Human recombinant activated protein C-coated stent for the prevention of restenosis in porcine coronary arteries

Activated protein C (APC), an endogenous protein, inhibits inflammation and thrombosis and interrupts the coagulation cascade. Here, we investigated the effect of human recombinant APC on the development of neointimal hyperplasia in porcine coronary arteries. Yukon Choice bare metal stents were coated with 2.6 mu g APC/mm(2). Under general anesthesia, APC-coated and bare stents were implanted in the left anterior descending and circumflex coronary arteries of 10 domestic pigs. During the 4-week follow-up, animals were treated with dual antiplatelet therapy and neointimal hyperplasia was evaluated via histology. Scanning electron microscopy indicated successful but unequal coating of stents with APC; nearly complete drug release occurred within 4 h. Enzyme-linked immunosorbent assay revealed that intracoronary stent implantation rapidly increased the levels of monocyte chemoattractant protein-1, an effect that was inhibited by APC release from the coated stent. Fibrin deposition and adventitial inflammation were significantly decreased 1 month after implanting APC-coated stents versus bare stents, paralleled by significantly smaller neointimal area (0.98 +/- 0.92 vs. 1.44 +/- 0.91 mm(2), P = 0.028), higher lumen area (3.47 +/- 0.94 vs. 3.06 +/- 0.91 mm(2), P = 0.046), and lower stenosis area (22.2 +/- 21.2 % vs. 32.1 +/- 20.1 %, P = 0.034). Endothelialization was complete with APC-coated but not bare (90 %) stents. P-selectin immunostaining revealed significantly fewer activated endothelial cells in the neointima in the APC group (4.6 +/- 1.9 vs. 11.6 +/- 4.1 %, P < 0.001). Thus, short exposure of coronary arteries to APC reduced inflammatory responses, neointimal proliferation, and in-stent restenosis, offering a promising therapy to improve clinical outcomes of coronary stenting. However, coating stents with APC for prolonged, controlled drug release remains technically challenging

Succinobucol-eluting stents increase neointimal thickening and peri-strut inflammation in a porcine coronary model

The aim of this study was to assess the efficacy of stent-based delivery of succinobucol alone and in combination with rapamycin in a porcine coronary model. Current drugs and polymers used to coat coronary stents remain suboptimal in terms of long term efficacy and safety. Succinobucol is a novel derivative of probucol with improved antioxidant and anti-inflammatory properties. Polymer-free Yukon stents were coated with 1% succinobucol (SucES), 2% rapamycin (RES) or 1% succinobucol plus 2% rapamycin solutions (SucRES) and compared with a bare metal stent (BMS). RESULTS: The in vivo release profile of SucES indicated drug release up to 28 days (60% drug released at 7 days). 41 stents (BMS, n = 11; SucES, n =10; RES, n = 10; SucRES, n = 10) were implanted in the coronary arteries of 17 pigs. After 28 days, mean neointimal thickness was 0.31 ± 0.14 mm for BMS, 0.51 ± 0.14 mm for SucES, 0.19 ± 0.11 mm for RES and 0.36 ± 0.17 mm for SucRES (p <0.05 for SucES vs. BMS). SucES increased inflammation and fibrin deposition compared with BMS (p <0.05), whereas RES reduced inflammation compared with BMS (p <0.05). In this model, stent-based delivery of 1% succinobucol using a polymer-free stent platform increased neointimal formation and inflammation following coronary stenting

Local MicroRNA Modulation Using a Novel Anti-miR-21–Eluting Stent Effectively Prevents Experimental In-Stent Restenosis

ObjectiveDespite advances in stent technology for vascular interventions, in-stent restenosis (ISR) because of myointimal hyperplasia remains a major complication.Approach and resultsWe investigated the regulatory role of microRNAs in myointimal hyperplasia/ISR, using a humanized animal model in which balloon-injured human internal mammary arteries with or without stenting were transplanted into Rowett nude rats, followed by microRNA profiling. miR-21 was the only significantly upregulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared with coronary artery disease specimen. We systemically repressed miR-21 via intravenous fluorescein-tagged-locked nucleic acid-anti-miR-21 (anti-21) in our humanized myointimal hyperplasia model. As expected, suppression of vascular miR-21 correlated dose dependently with reduced luminal obliteration. Furthermore, anti-21 did not impede reendothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increase in serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21-coated stents. Compared with bare-metal stents, anti-21-coated stents effectively reduced ISR, whereas no significant off-target effects could be observed.ConclusionThis study demonstrates the efficacy of an anti-miR-coated stent for the reduction of ISR

Local MicroRNA Modulation Using a Novel Anti-miR-21–Eluting Stent Effectively Prevents Experimental In-Stent Restenosis

OBJECTIVE: Despite advances in stent technology for vascular interventions, in-stent restenosis (ISR) due to myointimal hyperplasia (MH) remains a major complication. APPROACH AND RESULTS: We investigated the regulatory role of microRNAs in MH/ISR, utilizing a humanized animal model in which balloon-injured human internal mammary arteries (IMAs) with or without stenting were transplanted into RNU rats, followed by microRNA profiling. miR-21 was the only significantly up-regulated candidate. In addition, miR-21 expression was increased in human tissue samples from patients with ISR compared to coronary artery disease specimen. We systemically repressed miR-21 via intravenous FAM-tagged-LNA-anti-miR-21 (anti-21) in our humanized MH-model. As expected, suppression of vascular miR-21 correlated dose-dependently with reduced luminal obliteration. Further, anti-21 did not impede re-endothelialization. However, systemic anti-miR-21 had substantial off-target effects, lowering miR-21 expression in liver, heart, lung, and kidney with concomitant increased serum creatinine levels. We therefore assessed the feasibility of local miR-21 suppression using anti-21-coated stents. Compared to bare metal stents, anti-21-coated stents effectively reduced ISR, while no significant off-target effects could be observed. CONCLUSION: This is the first study to demonstrate the efficacy of an anti-miR-coated stent for the reduction of ISR