Effect of local delivery of L-arginine on in-stent restenosis in humans

To determine whether intramural administration of L-arginine reduces intimal thickening after optimal Palmaz-Schatz stent deployment in humans, 50 patients with native coronary artery disease who received a single Palmaz-Schatz stent were enrolled in this pilot study. Patients were randomized into 2 treatment groups: an L-arginine group (n = 25) and a saline group (n = 25). After stent deployment, L-arginine (600 mg/6 ml) or saline (6 ml) was locally delivered via the Dispatch catheter (Scimed) over 15 minutes. Serial angiography and intravascular ultrasound examinations (motorized pull-back at 0.5 mm/s) were performed before and after the procedure, and at 6-month follow-up. Measurements of stent area, lumen area, and neointimal area were computed within the stents at 1-mm intervals, by technicians who were blinded to the treatment assignment. Using Simpson's rule, stent, plaque, and lumen volumes, neointimal volume within the stent, and percent neointimal volume were measured before and after the procedure, and at 6-month follow-up. The 6-month volume data in quantitative coronary ultrasound showed that neointimal volume in the L-arginine group was significantly less than in the saline group (25 vs 39 mm(3); p = 0.049). Similarly, percent neointimal volume was significantly less in the L-arginine group at 6-month follow-up (17 +/- 13% vs 27 +/- 21%; p = 0.048). Thus, these results showed that local delivery of L-arginine reduces in-stent neointimal hyperplasia in humans, indicating that this approach may be a novel strategy to prevent in-stent restenosis.     

Atorvastatin stent coating does not reduce neointimal proliferation after coronary stenting

PURPOSE: Statins seem to be suitable for restenosis prevention via reduction of smooth muscle cell proliferation, anti-inflammatory effects, and improvement of endothelial function. The aim of the present study was to test the efficacy of an atorvastatin stent coating for restenosis inhibition in the porcine coronary stent model. METHODS AND RESULTS: Twenty stents (BiodivYsio Matrix LO, uncoated or with 56 microg atorvastatin load) were implanted in LAD and CX coronary arteries of 10 domestic pigs with an over stretch ratio of 1.25. Quantitative angiography and histomorphometry of the stented arteries asserted statistic equality of the baseline parameters between the control and treatment group. After 28 days, there was no significant difference in parameters describing in-stent restenosis (neointimal area 3.14 +/- 1.13 mm(2) [control] vs. 3.12 +/- 1.07 mm(2) [atorvastatin stent]; p = 0.978). However, there was a trend towards a lower degree of inflammation in the atorvastatin stent group. CONCLUSION: Atorvastatin stent coating showed a trend towards reduced local inflammation near the stent struts, but could not reduce neointimal formation in the porcine coronary over stretch model.     

Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model.

BACKGROUND: The long-term clinical efficacy of intracoronary stenting is limited by restenosis and delivery by the stent of agents inhibiting cell cycle progression should prevent in-stent neointimal hyperplasia. Carvedilol is an antioxidant that inhibits smooth muscle cell proliferation and migration, whereas probucol is a vascular protectant and reduces stent restenosis by improving the lumen dimension at the stent placement site. METHODS AND RESULTS: BiodivYsio phosphorylcholine-coated stents were dip-coated with carvedilol (5 mg/ml) or probucol (50 mg/ml) by immersion in respective methanol solutions. Twenty-four stents (carvedilol=8, probucol=8, control=8) were placed in 12 pigs and histopathologic analysis was done 4 weeks later. Histomorphometry of the carvedilol-coated stent group compared with the control groups showed that the neointimal area decreased by 42% (1.12+/-0.55 mm2 in the carvedilol group vs 1.92+/-0.52 mm2 in the control, p=0.004) and the lumen area increased by 20% (5.15+/-0.90 mm2 vs 4.17+/-0.87 mm2, p=0.008), resulting in a 43% reduction of the percent area stenosis (18.22+/-9.6% vs 31.9+/-9.2%, p=0.002). In the probucol-coated stent group, the lumen area, neointimal area, and %area stenosis did not different significantly from the control group. There were 7.7+/-2.97% proliferating nuclear cell antigen-positive cells in the carvedilol-coated stent group compared with 17.8+/-1.45% in the control group (p=0.0001) and 15.9+/-1.91% in the probucol group (vs control, p=NS). CONCLUSIONS: The carvedilol-coated stent, but not the probucol-coated one, inhibited neointimal hyperplasia in a porcine stent restenosis model.     

Presence of bone-marrow- and neural-crest-derived cells in intimal hyperplasia at the time of clinical in-stent restenosis

OBJECTIVE: Intralesional data of coronary target lesions following stent implantation are infrequent. In addition, there is ongoing controversy on the origin of neointimal cells. In this respect, several lines of evidence revealed bone-marrow-derived endothelial progenitor and dendritic cells (DCs) as well as neural-crest-derived cells (NCCs) to contribute to atherosclerosis. Therefore, the objective of the present study was to assess cellularity, cell type and origin of neointimal cells in in-stent restenosis (ISR). METHODS: Atherectomy specimens from 17 patients with coronary in-stent restenosis (n=10; time post-stenting 5+/-3 months) and with peripheral in-stent restenosis (n=7; 7+/-3 months) versus those from 10 patients with primary lesions were immunohistochemically examined for the presence of the determinants CD34, AC133, S100, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), nerve growth factor receptor (NGFR) and alpha-smooth muscle actin followed by computer-assisted morphometry. RESULTS: In-stent restenosis probes consistently demonstrated homogeneous hypercellularity (942+/-318 cells/mm(2)) compared to de novo lesions (347+/-120 cells/mm(2), P<0.001). alpha-smooth muscle actin positive cells occupied 67% of intimal cells in in-stent restenosis. As a key finding, expression of endothelial progenitor cells (CD34: 7.1+/-2.5% positive/total cells vs. 0.6+/-0.7%, P<0.001; AC133: 7.0+/-3.4% vs. 1.0+/-0.7%, P<0.001), dendritic cells (S100: 9.8+/-5.6% vs. 1.4+/-1.1%, P<0.001) and neural-crest-derived cells (GFAP: 7.9+/-2.4% vs. 3.1+/-1.0%; NSE: 4.4+/-2.6% vs. 1.3+/-1.6%; NGFR: 4.2+/-2.5% vs. 1.1+/-0.7%; each P<0.001) was significantly increased in in-stent restenosis compared to primary lesions. CONCLUSIONS: Bone-marrow- and neural-crest-derived cells, the most dendritic cells, are consistently present in in-stent restenosis, whereas alpha-smooth muscle actin positive cells constitute the largest intimal cell pool. Our data suggest the recruitment of primarily extravascular cells within neointima formation in human in-stent restenosis.     

Estrogen‐eluting stent implantation inhibits neointimal formation and extracellular signal‐regulated kinase activation

Objectives : The goal of this study was to evaluate the efficacy and the mechanism of 17β‐estradiol‐eluting stents on inhibiting neointimal formation of abdominal aortas in rabbits fed with high fat diet. Background : Animal experiments have shown that local delivery of estrogen reduced neointimal formation after coronary angioplasty. Preliminary trial of estrogen‐eluting stent implantation in patients with coronary disease also suggests a reduction in restenosis. Methods : We implanted 17β‐estradiol‐eluting stents, or control phosphorylcholine‐ coated stents, or bare metal stents of abdominal aortas in rabbits fed with high fat diet. Histology, immunohistochemistry, and Western blot analysis were used to assess the efficacy and mechanism of inhibiting neointimal formation of 17β‐estradiol‐eluting stents. Results : Western blot analysis revealed marked increase in ERK phosphorylation in 30 min after deployment of phosphorylcholine‐coated or bare metal stents, indicating activation of MAP kinase pathway. Immunohistochemistry showed intense staining of phospho‐ERK in the medial smooth muscle cells in stent‐implanted region. Extensive neointimal hyperplasia developed 12 weeks after stenting. In contrast, we observed significant inhibition of ERK phosphorylation and neointimal thickening in estrogen‐eluting stent‐implanted animals. Immunohistochemistry of factor VIII‐related antigen demonstrated an accelerated reendothelialization as compared with the bare metal stent or phosphorylcholine‐coated stent‐implanted controls. Conclusions : Current study suggests that estrogen‐eluting stents reduce neointimal formation and hence prevent restenosis after angioplasty possibly by inhibiting ERK activation in smooth muscle cells and promoting reendothelialization. © 2007 Wiley‐Liss, Inc.     

Low-energy gamma-emitting stents inhibit intimal hyperplasia with minimal "edge effects" in a pig coronary artery model.

PURPOSE: The objective of this study was to determine the effects of different doses of gamma-emitting radioactive stents on intimal hyperplasia in a porcine coronary stent model at 28 days. METHODS: Sixty-four bare stents and those coated with palladium-103 [activities of 0 (control), 0.5, 1.0, 2.0, and 4.0 mCi] were implanted in the coronary arteries of 32 pigs. Stented segments were evaluated by histomorphometry at 28 days. RESULTS: There was significantly more intima in the 0.5- and 1-mCi stents than in controls (4.27+/-0.52 and 4.71+/-1.13 vs. 1.71+/-0.61 mm(2); P<.0001). Neointimal formation in 2-mCi stents was similar to that in controls, while that in 4-mCi stents was reduced compared to that in controls (2.34+/-1.61 and 0.82+/-0.25 vs. 1.71+/-0.61 mm(2); P=NS and P<.05, respectively). Stent margin neointimal response was representative of that within the stent body, with nonsignficant modest increases in intimal area at adjacent nonstented segments in radioactive stent groups. There was a dose-dependent increase in inflammation scores. Radioactive stents had lower intimal smooth muscle and higher fibrin scores. There was an increase in adventitial fibrosis in 1- and 2-mCi stents versus controls (1.26+/-0.99, and 2.25+/-1.27 vs. 0.21+/-0.31; P<.001). CONCLUSION: Dose-response inhibition of in-stent hyperplasia with minimal "edge effects" occurs with low-energy gamma-emitting stents. An increased inflammatory response at higher doses in palladium-103 stents indicates that later follow-up studies are necessary.     

Particle debris from a nanoporous stent coating obscures potential antiproliferative effects of tacrolimus-eluting stents in a porcine model of restenosis.

Polymer stent coatings may not be suitable for drug elution because of inherent proinflammatory effects. A previous study suggested a beneficial effect of a stent eluting tacrolimus from a nanoporous ceramic aluminum oxide coating in a rabbit restenosis model. We investigated whether this stent is effective in preventing in-stent restenosis in a porcine restenosis model. Thirty-four juvenile swine underwent balloon overstretch injury and were subjected to implantation of either stainless steel (bare) stents, bare stents coated with nanoporous aluminum oxide alone, and coated stents eluting 50 and 180 mug of tacrolimus (FK506). In-stent restenosis was quantified at 1 and 3 months after stent placement by histomorphometry. A significant increase of neointimal hyperplasia was noted with the stents coated with aluminum oxide alone compared with bare stents (2.92 +/- 1.02 and 1.38 +/- 0.51 mm(2), respectively; P < 0.02). In all arteries containing coated stents, particle debris was found in the media and neointima, resulting in augmented vascular inflammation. In the group of stents coated with aluminum oxide, FK506 elution at a dose 180 mug reduced neointimal hyperplasia vs. no drug elution (1.66 +/- 0.49 vs. 2.92 +/- 1.02 mm(2); 180 mug vs. ceramic alone; P < 0.03). At a dose of 50 mug stent-based delivery of FK506, no reduction of neointimal hyperplasia was found (2.88 +/- 1.31 and 2.92 +/- 1.02 mm(2), respectively; P = NS; FK506 vs. ceramic alone). In summary, particle debris shed from a drug-eluting aluminum oxide coating of a stainless steel stent counteracts potential antiproliferative effects of stent-based tacrolimus delivery in a porcine model of restenosis. We propose that stent coatings eluting drugs need to be routinely tested for being tightly anchored into the stent surface. Alternatively, omission of any coating used as a drug reservoir may eliminate inflammatory particle debris after placement of drug-eluting stents.     

Paclitaxel-coated Gianturco-Roubin II (GR II) stents reduce neointimal hyperplasia in a porcine coronary in-stent restenosis model.

BACKGROUND: Drug-coated stents may treat both mechanisms of restenosis, namely, geometric remodeling and neointimal hyperplasia. Paclitaxel, an antimicrotubule agent, has been shown to inhibit smooth muscle cell proliferation and migration, and may be an excellent candidate for local elution from a stent platform. METHODS: To study the antirestenosis effects of drug-coated stents, we impregnated paclitaxel (175-200 microg/stent with programmed elution over 6 months) on Gianturco-Roubin II (GR II) stents. These stents and control stents without drugs were implanted in porcine coronary arteries (stent/artery approx. 1.1) and evaluated 4 weeks later. RESULTS: The vessel size and the stent-to-artery ratio were similar between the groups. However, at 4 weeks, the paclitaxel group had significantly reduced in-stent restenosis compared with the controls (51 +/- 27 versus 27 +/- 27% diameter stenosis, P < 0.05 and 669 +/- 357 versus 403 +/- 197 microm neointimal thickness, P < 0.05). This study further confirmed the biocompatibility of the polymer, with no foreign body reaction in any of the groups. CONCLUSIONS: This study shows that the paclitaxel-coated stents significantly reduced in-stent restenosis without eliciting inflammation.     

Oral mycophenolate mofetil prevents in-stent intimal hyperplasia without edge effect

Neointimal hyperplasia is in the forefront in in-stent restenosis. Prevention of in-stent restenosis is possible by reducing and inhibiting the hyperplasia of smooth muscle cells. The authors planned this study to test the hypothesis that when administered orally, mycophenolate mofetil (MMF) could inhibit in-stent neointimal hyperplasia. The study included 14 New Zealand rabbits. The rabbits were allocated to 2 different groups: Group 1 included 7 rabbits that were given MMF, 40 mg/kg/day by oral route. Group 2 included 7 rabbits that were not given MMF after the stenting. Sampling materials were taken before and after stenting by incising the artery so as to cover a 5-mm area. The samples taken from the edge of the stent in Group 1 showed focal neointimal cell proliferation, but it was less than that from the control group. Neointimal thickness was 0.048 +/-0.009 mm and neointimal area was 0.0925 +/-0.019 mm(2). Apparent neointimal cell proliferation and thickening of the intimal layer were observed in Group 2. Neointimal thickness at the stent edge was 0.147 +/-0.051 mm and the neointimal area was 0.154 +/-0.023 mm(2). The differences between groups in terms of neointimal thickness and neointimal area were statistically significant (p=0.001 for thickness and p=0.001 for area). In-stent artery samples of Group 1 showed that some subjects had no neointimal cell proliferation, while others had very limited focal intimal thickening. Neointimal thickening was 0.071 +/-0.003 mm and neointimal area was 0.073 +/-0.003 mm(2). In Group 2 apparent, and mostly focal, neointimal cell proliferation and formation of intimal layer were observed in the stent. Neointimal thickening was 0.154 +/-0.069 mm and neointimal area was 0.279 +/-0.059 mm(2). The comparison between groups showed significant differences (p=0.011 for thickness and p=0.001 for area). It was established in the third month that endothelialization was completed in both groups. Oral MMF decreased in-stent intimal hyperplasia without edge effect. It was concluded that for the prevention of in-stent restenosis, studies should be conducted for using systemic immunosuppressive treatments in humans as well.     

Thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in type 2 diabetic patients: an intravascular ultrasound study

OBJECTIVES: Thiazolidinedione treatment reduces neointimal tissue proliferation after coronary stent implantation in diabetic patients. However, in-stent restenosis still persists in patients treated with thiazolidinedione. The effect of thiazolidinedione treatment on the pattern of in-stent restenosis remains unclear. This study investigated whether thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in diabetic patients. METHODS: Volumetric intravascular ultrasound was performed at 6 months after coronary stent implantation in 76 patients with restenotic lesions who received either conventional anti-diabetic treatment (control group, n = 56) or thiazolidinedione treatment (thiazolidinedione group, n = 20). RESULTS: There were no significant differences between the two groups in stent volume (99 +/- 32 vs 90 +/- 20 mm3, respectively, p = 0.26) or in minimal lumen area in the stent (1.4 +/- 0.6 vs 1.6 +/- 0.5 mm2, respectively, p = 0.11). However, there were significant reductions in neointimal volume (56 +/- 25 vs 36 +/- 11 mm3, respectively, p < 0.01)and neointimal index (56 +/- 11% vs 41 +/- 8%, respectively, p < 0.01) in the thiazolidinedione group. Coefficient of variation of neointimal tissue accumulation was greater in the thiazolidinedione group (45.5%) than in the control group (25.2%). CONCLUSIONS: Intravascular ultrasound study demonstrated that together with reduction of overall neointimal tissue proliferation, thiazolidinedione treatment caused greater point-to-point heterogeneity in the neointimal tissue accumulation in restenotic lesions after coronary stent implantation. This finding strongly suggests that thiazolidinedione treatment attenuates diffuse in-stent restenosis in diabetic patients.     

Circulating monocytes and in-stent neointima after coronary stent implantation

OBJECTIVES: The aim of this study was to investigate the relationship between circulating monocytes and in-stent neointimal volume at six-month follow-up. BACKGROUND: In-stent neointimal hyperplasia is the main contributing factor to in-stent restenosis. There is increasing evidence that white blood cells (WBCs), especially monocytes, play a central role in restenosis after stent implantation. METHODS: We performed coronary stent implantation in 107 patients (107 lesions). Peripheral blood was obtained from all patients immediately before coronary angiography and every day for seven days after the intervention, and each WBC fraction count was analyzed. At scheduled six-month follow-up, all patients received angiographic and volumetric intravascular ultrasound analysis. RESULTS: The circulating monocyte count increased and reached its peak two days after stent implantation (from 350 +/- 167 to 515 +/- 149/mm3, p < 0.01). The maximum monocyte count after stent implantation showed a significant positive correlation with in-stent neointimal volume at six-month follow-up (r = 0.44, p < 0.0001). Other fractions showed neither significant serial changes nor a correlation with in-stent neointimal volume. Multiple regression analysis revealed that in-stent neointimal volume was independently correlated with stent volume immediately after implantation (r = 0.45, p < 0.0001) and maximum monocyte count (r = 0.35, p < 0.001). Angiographic restenosis, defined as percent diameter stenosis >50%, was observed in 22 patients (21%), and these patients showed a significantly larger maximum monocyte count than patients without restenosis (642 +/- 110 vs. 529 +/- 77/mm3, p < 0.01). CONCLUSIONS: Circulating monocytes increased after coronary stent implantation, and the peak monocyte count related to in-stent neointimal volume. Our results suggest that circulating monocytes play a role in the process of in-stent neointimal hyperplasia.     

First human experience with angiopeptin-eluting stent: a quantitative coronary angiography and three-dimensional intravascular ultrasound study.

Angiopeptin has been shown to reduce in-stent restenosis in various animal models. Meanwhile, BiodivYsio DD phosphorylcholine (PC)-coated stent provides a platform for local delivery of antiproliferative agents to the coronary artery. We studied the feasibility, safety, and impact on tissue growth of angiopeptin-eluting BiodivYsio DD PC-coated stents in human native de novo coronary lesions. We enrolled 14 patients (16 lesions) who underwent intravascular ultrasound (IVUS)-guided angiopeptin-eluting stent implantation in native coronary arteries between 3.0 and 4.0 mm in diameter with lesion length相似文献   

Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent

BACKGROUND: In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model. DESIGN: Randomized, blinded, prospective animal study. METHODS: Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week. RESULTS: Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days. CONCLUSION: Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.     

The effect of paclitaxel-eluting stents on restenosis]

OBJECTIVE: In our study we aimed to investigate the effects of paclitaxel-eluting stent on restenosis. METHODS: Sixteen porcine were randomly assigned to two groups (n=8 per group): control group animals received conventional stent implantation and study group animals -paclitaxel-eluting stent implantation. Both groups were treated with 300 mg acetylsalicylic acid and 75 mg clopidogrel daily. The degree of neointimal proliferation and effect of drug-eluting stent on restenosis were evaluated 6 weeks after by angiography and intravascular ultrasound (IVUS). RESULTS: Angiographic in-stent restenosis was lower in paclitaxel-eluting stent group (12.50 +/- 7.07% versus 41.25 +/- 28.50%, p=0.001). The IVUS data demonstrated that paclitaxel group animals had larger minimal lumen area (8.76 +/- 1.09 mm2 versus 6.23 +/- 3.10 mm2, p=0.028), smaller mean neointimal proliferation area (1.03 +/- 0.75 mm2 versus 3.55 +/- 2.86 mm2, p=0.01) and mean percent stenosis (10.71 +/- 8.10% versus 36.85 +/- 30.93%, p=0.01). CONCLUSION: This study suggests that drug-eluting stents may also have a preventive effect for the in-stent restenosis.     

Results of the Jostent coronary stent graft implantation in various clinical settings: procedural and follow-up results.

The Jostent coronary stent graft (CSG) is composed of a PTFE layer sandwiched between two stainless steel stents, initially introduced for the treatment of coronary perforations and aneurysms with excellent results. By providing a mechanical barrier, this stent design also may be beneficial in the treatment of complex ulcerated lesions and in-stent restenosis by preventing debris protrusion and neointimal proliferation through the stent struts. To evaluate the safety and efficacy of this stent graft, we implanted 78 CSGs in 70 patients for a broad range of indications, including coronary perforations, aneurysms, degenerated saphenous vein grafts, complex lesions, and in-stent restenosis. The primary angiographic success rate (95.9%) was high, and using intravascular ultrasound (IVUS) guidance during stent implantation and high inflation pressures (19.3 +/- 3.2 atm), stent expansion with optimal symmetry was achieved in 94.7%. One limitation of the Jostent CSG was the side-branch occlusion rate (18.6%) and the resulting non-Q-wave infarction rate in seven cases (mean CK elevation, 238 U/l), acute Q-wave MI in two cases, and transient ventricular fibrillation in one patient after occlusion of the proximal RCA side branch without further complications. Subacute stent thrombosis occurred in four cases (5.7%) 7 to 70 days after stent implantation, despite using combined antiplatelet therapy with aspirin (ASA), ticlopidine, and/or clopidogrel for 30 days. Angiographic follow-up was available in 56 patients (80.0%) after a mean of 159 +/- 49 days, and follow-up IVUS was available in 38 cases. The overall restenosis rate (> 50% diameter stenosis) was 31.6% manifest primarily as edge restenosis (29.8% stent edge vs. 8.8% stent center; P < 0.001). IVUS examinations showed a minimal late lumen loss of 0.4 +/- 2.2 mm(2) within the center of the stent graft vs. 3.2 +/- 2.3 mm(2) at the stent edges (P < 0.001). The restenosis rate in the prespecified subgroups was 33.3% for saphenous vein grafts (2/6 lesions), 30.0% in complex lesions (6/20 lesions), and 38.5% (10/26 lesions) for the treatment of in-stent restenosis. Implantation of the Jostent CSG is feasible and safe, even in complex lesion subsets, and is associated with high primary success rates provided major side branches are avoided. The use of this stent may require an extended time course of antiplatelet therapy. Frequent focal stent edge renarrowing influences the overall restenosis rate. However, in treatment of complex in-stent restenosis and vein graft lesions, stent grafts may offer benefit over conventional therapies. Covered stents such as the JoMed coronary stent graft may become essential for bailout treatment of coronary perforations.     

Intravascular ultrasound and quantitative coronary angiography assessment of late in-stent restenosis: in vivo human correlation and methodological implications.

Quantitative coronary angiography (QCA) is routinely used for assessment of strategies aimed at reducing in-stent restenosis. Yet QCA enables only the measurement of luminal variation of stented segments and, unlike intravascular ultrasound (IVUS), provides only an indirect estimation of late in-stent neointimal formation, which has a key role in the process of in-stent restenosis. The aims of the present study were to correlate the IVUS measurement of in-stent intimal hyperplasia (IH) with QCA indexes of restenosis, to find out whether QCA is an adequate surrogate of IVUS, and, using either QCA and IVUS data, to define the sample sizes needed to demonstrate the effectiveness of strategies to reduce in-stent restenosis. The database of the European Imaging Laboratory was used to screen 154 stents implanted between 1997 and 2001 and studied by IVUS at 6 +/- 1 months of follow-up. All cases underwent serial QCA assessment (preintervention, postintervention, and follow-up). Only 131 cases with single stent implantation in native coronary arteries were included in the study. Stent restenosis, defined as percent diameter stenosis (DS) > 50%, was present at QCA in 69 out of 131 cases (53%). Linear regression analyses were performed to correlate the amount of IH, calculated by IVUS as the average of all cross-section areas (CSA; mean % IH CSA) and QCA indexes of restenosis (late loss and % DS). A positive significant correlation was found between IVUS mean % IH CSA and QCA % DS (r = 0.74; P < 0.0001) and between IVUS mean % IH CSA and QCA late loss (r = 0.72; P < 0.0001). Based on IVUS measurements of mean % IH CSA, a total sample size of 74 stents would be required in a two-arm comparison to have 0.80 power to detect at 0.05 significant level a 30% difference between two compared groups. Alternatively, adopting the QCA late loss, 230 stents would be required. QCA measurements of late in-stent restenosis are well correlated with IVUS calculation of in-stent neointimal formation. IVUS assessment of IH allows smaller sample sizes than QCA to document significant reductions of in-stent restenosis. Therefore, the use of IVUS should be encouraged in comparison studies aimed at revealing significant neointimal differences in small sample size populations.     

Influence of stent design and deployment technique on neointima formation and vascular remodeling

A variety of different stent types is available for the treatment of coronary stenosis. However, in-stent restenosis remains the major limitation for the use of these devices. Intracoronary ultrasound (ICUS) in addition to coronary angiography provides precise measurements of coronary wall dimensions during stent implantation and of intimal hyperplasia during follow-up. The extent of coronary injury during stent implantation was shown to play an important role in neointima formation. It is characterized by endothelial exposure, intima laceration, and media permeation. Stent-induced coronary injury has been considered to depend on stent design and stent strut size with consecutive deep wall laceration. ICUS analysis showed a correlation between the stent design and the amount of neointimal tissue proliferation. The role of adventitial remodeling in the process of restenosis is discussed controversially. Post-procedural stent expansion may provoke adventitial remodeling. The stent design and stenting strategy determines the extent of peri- and post-procedural coronary injury. Post-procedural coronary morphologic changes and changes of the stent geometry depend upon the stent design. Beside further modifications as the use of drug-eluting stents the decrease of stent-related vessel injury should be an important criterion for the development of future stent design.     

Troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus: a serial intravascular ultrasound study

OBJECTIVES: The aim of the present study was to determine whether troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with non-insulin dependent diabetes mellitus (NIDDM). BACKGROUND: Increased in-stent restenosis in patients with diabetes mellitus is due to accelerated neointimal tissue proliferation after coronary stent implantation. Troglitazone inhibits intimal hyperplasia in experimental animal models. METHODS: We studied 62 stented lesions in 52 patients with plasma glucose levels (PG) > or = 11.1 mmol/liter at 2 h after 75 g oral glucose load. The study patients were randomized into two groups: the troglitazone group of 25 patients with 29 stents, who were treated with 400 mg of troglitazone, and the control group of 27 patients with 33 stents. All patients underwent oral glucose tolerance tests before and after their six-month treatment period. The sum of PG (sum of PG) and the sum of insulin levels (sum of IRI) were measured. Serial (postintervention and at six-month follow-up) intravascular ultrasound studies were performed. Cross-sectional images within stents were taken at every 1 mm, using an automatic pullback. Stent areas (SA), lumen areas (LA), and intimal areas (IA = SA - LA) were measured and averaged over a number of selected image slices. The intimal index was calculated as intimal index = averaged IA/averaged SA x 100%. RESULTS: There were no differences between the two groups before treatment in sum of PG (31.35 +/- 3.07 mmol/liter vs. 32.89 +/- 4.87 mmol/liter, respectively, p = 0.2998) and sum of IRI (219.6 +/- 106.2 mU/liter vs. 209.2 +/- 91.6 mU/liter, respectively, p = 0.8934). However, reductions in sum of PG at the six-month follow-up in the troglitazone group were significantly greater than those in the control group (-21.4 +/- 8.8% vs. -4.5 +/- 7.4%, respectively, p < 0.0001). Likewise, decreases in sum of IRI were greater in the troglitazone-treated group (-31.4 +/- 17.9% vs. -1.9 +/- 15.1%, respectively, p < 0.0001). Although, there were no differences between the two groups in SA at postintervention (7.4 +/- 2.2 mm2 vs. 7.3 +/- 1.7 mm2, respectively, p = 0.9482) and at follow-up (7.3 +/- 2.3 mm2 vs. 7.3 +/- 1.8 mm2, respectively, p = 0.2307), the LA at follow-up in the troglitazone group was significantly greater than that in the control group (5.3 +/- 1.7 mm2 vs. 3.7 +/- 1.7 mm2, respectively, p = 0.0002). The IA at follow-up in the troglitazone group was significantly smaller than that in the control group (2.0 +/- 0.9 mm2 vs. 3.5 +/- 1.8 mm2, respectively, p < 0.0001). This was also true for intimal index (27.1 +/- 11.5% vs. 49.0 +/- 14.4%, respectively, p < 0.0001). CONCLUSIONS: Serial intravascular ultrasound assessment shows that administration of troglitazone reduces neointimal tissue proliferation after coronary stent implantation in patients with NIDDM.     

Clinical and angiographic results of balloon-expandable intracoronary stents in right coronary artery stenoses

Balloon-expandable stents were placed successfully in 35 (95%) of 37 patients whose right coronary artery lesion was believed to have a poor short- or long-term prognosis with conventional balloon angioplasty because of prior restenosis or adverse lesion morphology. Quantitative angiography showed a reduction in stenosis diameter from 83 +/- 14% to 42 +/- 14% after conventional balloon dilation, with a further reduction to -3 +/- 12% after stent placement (p less than 0.001). There were no acute stent thromboses, but one patient (with two stents and unstented distal disease) developed subacute thrombosis on day 8 after self-discontinuation of warfarin and was treated with thrombolytic therapy and redilation. Follow-up angiography was performed at 4 to 6 months in 25 patients, demonstrating restenosis (83 +/- 13%) in 4 (57%) of 7 patients with multiple stents, but only 3 (17%) of 18 patients with a single stent (p less than 0.05). Six of the seven in-stent restenotic lesions were subtotal (80 +/- 12%) and were subjected to repeat conventional balloon angioplasty (postdilation stenosis 13 +/- 21%). The 18 patients without restenosis had a maximal in-stent diameter stenosis of 29 +/- 15%, corresponding to a maximal focal neointimal thickness of 0.68 +/- 0.26 mm within the stented segment. These preliminary results suggest that the Schatz-Palmaz stent may be a useful adjunctive device in the performance of coronary angioplasty.     

Vascular endothelial growth factor (VEGF)-eluting stents: in vivo effects on thrombosis, endothelialization and intimal hyperplasia

Local drug delivery by stent can reduce in-stent restenosis. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen. After stenting, the arterial wall is almost denuded of endothelium. This loss of endothelium contributes to the smooth muscle cell (SMC) proliferation seen in restenosis, since the endothelium actively inhibits SMC hyperplasia. Over time, the endothelium recovers and SMC hyperplasia is arrested. The capacity of VEGF-coated stents to accelerate re-endothelialization, and to therefore reduce restenosis and thrombosis, was tested in this study. Radiolabeled VEGF was absorbed onto stents and released over nine days in an in vitro perfusion circuit. VEGF-coated stents were deployed in arterial segments to study local tissue release. A New Zealand White rabbit iliac artery model for stent implantation was used. Re-endothelialization and thrombosis were assessed after seven days. Further animals were examined 28 days post-procedure for in-stent restenosis. Stented vessels were resin-embedded, sectioned and stained. Intimal thickening was calculated using computerized morphometry. In vitro, the stents released 80% of the initial load over nine days. At seven days, thrombus was significantly reduced (12.5 mg for controls versus 0 mg for VEGF; p = 0.014). No beneficial effect was seen on endothelialization, nor on intimal hyperplasia. Neointimal area was 2.2 0.9 mm2 for controls versus 2.4 1.8 mm2 for VEGF (p = 0.8). These VEGF-eluting stents do not accelerate re-endothelialization or inhibit restenosis. Stent thrombosis appears to be reduced, which may make these stents less thrombogenic and be valuable in higher-risk cases.