Author + information
- Received March 6, 2017
- Revision received June 16, 2017
- Accepted June 29, 2017
- Published online November 1, 2017.
- Hiroyoshi Mori, MDa,
- Qi Cheng, MDa,
- Christoph Lutter, MDa,
- Samantha Smith, MSa,
- Liang Guo, PhDa,
- Matthew Kutyna, MSa,
- Sho Torii, MDa,
- Emanuel Harari, MDa,
- Eduardo Acampado, DVMa,
- Michael Joner, MDa,
- Frank D. Kolodgie, PhDa,
- Renu Virmani, MDa and
- Aloke V. Finn, MDa,b,∗ ()
- ↵∗Address for correspondence:
Dr. Aloke V. Finn, CVPath Institute Inc., 19 Firstfield Road, Gaithersburg, Maryland 20878.
Objectives This study sought to investigate endothelial coverage and barrier protein expression following stent implantation.
Background Biodegradable polymer drug-eluting stents (BP-DES) have been purported to have biological advantages in vessel healing versus durable polymer DES (DP-DES), although clinical trial data suggest equipoise.
Methods Biodegradable polymer-sirolimus-eluting stents (BP-SES), durable polymer-everolimus-eluting stents (DP-EES), and bare-metal stents (BMS) were compared. In the rabbit model (28, 45, and 120 days), stented arteries underwent light microscopic analysis and immunostaining for the presence of vascular endothelium (VE)-cadherin, an endothelial barrier protein, and were subjected to confocal microscopy and scanning electron microscopy. A cell culture study in stented silicone tubes was performed to assess cell proliferation.
Results Light microscopic assessments were similar between BP-SES and DP-EES. BMS showed nearly complete expression of VE-cadherin at 28 days, whereas both DESs showed significantly less with results favoring BP-SES versus DP-EES (39% coverage in BP-SES, 22% in DP-EES, 95% in BMS). Endothelial cell morphologic patterns differed according to stent type with BMS showing a spindle-like shape, DP-EES a cobblestone pattern, and BP-SES a shape in between. VE-cadherin-negative areas showed greater surface monocytes regardless of type of stent. Cell proliferation was suppressed in both DESs with numerically less suppression in BP-SES versus DP-EES.
Conclusions This is the first study to examine VE-cadherin expression after DES. All DES demonstrated deficient barrier expression relative to BMS with results favoring BP-SES versus DP-EES. These findings may have important implications for the development of neoatherosclerosis in different stent types.
Percutaneous coronary artery intervention with drug-eluting stents (DES) is the most widely performed procedure to treat patients with symptomatic coronary artery disease (1). DES dramatically reduces in-stent restenosis rates as compared with bare metal stents (BMS) (2) but this is associated with delayed endothelial recovery and function necessitating longer dual antiplatelet therapy than is normally used in patients receiving BMS (3). Pharmacologic mammalian target of rapamycin (mTOR) inhibitors used in DES are well known to prevent endothelial proliferation (4). Moreover, pathologic studies show the incidence of neointimal atherosclerosis (neoatherosclerosis) within the stented segment is accelerated as compared with BMS, suggesting impaired endothelial barrier function as the underlying mechanism (5,6). We have previously shown exposure to limus mTOR inhibitors (i.e., sirolimus or everolimus) leads to impaired barrier function via Ca2+ mediated activation of protein kinase C-α and downstream disruption of the vascular endothelial cadherin (VE-cadherin) junctional formation in vascular endothelium (7).
Polymers are an essential component of DES because they control/slow drug release necessary for preventing long-term intimal formation and restenosis. However, polymers have been associated with rare local hypersensitivity reactions associated with delayed healing and stent thrombosis (8,9). Moreover, use of polymers also leads to prolonged exposure to mTOR inhibitors, which prevent endothelial recovery and function. Thus stents with bioabsorable polymers might limit the duration of drug retention in the arterial wall, reduce long-term drug exposure, and improve endothelial recovery and barrier function.
Here we tested this hypothesis by examining the vascular responses to durable polymer everolimus-eluting stents (DP-EES) (Xience, Abbott Vascular, California) versus biodegradable polymer sirolimus-eluting stents (BP-SES) (Ultimaster, Terumo, Kanagawa, Japan) in the rabbit iliac artery model of stenting. We focused our study on examining the vascular biocompatibility of each system and the endothelial response as defined by stent strut coverage and expression of the critical endothelial barrier protein VE-cadherin.
Abluminal and gradient coating biodegradable BP-SES (Ultimaster, Terumo), conformal coating DP-EES (Xience, Abbott Vascular, Santa Clara, California) and BMS (Kaname, Terumo, Tokyo, Japan) were used in this study (see Table 1 for particular details related to each stent).
The study protocol was approved by the Institutional Animal Care and Research Committee, MedStar Research Institute Animal Facility. A total of 45 healthy male New Zealand White rabbits (3.0 kg to 4.0 kg, Millbrook Laboratories, Amherst, Massachusetts) were included to this study. Under general anesthesia, the left and right iliac arteries were injured by balloon endothelial denudation. A 3.0 mm × 8 mm standard angioplasty balloon catheter was inflated in each distal iliac artery. Then, balloon catheter was withdrawn proximally in its inflated state to the level of the aortoiliac bifurcation. The balloon was deflated, repositioned in the distal iliac artery, and the vessel denudation was then repeated over the same region of the vessel initially denudated. Immediately following this, animals were randomized to receive a single DP-EES, BP-SES, or BMS (all 3.0 mm × 18 mm stents) in each iliac artery. Stents were deployed at their nominal inflation pressure to achieve a target device-to-artery ratio of 1.3:1, with 30 s of inflation. Single-dose intra-arterial heparin (150 IU/kg) was injected at the time of catheterization. Animals were administered aspirin (40 mg) orally 12 hours before stent implantation and once daily until euthanasia. Follow-up angiography using contrast media was performed to check stent patency before euthanasia at 28, 45, and 120 days, respectively. The arterial tree was perfused at 80 ± 20 mm Hg with heparinized Ringer lactate.
Sixteen arteries from 8 animals at 28 days were used for light microscopic analysis (BP-SES n = 8 arteries, DP-EES n = 4, and BMS n = 4 each). After perfusion, the arterial tree was fixed by continued gravity perfusion with 10% neutral buffered formalin. The stented iliac arteries were identified, and dissected free from the animal and cleaned of periadventitial tissue. The stented vessel segments were dehydrated in a graded series of ethanol and embedded in methylmethacrylate plastic. After polymerization, 2- to 3-mm segments were sawed from the proximal, mid, and distal portions of each stent. Sections of 4 to 6 μm thick were cut from each of the segments on a Leica (Wetzlar, Germany) RM2155 rotary microtome equipped with a tungsten carbide blade, mounted and stained with hematoxylin-eosin and Movat pentachrome stains (elastin stain). All sections were examined by light microscopy for the presence of inflammation, thrombus, neointimal formation, and vessel wall injury.
Morphometric analysis was performed with computer assist software (IP Lab Scanalytics, Rockville, Maryland) as previously described (10). Briefly, cross-sectional areas (stent and lumen) and neointimal thickness defined by the distance from the inner surface of each stent strut to the luminal border were measured. The percent stenosis was calculated using the following formula: (1−[lumen area/stent area]) × 100. Giant cell reaction was expressed as a percentage of the total number of struts with peristrut presence in each section. Vessel injury was scored according to Schwarz method (11). Inflammation score (0 to 4) and fibrin score (0 to 3) were semi-quantitatively scored for each section as previously described (10).
Confocal microscopy and scanning electron microscopy
Seventy-four stents from 37 animals were used for confocal and scanning electron microscopy (SEM). The stented iliac arteries were carefully excised and cleaned of adventitial tissue under a cell culture hood. The intact arterial segments were bisected longitudinally to expose the luminal surface, immersion-fixed in ice-cold acetone/methanol for 10 min, rinsed with phosphate-buffered saline, and submitted for immunohistochemical staining. Each stent half was processed for staining by anti-VE-cadherin antibody. Samples were initially incubated in 0.1% Triton X for 20 min and rinsed with phosphate-buffered saline. The stent half was then exposed overnight at 4°C to the anti-VE-cadherin antibody (dilution 1:200, R & D catalogue #AF1002, Minneapolis, Minnesota). The antibody reaction was visualized with an Alexa Fluor 555 donkey antigoat secondary antibody (dilution 1:150; Invitrogen, Carlsbad, California). DAPI (MilliporeSigma, Darmstadt, Germany) was used as the nuclear counter-stain.
The specimens were mounted “en face” on glass slides and images were acquired using a Zeiss (Oberkochen, Germany) LSM 700 laser confocal microscope equipped with ZEN imaging software (ZEN 2011 edition). For imaging analysis purposes, confocal z-stack images with tile imaging were acquired at ×10 magnification. Representative high-power fluorescent images of the luminal surface from the proximal, middle, and distal segments of the stent were also acquired using a ×20 objective with z-stack acquisition to document the ultrastructural morphological pattern of VE-cadherin expression. The percentage of VE-cadherin-positive endothelial staining was estimated visually. X and Y dimensions of endothelial cells were assessed from 8 randomly selected cells from ×20 images of the proximal, middle, and distal areas of the stent at 120 days, respectively. Cell shape index (Y dimension divided by X dimension) was used to describe differences in endothelial cell morphology.
Following confocal microscopic analysis, the stented artery halves designated for SEM were rinsed in 0.1 M sodium phosphate buffer and post-fixed in 1% osmium tetroxide for approximately 30 min. The samples were then dehydrated in a graded series of ethanol, critically point dried, and sputter-coated with gold. The specimens were visualized using a Hitachi Model S3400N or S3600N SEM (Hitachi, Tokyo, Japan). Low-power photographs (×15 magnification) were acquired of the luminal surface to estimate the degree of neointimal incorporation of the implant. From these images, strut coverage rates were semi-quantified by visual estimation from the proximal to distal end.
High-power SEM images (×400) from randomly selected areas were taken (3 areas from 3 stents at each time points). From these images, the numbers of surface monocytes (per mm2) were counted per high-power images. Corresponding areas from confocal microscopy were also identified and the numbers of surface monocytes were also stratified by corresponding VE-cadherin-positive versus VE-cadherin-negative areas without regard to stent type.
Endothelial cell culture study under flow condition in stented silicone tube
Silicone tubes (inner diameter, 2.70 mm) were made with Sylgard 184 material (Dow Corning, Midland, Michigan) as previously described (12). Silicone tubes were coated with 5 μg/mg fibronectin (Sigma F1141, Saint Louis, Missouri) for 24 h following 5-min treatment with 70% H2SO4. Stents were implanted in silicone tubes at nominal pressure. Tubes were seeded with 0.6 ml of human umbilical vein endothelial cells (Cell Applications, Inc., San Diego, California, passage 3 to 6) at the concentrations of 1,000,000 cells/ml. The tubes were rotated 90° every 30 min for 4 h to have even cell distribution. Then, the stented tubes were immersed in cell culture media (MesoEndo Cell Growth Medium, Cell Applications Inc.) for 20 h. The tubes were set under flow conditions (15 ml/min) using a peristaltic pump (ISMATEC ISM 933, Cole-Parmer, Wertheim, Germany) for 24 h (Online Figure 1). Bromodeoxyuridine (BrdU) was administrated to cell culture medium at the concentration of 10 μM.
The samples were fixed with 4% paraformaldehyde for 10 min and were processed for immunohistochemical staining for BrdU. Samples were initially incubated in 0.1% Triton X for 20 min and then in 2N HCL at 37° for 10 min. Samples were subsequently exposed overnight at 4°C to a primary antibody against BrdU (Novus NBP2-32922, Littleton, Colorado, dilution 1:400). The antibody reaction was visualized with an Alexa Fluor 488 donkey antimouse secondary antibody (Invitrogen, dilution 1:150). DAPI (Sigma D9564) was used as the nuclear counterstain. The samples were then mounted on glass slides and images were acquired with a Zeiss LSM 700 laser confocal microscope. For imaging analysis purposes, confocal z-stack images with tile imaging were acquired at ×10 magnification. Numbers of BrdU-positive cells were counted (numbers/mm2) per stent.
Continuous variables with normal distribution were expressed as mean ± SD. The continuous variables without normal distribution were expressed as median (25th and 75th percentile). The Shapiro-Wilk test was used to check for normality of data distribution. Vessel level comparisons were tested by generalized estimating equation method using linear model or gamma with log link model between BP-SES and others or between 120 days and other time points as appropriate. High-power images level comparisons were tested by generalized linear mixed model using gamma regression model. Generalized estimating equation or generalized linear mixed model were adjusted in a hierarchic manner (high-power images, vessel and animals). Matched pair comparisons of variables with non-normal distribution were tested by Wilcoxon signed rank test. In cell culture analysis, comparisons of variables with non-normal distribution were tested by the Kruskal-Wallis tests followed by Steel-Dwass post hoc analysis. SPSS software version 22 (IBM, Chicago, Illinois) or JMP 9 (SAS institute, Cary, North Carolina) were used for statistical analysis. P value of <0.05 was considered statistically significant.
All animals survived the study period. All stents were found evenly expanded and patent without stent fracture. Because of excessive postmortem clot (n = 8) or stent deformation (n = 6) occurring during processing, a total of 14 out of 74 stents in the confocal/SEM subset were excluded from analysis, leaving 60 stents for further analysis.
Figure 1 shows a representative image of light microscopy at 28 days. Morphometric analysis and histological assessment are shown in Table 2. Lumen area was significantly smaller and neointimal area and percent stenosis were significantly greater in BMS. There was no significant difference between DP-EES and BP-SES in luminal narrowing, inflammation score, struts with giant cells, and fibrin score at 28 days.
Confocal microscopy and SEM
Figure 2A shows a representative confocal picture at 120 days for VE-cadherin and quantitated data for VE-cadherin-positive areas by stent type are shown in Table 3. When present, VE-cadherin was expressed as expected on the endothelial cell borders. Percent VE-cadherin-positive area (%) was greatest in BMS at all time points (94.6% at 28 days, 97.9% at 45 days, and 100% at 120 days). However, both DESs showed significantly lower VE-cadherin expression versus BMS at 28-days, although BP-SES showed numerically greater percent VE-cadherin-positive area than DP-EES at all time points. Percent VE-cadherin-positive area in BP-SES was 39.4% at 28 days, 58.3% at 45 days, and 81.7% at 120 days; whereas that of DP-EES was 22.0% at 28 days, 41.9% at 45 days, and 60.6% at 120 days. Overall, the morphology of endothelial cells seemed to be different depending on stent type with cells taking on a spindle shape in BMS, whereas in DP-EES they were cobblestone-like and in BP-SES their appearance was an in-between rice-like shape (Figure 2B). Cell shape index (Y dimension divided by X dimension) at 120 days was greatest in BMS followed by BP-SES and DP-EES (9.3 [5.0 to 10.8 interquartile range (IQR)], 2.8 [2.5 to 3.1 IQR], and 1.5 [1.1 to 1.8 IQR], respectively). Significant differences were observed not only between BMS and BP-SES (p < 0.01) but also between BP-SES and DP-EES (p < 0.01).
Struts coverage rates by SEM are shown in Table 4 and representative low-power SEM images are shown in Figure 3. Strut coverage by SEM in BMS reached 100% at 28 days and remained fully covered at 45 days and 120 days. Struts coverage rates by SEM in BP-SES were 82.3% at 28 days, 97.1% at 45 days, and 99.8% at 120 days; whereas strut coverage in DP-EES was 67.2% at 28 days, 86.9% at 45 days, and 99.4% at 120 days. BP-SES showed significantly greater strut coverage than versus DP-EES at 28 days and 45 days. Both DESs showed progressive statistically significant increases in coverage as time progressed.
Although both DESs by 120 days were nearly completely covered by endothelial cells by SEM at 120 days, VE-cadherin expression in both DESs was incomplete with a significant number of endothelial cells showing lack of VE-cadherin expression (120 days; BP-SES 99.8% coverage by SEM vs. 81.7% VE-cadherin expression, p = 0.13; DP-EES 99.4% coverage by SEM vs. 60.6% VE-cadherin coverage, p = 0.03).
Figure 4 shows representative confocal and SEM matched images at 120 days. VE-cadherin-negative area shows greater surface monocytes adherence along cell junctions, whereas it is rare in VE-cadherin-positive areas. When the number of surface monocytes was stratified by presence versus absence of VE-cadherin regardless of stent types, VE-cadherin-negative endothelium showed greater number of surface monocytes as compared with VE-cadherin-positive endothelium at all time points (median value for the number of surface monocyte [n/mm2], 114 in VE-cadherin-positive staining endothelium versus 586 in VE-cadherin-negative staining endothelium at 28 days, p = 0.27; 116 vs. 411 at 45 days, p < 0.01; 86 vs. 200 at 120 days, p = 0.22). The number of surface monocytes as assessed by SEM did not show significant differences between different stent types at 28 days and 120 days but was significantly greater in DP-EES at 45 days (Online Table 1).
Endothelium cell proliferation in stented silicone tube
In an in vitro experiment using a stented silicone tube model (Figure 5, Table 5), endothelial cell proliferation assessed by BrdU was scarcely observed in DP-EES. However, greater proliferation was observed in BP-SES but it was not as great as in BMS. Although a significant difference was observed by multiple group comparison testing, post hoc analysis did not show significant difference between any 2 pairs.
DES continues to be widely used for the treatment of coronary artery disease, although the requirement for prolonged dual antiplatelet therapy and increased incidence of neoatherosclerosis continue to represent significant drawbacks to this technology (1,3,5). mTOR inhibitors in current generation DP-DES are known to delay endothelial recovery but their role in causing increased endothelial permeability, a likely trigger for neoatherosclerosis (6,7), remains unproven with respect to DES. BP metallic DES were designed to limit exposure of the arterial wall to both polymer and drug, and thus may improve endothelial recovery and function but this remains largely theoretical.
In the current study we examined for the first time the endothelial cell–specific barrier protein VE-cadherin expression in various types of stents in vivo. Both types of DES showed significantly less VE-cadherin expression and strut coverage as compared with BMS. BP-SES had a trend toward better outcomes with respect to endothelial recovery and junctional protein expression as compared with DP-EES in the rabbit iliac model. Histological responses by light microscopy to each stent were largely equivalent at 28 days.
When corresponding regions of the DES segments were simultaneously assessed by SEM and confocal microscopy, SEM analysis showed overall greater endothelial coverage compared with confocal microscopy staining for VE-cadherin, suggesting all DES tested here seem to delay endothelial expression of VE-cadherin, which suggests increased endothelial permeability. In selected regions of the stented segment showing an absence of VE-cadherin expression despite the confirmed presence of endothelial cells by SEM, VE-cadherin-negative endothelium had greater surface monocyte accumulation versus VE-cadherin-positive endothelium. Overall our results expand the understanding of the endothelial cell–specific responses to different polymer-coated DES technologies.
Endothelium injury and recovery
Coronary artery stenting causes complex endothelial injury beginning with endothelial denudation with inflammation characterized by neutrophil infiltration followed by migration of monocytes and macrophages (13). Subsequent secretion of inflammatory cytokines and growth factors stimulate the migration and proliferation of smooth muscle cells, promoting neointimal hyperplasia and restenosis (14). Endothelial injury is also accompanied by persistent fibrin, proteoglycan, and collagen deposition (15). Following these series of events, the endothelium of the stented artery should regain its function. Yet, it remains incompletely understood whether endothelial cells regain full functionality after DES. In this study, BMS showed the fastest endothelial coverage and most complete expression of the endothelial junctional protein VE-cadherin, whereas coverage and function were delayed in both DESs. The delayed endothelial recovery and decrease in VE-cadherin underscores why extended dual-antiplatelet therapy is necessary in DES in general. Although BP-SES showed numerically greater coverage and expression of VE-cadherin at all time-points versus DP-EES, the significance of these findings for clinical translation remains unclear, especially because both DESs lagged greatly behind BMS in both measures.
Importance of Ve-cadherin
Three major types of interendothelial junctions have been identified: 1) tight junctions; 2) gap junctions; and 3) adherence junctions (16). Of those, adherence junction play an important role in the control of vascular permeability (16). VE-cadherin is an endothelial-specific adhesion molecule and the major component in adherence junction (17). Deficiency of VE-cadherin was found not to affect assembly of endothelial cells in vascular plexus, but to impair their subsequent remodeling and maturation, causing lethality (18). Administration of anti-VE-cadherin antibody to mice caused increase in vascular permeability without modifying other types of inter endothelial junction molecules (19). Therefore, VE-cadherin is essential to maintain endothelium barrier function. In human atherosclerotic carotid arteries, neovessels with immunocompetent cells exhibit down regulation of VE-cadherin expression (20) and there is general agreement that VE-cadherin function provides an essential barrier against the development of atherogenesis. DESs accelerate neoatherosclerosis compared with BMS, although the exact reasons why this occurs remain unknown. We recently showed that sirolimus/everolimus induced decrease of VE-cadherin expression and increase of endothelial permeability in vitro (7,21). Here we confirm for the first time in an in vivo model of stenting that DESs delay VE-cadherin expression, which suggests that increased endothelial permeability might be the cause of accelerated neoatherosclerosis. Moreover, because abluminally coated BP-based DES reduces drug exposure time (22,23) it remains possible that long-term vascular permeability is improved at BP-SES. Our animal model data seem to suggest this, although the data for VE-cadherin expression for BP-SES versus DP-EES did not reach statistical significance.
In addition to loss of VE-cadherin expression, we also detected significant differences in endothelial cell morphology among DP-DES, BP-DES, and BMS. Under physiologic shear endothelial cells normally elongate, which is induced by cytoskeleton remodeling (24,25). This was readily appreciated in BMS where endothelial cells appeared spindle-shaped. In DP-DES endothelial cells took on a more cobblestone appearance and in BP-DES their shape was somewhat in-between these 2 patterns, perhaps consistent with shorter drug exposure time. Others have shown that mTOR inhibition in endothelial cells promotes the formation of actin stress fibers, although to the best of our knowledge the shape changes reported by us here within both DP-DES and BP-DES have never before been shown (26). Further work is needed to understand the clinical significance of these findings.
To date, clinical trial data examining head-to-head comparisons of current generation DP- and BP-DES have failed to show a clear-cut advantage for the latter. In both the CENTURY II (Clinical Evaluation of New TerUmo dRug-eluting coronary stent system in the treatment of patients with coronary artery disease) and EVOLVE II trials (A Prospective Randomized Multicenter Single-blind Non-inferiority Trial to Assess the Safety and Performance of the Evolution Everolimus-Eluting Monorail Coronary Stent System [Evolution Stent System] for the Treatment of a De novo Atherosclerotic Lesion), DP-EES was noninferior to similar strut thickness of BP-SES (Ultimaster) and BP-EES (SYNERGY, Boston Scientific, Natick, Massachusetts), respectively, for the composite primary endpoint of safety and efficacy (27,28). More recently, results of the BIO-RESORT trial (Very thin strut biodegradable polymer everolimus-eluting and sirolimus-eluting stents versus durable polymer zotarolimus-eluting stents in allcomers with coronary artery disease), a 3-arm, randomized, noninferiority trial examining the safety (cardiac death and target vessel-related myocardial infarction) and efficacy (target-vessel revascularization) of BP-EES and other BP-SES (ORSIRO, Biotronik, Berlin, German) stents compared with DP- zotarolimus-eluting stents (RESOLUTE INTEGRITY, Medtronic, California) were published (29). The primary finding was that both BP stents were noninferior to the DP- zotarolimus-eluting stents at 12 months (29). However, in most published studies, the duration of follow-up has been rather limited (i.e., 1 year), which might not be enough time to allow clinically important events, such as late restenosis caused by neoatherosclerosis or thrombosis, to accrue, especially in the presence of dual antiplatelet therapy. The data presented here suggest BP-SES are equivalent if not superior to DP-DES but whether these will translate into clinically meaningful differences in outcomes remains uncertain.
Vascular responses to the stents in healthy rabbit iliac arteries or endothelial cell cultures are likely different from those in diseased human arteries, which may limit the ability to generalize the current findings directly to clinical outcomes in humans. Exclusion of stents because of excessive amount of postmortem clot and stent deformation during processing meant we were not able to examine all stents implanted in the current study, although exclusion of specimens was done in blinded manner. Our data suggest the absence of VE-cadherin on vascular endothelial cells after DES might promote vascular permeability, although we did not actually test this using methodology, such as Evans blue dye.
Abluminal coating BP-DES showed significantly faster endothelium coverage and numerically greater expression of endothelial junctional VE-cadherin expression versus DP-EES. The morphologic pattern of endothelial cells was altered in DP-EES versus BMS, whereas in our in vitro stent model both DESs inhibited endothelial cell proliferation. Overall, our results suggest distinct advantages for BP-SES over DP-EES with respect to endothelial cell recovery and function but whether these translate into clinically meaningful advantages remains to be seen.
WHAT IS KNOWN? Neoatherosclerosis still remains a major problem with drug-eluting stent (DES). The mechanism of neoatherosclerosis in DES is thought to be impaired endothelium function, although it has not been clearly shown.
WHAT IS NEW? In this study, we show the expression of the endothelial barrier protein vascular endothelium-cadherin (VE-cadherin) in biodegradable polymer sirolimus-eluting stents (BP-SES), durable polymer everolimus-eluting stents (DP-EES), and bare metal stents at 3 different time points (28, 45, and 120 days). VE-cadherin expression was significantly delayed in both DESs favoring BP-SES versus DP-EES (39% coverage in BP-SES, 22% in DP-EES, 95% in bare metal stents, 28 days). The morphological pattern of endothelial cells covering BP-SES was closer to bare metal stents (typical spindle shape) compared with DP-EES. VE-cadherin-negative areas showed significantly greater surface monocytes than VE-cadherin-positive areas regardless of time point or type of stent.
WHAT IS NEXT? These findings may have important implications for the development of neoatherosclerosis in different stent types.
The authors thank Lila Adams, Edward Violette, Patty Wilson, and Deborah Howd for their technical support.
CVPath Institute has received research grants from Abbott Vascular, Atrium Medical, Boston Scientific, Biosensors International, Cordis–Johnson&Johnson, Medtronic CardioVascular, OrbusNeich Medical, and Terumo Corporation. Dr. Mori has received honorarium from Abbott Vascular Japan, Goodman, and Terumo Corporation. Dr. Torii has received honorarium from Abbott Vascular Japan, Terumo Corporation, and SUNRISE Lab. Dr. Joner is a consultant for Biotronik, Coramaze, AUM Medical, Orbus Neich; and has received honorarium from Biotronik, Boston Scientific, AstraZeneca, and Orbus Neich. Dr. Virmani has speaking engagements with Merck; receives honoraria from Abbott Vascular, Boston Scientific, Lutonix, Medtronic, and Terumo Corporation; and is a consultant for 480 Biomedical, Abbott Vascular, Medtronic, and W.L. Gore. Dr. Finn has sponsored research agreements with Boston Scientific and Medtronic CardioVascular; and is an advisory board member to Medtronic CardioVascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare metal stent(s)
- biodegradable polymer
- biodegradable polymer sirolimus-eluting stent(s)
- drug-eluting stent(s)
- durable polymer
- durable polymer everolimus-eluting stent(s)
- mammalian target of rapamycin
- scanning electron microscopy
- vascular endothelial
- Received March 6, 2017.
- Revision received June 16, 2017.
- Accepted June 29, 2017.
- 2017 American College of Cardiology Foundation
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