Most patients presenting with ACS or dying of cardiovascular death exhibit thrombus overlying a complicated coronary plaque [22, 23]. Although plaque rupture is considered the most frequent plaque complication responsible for ACS, alternative mechanisms of plaque instability triggering coronary thrombosis have been described in pathology studies [10], and, recently, in vivo using OCT [22, 24]. Among these, plaque erosion accounts for about one third of cases, particularly in young women and smokers, and calcified nodules for 5–8 % of cases [10, 22]. However, several other mechanisms can be responsible for ACS, such as a dynamic obstruction due to spasm of an epicardial coronary artery, coronary embolism, coronary dissection, intraplaque hemorrhage or hematoma [22, 25, 26]. This considerable variety of coronary substrates, along with the grade of deriving luminal thrombosis and the myocardial vulnerability to ischemia, can determine a spectrum of clinical presentations, ranging from sudden cardiac death (SCD) or acute myocardial infarction (AMI), with or without ST-segment changes, to unstable angina pectoris (UAP) [21]. In contrast, stable angina pectoris (SAP) arises from a mismatch of blood supply and demand, typically caused by a severe, flow-limiting stenosis without plaque disruption or local thrombosis [27]. Several OCT studies have tried to explore the differences among the various clinical presentations of CAD, with the goal of clarifying pathogenic mechanisms and identifying new diagnostic algorithms and therapeutic targets.

In 2005, our group investigated, for the first time, the differences in OCT coronary plaque features in patients with various clinical coronary presentations [6]. Specifically, the detailed coronary plaque characteristics at the culprit lesion were compared among patients with ST-elevation myocardial infarction (STEMI), non-ST-elevation ACS (including NSTEMI and UAP), and SAP. That study showed that the prevalence of lipid-rich plaques tended to be higher in patients with STEMI or NSTE-ACS than in those with SAP (90 % vs. 75 % vs. 59 %, respectively, p = 0.09). Importantly, there was a significant difference among the three groups in fibrous cap thickness (median value: 47.0 μm [STEMI] vs. 53.8 μm [NSTE-ACS] vs. 102.6 μm [SAP], p = 0.034) and in the prevalence of TCFA (72 % [STEMI] vs. 50 % [NSTE-ACS] vs. 20 % [SAP], p = 0.012) (Fig. 6.4). In contrast, patients with SAP showed a higher prevalence of calcifications compared to those with STEMI and NSTE-ACS (10 % [STEMI] vs. 15 % [NSTE-ACS] vs. 41 % [SAP], p = 0.049). These findings not only confirmed for the first time in living humans what had previously only been observed in cadavers [23], but also underscored the importance of thin fibrous cap and large lipid burden for plaque vulnerability and the development of ACS.

The degree and distribution of macrophage infiltration in relation to the clinical presentation were studied in this cohort [19]. Pathology studies had previously suggested the role of macrophages in plaque instability, with most of plaque ruptures showing high degrees of macrophage infiltration inside the fibrous cap [10]. In this in vivo OCT study, macrophage densities in culprit and non-culprit lesions were assessed in patients presenting with STEMI, UAP, and SAP, by measuring the normalized standard deviation of the RAW OCT signal, a method validated against histology by the same group [18] (See Fig. 6.2). Interestingly, lipid-rich plaques in patients with STEMI and UAP showed significantly greater macrophage density compared to those in stable patients (5.54 ± 1.48 % vs. 5.86 ± 2.01 % vs. 4.14 ± 1.81 %, p = 0.002 and p < 0.001, respectively). When STEMI and UAP were combined into a single group of patients with unstable presentation, even the macrophage density in fibrous plaques was higher than that measured in patients with a stable presentation (5.41 ± 1.10 % vs. 4.43 ± 1.46 %, p = 0.025). For every patient, there was significant correlation between the macrophage density at the culprit lesion and that at the non-culprit lesions (r = 0.66, y = 0.88x + 0.43, p = 0.01). Macrophage density was also greater at the ruptured sites of a plaque compared to at the adjacent non-ruptured sites (p = 0.002). Superficial macrophage infiltration (<50 μm from the luminal surface) was a stronger predictor of unstable clinical presentation compared to a deeper macrophage infiltration (>50 μm) in culprit lesions (p = 0.035), but not in non-culprit lesions. These results suggested, for the first time in vivo, the correlation between macrophage density and the severity of clinical presentation, with greater densities in patients with acute presentation as compared to those with stable clinical presentation [19]. Furthermore, these data proved the multi-focal nature of inflammation in symptomatic CAD, and the possible role of macrophages in the development of plaque rupture and acute coronary events [19]. The disruption of the fibrous cap is, in fact, a consequence of the imbalance between the strength of the fibrous cap and forces impinging on it [28]. In this context, activated macrophages, overexpressing matrix metalloproteinases (MMPs) and elastolytic cathepsins, may play an important role, by increasing collagen degradation, reducing collagen synthesis, and inducing the apoptosis of smooth muscle cells [29].

Inspired by pathology observations of differences in the morphology of a ruptured plaque depending on level of exertion at the time of the SCD [30], Tanaka et al. conducted an elegant study investigating the relation between the morphology of ruptured plaque and the level of patient activity at the onset of ACS [31]. Interestingly, the characteristics and location of plaque rupture appeared to correlate with the clinical scenario: specifically, patients developing ACS at rest, compared to those developing ACS during exertion, had a thicker fibrous cap (50 μm vs. 90 μm, p < 0.01), and were more likely to have a plaque ruptured at the shoulder (57 % vs. 93 %, p = 0.014), and overlying thrombus (73 % vs. 96 %, p = 0.04). In addition, fibrous-cap thickness correlated positively with the level of activity at the onset of ACS (Fig. 6.5). These results emphasized the concept that plaque rupture may not infrequently develop from thick-cap fibroatheroma, and that the level of patient activity at the time of the acute presentation may have a role in determining this event. Later on, the same group looked at the differences in culprit plaque morphologies between patients with STEMI and NSTEMI [32]. The prevalence of plaque rupture was higher in patients with STEMI compared to those with NSTEMI (70 % vs. 47 %, p = 0.033), as well as the prevalence of TCFA (78 % vs. 49 %, p = 0.008) and red thrombus (78 % vs. 27 %, p < 0.001). Interestingly, patients with STEMI showed more frequently a plaque rupture with an aperture against the direction of coronary flow compared to those with NSTEMI (46 % vs. 17 %, p = 0.036) (Figs. 6.6 and 6.7).

Due to the heterogeneous clinical presentation of ACS, classification schemes based on clinical features can be useful to stratify risk, predict prognosis, and establish adequate treatments. For instance, in patients presenting with UAP, the Braunwald clinical classification, which includes three different classes of severity, provides valuable prognostic information [33]. To investigate the relation between clinical presentation and plaque morphology in patients with UAP, Mizukoshi et al. [34] compared the detailed OCT culprit plaque characteristics among the three different classes of severity of UAP, according to the Braunwald clinical classification:

Only patients with primary angina (Braunwald class B) were included in the study; those with secondary or post-infarction angina (Braunwald class A and C, respectively) were excluded. Patients with class I showed a significantly higher prevalence of “ulcers” without any disruption compared to those with the other classes (32 % [class I] vs. 7 % [class II] vs. 8 % [class III], p = 0.003) (Fig. 6.8), and a smaller minimum lumen area (0.70 mm² [class I] vs. 1.80 mm² [class II] vs. 2.31 mm² [class III], p < 0.001). These findings may indicate a higher incidence of plaque erosion with subocclusive thrombosis in this group, and explain the typical symptoms of patients with class I, presenting with new onset angina or with a progressive crescendo pattern. In contrast, patients with class II presented more frequently with coronary spasm compared to those with class I and III (0 % [class I] vs. 33 % [class II] vs. 13 % [class III], p < 0.001) (See Fig. 6.8), suggesting that a dynamic obstruction may be the predominant mechanism in this group. Lastly, patients with class III had the thinnest fibrous cap (140 μm [class I] vs. 150 μm [class II] vs. 60 μm [class III], p < 0.001), as well as frequent plaque rupture (43 % [class I] vs. 13 % [class II] vs. 71 % [class III], p < 0.001) (See Fig. 6.8). This observation suggests that increased plaque vulnerability with subsequent disruption may be the baseline mechanism in most of patients with class III, and may explain the worse prognosis associated with this pattern of angina [35].

However, all the above mentioned studies using in vivo OCT imaging for plaque characterization were single-vessel studies, and therefore the results were derived from a limited part of the coronary vasculature. To overcome this limitation, a 3-vessel imaging study from the Massachusetts General Hospital (MGH) OCT Registry investigated the differences in plaque characteristics at non-culprit lesions between patients with ACS and those with a stable clinical presentation [36] (Figs. 6.9 and 6.10). Patients presenting with ACS had a larger number of lipid-rich plaques compared to the stable patients (1.9 ± 1.4 vs. 1.1 ± 1.1, p = 0.013), confirming the data from previous single-vessel OCT studies and angioscopy studies [37, 38]. In addition, lipid plaques were characterized by a wider lipid arc, greater lipid length, larger lipid volume index, and thinner fibrous cap in patients with ACS compared to those with SAP (See Fig. 6.9). Notably, the prevalence of TCFA was significantly higher in patients with ACS than in those with SAP (64.7 % vs. 14.9 %, p < 0.001), as well as the prevalence of macrophage accumulation (82.4 % vs. 37.9 %, p = 0.001) and thrombus (29.4 % vs. 1.1 %, p < 0.001) (See Fig. 6.10). These results emphasized the panvascular nature of atherosclerosis, and the presence of greater plaque vulnerability in the coronary tree of patients with ACS than those with SAP, which may lead to higher rate of recurrent ischemic events. Interestingly, the prevalence of plaque disruption at non culprit lesions was also greater in patients with ACS than in those with stable clinical presentation, although the difference was not statistically significant. Lastly, although the prevalence of intimal neovascularization was not different between the two groups, patients with ACS had microchannels with a more superficial location (See Fig. 6.10). Neovascularization may play a role in plaque vulnerability [14] and progression [16], through the recruitment of inflammatory cells and the promotion of lipid accumulation within atherosclerotic plaque [39]. A more superficial location of neovascularization might reflect an advanced stage of atherosclerosis; however, this hypothesis needs to be confirmed in future studies. Although this study analyzed the detailed coronary plaque characteristics in patients with ACS, potential differences in non-culprit plaque characteristics in relation to various culprit plaque morphologies had not yet been investigated. As shown by pathology [10] and in vivo imaging studies [22], different types of culprit plaques are characterized by specific underlying morphologic characteristics, and are associated with different clinical presentations. In light of the systemic nature of atherosclerosis, it is reasonable to hypothesize that non-culprit plaques might have different characteristics based on the specific culprit plaque morphology. This was tested in a 3-vessel OCT study comparing the non-culprit plaque characteristics between patients with plaque rupture and those with non-ruptured plaque at the culprit lesion [40]. Patients with ACS caused by plaque rupture showed a higher prevalence of lipid-rich plaques, TCFA, and additional disruption in non-culprit lesions compared to those with a non-ruptured culprit plaque. Patients with ACS caused by a plaque rupture had a TCFA at a remote site in 52.9 % of cases, and an additional disruption in 35.3 % of cases, which localized more frequently in the culprit artery. These data indicated the presence of pancoronary vulnerability in patients with ACS caused by plaque rupture, which may explain the multifocal instability observed during the acute phase, and may be responsible of recurrent cardiac events (Fig. 6.11). It is conceivable that this subset of high-risk patients might benefit from aggressive systemic anti-inflammatory treatments [41] or new lipid-lowering therapies (e.g., PCSK9 inhibitors) [42], in addition to the standard antiplatelet and statin therapies. Further studies are warranted to confirm this hypothesis.