sirolimus and Constriction--Pathologic

Several randomized controlled trials (RCTs) have shown the superiority of some of these technologies over balloon angioplasty, but direct comparisons between these treatment options are lacking. The authors conducted a network meta-analysis of RCTs comparing bare nitinol stents, covered nitinol stents, paclitaxel- or sirolimus-eluting stents (PES or SES), and paclitaxel-coated balloons (PCB) with plain balloon angioplasty or with each other in the femoropopliteal artery (PROSPERO registry: CRD42013004845).. Sixteen RCTs comprising 2532 patients with 4227 person-years of follow-up were analyzed on an intention-to-treat basis. Bayesian random effects Poisson and binomial models were used for mixed treatment comparisons (WinBUGS). Clinical heterogeneity was accounted for by incorporating a meta-regression model on trial-specific baseline risk. End points included technical success, vascular restenosis, target lesion revascularization, and major amputations. Pairwise odds ratios and rate ratios (ORs and RRs) of absolute treatment effects were calculated, and the probabilities of each treatment being best are reported. Summary estimates are reported as the posterior median and associated credible intervals (CrIs) that serve the same purpose as confidence intervals in the context of the Bayesian framework. Extensive sensitivity, meta-regression, and network consistency analyses were performed to evaluate heterogeneity.. Technical success was highest with covered stents (pooled OR, 13.6; 95% CrI, 3.3-31.1, probability best 82%) followed by uncovered stents (pooled OR, 7.0; 95% CrI, 2.6-129, probability best 18%) when compared with balloon angioplasty (reference treatment). Vascular restenosis was lowest with PES (RR, 0.43; 95% CrI, 0.16-1.18, probability best 45%) followed by PCB (RR, 0.43; 95% CrI, 0.26-0.67, probability best 42%). Target lesion revascularization was lowest with PCB (RR, 0.36; 95% CrI, 0.23-0.55, probability best 56%) followed by PES (RR, 0.42; 95% CrI, 0.16-1.06, probability best 33%). Major amputations were rare in all treatment and control groups (pooled amputation rate of 0.7 events per 100 person-years).. Immediate technical success is better with the use of covered stents, whereas paclitaxel-eluting stents and paclitaxel-coated balloons offer the best long-term results in the femoropopliteal artery.

Topics: Alloys; Amputation, Surgical; Angioplasty, Balloon; Bayes Theorem; Cardiovascular Agents; Coated Materials, Biocompatible; Constriction, Pathologic; Drug-Eluting Stents; Equipment Design; Femoral Artery; Humans; Limb Salvage; Odds Ratio; Paclitaxel; Peripheral Arterial Disease; Popliteal Artery; Prosthesis Design; Randomized Controlled Trials as Topic; Recurrence; Risk Factors; Sirolimus; Stents; Treatment Outcome; Vascular Access Devices

Topics: Angioplasty; Animals; Clinical Trials as Topic; Coated Materials, Biocompatible; Constriction, Pathologic; Drug-Eluting Stents; Endothelium, Vascular; Humans; Lactic Acid; Metals; Polyesters; Polymers; Postoperative Complications; Sirolimus

This manuscript reviews the controversy regarding the role of intravascular brachytherapy in the setting of growing use of drug eluting stents. The utility of intravascular brachytherapy is being rethought in relation to its use after the placement of drug eluting stents. Even with in-stent stenosis, the role of intravascular brachytherapy is decreasing primarily due to the simplicity of placement of drug eluting stents and the complexity of performing intravascular brachytherapy.. The impact of drug eluting stents is already decreasing the clinical impact of in-stent stenosis. The published pivotal clinical restenosis rates from both the Pacitaxil (TAXUS IV) and Sirolimus (SIRIUS) drug eluting stents suggests that the need to perform intravascular brachytherapy will be in fewer than one in 20 patients. Recently reported registry data from Europe and the United states demonstrates the equivalence drug eluting stent implantation to intravascular brachytherapy for in-stent stenosis of bare metal stents. The role of intravascular brachytherapy for in-stent stenosis of drug eluting stents is very much in question.. This manuscript reviews the impact of Drug Eluting Stents in the practice of interventional cardiology and suggests that the need for intravascular brachytherapy will significantly decrease. Whether we will need this therapy at all is very controversial.

Topics: Angioplasty, Balloon, Coronary; Brachytherapy; Constriction, Pathologic; Humans; Paclitaxel; Sirolimus; Stents

Drug-coated balloon (DCB) angioplasty with paclitaxel-eluting devices is an established treatment for coronary in-stent restenosis (ISR). Biolimus A9™ (BA9), a sirolimus analogue with enhanced lipophilicity, may facilitate enhanced local drug delivery into vascular tissue. A novel DCB coated with Biolimus A9™ represents an alternative to traditional paclitaxel- and sirolimus-coated devices. Hence, we sought to investigate the safety and efficacy of this novel DCB in the treatment of coronary ISR.. REFORM (NCT04079192) is a prospective, multicenter, single blind, randomized controlled trial comparing the BA9-DCB (Biosensors Europe SA, Morges, Switzerland) to the paclitaxel-coated SeQuent® Please DCB (Braun Melsungen AG, Germany) in the treatment of coronary ISR. A total of 201 patients with coronary artery disease and an indication for interventional treatment of ISR in a bare-metal stent (BMS) or drug-eluting stent (DES) have been randomized 2:1 to receive treatment with the BA9- or the paclitaxel-DCB comparator. Patients were enrolled across 24 investigational centers in Europe and Asia. The primary endpoint is percent diameter stenosis (%DS) of the target segment as assessed by quantitative coronary angiography (QCA) at 6 months. Key secondary endpoints are in-stent late lumen loss, binary restenosis, target lesion failure, target vessel failure, myocardial infarction and death at 6 months. Subjects will be followed for 24 months from enrolment.. The REFORM trial will seek to prove that the BA9-DCB is non-inferior to the standard paclitaxel-DCB comparator in the treatment of coronary ISR with respect to %DS at 6 months and has similar safety characteristics.

Topics: Cardiovascular Agents; Coated Materials, Biocompatible; Constriction, Pathologic; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Humans; Paclitaxel; Pharmaceutical Preparations; Prospective Studies; Single-Blind Method; Sirolimus; Treatment Outcome

The aim of this pilot clinical study is to evaluate the safety and efficacy of the. This is an investigator-initiated prospective single-center, non-blinded single-arm trial. Forty patients with clinically significant de novo or recurrent stenoses in a mature AVF circuit will be recruited. All stenotic lesions will be prepared with high pressure non-compliant conventional balloon angioplasty (CBA) prior to deployment of the Sustained-Release Selution™ sirolimus drug-eluting balloon. The primary efficacy endpoint is 6-month target lesion primary patency and the primary safety endpoint is freedom from localized or systemic serious adverse events through 30 days. Secondary endpoints of interest include technical and clinical success rates and circuit access patency at 3 and 6 months. Follow-up will occur for 2 years for those patients whose AVFs remain patent. Pharmacokinetic and histological animal safety studies performed with the Selution™ coating formulation showed prolonged arterial tissue retention of sirolimus with therapeutic levels up to 60 days and non-toxic and rapidly declining blood levels. Histological results in animal models demonstrated safety, freedom from intraluminal thrombus, reduction in restenosis by sirolimus elution compared to CBA, and no evidence of embolic phenomena indicative of adverse particulate effects.. Long release sirolimus coated balloons may serve as a promising novel alternative therapy to paclitaxel-based technology for treating conduit stenosis secondary to neointimal hyperplasia. Pre-clinical pharmacokinetic and histological animal data are encouraging and provide suggestion of safety and efficacy in this setting. This single-center trial will provide a first step toward demonstration of efficacy and safety of this device for treatment of stenotic fistulas.

Topics: Angioplasty, Balloon; Arteriovenous Fistula; Coated Materials, Biocompatible; Constriction, Pathologic; Humans; Paclitaxel; Pilot Projects; Prospective Studies; Renal Dialysis; Sirolimus; Treatment Outcome; Vascular Patency

Peripheral arterial disease is a progressive atherosclerotic disease with symptoms ranging from an intermittent claudication to acute critical limb ischemia and amputations. Drug-coated balloons and stents were developed to prevent neo-intimal proliferation and restenosis after percutaneous transluminal angioplasty. Randomized controlled trials showed that drug-coated, notably paclitaxel-coated, devices reduce restenosis, late lumen loss, and the need for target lesion re-vascularization compared with uncoated ones. However, the size of these trials was too small to prove superiority for "hard" clinical outcomes. Moreover, available studies were characterized by too restrictive eligibility criteria. Finally, it remains unclear whether paclitaxel-coated balloons may impair long-term survival. Alternative drug-coated balloons, the so-called limus-based analogs, have been approved for clinical use in patients with peripheral arterial disease. By encapsulating sirolimus in phospholipid drug nanocarriers, they optimize adhesion properties of sirolimus and provide better bioavailability.. In this investigator-initiated all-comer open-label phase III randomized controlled trial, we will evaluate whether sirolimus-coated balloon angioplasty is non-inferior and eventually superior, according to a predefined hierarchical analysis, to uncoated balloon angioplasty in adults with infra-inguinal peripheral arterial disease requiring endovascular angioplasty. Key exclusion criteria are pregnancy or breastfeeding, known intolerance or allergy to sirolimus, and participation in a clinical trial during the previous 3 months. The primary efficacy outcome is the composite of two clinically relevant non-subjective "hard" outcomes: unplanned major amputation of the target limb and endovascular or surgical target lesion re-vascularization for critical limb ischemia occurring within 1 year of randomization. The primary safety outcome includes death from all causes.. By focusing on clinically relevant outcomes, this study will provide useful information on the efficacy and safety of sirolimus-coated balloon catheters for infra-inguinal peripheral arterial disease in a representative ("all-comer") population of unselected patients. As regulatory agencies had raised safety concerns in patients exposed to paclitaxel-coated devices (versus uncoated ones), collect mortality data up to 5 years after randomization will be collected.. ClinicalTrials.gov NCT04238546.

Topics: Angioplasty, Balloon; Clinical Trials, Phase III as Topic; Coated Materials, Biocompatible; Constriction, Pathologic; Femoral Artery; Humans; Paclitaxel; Peripheral Arterial Disease; Popliteal Artery; Randomized Controlled Trials as Topic; Sirolimus; Treatment Outcome; Vascular Patency

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon; Cardiovascular Agents; Coated Materials, Biocompatible; Constriction, Pathologic; Delayed-Action Preparations; Female; Femoral Artery; Germany; Humans; Ischemia; Limb Salvage; Male; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Prospective Studies; Recovery of Function; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Vascular Patency

A novel self-expanding drug-eluting stent was designed to release everolimus 225 μg/cm(2) to prevent restenosis following peripheral arterial intervention. The purpose of this study was to measure the pharmacokinetic profile of everolimus following stent implantation.. One hundred four patients with symptomatic peripheral arterial disease underwent implantation of everolimus-eluting stents in the femoropopliteal arteries. In a prespecified subset of 26 patients, blood samples for assay of everolimus content were collected prior to stent implantation, at 1, 4, and 8 hours postprocedure, prior to discharge, and at 1 month postprocedure.. A total of 39 stents, ranging from 28 mm to 100 mm in length, were implanted in 26 patients, resulting in a total delivered everolimus dose range of 3.0 to 7.6 mg. Following the procedure, the maximum observed everolimus blood concentrations (C(max)) varied from 1.83 ± 0.05 ng/mL after implantation of a single 80-mm stent to 4.66 ± 1.78 ng/mL after implantation of two 100-mm stents. The mean time to peak concentration (T(max)) varied from 6.8 hours to 35 hours. The pharmacokinetics of everolimus were dose-proportional in that dose-normalized C(max) and area under the curve values were constant over the studied dose range.. After implantation of everolimus-eluting self-expanding stents in the femoropopliteal arteries, systemic blood concentrations of everolimus are predictable and considerably lower than blood concentrations observed following safe oral administration of everolimus.

Topics: Aged; Cardiovascular Agents; Constriction, Pathologic; Drug-Eluting Stents; Endovascular Procedures; Europe; Everolimus; Female; Femoral Artery; Humans; Male; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Prospective Studies; Prosthesis Design; Recurrence; Sirolimus; Treatment Outcome

Critical limb ischemia, the most severe form of peripheral arterial disease, results in extremity amputation if left untreated. Endovascular recanalization of stenotic or occluded infrapopliteal arteries has recently emerged as an effective form of therapy, although the duration of patency is typically limited by restenosis. Recently, it has been suggested that drug-eluting stents originally developed for the coronary arteries might also be effective in preventing restenosis in the infrapopliteal arteries. This prospective, randomized, controlled clinical trial tested the hypothesis that treatment of infrapopliteal arterial occlusive lesions with an everolimus-eluting stent (Xience V) would provide superior patency to treatment with a bare-metal stent (Multi-Link Vision).. A sample size of 140 patients was planned to be enrolled at five European investigative sites. The primary end point was arterial patency at 12 months, defined as the absence of ≥50% restenosis based on quantitative analysis of contrast angiography.. Between March of 2008 and September of 2009, 74 patients were treated with Xience V and 66 patients were treated with Vision. After 12 months, the primary patency rate after treatment with Xience V was 85% compared with 54% after treatment with Vision (P = .0001). Treatment with Xience V significantly reduced mean in-stent diameter stenosis (21% ± 21% vs 47% ± 27%; P < .0001) and mean in-stent late lumen loss (0.78 ± 0.63 vs 1.41 ± 0.89 mm; P = .001). There were no differences in the percentage of patients receiving a designation of Rutherford class 0 or 1 at the 12-month follow-up visit (56% for Vision, vs 60% for Xience V; P = .68). Major extremity amputations were rare in both groups (two for Vision and one for Xience V). The use of the Xience V stent significantly reduced the need for repeat intervention: freedom from target lesion revascularization was 91% for Xience V vs 66% for Vision (P = .001).. Treatment of the infrapopliteal occlusive lesions of critical limb ischemia with everolimus-eluting stents reduces restenosis and the need for reintervention compared with bare metal stents.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty; Arterial Occlusive Diseases; Cardiovascular Agents; Constriction, Pathologic; Critical Illness; Drug-Eluting Stents; Europe; Everolimus; Female; Humans; Ischemia; Kaplan-Meier Estimate; Limb Salvage; Male; Metals; Middle Aged; Popliteal Artery; Prospective Studies; Prosthesis Design; Radiography; Recurrence; Risk Assessment; Risk Factors; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

A novel self-expanding drug-eluting stent was designed to slowly release everolimus to prevent restenosis following peripheral arterial intervention. The purpose of the first-in-human Superficial Femoral Artery Treatment with Drug-Eluting Stents (STRIDES) trial was to evaluate the safety and efficacy of this device for the treatment of symptomatic superficial femoral and proximal popliteal arterial occlusive disease.. One hundred four patients were enrolled at 11 European investigative centers in a prospective, nonrandomized, single-arm trial. The patients had severe symptomatic vascular disease, including a significant proportion of patients with critical limb ischemia (17%), diabetes (39%), and single-vessel outflow (26%). The mean lesion length was 9.0 ± 4.3 cm. Ninety-nine percent of patients were available for 12-month follow-up, including duplex imaging in 90% and arteriography in 83%. Clinical improvement, defined as a sustained decrease in Rutherford-Becker clinical category, was achieved in 80% of patients. Primary patency (freedom from ≥50% in-stent restenosis) was 94 ± 2.3% and 68 ± 4.6% at 6 and 12 months, respectively. Plain radiographic examination of 122 implanted devices at 12 months revealed no evidence for stent fracture.. The everolimus-eluting self-expanding nitinol stent can be successfully implanted in patients with severe peripheral arterial disease with favorable outcomes and clinical improvements observed in the majority of patients.

Topics: Aged; Angioplasty; Ankle Brachial Index; Cardiovascular Agents; Constriction, Pathologic; Drug-Eluting Stents; Europe; Everolimus; Female; Femoral Artery; Humans; Kaplan-Meier Estimate; Limb Salvage; Male; Middle Aged; Peripheral Arterial Disease; Popliteal Artery; Prospective Studies; Prosthesis Design; Radiography; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Patency

The aim of this study was to assess, after 2 years of follow-up, the safety, efficacy, and cost-effectiveness of a zotarolimus-eluting stent (ZES) compared with a paclitaxel-eluting stent (PES) in patients with native coronary lesions.. Early drug-eluting stents were associated with a small but significant incidence of very late stent thrombosis (VLST), occurring >1 year after the index procedure. The ZES has shown encouraging results in clinical trials.. The ENDEAVOR IV trial (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions), a randomized (1:1), single-blind, controlled trial (n = 1,548) compared ZES versus PES in patients with single de novo coronary lesions. Two-year follow-up was obtained in 96.0% of ZES and 95.4% of PES patients. The primary end point was target vessel failure (TVF), and safety end points included Academic Research Consortium-defined stent thrombosis. Economic end points analyzed included quality-adjusted survival, medical costs, and relative cost-effectiveness of ZES and PES.. The TVF at 2 years was similar in ZES and PES patients (11.1% vs. 13.1%, p = 0.232). There were fewer myocardial infarctions (MIs) in ZES patients (p = 0.022), due to fewer periprocedural non-Q-wave MIs and fewer late MIs between 1 and 2 years. Late MIs were associated with increased VLST (PES: 6 vs. ZES: 1; p = 0.069). Target lesion revascularization was similar comparing ZES with PES (5.9% vs. 4.6%; p = 0.295), especially in patients without planned angiographic follow-up (5.2% vs. 4.9%; p = 0.896). The cost-effectiveness of ZES and PES was similar.. After 2 years of follow-up, ZES demonstrated efficacy and cost-effectiveness comparable to PES, with fewer MIs and a trend toward less VLST. (The ENDEAVOR IV Clinical Trial: A Trial of a Coronary Stent System in Coronary Artery Lesions; NCT00217269).

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Constriction, Pathologic; Coronary Angiography; Coronary Artery Disease; Cost-Benefit Analysis; Drug-Eluting Stents; Female; Health Care Costs; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Models, Economic; Myocardial Infarction; Paclitaxel; Prospective Studies; Prosthesis Design; Quality of Life; Quality-Adjusted Life Years; Risk Assessment; Single-Blind Method; Sirolimus; Time Factors; Treatment Outcome; United States

To report the 1-year angiographic and clinical outcome from a prospective single-center study investigating the infrapopliteal application of sirolimus-eluting versus bare metal stents in patients with critical limb ischemia (CLI) who underwent below-the-knee endovascular revascularization.. Stenting was performed as a bailout procedure for suboptimal angioplasty results (flow-limiting dissection, elastic recoil, or postangioplasty residual stenosis >30%). In the first 29 patients, infrapopliteal stenting was performed with bare metal stents (group B) and with sirolimus-eluting stents in the other 29 patients (group S).. Below-the-knee angioplasty and stenting involved 65 lesions in 40 infrapopliteal arteries of 29 limbs in group B and 66 lesions in 41 infrapopliteal arteries of 29 limbs in group S. Baseline comorbidities (hyperlipidemia and symptomatic cardiac and carotid disease) were more pronounced in group S (p<0.05). At 6 months, sirolimus-eluting stents demonstrated significantly higher primary patency (OR 5.625, 95% CI 1.711 to 18.493, p = 0.004) and decreased in-stent binary restenosis (OR 0.067, 95% CI 0.021 to 0.017, p<0.001) and in-segment binary restenosis (OR 0.229, 95% CI 0.099 to 0.533, p = 0.001). After 1 year, sirolimus-eluting stents were steadily associated with increased primary patency (OR 10.401, 95% CI 3.425 to 31.589, p<0.001) and significantly less in-stent (OR 0.156, 95% CI 0.060 to 0.407, p<0.001) and in-segment (OR 0.089, 95% CI 0.023 to 0.349, p = 0.001) binary restenosis. In addition, sirolimus-eluting stents were associated with significantly fewer cumulative target lesion reinterventions at 6 months (OR 0.057, 95% CI 0.008 to 0.426, p = 0.005) and 1 year (OR 0.238, 95% CI 0.067 to 0.841, p = 0.026). No significant differences between groups B and S were noted at 1 year with respect to mortality (10.3% versus 13.8%, respectively), minor amputation (17.2% versus 10.3%), or limb salvage (100% versus 96%).. The application of sirolimus-eluting stents reduces the restenosis rate in the infrapopliteal arteries and the rate of repeat endovascular procedures the first year after treatment.

Topics: Aged; Angiography, Digital Subtraction; Angioplasty, Balloon; Cardiovascular Agents; Constriction, Pathologic; Female; Follow-Up Studies; Humans; Ischemia; Leg; Male; Metals; Odds Ratio; Popliteal Artery; Prospective Studies; Prosthesis Design; Research Design; Secondary Prevention; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

To Compare the efficacy and safety of Rapamycin (Cypher) and Paclitaxel (TAXUS) eluting stents for multi-vessel coronary diseases.. From June 2003 to December 2004, a total of 416 patients with multi-vessel coronary diseases were randomly treated with Rapamycin (n = 210) and Paclitaxel (n = 206) eluting stents. Patients with left main lesion, acute myocardial infarction, revascularization were not included. Acute and long-term outcomes were compared between the two groups.. Baseline clinical characteristics, including risk factors of coronary heart disease, coronary lesion type, heart function, rates of success and complication of percutaneous coronary intervention procedure in the two groups were comparable. Number of stents implanted was not significantly different between the two groups (3.24 +/- 1.25 vs 3.19 +/- 1.38, P > 0.05). Mean follow-up duration was (19.5 +/- 8.9) months. Follow-up rate (96.2 vs 95.1%), angina pectoris reoccurrence (4.0 vs 6.1%), restenosis (7.1 vs 9.6%), major adverse cardiac event (6.4 vs 8.8%) and event free survival (93.1 vs 91.3%) during follow-up were not significantly different between the two groups. Subacute stent thrombosis rate tended to be higher in Paclitaxel eluting stent group compared with Rapamycin eluting stent group (1.0% vs 0.5%, P > 0.05). At 6 to 9 months angiographic follow-up, the in-stent minimal lumen diameter (MLD) and the in-segment MLD were similar between the two groups.. Satisfactory acute and long term outcomes for patients with multi-vessel coronary disease were achieved by both Cypher and TAXUS stent implantation and the safety and efficacy of the two kinds of stents were comparable.

Topics: Angioplasty, Balloon, Coronary; Constriction, Pathologic; Coronary Disease; Drug-Eluting Stents; Follow-Up Studies; Humans; Paclitaxel; Sirolimus; Treatment Outcome

Stent implantation for obstructive femoropopliteal artery disease has been associated with poor long-term outcomes. This study evaluated the effectiveness of shape memory alloy recoverable technology (SMART) nitinol self-expanding stents coated with a polymer impregnated with sirolimus (rapamycin) versus uncoated SMART Stents in superficial femoral artery obstructions.. Thirty-six patients were recruited for this double-blind, randomized, prospective trial. All patients had chronic limb ischemia and femoral artery occlusions (57%) or stenoses (average lesion length, 85 +/- 57 mm). Patients were eligible for randomization after successful guidewire passage across the lesion. Eighteen patients received sirolimus-eluting SMART Stents and 18 patients received uncoated SMART Stents. The primary end point of the study was the in-stent mean percent diameter stenosis, as measured by quantitative angiography at 6 months. The instent mean percent diameter stenosis was 22.6% in the sirolimus-eluting stent group versus 30.9% in the uncoated stent group (P = 0.294). The in-stent mean lumen diameter was significantly larger in the sirolimus-eluting stent group (4.95 mm versus 4.31 mm in the uncoated stent group; P = 0.047). No serious adverse events (death or prolonged hospitalization) were reported.. The use of sirolimus-eluting SMART Stents for superficial femoral artery occlusion is feasible, with a trend toward reducing late loss compared with uncoated stents. The coated stent also proved to be safe and was not associated with any serious adverse events.

Topics: Aged; Arterial Occlusive Diseases; Constriction, Pathologic; Drug-Eluting Stents; Female; Femoral Artery; Humans; Immunosuppressive Agents; Intermittent Claudication; Male; Radiography; Recurrence; Sirolimus; Stents; Treatment Outcome

Topics: Carotid Arteries; Constriction, Pathologic; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Humans; Male; Sirolimus; Stents; Treatment Outcome

A decade ago, the iopromide-paclitaxel coated balloon (iPCB) was added to the cardiologist's toolbox to initially treat in-stent restenosis followed by the treatment of de novo coronary lesions. In the meantime, DES technologies have been substantially improved to address in-stent restenosis and thrombosis, and shortened anti-platelet therapy. Recently, sirolimus-coated balloon catheters (SCB) have emerged to provide an alternative drug to combat restenosis.. The objective of this study is to determine the safety and efficacy of a novel crystalline sirolimus-coated balloon (cSCB) technology in an unselective, international, large-scale patient population. Percutaneous coronary interventions of native stenosis, in-stent stenosis, and chronic total occlusions with the SCB in patients with stable coronary artery disease or acute coronary syndrome were included. The primary outcome variable is the target lesion failure (TLF) rate at 12 months, defined as the composite rate of target vessel myocardial infarction (TV-MI), cardiac death or ischemia-driven target lesion revascularization (TLR). The secondary outcome variables include TLF at 24 months, ischemia driven TLR at 12 and 24 months and all-cause death, cardiac death at 12 and 24 months.. Since there is a wealth of patient-based all-comers data for iPCB available for this study, a propensity-score matched analysis is planned to compare cSCB and iPCB for the treatment of de novo and different types of ISR. In addition, pre-specified analyses in challenging lesion subsets such as chronic total occlusions will provide evidence whether the two balloon coating technologies differ in their clinical benefit for the patient.. ClinicalTrials.gov Identifier: NCT04470934.

Topics: Angioplasty; Cardiovascular Agents; Clinical Trials as Topic; Constriction, Pathologic; Coronary Artery Disease; Coronary Restenosis; Drug-Eluting Stents; Humans; Paclitaxel; Sirolimus; Treatment Outcome

The safety and efficacy of drug-eluting balloon on the treatment of intracranial atherosclerotic stenosis (ICAS) remain unclear. Here, we present our observation in a cohort study on the safety and efficacy of rapamycin-eluting balloon for patients with ICAS.. A total of 80 ICAS patients with stenosis degree of 70-99% were included. All patients were treated with rapamycin-eluting balloon and were followed up for 12 months after operation.. All patients were successfully treated, where the mean stenosis severity reduced from 85.1 ± 7.6 to 6 ± 4.9%. 8 patients experienced immediate post-operational complications. Two patients passed away during the first month of the follow-up period. Recurrent ischemic syndrome and angiographic restenosis only appeared 7 days after operation. During later follow-up period, none of the patients had clinical angiographic restenosis or needed target vessel revascularization.. Our data suggest that intracranial stenting with rapamycin-eluting balloon seems to be safe and effective, although more clinical data are needed to support this notion.

Topics: Cohort Studies; Constriction, Pathologic; Coronary Angiography; Coronary Restenosis; Drug-Eluting Stents; Humans; Intracranial Arteriosclerosis; Sirolimus; Stents; Treatment Outcome

Laryngotracheal stenosis (LTS) is pathologic fibrotic narrowing of the larynx and trachea characterized by hypermetabolic fibroblasts and CD4+ T cell-mediated inflammation. However, the role of CD4+ T cells in promoting LTS fibrosis is unknown. The mTOR signaling pathways have been shown to regulate the T cell phenotype. Here we investigated the influence of mTOR signaling in CD4+ T cells on LTS pathogenesis. In this study, human LTS specimens revealed a higher population of CD4+ T cells expressing the activated isoform of mTOR. In a murine LTS model, targeting mTOR with systemic sirolimus and a sirolimus-eluting airway stent reduced fibrosis and Th17 cells. Selective deletion of mTOR in CD4+ cells reduced Th17 cells and attenuated fibrosis, demonstrating CD4+ T cells' pathologic role in LTS. Multispectral immunofluorescence of human LTS revealed increased Th17 cells. In vitro, Th17 cells increased collagen-1 production by LTS fibroblasts, which was prevented with sirolimus pretreatment of Th17 cells. Collectively, mTOR signaling drove pathologic CD4+ T cell phenotypes in LTS, and targeting mTOR with sirolimus was effective at treating LTS through inhibition of profibrotic Th17 cells. Finally, sirolimus may be delivered locally with a drug-eluting stent, transforming clinical therapy for LTS.

Topics: Animals; Constriction, Pathologic; Drug-Eluting Stents; Fibrosis; Humans; Laryngostenosis; Mice; Sirolimus; Th17 Cells; TOR Serine-Threonine Kinases; Tracheal Stenosis

Ureteral stricture caused by holmium: YAG laser lithotripsy is one of the most challenging issues for urologists. Currently, evidence for rapamycin application in reducing ureterostenosis is not sufficient. This study aimed to assess the inhibition of ureteral stricture of rapamycin-eluting stents in vitro and in vivo. A bilayered drug-eluting ureteral stent consisted of drug blending with poly (lactic-co-glycolic acid) (PU/drug stent), which was over-layered by polycaprolactone (PCL) by ultrasonic atomizing spraying. Stent morphology was observed by scanning electron microscope. A kidney-ureter-bladder model was established to simulate the stents-releasing condition, and high-performance liquid chromatography was used to measure the drug release rate. The inhibitory proliferation was detected by CCK-8. The bladder of rats was injured through electro tome, and stents were implanted for 7, 14, and 28 days. The effects of drug-eluting stents was investigated by hematoxylin-eosin staining, immunofluorescence staining, real-time quantitative polymerase chain reaction and western blot. The bilayered stents could block the burst loss of the drug and maintained a sustained delivery period because of the 5.3 μm thickness of the PCL layer. The relative growth rates of cells plotted inhibitory effect on the proliferation of human urethral scar fibroblast cells. For in vivo results of 28 days, the bilayered stent maintained structural integrity and induced less deposition of crystals, thinner and less lamina propria connective tissues were formed, and α-SMA and TGF-β1 were downregulated. Bilayered rapamycin-eluting stent is significantly effective in alleviating fibrosis in in vitro and in vivo models. STATEMENT OF SIGNIFICANCE: The occurrence of ureteral stricture resulting from holmium: YAG laser lithotripsy presents a significant challenge for urologists. Traditional double J stents have not been proven to offer a shorter indwelling time or improved inhibition of tissue blocking. While drug-eluting stents containing rapamycin, paclitaxel, and other substances have been extensively used in treating artery stenosis, there is insufficient evidence supporting their application in reducing ureterostenosis. Consequently, a biodegradable polymer ureteric scaffold incorporating rapamycin was fabricated in this study, employing ultrasonic atomization spraying technology to optimize the bilayers composed of 75/25 poly (lactic-co-glycolic acid) (PLGA) and polycaprolactone (

Topics: Animals; Constriction, Pathologic; Drug-Eluting Stents; Holmium; Humans; Lithotripsy, Laser; Rats; Sirolimus; Stents

Following vein grafting, the vein must adapt to arterial hemodynamics, which can lead to intimal hyperplasia (IH) and restenosis. Moreover, endothelial-to-mesenchymal transition (EndMT) components are highly associated with IH. Therefore, in this study, we aimed to design an extravascular film loaded with rapamycin (extravascular rapamycin film [ERF]) to limit vein graft stenosis. The film exhibited stable physicochemical properties as well as in vivo and in vitro biocompatibility. In vivo, the film inhibited the EndMT by activating the autophagy pathway. Moreover, rapamycin enhanced this biological effect. Collectively, these findings highlighted the applicability of ERF as a new therapeutic target for preventing vein graft restenosis.

Topics: Autophagy; Constriction, Pathologic; Humans; Hyperplasia; Sirolimus

Paclitaxel-coated balloons (PCBs) are a preferred treatment option for coronary in-stent restenosis. To date, data from randomized trials of alternative drug coatings are lacking. The aim of the randomized Malaysian and German-Swiss randomized trials was to investigate a novel sirolimus-coated balloon (SCB) compared with a PCB in in-stent restenosis.. One hundred one patients with drug-eluting stent in-stent restenosis were enrolled in 2 identical randomized trials comparing the novel SCB (SeQuent SCB, 4 μg/mm²) with the clinically proven PCB (SeQuent Please, 3 μg/mm²). Primary end point was angiographic late lumen loss at 6 months. Secondary end points included procedural success, major adverse cardiac events, and individual clinical end points such as stent thrombosis, cardiac death, target lesion myocardial infarction, clinically driven target lesion revascularization, and binary restenosis.. Quantitative coronary angiography revealed no differences in baseline parameters. After 6 months, in-segment late lumen loss was 0.25±0.57 mm in the PCB group versus 0.26±0.60 mm in the SCB group. Mean difference between SCB and PCB was 0.01 (95% CI, -0.23 to 0.24). Noninferiority at a predefined margin of 0.35 was shown. Clinical events up to 12 months did not differ between the groups.. This first-in man comparison of a novel SCB with a crystalline coating showed similar angiographic and clinical outcomes in the treatment of coronary drug-eluting stent in-stent restenosis compared with PCB.. URL: https://www.. gov; Unique identifier: NCT02996318, NCT03242096.

Topics: Angioplasty, Balloon, Coronary; Constriction, Pathologic; Coronary Restenosis; Drug-Eluting Stents; Humans; Paclitaxel; Polychlorinated Biphenyls; Randomized Controlled Trials as Topic; Sirolimus; Stents; Treatment Outcome

Percutaneous coronary intervention (PCI) is an effective treatment for acute myocardial infarction, but the postoperative in-stent re-stenosis (ISR) remains a major risk factor that affects the prognosis of PCI. Clinically, drug-eluting stents (DES) are widely applied to prevent and treat ISR. However, only a few stent coating drugs are currently available for clinical use, including paclitaxel and rapamycin (sirolimus) and their derivatives. These stent-coated drugs have led to a decrease in restenosis rates, but the major adverse outcomes, such as delayed endothelial healing and increased in-stent thrombosis, seriously reduce their therapeutic effects.. Herein, we explored the potential efficacy of Euonymine (Euo), an alkaloid extracted from Tripterygium Hypoglaucum (Levl) Hutch (THH, Lei gong Teng), for the prevention against ISR after PCI.. Our study depicts the potential efficacy of Euo in treating ISR and explores its mechanism with in vitro and in vivo models.. Primary vascular smooth muscle cells (VSMCs) from the rabbit thoracic aorta were cultured, and the proliferation and migration of VSMCs were monitored. Apoptosis was measured by Transmission Electron Microscopy and TUNEL staining assay. Protein and gene levels were measured to explore the underlying molecular mechanisms. In vivo models of porcine coronary implantation and rabbit carotid balloon injury are used to validate the efficacy of Euo in inhibiting ISR after PCI.. With an ox-LDL-injured cell model, we showed that Euo suppressed the proliferation and migration of the rabbit thoracic aorta primary VSMCs, while inducing their apoptosis. We next established a rabbit carotid balloon injury model in which the phosphorylation levels of PI3K and AKT1 (Ser473) as well as mTOR activity were significantly elevated compared to the sham-operated control. These activities were significantly attenuated by the Euo intervention. Additionally, the balloon angioplasty significantly increased the expression of Bcl-2, while decreased the expression of Bax and caspase-3. Euo intervention significantly increased the ratio of Bax/Bcl-2 and the level of caspase-3. Taken together, Euo may enhance the VSMCs contractile phenotype by modulating the PTEN/AKT/mTOR signaling pathway. Furthermore, with two in vivo models, the porcine coronary artery implantation model, and the rabbit carotid balloon injury model, we demonstrated that Euo-eluting stents indeed inhibited ISR after PCI.. For the first time, this study delineates the potential efficacy of Euo, derived from Tripterygium Hypoglaucum (Levl) Hutch, in ameliorating ISR after PCI with two in vivo models. The phytochemical targets PTEN/AKT/mTOR signaling pathway to increase the contractile phenotype of VSMCs and exerts anti-proliferative, anti-migratory as well as pro-apoptotic effects, thereby inhibiting the ISR.

Topics: Animals; bcl-2-Associated X Protein; Caspase 3; Constriction, Pathologic; Coronary Angiography; Coronary Restenosis; Muscle, Smooth, Vascular; Paclitaxel; Percutaneous Coronary Intervention; Phenotype; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Rabbits; Risk Factors; Signal Transduction; Sirolimus; Swine; TOR Serine-Threonine Kinases; Treatment Outcome

Non stent-based local drug delivery with drug-coated balloon (DCB) is an alternative to drug-eluting stent with favorable clinical applicability in the treatment of selected coronary lesions. Our purpose was to report the initial performance, safety and efficacy evaluations of a novel sirolimus-coated balloon in the treatment of coronary lesions.. This was a phase I (first-in-man), prospective, multicenter, single-arm trial evaluating the novel SELUTION SLR™ DCB (M.A. Med Alliance SA, Nyon, Switzerland), which incorporates a polymeric microsphere-based technology for controlled and continuous release of sirolimus, in the treatment of de novo or restenotic lesions.. A total of 56 patients/lesions were enrolled between November/2018 and March/2019. Diabetes was found in 46.6 %, and de novo lesions represented 79.6 % of cases. Device and procedural/clinical success were 100 % and 96.4 %, respectively. There was only one major adverse cardiac event (target lesion revascularization) reported at late follow-up. By quantitative coronary angiography analysis, mean % diameter stenosis was 30.5 ± 16.7 %, late lumen loss was 0.26 ± 0.45 mm and angiographic binary restenosis occurred in 4 of 45 cases at 6-month angiographic follow-up.. The novel SELUTION sirolimus-coated balloon demonstrated safety and efficacy in the treatment of diseased coronary vessels, including absence of mortality and relatively low late lumen loss at late follow-up.

Topics: Constriction, Pathologic; Drug-Eluting Stents; Humans; Prospective Studies; Sirolimus; Technology

Evaluate the efficacy of systemic sirolimus (rapamycin) in preventing in-stent stenosis (ISS) in pediatric intraluminal pulmonary vein stenosis (PVS). Report the adverse events related to sirolimus therapy. There is a high incidence of ISS following stent implantation in PVS. The use of sirolimus in preventing ISS has not been reported. Retrospective review of all patients who received sirolimus (8 week course) for treatment of ISS for PVS between January 2013 and June 2018. Forty stents (37 bare metal, 3 drug-eluting) in 20 patients were treated with sirolimus; 20 at the time of implantation (primary prevention [1P]) and 20 following documented ISS requiring transcatheter reintervention (secondary prevention [2P]). Treated patients were young (median 2 y/o [0.7-5.7]) and most had PVS associated with congenital heart disease (75%, 15/20; 4/15 with TAPVC). In the 1P group, 85% (17/20) of stents were without significant (< 50%) ISS at median of 102 days (range 56-527); the growth rate of ISS in this group was 7.5 ± 7.1%/month. In the 2P group, most stents had a slower growth rate of ISS after sirolimus therapy compared to pre-treatment (median 3.7 [- 0.2 to 13.1] vs. 10.4 [1.3 to 19.5] %/month; p < 0.001). One patient developed pneumonia on drug while concurrently taking another immunosuppressive agent. No other serious adverse events were related to sirolimus therapy. Systemic sirolimus slows the growth rate of ISS following stent implantation in PVS compared to pre-treatment rates and was administered safely in a small number of pediatric patients with complex heart disease.

Topics: Aged; Child, Preschool; Constriction, Pathologic; Female; Humans; Immunosuppressive Agents; Infant; Male; Middle Aged; Retrospective Studies; Sirolimus; Stenosis, Pulmonary Vein; Stents; Treatment Outcome

Endovascular therapy in peripheral intervention has grown exponentially in the past decade, but the issue of high restenosis rates in lower extremity arteries still persist. While drug-coated balloons (DCB) have been the device of choice, recent controversary regarding the long-term safety of paclitaxel have raised concern over current DCBs. In our study, we proposed that the direct injection of a sirolimus nanoliposomal formulation (Nanolimus) using a infusion catheter can attenuate inflammation response in injured vessels. In vitro characterization showed retention of the nanoliposomes size and detectable drug amount up to 336 days in storage. For in vivo study, four female, mixed breed swines were subjected to balloon injury of the femoral arteries before treatment with either injection of saline (n = 4) or Nanolimus (n = 12) using the Bullfrog catheter. Pharmacokinetic analysis demonstrated sustained sirolimus release in the arteries and undetectable systemic drug level at 28 days. Arteries treated with Nanolimus showed significant reduction in neointima area (0.2 ± 0.3 mm

Topics: Animals; Constriction, Pathologic; Female; Femoral Artery; Lower Extremity; Neointima; Paclitaxel; Sirolimus; Swine

The BiOSS LIM stent is a dedicated device for the treatment of bifurcation lesions that present a proximal and distal part with two different diameters and a middle zone with two connecting struts facilitating side branch rewiring. In this study, after implanting the BiOSS LIM stent in the left main, rewiring to the side branch was easier compared to standard metallic stent. The device may be very useful in the treatment of bifurcation lesions for provisional stenting strategies or for two-stent strategies such as T-stenting or T-and-Protruding (TAP).

Topics: Constriction, Pathologic; Coronary Artery Disease; Coronary Stenosis; Drug-Eluting Stents; Humans; Sirolimus; Stents; Treatment Outcome

Develop a drug-eluting stent construct with a reliable drug-release profile and adequate mechanically stability for a trial in a small animal model of laryngotracheal stenosis (LTS), a debilitating pathologic narrowing of the airway leading to significant shortness of breath.. Biodegradable, biocompatible stents containing 1.0% rapamycin made of PLLA-PCL (70% Poly-l-Lactide and 30% Polycaprolactone blend) and 50 : 50 PDLGA (Poly(dl-lactide-co-glycolide)) were compared. Mechanical strength testing and drug elution rates using high performance liquid chromatography analysis (HPLC) was assessed. Next, efficacy of stent elution on LTS derived scar fibroblasts. Finally, stents were placed in situ in an LTS mouse model.. The PLLA-PCL stent construct exhibited greater mechanical strength compared to the PDLGA stent over a 4-week period (Young's Modulus (PLLA-PCL) = 13.82; Young's Modulus (PDLGA) = 4.015). Moreover, the PLLA-PCL stent showed a reliable rapamycin release profile for 6 weeks (30% elution for PLLA-PCL stents compared to <1% elution for PDLGA). Collagen 1 (p < 0.05) and fibroblast cell proliferation were decreased in vitro when treated with the rapamycin stent. In vivo, the rapamycin stent reduced lamina propria thickness (p < 0.05) and collagen 1(p < 0.05), collagen 3, TGF-B (p < 0.05) and a-SMA (p < 0.05).. The PLLA-PCL construct demonstrated superior mechanical strength and greater drug elution compared to PDLGA stents. We demonstrated the feasibility of testing this drug-eluting stent in vivo, showing that the rapamycin-eluting stent treats fibrosis. To our knowledge this is the first study to deploy a drug-eluting stent to treat tracheal pathology in an animal model. Optimization of a rapamycin-eluting PLLA-PCL stent for translational investigation will lead to improved treatment strategies of LTS.

Topics: Animals; Constriction, Pathologic; Drug Carriers; Drug-Eluting Stents; Engineering; Feasibility Studies; Humans; Immunomodulation; Larynx; Materials Testing; Mechanical Phenomena; Mice; Polyesters; Safety; Sirolimus; Trachea

Benign biliary stricture (BBS) is highly refractory. Currently, there is no effective strategy for prevention of BBS recurrence. The aim of this study is to establish a novel BBS rabbit model and to investigate the efficacy of biliary infusion with anti-proliferative medications for treating BBS.. A BBS model was established via surgical injury and biliary infection. The biliary infusion tube was inserted into the common bile duct via the stump of cystic duct after cholecystectomy. Biliary infusions with Rapamycin, Pirfenidone and Fasudil were performed daily during the 4 weeks following the surgery. The wall thickness and luminal area of the bile duct were assessed.. All rabbits formed BBS after surgery. The mortality rate was 13% (8/60) and tube withdrawal rate was 4% (2/48). The thickness of the bile duct wall was significantly reduced; whereas the luminal area of the bile duct was dramatically enlarged in the Rapamycin or the Pirfenidone treated group, compared to the saline treated group. Furthermore, the local treatment significantly decreased the levels of proliferation makers, including PCNA, Collagen I and fibrogenic mediators, including ACTA2 and TGF-beta.. We have established a novel animal model for BBS formation. We have further demonstrated that biliary infusion with Rapamycin or Pirfenidone limits the biliary strictures through inhibiting the proliferation of the bile duct wall in this model. This may represent a new avenue for preventing biliary restenosis.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Antineoplastic Agents; Biliary Tract Diseases; Constriction, Pathologic; Disease Models, Animal; Drug Evaluation, Preclinical; Pyridones; Rabbits; Secondary Prevention; Sirolimus; Vasodilator Agents

The aim of this study was to assess prospectively the effectiveness and safety of a new version of the dedicated bifurcation BiOSS stent, the sirolimus-eluting BiOSS LIM, for the treatment of distal left main (LM) stenosis.. This was a prospective international registry which enrolled patients with NSTE-ACS or stable angina. Provisional T-stenting was the mandated strategy. The primary endpoint was the cumulative rate of cardiac death, myocardial infarction (MI) and target lesion revascularisation (TLR) at 12 months. Twelve-month quantitative coronary angiography endpoints included late lumen loss and percent diameter stenosis. A total of 74 patients with distal LM stenosis were enrolled. Seventy-three of the 74 patients (aged 67±9 years, 23% women, 20.3% NSTE-ACS, SYNTAX score 22.4±4.4) were successfully treated with the BiOSS LIM stent, with additional side branch placement of regular DES in 11 patients (14.9%). Periprocedural MI occurred in one (1.4%) patient. The 12-month MACE rate was 9.5% without cardiac death or definite stent thrombosis. TLR and MI rates were 6.8% (n=5) and 2.7% (n=2), respectively.. The use of the BiOSS LIM dedicated bifurcation stent for the treatment of distal LM stenosis was feasible and safe, with promising long-term clinical effectiveness.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty, Balloon, Coronary; Constriction, Pathologic; Coronary Angiography; Coronary Restenosis; Coronary Stenosis; Drug-Eluting Stents; Female; Humans; Male; Middle Aged; Myocardial Infarction; Paclitaxel; Prospective Studies; Registries; Sirolimus; Time; Treatment Outcome

To determine whether intramural administration of rapamycin (RPM)-loaded polylactic-polyglycolic acid (PLGA) nanoparticles (NPs) can reduce intimal thickening and affect the mRNA expressions of matrix metalloproteinase (MMP)-2, tissue inhibitor of metalloproteinase (TIMP)-2 and p27(kipl) in a coronary injury-stenosis model of minipigs.. Twenty eight minipigs were randomly separated into four groups: saline group (n=7), blank PLGA NPs group (5.0 mg/ml)(n=7), RPM group (1.0 mg/ml)(n=7), and RPM-PLGA NPs(5.0 mg/ml)group (n=7), respectively. Different treatments were intracoronary locally delivered via a Dispatch™ catheter for 10 minutes. Serial angiography was performed pre-and post-modeling 30 days and the percent stenosis degree was assessed. Hematoxylin-Eosin (HE) staining, Weigert's resorcin fuchsin staining and picric acid-sirius red staining were used for morphometric analysis. Immunohistochemistry was performed to assess the levels of proliferating cell nuclear antigen (PCNA), MMP-2, and TIMP-2 at early and late time points, respectively. The expression of p27(kip1) mRNA was detected by in situ hybridization staining.. Data from 21 minipigs had been collected at the end of the experiment with 6, 4, 5, and 6 from the former mentioned 4 groups, respectively. For the instant injury index, there was no significant difference among the four groups. The percent stenosis degree of RPM-PLGA NPs group was significantly lower than that of the other three groups respectively (all P< 0.05). The neointima area, net external elastic lamina area to external elastic laminal area ratio, and proliferative index of RPM-PLGA NPs group were significantly less than those of the other three groups, with all the P values less than 0.05. The mean value of integral optical density of p27(kip1)mRNA expression of RPM-PLGA group was 0.35 ± 0.06, higher than that of blank PLGA NPs group (0.12 ± 0.05, P< 0.01), saline group (0.16 ± 0.03, P< 0.05), and RPM group (0.15 ± 0.03, P< 0.05), respectively. The MMP-2/TIMP-2 ratio and the positive expression index of PCNA in RPM-PLGA group were lower than that of the other groups (P< 0.05).. Locally delivered rapamycin-loaded PLGA NPs significantly reduces MMP-2/TIMP-2 ratio and PCNA expression, increases p27(kip1) mRNA expression and significantly relieves percent stenosis degree and shows excellent acute procedural results in the minipig interventional coronary artery oversized balloon injury model. The results from minipig model further support that this approach could be a potential clinical procedure for vascular proliferative disease.

Topics: Animals; Constriction, Pathologic; Disease Models, Animal; Lactic Acid; Nanoparticles; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Sirolimus; Swine; Swine, Miniature

To evaluate the effects of intrathecal injection of rapamycin on pain threshold and spinal cord glial activation in rats with neuropathic pain.. Healthy 30 male Sprague Dawley (SD) rats were randomly divided into six groups (n = 5 in each group): (1) control group without any treatments; (2) chronic constriction injury (CCI) group; (3) Early-rapamycin group with intrathecal injection of rapamycin 4 hours after CCI days; (4) Early-vehicle group with intrathecal injection of DMSO; (5) Late-rapamycin group with intrathecal injection of rapamycin 7 days after CCI; (6) Late-vehicle group with intrathecal injection of DMSO 7 days after CCI. Rapamycin or DMSO was injected for 3 consecutive days. Mechanical and thermal threshold were tested before and after the CCI operation. Lumbar segment of spinal cords was tested for glial fibrillary acidic protein (GFAP) by immunohistochemistry on 14th day after operation.. Mechanical and thermal hyperalgesia emerged on fourth day were maintained till fourteenth day after operation. After intrathecal injection of rapamycin 4 hours or 7 days after CCI, mechanical and thermal threshold significantly increased compared to injection of DMSO. The area of GFAP positive and the mean density of GFAP positive area in the dorsal horn of the ipsilateral side greatly increased in rapamycin-treated groups.. Intrathecal injection of rapamycin may attenuate CCI-induced hyperalgesia and inhibit the activation of astrocyte.

Topics: Analgesics; Animals; Astrocytes; Chronic Disease; Constriction, Pathologic; Disease Models, Animal; Glial Fibrillary Acidic Protein; Hot Temperature; Hyperalgesia; Injections, Spinal; Male; Neuralgia; Pain Threshold; Random Allocation; Rats, Sprague-Dawley; Sciatic Nerve; Sirolimus; Spinal Cord; Touch

To investigate whether temporary placement of a paclitaxel or rapamycin eluting stent is more effective to reduce stenting induced inflammatory reaction and scaring than a bared stent in benign cardia stricture models.. Eighty dog models of stricture were randomly divided into a control group (CG, n=20, no stent insertion), a bare stent group (BSG, n=20), a paclitaxel eluting (Pacl-ESG, n=20) and a rapamycin eluting stent group (Rapa-ESG, n=20), with one-week stent retention. Lower-oesophageal-sphincter pressure (LOSP), 5-minute barium height (5-mBH) and cardia diameter were assessed before, immediately after the procedure, and regularly for 6 months. Five dogs in each group were euthanized for histological examination at each follow-up assessment.. Stent insertion was well tolerated, with similar migration rates in three groups. At 6 months, LOSP and 5-mBH improved in Pacl-ESG and Rapa-ESG compared to BSG (p<0.05), with no difference between Pacl-ESG and Rapa-ESG (p>0.05). Cardia kept more patency in the Pacl-ESG and Rapa-ESG than in BSG (p<0.05). Reduced peak inflammatory reactions and scarring occurred in the Pacl-ESG and Rapa-ESG compared to BSG (p<0.05), with a similar outcome in the Pacl-ESG and Rapa-ESG (p>0.05).. Paclitaxel or rapamycin-eluting stents insertion led to better outcomes than bare stents in benign cardia stricture models.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Cardia; Cicatrix; Constriction, Pathologic; Disease Models, Animal; Dogs; Drug-Eluting Stents; Esophageal Sphincter, Lower; Esophageal Stenosis; Female; Humans; Inflammation; Male; Manometry; Paclitaxel; Random Allocation; Sirolimus; Time Factors

The aim of the current study was to assess whether placement of the biodegradable rapamycin-eluting nano-fiber membrane-covered metal stent is followed by less fibroblast proliferation and tissue hyperplasia compared with bare stents in experimental stricture in a dog model.. A total of 80 dog models of stricture were randomly divided into a control group (n = 20, no stent insertion), a bare stent group (BSG, n = 20, 1-week retention), and two drug-eluting stent sub-groups (DESG-1w, n = 20, 1-week retention; DESG-4w, n = 20, 4-week retention). Lower esophageal sphincter (LES) pressure, 5-minute barium height (5-mBH), and cardia diameter were assessed before, immediately after the procedure, and regularly thereafter for 6 months. Five dogs in each group were euthanized for histological examination at each follow-up assessment.. Stent insertion was well tolerated, with similar migration rates (0 % in BSG vs. 7.5 % in DESGs; P = 0.5441). At 6 months, LES pressure and 5-mBH improved in DESG-1w (26.70 ± 5.02 mmHg and 6.50 ± 2.98 cm) and DESG-4w (20.16 ± 5.50 mmHg and 1.54 ± 0.98 cm) compared with BSG (39.94 ± 5.22 mmHg and 11.1 ± 5.46 cm) (P < 0.05), with DESG-4w being more stable than DESG-1w (P < 0.05). The cardia maintained greater patency in the DESGs (7.10 ± 3.09 mm in DESG-1w; 9.16 ± 3.77 mm in DESG-4w) than in the BSG (1.86 ± 2.45 mm; P < 0.05). Reduced peak inflammatory reactions and scarring occurred in DESGs compared with the BSG (P < 0.05), with a better outcome in DESG-4w than in DESG-1w (P < 0.05).. In this experimental stricture model, rapamycin-eluting stents were more effective than bare stents for the reduction of fibroblast proliferation and tissue hyperplasia after stent placement. Furthermore, 4-week retention of the drug-eluting stent led to a better outcome than 1-week retention.

Topics: Absorbable Implants; Animals; Cardia; Cell Proliferation; Constriction, Pathologic; Disease Models, Animal; Dogs; Drug-Eluting Stents; Esophageal Sphincter, Lower; Esophageal Stenosis; Female; Fibroblasts; Immunosuppressive Agents; Male; Manometry; Nanofibers; Pressure; Random Allocation; Sirolimus

Sirolimus-eluting stent therapy has achieved considerable success in overcoming coronary artery restenosis. However, there remain a large number of patients presenting with restenosis after the treatment, and the source of its persistence remains unclarified. Although recent evidence supports the contribution of vascular stem/progenitor cells in restenosis formation, their functional and molecular responses to sirolimus are largely unknown.. Using an established technique, vascular progenitor cells were isolated from adventitial tissues of mouse vessel grafts and purified with microbeads specific for stem cell antigen-1. We provide evidence that vascular progenitor cells treated with sirolimus resulted in an induction of their migration in both transwell and wound healing models, clearly mediated by CXCR4 activation. We confirmed the sirolimus-mediated increase of migration from the adventitial into the intima side using an ex vivo decellularized vessel scaffold, where they form neointima-like lesions that expressed high levels of smooth muscle cell (SMC) markers (SM-22α and calponin). Subsequent in vitro studies confirmed that sirolimus can induce SMC but not endothelial cell differentiation of progenitor cells. Mechanistically, we showed that sirolimus-induced progenitor-SMC differentiation was mediated via epidermal growth factor receptor and extracellular signal-regulated kinase 1/2 activation that lead to β-catenin nuclear translocation. The ablation of epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, or β-catenin attenuated sirolimus-induced SM-22α promoter activation and SMC differentiation.. These findings provide direct evidence of sirolimus-induced progenitor cell migration and differentiation into SMC via CXCR4 and epidermal growth factor receptor/extracellular signal-regulated kinase/β-catenin signal pathways, thus implicating a novel mechanism of restenosis formation after sirolimus-eluting stent treatment.

Topics: Active Transport, Cell Nucleus; Adult Stem Cells; Adventitia; Animals; Antigens, Ly; beta Catenin; Biomarkers; Calcium-Binding Proteins; Calponins; Cell Proliferation; Cells, Cultured; Chemotaxis; Constriction, Pathologic; Enzyme Activation; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Membrane Proteins; Mice; Microfilament Proteins; Muscle Proteins; Myocytes, Smooth Muscle; Receptors, CXCR4; RNA Interference; Signal Transduction; Sirolimus; Time Factors; Tissue Scaffolds; Transfection

Endovascular interventions on peripheral arteries are limited by high rates of restenosis. Our hypothesis was that adventitial injection of rapamycin nanoparticles would be safe and reduce luminal stenosis in a porcine femoral artery balloon angioplasty model.. Eighteen juvenile male crossbred swine were included. Single-injury (40%-60% femoral artery balloon overstretch injury; n=2) and double-injury models (endothelial denudation injury 2 weeks before a 20%-30% overstretch injury; n=2) were compared. The double-injury model produced significantly more luminal stenosis at 28 days, P=0.002, and no difference in medial fibrosis or inflammation. Four pigs were randomized to the double-injury model and adventitial injection of saline (n=2) or 500 μg of nanoparticle albumin-bound rapamycin (nab-rapamycin; n=2) with an endovascular microinfusion catheter. There was 100% procedural success and no difference in endothelial regeneration. At 28 days, nab-rapamycin led to significant reductions in luminal stenosis, 17% (interquartile range, 12%-35%) versus 10% (interquartile range, 8.3%-14%), P=0.001, medial cell proliferation, P<0.001, and fibrosis, P<0.001. There were significantly fewer adventitial leukocytes at 3 days, P<0.001, but no difference at 28 days. Pharmacokinetic analysis (single-injury model) found rapamycin concentrations 1500× higher in perivascular tissues than in blood at 1 hour. Perivascular rapamycin persisted ≥8 days and was not detectable at 28 days.. Adventitial nab-rapamycin injection was safe and significantly reduced luminal stenosis in a porcine femoral artery balloon angioplasty model. Observed reductions in early adventitial leukocyte infiltration and late medial cell proliferation and fibrosis suggest an immunosuppressive and antiproliferative mechanism. An intraluminal microinfusion catheter for adventitial injection represents an alternative to stent- or balloon-based local drug delivery.

Topics: Adventitia; Angioplasty, Balloon; Animals; Arteritis; Cell Movement; Cell Proliferation; Constriction, Pathologic; Disease Models, Animal; Dose-Response Relationship, Drug; Femoral Artery; Fibrosis; Injections, Intra-Arterial; Leukocytes; Male; Nanoparticles; Sirolimus; Swine; Tunica Media

The aim was to investigate the 7-year clinical outcomes of patients treated with either drug-eluting stents (DES) or bare-metal stents (BMS) for saphenous vein graft disease (SVG).. Atherosclerotic disease in SVG has several peculiarities which make it difficult to extrapolate outcomes of the use of DES as compared to BMS, from outcomes observed in native coronary arteries. To date no long-term safety and efficacy results for DES in SVG have been published.. Between January, 2000 and December, 2005 a total of 250 consecutive patients with saphenous vein graft disease were sequentially treated with DES (either sirolimus- or paclitaxel-eluting stents) or with BMS. Yearly follow-up was performed.. At 87 months (7.25 years), a total of 101 patients died (58 [46%] in the BMS group and 43 [42%] in the DES group, P-value= 0.4). There was no significant difference in the combined endpoint mortality or myocardial infarction. Cumulative target vessel revascularisation (TVR) was higher in the BMS group compared to the DES group (41% vs. 29%, respectively; adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI]: 0.39-1.0). The cumulative incidence of major adverse cardiac events was 73% vs. 68% in the BMS and DES groups, respectively (adjusted HR 0.93, 95% CI: 0.67-1.3).. In the present study, the unrestricted use of DES for SVG lesions appeared safe and effective up to 7.25 years- and the use of DES resulted in a clinically relevant lower rate of TVR.

Topics: Aged; Angioplasty, Balloon, Coronary; Cardiovascular Agents; Chi-Square Distribution; Constriction, Pathologic; Coronary Angiography; Coronary Artery Bypass; Drug-Eluting Stents; Female; Graft Occlusion, Vascular; Humans; Kaplan-Meier Estimate; Male; Metals; Middle Aged; Myocardial Infarction; Netherlands; Paclitaxel; Predictive Value of Tests; Proportional Hazards Models; Prosthesis Design; Risk Assessment; Risk Factors; Saphenous Vein; Sirolimus; Stents; Time Factors; Treatment Outcome

Haemodialysis vascular access dysfunction caused by aggressive venous neointimal hyperplasia is a major problem for haemodialysis patients with synthetic arteriovenous (AV) grafts. Several different strategies to prevent venous stenosis by inhibiting smooth muscle cell proliferation and migration using local delivery of potent antiproliferative agents are currently under investigation. We performed this study to evaluate the efficacy of sirolimus-eluting vascular grafts in preventing stenosis and to compare the effectiveness of sirolimus-coated grafts with that of paclitaxel-coated vascular grafts that we characterized in a previous study.. AV grafts were implanted laterally between the common carotid artery and external jugular vein of 14 female Landrace pigs. Three types of grafts were implanted: grafts coated with 1.08 μg/mm(2) sirolimus (low dose, n = 6), grafts coated with 2.41 μg/mm(2) sirolimus (high dose, n = 2) and uncoated control grafts (n = 6). Animals were sacrificed 6 weeks after surgery. Cross-sections of the venous anastomoses were analysed to determine the percentage of luminal stenosis in each group, and immunohistochemistry was performed to identify the cellular phenotypes of the neointimal hyperplasia and tissues adjacent to the implanted grafts.. Compared with the control group, neointimal hyperplasia in the venous anastomoses of the groups implanted with sirolimus-coated vascular grafts was significantly suppressed without infection. The mean ± standard error values for the percentage of luminal stenosis were 75.7 ± 12.7% in the control group and 22.2 ± 1.41% in the low-dose sirolimus-coated group. Myofibroblasts and fibroblasts were the major cell types found in the neointimal hyperplasia.. Neointimal hyperplasia was effectively suppressed by sirolimus-eluting grafts. However, the inhibitory effects of sirolimus-eluting grafts were weaker than those observed for paclitaxel-coated grafts in our previous study.

Topics: Animals; Arteriovenous Shunt, Surgical; Carotid Arteries; Cell Proliferation; Constriction, Pathologic; Female; Graft Occlusion, Vascular; Hyperplasia; Jugular Veins; Models, Animal; Neointima; Paclitaxel; Polytetrafluoroethylene; Renal Dialysis; Sirolimus; Swine; Vascular Grafting

To evaluate the effect of a polymer-free Biolimus A9-eluting stent [BioFreedom (BF)], compared with that of a biodegradable polymer-based Biolimus A9-eluting stent [BioMatrix Flex (BMF)] and a bare metal stent (BMS) in balloon denuded and radiated hypercholesterolemic rabbit iliac arteries.. Rabbits were fed with 1% cholesterol diet (n = 14) for 14 days, both iliac arteries were balloon denuded and radiated, and then rabbits were switched to 0.15% cholesterol diet. After 4 weeks, BF (n = 8), BMF (n = 8), and BMS (n = 8) were deployed in denuded and radiated areas. Four weeks later animals were euthanized, arterial segments were processed for morphometry.. The neointimal area in vessels implanted with BF stents was significantly less than that seen in vessels implanted with BMS (0.90 mm(2) ± 0.14 vs. 1.29 mm(2) ± 0.23, P <0.01). Percent fibrin and fibrin score were higher with BMF stents compared to BMS (P <0.03 and <0.04) and giant cell number was significantly higher with both BMF and BF stents (P < 0.01 for both). Percent endothelialization was significantly higher and % uncovered struts were lower with BMS compared to either BMF or BF stents (P < 0.05 for both).. This study demonstrates that compared to BMS, BF stents significantly decreased neointimal hyperplasia.

Topics: Absorbable Implants; Angioplasty, Balloon; Animals; Atherosclerosis; Cardiovascular Agents; Constriction, Pathologic; Disease Models, Animal; Drug-Eluting Stents; Fibrin; Hypercholesterolemia; Hyperplasia; Iliac Artery; Inflammation; Male; Metals; Neointima; Plaque, Atherosclerotic; Polymers; Prosthesis Design; Rabbits; Sirolimus; Stents; Time Factors

To present the 5-year angiographic and clinical results of a retrospective registry assessing the performance of sirolimus-eluting stents (SES) in the treatment of infrapopliteal atherosclerotic disease.. From 2004 to 2009, 158 patients (95 men; mean age 71.9 years) with chronic lower limb ischemia (Rutherford categories 3-6) underwent primary SES placement in focal infrapopliteal lesions. The angiographic endpoint was patency, defined as freedom from in-stent stenosis (ISS) >50%. Clinical endpoints were death, amputation, and bypass surgery. Results were correlated with patient and lesion characteristics and cumulative outcomes were assessed with Kaplan-Meier analysis.. Technical success was achieved in all cases. The primary patency rates were 97.0% after 6 months, 87.0% after 12 months, and 83.8% at 60 months. In-stent stenosis was predominantly observed in the first year after stent placement. Female gender was associated with a higher rate of ISS. During clinical follow-up of 144 (91%) patients over a mean 31.1±20.3 months, there were 27 (18.8%) deaths, 4 (2.8%) amputations, and no bypass surgery. Clinical status improved in 92% of the patients with critical limb ischemia (CLI) and 77% of the patients suffering from claudication (p=0.022).. Treatment of focal infrapopliteal lesions with SES showed encouraging long-term angiographic results in this registry. Clinical improvement was evident, but more pronounced in CLI patients than in patients suffering from claudication. Further studies are needed to evaluate the potential clinical benefit of SES as compared to balloon angioplasty or bare metal stents in the treatment of infrapopliteal lesions.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty, Balloon; Atherosclerosis; Cardiovascular Agents; Chi-Square Distribution; Chronic Disease; Constriction, Pathologic; Drug-Eluting Stents; Female; Germany; Humans; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Middle Aged; Popliteal Artery; Proportional Hazards Models; Prosthesis Design; Radiography; Registries; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Time Factors; Treatment Outcome; Vascular Patency; Vascular Surgical Procedures

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17±0.07 mm vs. 0.28±0.11 mm) and area percent stenosis (22±9% vs. 35±12%) were significantly reduced (p<0.05) by the AC-SES compared to the BMS 30 days after stent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity.

Topics: Animals; Anti-Inflammatory Agents; Constriction, Pathologic; Coronary Vessels; Crystallization; Drug Delivery Systems; Drug-Eluting Stents; Lactic Acid; Models, Biological; Neointima; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Sirolimus; Swine; Tunica Media

Topics: Aged, 80 and over; Constriction, Pathologic; Coronary Angiography; Drug-Eluting Stents; Graft Occlusion, Vascular; Humans; Immunosuppressive Agents; Male; Mammary Arteries; Postoperative Complications; Saphenous Vein; Sirolimus; Tomography, X-Ray Computed; Vascular Diseases; Vascular Grafting

Pulmonary vein (PV) stenosis (PVS) is a complication of radiofrequency PV isolation (PVI). Reported restenosis rates after balloon dilatation and bare-metal stent implantation are high. Drug-eluting stent implantation (DES) has not been reported in the setting of PVS.. Patients suspected of having PVS after PVI based on clinical symptoms and transesophageal echocardiography (TEE) follow-up (FU) were referred for PV DES. One or more branches of the affected PV as documented by angiography were stented (paclitaxel or zotarolimus DES). Follow-up consisted of repeat PV angiography and TEE. Over a period of 2 years, five patients were treated with a total of eight DES. A paclitaxel DES was used in seven of eight implants. Mean FU was 12 ± 14 months during which all patients remained asymptomatic. Transesophageal echocardiography Doppler maximal flow velocity (V(max)) of the affected PVs rose from 58 ± 6 cm/s pre-PVI to 207 ± 20 cm/s pre-DES (+358%, P < 0.0001). After DES, V(max) decreased acutely with 86 ± 15 cm/s (-58%, P < 0.01). During FU, V(max) remained stable in three patients and increased moderately in one. Angiography at 3 months confirmed absence of restenosis in the first three patients and moderate (40%) restenosis in one patient. In one patient, an increase of V(max) back to pre-DES values correlated with a 65% peri-stent stenosis, treated with a redo DES. In total, after seven primary DES only one (asymptomatic) proximal margin restenosis required re-stenting.. Initial experience with DES for PV stenosis suggests an excellent stent patency rate. Transesophageal echocardiography Doppler measurements provide a viable way of monitoring stent patency.

Topics: Adult; Aged; Atrial Fibrillation; Catheter Ablation; Constriction, Pathologic; Drug-Eluting Stents; Echocardiography, Transesophageal; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Paclitaxel; Pulmonary Veins; Retrospective Studies; Secondary Prevention; Sirolimus; Treatment Outcome; Vascular Diseases

To report the long-term outcomes of a single-center prospective study investigating primary placement of everolimus-eluting metal stents for recanalization of long infrapopliteal lesions compared to a matched historical control group treated with plain balloon angioplasty and provisional placement of bare metal stents in a bailout manner.. The study included 81 patients (63 men; mean age 71 years, range 45-85) suffering from critical limb ischemia (CLI) and angiographically proven long-segment (at least 1 lesion >4.5 cm) de novo infrapopliteal artery disease who underwent below-the-knee revascularization with either primary placement of everolimus-eluting stents (n = 47, 51 limbs, 102 lesions) or angioplasty and bailout bare metal stenting (n = 34, 36 limbs, 72 lesions). Clinical and angiographic follow-up was collected at regular time intervals. Primary clinical and angiographic endpoints included patient survival, major amputation-free survival, angiographic primary patency, angiographic binary restenosis (>50%), and overall event-free survival. Results were stratified according to endovascular treatment received. Multivariable Cox proportional hazards regression analysis was applied to adjust for confounding factors of heterogeneity.. Baseline demographics were well matched. No significant differences were identified between the 2 groups with regard to overall 3-year patient survival (82.2% versus 65.7%; p = 0.90) and amputation-free survival (77.1% versus 86.9%; p = 0.20). Up to 3 years, lesions fully covered with everolimus-eluting stents were associated with significantly higher primary patency [hazard ratio (HR) 7.98, 95% CI 3.69 to 17.25, p < 0.0001], reduced binary restenosis (HR 2.94, 95% CI 1.74 to 4.99, p < 0.0001), and improved overall event-free survival (HR 2.19, 95% CI 1.16 to 4.13, p = 0.015) versus the matched historical control group.. Primary infrapopliteal everolimus-eluting stenting for CLI treatment significantly inhibits restenosis and improves long-term angiographic patency and overall patient event-free survival compared to balloon angioplasty and bailout bare metal stenting.

Topics: Aged; Aged, 80 and over; Amputation, Surgical; Angioplasty, Balloon; Arterial Occlusive Diseases; Cardiovascular Agents; Constriction, Pathologic; Critical Illness; Disease-Free Survival; Drug-Eluting Stents; Everolimus; Female; Greece; Humans; Ischemia; Kaplan-Meier Estimate; Lower Extremity; Male; Metals; Middle Aged; Popliteal Artery; Proportional Hazards Models; Prospective Studies; Radiography; Risk Assessment; Risk Factors; Sirolimus; Stents; Time Factors; Treatment Outcome; Vascular Patency

Clinical experience with coronary stent implantation in children is very limited. In-stent restenosis, thrombosis, and aneurysm formation are known complications. Recently, fracture of a drug-eluting stent was reported to be a cause of in-stent restenosis, but the natural course of stent fracture and proper management options remain uncertain. This report describes the case of a 7-year-old boy with a sirolimus-eluting stent implanted to treat stenosis of a coronary artery bypass graft who showed complete stent fracture and aneurysm formation. During the 2-year follow-up period, the boy experienced complete regression of the aneurysm without in-stent restenosis.

Topics: Child; Constriction, Pathologic; Coronary Aneurysm; Coronary Angiography; Coronary Artery Bypass; Drug-Eluting Stents; Humans; Male; Prosthesis Failure; Remission, Spontaneous; Sirolimus; Subclavian Artery

Topics: Bile Duct Diseases; Biopsy; Constriction, Pathologic; Cyclosporine; Humans; Liver; Liver Cirrhosis; Liver Failure; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Sarcoidosis; Sarcoidosis, Pulmonary; Sirolimus; Time Factors; Treatment Outcome

To determine the efficacy of sirolimus-eluting bioabsorbable magnesium alloy stents (SEBMAS) in restenosis prevention.. A balloon-expandable bioabsorbable magnesium alloy stent (BMAS) was created and coated with biodegradable poly(lactic acid-co-trimethylene carbonate) that contained the antiproliferative drug sirolimus (140 ± 40 µg/cm²). Both the uncoated BMAS and the coated SEBMAS were deployed 2 cm apart in balloon-injured infrarenal abdominal aortas of 20 New Zealand white rabbits. The stented aortic segments were removed at 30, 60, 90, and 120 days (5 rabbits per interval) after implantation. The average stent strut sectional area of each group was measured to evaluate the degree of magnesium corrosion and to forecast the biodegradation time profile of the magnesium stent. Histology and histopathology of the sectioned stented aortic segments were performed to evaluate neointima formation, endothelialization, and inflammation.. The SEBMAS degraded gradually after being implanted into the rabbit aorta, and total biocorrosion occurred after ~120 days. In all groups, the lumen area was significantly greater, but the neointimal area was significantly smaller in SEBMAS segments compared with the uncoated BMAS segments (p < 0.05) at all time points. There was no significant difference in the injury or inflammation scores between the groups. Endothelialization was delayed at 30 days in the SEBMAS segments vs. the uncoated BMAS segments.. SEBMAS further reduces intimal hyperplasia and improves the lumen area when compared to uncoated BMAS; however, it delays vascular healing and endothelialization.

Topics: Alloys; Angioplasty; Animals; Aorta, Abdominal; Aortic Diseases; Arterial Occlusive Diseases; Cardiovascular Agents; Cell Proliferation; Coated Materials, Biocompatible; Constriction, Pathologic; Dioxanes; Disease Models, Animal; Drug-Eluting Stents; Endothelial Cells; Hyperplasia; Lactic Acid; Magnesium; Male; Polyesters; Polymers; Prosthesis Design; Rabbits; Secondary Prevention; Sirolimus; Time Factors; Wound Healing

To explore the effects of pretreatment of carbopol-encapsulated rapamycin-loaded nanoparticles (RPM-NP) on vein graft stenosis in a rabbit vein graft model.. A segment of common carotid artery was replaced with a segment of external jugular vein in 40 rabbits. They were separated into four treatment groups, i.e. Group A: vein grafts were pretreated with intraluminal RPM-NP perfusion; Group B: peripheral venous veins were injected with RPM-NP; Group C: vein grafts received an equivalent perfusion of empty vehicle; Group D: vein grafts received no treatment. At Day 28 post-operation, the grafts and normal veins were harvested for histological examinations to analyze the indicators of intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index.. At Day 28 post-operation, the intimal/media thickness ratios were 0.26 ± 0.02, 0.73 ± 0.05, 0.71 ± 0.04, 0.69 ± 0.03 and 0.24 ± 0.01 in Groups A, B, C and D and the normal vein; the collagen volume index 0.24 ± 0.03, 0.56 ± 0.06, 0.53 ± 0.07, 0.49 ± 0.08 and 0.21 ± 0.01 respectively. Compared with the normal veins, the pathological indicators of vein graft intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index had significant differences in Groups B, C and D (all P < 0.05). But there were no significant differences among 3 groups (all P > 0.05). Compared with the normal vein, the parameters of vein graft intimal thickness, internal diameter, intimal/media thickness ratio and collagen volume index had no significant difference in Group A (all P > 0.05). But as compared with other groups, these indicators had statistical significant difference in Group A (all P < 0.05).. The local pretreatment of isolated vein with rapamycin nanoparticles may inhibit neointimal hyperplasia and prevent effectively vein graft stenosis.

Topics: Animals; Carotid Artery, Common; Constriction, Pathologic; Endothelium, Vascular; Female; Graft Occlusion, Vascular; Male; Nanoparticles; Rabbits; Sirolimus; Veins

In previous studies, the minimal luminal diameter (MLD) of lesions treated with a bare metal stent (BMS) was shown to improve from 6 months to 3 years. However, the long-term response to a sirolimus-eluting stent (SES) implantation remains unclear.. To evaluate 6-month, 12-month and 3-year outcomes, clinical and angiographic follow-up data were analyzed for 367 consecutive patients (506 de novo lesions) who underwent successful SES implantation compared to follow-up data for 617 consecutive patients (802 de novo lesions) who underwent BMS implantation. Clinical follow-up information was obtained for 363 SES-treated patients (98.9%) and 581 BMS-treated patients (94.2%) at 1 year, and 334 SES-treated patients (91.0%) and 566 BMS-treated patients (91.7%) at 3 years. At 3 years, there were no significant differences in the cumulative cardiac death and myocardial infarction. Target lesion revascularization (TLR) rates were significantly higher in BMS-treated patients than in SES-treated patients. In BMS-treated patients, most TLR was performed within 450 days, however, after 450 days, the TLR rate was significantly lower than that for the SES-treated patients. In quantitative coronary angiographic data, among lesions that required no revascularization at the initial 12-month follow up, MLD increased significantly from the 12-month to the 3-year follow-up angiography in BMS-treated lesions. However, MLD decreased significantly in SES-treated lesions.. From a 12-month follow-up to a 3-year follow-up, stenosis in BMS-treated lesions regressed, but stenosis in SES-treated lesions progressed. And late TLR was more frequently required in the SES-treated patients.

Topics: Aged; Aged, 80 and over; Constriction, Pathologic; Death; Disease Progression; Drug-Eluting Stents; Female; Humans; Incidence; Male; Middle Aged; Myocardial Infarction; Retrospective Studies; Sirolimus; Stents; Treatment Outcome

To report 12-month outcomes following application of sirolimus-eluting stents (SES) in infrapopliteal arteries in patients with chronic limb ischemia.. A prospective single-center study was conducted involving 146 consecutive patients (102 men; mean age 73+/-9 years) with Rutherford-Becker categories 2 to 5 lower limb ischemia who underwent SES placement. The average degree of stenosis at baseline was 86%+/-5%; there were 44 (30%) occlusions. The main study endpoint was the 1-year primary patency rate, defined as freedom from in-stent restenosis (luminal narrowing > or =70%) detected with angiography or, if appropriate, with duplex ultrasound. Secondary endpoints included the 6-month primary patency rate, secondary patency rate, ankle-brachial index (ABI), and changes in the Rutherford-Becker classification.. Fifteen (10%) patients were lost to follow-up, and 27 (18%) patients died during the follow-up period, leaving 104 patients undergoing the 6- and 12-month follow-up examinations. After 6 months and 1 year, the primary patency rates were 88.5% and 83.7%, respectively. The mean ABI increased from 0.6+/-0.4 at baseline to 0.8+/-0.2 after 6 months and remained significantly improved during 1-year follow-up (p<0.0001). The mean Rutherford-Becker classification decreased from 3.3+/-0.8 at baseline to 0.9+/-1.1 (p<0.0001) after 1 year.. Treatment of infrapopliteal arteries with SES yields encouraging long-term results that compare favorably with previously published data on bare metal stents or plain balloon angioplasty.

Topics: Aged; Aged, 80 and over; Angioplasty, Balloon; Ankle Brachial Index; Arterial Occlusive Diseases; Cardiovascular Agents; Chronic Disease; Constriction, Pathologic; Disease-Free Survival; Drug-Eluting Stents; Female; Germany; Humans; Ischemia; Kaplan-Meier Estimate; Logistic Models; Lower Extremity; Male; Middle Aged; Odds Ratio; Popliteal Artery; Prospective Studies; Prosthesis Design; Radiography; Recurrence; Registries; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Ultrasonography, Doppler, Duplex; Vascular Patency

Topics: Angioplasty, Balloon; Arterial Occlusive Diseases; Cardiovascular Agents; Chronic Disease; Constriction, Pathologic; Drug-Eluting Stents; Humans; Ischemia; Limb Salvage; Lower Extremity; Popliteal Artery; Prosthesis Design; Recurrence; Risk Assessment; Risk Factors; Severity of Illness Index; Sirolimus; Time Factors; Treatment Outcome; Vascular Patency

Topics: Cardiac Catheterization; Constriction, Pathologic; Drug-Eluting Stents; Equipment Failure; Everolimus; Follow-Up Studies; Heart Transplantation; Humans; Incidence; Recurrence; Sirolimus; Transplantation, Homologous; Ultrasonography, Interventional; Vascular Diseases

The introduction of the drug-eluting stent (DES) has revolutionized the field of interventional cardiology during the past decade. Initial pivotal randomized clinical trials showed a large reduction in restenosis rates and the need for repeat intervention with DES compared with bare-metal stents. The three main components of a DES are 1) the stent platform, 2) a coating facilitating elution of the drug (mostly a polymer), and 3) a antiproliferative/anti-inflammatory drug. Currently, two classes of drugs are widely used in DES, Taxanes, including its best-known member Paclitaxel, and Rapamycins, which include Sirolimus and its analogues such as Everolimus, Zotarolimus and Biolimus A9. The first DES to receive United States Food and Drug Administration approval was the Sirolimus-eluting stent. Recently, two other stent types eluting a Sirolimus-analogue were approved; the Zotarolimus-eluting stent and the Everolimus-eluting stent. Biolimus A9-eluting stents, using biodegradable polymers, are currently approved and marketed outside of the United States. This review article focusses on the clinical studies that have been performed with DES eluting Sirolimus or its analogues.

Topics: Constriction, Pathologic; Everolimus; Humans; Sirolimus; Stents

No data are currently available on the role of oral sirolimus in the prevention of recurrent stenosis in the periphery. We report the effects of oral sirolimus in the prevention of recurrent infrainguinal obstructions in patients with complex peripheral arterial disease. Three patients with ischemic rest pain of the lower limbs and repeated short-term need for surgical and/or endovascular revascularization: 9 times within 12 months, 7 times within 15 months, 11 times within 26 months, respectively. Oral sirolimus on a case by case basis, resulted in less frequent restenosis and longer intervention-free intervals: three re-interventions within 37 months in the first patient, one balloon angioplasty within 17 months in the second, and three re-interventions within 21 months in the third patient, respectively. Side effects, in particular dyspepsia and diarrhoea, were mild and tolerable. To our knowledge, this is the first report to show that oral sirolimus was successfully administered in patients with recurrent excessive neointimal proliferation after revascularization of peripheral arterial lesions lowering the necessity of re-intervention and hence prolonging intervention-free intervals.

Topics: Administration, Oral; Aged; Angioplasty, Balloon; Cardiovascular Agents; Constriction, Pathologic; Female; Humans; Ischemia; Lower Extremity; Male; Middle Aged; Peripheral Vascular Diseases; Reoperation; Saphenous Vein; Secondary Prevention; Sirolimus; Thrombectomy; Treatment Failure; Vascular Surgical Procedures

Cardiomyocyte hypertrophy differs according to the stress exerted on the myocardium. While pressure overload-induced cardiomyocyte hypertrophy is associated with depressed contractile function, physiological hypertrophy after exercise training associates with preserved or increased inotropy. We determined the activation state of myocardial Akt signaling with downstream substrates and fetal gene reactivation in exercise-induced physiological and pressure overload-induced pathological hypertrophies. C57BL/6J mice were either treadmill trained for 6 weeks, 5 days/week, at 85-90% of maximal oxygen uptake (VO(2max)), or underwent transverse aortic constriction (TAC) for 1 or 8 weeks. Total and phosphorylated protein levels were determined with SDS-PAGE, and fetal genes by real-time RT-PCR. In the physiologically hypertrophied heart after exercise training, total Akt protein level was unchanged, but Akt was chronically hyperphosphorylated at serine 473. This was accompanied by activation of the mammalian target of rapamycin (mTOR), measured as phosphorylation of its two substrates: the ribosomal protein S6 kinase-1 (S6K1) and the eukaryotic translation initiation factor-4E binding protein-1 (4E-BP1). Exercise training did not reactivate the fetal gene program (beta-myosin heavy chain, atrial natriuretic factor, skeletal muscle actin). In contrast, pressure overload after TAC reactivated fetal genes already after 1 week, and partially inactivated the Akt/mTOR pathway and downstream substrates after 8 weeks. In conclusion, changes in opposite directions of the myocardial Akt/mTOR signal pathway appears to distinguish between physiological and pathological hypertrophies; exercise training associating with activation and pressure overload associating with inactivation of the Akt/mTOR pathway.

Topics: Adaptor Proteins, Signal Transducing; Animals; Aorta, Thoracic; Cardiomegaly; Carrier Proteins; Cell Cycle Proteins; Cell Size; Constriction, Pathologic; Echocardiography; Enzyme Activation; Eukaryotic Initiation Factors; Exercise Test; Female; Heart Ventricles; Hypertrophy; Mice; Mice, Inbred C57BL; Models, Biological; Myocardium; Myocytes, Cardiac; Phosphoproteins; Phosphorylation; Physical Conditioning, Animal; Protein Kinases; Proto-Oncogene Proteins c-akt; Random Allocation; Ribosomal Protein S6 Kinases; Serine; Signal Transduction; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Drug eluting stents prevent vascular restenosis but can delay endothelial healing. A rabbit femoral artery model of stenosis formation after vascular injury was used to study the effect of intramural delivery of alpha(v)beta(3)-integrin-targeted rapamycin nanoparticles on vascular stenosis and endothelial healing responses.. Femoral arteries of 48 atherosclerotic rabbits underwent balloon stretch injury and were locally treated with either (1) alpha(v)beta(3)-targeted rapamycin nanoparticles, (2) alpha(v)beta(3)-targeted nanoparticles without rapamycin, (3) nontargeted rapamycin nanoparticles, or (4) saline. Intramural binding of integrin-targeted paramagnetic nanoparticles was confirmed with MR molecular imaging (1.5 T). MR angiograms were indistinguishable between targeted and control arteries at baseline, but 2 weeks later they showed qualitatively less luminal plaque in the targeted rapamycin treated segments compared with contralateral control vessels. In a first cohort of 19 animals (38 vessel segments), microscopic morphometric analysis of the rapamycin-treated segments revealed a 52% decrease in the neointima/media ratio (P<0.05) compared to control. No differences (P>0.05) were observed among balloon injured vessel segments treated with alpha(v)beta(3)-targeted nanoparticles without rapamycin, nontargeted nanoparticles with rapamycin, or saline. In a second cohort of 29 animals, endothelial healing followed a parallel pattern over 4 weeks in the vessels treated with alpha(v)beta(3)-targeted rapamycin nanoparticles and the 3 control groups.. Local intramural delivery of alpha(v)beta(3)-targeted rapamycin nanoparticles inhibited stenosis without delaying endothelial healing after balloon injury.

Topics: Angioplasty, Balloon; Animals; Anti-Bacterial Agents; Constriction, Pathologic; Drug-Eluting Stents; Endothelium, Vascular; Femoral Artery; Integrin alphaVbeta3; Magnetic Resonance Imaging; Male; Nanomedicine; Nanoparticles; Rabbits; Sirolimus

Topics: Angioplasty, Balloon; Animals; Anti-Bacterial Agents; Atherosclerosis; Cardiovascular Diseases; Constriction, Pathologic; Endothelium, Vascular; Femoral Artery; Humans; Nanomedicine; Nanoparticles; Rabbits; Sirolimus

Sirolimus (SRL), an inhibitor of human arterial smooth muscle cell (ASMC) proliferation and migration, prevents in-stent restenosis (ISR). Little is known about the effect of SRL on the extracellular matrix (ECM) component, hyaluronan, a key macromolecule in neointimal hyperplasia and inflammation. In this study, we investigated SRL regulation of the synthesis of hyaluronan by cultured human ASMC and the effect of SRL on hyaluronan mediated monocyte adhesion to the ECM. Hyaluronan production on a per cell basis was significantly inhibited by SRL at 4 days and remained so through 10 days. This reduction was correlated with reduced levels of hyaluronan synthase mRNAs while hyaluronan degradation rates were unchanged. Poly I:C, a viral mimetic, caused increased hyaluronan accumulation by ASMC cell layers and this increase was inhibited by SRL. The inhibition was paralleled by a reduction in hyaluronan-dependent monocyte adhesion to the ECM. This study demonstrates that SRL not only regulates the proliferation of ASMC but reduces the production of hyaluronan by these cells. This alteration in ECM composition results in reduced monocyte adhesion to the ECM in cultures of ASMC. Alterations in hyaluronan accumulation may contribute to the inhibition of ISR that is achieved by SRL.

Topics: Arteries; Cell Adhesion; Cell Movement; Cell Proliferation; Constriction, Pathologic; Extracellular Matrix; Humans; Hyaluronic Acid; Immunosuppressive Agents; Inflammation; Monocytes; Muscle, Smooth; Sirolimus; Time Factors

Endovascular treatment of vertebral artery stenosis and subclavian artery stenosis are low-risk procedures, but there are few reports of the best approach for subclavian-vertebral artery stenoses where there is an ostial stenosis of a vertebral artery that arises from a stenosed segment of the subclavian artery. This is a report of two cases with subclavian-vertebral artery stenosis that were treated with two different techniques. One-year follow up demonstrated widely patent stents. Also, to our knowledge, this is the first report of the use of the crush-stenting technique using drug-eluting stents in subclavian-vertebral artery bifurcation lesions.

Topics: Adult; Aged; Catheterization; Constriction, Pathologic; Female; Humans; Immunosuppressive Agents; Prostheses and Implants; Radiography; Sirolimus; Stents; Subclavian Artery; Vertebral Artery

The aim of this study was to examine the anti-inflammatory effect of abciximab-coated stent in a porcine coronary overstretch restenosis model. Ten abciximab-coated stents, ten sirolimus-eluting stents (SES), and ten paclitaxel-eluting stents (PES) were deployed with oversizing (stent/artery ratio 1.3:1) in porcine coronary arteries, and histopathologic analysis was done at 28 days after stenting. There were no significant differences in the neointima area normalized to injury score and inflammation score among the three stent groups (1.58 +/- 0.43 mm(2), 1.57 +/-0.39 mm(2) in abciximab-coated stent group vs. 1.69 +/- 0.57 mm(2), 1.72 +/- 0.49 mm(2) in the SES group vs. 1.92 +/- 0.86 mm(2), 1.79 +/- 0.87 mm(2) in the PES group, respectively). In the neointima, most inflammatory cells were lymphohistiocytes. Significant positive correlations were found between the extent of inflammatory reaction and the neointima area (r=0.567, p<0.001) and percent area stenosis (r=0.587, p<0.001). Significant correlations were found between the injury score and neointimal area (r=0.645, p<0.001), between the injury score and the inflammation score (r=0.837, p<0.001), and between the inflammation score and neointimal area (r=0.536, p=0.001). There was no significant difference in the inflammatory cell counts normalized to injury score among the three stent groups (75.5 +/- 23.1/microL in abciximabcoated stent group vs. 78.8 +/- 33.2/microL in the SES group vs. 130.3 +/- 46.9/microL in the PES group). Abciximab-coated stent showed comparable inhibition of inflammatory cell infiltration and neointimal hyperplasia with other drug-eluting stents in a porcine coronary restenosis model.

Topics: Abciximab; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Arteries; Constriction, Pathologic; Coronary Restenosis; Disease Models, Animal; Drug-Eluting Stents; Female; Hyperplasia; Immunoglobulin Fab Fragments; Inflammation; Paclitaxel; Sirolimus; Swine; Tunica Intima

Rapamycin is a specific inhibitor of the mammalian target of rapamycin (mTOR). We recently reported that administration of rapamycin before exposure to ascending aortic constriction significantly attenuated the load-induced increase in heart weight by approximately 70%.. To examine whether rapamycin can regress established cardiac hypertrophy, mice were subjected to pressure overload (ascending aortic constriction) for 1 week, echocardiography was performed to verify an increase in ventricular wall thickness, and mice were given rapamycin (2 mg x kg(-1) x d(-1)) for 1 week. After 1 week of pressure overload (before treatment), 2 distinct groups of animals became apparent: (1) mice with compensated cardiac hypertrophy (normal function) and (2) mice with decompensated hypertrophy (dilated with depressed function). Rapamycin regressed the pressure overload-induced increase in heart weight/body weight (HW/BW) ratio by 68% in mice with compensated hypertrophy and 41% in mice with decompensated hypertrophy. Rapamycin improved left ventricular end-systolic dimensions, fractional shortening, and ejection fraction in mice with decompensated cardiac hypertrophy. Rapamycin also altered the expression of some fetal genes, reversing, in part, changes in alpha-myosin heavy chain and sarcoplasmic reticulum Ca2+ ATPase.. Rapamycin may be a therapeutic tool to regress established cardiac hypertrophy and improve cardiac function.

Topics: Adaptation, Physiological; Animals; Aorta; Aortic Diseases; Cardiomegaly; Cell Size; Constriction, Pathologic; Drug Evaluation, Preclinical; Gene Expression Regulation; Male; Mice; Myocytes, Cardiac; Organ Size; Phosphorylation; Protein Kinases; Protein Processing, Post-Translational; Ribosomal Protein S6; Sirolimus; Stroke Volume; TOR Serine-Threonine Kinases

Drug eluting stents (DES) release drugs that inhibit tissue growth in narrowed coronary arteries in an effort to prevent restenosis, a renarrowing of the artery. Several types of DES are under investigation in clinical trials; however, none are currently approved for use in Canada. Preliminary trial data are encouraging, demonstrating greater lumen diameter and reduced restenosis with DES versus uncoated stents. If DES prove to be more effective than uncoated stents in the treatment and/or prevention of restenosis, this technology may diffuse rapidly. The total health care costs, including the cost of the stents, post-intervention therapy and possible re-intervention costs, will require assessment to determine the ultimate impact of DES.

Topics: Angioplasty, Balloon, Coronary; Canada; Clinical Trials as Topic; Constriction, Pathologic; Coronary Disease; Coronary Vessels; Cost-Benefit Analysis; Drug Approval; Drug Delivery Systems; Europe; European Union; Humans; Paclitaxel; Sirolimus; Stents; Treatment Outcome