Conventional PCI including BMS deployment had an Achilles’ heel; in-stent restenosis (ISR) occurred in more than 20 % of the cases [9, 10]. To overcome this Achilles’ heel, a new concept of coronary stents, DESs were developed such as SES and paclitaxel-eluting stents (PES). Since their introduction, these two types of DESs have been broadly used, and the Achilles’ heel associated with ISR was almost completely solved because of low frequency of the DES-ISR below 10 % [11, 12]. However, an unanticipated new problem emerged following DES use: late and very late stent thrombosis with high mortality rate [13]. Several mechanisms of the stent thrombosis have been considered to be responsible, including delayed neointimal formation [14], hypersensitivity reaction to the stent polymer [15], and neoatherosclerosis [1]. In the BMS era, 6-month follow-up angioscopy revealed that thick, smooth, and white neointima fully covered the stent struts and there were no thrombi within the BMS segment; the struts could not be seen, even after ACS that has complex yellow plaque and massive thrombi in its culprit lesion [2, 3]. Thus, this phenomenon was understood to be the effect of plaque stabilization, sealing, or whitening (bihaku in Japanese) [3]. Following the introduction of the first-generation DESs, similar effect of DESs on plaque stabilization was expected; however, contrary to the expectation, plaque healing of first-generation DESs was completely different from the BMS [16]. In 2006, we firstly reported the formation of yellow neointima 3 months after SES implantation [7]. In the study, we clearly demonstrated that the frequency of yellow plaque increased from 29 % immediately after stenting to 86 % of the follow-up (Fig. 17.2). Figure 17.3 shows that the white plaque had changed to yellow neointima, and we concluded that this phenomenon represented plaque destabilization by SES implantation. It was also speculated that the mechanisms of plaque destabilization involved thinning of fibrous cap as apoptosis due to a pharmacological effect of sirolimus [17] or polymer-induced inflammation of the plaque [15]. In those days, the phenomenon was not considered to be neoatherosclerosis. To investigate when yellow neointima appeared, we performed angioscopic observation at different follow-up periods. Surprisingly, a quarter of the patients had yellow neointima within 4 months and about half had that within 8 months (Fig. 17.4). Why the frequencies of yellow neointimal formation was different between the first and second reports? It was speculated that diversity of baseline patients and lesion characteristics made the differences. First report included ACS cases, whereas second report excluded ACS cases. Atherogenesis progressed in short term following SES implantation. Up to now, there is no data regarding the long-term prognosis of yellow neointima of SES. In comparison between SES and PES, yellow-plaque grade was higher in SES than in PES, as Fig. 17.5 shows [18]. This result suggested higher atherogenic potential of SES compared to PES. A recent pathological study has clarified the mechanisms of neoatherosclerosis after stent implantation (See Sect. 17.6) [1].

Considering the disadvantages of the first-generation DESs, drug pharmacokinetics and drug-carrying polymers improved for the next generation of DESs. In the fast-release zotarolimus-eluting stent (E-ZES), at least 90 % of the drug releases within two weeks of its implantation. Thus, the drug release of E-ZES is earlier than the first-generation DESs. Approach of everolimus-eluting stent (EES) is different from the first-generation DES, and the DES has more biocompatible polymer. Although problems caused by stent polymer of the first-generation DESs are almost solved, some of them may remain. Figure 17.10 shows the presence of a yellow plaque in the segments of E-ZES and EES one year after their implantation in patients with ACS and non-ACS. The grade of yellow plaque was significantly higher in the EES group, among ACS patients, than ACS and non-ACS in E-ZES groups and non-ACS in EES group. The exact reasons for the presence of the yellow plaque are unclear. Residual yellow plaque underneath the struts may be observed through the thin neointima, or atherogenic yellow neointima may appear as well as the first-generation DESs. Whether or not, such stent segment seems to be angioscopically vulnerable lesion [23].