Using intravascular OCT, Takano et al. [11] for the first time demonstrated that fibrous neointima could transform into lipid-laden neointima in the chronic phase after BMS implantation. In their study, 67 % of BMS demonstrated conversion to lipid-laden neointima after 5 years of implantation, and plaque angiogenesis (neovascularization) was also observed significantly more frequently in the late phase (>5 years) than in the early phase (<1 year). Remarkably, neoatherosclerotic changes were observed in the BMS without angiographic restenosis. They also found disruption of the fibrous cap and thrombus formation associated with neoatherosclerotic changes, suggesting a potential role of neoatherosclerosis in late stent failure. In selected cases with restenosis, Habara et al. [38] compared the morphological characteristics of neointima either very late (>5 years) or early after BMS implantation. Almost 90 % of the BMS restenotic lesions that occurred in the very late phase were accompanied by neoatherosclerotic changes, and peri-stent and intra-neointimal microvessels were more frequently observed in in-stent restenosis occurring in the very late phase.

Neoatherosclerosis occurs more evidently in DES compared with BMS. Kang et al. [39] showed that of 50 restenotic lesions in DES that were on average 32 months old, 90 % of neointima contained lipid accumulation, and 10 % demonstrated calcium deposits. In addition, 52 % showed in-stent thin-cap fibroatheroma (TCFA) and 29 (58 %) had at least one in-stent neointimal rupture. Patients presenting with unstable angina showed a significantly thinner fibrous cap (55 m vs 100 m, P < 0.006) and higher incidence of TCFA (75 % vs 37 %, P < 0.008), intimal rupture (75 % vs 47 %, P < 0.044), and intraluminal thrombus (80 % vs 43 %, P < 0.010) than stable patients. Interestingly, fibrous cap thickness negatively correlated with follow-up time (r = −0.318, P < 0.024) after stent implantation. Compared with DES implanted more recently than 20 months, those placed at least 20 months prior to the study had a higher incidence of TCFA (69 % vs 33 %, P < 0.012) and red thrombus (27 % vs 0 %, P < 0.007). Patients with unstable angina demonstrated an increasing number of unstable findings on OCT, including TCFA, neointima rupture, and thrombus. The authors showed that in-stent neoatherosclerosis possibly correlates with DES failure, especially late after implantation.

As previously mentioned, there are substantial differences between BMS and DES in terms of the incidence and time course of neoatherosclerosis development. Yonetsu et al. [40] recently used OCT to compare the characteristics of neoatherosclerosis in 56 BMS and 82 DES cases. They categorized 138 stents with neointima (>100 μm) based on time since implantation: early phase (<9 months), intermediate phase (9–48 months), and delayed phase (>48 months) [40]. In the early phase, a greater incidence of lipid-laden plaque (37 % vs 8 %, p < 0.02) was found in DES than in BMS. This relation was also evident in the intermediate phase. In the delayed phase, however, incidence of neoatherosclerosis was similar between the two stent types in total. A similar pattern was observed regarding the incidence of lipid-rich plaque (LRP), defined as a plaque with a lipid arc >90° (Fig.12.4). These findings support previous pathological data showing earlier development of neoatherosclerosis in DES than in BMS [20]. In addition, in both stent types the incidence of lipid-laden plaque, intra-intimal neovascularization, and TCFA were significantly greater in cases with symptomatic restenosis than in those with asymptomatic restenosis. Thus, lipid-rich neoatherosclerosis develops inside stents earlier in DES than in BMS. After 48 months, most restenotic stents will have developed lipid-laden neointima in both groups. The same group [41] demonstrated that cutoff durations for the development of neoatherosclerosis in DES and BMS were 14 and 55 months, respectively.

The precise mechanism of neoatherosclerosis development remains unknown, but recent OCT studies have provided important clues in this regard.

Tian et al. [42] studied the spatial distribution of neoatherosclerotic changes and evaluated the relation between neoatherosclerosis and tissue characteristics around the stent edge reference segment. In their study, neoatherosclerosis was (1) more frequent in the proximal and distal sections than in the mid-sections of stents, (2) more frequently observed in stents with neointimal formation of microvessels, and (3) significantly more frequent when the adjacent plaque in the edge reference segment was rich in lipid content. These findings suggest that introduction of microvessels into neointima plays an important role in the formation of neoatherosclerosis, and that lipid-rich segments adjacent to stent edges are important in the formation of microvessels that supply blood during neointimal and neoatherosclerotic development.

Furthermore, a recent study by Vergallo et al. showed a positive correlation between the degree of neointimal hyperplasia and the presence of neointimal lipid accumulation [43]. They observed that stents of both types with greater neointimal thickness had a significantly greater prevalence of lipid-laden neointima, but the time course of neoatherosclerotic changes were different between BMS and DES (Fig. 12.5). Additionally, in DES, the magnitude of lipid accumulation was positively related to the degree of neointimal hypertrophy. This association was independent of stent type and time since implantation, and suggests a possible pathogenic link between the two processes. These results agree with data from a previous OCT study, in which neoatherosclerosis was more frequently identified in patients with restenosis than without restenosis [27]. Neointimal hypertrophy and neoatherosclerosis might share similar underlying mechanisms involving chronic inflammation and endothelial dysfunction, as suggested by the involvement of proinflammatory cytokines and the impairment of the nitric oxide pathway. In addition, the extensive neointimal hypertrophy that typically develops inside BMS likely maintains and amplifies flow disturbances inside the stent (restenosis-induced low endothelial shear stress: ESS), favoring further neointimal proliferation and ultimately resulting in neoatherosclerotic degeneration. This “ESS hypothesis” could explain the late occurrence of neoatherosclerosis and its preferential edge location observed in BMS. In contrast, incompetent and incomplete endothelialization after DES implantation induces an inflammatory response stimulating neointimal growth and lipid deposition into the subendothelial space, causing earlier development of neoatherosclerosis compared with BMS.

The predictive factors for the development of neoatherosclerosis have not been established. Yonetsu et al. [41] examined 179 stents in 151 patients and evaluated the influence of patient characteristics, stent type, and time since stent implantation (stent age) on the development of lipid-laden neointima or calcification inside the stents (Table 12.1). In multivariate analysis, stent age ≥48 months, all subtypes of DES, current smoking, chronic kidney disease, and use of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II receptor blockade (ARB) remained independent predictors for neoatherosclerosis. Because current smoking and chronic kidney disease are established risk factors for native coronary atherosclerosis, a similar mechanism is likely to be involved in neoatherosclerosis formation. In addition, these results may support the importance of secondary prevention after stent implantation regardless of stent type. It is interesting that ACE-I and ARB were protectively correlated with neoatherosclerosis. These drugs are widely used to reduce cardiovascular events in the secondary prevention of coronary heart disease [44, 45]. Moreover, it has been reported that pharmacologic therapy with ACE-I or ARB reduces neointima proliferation and restenosis after stent implantation [46, 47]. Prospective studies to evaluate the effects of ACE-I and ARB on the prevention of neoatherosclerosis are warranted.