuation. Additionally, with inability of IVUS and OCT to visualize or determine actual composition of lipidic plaques due to signal drop‐out, NIRS offers a more reliable and quantitative detection of lipid core plaques than other intravascular imaging methods. On the other hand, a potential limitation of NIRS may be its inability to assess the depth of a lipid core and the measurement of lipid volume.
Figure 1.6 NIRS IVUS imaging of vulnerable plaque. Lipid rich plaque (yellow at left and right images): cross sectional image (left hand) and lon‐gitudinal pullback image with its chemogram (right hand).
Lipid rich plaques
The common denominator for plaque rupture causing ACS is lipid accumulation, either as a lipid core or lipid pools [115]. This has been proved in a study that compared ACS culprit sites with lesions responsible for stable CAD using NIRS [164]. Subsequently, it has been shown that NIRS‐IVUS is highly specific for the identification of ST‐elevation myocardial infarction (STEMI) [165] and non‐ST‐elevation myocardial infarction [166]. According to these studies, a maximum LCBI4mm >400 was the