In-stent Neointimal Growth Research Articles

Provinols™, a Polyphenolic Extract of Red Wine, Inhibits In-Stent Neointimal Growth in Cholesterol-Fed Rabbit.

Background/Objectives: Epidemiological studies indicate a potential correlation between the consumption of polyphenols and a reduced risk of developing cardiovascular disorders. The present study investigates the potential of a red wine polyphenol oral extract, Provinols™, to reduce neointimal hyperplasia following angioplasty in a hypercholesterolemic rabbit model. Methods: New Zealand white rabbits were fed 1% cholesterol-enriched chow for a period of eight weeks prior to the induction of iliac balloon injury and subsequent stent placement. Following the implantation of the stent, Provinols™ (20 mg/kg/day) or an identical placebo was administered orally for a period of four weeks in a randomized manner. Twenty-eight days following the stenting procedure, the arteries were harvested after euthanasia and subjected to histology assignment analysis. Results: The administration of Provinols™ did not result in a statistically significant change in either blood pressure or plasma cholesterol levels. However, Provinols™ treatment led to a notable reduction in the growth of the intima within the stented area, as well as a reduction in the thickness and surface area of the intima. It is of note that treatment with Provinols™ was associated with a reduction in the accumulation of fat within the arteries and a diminished inflammatory response to injury. Conclusions: The findings demonstrate that oral administration of Provinols™ has the potential to reduce in-stent neointimal growth and lipid deposition, likely due to its anti-inflammatory properties in iliac arteries from hypercholesterolemic rabbits. Additionally, these findings provide an evidence-based rationale for the potential therapeutic benefits of plant-derived polyphenols in the prevention of restenosis associated with stent placement.

Angioscopic evaluation after venous stents

BackgroundVenous stenting is increasingly used to manage femoro-ilio-caval venous outflow obstruction/stenosis due to post-thrombotic syndrome. Although the safety, efficacy, and long-term patency of venous stents have been reported, re-interventions due to stent occlusion and in-stent restenosis (ISR) have also been reported. The mechanism of ISR and the in-stent neointimal growth after venous stenting remains unclear. We performed angioscopy to evaluate intraluminal details after venous stenting, allowing real-time direct visualization of the vessel lumen. MethodsTen angioscopic procedures in four patients with post-thrombotic syndrome were performed. All evaluated vessels were stented iliac veins, and their native pathology was chronic post-thrombotic occlusion. Nine procedures in three patients underwent serial evaluation of the neointimal changes after stent implantation to study the natural time course of neointimal proliferation/coverage over the stent. The serial follow-up angioscopic evaluations were performed at the end of the venous stent deployment procedure, and at 6 months, 12 months, and 24 months. One procedure was performed 1 month after the stent implantation to evaluate ISR, which was observed at the first month of routine stent surveillance. A 5.7F angioscope was used to visualize the target veins. Continuous irrigation was used to displace blood and clear the visual field. ResultsAt 6 months after stent implantation, stent struts were covered by a thin neointima in two of the three patients. The struts were partially covered in one patient, but there was little neointimal growth overall. Neointimal coverage increased over time, and at 12 months stent struts in 2 patients were almost completely covered. There was no significant change between the 12 and 24 months after stent implantation. In the ISR case, angioscopy demonstrated an overgrown thickened neointima, and the stent struts were fully embedded and invisible in the entire stented area. No thrombus and no webs or trabeculae were found in the area evaluated as an ISR lesion. ConclusionsAt 6 months after stent placement, the stent struts were almost covered by a neointima. The stent struts were completely covered 1 year after stent implantation. Neointimal coverage was unchanged from the 1-year follow-up to the 2-year follow-up, suggesting that neointimal proliferation proceeded gradually with subsequent neointimal remodeling up to 1 year. The cause of ISR might be the overgrown thickened neointima rather than the formation of thrombosis.

TCT-362 Relation between renal function and neointimal tissue characteristics after drug-eluting stent implantation: virtual histology-intravascular ultrasound analysis

Introduction: Patients with chronic kidney disease (CKD) had more mortality, myocardial infarction, repeat revascularization, and bleeding complication after percutaneous coronary intervention compared with those with patients with normal renal function. Hypothesis: It has been suggested that renal insufficiency may predict cardiovascular events due to an association with more severe coronary artery disease. However, few data are available about neointimal tissue characteristics according to the renal function after drug-eluting stent (DES) implantation. Therefore, the purpose of the present study was to attempt to assess the neointimal tissue components between patients with CKD and those without CKD using virtual histology-intravascular ultrasound (VH-IVUS). Methods: We compared neointimal tissue components between patients with CKD [n=19, estimated creatinine clearance (CrCl) Results: Mean follow-up durations between DES implantation and follow-up VH-IVUS study were 12.0±4.1 months in CKD group and 11.4±5.6 months in non-CKD group ( p = 0.519). At follow-up, neointima volume was significantly greater (72±47 mm 3 vs. 47±26 mm 3 , p p = 0.012) in CKD group compared with non-CKD group. There was negative correlation between CrCl and neointima volume ( r = -0.250, p r = -0.034, p = 0.591). Only independent predictor of follow-up %neointima NC volume ≥10% was neointima volume (odds ratio 1.025, 95% confidence interval 1.013-1.036, p Conclusions: Renal function was associated with in-stent neointimal growth, but it was not associated with neointima NC formation, instead the amount of neointima was associated with more neoatherosclerosis in patients who underwent DES implantation.

Relation between renal function and neointimal tissue characteristics after drug-eluting stent implantation: Virtual histology-intravascular ultrasound analysis

BackgroundFew data are available about neointimal tissue characteristics after drug-eluting stent (DES) implantation in patients with decreased renal function. We used virtual histology-intravascular ultrasound (VH-IVUS) to assess the neointimal tissue characteristics according to the baseline renal function. MethodsWe compared neointimal tissue components between patients with chronic kidney disease (CKD) [n=19, estimated creatinine clearance (CrCl) <60mL/min] and those without CKD (n=229). The region of interest was placed between the luminal border and the inner border of the stent struts and tissue components were reported as percentages of neointimal volume. ResultsMean follow-up durations between DES implantation and follow-up VH-IVUS study were 12.0±4.1 months in the CKD group and 11.4±5.6 months in the non-CKD group (p=0.519). At follow-up, neointima volume was significantly greater (72±47mm3 vs. 47±26 mm3, p<0.001) and %neointima necrotic core (NC) volume was significantly greater (25.0±11.4% vs. 17.9±10.2%, p=0.012) in the CKD group compared with the non-CKD group. There was negative correlation between CrCl and neointima volume (r=−0.250, p<0.001), however, there was no significant correlation between CrCl and %neointima NC volume (r=−0.034, p=0.591). The only independent predictor of follow-up %neointima NC volume ≥10% was neointima volume (odds ratio 1.025, 95% confidence interval 1.013–1.036, p<0.001). ConclusionsRenal function was associated with in-stent neointimal growth, but it was not associated with neointima NC formation. Instead, the amount of neointima was associated with more neoatherosclerosis in patients who underwent DES implantation.

TCT-467: Quantitative OCT Analysis of In-stent Neointimal Growth after Implantation of ABSORB™ BVS in a Diabetic Animal Model

TCT-467: Quantitative OCT Analysis of In-stent Neointimal Growth after Implantation of ABSORB™ BVS in a Diabetic Animal Model

Cytokines release inhibition from activated monocytes, and reduction of in-stent neointimal growth in humans

ObjectiveAtherosclerosis and restenosis are largely ruled by inflammation. The aim of this study was to test the effects of a short-course, high-dose oral prednisone on the release of interleukin-6 (IL-6) and tumour necrosis factor (TNF)-α from circulating monocytes and on the neointimal growth that follows bare metal stent (BMS) implantation. In a sub-group of patients activated NF-κB was also evaluated. MethodsOut of 40 patients with coronary artery disease treated with BMS implantation, 20 were randomly assigned to receive oral prednisone during 40 days according to a standardized protocol. In non-stimulated and stimulated (LPS and PMA) monocytes we evaluated the release of IL-6 and TNF-α, and NF-κB p50 subunit translocation at baseline, at 10 and 30 days. Late luminal loss (LLL) 9 months after angioplasty was calculated by quantitative coronary angiography. ResultsPlasma concentrations of prednisone correlated inversely with IL-6 and TNF-α release (R2=0.45, p=0.04 and R2=0.69, p=0.005, respectively) and NF-κB activation from monocytes (R2=0.58, p=0.01). The reduction of TNF-α release and NF-κB activation were significantly related (R2=0.56, p=0.01). Prednisone patients showed a significantly larger reduction of cytokine release and NF-κB activation compared to non-treated patients, at 10 days and 30 days. LLL was lower in the prednisone group (0.44±0.35mm versus 0.80±0.53mm, p=0.02) and correlated with reduction of TNF-α (R2=0.41, p=0.01). ConclusionsHigh doses of oral prednisone reduce NF-κB pathway activation and pro-inflammatory cytokine release in circulating activated monocytes of patients treated with coronary stenting. TNF-α release reduction correlates with decreased LLL.

TCT-493: Cytokine Release Inhibition From Activated Monocytes, and Reduction of In-Stent Neointimal Growth in Humans

TCT-493: Cytokine Release Inhibition From Activated Monocytes, and Reduction of In-Stent Neointimal Growth in Humans

From Systemic Shotgun to Site-Specific Nanoparticle-Targeted Delivery

Since the introduction of percutaneous techniques for the relief of symptomatic obstructive atherosclerotic coronary artery disease in the late 1970s, the major Achilles heel was restenosis. After nearly 3 decades of study, the cellular and molecular biology of this complex response to injury is now far better understood and includes the role of thrombosis, cellular proliferation, inflammation, matrix production, and elastic recoil.1,2 Some 15 years ago there was enthusiastic interest in the concept of “site specific” or “direct delivery” of antiproliferative or anticoagulant therapies.3–6 Edelman et al reported on the inhibition of SMC proliferation after vascular injury by surgical placement of heparin-impregnated polymer matrix in the periadventitial tissue of rat carotid arteries.3 At that time a catheter-based porous balloon catheter became available for “site specific” delivery7 but failed to be effective in limiting restenosis in an atherosclerotic rabbit femoral artery injury model.4 Although labeled heparin could be demonstrated to be present in the injured vessel wall, retention time of the drug and potential additional injury created by a jet effect of the porous balloon catheter were cited as potential explanations for the lack of efficacy. Subsequently, the concept of local delivery remained dormant and a multitude of clinical trials using systemically administered pharmacological agents to reduce or prevent restenosis demonstrated no benefit.8 See accompanying article on page 1960 In the late 1980s and early 1990s, coronary stents, providing the necessary scaffolding to prevent elastic recoil become the new standard for the percutaneous treatment of obstructive …

Site-Specific Targeting of Nanoparticle Prednisolone Reduces In-Stent Restenosis in a Rabbit Model of Established Atheroma

TRM-484 is a novel drug consisting of nanoparticles of prednisolone with high affinity to chondroitin sulfate proteoglycans (CSPGs). This may allow for neointimal suppression via directed targeting to areas of injury at systemic concentrations low enough to avoid adverse side effects known to occur with oral delivery of steroids. Atherosclerotic New Zealand white Rabbits were implanted with bare metal stents and randomized to receive intravenous TRM-484 at doses of 1 mg/kg or 0.32 mg/kg starting at the day of stenting and continuing 3 times a week for the duration of the study. Control animals received empty liposomes (placebo) or saline infusion. Stented arterial segments were harvested at 42 days and processed for histomorphometry and immunohistochemistry. Tissue and plasma levels were determined along with confocal microscopic analysis to determine distribution of rhodamine-labeled TRM-484 at various time points. TRM-484 was exclusively observed at sites of stent-induced injury, with absence of drug in contralateral nonstented arteries. Tissue concentration of stented arteries exceeded that of contralateral nonstented arteries by 100-fold 24 hours after administration of 1 mg/kg TRM-484 and resulted in significant reduction of percent stenosis compared to saline and placebo treated rabbits (22.5+/-4.4 versus 31.0+/-8.4 and 29.5+/-8.1%, P<0.03). TRM-484 at doses of 1 mg/kg resulted in significant suppression of in-stent neointimal growth in atherosclerotic rabbits. Site-specific targeting by this nanoparticle steroid in injured atherosclerotic areas might be a valuable and cost-effective approach for the prevention of in-stent restenosis.

Pioglitazone Inhibits In-Stent Restenosis in Atherosclerotic Rabbits by Targeting Transforming Growth Factor-β and MCP-1

Although emerging data from preclinical and clinical studies suggests a reduction of in-stent restenosis with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, the reduction of neointimal growth via anti-inflammatory mechanisms has not been explored. Hypercholesterolemic New Zealand White rabbits (n=45) received bilateral balloon-expandable stents implanted into atherosclerotic iliac arteries. Animals were randomized to oral pioglitazone 3 (low dose) or 10 mg/kg per day (high dose) started on the day of stent implantation; control rabbits received placebo. Tissue harvest was performed 28 days after stenting, and stented segments underwent histology, morphometry, immunostaining for macrophages, and scanning electron microscopy. In selected animals, stented arterial segments were placed in organoid culture for 48 hours, and the conditioned media was assayed for 23 different cytokines. There was a 21% reduction in neointimal area for high-dose pioglitazone treated versus placebo rabbits (P<0.005), which was associated with a significant reduction of neointimal macrophages. Analysis of conditioned media revealed an 82% and 74% reduction in the release of monocyte chemoattractant protein-1 (MCP-1) (P<0.007) and transforming growth factor (TGF)-beta1 (P<0.01), respectively, in stented segments from animals treated with 10 mg/kg per day pioglitazone versus placebo. Oral pioglitazone suppresses in-stent neointimal growth by limiting local inflammatory pathways and may be useful as an adjunctive therapy in patients undergoing percutaneous interventions.

Optimal dosing and duration of oral everolimus to inhibit in-stent neointimal growth in rabbit iliac arteries

Everolimus is an orally active derivative of sirolimus. Oral administration of rapamycin is efficacious in the reduction of neointima formation and clinical restenosis; however, its optimal dose and duration have not been determined. New Zealand White rabbits were divided into three groups. The first (low-dose) group received 1.5 mg/kg everolimus 1 day before stenting, followed by 0.75 mg/kg/day everolimus for 28 days. The second (high-dose) group received 6 mg/kg everolimus 1 day before, on the day of, and on the day after stenting, followed by 2 mg/kg/day for 4 days. The third (placebo) group received a matching volume of vehicle similar to that of Group 2. Twenty-eight days after stenting, animals were euthanized and morphometry was performed. In the high-dose group, circulating everolimus levels corresponded with administrated dose levels; by Day 12, no circulating everolimus could be detected. In the low-dose everolimus group, levels remained constant up to 28 days. When compared with placebo, low-dose everolimus was associated with a significant reduction in medial thickness (32%), neointimal area (60%), and percent stent stenosis (33%); however, high-dose everolimus had no significant effect. In conclusion, oral everolimus suppresses in-stent neointimal growth in rabbit iliac arteries. Four weeks of low-dose everolimus is more effective than 7 days of high-dose everolimus.

Preinterventional peak monocyte count and in-stent intimal hyperplasia after coronary stent implantation in human coronary arteries

The mechanism of restenosis after stent implantation principally is neointimal hyperplasia. There is evidence that monocytes play a important role in in-stent restenosis (ISR) after stent implantation. This study assessed the relationship between preinterventional peak monocyte count and neointimal growth after successful stent implantation. We performed coronary stent implantation in 85 patients (85 de novo lesions). Peripheral blood sample was obtained in all patients every 12 h before coronary angiography for measurement of peripheral monocytes. All patients received angiographic and intravascular ultrasound (IVUS) follow-up at 6 months after stenting. The preinterventional circulating monocyte count was significantly higher in the ISR group than that in the group without ISR (654 +/- 62/vs. 461 +/- 222/mm3, p < 0.001) and was significantly higher in the reintervention group than that in the no-reintervention group (660 +/- 72/ vs. 470 +/- 216/mm3, p< 0.001). The incidence of ISR and repeat intervention associated with preinterventional monocyte count was highest among the patients in the highest tertile, who were at a 2.64-fold increased risk of ISR and 3.22-fold increased risk of repeat intervention compared with the patients in the lowest tertile. A significant positive correlation was found between preinterventional peak monocyte count and preinterventional plaque and media cross-sectional area and follow-up neointima area (r = 0.311, p = 0.007, r = 0.465, p < 0.001, respectively). The neointima area associated with preinterventional monocyte count was largest among the patients in the highest tertile, that is, 2-fold larger than that of the patients in the lowest tertile (p < 0.001) and 1.44-fold larger than that of the patients in the middle tertile (p = 0.001). Our results suggest that circulating preinterventional monocytes play a principal role in the process of in-stent neointimal growth after successful stent implantation.

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Editorial Comment: Reduction in Calcineurin Inhibitor Exposure and Maintenance of Effective Immunosuppression: Clinical Experience with Everolimus (Certican)

Oral rapamycin to prevent human coronary stent restenosis: A pilot study

Background Recent human trials with rapamycin-eluting stents have shown very low restenosis rates. However, the high costs of these devices preclude their use in routine angioplasty, especially when considering multiple stenting. We evaluated whether orally administered rapamycin inhibits in-stent neointimal growth in patients with unstable angina. Methods We enrolled 15 patients successfully treated with the implantation of a single stent in a single de novo lesion in native coronary arteries. Correct stent expansion and apposition were corroborated with intravascular ultrasound scanning in all patients. Patients received aspirin, clopidogrel, and atorvastatin for 6 months. Rapamycin was administered in a loading dose of 5 mg, followed by 2 mg/day for 4 weeks. Results The reference diameter was 3.4 ± 0.4 mm, lesion length was 11.2 ± 2 mm, lesion type B1 was 36%, and lesion type B2 was 64%. After the procedure, in-stent minimal lumen diameter and diameter stenosis (DS) were 3.3 ± 0.4 mm and 0.3% ± 7.5%, respectively. At 10 days, plasma levels of rapamycin were 7.95 ± 2.6 ng/mL. At 6 months, angiographic determinations demonstrated an in-stent minimal lumen diameter of 2 ± 1 mm, an in-stent DS of 41.3% ± 28.0%, and an in-stent late loss of 1.4 ± 1.1 mm. Binary restenosis (>50% DS) was present in 6 of 15 patients (40%). Target lesion revascularization (coronary artery bypass grafting) was performed in 2 of 15 patients (13.3%). There were no serious adverse events during the 6-month period of follow-up, but 1 patient had severe heartburn caused by esophagitis, and another patient had herpes zoster at the end of the protocol. Conclusions Oral rapamycin was well tolerated, but did not suppress in-stent neointimal growth in this small group of patients.

Oral everolimus inhibits in-stent neointimal growth.

Rapamycin (sirolimus)-eluting stents are associated with reduced restenosis rates in animal studies and initial human trials. The present study evaluated whether orally administered everolimus (a macrolide of the same family as sirolimus) inhibits in-stent neointimal growth in rabbit iliac arteries. New Zealand white rabbits were randomized to everolimus 1.5 mg/kg per day starting 3 days before stenting and reduced to 1 mg/kg per day from days 14 to 28 (group 1), everolimus 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days (group 2), or matching placebo for each group. Drugs were administered by oral gavage. Stents were deployed in both iliac arteries, and arteries were harvested 28 days after stenting. Group 1 everolimus-treated rabbits experienced weight loss and anorexia, which resolved after the everolimus dose was lowered on day 14. Group 2 animals were healthy for the duration of everolimus dosing. Both everolimus treatment groups significantly reduced in-stent neointimal growth (46% reduction and 42% reduction in intimal thickness in groups 1 and 2, respectively). In group 2 everolimus-treated animals, the neointima was healed or healing, characterized by stent struts covered by a thin neointima, overlying endothelial cells, and only small foci of fibrin. Scanning electron microscopy showed >80% stent surface endothelialization in group 2 everolimus-treated rabbits. Oral everolimus suppresses in-stent neointimal growth in the rabbit iliac artery. At a dose of 1.5 mg/kg given 1 day before stenting followed by 0.75 mg/kg per day for 28 days, everolimus was well tolerated and was associated with significant neointimal healing.