2.3 Statistical analysis
Statistical analysis was performed with JMP Pro 12.2.0 (SAS, Cary, NC). Continuous variables are described as mean (standard deviations) or median (interquartile range [IQR]). Nonparametric parameters were analyzed using the Wilcoxon or Kruskal-Wallis test, and are expressed as median (IQR). P values of <.05 were regarded as statistically significant.
To investigate the relationship between preexisting atherosclerotic lesions and neointimal thickness on the stent struts, we analyzed 3459 struts from 20 stents in 15 patients. The patients’ baseline characteristics are summarized in Table 1. The coronary risk factors identified were as follows: hypertension in 86.7%, diabetes mellitus in 66.7%, dyslipidemia in 93.3%, and smoking in 53.3% of the patients. Among the patients, 86.7% and 66.7% were receiving statins and beta-blockers, respectively. The mean follow-up period after stent deployment to follow-up OCT was 264 days.
The following stents were used: Nobori biolimus-eluting stents (BESs; Terumo; n = 7), Xience everolimus-eluting stents (EESs; cobalt-chromium [Co-Cr] EES, Abbot Vascular, Santa Clara, CA; n = 9), and Promus premier EESs (platinum-chromium [Pt-Cr] EESs; Boston Scientific, Marlborough, MA; n = 4). Vessel lesion and American Heart Association (AHA) type, median stent size and length, and the ratio of the plaque characteristics under the struts are shown in Table 2. In the OCT evaluation at the time of stent deployment, the median under-expansion ratio was 0.90, the mal-apposed strut ratio was 1.7%, and the median mal-apposed distance was 190 μm.
In the present study, there were no cases of angiographic in-stent restenosis after DES implantation. OCT findings are shown in Table 3. Of the 3459 struts, 3315 (95.8%) were covered with neointima (median, 70 μm; IQR, 40–140 μm). The neointimal thickness of the struts on the non-calcified lesions (fibrous and lipid-rich lesions) was 80 μm (IQR, 40–140 μm). The neointimal thickness of the calcified plaque lesion was thinner than that of the non-calcified lesion (20 μm vs 80 μm; P < .001). The median neointimal thicknesses of the stent struts on calcified, fibrous, and lipid-rich lesions were 20 μm (IQR, 10–50 μm), 70 μm (IQR, 40–140 μm), and 90 μm (IQR, 50–170 μm), respectively. Statistically significant differences in median neointimal thickness on the stent struts were found among the calcified, fibrous, and lipid-rich lesions (Fig. 2). The neointimal thickness of the stent struts on the calcified lesions was thinner than that of the struts on fibrous and lipid-rich lesions (20 μm vs 70 μm, P < .001; 20 μm vs 90 μm, P < .001). The neointimal thickness of the struts on the lipid-rich lesions was thicker than that of the struts on the fibrous lesions (90 μm vs 70 μm, P < .001). These differences were observed regardless of the type of second-generation DES (Table 4). No significant relationship was found between neointimal thickness and follow-up period. The multivariate analysis of neointimal thickness revealed that diabetes had a weak correlation with R = 0.20, and statin use had a weak correlation with R = 0.28. In the comparison of the types of stent neointimal thickness, a weak correlation was found with Co-Cr EES and others (R = −0.23), and with Pt-Cr EES and others (R = 0.20). Stent diameter, lesion characteristics, under-expansion ratio, and malapposition were not correlated with the thickness of the neointima.
4.1 Pathophysiology of neointimal formation after DES implantation
In the present study, we investigated the relationship between neointimal thickness after second-generation DES implantation and the characteristics of preexisting atherosclerotic lesions by using OCT. The main findings of this study are as follows: most of the struts were covered with neointima after second-generation DES implantation; the median neointimal thickness on stent struts was statistically significantly different among the calcified, fibrous, and lipid-rich lesions; and these differences were observed regardless of the type of second-generation DES.
Numerous studies have demonstrated that in-stent restenosis is caused by neointimal proliferation. The neointima is mainly composed of smooth muscle cells, and early thrombus formation and acute inflammation are followed by neointimal growth after stent implantation. Medial injury and lipid core penetration through struts further exacerbate inflammation. Our group showed the important roles of monocytes and neutrophil infiltrations in the development of exuberant neointimal proliferation of in-stent restenosis.[13,15–18] Infiltrated monocytes and neutrophils, and activated platelets have been shown to promote low-density lipoprotein oxidation, which stimulates the proliferation and migration of smooth muscle cells via induction of the platelet-derived growth factor.[16,18,20] To reduce neointimal formation, the DES releases drugs that impede smooth muscle proliferation and migration; however, these drugs also impair the normal healing process of the injured arterial wall.[21,22]
4.2 Relationship between neointimal thickness and underlying plaque of preexisting atherosclerotic lesions
As the conditions of the endothelium differ depending on the plaque characteristics, we can reasonably speculate that preexisting atherosclerotic lesion characteristics affect neointimal formation after stent placement. A previous study showed that the neointimal volume in the calcified plaque-containing cross-section was smaller than that in other lesions in an IVUS study. The neointima was also reported to grow thicker on lipid-rich lesions than on other lesions after second-generation DES deployment in an OCT study. Consistent with these reports, the present OCT study demonstrated that neointimal thickness was greater on the lipid-rich lesions than on the calcified lesions after second-generation DES implantation. Owing to the few smooth muscle cells in the calcified plaque, neointimal hyperplasia rarely occurs. On the other hand, because lipid plaque induces inflammation, more intimal proliferation is anticipated to progress. In some previous studies using angioscopy, the presence of yellow plaque was more frequently found in the implanted area of the DES than in the BMS area. Many reports also indicated that the function of regenerated endothelial cells was decreased. In addition, with scanning electron microscopy, regenerated endothelial cells after Cypher stent implantation have been reported to have a more immature shape than BMS. Thus, we suggest that an immature endothelial barrier allows blood lipid migration into the neointima after DES. An experimental study showed that eNOS and CD31 expression levels were lower in the injured carotid arteries than in the uninjured carotid arteries after balloon angioplasty. We suggest that a relationship exists between plaque characteristics before PCI and endothelial regeneration. Stent struts placed on the lesions with lipid-rich plaque are thought to have a thickened neointima. Thus, the risk for restenosis due to neointimal proliferation in the future and the possibility of the appearance of neoatherosclerosis due to neointimal proliferation may increase. Indolfi et al reported a case of higher neointimal formation after bioresorbable vascular scaffold (BVS) implantation. In this case, most of the neointima were well thickened, showing a heterogenous or layered pattern by OCT, although relatively thin heterogeneous neointima were partially recognized. The preexisting plaques before BVS implantation were mostly lipid-rich plaques with a necrotic core.
Coronary calcification is known to be associated with advanced age; sex; smoking; and the presence of diabetes mellitus, hypertension, and renal dysfunction.[26,27] In addition, insufficient stent expansion, stent malapposition, and polymer damage of DESs sometimes occur in calcified lesions after PCI. These phenomena were suggested to lead to less acute lumen gain and more late lumen loss because of excessive neointimal proliferation. By contrast, the risk for stent thrombosis after stent deployment in calcified lesions is potentially higher than that in non-calcified lesions. Additional histological studies have also revealed that the most powerful predictor for stent thrombosis is insufficient, immature endothelial coverage. Retardation of re-endothelialization on the stent strut in calcified lesions can be the cause of the neointimal proliferation that follows DES implantation. In the present OCT study, we found that the neointimal thickness of stent struts in calcified lesions was thinner than that in non-calcified lesions after stent implantation. These results suggest retardation of the re-endothelialization on stent struts in calcified lesions.
4.3 Clinical implication
The ratio of the neointima coverage was increased with the second-generation DES as compared with the first-generation DES. However, our present findings indicate that not all struts were homogeneously neointimalized even after deploying the second-generation DES and that the thickness of the neointima was affected by the preexisting plaque characteristics. These findings suggest that the difference in characteristics of the plaque under the strut causes a heterogeneous neointimal development and increases the risk for restenosis. Moreover, insufficient neointimal development in the calcified lesion could cause thrombosis in the chronic phase. Evaluating the nature of the preexisting lesion during stent placement may predict the risk for future restenosis and thrombosis.
This study had several limitations. First, because this study was retrospective and included a small number of patients, a hypothesis was proposed on the basis of the study results. In addition, the follow-up period had some variations, the clustering effects were difficult to adjust, and selection bias could not be completely excluded. Second, during the OCT analysis, the post-stent deployment and follow-up stent lesions were not completely the same. Third, although malapposed strut distance and ratio may be related to the neointimal thickness, we could not analyze the aforementioned relationship because of the small number of malapposed struts. Fourth, neointimal tissues were analyzed using OCT but were not classified using pathological methods. Thus, prospective studies that include more cases and pathological examination are needed. Finally, in our study, the proportion of calcified plaques was low, and that of lipid-rich or fibrous plaques was high. The influence of such plaque distribution cannot be completely denied statistically.
In conclusion, neointimal coverage after second-generation DES implantation has a close relationship with preexisting atherosclerotic lesion characteristics. Evaluating the lesion characteristics during stent placement using OCT may predict the risk for future restenosis and thrombosis.
Conceptualization: Kenichi Sugioka, Makiko Ueda.
Investigation: Yohta Nomoto, Masashi Nakagawa, Nobuyuki Shirai.
Project administration: Masashi Nakagawa.
Supervision: Keiko Kajio, Kazuki Mizutani, Takanori Yamazaki, Kimio Kamimori, Yasuhiro Izumiya, Minoru Yoshiyama.
Validation: Yohta Nomoto, Masashi Nakagawa.
Writing – original draft: Yohta Nomoto.
Writing – review & editing: Yasuhiro Izumiya, Minoru Yoshiyama.
Yohta Nomoto orcid: 0000-0001-5153-9071.
Yasuhiro Izumiya orcid: 0000-0003-2332-9151.
Minoru Yoshiyama orcid: 0000-0002-3197-0494.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
drug-eluting stent; neointimal thickness; optical coherence tomography; plaque characteristic