| BackgroundThe late-acquired stent malapposition (LASM) is an finding which has separation of at least 1 stent strut from the arterial wall intima that does not overlap a side-branch, with evidence of blood flow (speckling) behind the strut, where the immediate postimplantation intravascular ultrasound (IVUS) revealed complete apposition of the stent to the vessel wall. LASM may occur both after drug-eluting stent (DES) and bare-metal stent (BMS) implantation. The incidence of LASM is significantly higher in DES compared with BMS (0%～25% vs.0～6%, respectively). It has proved that the main cause of LASM is regional positive remodeling, which means a regional increase in external elastic membrane area (EEMA). However, the mechanism of regional positive remodeling after stent implantation still remains unknown.Objective1. To study the incidence and degree of vascular positive remodeling after BMS or DES implantation via performing iliac arterial stent implantation in atherosclerotic rabbit models.2. To observe the inflammatory reaction, vascular smooth muscle cell (VSMC) apoptosis and proliferation, matrix metalloproteinase (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) expression of vascular tissue after BMS and DES implantation, investigate those indicators in their relation to vascular positive remodeling, in hope to reveal the mechanism of vascular positive remodeling and LASM.Methods60 male New Zealand rabbits fed on high fat diet for 1 week and then had bilateral iliac artery balloon catheter injury. Immediately following the operation, all subjects were maintained on high fat diet for 8 weeks and then had iliac arterial stent implantation. IVUS was applied pre-operatively and post-operatively. One types of 4 stents, including BMS, permanent polymer sirolimus-eluting stent (PPSES), biodegradable polymer sirolimus-eluting stent (BPSES) and polymer-free sirolimus-eluting stent (PFSES), was implanted at the detected atherosclerotic stenotic lesions in an animal subject. Post-operatively, all subjects received both ordinary diet and a dual antiplatelet therapy of aspirin and clopidogrel for 8 weeks. At the end of the experiment, the total of 53 survived animals is composed of 12 in BMS,14 in PPSES,13 in BPSES and 14 in PFSES. Iliac arterial angiography and IVUS as follow ups were conducted on all survived animal subjects. The ratio of follow-up EEMA to post-stent implantation was defined as remodeling ratio, which with a value beyond 1.05 is categorized into the vascular positive remodeling (VPR) group. Any remodeling ratio value lower than 0.95 was catagorized into the vascular negative remodeling group. Any remodeling ratio value in between 0.95 and 1.05 was considered no remodeling. The negative remodeling group and the group considered as no modeling were combined into the vascular non-positive group (NPR).Meanwhile, histomorphometry measurement, Verhoeff-Van Geison staining, pathological scores, and inflammatory reaction on a specimen of iliac artery, and immunohistochemistry to detect proliferating cell nuclear antigen (PCNA), matrix metalloproteinase-2 (MMP-2), and tissue inhibitor of metalloproteinase-2 (TIMP-2) expression, and terminal deoxynucleotidyl transferase-mediate dUTP-biotin nick end labeling assay (TUNEL) to detect cell apoptosis were all analyzed in relation to vascular positive remodeling.ResultsThe incidence of vascular positive remodeling was 25.00%(3/12) in BMS group, 42.86%(6/14) in PPSES group,30.77%(4/13) in BPSES group, and 28.57%(4/14) in PFSES group. There was no statistical significance among the 4 groups. The follow-up EEMA minus post-stent implantation (△EEMA) was-0.51±0.54mm2, 0.86±0.38mm2,0.67±0.41mm2,0.05±0.27 mm2, respectively. As compared with BMS group, PPSES group and BPSES group demonstrated significantly larger△EEMA, while PFSES group had no significant difference. The difference between PPSES group and BPSES group was not significant differently. For the VPR groups,△EEMA was 0.96±0.45mm2,2.47±0.35mm2.2.59±0.57mm2,1.23±0.24 mm2 in BMS group, PPSES group, BPSES group, PFSES group, respectively. As compared with BMS group, PPSES group and BPSES group presented significantly larger△EEMA, while PFSES group had no significant difference. The difference between PPSES group and BPSES group was not significant differently. LASM occurred in 2 stents, one was PPSES; the other was BPSES. The EEMA, AEEMA, LSM cross section area of PPSES was 13.03mm2,2.92mm2,4.30mm2, respectively; while the EEMA,△EEMA, LSM cross section area of BPSES was 13.86mm2,3.32mm2,2.20mm2, respectively.The rupture and degradation of elastic and collagen fibers was not observed in each group. The inflammatory area was 0.03±0.03 mm2,0.14±0.11 mm2,0.05±0.04 mm2,0.00±0.00 mm2 in BMS group, PPSES group, BPSES group, PFSES group, respectively; The number of inflammatory cells per inflammatory area was 2.87±1.22×103/mm2,7.49±5.85×103/mm2,4.38±4.05×103/mm2,0.00q0.00×103/mm2, respectively. As compared with BMS, BPSES and PFSES group, PPSES presented larger inflammatory area and more inflammatory cells. The proliferation index (PI) was 61.35±8.98%,29.50±5.47%,28.59±7.05%,16.85±5.30% in BMS group, PPSES group, BPSES group and PFSES group, respectively. PPSES, BPSES and PFSES group demonstrated lower PI value as compared with BMS group; PPSES and BPSES group demonstrated higher PI as compared with PFSES group. The apoptosis index (AI) was 14.16±3.48%,24.50±3.17%,24.69±2.58%,60.20±2.40% in BMS group, PPSES group, BPSES group and PFSES group, respectively. PPSES, BPSES and PFSES group presented higher AI value as compared with BMS group; PPSES and BPSES group presented lower PI as compared with PFSES group. The average optical density (AOD) of MMP-2 was 0.16±0.07,0.15±0.21,0.13±0.01,0.07±0.03 in BMS group, PPSES group, BPSES group and PFSES group, respectively. PFSES group demonstrated lower AOD value of MMP-2 as compared with the other 3 groups. There was no significant difference in AOD of TIMP-2 among all the groups.The VPR group in both PPSES and BPSES presented larger inflammatory area and more number of inflammatory cells per inflammatory area than their NPR rival groups. The VPR group in PPSES demonstrated lower PI value than its NPR rival group, while the VPR group in both BPSES and PFSES group demonstrated higher PI than their NPR rival groups. The VPR group in PPSES, BPSES and PFSES group demonstrated higher AI than their NPR rival groups, especially in the PPSES group. The VPR group in PPSES and BPSES group presented lower MMP-2 expression than their NPR rival groups. The VPR group in PPSES group presented increased TIMP-2 expression than its NPR rival group.There was statistically positive correlation between AI and△EEMA(r=0.275, P＜0.05), so was between AOD of MMP-2 and△EEMA (r=0.550, P＜0.05)Conclusions 1. The degree of vascular positive remodeling was more prominent in SES with polymer coating than SES without polymer coating after stent implantation.2. The course of vascular positive remodeling was associated with VSMC apoptosis and increased MMP-2 expression after stent implantation. VSMC apoptosis/ proliferation imbalance was related to the effect of rapamycin and local inflammatory reaction induced by polymer coating, MMPs/TIMPs imbalance was related to the local inflammatory reaction induced by polymer coating.
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