Fig. 15.1
Definitions of neointimal coverage grades. Neointimal coverage grades were defined as follows: grade 0, stent struts fully visible, similar to immediately after implantation; grade 1, stent struts bulged into the lumen and, although covered, were still transparently visible; grade 2, stent struts were embedded by the neointima but were seen translucently; grade 3, stent struts fully embedded and invisible on coronary (Reproduced with permission from the American College of Cardiology, partially modified [4])
Fig. 15.2
Images of thrombi detected by coronary angioscopy. The upper images show thrombi adhering to the site of incomplete neointimal coverage (i.e., grade 0/1). The lower images show complete neointimal coverage (i.e., grade 2/3). Thrombus adhesion to the complete neointima is rare. White thrombi in Cypher-SES are indicated with open yellow arrows. Of note is the fact that thrombi observed with Taxus-PES in the upper-right panel show the extended areas of adhesion as compared with Cypher-SES. SES sirolimus-eluting stent, PES paclitaxel-eluting stent (Reproduced with permission from Medialpha (Coronary Intervention vol. 9, no. 1), partially modified)
The grades of not only NIC but also reendothelialization need to be determined to assess arterial healing because endothelial coverage rather than NIC is the goal after stent implantation. The presence or absence of endothelial cells is difficult to be assessed by CAS. As described above, nevertheless, CAS allows the indirect assessment of reendothelialization through the evaluation of NIC grade and thrombus adhesion. Finn et al. described that incomplete NIC, which is morphometrically quantified with the ratio of uncovered to total stent struts per section, is the most powerful morphologic surrogate indicator of endothelialization [10]. CAS is also a useful tool for evaluating the intravascular conditions at the site of abnormal vascular response after DES implantation, as typified by the peri-stent contrast staining [11].
15.3 Coronary Angioscopic Findings After Sirolimus-Eluding Stent (Cypher-SES) Implantation
A large number of studies are available that have reported on the first-generation DESs including Cypher-SES. We used the abovementioned grades of NIC to compare dominant NIC at 3–6 months after the implantation of Cypher-SES and BMS. Consequently, all 22 BMSs had complete NIC (grade 2/3) in contrast to Cypher-SES, in 87 % of which incomplete NIC (grade 0/1) was rated as dominant NIC (Fig. 15.3) [2]. Namely, the images of CAS were remarkably different between BMS and Cypher-SES. Furthermore, we observed time-course changes in NIC grades up to 2 years after Cypher-SES implantation. In consequence, we found no changes in NIC grades at 4 months to 1 year after implantation. Although a minority of Cypher-SES showed NIC grade progression at 1–2 years after implantation, 71 % of implanted Cypher-SES showed NIC grade 1 still at 2 years after implantation (Fig. 15.4) [3]. We found yellow plaques in 71 % of Cypher-SES at 4 months after implantation and observed the plaques also at 2 years after implantation. Takano et al. also observed time-course changes in 20 Cypher-SES and found both 20 % of Cypher-SES uncovered and subclinical thrombus formation in 30 % of the Cypher-SES at 2 years after implantation [12]. It is very rare to find thrombus adhesion at the site of BMS implantation at this stage [13]. Furthermore, Oyabu et al. reported that thrombus adhesion after Cypher-SES implantation was found predominantly at the site where a substent yellow plaque was present [14]. Yellow plaques with thrombus seem to be more vulnerable than those without thrombus [15].
Fig. 15.3
Distributions of dominant neointimal coverage grades at 3–6 months after the implantation of BMS and SES. Neointimal coverage was more complete with bare-metal stent compared than with the sirolimus-eluting stent (P < 0.000). BMS bare-metal stent, SES sirolimus-eluting stent (Reproduced with permission from the American College of Cardiology [2])
Fig. 15.4
Serial changes in neointimal coverage grades in 17 SESs and 11 BMSs. Seventy-six percent of SES showed NIC grade 1, while 91 % of BMS showed NIC grade 3 at the first follow-up. NIC grade 3 was noted with BMS at all follow-ups except for 1 stent that showed NIC grade 2. In contrast, the lower grades (0–2) of NIC were noted with SES. SES showed no increases in NIC grades at the second and third follow-ups. However, 3 SES showed one-grade increases in NIC grades at the third follow-up. SES sirolimus-eluting stent, NIC neointimal coverage, BMS bare-metal stent, open circle, SES (n = 17); solid circle, BMS (n = 11) (Reproduced with permission from American Heart Association, partially modified [3])
Pathological research has reported long-term incomplete reendothelialization by Cypher-SES [16] and inflammation induced by its polymer [17]. It is known that neoatherosclerosis progression is accelerated at the site of Cypher-SES implantation in association with these changes; this event is also considered as one of the contributing factors for LVLST [18]. The rapid progression of a yellow plaque underneath the stent struts and the presence of the yellow neointima on the stent were considered as the angioscopic manifestations of this event [19]. Attempts (e.g., employment of a highly biocompatible polymer) are being made to solve these issues in the development of next-generation DESs. The comparison of angioscopic findings between Cypher-SES and other DESs is useful for the assessment not only of arterial healing after DES implantation but also of these issues.
15.4 Can Cypher-SES Implantation Achieve the Plaque-Sealing Effect?
An intracoronary plaque with a more intense yellow tone is considered to involve a higher risk of developing acute coronary syndromes (ACS) because of the thinner fibrous cap covering lipid components [20]. The neointima formed after BMS implantation covers not only the stent but also the yellow plaque and thrombus that are present underneath the stent. The plaque present at the site of stent implantation is considered stabilized by this coverage as if being a plaque that is covered with a thick fibrous cap; this is called the plaque-sealing effect [21]. In fact, a study on the 5-year clinical outcomes of BMS-implanted patients with respect to the incidence of clinical events (death, myocardial infarction, revascularization, heart failure, or hospitalization for ACS), which were attributed to the implantation than non-implantation sites of BMS, described that the incidence was higher at the non-implantation site of BMS than at the implanted site of BMS at 1 or more years after implantation—the stage later than the phase of predilection for ISR [22]; we consider the involvement of the plaque-sealing effect after BMS implantation in this observation. Cypher-SES was successful in reducing the incidence of ISR by the suppression of neointimal proliferation but probably does not allow us to expect the plaque-sealing effect as suggested by coronary angioscopic findings. When Cypher-SES is implanted in a lipid-rich plaque and a ruptured plaque becomes bulged into the lumen, this highly thrombogenic plaque involves the risk of being uncovered by the neointima and consequently being exposed to the blood flow for a long time; this event is also considered as a contributing factor for LVLST. An observational study using Cypher-SES, which lasted as long as 5 years, described that the annual incidences of LVLST did not decrease with time, reaching ~0.33 % [23]. Furthermore, an angioscopic study, which observed time-course changes in NIC at the stage later than 5 years after Cypher-SES implantation, indicated the persistence of incomplete NIC and subclinical thrombosis [24]. Delayed arterial healing as observed by CAS cannot be necessarily considered as a direct cause of LVLST [25]. However, we consider it essential to provide the long-term careful monitoring of Cypher-SES-implanted patients. In fact, we encountered a patient who developed very late stent thrombosis (VLST) at 5 years after Cypher-SES implantation, in whom we considered the uncovered stent struts as the main cause of VLST based on findings from CAS and optical coherence tomography [26].
15.5 Coronary Angioscopic Findings After Paclitaxel-Eluting Stent (Taxus-PES) Implantation
Taxus-PES, which became clinically applicable subsequently to Cypher-SES, showed a slightly greater in-stent late loss than that of Cypher-SES. We conducted CAS at 8 months after the implantation of 30 Taxus-PESs and compared them with 36 Cypher-SESs. Consequently, the majority of Cypher-SES indicated NIC grade 1 in contrast to Taxus-PES, 40 % of which indicated NIC grade 3; NIC grades 0–2 were equally distributed in the remaining Taxus-PES (Fig. 15.5) [5]. As a characteristic finding, furthermore, Taxus-PES frequently exhibited heterogeneous NIC—the concomitant presence of different NIC grades—within the same stent. Takano et al. had previously pointed up the heterogeneous neointimal growth inside Cypher-SES [12]. We found the relevant heterogeneity in 47 % of Cypher-SES. In contrast, 74 % of Taxus-PES exhibited heterogeneous NIC; two-grade NIC differences were found in 26 % of this subgroup of Taxus-PES (Figs. 15.6 and 15.7) [5]. Thus, Taxus-PES indicated the high heterogeneity not only of dominant NIC among the stents but also of NIC within the same stents. Other investigators have also reported on this heterogeneous neointimal formation [6, 27]. The fact that paclitaxel has a narrow therapeutic window has been mentioned as a cause of heterogeneous neointimal formation. Namely, we consider that the profile of the drug—the potent suppression of neointimal proliferation by a high local concentration of paclitaxel and the insufficient suppression of the proliferation by a low local concentration of the drug—resulted to appear in a salient manner. We found the equivalent detection rates of yellow plaques (83 % and 78 % for Taxus-PES and Cypher-SES, respectively; P = 0.76) and the rather higher incidence of thrombus adhesion (43 % and 19 % for Taxus-PES and Cypher-SES, respectively; P = 0.04) [5]. Of particular note, furthermore, Cypher-SES showed thrombi that were mural, small, and localized. In contrast, Taxus-PES notably exhibited thrombi that extended more broadly as compared with Cypher-SES (Fig. 15.2). The follow-up assessments of serial CAS at 6 and 18 months after Taxus-PES implantation described the persistence of thrombus adhesion [28]. The significance of thrombus adhesion that is a characteristic of Taxus-PES is unknown. However, we deem it necessary to provide careful follow-up also for Taxus- or PES-implanted patients.
Fig. 15.5
Distributions of dominant neointimal coverage grades at 8 months after the implantation of PES and SES. Although 72 % of SES showed dominant NIC grade 1, PES showed the extended distributions of NIC grades. PES vs. SES, P = 0.0006 by chi-square test. SES sirolimus-eluting stent, NIC neointimal coverage, PES paclitaxel-eluting stent (Reproduced with permission from the American College of Cardiology [5])
Fig. 15.6
Coronary angioscopically assessed homogeneous and heterogeneous neointimal formation of PES and SES. Forty-seven percent of SES showed the heterogeneous neointimal formation that was coronary angioscopically assessed as one-grade difference in NIC grade. Fifty-three percent demonstrated the homogeneity of NIC. In contrast, 74 % of PES showed heterogeneous NIC, 48 % showed one-grade difference in NIC grade, and 26 % showed two-grade difference in NIC grade. PES vs. SES, P = 0.002 by chi-square test. SES sirolimus-eluting stent, NIC neointimal coverage, PES paclitaxel-eluting stent (Reproduced with permission from the American College of Cardiology [5])
Fig. 15.7
Coronary angiograms and angioscopic images at 8 months after the tandem implantation of SES and PES. Coronary angiograms at follow-up revealed no restenosis at the segment of SES (3.5 mm × 23 mm) and PES (3.5 mm × 24 mm) implanted in tandem. The angioscopic images of SES showed the homogeneous neointimal formation angioscopically assessed as NIC grade 1. In contrast, PES showed the heterogeneous neointimal formation that was angioscopically assessed as two-grade difference in NIC grade; dominant NIC was grade 2 in PES; the distal segment showed NIC grade 0, with mural red thrombi adhered to yellow plaques and the naked stent struts. SES sirolimus-eluting stent, PES paclitaxel-eluting stent, NIC neointimal coverage. Dashed blue line = SES implantation site, dashed red line = PES implantation site. GW = guide wire (Reproduced with permission from the American College of Cardiology [5])
15.6 Coronary Angioscopic Findings After Zotarolimus-Eluting Stent (Endeavor-ZES) Implantation
Endeavor-ZES is a DES that has shown the greatest value of late loss among DESs ever examined. A foreign clinical study using Endeavor-ZES showed a late loss value of about 0.6 mm [29], and Endeavor-ZES has a greater incidence of target lesion revascularization (TLR) as compared with Cypher-SES [30]. Therefore, Endeavor-ZES turned to be a DES not for active use in the clinical settings. Nevertheless, we conjecture that Endeavor-ZES may indicate distinctive arterial healing because of its great late loss in comparison with other DESs. Hence, we conducted CAS in patients implanted with 14 Endeavor-ZES at 8 months after implantation. Consequently, 10 (71 %) and 4 (29 %) Endeavor-ZES exhibited NIC grade 3 and grade 2, respectively (Figs. 15.8 and 15.9). Furthermore, a yellow plaque and thrombus adhesion were observed only with 2 (14 %) and 1 (7 %), respectively [4]. Thus, Endeavor-ZES indicated findings similar to those of BMS. Furthermore, dominant NIC grade showed similar distributions at both 4 and 8 months after Endeavor-ZES implantation [8]. Studies have described that Endeavor-ZES, which allows the early achievement of complete NIC, also permits the attainment of early reendothelialization [31, 32]. Our previous study [8] supported the results from a study demonstrating that Endeavor-ZES enabled the shift from dual to single antiplatelet therapy at as early as 3 months after implantation and that the incidence of late stent thrombosis did not increase thereafter [33, 34]. We consider, based on coronary angioscopic findings, that Endeavor-ZES is a potential option to substitute BMS in high-risk patients for long-term dual antiplatelet therapy (DAPT).
Fig. 15.8
Coronary angioscopic classification of neointimal coverage at 8 months after the implantation of ZES and SES. Seventy-one percent of ZES showed NIC grade 3, while 6 % of SES showed NIC grade 3. Neither grade 0 nor grade 1 was found with ZES. The shadowed portion indicates the incidence of thrombus adhesion. ZES vs. SES, P = 0.0004. ZES zotarolimus-eluting stent, NIC neointimal coverage, SES sirolimus-eluting stent (Reproduced with permission from the American College of Cardiology [4])
Fig. 15.9
Coronary angioscopic images at 8 months after the implantation of SES and ZES. The left panels (a, b) show a SES (3.5 mm × 23 mm), and the right panels (c, d) show a ZES (3.5 mm × 23 mm), both implanted at the proximal portion of the right coronary artery (a, c). Follow-up angiograms revealed no restenosis (b). The coronary angioscopic images of SES indicated NIC grade 1 along the entire segment of the stent, with mural red thrombus adhesion to the proximal end of the stent. Furthermore, yellow plaques were observed underneath the stent (the entire segment of the stent implanted in the vascular wall was yellow) (d). In contrast, ZES showed NIC grade 3 along its entire segment. Yellow plaques were present in the distal native coronary artery adjacent to the distal end of the stent. The vascular wall showed mild yellow saturation, while the stent was covered with the white-gray neointima showing no yellow plaques (d, bottom image). SES sirolimus-eluting stent; ZES zotarolimus-eluting stent; NIC neointimal coverage; open arrow, mural red thrombus; solid arrow, boundary line of NIC; GW guide wire (Reproduced with permission from the American College of Cardiology [4])
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