| OBJECTVES Several clinical studies have revealed some contradictory results of efficiency and safety between first-generation drug-eluting stents (SES) and second-generation drug-eluting stents (ZES). Compared to SES, the therapeutic effects of ZES have not been determined yet, especially for long lesion vessels that need overlapping stents implantation. More basic researches are needed to investigate the accurate pathophysiology caused by SES and ZES in order to solve the current clinical problems. Therefore the purpose of this study is to evaluate the effects and underlying mechanism altered at the sites of overlapping SES or ZES and the segments distal to stents. This study will provide more powerful evidence for choosing ideal drug-eluting stents in clinical world.METHODS 18 pigs received overlapping stent pairs in each of two coronary arteries with randomization to BMS, SES or ZES by vessels.1. Stented segments for histopathologic analysis were stained with Movat-Pentachrome (MP) and hematoxylin-eosin (HE). Slides with MP staining were analyzed for neointimal area, neointimal thickness and restenosis; Slides with HE staining were used for evaluation of artery healing, including reendothelialization, inflammation, fibrin deposition and medial necrosis.2. Four overlapping-stented arteries in each group were collected for DNA microarray analysis. The data were collected and calculated with Affymetric genechip operating software. To identify differentially expressed genes, signal log ratio was estimated for the magnitude and direction of change in a transcript when SES or ZES group was compared with BMS. The physiological processes related with altered gene expression in each group were analyzed by Gene ontology (GO) annotations.3. Endothelium-dependent and endothelium-independent relaxation and contraction in arterial segments distal to stents were measured with acetylcholine-challenge assay in vivo and organ chamber tensiometry in vitro. The plasma from coronary sinus were collected and used to examine the level of 8-isoprostane. Superoxide anion production at distal stented segments were measured by lucigenin luminometry. The expression of eNOS, Akt and pAkt were assayed by Western blot.RESULTS 1. All animals tolerated the interventional procedures without adverse cardiac or systemic events. There was no difference in baseline and follow-up reference vessel diameter measurement among the three groups. In concordance with the QCA data, the histomorphometry intimal thickness and cross-sectional area of the neointima showed no detectable differences among groups.2. SES arteries, especially at the overlapping regions, had significantly severe peri-strut adverse response, including inflammatory cell infiltration, fibrin deposits, and medial necrosis as compared to BMS and ZES. In addition, potentially early atherosclerosis was observed at overlapping regions in SES, which presented as foamy macrophage infiltrates as well as mineral-like material deposition within the neointima. Implantation of overlapping SES resulted in a marked increase in interleukins and chemokines compared to BMS and ZES. Genes related to oxidative stress and pro-atherosclerosis were also significantly elevated in SES. In contrast, the anti-atherosclerotic genes were dramatically decreased in SES vs. BMS and ZES.3. Acetylcholine infusion induced significant vasoconstriction in the distal non-stented conduit artery implanted with SES as compared to BMS and ZES. Dose-dependent increasing contractile response to ET-1 was observed in SES vs. BMS and ZES, although there was no significant difference among groups. The contraction to PGF2α/40 mM KC1 was not promoted for overlapping SES at distal segments when in presence of NO synthetase inhibitor L-NAME, indicating that nitric oxide pathway may be impaired in SES. Densitometry analysis demonstrated that significantly increasing eNOS and pAkt protein expression occurred at the distal non-stented segments following ZES vs. BMS and SES. CONCLUSION 1. Compared with SES, ZES attenuated the delayed arterial healing and inflammation was dampened at sites of overlapping segments. SES stents induced greater fibrin deposition, medial cell loss, eosinophils infiltration. Moreover, neoatherosclerosis in neointimal was only found in overlapping SES. All these findings suggest that ZES is superior to SES in clinical implication.2. Abnormal endothelium-dependent relaxation at non-stented coronary conduit arteries was observed at 28 days after overlapping-SES implantation compared to ZES. Overlapping ZES implantation has the potential role in protection of endothelium function. Increased oxidative strees is the possible reason for endothelium dysfunction in vessel segments distal to stents. |
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