Abstract: Objective. We sought to evaluate the characteristics of in-stent restenosis (ISR) lesions with microvessels, detected by an optical coherence tomography (OCT). Background. No sufficient in vivo data exist regarding microvessel characteristics in ISR lesions. Methods. Among 78 ISR lesions (drug-eluting stent, n = 72; bare-metal stent, n = 6) in our OCT registry database, visible microvessels were detected in 21 (27%). Microvessels were defined as low backscattering structures <200 μm in diameter on OCT. Clinical, angiographic, and OCT findings were compared between lesions with and without microvessels. Results. Lesions with microvessels had a larger reference vessel diameter (2.90 ± 0.47 mm vs 2.58 ± 0.42 mm; P=.009) and post-stent minimum lumen diameter (2.76 ± 0.29 mm vs 2.54 ± 0.39 mm; P=.033) than those without microvessels. From OCT findings at the segment with minimal lumen cross-sectional area (CSA), neointimal hyperplasia (NIH) CSA (5.4 ± 1.7 mm2 vs 4.2 ± 2.1 mm2; P=.024) and percent NIH CSA (NIH CSA × 100/stent CSA) were significantly greater in lesions with microvessels (79 ± 12% vs 67 ± 16%; P=.001). On multivariate analysis, reference vessel diameter (odds ratio [OR], 4.64; 95% confidence interval [CI], 1.05-20.4; P=.043) and percent NIH CSA at the segment with minimal lumen CSA (OR, 1.06; 95% CI, 1.01-1.12; P=.021) were independent predictors of microvessels. From receiver operating characteristic analysis, the cut-off values of reference vessel diameter and percent NIH CSA predicting the presence of microvessels were 3.1 mm and 74%, respectively. Conclusions. Visible microvessels in ISR lesions might be associated with increased vessel size and extent of NIH.
J INVASIVE CARDIOL 2012;24:116–120
Key words: optical coherence tomography, restenosis, stent
Many attempts have been made to find the mechanisms or factors related to excessive neointimal hyperplasia (NIH), which causes in-stent restenosis (ISR) after stent implantation.1-3 From an autopsy study, it was suggested that extensive neovascularization at sites of stent restenosis may play a key role in neointimal proliferation, progression, and further aggravation of neoatherosclerosis.4 However, minimal in vivo data exist regarding in-stent neovascularization or characteristics of the neointima. Optical coherence tomography (OCT), a newly developed intracoronary imaging modality, has provided high-resolution cross-sectional images of tissues and enabled identification of microstructures that could not be visualized by previous standard imaging tools such as intravascular ultrasound.5-7 A previous OCT study reported in vivo identification of visible microvessels that were suggestive of neovascularization within NIH.7 Therefore, we hypothesized that ISR lesions with microvessels may have different neointimal characteristics than those without microvessels. Clinical, angiographic, and OCT findings of lesions with microvessels were compared to those of lesions without microvessels.
This study included 78 lesions in 70 patients that were identified as ISR from the OCT follow-up registry database at our institute.8,9 Inclusion and exclusion criteria for follow-up OCT procedures have been previously reported.8,9 All available stents including drug-eluting stents (DES) and bare-metal stents (BMS) were evaluated in this OCT registry. Specifically, DES in this OCT follow-up registry were coated with sirolimus (Cypher; Cordis Corporation), paclitaxel (Taxus; Boston Scientific), everolimus (Xience, Abbott Vascular), or zotarolimus (Endeavor Sprint or Resolute; Medtronic). Stent selection at the time of coronary intervention was at the physician’s discretion. Stent implantation was performed using conventional techniques. In DES cases, dual antiplatelet therapy (aspirin and clopidogrel) was given to all patients until follow-up angiogram and OCT were performed. The study protocol was approved by the institutional review board of our institutions, and written informed consent was obtained from all patients before the procedure.
Quantitative coronary angiography analysis was performed using an offline quantitative coronary angiography system (CASS system II; Pie Medical Imaging) before and after stent implantation and at follow-up angiogram. The minimal lumen diameter (MLD) of the treated coronary segments and reference segment diameter were measured in the view that was the most severe and not foreshortened at each time. Angiographic late loss was defined as the difference between follow-up and postprocedure MLD. Angiographic restenosis was defined as diameter stenosis of more than 50% inside the stent or 5 mm segment proximal or distal to the stent.2 The patterns of angiographic ISR were classified as suggested by Mehran et al.10
OCT examination using a conventional OCT system (Model M2 Cardiology Imaging System; LightLab Imaging) with a motorized pull-back system at 1.0 mm/s was previously described.8,9 OCT analysis was performed by an independent investigator blinded to patient and procedural information. The region of interest included the stented segments and adjacent segments (5 mm proximal and distal to the stent margins). Cross-sectional OCT images were analyzed at 1 mm intervals (every 15 frames). Inadequate images, including noncircumferential cross-sections, poor image quality, or cross-sections with major side branches (diameter ≥2.0 mm), were excluded from this analysis. Stent and luminal cross-sectional areas (CSAs) were measured at 1 mm intervals, and NIH CSA was calculated as the stent CSA minus the luminal CSA. Percent NIH CSA was calculated as NIH CSA × 100/stent CSA. Mean values are reported in this study. The thickness of NIH was measured as the distance between the endoluminal surface of the neointima and the stent strut.11 An uncovered strut was defined as having an NIH thickness of 0 µm.11 A malapposed strut was defined as a strut that had detached from the vessel wall (Cypher ≥160 μm; Taxus ≥130 μm; Endeavor Sprint or Resolute ≥110 μm; Xience ≥100 μm).11-13 The percentage of malapposed or uncovered struts in each stented lesion was calculated as (number of malapposed or uncovered struts/total number of struts in all cross-sections of the lesion) × 100.
In qualitative OCT assessment, visible microvessels were defined as the well-delineated low backscattering structures <200 μm in diameter and showing a trajectory within the vessel.7 Representative cases of microvessels are shown in Figure 1. Neointimal tissue morphology was classified into homogenous, heterogeneous, or layered appearance based on optical properties and backscattering pattern in the segment with maximal luminal narrowing, as defined in a previous OCT study.7 Thrombus was defined as a signal rich, low or high backscattering, irregular mass protruding into the lumen; or an intraluminal mass unconnected from the surface of vessel wall that had signal-free shadowing on the OCT image (more than 250 μm at the thickest point).8 All lesions were evaluated by OCT before any interventional procedure to avoid injury to restenotic tissues.
Statistical analyses were performed using Statistical Analysis System software Version 9.1.3 (SAS Institute). Categorical data are presented as numbers and percentages, and were compared using Chi-square statistics or Fisher’s exact test. Continuous data are presented as mean ± standard deviation and compared using the Student’s t-test. If the distributions were skewed, a nonparametric test was used. To determine the independent predictors of microvessel presence in neointimal tissue, multivariate logistic regression analysis was conducted. The variables with P<.1 on univariate analysis were included. For the cut-off values of the independent predictors of microvessel presence on multivariate logistic regression analysis, receiver operating characteristic (ROC) curve analysis was performed.
Microvessels were detected in 21 of 78 ISR lesions (27%). Baseline clinical characteristics of ISR lesions with and without microvessels are summarized in Table 1. There were no significant differences in baseline clinical characteristics between the two groups. Baseline angiographic and procedural characteristics are shown in Table 2. Reference vessel diameter, postprocedural MLD, and implanted stent diameter were significantly larger in lesions with microvessels. The incidences of ISR lesions with microvessels were not statistically different between BMS (3 of 6 lesions, 50%) vs DES (18 of 72 lesions, 25%; P=.335) or between paclitaxel-eluting stents (7 of 29 lesions, 24%) vs other DES (11 of 43 lesions, 26%; P=1.000). Results of OCT analysis are shown in Table 3. There was a tendency toward a longer time interval from stent implantation to follow-up OCT in the lesions with microvessels. From OCT findings at the segment with minimal lumen CSA, NIH CSA (5.4 ± 1.7 mm2 vs 4.2 ± 2.1 mm2; P=.024) and percent NIH CSA (79 ± 12% vs 67 ± 16%; P=.001) were significantly greater in lesions with microvessels. On multivariate logistic regression analysis, reference vessel diameter (odds ratio [OR], 4.64; 95% confidence interval [CI], 1.05-20.4; P=.043) and percent NIH CSA at the segment with minimal lumen CSA (OR, 1.06; 95% CI, 1.01-1.12; P=.021) were independent predictors of microvessel presence. From the receiver operating characteristic curve analysis, the cut-off values of reference vessel diameter and percent NIH CSA to predict the presence of microvessels were 3.1 mm (area under the curve [AUC], 0.698; 95% CI, 0.540-0.857; P=.013; sensitivity, 53%; specificity, 89%) and 74% (AUC, 0.731; 95% CI, 0.612-0.850; P=.002; sensitivity, 76%; specificity, 68%), respectively (Figures 2A and 2B). Based on the cut-off values, the incidences of microvessels on OCT were compared. Lesions with reference vessel diameter ≥3.1 mm or percent NIH CSA ≥74% showed significantly higher incidence of microvessels than those with reference vessel diameter <3.1 mm (65% vs 16%; P<.001) or percent NIH CSA <74% (46% vs 12%; P<.001), respectively. When the incidences of microvessels were compared among the four groups based on the cut-off values of reference vessel diameter and percent NIH CSA, the lesions with reference vessel diameter ≥3.1 mm and percent NIH CSA ≥74% (80%) showed the highest incidence of microvessels compared to the other lesions (P<.001; Figure 2C).
The current OCT study showed that ISR lesions with microvessels had different neointimal characteristics compared to those without microvessels, and the most determining correlates of microvessels in ISR lesions were reference vessel diameter and percent NIH CSA. The cut-off values of reference vessel diameter and percent NIH CSA predicting the presence of microvessels on OCT were 3.1 mm and 74%, respectively. No clinical correlates with the presence of microvessels were found in this study.
Neovascularization within the neointima has been already reported based on previous animal models and histopathologic studies.4,14 Kwon et al previously reported that marked disorganized angiogenesis was noted on microscopic computed tomography in balloon-injured porcine coronary arteries.14 In a postmortem pathologic study, Komatsu et al demonstrated that extensive neovascularization was observed at the sites of BMS restenosis, suggestive of its role in atherosclerotic progression and organization of mural thrombi.4 In addition, the presence of neovascularization in DES restenosis has been described in prior histological studies.3,15,16 Although microvessels might be expected to be involved in stent failure, most prior studies did not evaluate live patients, but were autopsy or histopathologic studies, in which the sample size was too small to perform analyses of clinical or angiographic factors.3,4,14-16 OCT has recently enabled visualization of in-stent neovascularization in live patients due to its high resolution and delineation.6,7 Gonzalo et al reported identification of visible microvessels within neointimal tissue.7 In an OCT study of BMS restenosis, Takano et al reported that expansion of neovascularization from peristent to intra-intimal areas contributed to neointimal atherosclerotic progression.17 As a result, microvessels within the neointima might be related to restenosis by the excessive neointimal growth following stent implantation. However, little is known about the potential role of the microvessels identified by OCT in ISR or the major correlates of microvessels. Therefore, we investigated the factors related to microvessels on OCT using a relatively large number of ISR lesions. Our OCT study demonstrated that ISR lesions with microvessels had specific characteristics and the most determining correlates were reference vessel diameter and percent NIH CSA at the segments with minimal luminal CSA. Based on these two determinants, microvessels were most frequently identified in ISR lesions with excessive amounts of NIH in large vessels. These results suggest that neovascularization presenting as microvessels on OCT would be an important finding in ISR lesions with the excessive NIH in large vessels.
This study has several limitations. First, ISR lesions located at the left main or ostium of major epicardial coronary arteries could not be evaluated because this study used time domain OCT, which requires balloon occlusion. Therefore, our OCT study could not represent all ISR lesions. Second, we did not perform quantitative analyses, such as the measurement of the number, area, or total volume of microvessels detected by OCT. Third, although we used the same definitions regarding qualitative OCT assessment as shown in the previous study for the identification of microvessels of ISR lesions on OCT,7 a validation study will be needed to confirm whether the structures strongly suggestive of microvessels are the real newly formed vascular structures. Finally, in spite of a relatively larger sample size in this study, the number of enrolled ISR lesions was insufficient to investigate the definite relationship between clinical determinants and the presence of microvessels.
This follow-up OCT study suggested that ISR lesions with microvessels have different characteristics of NIH compared to those without microvessels.
This study was supported in part by a grant from the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare & Family Affairs, Republic of Korea (No. A085012 and A102064); a grant from the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (No. A085136); and the Cardiovascular Research Center, Seoul, Korea.
- Mintz GS, Nissen SE, Anderson WD, et al. American College of Cardiology clinical expert consensus document on standards for acquisition, measurement and reporting of intravascular ultrasound studies (IVUS): a report of the American College of Cardiology task force on clinical expert consensus documents. J Am Coll Cardiol. 2001;37(5):1478-1492.
- Lemos PA, Saia F, Ligthart JM, et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation. 2003;108(3):257-260.
- Chieffo A, Foglieni C, Nodari RL, et al. Histopathology of clinical coronary restenosis in drug-eluting versus bare-metal stents. Am J Cardiol. 2009;104(12):1660-1667.
- Komatsu R, Ueda M, Naruko T, et al. Neointimal tissue response at sites of coronary stenting in humans: macroscopic, histological, and immunohistochemical analyses. Circulation. 1998;98(3):224-233.
- Jang IK, Bouma BE, Kang DH, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. J Am Coll Cardiol. 2002;39(4):604-609.
- Guagliumi G, Sirbu V. Optical coherence tomography: high resolution intravascular imaging to evaluate vascular healing after coronary stenting. Catheter Cardiovasc Interv. 2008;72(2):237-247.
- Gonzalo N, Serruys PW, Okamura T, et al. Optical coherence tomography patterns of stent restenosis. Am Heart J. 2009;158(2):284-293.
- Kim JS, Hong MK, Fan C, et al. Intracoronary thrombus formation after drug-eluting stents implantation: optical coherence tomographic study. Am Heart J. 2010;159(2):278-283.
- Kim U, Kim JS, Kim JS, et al. The initial extent of malapposition in ST-elevation myocardial infarction treated with drug-eluting stent: the usefulness of optical coherence tomography. Yonsei Med J. 2010:51(3);332-338.
- Mehran R, Dangas G, Abizaid AS, et al. Angiographic patterns of in-stent restenosis: classification and implications for long-term outcome. Circulation. 1999;100(18):1872-1878.
- Tanigawa J, Barlis P, Di Mario C. Intravascular optical coherence tomography: optimisation of image acquisition and quantitative assessment of stent strut apposition. EuroIntervention. 2007;3(1):128-136.
- Tanigawa J, Barlis P, Dimopoulos K, et al. The influence of strut thickness and cell design on immediate apposition of drug-eluting stents assessed by optical coherence tomography. Int J Cardiol. 2009;134(2):180-188.
- Choi HH, Kim JS, Yoon DH, et al. Favorable neointimal coverage in everolimus-eluting stent at 9 months after stent implantation: comparison with sirolimus-eluting stent using optical coherence tomography. Int J Cardiovasc Imaging. 2011 Mar 26. (Epub ahead of print). doi 10.1007/s10554-011-9849-7.
- Kwon HM, Sangiorgi G, Ritman EL, et al. Adventitial vasa vasorum in balloon-injured coronary arteries: visualization and quantitation by a microscopic three-dimensional computed tomography technique. J Am Coll Cardiol. 1998;32(7):2072-2079.
- Schwartz RS, Chronos NA, Virmani R. Preclinical restenosis models and drug-eluting stents: still important, still much to learn. J Am Coll Cardiol. 2004;44(7):1373-1385.
- van Beusekom HM, Saia F, Zindler JD, et al. Drug-eluting stents show delayed healing: paclitaxel more pronounced than sirolimus. Eur Heart J. 2007;28(8):974-979.
- Takano M, Yamamoto M, Inami S, et al. Appearance of lipid-laden intima and neovascularization after implantation of bare-metal stents extended late-phase observation by intracoronary optical coherence tomography. J Am Coll Cardiol. 2009;55(1):26-32.
From the 1Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea, 2Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted October 24, 2011, provisional acceptance given November 3, 2011, final version accepted November 15, 2011.
Address for correspondence: Myeong-Ki Hong, MD, PhD, Division of Cardiology, Yonsei Cardiovascular Center, and Severance Biomedical Science Institute, Yonsei University College of Medicine, 250 Seongsanno, Seodaemun-gu, Seoul 120-752, Korea. Email: firstname.lastname@example.org