Porcine Coronary Injury Model Research Articles

A Promising Approach for Improving the Coating Stability and In Vivo Performance of Biodegradable Polymer-Coated Sirolimus-Eluting Stent.

Several developments are in progress for improving the performance of drug-eluting stents (DESs) including use of biodegradable polymers, polymer-free DES, fully bioabsorbable stents, and so on. The commercially available DESs still suffer from polymer defects that could affect the performance of a DES through a series of adverse events such as coating delamination and/or peeling-off that lead to non-uniform local drug distribution, restenosis, and thrombosis. The goal of this work was to enhance the stability of drug-in-polymer matrix coating on a stent metal surface through surface modification. The cobalt–chromium (Co–Cr) surface was chemically modified using poly(dopamine) (PDA) nano-coating and poly(L-lactide) (PLLA) nano-brush in order to be applied to a biodegradable polymer-coated DES. The biodegradable polymer loaded with sirolimus was coated using an ultrasonic spray coating instrument. The coating morphology on all samples showed a very smooth and uniform coating. The stability of the coating was evaluated for 2 months under the circulation system in which the drug-in-polymer coating on the PLLA brush-modified stent presented the most stable coating behavior as compared to other samples. The in vitro sirolimus release study from both unmodified and modified stents was studied in phosphate-buffered saline (PBS), and the modified stents showed slower sirolimus release profile as compared to unmodified stents. In vivo study was performed in a porcine coronary artery injury model for 28 days. The percentage of in-stent restenosis area (ISR) for PLLA brush-modified sirolimus-eluting stent (SES) decreased significantly as compared to unmodified SES and bare metal stent (BMS). This study demonstrated that the modification of stent surface using PLLA brushes affects in vitro and in vivo performance effectively to be applied for biodegradable polymercoated DES.

Nitric Oxide Releasing Coronary Stent: A New Approach Using Layer-by-Layer Coating and Liposomal Encapsulation.

The sustained or controlled release of nitric oxide (NO) can be the most promising approach for the suppression or prevention of restenosis and thrombosis caused by stent implantation. The aim of this study is to investigate the feasibility in the potential use of layer-by-layer (LBL) coating with a NO donor-containing liposomes to control the release rate of NO from a metallic stent. Microscopic observation and surface characterizations of LBL-modified stents demonstrate successful LBL coating with liposomes on a stent. Release profiles of NO show that the release rate is sustained up to 5 d. In vitro cell study demonstrates that NO release significantly enhances endothelial cell proliferation, whereas it markedly inhibits smooth muscle cell proliferation. Finally, in vivo study conducted with a porcine coronary injury model proves the therapeutic efficacy of the NO-releasing stents coated by liposomal LBL technique, supported by improved results in luminal healing, inflammation, and neointimal thickening except thrombo-resistant effect. As a result, all these results demonstrate that highly optimized release rate and therapeutic dose of NO can be achieved by LBL coating and liposomal encapsulation, followed by significantly efficacious outcome in vivo.

Mechanisms of tissue uptake and retention of paclitaxel-coated balloons: impact on neointimal proliferation and healing

BackgroundThe efficacy of paclitaxel-coated balloons (PCB) for restenosis prevention has been demonstrated in humans. However, the mechanism of action for sustained drug retention and biological efficacy following single-time drug delivery...

Anti-CD133 antibody immobilized on the surface of stents enhances endothelialization.

Drug eluting stents successfully reduce restenosis at the cost of delayed reendothelialization. In recent years, a novel concept to enhance reendothelialization using anti-CD34 antibody coated stents which capture circulating progenitor cells (EPCs) has been developed with conflicting clinical results. CD133 is a glycoprotein expressed on circulating hematopoietic and putative endothelial-regenerating cells and may be superior to CD34 for EPCs capture stents. In the present study, anti-CD133 antibody has been successfully immobilized to the biodegradable polymeric coating material by covalent conjugation. We explore whether anti-CD133 antibody coated stents (CD133 stents) might accelerate reendothelialization in comparison with bare metal stents (BMS) through the superior ability to capture EPCs. The in vitro cell culture results indicate that anti-CD133 antibody functionalized polymer film significantly promotes CD133 positive cells attachment and growth compared with the unfunctionalized polymer film. In the semi-in vivo arteriovenous shunt model CD133 stents demonstrate much quicker specific capturing of EPCs from the blood stream than BMS within 6 hours. In a porcine coronary artery injury model CD133 stents show more effective reendothelialization in short term compared with BMS, while no significant difference in endothelial function recovery was observed between these two groups within 6-month followup.

Impact of Parallel Micro-Engineered Stent Grooves on Endothelial Cell Migration, Proliferation, and Function

Stent luminal surface characteristics influence surface endothelialization. We hypothesize that luminal stent microgrooves created in the direction of coronary flow accelerate endothelial cell migration, resulting in lower levels of neointimal formation. Surface coverage efficiency was evaluated in vitro by allowing human aortic endothelial cells (HAEC) to migrate onto microgrooved (G) or smooth (NG) surfaces. HAEC functionality was assessed by proliferation rate, apoptosis rate, nitric oxide production, and inflammatory markers TNF-α and VCAM-1 expression. Early endothelialization and restenosis studies were performed using the porcine coronary injury model. Stainless steel stents of identical design with (GS) and without (NGS) luminal microgrooves were used. The commercially available Multi-Link Vision (MLVS) stent of identical design was used as a control. The degree of GS and NGS surface endothelialization was compared at 3 days. Biocompatibility and tissue response outcomes were evaluated at 28 days. The in vitro study demonstrated that at 7 days the presence of surface microgrooves increased HAEC migration distance >2-fold. Cell proliferation rate and nitric oxide production were increased and apoptosis rate was decreased. There was no difference in inflammatory marker expression. At 3 days, coronary artery stent endothelialization was significantly increased in GS compared with NGS (81.3% versus 67.5%, P=0.0002). At 28 days, GS exhibited lower neointimal thickness compared with either NGS (21.1%, P=0.011) or MLVS (40.8%, P=0.014). Parallel microgrooves on coronary stent luminal surfaces promote endothelial cell migration and positively influence endothelial cell function, resulting in decreased neointimal formation in the porcine coronary injury model.

Polycarbonate urethane films modified by heparin to enhance hemocompatibility and endothelialization

AbstractPolyurethane with pendant carboxyl groups was synthesized by a two‐step reaction using methylene diphenyl diisocyanate as hard segments, polycarbonate diols as soft segments and 2,2‐bis(hydroxymethyl) propionic acid as chain extenders. The surfaces of the casting polymer films were further covalently conjugated with heparin as confirmed by Fourier transform infrared spectroscopy. The associated surface‐exposed heparin content was measured to be 1.92 µg cm−2 and was shown to be active. Meanwhile, surface hydrophobicity decreased after heparin modification. Heparin immobilization greatly improved the hemocompatibility of polyurethane films both in vitro and in vivo. The in vitro cell responses revealed that the expression of proinflammatory markers CD106 and CD62E of human vein endothelial cells was significantly suppressed on the surfaces of the heparinized polyurethane films, while the affinity and proliferation of the cells were improved. The in vivo performance of this material before and after heparin modification was evaluated as a stent coating material in a porcine coronary artery injury model. Histological analysis indicated that heparinized polyurethane induced mild foreign body reactions and inflammation, which were much lower than those induced by unmodified polyurethane. Heparin immobilization also accelerated the endothelialization process on the surface of the polymer‐coated stents when implanted in porcine coronary arteries. More detailed long‐term studies are needed to confirm the biostability of the heparin and the endothelialized surfaces. Copyright © 2012 Society of Chemical Industry

Heparin-immobilized polymers as non-inflammatory and non-thrombogenic coating materials for arsenic trioxide eluting stents

We have synthesized heparin-immobilized copolymers of l-lactide (LA) and 5-methyl-5-benzyloxycarbonate-1,3-dioxan-2-one (MBC) as non-inflammatory and non-thrombogenic biodegradable coating materials. These copolymers were used in fabricating arsenic trioxide (As 2O 3)-eluting stents to reduce the late-stage adverse events, such as thrombosis, localized hypersensitivity and inflammation, that occur when applying stents to treat coronary artery diseases. Heparinized copolymers effectively reduced platelet adhesion and protein adsorption while increasing the plasma recalcification time and thromboplastin time in vitro. Histological analysis of the polymer-coated stents in a porcine coronary artery injury model indicated that one heparinized copolymer (Hep-Co90, LA:MBC = 90:10), with the highest LA content of 90% and the lowest degradation rate, induced the least foreign body reactions and inflammation, which were as small as those induced by bare metal stents. Consequently, Hep-Co90 was used as the stent coating material for local As 2O 3 delivery. Histomorphometric evaluations suggested no significant difference between bare metal stents and As 2O 3-eluting stents at 1 and 3 months post-implantation. At 6 months, the lumen area in the porcine coronary arteries treated with As 2O 3-eluting stents is 32.4% higher than those treated with bare metal stents while the neointimal area, neointimal thickness and stenosis rate decreased by 25.8%, 32.5% and 31.2%, respectively. The As 2O 3-eluting stent using Hep-Co90 as the drug carrier and stent coating material presented in this study represents a novel promising device in preventing in-stent restenosis.

Long‐term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor‐kappaB and activator protein 1 activation in pigs

The optimal duration of clopidogrel treatment following percutaneous coronary intervention (PCI) and the patient population that would benefit most are still unknown. In a porcine coronary injury model, we tested two different durations of clopidogrel treatment on severely or moderately injured arteries and examined the arterial response to injury. To understand the molecular mechanism, we also investigated the effects on transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1). In 24 cross-bred pigs, one coronary artery was only moderately injured by percutaneous transluminal coronary angioplasty (PTCA) and one coronary artery was severely injured by PTCA and subsequent beta-irradiation (Brachy group). Animals received 325 mg aspirin daily for 3 months and 75 mg clopidogrel daily for either 28 days [short-term (ST) clopidogrel group] or 3 months [long-term (LT) clopidogrel group]. After 3 months, the number of proliferating cells per cross-section differed significantly between ST and LT in both injury groups (PTCA(ST) 90.2 +/- 10.3 vs. PTCA(LT )19.2 +/- 4.7, P < 0.05; Brachy(ST) 35.8 +/- 8.4 vs. Brachy(LT) 7.5 +/- 2.0, P < 0.05). Similar results were seen for inflammatory cells (CD3(+) cells): PTCA(ST) 23.5 +/- 3.55 vs. PTCA(LT )4.67 +/- 0.92, P < 0.05; Brachy(ST) 83.17 +/- 11.17 vs. Brachy(LT) 20 +/- 4.82, P < 0.05). Long-term administration also reduced the activity of NF-kappaB and AP-1 by 62-64% and 42-58%, respectively. However, the effects of different durations of clopidogrel administration on artery dimensions were not statistically significant. Regarding inflammation and transcription factor activity at the PCI site, long-term clopidogrel administration is superior to short-term administration, especially in severely injured arteries. Transferring our results to the human situation, patients with more severely diseased arteries may benefit from a prolonged clopidogrel medication after PCI.

The effect of a layer-by-layer chitosan–heparin coating on the endothelialization and coagulation properties of a coronary stent system

A biomacromolecular layer-by-layer coating process of chitosan/heparin onto a coronary stent is designed for the acceleration of the re-endothelialization and healing process after coronary stent deployment. The results of in vitro culturing of porcine iliac artery endothelial cells as well as the measurements of the APTT, PT and TT supported the rationale that the combination of chitosan and heparin could bring both endothelial cell compatibility and haemocompatibility to the stent surface. A porcine coronary injury model and arteriovenous shunt model were used for the further evaluation of the application of this kind of surface-modified stainless steel stent in vivo. The final results proved that this facile coating approach could significantly promote re-endothelialization and was safer compared with bare metal stents for its much improved anticoagulation property.

Neointimal suppression in response to the PROMUS everolimus-eluting coronary stent compared to the bare Liberté stent in the 30% overstretch porcine coronary injury model at 10, 30, and 90 days

Neointimal suppression in response to the PROMUS everolimus-eluting coronary stent compared to the bare Liberté stent in the 30% overstretch porcine coronary injury model at 10, 30, and 90 days

Functional properties of a novel mutant of staphylokinase with platelet-targeted fibrinolysis and antiplatelet aggregation activities

The present study was performed to characterize the functional properties of RGD-SAK, a novel mutant of staphylokinase (SAK). Biochemical analysis indicated that RGD-SAK maintained the similar structure and the fibrinolytic function of SAK. Measurement of platelet binding activity in vitro demonstrated that RGD-SAK had a much higher affinity with platelets than SAK. In vitro platelet-rich clot lysis assay demonstrated that the engineered mutant outperformed the non-manipulated SAK. The time required for 50% platelet-rich clot lysis was reduced significantly across different concentrations of RGD-SAK comparing with SAK. Meanwhile, RGD-SAK was found to inhibit ADP-induced platelet aggregation in a concentration-dependent manner while SAK had negligible effect on platelet aggregation. In concordance, further study in a porcine coronary balloon injury model demonstrated the efficacy of RGD-SAK for the lysis of platelet-rich coronary blood clots and for the prevention of reocclusion after thrombolysis. These results suggested that RGD-SAK may serve as a potential thrombolytic agent with platelet-targeted fibrinolysis and antiplatelet aggregation activities.

Inhibition of vascular remodelling in a porcine coronary injury model by herbal extract XS0601

BackgroundArterial remodelling is a major pathologic change of restenosis after percutaneous coronary intervention (PCI). Our previous studies showed that XS0601 (consisting of Chuangxingol and paeoniflorin) had some effects on the prevention of restenosis after PCI. Therefore, the purpose of this study was to examine whether and how its mechanism was related to the regulation of the arterial remodelling after endothelial injury by balloon dilation.MethodsTwenty Chinese mini-pigs were randomized into four groups: control, probucol, low-dose XS0601 and high-dose XS0601 group before oversized balloon injury of the left anterior descending coronary arteries. Starting from two days before balloon injury, the mini-pigs in the treated group were administered with probucol (2 g/day) and XS0601 (0.02 g/kg/day for low dose; 0.04 g/kg/day for high dose) for four weeks after balloon injury. The animals receiving balloon injury alone were used as control. Morphometric and angiographic analysis of the injured arteries were performed.ResultsThe contribution of intimal hyperplasia and arterial remodelling to angiographic late lumen loss was 41% and 59% respectively. XS0601 markedly inhibited proliferation of smooth muscle cells (SMCs) and transformation of SMCs from contractile to synthetic phenotype in neointima, inhibited hyperplasia-related indices of morphometric analysis and reduce late angiographic lumen loss. The reduction of the late angiographic lumen loss resulting from vascular remodelling was greater after XS0601 treatment.ConclusionBoth intimal hyperplasia and vascular remodelling are attributed to late lumen loss in this porcine coronary injury model. XS0601 markedly reduced angiographic late lumen loss resulting from intimal hyperplasia, vascular remodelling and XS0601 may be a potential agent to prevent restenosis after PCI.

LB30057, a Direct Thrombin Inhibitor, the Effect of Restenosis in Porcine Coronary Injury Model

Background and Objectives:In a previous study, LB30057 was found to inhibit smooth muscle cell proliferation in a dose dependent manner, and prolonged 14-day oral administration of LB30057 is effective in reducing the neointimal hyperplasia in a rat carotid balloon injury model. The prolonged administration of LB30057, an orally active direct thrombin inhibitor, was evaluated and found to be a potential inhibitor of restenosis in a porcine coronary injury model. Materials and Methods:An oversized balloon injury and a stent injury were given to the right coronary artery and left anterior descending artery, respectively, in the porcine model. LB30057 (50 mg/kg) or a placebo was administrated for 28 days, using an osmotic pump, starting 6 hours prior to the injury until sacrifice on the 28th day. The drug concentration and antithrombotic effects (aPTT, thrombin-anti thrombin complex levels) were measured, and a histo-morphometric analysis performed 28 days later. Results:The drug concentrations were 271±124 and 67±52 ng/mL on days 1 and 28 after injury in the drug group. The TAT (thrombin-antithrombin complex) levels were significantly lower in the drug than the control group on the 2 and 7 days after injury (p<0.05). There were no significant differences in the injury scores, and the luminal, intimal and medial areas between the two groups. Conclusion:Prolonged administration of LB30057, using an osmotic pump, was not effective in reducing the restenosis in our pig coronary injury model. (Korean Circulation J 2005;35:15-21)

Local delivery of 17β-estradiol improves reendothelialization and decreases inflammation after coronary stenting in a porcine model

In the current study, we investigated the effect of local intravascular delivery of 17beta-estradiol (17beta-E) on subsequent in-stent neointimal hyperplasia. Twenty-seven stents were implanted in coronary arteries of juvenile swine. Coronary arteries were randomized to local treatment with 17beta-E or no drug therapy (control-vehicle treated). Twenty-eight days post-treatment, angiographic images revealed an improved minimal lumen diameter (2.2 +/- 0.2 vs. 1.3 +/- 0.2 mm, P < 0.005) and a reduction of late lumen loss (1.7 +/- 0.2 vs. 2.3 +/- 0.1 mm, P < 0.01) in 17beta-E-treated vessels compared to control-vehicle treated. Histological analyses showed a reduction of stenosis (51.49 +/- 6.75 vs. 70.86 +/- 6.24%, P < 0.05), mean neointimal thickness (0.51 +/- 0.07 vs. 0.83 +/- 0.14 mm, P < 0.05) and inflammation score (1.29 +/- 0.28 vs. 2.85 +/- 0.40, P < 0.05) in 17beta-E-treated arteries compared to control-vehicle treated arteries. Immunohistochemistry analyses revealed a reduction of proliferating smooth muscle cells and increased in-stent reendothelialization in 17beta-E-treated arteries. Finally, we observed a correlation between neointimal hyperplasia and inflammation score, which in turn, was inversely related to reendothelialization. Locally delivered, 17beta-E is inhibiting the inflammatory response and smooth muscle cells proliferation and improving vascular reendothelialization which together are contributing to reduce in-stent restenosis in a porcine coronary injury model. Together, these data demonstrate the potential clinical application of 17beta-estradiol to improve vascular healing and prevent in-stent restenosis.

Comparison of the Cobalt Alloy and Stainless Steel Core® Stent in a Porcine Coronary Restenosis Model

Background and Objectives:The stent material and thickness may influence the rate of restenosis following coronary artery stenting. A thin strut cobalt-alloy stent has been developed in an attempt to reduce the restenosis rate, while maintaining the radiopacity and radial strength. The purpose of this study was to compare a stainless steel Core stent (thickness: 90 μm/HUMED Co. Ltd, Korea) with that of a cobalt alloy Core stent (thickness: 60 μm/HUMED Co. Ltd, Korea) in a porcine coronary stent restenosis model. Materials and Methods:The cobalt alloy (Co-alloy) and stainless steel (SS) stents were implanted in 24 porcine coronary arteries. Four weeks after stenting, the pigs were sacrificed after quantitative coronary angiography (QCA). The coronary arteries were perfusion-fixed and stained, and a pathological examination performed by computer-aided histomorphometry. Results: The minimal luminal diameter at 4 weeks was larger in the Co-alloy than the SS group according to the QCA (1.8±0.8 mm vs. 2.7±0.8 mm, p=0.019). The neointimal area was significantly smaller in the Co-alloy than the SS group (1.96±0.68 mm vs. 0.89±0.27 mm, p<0.001). The intima/media area ratio was significant lower in the Co-alloy than the SS group (1.33±0.46 vs. 0.69±0.21, p=0.003). Conclusion:The thin strut cobalt alloy Core stent significantly reduces the neointimal formation compared to the stainless steel Core stent in a porcine coronary stent injury model. (Korean Circulation J 2005;35:507-512)

Intramural delivery of recombinant apolipoprotein A-IMilano/phospholipid complex (ETC-216) inhibits in-stent stenosis in porcine coronary arteries.

We have previously demonstrated vasculoprotective effects after repeated intravenous administration of recombinant apolipoprotein A-IMilano (apoA-Im)/phospholipid complex. In this study, we sought to determine the effects of local recombinant apoA-Im/1-palmitoyl,2-oleoyl phosphatidylcholine complex (ETC-216) delivered intramurally via the Infiltrator catheter on luminal narrowing in a porcine coronary artery stent overstretch injury model. In twelve domestic swine ( approximately 25 kg), two arteries each were infiltrated with 0.4 mL ETC-216 (14 mg/mL) or vehicle control immediately before deployment of GFX stents (stent:artery ratio=1.3:1). Animals were euthanized at day 28, and evaluation by QCA revealed a significant improvement in mean lumen loss index with ETC-216 treatment (21+/-22% versus 43+/-13% lumen loss; P=0.01). Histomorphometric analysis showed that ETC-216 treatment significantly reduced the intimal area (6.7+/-1.5 versus 5.2+/-1.4 mm2, -22%; P=0.02) and the stenosis index (0.76+/-0.15 versus 0.59+/-0.15; P=0.01), and increased the lumen area (2.1+/-1.4 versus 3.7+/-1.8 mm2, +76%; P=0.02). Regression analysis showed significant differences in lumen area (P=0.004), neointimal area (P=0.003), stenosis index (P=0.001), and neointimal thickness (P=0.003) adjusted for injury score in favor of ETC-216. A single intramural administration of ETC-216 significantly inhibited injury-induced luminal narrowing in the porcine stent overstretch model through reduction of intimal hyperplasia. These data show that local intracoronary delivery of ETC-216 may be useful to prevent restenosis after coronary stenting.

Inhibition of NFkappaB activation using cis-element 'decoy' of NFkappaB binding site reduces neointimal formation in porcine balloon-injured coronary artery model.

Application of DNA technology to regulate the transcription of disease-related genes has important therapeutic potential. The transcription factor NFkappaB plays a pivotal role in the transactivation of inflammatory and adhesion molecule genes, leading to vascular lesion formation. Double-stranded DNA with high affinity for NFkappaB may be introduced as 'decoy' cis elements to bind NFkappaB and block the activation of genes mediating inflammation, resulting in effective drugs for treating intimal hyperplasia. In this study, we tested the feasibility of NFkappaB decoy therapy to treat neointimal formation in a porcine coronary artery balloon injury model as a pre-clinical study. An angioplasty catheter was introduced into the left anterior descending coronary artery of the pig to cause vascular injury. First, we tested the feasibility of transfection of FITC-labeled NFkappaB decoy ODN using a hydrogel balloon catheter. Fluorescence due to NFkappaB decoy ODN could be detected throughout the medial layer. Therefore, we transfected NFkappaB decoy ODN into the balloon-injured LAD using a hydrogel catheter. Histological evaluation demonstrated that the neointimal area in the balloon-injured artery was significantly reduced by NFkappaB decoy ODN as compared to scrambled decoy ODN at 1 week after single transfection, accompanied by a significant reduction in PCNA-positive stained cells (P < 0.01). Interestingly, the reduction of ICAM-positive staining was observed, accompanied by the inhibition of migration of macrophages. Of importance, intravascular ultrasound (IVUS) confirmed that neointimal area in the balloon-injured artery was significantly reduced by NFkappaB decoy ODN at 4 weeks after transfection (P < 0.01). Interestingly, the inhibition of neointimal area was only limited to the lesion transfected with NFkappaB decoy ODN, while other lesions without NFkappaB decoy ODN demonstrated a marked increase in neointimal formation. Here, we report the successful in vivo transfer of NFkappaB decoy ODN using a hydrogel catheter to inhibit vascular lesion formation in balloon-injured porcine coronary artery.

Effectiveness of radioactive tungsten source in the prevention of restenosis in stented porcine coronary arteries

Purpose : Intracoronary radiation has shown the potential to inhibit neointimal proliferation in porcine models of restenosis. The objective of this study was to determine whether intracoronary radiation using a new coiled wire of tungsten-188 ( 188W), a pure β emitter (half-life 69.4 days) is safe. In addition, a dose of 0 Gy, 18 Gy, or 25 Gy prescribed to 2 mm from the center of the source and delivered intraluminally is sufficient to prevent restenosis and free from adverse effects. Methods and Materials : Ten domestic swine underwent 13-mm stent implantation (SI) into two arteries, left anterior descending plus either the left circumflex or right coronary artery. After SI, a closed-end lumen radiation catheter was inserted to the treated artery and a 40-mm coiled 188W source was manually delivered to cover the stented segment and its margins. A total of 20 arteries were randomized to treatment with a radiation dose of 0, 18 Gy, or 25 Gy delivered to 2 mm depth from the center of the source. Four weeks after the procedure, the swine underwent angiography and intravascular ultrasound using automated pullback at 0.5 mm/s. before being killed and the arteries perfusion fixed. Histopathologic and histomorphometric analyses were performed at 28 days after injury and radiation. Results : Irradiation with 188W at a dose of 25 Gy after SI significantly inhibited neointima formation (intimal area: 1.05 ± 0.64 vs. 2.75 ± 0.99 mm 2, p < 0.01) and at an 18 Gy dose of radiation (intimal area: 1.73 ± 0.49 vs. 2.75 ± 0.99 mm 2), as compared to controls. One artery receiving 18 Gy and two arteries receiving 25 Gy were totally occluded at follow-up due to thrombus formation but no edge stenosis was observed in any of the irradiated arteries. Conclusions : Intracoronary radiation therapy using a new coiled wire of 188W source delivered after SI appeared to be safe and well tolerated. The radiation doses demonstrated efficacy in reducing neointima formation in the porcine coronary stent injury model.

Molecular strategy using cis-element 'decoy' of E2F binding site inhibits neointimal formation in porcine balloon-injured coronary artery model.

Transcription factor E2F plays a pivotal role in the transactivation of cell cycle regulatory genes, leading to vascular lesion formation. Double-stranded DNA with high affinity for E2F as 'decoy' cis elements may block the activation of genes mediating the cell cycle, resulting in an effective therapeutic agent for treating intimal hyperplasia. In this study, we tested the feasibility of E2F decoy therapy to treat neointimal formation in a porcine coronary artery balloon injury model. An angioplasty catheter was inserted in the left anterior descending coronary artery of pigs to cause vascular injury. Initially, we tested the feasibility of transfection of FITC-labeled E2F decoy ODN using a hydrogel balloon catheter. Fluorescence due to E2F decoy ODN could be detected throughout the medial layer. Therefore, we transfected E2F decoy ODN into the balloon-injured artery using hydrogel catheter. Of importance, intravascular ultrasound (IVUS) and histological evaluation demonstrated that plaque area in the balloon-injured artery was significantly reduced by E2F decoy ODN compared with mismatched decoy ODN at 1 month after a single transfection (P < 0.01). In contrast, luminal and total vessel areas were significantly increased in vessels treated with E2F decoy ODN as compared with mismatched decoy. Endothelial function after angioplasty was not affected by E2F decoy transfection. Finally, we tested the acute toxicity of E2F decoy ODN in monkeys, and no apparent side-effects were detected. Here, we report the successful in vivo transfer of E2F decoy ODN using a hydrogel catheter to inhibit vascular lesion formation in balloon-injured porcine coronary artery without any apparent side-effects.

Local delivery of nitric oxide from an eluting stent to inhibit neointimal thickening in a porcine coronary injury model.

To assess the effect of a NO-eluting stent on reducing neointimal thickening in a porcine coronary artery stent injury model, sodium nitroprusside (SNP), a NO donor, was incorporated into polyurethane (PU) polymer and coated onto metallic coil stents, and two types of stents with thin and thick barrier coatings were characterized. In vivo biological activity of the NO-eluting stents was assessed by measurement of coronary arterial cGMP levels in 32 pigs/64 arteries at days 1, 2, 7 and 14. Morphometric analyses were performed in 16 pigs to determine the effect of NO-eluting stents on neointimal hyperplasia 28 days following arterial injury. The SNP-coated stents released NO in a controlled manner for up to 4 weeks in the in vitro experiments and an increase in local tissue cGMP levels was demonstrated for up to 14 days. The neointimal area at 28 days was not diminished, however, by NO eluded from either stents of thin or thick barriers (control bare stent - 0.66 mm2, control PU stent - 0.68 mm2, SNP-PU thin coating stent - 0.78 mm2, SNP-PU thick coating stent - 0.85 mm2; all p=NS). In conclusion, the SNP-coated polymer stent exerted a local biological effect on the arterial wall, with sustained elevation of cGMP level. Although local delivery of NO from this device did not reduce neointimal hyperplasia in this porcine model, this polymer-coated stent might be a promising tool for administration of other agents that may modify the reparative tissue responses leading to restenosis.