There were 156 segments used to analyze the incidence of NC abutting to the lumen. In EXCEL group, the overall incidence of NC abutting to the lumen was 44% (proximal 18%, stented site 14% and distal 12%). On the contrary, in CYPHER group, this overall incidence increased up to 63% (proximal 19%, stented site 28% and distal 16%) compared with EXCEL group (P <0.05, Figure 3A). No difference had been found in each group with regard to the distribution of NC abutting to the lumen among all three segments. There was no significant change regarding the incidence of NC abutting to the lumen either in proximal (Figure 3B) or distal (Figure 3D) stent edge between the two groups. However, when compared with stented segments each other, the CYPHER-treated segments had a significant higher incidence of NC abutting to the lumen through the stent struts (73% vs. 36%, P <0.01, Figure 3C). In addition, more multiple NC abutting to the lumen was observed in CYPHER group (overall: 63% vs. 36%, P <0.05, Figure 4A). No obvious difference among the distribution of multiple NC abutting to the lumen in all three segments was shown in each group (proximal 18%, stented site 10% and distal 8% in EXCEL; proximal 19%, stented site 32% and distal 12% in CYPHER. Furthermore, when the stented segments with NC abutting to the lumen had been taken into account only, CYPHER-treated lesions tented to contain more multiple NC abutting to the lumen through the stent struts than EXCEL-treated lesions (74% vs. 33%), although there was no statistically significant difference between them (P=0.06, Figure 4C). The same trend was observed at proximal (Figure 4B) and distal (Figure 4D) stent edges between the two groups.
In this VH-IVUS study, it was mainly demonstrated that a greater frequency of stable lesion morphometry during follow-up was shown in lesions treated with BSESs compared with lesions treated with DSESs. Furthermore, it was similar that the stent struts were interpreted in VH-IVUS images as a red halo surrounding the white stent metal at follow-up in both BSES and DSES.
However, in present study, none of the patients had VH-IVUS pre- or post-intervention immediately, the results remained convincing to some extent. First, previous intravascular ultrasound study showed that LDL cholesterol level during follow-up was the only independent predictor of changes in coronary plaque size. When patients achieved a LDL cholesterol level <100 mg/dl (approximately equal to 2.59 mmol/L) during follow-up, regression or no progression of coronary plaque was expected.15 Other intravascular ultrasound studies showed that the DES did not affect plaque burden located behind the struts.13,16 In this study, the LDL levels during follow-up in the two groups were both <100 mg/dl. And that no differences had been found among the volumes of EEM, lumen or PBS between two groups, implied that with similar plaque burden preinterventian no differences had been detected during follow-up. These suggested that the unstable lesion morphometry observed in DSES-treated lesions during follow-up should not be the result of plaque progression.
Second, it has been already reported that the struts of DES are misinterpreted by VH-IVUS as areas of “DC surrounding NC”, and there is no change between postintervention immediately and follow-up.13,14 Moreover, this red “halo” is presumably an artifact and should not be interpreted as peristrut inflammation or NC when observed at follow-up.13,14 Although this artifact could led to a directly proportional increase in the area coded as NC in VH-IVUS, these increase strictly follow a linear, indicating that it may be amenable to mathematical correction.17 Compared with EXCELTM SES, Cypher-SelectTM SES has a thicker metal strut (140 μm vs. 119μm).10,18 It suggests that the PBS in lesions treated with Cypher-SelectTM SESs may have more NC area induced by the stent struts with the same stent size. In contrast, with similar diameter and length of the stent, the relative NC volume in PBS, in present study, was higher in BSES-treated lesions, which could not be caused by the increase of artifacts aroused from the addition of the struts.
Third, different plaque characteristics preintervention (stable or vulnerable plaque) have an important impact on the results in the present study. Characteristics of vulnerable plaque mainly include localized expansive enlargement of the vessel wall (“positive remodeling”), microcalcification within the plaque and VH-TCFA. No matter which type of vulnerable plaque mentioned above, all of them have a common feature containing a large amount of NC. Kim et al19 demonstrated that DES implantation into a TCFA results in NC contact with the lumen in almost 50% of lesions. Recently, Hong et al20 indicated that baseline relative NC at the minimum lumen area site was an independent predictor of plaque progression during follow-up. However, in this study, BSES-treated lesions had a larger proportion of NC than DSES-treated lesions. Even so, they still showed stable morphometry, no matter whether this greater proportion of NC was existed before or after intervention and during follow-up.
Finally, statin therapy also has an important impact on the results of present study due to the capacity to change the plaque composition during follow-up. Nasu et al21 reported that one-year lipid-lowering therapy by fluvastatin showed significant regression of plaque volume and alterations in atherosclerotic plaque composition with a significant reduction of fibro-fatty volume, however, NC and DC volumes remained unchanged. Another recent study suggested that the usual dose of statin cannot change NC or DC easily compared to fibrotic tissue or fibrofatty.20 Moreover, patients of both two groups received the same statin therapy with atorvastatin 20 mg/d after PCI without intermission. Consequently, the lower proportion of NC in DSES-treated lesions behind the struts was also not the result of statin therapy, but more likely due to the NC content existing before intervention or postintervention immediately.
The major reason for this stable morphometry of lesions treated with BSESs during follow-up was BSES produced less toxicity to the arterial wall and facilitated neointimal healing as a result of polymer coating on DES surface biodegraded as time went by. Because the durable presence of polymer surface coating may be one of the principal reasons for localized arterial wall inflammation, hypersensitivity reactions, delayed or incomplete neointimal healing, and induction of stent thrombosis.7,8 At present study, as two types of the stents used in present study have the similar properties in terms of drug and metal,10,22,23 it is deemed that the biodegradable polymer on BSES surface should be the major cause of this phenomenon. Moreover, the unique abluminal coating of the EXCEL stent, that is, only located on the outside surface facing vessel wall, can minimize the possible adverse effects of polymer on vascular healing while allowing controlled unidirectional drug release.10
Although in this study, except six lesions, most of the DES-treated lesions were uncovered with neointima in the VH-IVUS images, this stable morphometry in lesions treated with BSESs was still probably a consequence of facilitating neointimal healing as polymer coating on DES surface biodegraded. BSES and DSES used in present study have the similar in-stent late lumenal loss, compared with the previous studies (0.12 mm and 0.19 mm).10,24 It suggests that the in-stent neointima hyperplasia is parallel with the former reports. In addition, prior studies showed that VH-IVUS has an axial resolution of 150 μm and spatial accuracy of 240 μm,25 and most of the struts of DES with neointimal thickness <100 μm at 6-12 months follow-up.26 Moreover, 75% of the stented segments do not exhibit neointimal hyperplasia during follow-up.16 Accordingly, the VH-IVUS images of struts appearing uncovered with neointima were mainly due to the reasons mentioned above.
Pathologic studies have proposed that a thin-capped fibroatheroma (cap thickness <65 μm) is a precursor of plaque rupture.27 VH-TCFA is used to describe this vulnerable plaque in VH-IVUS images defined as focal, NC-rich (≥10% of the plaque cross-sectional area) plaques (≥40% plaque burden) in contact with the lumen.28 The NC abutting to the lumen through the struts could represent lesion vulnerability after stenting by VH-IVUS.13 The persistence of a thin-capped fibroatheroma behind stent struts might contribute to future coronary thrombosis. As reported in prior trials, EXCELTM SES has a lower cumulative rate of MACE than Cypher-SelectTM SES (range: 2.7%-4.8% vs. 5.8%-6.51%), and a lower incidence of late stent thrombosis (range: 0-0.34% vs. 0.19%-0.50%) at 9-12 months follow-up.10,23,24,29-31 This stable morphometry in lesions treated with BSESs could be one of the major causes for the above decrease. The results of Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) trial32 has indicated that the combination of large plaque burden (>70%), small minimum lumen diameter (≤4 mm2) and a large NC without a visible cap (VH-TCFA) can identify the lesions which are at especially high risk for future adverse cardiovascular events (predictive incidence=18.2%). However, approximately 12% of patients develop MACE from non-culprit lesions during 3 years of follow-up, which was less than the expected result and likely attributed to the optimal medical therapy. Therefore, the effects of this stable morphometry on clinical prognosis still remain a controversy, and long-term clinical follow-up is needed in future.
This study had several limitations. First, the sample was relatively small. Second, VH-IVUS data pre- and post-intervention were not available. Third, VH-IVUS images were acquired at every R-peak during continuous ECG registration and some lesion information were lost as a result. Fourth, VH-IVUS has not been validated for neointimal hyperplasia. Finally, tissue structures beyond the resolution of VH-IVUS can not be identified with VH-IVUS.
In conclusion, by VH-IVUS analysis at follow-up, a greater frequency of stable lesion morphometry was shown in lesions treated with BSESs compared with lesions treated with DSESs. The major reason was BSES produced less toxicity to the arterial wall and facilitated neointimal healing as a result of polymer coating on DES surface biodegraded as time went by.
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