Serial Evaluation of Vascular Response After Implantation of a New Sirolimus-Eluting Stent with Bioabsorbable Polymer (MISTENT): An Optical Coherence Tomography and Histopathological Study

Abstract: Background. Novel vascular scaffolds aim at equipoise between safety and efficacy. Intravascular optical coherence tomography (OCT) allows in-vivo serial assessment of stent-vessel interactions with high resolution and frequent sampling and may complement histology assessment. We investigated the vascular response to a novel absorbable coating sirolimus-eluting stent (AC-SES) by means of serial OCT and histology evaluation in a porcine model. Methods. One AC-SES and one bare-metal stent (BMS) were implanted in separate coronary arteries of three Yucatan mini-swine. Serial OCT was performed post procedure and at 3-, 28-, 90-, and 180-day follow-up. Normalized optical density (NOD) was used for the assessment of tissue response over time. Histological evaluation was performed at day 180. Results. A total of 6408 stent struts were analyzed. OCT revealed 100% of struts covered at 28 days, and a significant difference in NOD from 3 to 28 days (0.64 ± 0.07 vs 0.71 ± 0.05, respectively; P<.001) in the AC-SES group. Neointimal thickness was 0.14 ± 0.08 mm, 0.17 ± 0.11 mm, and 0.16 ± 0.09 mm in the AC-SES group and 0.18 ± 0.10 mm, 0.14 ± 0.09 mm, and 0.10 ± 0.08 mm in the BMS group, while rates of uncovered struts were 0%, 0%, and 3.1% and 1.4%, 7.8%, and 21.5%, respectively, at 28, 90, and 180 days. Minimal inflammation and a mature endothelialization were demonstrated in both groups by histology. Conclusion. OCT serial assessment of vascular response suggested NIH maturation 28 days following AC-SES implantation in pigs. These findings, coupled with histological demonstration of low inflammation scores and complete endothelial coverage as measured at 180 days, suggest a satisfactory healing response to AC-SES.

J INVASIVE CARDIOL 2012;24(11):560-568

Key words: optical coherence tomography, drug-eluting stent, percutaneous coronary intervention

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Drug-eluting stents (DESs) markedly reduce the rates of restenosis when compared with bare-metal stents (BMSs).¹ Nevertheless, arterial healing impairment due to a number of potentially causative factors, including inhibited cellular proliferation, inflammatory response, and stent design, has been linked with increased risk of late DES thrombosis.^2-4 Indeed, the most powerful morphometric predictor of late stent thrombosis according to a postmortem pathology study was the ratio of uncovered (non-endothelialized) struts to total struts per section.⁵ Whether these pathological findings reflect continued vascular reaction to durable polymer, which covers the entire surface of most DESs, or cell cycle inhibitory effects of the drugs is difficult to determine.⁶ Therefore, attempts to improve DES safety have focused both on optimizing drug delivery and reducing vessel exposure to polymers.^7-10 A novel absorbable-coating sirolimus-eluting stent (AC-SES; MiStent sirolimus-eluting stent, Micell Technologies) was developed using a coating technology that increased control of drug release and an absorbable polymer matrix that was eliminated within 90 days after implantation.¹¹

Intravascular optical coherence tomography (OCT) is a light-based imaging modality that provides high-resolution (~10 µm) imaging, enabling assessment of important morphometric parameters, such as stent strut coverage and apposition.^12,13 OCT has the potential to complement standard histology to assess novel DES platforms by allowing in vivo serial evaluation of stent vessel interactions at a micron-scale level coupled with frequent sampling (0.2 mm intervals), without the need for tissue preparation. In this study, both serial OCT and terminal histological assessments were used to provide a comprehensive evaluation of the vascular response following AC-SES implantation.

Methods

Device description. The AC-SES is a novel, balloon-expandable, laser-cut, cobalt-chromium alloy stent (Figure 1) with non-deformable 64-µm thick struts. The stent coating (approximately 3-5 µm thick on the luminal and 10-15 µm thick on the abluminal stent surfaces) consists of polylactide-coglycolic acid and sirolimus, an antiproliferative drug already used in the Food and Drug Administration (FDA)-approved Cypher DES; however, stable crystalline particles of sirolimus are used in AC-SES. The coating is cleared from the stent in 45-60 days and the polymer is completely absorbed in the tissue within a period of 3 months post implant (Figure 2). The same 64 μm cobalt-chromium stent (Eurocor BMS [EuroCor GmbH]) without any coating applied was used as a control in this study, as it is the underlying stent platform of the AC-SES.

Porcine procedures and follow-up. Porcine coronary artery implants and subsequent histopathology and histomorphometry analyses were performed at CBSET, Inc. (Lexington, Massachusetts) using laboratory standard operating procedures in compliance with the US Department of Agriculture Animal Welfare Act and its amendments, as well as with the guidelines described in the Guide for the Care and Use of Laboratory Animals.¹⁴ Under deep anesthesia (ketamine, 20 mg/kg and thiopental, 500 mg) and mechanical ventilation, arterial access of  three Yucatan mini-swine weighing 50-85 kg were obtained with 6 Fr arterial sheaths in the carotid artery. Coronary arteries were selectively cannulated with standard 6 Fr guiding catheters; each animal received one AC-SES and one BMS in separate coronary arteries with balloon-to-artery ratio of 1.1:1. Coronary angiography and OCT were performed at baseline, and at 3, 28, 90, and 180 days after stent implantation.

Quantitative angiographic analysis. Quantitative coronary angiography was done at baseline and at 180-day follow-up. Digital coronary angiograms were analyzed offline by an independent core laboratory using validated quantitative methods.¹⁵

OCT imaging acquisition and analysis. OCT images were acquired with a commercially available system (C7-XR OCT Intravascular Imaging System; St. Jude Medical) after intracoronary administration of 50-200 µg nitroglycerin through conventional guiding catheters. A 0.014˝ guidewire was positioned distally and the OCT catheter (C7 Dragonfly, St. Jude Medical) was advanced to the distal end of the stent. The entire length of the region of interest was scanned using the integrated automated pullback device at 20 mm/s. During image acquisition, coronary blood flow was replaced by hand injections of contrast. All images were digitally stored and submitted to core laboratory offline evaluation and subsequent analysis using proprietary software (St. Jude Medical). The images were analyzed by two experienced OCT analysts (GA and DC) blinded to group allocation, and reviewed by a third reader (HY). All cross-sectional images (frames) were initially screened for quality assessment and excluded from analysis if any portion of the image was out of the screen, a side branch occupied >45° of the cross-section, or the image had poor quality caused by residual blood or sew-up artifact.¹⁶ At 3-day follow-up, a qualitative binary evaluation for coverage (ie, fibrin) of stent struts was performed at 0.6 mm intervals; a strut was considered covered when tissue was visible over its entire circumference. Strut-level analysis, lumen, stent, NIH areas, and volumes were performed considering every three frames (0.6 mm intervals) along the entire target segment. These parameters were calculated in a similar fashion for baseline and at 28, 90, and 180 days.¹⁷ Highly reproducible measurements for strut apposition and coverage using the described methodology have been reported.¹⁸ Qualitative imaging assessment was performed in every frame at all the time points for the presence of abnormal intrastent tissue (AIT). We defined AIT as any mass protruding beyond the stent struts into the lumen, with irregular surface and a sharp intensity gap between mass and neointimal tissue.^19,20

Optical density of stent strut coverage analysis. Based on OCT imaging properties, we evaluated the pixel intensity (optical density) of stent strut covering tissue (ODT) localized in the inner side of the struts, normalized for the optical density of the stent struts (ODS). A good correlation between ODT/ODS [named normalized optical density (NOD)] and morphologic information provided by both light and electron microscopy has been described previously in a porcine model.²¹ Hence, randomly chosen stent struts were evaluated at all time points to demonstrate longitudinal changes in NOD of stent strut coverage as assessed by OCT. A region of interest was manually drawn by 2 experienced OCT analysts (GA and DC) and the values of ODT and ODS were obtained automatically using a proprietary computer-assisted analysis software (St. Jude Medical). The results were reviewed by a third analyst (EM). NOD at 3 and 180 days served as references, assuming that the tissue covering stent struts was mostly fibrin in the former.^21,22 Conversely, the coverage of the stents at 180 days was essentially composed of neointima as shown by histology in the present study. Thus, the present study NOD ranges for fibrin and neointimal tissue were established based on these results.

Histology and histomorphometry. An experienced pathologist (JS) who was blinded to the groups performed all histomorphometric and histological analysis. Transverse sections of non-stented vessel were obtained within approximately 5 mm of the proximal and distal ends of the stent. All vessel sections were stained with hematoxylin and eosin (H&E) and a tissue elastin stain (eg, Verhoeff’s), utilizing previously published methods.²³ Distal, middle, and proximal sections from each of the stented coronary arterial segments were evaluated. For each histological section, lumen area and diameters, internal (IEL) and external elastic layer (EEL) bounded area, and stent area were directly measured using standard light microscopy and computer-assisted image measurement systems (Olympus Micro Suite Biological Suite). Neointimal thickness ([IEL diameter-lumen diameter]/2) and percent area stenosis (neointimal area/[lumen area + neointimal area] x 100) were calculated.

The inflammation score was determined by the degree and extent of inflammation on a per-strut basis and the average was calculated per plane (ie, proximal, middle, and distal) and stent. The score was graded as follows: 0 when there were no cells present; 1 for fewer than 20 cells associated with stent strut; 2 when there were greater than 20 cells associated with stent strut, with or without tissue effacement and little to no impact on tissue function; 3 for >20 cells associated with stent strut with effacement of adjacent vascular tissue and adverse impact on tissue function. The injury score matrix was calculated in a similar fashion and was graded according to previously published expert consensus.²⁴ Briefly, a score of 0 represented no injury with IEL intact; 1 = disruption of IEL; 2 = disruption of tunica media; and 3 = disruption of EEL/adventitia. Endothelialization, adventitial fibrosis, and neointimal maturation were scored as detailed in Table 1.

Statistical analysis. All statistical analyses were performed using SAS (version 9.2) software (SAS Institute) and statistical significance was assessed at the .05 level. Continuous variables are expressed as mean ± standard deviation, and categorical variables are expressed as counts and percentages. For OCT measurement, given the hierarchical nature of the data (stent struts nested within frame nested within lesion nested within pig), multilevel mixed models, which can address random effects at lesion and subject levels, were used for comparisons of binary and continuous outcomes. For lesion level QCA and histology analysis, paired t-test was used for comparison between two stent types. A mixed effects model was used to compare and estimate correlation coefficient between measurements from histomorphometry and OCT with repeated observations. Receiver-operating characteristic (ROC) analysis was used to compare diagnostic accuracy of optical density analysis of stent strut coverage for detecting fibrin- versus neointima-covered stent struts.

Results

Six stents (three AC-SESs and three BMSs) were successfully implanted in different porcine epicardial coronary arteries. No complications were identified either during stent deployment or at follow-up assessments. Following stent placement, OCT was successfully performed in all animals at baseline, and at 3-, 28-, 90-, and 180-day follow-up. Blood samples were taken as part of the pharmacokinetic analyses. All animals survived until the last follow-up time point of the study (180 days), when they were euthanized.

Quantitative coronary angiography. Quantitative coronary angiography results obtained post procedure and at 180 days are represented in Table 2. The effectiveness parameters evaluated (ie, late lumen loss, binary restenosis, and percentage diameter stenosis) were equivalent between the groups, in concordance with OCT findings.

Intravascular optical coherence tomography assessment. A total of 6408 stent struts in 749 cross-sections were analyzed. Only 7.9% of the frames, equally distributed between the groups, were considered not suitable for analysis. Baseline OCT results were equivalent between the groups and are reported in Table 3.

Longitudinal OCT assessments are summarized in Table 4 and represented in Figure 3. At 3 days, 22% of the stent struts in the control group and 17.8% in the treatment group (P=.917) were covered by low-intensity, irregular tissue, suggestive of fibrin. Stent strut coverage was completed by 28 days in the AC-SES group and remained unchanged through 180 days. Furthermore, no stent strut malapposition was identified at 28 and 90 days following AC-SES implantation. Interestingly, at 180 days, newly acquired stent malapposition was observed in both groups. While the 2.1% rate of malapposition observed in the AC-SES group was not statistically different from prior assessments (P=.685), there were 17.4% of struts malapposed in the control group, reflecting a significant increase in malapposition rates from 28 days post implant. A progressive increase in the rates of uncovered struts over time was observed in the control group driven by an abnormal remodeling response in one of the pigs. There was no AIT identified at any time points.   

Normalized optical density of stent strut coverage. There were 911 struts completely covered by tissue at the 3, 28, 90, or 180 days analyzed. A significant difference in NOD from 3 to 28 days was observed in the AC-SES group (0.64 ± 0.07 vs 0.71 ± 0.05, respectively; P<.001). There were no differences in NOD between 3 and 28 days (0.66 ± 0.06 vs 0.68 ± 0.06, respectively; P=NS) in the BMS group, reaching statistical significance at 90 days (0.70 ± 0.05; P=.007 vs 3 days). The diagnostic accuracy of NOD was assessed by ROC curve (Figure 4) for the differentiation between fibrin-rich tissue (3-day) and neointimal coverage (180-day) in BMS (AUC = 0.792) and AC-SES (AUC = 0.791) groups. For the BMS group, the best cut-off value to identify fibrin was ≤0.700 (sensitivity, 72.7%; specificity, 71.4%; accuracy, 72.1%); for the AC-SES group the corresponding cut-off value was ≤0.685 (sensitivity, 72.8%; specificity, 72.3%; accuracy, 72.6%). The negative and positive predictive values were 71.4% and 72.7% for the BMS group and 70.8% and 74.3% for the AC-SES group.

At day 90, the maturation of the tissue covering stent struts as assessed by NOD was equivalent between groups. Percentage of fibrin was 45.5% and 45.9%, respectively, for BMS and AC-SES groups (P=.939). At 180 days, the same evaluation revealed reduction of fibrin-rich tissue in  BMS and AC-SES groups to 28.5% and 27.7%, respectively (P=.899).

Histology. No animals were found dead or terminated early for this study. There were no macroscopic observations noted at necropsy. Six stented arteries in each group (3 with AC-SES and 3 with BMS) were evaluated. The inflammation score was low and equivalent between groups (0.24 ± 0.23 for AC-SES group and 0.54 ± 0.14 for BMS group; P>.05); the inflammatory cells were composed primarily of histiocytes and multinucleated giant cells, regardless of the group (Figure 5). No granulomatous inflammation was identified. Overall incidence and magnitude of injury was slightly decreased in the AC-SES group (<10%; limited to grade 2) when compared to the BMS group (24%; grades 1-3), although not statistically significant (P>.05). Neointimal maturation score matrix was complete with AC-SES and BMS (3.0 ± 0.00 in both groups). Fibrin was virtually absent and comparable between the groups; moreover, adventitial fibrosis, which is characterized by collagen bundles intermixed with fibroblasts, was minimal and no differences were revealed (1.11 ± 0.84 in AC-SES group vs 1.00 ± 1.00 in BMS group; P>.05). Endothelialization score was equivalent and less than complete in both groups, although slightly higher in AC-SES group when compared to BMS group (3.22 ± 0.38 vs 2.67 ± 0.58, respectively; P>.05). Neointimal vascularization was rare and occurred exclusively in the BMS group.

Histomorphometry. At 180 days, NIT was not statistically different between the AC-SES and BMS groups (0.14 ± 0.05 mm vs 0.22 ± 0.10 mm, respectively; P>.05). Percent area stenosis and neointimal area revealed the same tendency (19 ± 8% vs 27 ± 11%,  and 1.13 ± 0.35 mm2 vs 1.77 ± 0.75 mm2, respectively, P>.05 for both comparisons). No differences were established regarding tunica media area and lumen to artery ratio between the groups. Excellent correlation was demonstrated between histomorphometry and OCT measurements regarding lumen area (r = 0.911) and diameter (r = 0.897), stent area (r = 0.948) and diameter (r = 0.952), as well as in minimal luminal area (r = 0.973) and maximum percentage stenosis (r = 0.858). Nevertheless, a poor correlation was observed between the methods for the assessment of neointimal area (r = 0.330) and thickness (r = 0.361), as well as for percentage stenosis (r = 0.460) (Table 5).

Discussion

Our study evaluated coronary arterial response following the implantation of the novel AC-SES combining serial imaging assessment using OCT with standard histology. The serial evaluations of arterial response to AC-SES from the time of stent implantation through 180 days of follow-up provided the following observations: (1) the majority of the proliferative response in this porcine non-diseased model, depicted by the magnitude of neointimal proliferation and strut coverage, occurred in the first 28 days after AC-SES implantation; (2) thereafter, no changes were revealed in the proportion of strut coverage and amount of neointimal hyperplasia at 90 and 180 days; and (3) 100% of the postprocedure malapposition was resolved by 28-day follow-up.

OCT and histomorphometry findings. The present study illustrates the complementary role of in vivo and ex vivo high-resolution imaging strategies to assess the impact of novel endovascular technologies. Histology remains the gold standard for tissue characterization and can provide unique information regarding the type and maturation of the tissue covering stent struts, presence of associated inflammation, fibrin, or necrosis. OCT enables serial in vivo assessments of stent-vessel interactions at a micron-scale level (~10 µm) without the limitations associated with tissue preparation (ie, tissue shrinkage). Hence, morphometric parameters, such as stent strut coverage as well as lumen and stent areas and diameters can be followed serially with low intra- and interobserver variability and high accuracy as shown by others and in the present data.^13,21,25
The ability to differentiate fibrin from NIH is important in the evaluation of the vascular response after stent implantation, since the presence of excessive residual fibrin has been associated with delayed healing and stent thrombosis.^2,3 This study provided the first observation of changes in optical properties of the tissue covering stent struts using a commercially available Fourier-Domain OCT system. Templim et al had shown a difference in NOD between fibrin and NIH using a different OCT system (Terumo OFDI system, Terumo R&D Center) compared with electron microscopy as the gold standard.²¹ Our study applied similar methodology and demonstrated significant differences in NOD of tissue covering AC-SES between 3 and 28 days, suggestive of NIH maturation. Furthermore, serial OCT imaging suggested progressive reduction of fibrin content and its replacement by neointimal tissue that was shown to be equivalent in both groups at 90 and 180 days. This suggests a similar vascular response pattern between AC-SESs and BMSs.

Importance of stent strut coverage and apposition. Although a rare clinical condition, stent thrombosis raises a great concern due to its high associated morbidity and mortality.^26,27 Incomplete stent strut coverage was identified in postmortem studies as a powerful predictor of late DES thrombosis.5 Moreover, stent strut malapposition (markedly the late acquired type), which is more common after DES than BMS implantation, has also been associated with this phenomenon.28 In our study, we observed early, complete “healing” after AC-SES implantation, demonstrated by 100% of stent strut coverage coupled with no malapposition at 28 days. These results were maintained through 180 days. Taken together, the present data suggest a desirable safety profile for the AC-SES technology and support further evaluation in clinical trials. Conversely, a significant increase over time in the luminal area of the artery implanted with a BMS in one of the pigs (6.15 ± 0.53 mm2, 6.39 ± 0.36 mm2, and 7.65 ± 0.52 mm2 for 28, 90, and 180 days, respectively; P<.001 for the comparisons between 28 and 180 days, and 90 and 180 days) led to a statistically significant increase in the rates of uncovered and malapposed struts in the BMS group. No signs of exacerbated inflammation were identified by histology in this particular artery.

Favorable vascular compatibility of AC-SES. This study demonstrated a mature neointimal tissue with generalized organized smooth muscle cells with minimal presence of fibrin in both groups at 180 days. A postmortem pathological study previously observed persistent fibrin deposition and poor endothelialization of stents deployed in patients who died from late stent thrombosis.² Endothelialization was similar between the BMS and AC-SES groups in the present study and the amount of fibrin was reduced over time in both groups as demonstrated by OCT.

Inhibition of exacerbated NIH sustained over time. Concerns about late  progression of neointimal proliferation were previously raised in a preclinical report after serial histological assessments until day 18029 and in two clinical studies assessing Cypher stents up to 4 years post implantation by means of  OCT.^30,31 Although sirolimus is the drug eluted from AC-SES and Cypher stents, sustained inhibition of NIH by AC-SES with no evidence of late “catch-up” was observed in the present study. Whether these promising results are explained by the use of biodegradable polymer and thin cobalt-chromium platform in the AC-SES remains to be investigated. Nevertheless, the present study findings suggest long-term efficacy in NIH inhibition and support testing of this novel platform in clinical trials.

Study limitations. There are limitations that should be taken into account when interpreting our findings. Inherent to most preclinical device investigations is the lack of direct correlation between vascular response in non-diseased animal models and human diseased coronary arteries. Moreover, a time difference in the healing process (5 to 6 times faster in the porcine model) between humans and swine models should be considered. Nevertheless, the porcine model has been considered the standard preclinical model for the evaluation of novel DESs, since the stages of healing are comparable to those found in humans.²³

We assumed that the coverage of stent struts at the 3-day time point was composed mostly of fibrin-rich tissue based on previous preclinical data,^21,22 as histology at this time frame was not performed in the present study. In spite of longitudinal analysis of 6408 stent struts utilizing high-resolution imaging by both OCT and histology, the study sample size was small. Therefore, if one pig has an abnormal vascular response, as witnessed by the malapposition rates in the BMS group in our study, that effect can be magnified to hundreds of struts, limiting more definitive conclusions.

Conclusion

Longitudinal examination by means of OCT reveals early coverage, sustained NIH inhibition, and progressive NIH maturation following AC-SES implantation. These findings coupled with low inflammation scores and a mature endothelial coverage at 180 days suggest a satisfactory vascular response to AC-SES. OCT plays a complementary role to histology, allowing serial longitudinal assessments in preclinical models.

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From the ¹Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, ²Concord Biomedical Sciences & Engineering Technologies (CBSET), Inc, Lexington, Massachusetts, and ³Micell Technologies, Inc, Durham, North Carolina.
Disclosures: Dr Bezerra and Dr Costa report honoraria and research grants from St Jude Medical. Dr Attizzani reports consultant honoraria from St Jude Medical. Wenda Carlyle and Dr McClain are employees of Micell Technologies, Inc; Dr McLain is the assignee of patents associated with the MISTENT SES and has stock options as part of his employment. Dr Spognardi and Dr Stanley report that CBSET, Inc performed the animal study for Micell Technologies, Inc. The remaining authors have no conflicts of interest to declare.
Manuscript submitted March 21, 2012, provisional acceptance given May 16, 2012, final version accepted June 19, 2012.
Address for correspondence: Marco A. Costa, MD, PhD, FACC, FSCAI, Professor of Medicine; Director, Interventional Cardiovascular Center; Director, Research and Innovation Center, Harrington Heart and Vascular Institute, University Hospitals Case Medical Center, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106. Email: marco.costa@uhhospitals.org