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Parenteral and enteral nutrition support are key components of care for various medical and physiological conditions in infants, children, and adults. Nutrition support practices have advanced over time, driven by the goals of safe and sufficient delivery of needed nutrients and improved patient outcomes. These advances have been, and continue to be, dependent on research and development studies. Such studies address aspects of enteral and parenteral nutrition support: formulations, delivery devices, health outcomes, cost-effectiveness, and related metabolism. The studies are supported by public funding from the government and by private funding from foundations and from the nutrition support industry. To build public trust in nutrition support research findings, it is important to underscore ethical research conduct and reporting of results for all studies, including those with industry sponsors. In 2019, American Society for Parenteral and Enteral Nutrition's (ASPEN's) Board of Directors established a task force to ensure integrity in nutrition support research that is done as collaborative partnerships between the public (government and individuals) and private groups (foundations, academia, and industry). In this ASPEN Position Paper, the Task Force presents principles of ethical research to guide administrators, researchers, and funders. The Task Force identifies ways to curtail bias and to minimize actual or perceived conflict of interests, as related to funding sources and research conduct. Notably, this paper includes a Position Statement to describe the Task Force's guidance on Public-Private Partnerships for research and funding. This paper has been approved by the ASPEN Board of Directors.

Context: Metatarsal stress fractures are common in cleated-sport athletes. Previous authors have shown that plantar loading varies with footwear, sex, and the athletic task. Objective: To examine the effects of shoe type and sex on plantar loading in the medial midfoot (MMF), lateral midfoot (LMF), medial forefoot (MFF), middle forefoot (MidFF), and lateral forefoot (LFF) during a jump-landing task. Design: Crossover study. Setting: Laboratory. Patients or Other Participants: Twenty-seven recreational athletes (14 men, 13 women) with no history of lower extremity injury in the last 6 months and no history of foot or ankle surgery. Main Outcome Measure(s): The athletes completed 7 jumping trials while wearing bladed-cleat, turf-cleat, and running shoes. Maximum force, contact area, contact time, and the force-time integral were analyzed in each foot region. We calculated 2 × 3 analyses of variance (α = .05) to identify shoe-condition and sex differences. Results: We found no shoe × sex interactions, but the MMF, LMF, MFF, and LFF force-time integrals were greater in men (P < .03). The MMF maximum force was less with the bladed-cleat shoes (P = .02). Total foot and MidFF maximum force was less with the running shoes (P < .01). The MFF and LFF maximum forces were different among all shoe conditions (P < .01). Total foot contact area was less in the bladed-cleat shoes (P = .01). The MMF contact area was greatest in the running shoes (P < .01). The LFF contact area was less in the running shoes (P = .03). The MFF and LFF force-time integrals were greater with the bladed-cleat shoes (P < .01). The MidFF force-time integral was less in the running shoes (P < .01). Conclusions: Independent of shoe, men and women loaded the foot differently during a jump landing. The bladed cleat increased forefoot loading, which may increase the risk for forefoot injury. The type of shoe should be considered when choosing footwear for athletes returning to activity after metatarsal stress fractures.

Background— Early clinical studies demonstrated the feasibility of local paclitaxel delivery in reducing restenosis after treatment of de novo coronary lesions in small patient populations. Methods and Results— We conducted a randomized, double-blind trial of 536 patients at 38 medical centers evaluating slow-release (SR) and moderate-release (MR) formulations of a polymer-based paclitaxel-eluting stent (TAXUS) for revascularization of single, primary lesions in native coronary arteries. Cohort I compared TAXUS-SR with control stents, and Cohort II compared TAXUS-MR with a second control group. The primary end point was 6-month percent in-stent net volume obstruction measured by intravascular ultrasound. Secondary end points were 6-month angiographic restenosis and 6- and 12-month incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and repeat revascularization. At 6 months, percent net volume obstruction within the stent was significantly lower for TAXUS stents (7.9% SR and 7.8% MR) than for respective controls (23.2% and 20.5%; P P P =0.0002). The incidence of major adverse cardiac events at 12 months was significantly lower ( P =0.0192) in the TAXUS-SR (10.9%) and TAXUS-MR (9.9%) groups than in controls (22.0% and 21.4%, respectively), predominantly because of a significant reduction in repeat revascularization of the target lesion in TAXUS-treated patients. Conclusions— Compared with a bare metal stent, paclitaxel-eluting stents reduced in-stent neointimal formation and restenosis and improved 12-month clinical outcome of patients with single de novo coronary lesions.

Aims: Defining vessel diameters and angles that comprise coronary side-branch intersections could assist in tailoring treatments to match anatomy, improve haemodynamic flow, and minimise mechanical trauma. We sought to characterise intersections of main vessels and side-branches by measuring actual diameters, angles, and shapes at the ostia in human coronary arteries. Methods and results: Polymer casts were created using coronary trees from 23 adult cadaver hearts. Seventy-five arterial intersections between main vessels and side-branches were captured using the combination of a microscope (Smartscope MVP100) and computer program (Gage-X metrology software) specifically calibrated for video-based inspection and measurement (34-fold magnification). The intersection between main vessels and side-branches was a multifaceted, curvilinear transition rather than a bisecting angle. The shape of the ostia was typically elliptical rather than circular. Mean diameters were 2.88 mm in proximal main vessels, 2.34 mm in ostia, and 2.00 mm in side-branches (first-level branches). Obtuse proximal (150 degrees) and distal (111 degrees) angles with accentuated side-branch taper create a "barn door" effect with wider curvature at the bottom. Conclusions: Matching treatments to these various forms of asymmetry at the main vessel-to-side-branch intersection may minimise injury and optimise scaffolding, and haemodynamic flow.

Objectives: The multicenter, single-arm BEACH (Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients) evaluated outcomes in high-surgical-risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EX/EZ Emboli Protection System (Boston Scientific, Natick, Massachusetts). Background: Carotid artery stent (CAS) placement offers a less invasive alternative for high-risk surgical carotid endarterectomy (CEA) patients. Methods: The trial enrolled 480 pivotal patients who were candidates for carotid revascularization but considered high surgical risk due to pre-specified anatomic criteria and/or medical comorbidities. The primary end point (all stroke, death, or Q-wave myocardial infarction [MI] through 30 days; non-Q-wave MI through 24 h; and ipsilateral stroke or neurologic death through 1 year) was compared with a proportionally weighted objective performance criterion (OPC) of 12.6% for published surgical endarterectomy results in similar patients, plus a pre-specified noninferiority margin of 4%. Results: Among pivotal patients, 41.2% were at high surgical risk due to comorbid risk factors, and 58.8% due to anatomic risk factors; 76.7% were asymptomatic with flow-limiting carotid stenosis >80%. At 1 year, the composite primary end point occurred in 8.9% (40 of 447), with a repeat revascularization rate of 4.7%. With an upper 95% confidence limit of 11.5% for the primary composite end point, the BEACH trial results met the pre-specified criteria for noninferiority relative to the calculated OPC plus noninferiority margin (16.6%) for historical surgical CEA outcomes in similar patients (p < 0.0001 for noninferiority). Conclusions: The BEACH trial results demonstrate that CAS with the WALLSTENT plus FilterWire embolic protection is non-inferior (equivalent or better than) to CEA at 1-year in high-surgical-risk patients (Boston Scientific Embolic Protection, Inc. [EPI]: A Carotid Stenting Trial for High-Risk Surgical Patients [BEACH]; http://clinicaltrials.gov/ct2/show/NCT00316108?term=NCT00316108r NCT00316108).

Late loss has been used as a reliable surrogate end point for evaluation and differentiation of short-term performance of drug-eluting stents. This study investigated the consistency between angiographic and intravascular ultrasound (IVUS) outcomes of late lumen loss (late loss) and neointimal growth to measure restenotic plaque load in TAXUS and bare metal stents. The randomized TAXUS II trial evaluates the polymer-based paclitaxel-eluting TAXUS stent in slow- and moderate-release formulations. Serial angiographic and IVUS analyses were available in 155 event-free patients (bare metal stent, 74; TAXUS stent, 81) after the procedure, at 6 months, and at 2 years. For this subanalysis, quantitative coronary angiographic (QCA) and IVUS measurements were used to derive late loss and neointimal volume. From after the procedure to 6 months, quantitative coronary angiography and IVUS showed matching results for the 2 groups with significant decreases in late loss and neointimal volume in the TAXUS versus the control group. From 6 months to 2 years, QCA and IVUS measurements also showed results similar to those in the control group, demonstrating neointimal compaction over time. However, in the TAXUS group, QCA late loss showed a nonsignificant decrease from 6 months to 2 years, whereas IVUS neointimal volume increased. In conclusion, although QCA and IVUS results were similar over the first 6 months, long-term assessment of changes in restenotic plaque load showed discrepant findings for the TAXUS. These findings suggest the need for critical reevaluation of current end points and the use of more precise techniques to detect lumen and stent boundaries.

The use of a medical device outside of its approved label is commonly referred to as “off-label use.” Off-label use arises when physicians see the opportunity to leverage an approved therapy for an unmet patient need. This practice typically occurs on a case by case basis without clear documentation of indication, frequency, or outcomes. Sponsors have a responsibility to consider formal indication expansion depending on the actual use, how well the therapy fits the unmet need, product iteration cycles, adoption speed, resource demands, and the clinical risk to benefit ratio. This responsibility is particularly relevant for breakthrough technologies where adoption patterns can span a variety of uses. For Boston Scientific's drug-eluting stent program, a surveillance program was developed in collaboration with the FDA to compile information on practice patterns and safety outcomes for the TAXUS® Express2™ Paclitaxel-Eluting Coronary Stent System. The ARRIVE program has used a Web-based format to collect real-time data on TAXUS stent use. This >7,000 patient registry documents both on-label and off-label use and key safety measures for the TAXUS stent. This real-world registry has successfully provided a data-driven approach to BSC's product development strategy, including the initiation of formal label expansion programs. For complex or combination products, more innovative ways of capturing risk to benefit data are needed to define off-label use and to maximize the potential therapeutic utility as supported by safety data.

Objectives This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention. Background Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up. Methods We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582). Results The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of $572 per patient with incremental cost-effectiveness ratios of $4,678 per TVR avoided and $47,798/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was $97 per patient with cost-effectiveness ratios of $760 per TVR event avoided and $5,105/QALY gained. Conclusions In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.

Objectives The objectives of the study were to evaluate the effect of angiographic follow-up on revascularization rates in the TAXUS-IV trial and to determine whether the relative benefit of paclitaxel-eluting stent implantation compared with bare metal stent implantation was modified by angiographic follow-up. Background Although several clinical trials have demonstrated that drug-eluting stents (DES) reduce restenosis compared with bare-metal stents (BMS), virtually all of these studies have incorporated angiographic follow-up. Methods In the TAXUS-IV trial, 1,314 percutaneous coronary intervention patients were randomized to receive paclitaxel-eluting stents (PES) (n = 662) or identical-appearing BMS (n = 652). Clinical outcomes were compared, stratified by assignment to angiographic follow-up or clinical follow-up alone. Results Compared with clinical follow-up alone, angiographic follow-up patients had a significantly higher rate of target vessel revascularization (TVR) at 1 year (adjusted hazard ratio [HR] 1.46; p = 0.04), with similar relative increases in PES and BMS patients. Because PES reduced TVR by ∼60% regardless of type of follow-up, assignment to angiographic follow-up tended to overestimate the absolute benefit of PES relative to clinical follow-up alone. In contrast, assessment of end points immediately before the time of follow-up angiography led to substantial underestimation of the absolute benefit of PES implantation. Conclusions Performance of mandatory angiographic follow-up increases rates of TVR among patients receiving both BMS and PES and overestimates the absolute clinical benefits of PES relative to clinical follow-up alone. Nonetheless, PES substantially reduces TVR regardless of assignment to mandatory angiographic follow-up or not. Future studies designed to determine the true clinical benefits of DES should either forgo routine angiographic follow-up or separate the time of repeat angiography from the primary clinical end point by as long as possible.

OBJECTIVES To address the safety and efficacy of drug-eluting stents (DES) in the treatment of intermediate lesions, we performed a pooled analysis of four randomized DES versus bare-metal stent (BMS) trials and assessed outcomes among patients with intermediate lesions. BACKGROUND Before the introduction of DES, intermediate coronary lesions were commonly managed based on physiologic or anatomic assessment of lesion severity. The DES may challenge this paradigm. METHODS The study population involved 167 of 2,478 randomized patients (6.7%) with intermediate lesions (diameter stenosis

Background: The BEACH trial evaluated the outcomes of carotid artery stent placement with distal emboli protection, using the Carotid Wallstent® and the FilterWire EX®/EZTM, in patients at high surgical risk for carotid endarterectomy (CEA). Methods: We enrolled 747 patients at high surgical risk for CEA due to prespecified anatomical criteria and/or medical comorbidities. The trial included both symptomatic (>50% carotid artery stenosis) as well as asymptomatic (>80% carotid artery stenosis) high surgical risk patients. Three groups of patients were included in the trial. The Roll-in (R) group (n = 189/747, [25%]) included up to nine patients per site for familiarization of the device and protocol; the Pivotal (P) group (n = 480/747, [65%]) was intended for presentation to the FDA for consideration of device approval; and a Bilateral (B) registry group (n = 78/747, [10%]) was included because of the need to treat patients with bilateral carotid artery disease. In the 480 Pivotal patients, anatomic criteria represented the most frequent high-risk surgical category for enrollment (58.8%), followed by prior CEA (34.2%), multivessel (≥2) coronary artery disease (21.7%), and contralateral carotid occlusion (18.1%). Results: The technical success rate for stent deployment and FilterWire EX/EZ deployment and retrieval was 98.2%. The mean postprocedure angiographic diameter stenosis in the Pivotal group was reduced to 10.8%, while the overall procedure success rate (

Background— Intracoronary polymer-based stent delivery of paclitaxel has been shown to be effective in reducing restenosis in simple coronary lesions, but the evidence base for contemporary use in longer, more complex coronary stenoses is lacking. Methods and Results— TAXUS VI is a prospective, multicenter, double-blind, randomized trial assessing clinical and angiographic outcomes of the TAXUS Moderate Release paclitaxel-eluting stent in the treatment of long, complex coronary artery lesions. Four hundred forty-eight patients at 44 sites were randomized (1:1) between a drug-eluting TAXUS Express 2 and an uncoated Express 2 control stent. Per protocol, the 9-month follow-up included an angiographic reevaluation in all patients. The primary end point was the rate of target-vessel revascularization 9 months after the study procedure; secondary end points included the rate of target-lesion revascularization and binary restenosis at follow-up. Mean lesion length in the study was 20.6 mm, with a mean stent-covered length of 33.4 mm. Of all lesions, 55.6% were classified as complex lesions (type C of the AHA/ACC classification). At 9 months, target-vessel revascularization was 9.1% in the TAXUS group and 19.4% in the control group ( P =0.0027; relative reduction, 53%). Target-lesion revascularization was reduced from 18.9% to 6.8%, respectively ( P =0.0001). The incidence of major adverse cardiac events was similar in the 2 groups, 16.4% and 22.5% in TAXUS and control, respectively ( P =0.12), including comparable rates for acute myocardial infarction. Binary restenosis in the stented area was reduced from 32.9% in the control group to 9.1% in the TAXUS patients ( P Conclusions— The finding that the TAXUS Moderate Release stent system is safe and effective in the treatment of long, complex coronary artery lesions provides the evidence base for the more widespread use of drug-eluting stents in contemporary clinical practice.

The enzyme dipeptidyl peptidase-IV (DPP-4) inactivates the incretin hormone glucagon-like peptide-1 (GLP-1). Because GLP-1 has therapeutic effects in patients with type 2 diabetes, but its potential is limited by a short half-life, DPP-4 inhibition is a promising approach to diabetes treatment. This study examined acute (single dose) and chronic (once-a-day dosing for 21 days) effects of the DPP-4 inhibitor vildagliptin (0.03-10 mg/kg) on plasma DPP-4 activity, intact GLP-1, glucose, and insulin after an oral glucose load in insulin-resistant Zucker fatty rats and acute effects in mildly insulin-resistant high-fat-fed normal rats. A single oral dose of vildagliptin in Zucker rats produced a rapid and dose-related inhibition of DPP-4: the minimum effective dose (MED) was 0.3 mg/kg. Glucose-induced increases of intact GLP-1 were greatly but similarly enhanced by vildagliptin at doses > or =0.3 mg/kg. Postload glucose excursions decreased, and the insulinogenic index (Deltainsulin/Deltaglucose at 10 min) increased, with an MED of 0.3 mg/kg and a maximally effective dose of 3 mg/kg. The effects of vildagliptin after chronic treatment were nearly identical to those of acute administration, and vildagliptin had no effect on body weight. In fat-fed normal rats, vildagliptin (3 mg/kg) also decreased postload glucose excursions and increased the insulinogenic index, but these effects were smaller than those in Zucker rats. Thus, vildagliptin is an orally effective incretin enhancer with antihyperglycemic activity in insulin-resistant rats and exhibits no tachyphylaxis. GLP-1-mediated augmentation of glucose-induced insulin release seems to make the major contribution to the antidiabetic properties of vildagliptin.

Objectives We sought to examine the efficacy of paclitaxel-eluting stent implantation in the left anterior descending coronary artery (LAD). Background Restenosis and recurrent cardiac events after percutaneous intervention are more common for lesions in the LAD than other native coronary arteries, and often necessitate bypass surgery. Drug-eluting stents may improve the long-term prognosis of this high-risk group. Methods In the TAXUS-IV trial, 1,314 patients with single de novo coronary lesions were assigned to implantation of the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical bare-metal stent; 536 (41%) randomized patients had LAD lesions. Results Baseline characteristics of patients with LAD lesions were well-matched between the randomized groups. Late lumen loss at nine months after paclitaxel-eluting and control stent implantation were 0.28 ± 0.51 mm and 0.54 ± 0.57 mm, respectively (p = 0.0004), and binary restenosis rates were 11.3% and 26.9%, respectively (p = 0.004). At one year, major adverse cardiac events (MACE) occurred in 13.5% of TAXUS-treated patients versus 21.2% treated with the control stent (p = 0.01). The need for bypass surgery at one year was reduced among patients randomized to the TAXUS stent (2.6% vs. 6.3%, p = 0.02). In the proximal LAD subgroup (n = 126), the one-year target vessel revascularization rate was 7.9% with the TAXUS stent and 18.6% with the bare-metal stent (p = 0.009). Conclusions Compared to bare-metal stents, implantation of polymer-based, paclitaxel-eluting stents in LAD lesions is safe, and reduces angiographic restenosis and MACE one year. Notably, the need for bypass graft surgery due to restenosis is reduced after TAXUS stent implantation in LAD lesions.

Objectives We sought to determine the safety and efficacy of polymer-regulated site-specific delivery of paclitaxel in patients with diabetes mellitus undergoing stent implantation. Background Percutaneous coronary intervention in patients with diabetes is associated with high rates of restenosis and repeat revascularization due to excessive neointimal proliferation, a process that may be blunted with the site-specific delivery of paclitaxel. Methods In the TAXUS-IV trial, 1,314 patients were prospectively randomized to the slow rate-release polymer-based paclitaxel-eluting TAXUS stent or the bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). Medically treated diabetes was present in 318 patients (24%), 105 of whom required insulin. Results Among patients with diabetes, the TAXUS stent, compared to the bare-metal stent, reduced the rate of 9-month binary angiographic restenosis by 81% (6.4% vs. 34.5%, p Conclusions The site-specific delivery of paclitaxel after coronary stent implantation is highly effective in reducing clinical and angiographic restenosis in patients with diabetes mellitus.

Objectives The aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition. Background The TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy. Methods In the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up. Results No baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 ± 43 mm3vs. 104 ± 44 mm3, p = 0.005), due to a reduction in neointimal volume (18 ± 18 mm3vs. 41 ± 23 mm3, p Conclusions Polymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition.

Objectives We sought to investigate the outcomes of paclitaxel-eluting stent implantation in patients with unstable angina or non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). Background Whether the paclitaxel-eluting stent is safe and effective in patients with acute coronary syndromes (ACS) is unknown. Methods In the TAXUS-IV trial, 1,314 patients with stable or unstable ischemic syndromes undergoing PCI were randomized to treatment with either the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). The results were stratified by the acuity of the presenting clinical syndrome. Results Acute coronary syndromes were present in 450 patients (34.2%), 237 of whom were assigned to paclitaxel-eluting stents and 213 to bare-metal stents. The baseline and procedural characteristics were well matched between the groups. Clinical outcomes at 30 days were similar with both stents. At one-year follow-up, patients with ACS assigned to the paclitaxel-eluting stent compared to the control stent had strikingly lower rates of target lesion revascularization (TLR) (3.9% vs. 16.0%, p Conclusions The use of the paclitaxel-eluting TAXUS stent was safe in patients with unstable ischemic syndromes, and was associated with marked reduction of ischemia-driven TLR and adverse cardiac events at one year.

The effect of obesity on repeat coronary revascularization and restenosis in patients who undergo stent implantation has not been reported. We therefore examined the database from the multicenter randomized TAXUS-IV trial to determine the effect of body mass index (BMI) on outcomes after bare-metal and drug-eluting stent implantation. In TAXUS-IV, patients were randomized to receive a slow-release, polymer-based, paclitaxel-eluting stent or a bare-metal stent. Outcomes were stratified by baseline BMI. Of the 1,307 randomized patients who had documented BMI, 233 (17.8%) had normal weight (BMI25 kg/m2), 531 (40.6%) were overweight (BMIor =25 to 30 kg/m2), and 543 (41.5%) were obese (BMIor =30 kg/m2). Patients who had been assigned to receive bare-metal stents and were overweight and obese compared with those who had normal weight had higher rates of 9-month binary restenosis (29.2% and 30.5% vs 9.3%, respectively; p = 0.01) and 1-year major adverse cardiac events (20.8% and 23.2% vs 11.1%, respectively; p = 0.02), whereas rates of these events did not differ significantly among those who received a paclitaxel-eluting stent (7.6% and 9.3% vs 4.9%, respectively for binary restenosis; p = 0.65; 11.3% and 10.4% vs 10.1%, respectively; p = 0.82 for major adverse cardiac events). By multivariate analysis, BMIor =30.0 kg/m2 independently predicted binary restenosis (hazard ratio 4.26, p = 0.005), 1-year target vessel revascularization (hazard ratio 1.95, p = 0.04), and major adverse cardiac events (hazard ratio 1.95, p = 0.004) in patients who received bare-metal stents but not paclitaxel-eluting stents. In conclusion, obesity is an important risk factor for clinical and angiographic restenosis and for composite major adverse cardiac events in patients who receive bare-metal stents. Paclitaxel-eluting stents attenuate the increased risk associated with obesity, such that the intermediate-term prognosis after percutaneous coronary intervention is independent of weight.

Background— The purpose of this study was to evaluate long-term vascular responses as long as 2 years after implantation of polymer-based, paclitaxel-eluting stents in contrast to uncoated stents. Methods and Results— TAXUS II is a randomized, double-blind trial comparing slow-release (SR) and moderate-release (MR) TAXUS stents with bare-metal control stents (BMSs). One hundred sixty-one event-free patients (SR, 43; MR, 41; and BMS, 77) underwent serial intravascular ultrasound (IVUS) analysis after the procedure and at 6 months and 2 years. At 2 years, neointimal responses continued to be significantly suppressed in the SR and MR groups when compared with the BMS group (BMS, 1.49±1.12 mm 2 ; SR, 0.94±0.76 mm 2 [ P =0.004]; and MR, 1.06±0.90 mm 2 [ P =0.02]). Between 6 months and 2 years, the BMS group showed compaction of the neointima (Δ, −0.22±1.05 mm 2 [ P =0.08]). In contrast, both the SR and MR groups exhibited an increase (Δ SR, 0.30±0.76 mm 2 ( P =0.01); MR, 0.41±0.94 mm 2 [ P =0.009]). Between 6 months and 2 years, the initial increase in plaque outside the stent regressed in the BMS and SR groups to levels comparable to those after the procedure, whereas expansive remodeling partially regressed in the MR group (Δ between after the procedure and 2 years BMS, −0.34±1.28 mm 2 [ P =0.05]; SR, −0.02±1.40 mm 2 [ P =0.93]; MR, 0.32±1.56 mm 2 [ P =0.27]). Conclusions— The 2-year follow-up demonstrates that neointimal suppression was dose independent and that this effect was still sustained at 2 years. However, the increase in area outside the stent seen at 6 months regressed to different extents in a dose-dependent manner at 2 years.

Background— The clinical impact of late incomplete stent apposition (ISA) for drug-eluting stents is unknown. We sought to prospectively investigate the incidence and extent of ISA after the procedure and at 6-month follow-up of paclitaxel-eluting stents in comparison with bare metal stents (BMS) and survey the clinical significance of ISA over a period of 12 months. Methods and Results— TAXUS II was a randomized, double-blind study with 536 patients in 2 consecutive cohorts comparing slow-release (SR; 131 patients) and moderate-release (MR; 135 patients) paclitaxel-eluting stents with BMS (270 patients). This intravascular ultrasound (IVUS) substudy included patients who underwent serial IVUS examination after the procedure and at 6 months (BMS, 240 patients; SR, 113; MR, 116). The qualitative and quantitative analyses of ISA were performed by an independent, blinded core laboratory. More than half of the instances of ISA observed after the procedure resolved at 6 months in all groups. No difference in the incidence of late-acquired ISA was observed among the 3 groups (BMS, 5.4%; SR, 8.0%; MR, 9.5%; P =0.306), with a similar ISA volume (BMS, 11.4 mm 3 ; SR, 21.7 mm 3 ; MR, 8.5 mm 3 ; P =0.18). Late-acquired ISA was the result of an increase of vessel area without change in plaque behind the stent. Predictive factors of late-acquired ISA were lesion length, unstable angina, and absence of diabetes. No stent thrombosis occurred in the patients diagnosed with ISA over a period of 12 months. Conclusions— The incidence and extent of late-acquired ISA are comparable in paclitaxel-eluting stents and BMS. ISA is a pure IVUS finding without clinical repercussions.

Objectives The Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial was a multicenter, randomized, open-label trial comparing the safety and performance of 13- and 17-mm QuaDDS stents (n = 126) (Quanam Medical Corp., Santa Clara, California/Boston Scientific Corp., Natick, Massachusetts) versus uncoated control stents (n = 140) in focal, de novo coronary lesions. Background The pioneering drug-delivery QuaDDS stent used four to six acrylate polymer sleeves, each loaded with 800 μg of the paclitaxel derivative 7-hexanoyltaxol. Methods Clinical end points were assessed at 1, 6, and 12 months post procedure. Quantitative coronary angiography and intravascular ultrasound were performed post procedure and at six-month follow-up. Results In the QuaDDS group, early stent thrombosis and myocardial infarction (MI) rates were significantly higher, leading to premature cessation of enrollment. For the QuaDDS group, the stent thrombosis rate increased from 3.2% to 10.3% between 1 and 12 months, associated with increased non–Q-wave MI and death rates. The angiographic restenosis rate at six months was reduced from 32.7% (control) to 7.4% (p Conclusions Despite angiographic indications of potential anti-restenotic benefit, increased rates of stent thrombosis, MI, and cardiac death associated with the QuaDDS stent show an unacceptable safety profile.

Background— The safety and efficacy of the slow-release, polymer-based, paclitaxel-eluting stent after implantation in a broad cross section of de novo coronary lesions at 1 year are unknown. Methods and Results— In the TAXUS-IV trial, 1314 patients with single de novo coronary lesions 10 to 28 mm in length, with reference-vessel diameter 2.5 to 3.75 mm, coverable by a single study stent, were prospectively randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical-appearing bare-metal EXPRESS stent. By actuarial analysis, the TAXUS stent compared with the bare-metal stent reduced the 12-month rates of target-lesion revascularization by 73% (4.4% versus 15.1%, P P P P P =0.007), target-vessel revascularizations (2.4% versus 5.8%, P =0.002), and major adverse cardiac events (2.4% versus 6.3%, P =0.0009) in the paclitaxel-eluting stent than in the control stent group, respectively. Conclusions— The relative efficacy reported at 9 months for the polymer-based, paclitaxel-eluting TAXUS stent compared with the EXPRESS stent is preserved and continues to increase at 1 year, with no safety concerns apparent.

Background— On the basis of brachytherapy experience, edge stenosis has been raised as a potential limitation for drug-eluting stents. We used serial intravascular ultrasound (IVUS) to prospectively analyze vessel responses in adjacent reference segments after implantation of polymer-controlled paclitaxel-eluting stents. Methods and Results— TAXUS II was a randomized, double-blind trial with 2 consecutive patient cohorts that compared slow-release (SR) and moderate-release (MR) paclitaxel-eluting stents with control bare metal stents (BMS). By protocol, all patients had postprocedure and 6-month follow-up IVUS. Quantitative IVUS analysis was performed by an independent core laboratory, blinded to treatment allocation, in 5-mm vessel segments immediately proximal and distal to the stent. Serial IVUS was available for 106 SR, 107 MR, and 214 BMS patients. For all 3 groups, a significant decrease in proximal-edge lumen area was observed at 6 months. The decrease was comparable (by ANOVA, P =0.194) for patients in the SR (−0.54±2.1 mm 2 ) and MR (−0.88±1.9 mm 2 ) groups compared with the BMS (−1.02±1.9 mm 2 ) group. For the distal edge, a significant decrease in lumen area was only observed with BMS (−0.91±2.0 mm 2 , P 2 ) and MR (−0.19±1.7 mm 2 ) stents ( P 2 , P =0.011) but not the distal edges of BMS and at neither edge of SR or MR stents. Conclusions— The marked reduction in in-stent restenosis with SR or MR stents is not associated with increased edge stenosis at 6-month follow-up IVUS. In fact, compared with BMS, there is instead a significant reduction in late lumen loss at the distal edge with TAXUS stents.

Restenosis after coronary stenting necessitates repeated percutaneous or surgical revascularization procedures. The delivery of paclitaxel to the site of vascular injury may reduce the incidence of neointimal hyperplasia and restenosis.At 73 U.S. centers, we enrolled 1314 patients who were receiving a stent in a single, previously untreated coronary-artery stenosis (vessel diameter, 2.5 to 3.75 mm; lesion length, 10 to 28 mm) in a prospective, randomized, double-blind study. A total of 652 patients were randomly assigned to receive a bare-metal stent, and 662 to receive an identical-appearing, slow-release, polymer-based, paclitaxel-eluting stent. Angiographic follow-up was prespecified at nine months in 732 patients.In terms of base-line characteristics, the two groups were well matched. Diabetes mellitus was present in 24.2 percent of patients; the mean reference-vessel diameter was 2.75 mm, and the mean lesion length was 13.4 mm. A mean of 1.08 stents (length, 21.8 mm) were implanted per patient. The rate of ischemia-driven target-vessel revascularization at nine months was reduced from 12.0 percent with the implantation of a bare-metal stent to 4.7 percent with the implantation of a paclitaxel-eluting stent (relative risk, 0.39; 95 percent confidence interval, 0.26 to 0.59; P0.001). Target-lesion revascularization was required in 3.0 percent of the group that received a paclitaxel-eluting stent, as compared with 11.3 percent of the group that received a bare-metal stent (relative risk, 0.27; 95 percent confidence interval, 0.16 to 0.43; P0.001). The rate of angiographic restenosis was reduced from 26.6 percent to 7.9 percent with the paclitaxel-eluting stent (relative risk, 0.30; 95 percent confidence interval, 0.19 to 0.46; P0.001). The nine-month composite rates of death from cardiac causes or myocardial infarction (4.7 percent and 4.3 percent, respectively) and stent thrombosis (0.6 percent and 0.8 percent, respectively) were similar in the group that received a paclitaxel-eluting stent and the group that received a bare-metal stent.As compared with bare-metal stents, the slow-release, polymer-based, paclitaxel-eluting stent is safe and markedly reduces the rates of clinical and angiographic restenosis at nine months.

Background— The TAXUS NIRx stent (Boston Scientific Corp) provides local delivery of paclitaxel via a slow-release polymer coating. The TAXUS I trial was the first in-human experience evaluating safety and feasibility of the TAXUS NIRx stent system compared with bare NIR stents (control) (Boston Scientific Corp) for treatment of coronary lesions. Methods and Results— The TAXUS I trial was a prospective, double-blind, three-center study randomizing 61 patients with de novo or restenotic lesions (≤12 mm) to receive a TAXUS (n=31) versus control (n=30) stent (diameter 3.0 or 3.5 mm). Demographics, lesion characteristics, clinical outcomes were comparable between the groups. The 30-day major adverse cardiac event (MACE) rate was 0% in both groups ( P =NS). No stent thromboses were reported at 1, 6, 9, or 12 months. At 12 months, the MACE rate was 3% (1 event) in the TAXUS group and 10% (4 events in 3 patients) in the control group ( P =NS). Six-month angiographic restenosis rates were 0% for TAXUS versus 10% for control ( P =NS) patients. There were significant improvements in minimal lumen diameter (2.60±0.49 versus 2.19±0.65 mm), diameter stenosis (13.56±11.77 versus 27.23±16.69), and late lumen loss (0.36±0.48 versus 0.71±0.48 mm) in the TAXUS group (all P 3 ) group compared with the control group (21.6 mm 3 ) ( P Conclusions— In this feasibility trial, the TAXUS slow-release stent was well tolerated and showed promise for treatment of coronary lesions, with significant reductions in angiographic and intravascular ultrasound measures of restenosis.

Provision of adequate T cell costimulation is critical for the development of acute and chronic allograft rejection. We have previously reported that early blockade of CD28-B7 T cell costimulation prevents the development of graft arteriosclerosis, in the LEW into F344 rat cardiac transplant model. In this study, we used the same model to examine the requirement for CD28-B7-mediated T cell costimulation in the progression of established chronic rejection and examined the individual roles of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules. Late blockade of CD28-B7 T cell costimulation by the fusion protein CTLA4Ig, which binds both CD80 and CD86, attenuated the development of transplant arteriosclerosis, mononuclear cell infiltration, and parenchymal fibrosis in this model. Selective blockade of CD80 using the mutant fusion protein Y100F was as effective as CTLA4Ig in this regard. In contrast to CTLA4Ig, blockade of CD80 alone by Y100F was ineffective at preventing early graft loss and prolonging graft survival when given early after transplantation. This study is the first to demonstrate that late blockade of CD28-B7 T cell costimulation interrupts chronic cardiac allograft rejection, and it indicates the importance of continued T cell activation in this process. This study further defines functional differences between CD80 and CD86 costimulatory molecules in vivo.

Background —To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection. Methods and Results —At day 55 after transplantation, cardiac grafts placed into STAT4 −/− (n=10) had reduced frequency (24±2%) and severity (9±4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70±12% [ P P 32 P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-γ ( P P + mononuclear cells (99±27 cells/mm 3 compared with 551±168 cells/mm 3 in wild-type controls [ P P P Conclusions —Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.

Background: Mice with target gene deletions were used in an immunosuppressed, heterotopic mouse cardiac transplant model to investigate the effects of simultaneous deficiencies of ICAM-1 and P-selectin on late cardiac rejection. Methods To determine the contribution of donor sources of ICAM-1 and P-selectin, ICAM-1/P-selectin gene deficient (I/P −/−) ( n = 7) or wild type ( n = 6) donor hearts were placed into CBA recipients. To study recipient sources of ICAM-1 and P-selectin, wild type donor hearts were placed into I/P −/− ( n = 7) or wild type ( n = 13) recipients. Recipients received a 30-day course of anti-CD4/8 mAb. Results I/P −/− donor allografts had prolonged survival (52–57 days) compared with wild type allografts (49–51 days). I/P −/− donor allografts underwent parenchymal rejection with mononuclear cell infiltration and developed α-smooth muscle actin positive vascular thickening (30 ± 7% luminal occlusion, n = 78 vessels). Wild type allografts had parenchymal rejection with vascular medial necrosis and an absence of arteriosclerotic thickening (10 ± 8%, n = 75, p = 0.008). Using the reverse combination, allografts from I/P −/− or wild type recipients had similar graft survival (50–57 days), comparable but variable degrees of parenchymal rejection, and comparable vascular occlusion (22 ± 15% vs 28 ± 19%, p = 0.442). Conclusion We have shown that donor and recipient sources of ICAM-1 and P-selectin may have independent roles in leukocyte trafficking to the graft. Simultaneous interruption of donor ICAM-1 and P-selectin delays onset of parenchymal rejection. However, donor I/P deficiency permits arteriosclerotic development, perhaps by attenuating the alloimmune injury. In contrast, recipient deficiency alone does not altergraft outcomes suggesting that the donor is the critical site of ICAM-1 and P-selectin.

It has been reported previously that one-third of protocol renal biopsies in asymptomatic, biochemically stable renal transplant recipients in the first 6 mo show unsuspected subclinical graft rejection (both infiltrate and tubulitis) and that subclinical rejection is a risk factor for chronic renal dysfunction. This study was performed to determine whether differences in phenotype or activation status of graft-infiltrating cells underlie these different manifestations of acute rejection. Biopsies with normal histology (n = 10), subclinical rejection (n = 13), and clinical rejection (n = 9) were studied using immunohistochemistry and computerized image analysis. Subclinical and clinical rejections had similar histologic Banff scores. Univariate analysis showed a trend for a higher infiltration with CD8+ (P = 0.053) and CD68+(P = 0.06) cells in clinical rejection. Of the activation markers studied (CD25, perforin, tumor necrosis factor-alpha), only allograft inflammatory factor-1+-activated macrophages were significantly (P = 0.014) increased in the infiltrate of clinical rejection biopsies. These data suggest that activated macrophages or their products are responsible for acute renal dysfunction associated with clinical rejection episodes.

This article reviews macrophage biology in general, macrophage activation in the transplanted organ, and potential roles of the macrophage in chronic rejection and arteriosclerosis.

BACKGROUND To evaluate cardiac allografts from recipients that had achieved peripheral tolerance after transient CD4+ T cell depletion, we analyzed cellular infiltrate, cytokine expression, and vascular thickening. Long-surviving cardiac allografts from tolerant recipients were compared with acutely rejecting allografts and isografts. METHODS AND RESULTS In CBA mice treated with anti-CD4 (GK1.5, 0.5 mg intraperitoneally on days 1-28), BALB/c cardiac allografts survived >100 days. These recipients were tested for tolerance at >70 days, by challenge with donor and third-party (C57BL/6) skin grafts. BALB/c skin grafts survived >30 days, although C57BL/6 skin was rejected in

To compare regulatory effects of NOS2 in acute and chronic cardiac allograft rejection, we used NOS2 knockout mice as recipients in a cardiac transplant model. To study acute and chronic rejection separately but within the same genetic strain combination, we compared allografts placed into recipients without or with immunosuppression (anti-CD4/8 for 28 days). NOS2 mRNA and protein expression were compared using 32 P-RT-PCR and immunohistochemistry. In our acute rejection model, NOS2 was predominately localized to graft-infiltrating immune cells. At day 7, grafts in NOS2-deficient recipients ( n = 7) showed reduced inflammatory infiltrates and myocyte damage resulting in significantly lower rejection scores (1.6 ± 0.4) compared to wild-type controls ( n = 18; 2.8 ± 0.2, P = 0.002). In contrast, in our chronic rejection model, additional NOS2 expression was localized to graft-parenchymal cells. At day 55, grafts in NOS2-deficient recipients ( n = 12) showed more parenchymal infiltration and parenchymal destruction (rejection score 3.8 ± 0.1) than wild-type controls ( n = 15; 1.6 ± 0.2, P P

Background —Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening. Methods and Results —To determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic cardiac rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 −/− recipients (n=13) was compared with that in wild-type recipients (n=15). Computer-assisted analysis of all elastin-stained vessels (n=283) showed significantly increased luminal occlusion (77.1±9.4% versus 40.8±13.6%, P P =.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differentiation (Th 1 /Th 2 ) and neointimal smooth muscle cell accumulation. Normalized mRNA levels for Th 1 - (signal transducer and activator of transcription [STAT] 4, interleukin [IL]-2, interferon-γ) and Th 2 - (STAT 6, IL-4, and IL-5) associated factors were comparable in both groups. In contrast, quantitative analysis of the α-actin–positive area showed a significant increase in the contribution of smooth muscle cells within the neointima in allografts from NOS2 −/− recipients (28.2±2.0%) compared with wild-type controls (13.2±2.3%; P Conclusions —NOS2 plays a protective role in the development of transplant arteriosclerosis, suppressing neointimal smooth muscle cell accumulation.

Abstract We evaluated inflammatory activation and vascular thickening in a heterotopic murine heart transplant model. C57BL/6J recipient mice received anti-CD4 therapy (days 1 to 4 after transplantation) or sustained, combined anti-CD4/CD8 therapy (days 1 to 4, weekly thereafter). Morphometric analysis of grafts (>95 days) found the mean percentage of vessel occlusion to be 51.7% in allografts treated with anti-CD4, 8.3% in allografts treated with sustained anti-CD4/CD8, and 6.7% in isografts. Mean transcript levels of the adhesion molecules P-selectin, intercellular adhesion molecule 1 (ICAM-1), and leukocyte function-associated antigen 1 (LFA-1) and the cytokines interleukin 4 (IL-4), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), allograft inflammatory factor 1 (AIF-1), and monocyte chemoattractant protein 1 (MCP-1) were measured with reverse transcription–polymerase chain reaction [RT-PCR] assays using deoxycytidine triphosphate radiolabeled with phosphorus 32 [ 32 P-dCTP]. The assays were normalized against glyceraldehyde-3-phosphate dehydrogenase [G3PDH] Levels were found to be significantly higher in the anti-CD4 group than in the anti-CD4/CD8 group. A strong correlation was also found between the percentage of luminal occlusion and the expression of these markers of inflammation ( r =.92-.99, P

Background If complement (C) activation is prevented or the host is C depleted, discordant vascularized xenografts undergo delayed xenograft rejection (DXR), characterized by graft infiltration by macrophages (MO) and natural killer (NK) cells, endothelial cell activation, and widespread fibrin deposition. Given a lack of effect of T cell-directed therapies on development of DXR, we evaluated two novel agents, 15-deoxyspergualin (DSG) and leflunomide (LEF), with reported anti-B-cell and/or anti-MO actions. Methods. DSG and LEF were administered to C-depleted, splenectomized rat recipients of guinea pig cardiac xenografts, and their effects on graft survival and production of anti-guinea pig antibodies were determined. Serial intragraft events were studied by immunohistology using monoclonal antibodies to rat leukocytes, cytokines, and novel proteins, including rat MO lectin, which in other systems is important to MO binding, activation, and target cell killing. Results. Median graft survival was 62 hr in cobra venom factor (CVF)-treated controls versus 108 hr (DSG), 129 hr (LEF), and 120 hr (DSG and LEF; all groups P

Chronic rejection is a T cell-dependent process and blockade of the CD28-B7 T-cell costimulatory activation pathway by the fusion protein CTLA4Ig has been shown to prevent the development of accelerated graft arteriosclerosis in a rat model of chronic cardiac allograft rejection. The effectiveness of T-cell costimulatory blockade at preventing chronic allograft rejection in a clinically relevant model in combination with cyclosporine therapy has not been investigated. Using the well-established LEW into F334 heterotopic cardiac allograft model, we show that when cyclosporine is administered in combination with CTLA4Ig, it abrogates the previously demonstrated protective effect of CTLA4Ig in preventing chronic allograft rejection. Long-term surviving allografts from animals treated with a combination of cyclosporine and CTLA4Ig had a mean vascular luminal occlusion of 42.2%, affecting more than 90% of graft vessels due to accelerated arteriosclerosis. This was associated with up-regulation of intragraft expression of mRNA for CD4, the costimulatory molecule B7, the T-cell cytokine interferon-gamma, monocyte chemoattractant protein-1, and the fibrogenic growth factor transforming growth factor-beta; all have been previously shown to be associated with development of chronic rejection in this model. In comparison, the addition of donor splenocytes to the combination of CTLA4Ig and cyclosporine therapy protocol significantly reduced the amount of arteriosclerosis; mean vascular luminal occlusion was 11.3%, affecting approximately 50% of vessels. This was associated with decreased intragraft expression of CD4, B7, interferon-gamma, monocyte chemoattractant protein-1, and transforming growth factor-beta. These data indicate that the mechanism of action of CTLA4Ig in attenuating chronic rejection is cyclosporine sensitive, and that strategies implying combination of CTLA4Ig and cyclosporine may not be clinically desirable. Administration of donor antigen may be necessary if CTLA4Ig and cyclosporine are to be combined, to prevent the process of chronic rejection.

A key manifestation of chronic rejection is an obliterative arteriosclerosis. Myointimal thickening in the vessel is preceded by an endothelialitis involving accumulation of host mononuclear cells in the perivascular and intimal spaces. We report a paratopic LEW-to-F344 rat carotid artery transplantation model developed to study the cells, cytokines, and inflammatory response associated with this early phase of vascular immune injury. Compared with contralateral control arteries and isografts, LEW-to-F344 carotid allografts develop intimal thickening with mononuclear cell infiltration that persists (days 20, 45, 75, 90, and 120). Allografted vessels had dense collections of intimal and adventitial leukocytes (CD45+) consisting of equal numbers of T cells and macrophages. There were small but variable numbers of intimal smooth muscle cells. Intimal cells showed dense staining for tumor necrosis factor-α, interleukin-8, platelet-derived growth factor, iNOS, and ICAM and weaker labeling for interleukin-1β and interleukin-6. There was also prominent staining for interleukin-4 and interleukin-7 with no detectable interferon-γ or interleukin-2 staining and high titer labeling for IgG1 (but not IgG2). The predominance of the T cell infiltrate coupled with interleukin-4 and IgG1 expression in carotid allografts is consistent with a TH2 response. This contrasts with balloon-injured rat carotids, which evoke a macrophage-dependent proliferative response. These findings demonstrate that there are distinct as well as common activation pathways in various forms of vascular injury and the LEW-to-F344 carotid model provides the opportunity to gain insight into molecular mechanisms regulating alloimmune injury in the vessel.

Lewis-to-F344 rat cardiac allografts develop chronic rejection and arteriosclerotic lesions rich in mononuclear cells (especially macrophages). This study was performed to determine whether cytokine pathways associated with macrophage activation are upregulated in hearts undergoing chronic rejection. Gene transcript levels for IFN-gamma, monocyte chemoattractant protein-1 (MCP-1), and IL-6 were measured with reverse-transcription PCR assays optimized for each gene. Gene products were confirmed by immunohistology. For all three genes, transcript levels in rat cardiac allografts increased significantly on day 7 and remained elevated on days 14 and 28 posttransplantation, as compared with naive hearts, paired host hearts, and syngrafts (P < 0.006). For the inducible genes IFN-gamma and MCP-1, high transcript levels in cardiac allografts were in contrast with low levels in host spleens. On the other hand, transcript levels for the basally expressed gene IL-6 were elevated in both organs. Immunostaining confirmed allograft-specific expression for all three cytokines and localized the gene products to infiltrating mononuclear cells in the interstitium and vasculature. The sustained expression of these cytokines in cardiac allografts undergoing chronic rejection supports the widely held hypothesis that the intimal changes associated with transplant arteriosclerosis are mediated by cellular activation and cytokine production.

Background:For persons with unicompartment knee osteoarthritis (OA), off-unloader braces are a mechanical intervention designed to reduce pain, improve physical function, and possibly slow disease progression. Pain relief is thought to be mediated by distracting the involved compartment via external varus or valgus forces applied to the knee. In so doing, tibiofemoral alignment is improved, and load is shifted off the degenerative compartment, where exposure to potentially damaging and provocative mechanical stresses are reduced.Objectives:To provide a synopsis of the evidence documented in the scientific literature concerning the efficacy of offloader knee braces for improving symptomatology associated with painful disabling medial compartment knee OA.Search Strategy:Relevant peer-reviewed publications were retrieved from a MEDLINE search using the terms with the reference terms osteoarthritis, knee, and braces (per Medical Subject Headings), plus a manual search of bibliographies from original and review articles and appropriate Internet resources.Results:For persons with combined unicompartment knee OA and mild to moderate instability, the strength of recommendation reported by the Osteoarthritis Research Society International in the ability of off-loader knee braces to reduce pain, improve stability, and diminish the risk of falling was 76% (95% confidence interval, 69%–83%). The more evidence the treatment is effective, the higher the percentage.Conclusions:Given the encouraging evidence that off-loader braces are effective in mediating pain relief in conjunction with knee OA and malalignment, bracing should be fully used before joint realignment or replacement surgery is considered. With the number of patients with varus deformities and knee pain predicted to increase as the population ages, a reduction of patient morbidity for this widespread chronic condition in combination with this treatment modality could have a positive impact on health care costs and the economic productivity and quality of life of the affected individuals.

Plasma lipids, lipoproteins, and apolipoproteins were measured in 123 female and 57 male Mvskoke Indians, a population of American Indians with a high prevalence of non-insulin-dependent diabetes mellitus (NIDDM). Dietary patterns were assessed with a food-frequency questionnaire. There were no differences in total cholesterol, low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), apolipoproteins A-I or B in female Indians with and without diabetes. In males with diabetes, however, LDL-C was lower. Triglyceride and fasting plasma glucose were higher in subjects with diabetes. Total cholesterol and LDL-C were lower and HDL-C was higher than age and sex-matched Lipid Research Clinics values, especially for subjects with diabetes. This is surprising given that the diet of Mvskoke Indians contains foods high in total fat, saturated fatty acids, and cholesterol. We may explain, in part, the low incidence of coronary heart disease in this population.

The purpose of this study was to examine the potential impact of pulmonary artery (PA) catheter placement on short-term management decisions in the medical intensive care unit (ICU). One hundred three patients were examined over an 18-month period. The predominant indications for PA-catheter placement included refractory congestive heart failure, airspace disease, uncertain cardiac filling pressures, or hypotension. In 58 (56%) of the 103 patients, management recommendations changed as a direct result of knowledge gained by PA catheter placement. These changes involved fluid therapy recommendations in 41 patients, vasopressor use in 17 patients, intravenous vasodilator use in 24 patients, and recommendations for the use of inotropic agents in 15 patients. Although 18 patients experienced early or late complications, major events were limited to a single pneumothorax requiring chest tube insertion and four episodes of bacteremia. No deaths were directly attributable to the catheter insertion. In critically ill patients in the medical intensive care unit, PA-catheter placement leads to changes in recommendations for management in a substantial portion of patients with little risk of life-threatening complications in those who receive such invasive monitoring.

To determine whether the great vessels were subject to transplantation-associated arteriosclerosis (graft vascular disease) we studied sections of aorta and pulmonary arteries from 19 cardiac explant cases. Sections of the same vessels from five autopsied hearts from patients who had received liver and/or kidney transplants with immunotherapy as well as from eight recipient hearts served as controls. In addition, eight donor hearts (three aortae and eight pulmonary arteries) that were not used for heart transplantation were examined. Intimal proliferation was noted in the aorta but affected the pulmonary arteries only slightly, whereas the vasa vasorum of both vessels were involved and were occluded or stenosed by thickened intima containing recanalized capillaries. On morphometric study the ratio of intima to media in the aorta was significantly higher in the heart transplant group than in the control group (0.14 +/- 0.14 [n = 19] v 0.02 +/- 0.02 [n = 16]; P.01). This intimal thickening was not correlated with the use of cyclosporine or with other clinicopathologic factors. The cytomegalovirus infection rate was higher in the heart transplant group (85%) than in the control group (40%).

Despite recognition of chronic vascular injection by numerous investigators since the beginning of experimental and solid organ transplantation, the pathogenesis of graft arteriosclerosis remains poorly understood. We have defined a reproducible model of this disease by transplanting heterotopic cardiac grafts across minor histocompatibility barriers using inbred strains of rat. We found that long-term surviving Lewis grafts in untreated F344 recipients are subjected to a chronic rejection process which results in the development of diffuse graft arteriosclerotic lesions, indistinguishable in appearance from those seen in human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions, made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of serial rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 appears to lead to early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR confirms that MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting that this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF, and IL-1 in vascular lesions suggests that these growth factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts. Hypercholesterolemia did not enhance the severity of lesion development in long-term surviving allografts, suggesting that lipid levels are not a major etiologic factor in graft arteriosclerotic lesion formation in the Lewis-F344 model. Finally, the dietary manipulation of EFAD reduced graft infiltration by mononuclear cells and markedly diminished arterial lesion development in chronically rejecting grafts. Heparin anologues have previously been shown to inhibit proliferative vascular smooth muscle cell lesions in rats following endothelial injury (Clowes & Karnovsky 1977), and we are currently assessing the role of heparin in the therapy of graft arteriosclerosis in the Lewis-F344 model. We are also investigating the role of CD4-positive mononuclear cells in the pathogenesis of lesion development, using the anti-CD4 monoclonal antibody BWH-4 to deplete recipients of CD4-positive cells (Sayegh et al. 1991). In summary, our studies in the Lewis-F344 model suggest that monocyte/macrophages play an important role in the pathogenesis of cardiac graft arteriosclerosis. Future studies utilizing this model should help further elucidate the mechanisms resulting in--and help define potential therapies for--chronic rejection in cardiac transplantation.

Aims: To provide insight on the patients with long lesions that received multiple, overlapping stents by reporting clinical outcomes, together with a detailed angiographic and intravascular ultrasound analysis of the overlap zone. Methods and results: TAXUS VI is a prospective, multicentre, double-blind, trial, specifically designed to assess outcomes of paclitaxel-eluting stents in longer lesions by randomising 446 patients (1:1) between a drug-eluting TAXUS™ Express 2 Moderate Release (MR) and an uncoated Express 2 control stent. Multiple overlapping stents were implanted in 124 patients (27.8%) and are the subject of this report. Clinical, angiographic and IVUS outcomes at nine months were compared in the overlap group for patients receiving the TAXUS™ Express 2 MR stent and the uncoated Express 2 stent. In the overlap group, mean lesion length was 25.1 mm with a mean stent length of 43.6 mm. At nine months, TVR was reduced by 94% from 25.0% to 1.6% in the TAXUS patients compared with control (p=

BackgroundDevelopmental dysplasia of the hip (DDH) is a condition in which bone growth irregularities subject articular cartilage to higher mechanical stresses, increase susceptibility to subluxation, and elevate the risk of early osteoarthritis. Study objectives were to calculate three-dimensional cartilage contact stresses and to examine increases of accumulated pressure exposure over a gait cycle that may initiate the osteoarthritic process in the human hip, in the absence of trauma or surgical intervention.MethodsPatient-specific, non-linear, contact finite element models, constructed from computed tomography arthrograms using a custom-built meshing program, were subjected to normal gait cycle loads.ResultsPeak contact pressures for dysplastic and asymptomatic hips ranged from 3.56 – 9.88 MPa. Spatially discriminatory cumulative contact pressures ranged from 2.45 – 6.62 MPa per gait cycle. Chronic over-pressure doses, for 2 million cycles per year over 20 years, ranged from 0.463 – 5.85 MPa-years using a 2-MPa damage threshold.ConclusionThere were significant differences between the normal control and the asymptomatic hips, and a trend towards significance between the asymptomatic and symptomatic hips of patients afflicted with developmental dysplasia of the hip. The magnitudes of peak cumulative contact pressure differed between apposed articular surfaces. Bone irregularities caused localized pressure elevations and an upward trend between chronic over-pressure exposure and increasing Severin classification.

Objectives: The purpose of this study was to evaluate the clinical and angiographic outcomes of the Symbiot ePTFE covered stent versus bare metal stents (BMS) for the treatment of saphenous vein graft (SVG) disease. Background: The Symbiot stent was developed to reduce periprocedural complications, by potentially preventing distal embolization, and to serve as a possible barrier to cell migration, thus reducing restenosis. Methods: Symbiot III is a prospective, randomized trial of 400 patients at 45 US sites, with 201 patients in the Symbiot group and 199 in the BMS group. Randomization was stratified based on the intended use of embolic protection devices and glycoprotein IIb/IIIa inhibitors. The primary endpoint was percent diameter stenosis (%DS) as measured by quantitative coronary angiography at 8 months. Secondary endpoints included MACE (cardiac death, MI, TVR). Results: The groups were well matched for all baseline clinical and lesion characteristics. At 8 months, %DS was comparable between groups (30.9% Symbiot, 31.9% BMS, P = 0.80). Although the rates of binary restenosis in the stented segment were similar (29.1% Symbiot, 21.9% BMS, P = 0.17), more patients in the Symbiot group had binary restenosis at the proximal edge (9.0% Symbiot, 1.8% BMS, P = 0.0211). There was no difference in the incidence of MACE between groups (30.6% Symbiot, 26.6% BMS, P = 0.43). Conclusions: This study failed to show an advantage for the Symbiot stent in the treatment of degenerated SVGs. This PTFE covered stent does not appear to act as a barrier to prevent restenosis. © 2006 Wiley-Liss, Inc.

ContextRestenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although subsequent recurrence rates are high, with vascular brachytherapy (VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established.ObjectiveTo investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries.Design, Setting, and PatientsProspective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5-3.75 mm; lesion length, ≤46 mm).InterventionsPatients were randomly assigned to undergo angioplasty followed by VBT with a β source (n = 201) or paclitaxel-eluting stent implantation (n = 195). Clinical and angiographic follow-up at 9 months was scheduled in all patients.Main Outcome MeasureIschemia-driven target vessel revascularization at 9 months.ResultsDiabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic target lesion revascularization were 27 (13.9%) vs 12 (6.3%) (relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P = .01); for ischemic target vessel revascularization, 34 (17.5%) vs 20 (10.5%) (RR, 0.60; 95% CI, 0.36-1.00; P = .046); and for overall major adverse cardiac events, 39 (20.1%) vs 22 (11.5%) (RR, 0.57; 95% CI, 0.35-0.93; P = .02), with similar rates of cardiac death or myocardial infarction (10 [5.2%] vs 7 [3.7%]; RR, 0.71; 95% CI, 0.28-1.83; P = .48) and target vessel thrombosis (5 [2.6%] vs 3 [1.6%]; RR, 0.61; 95% CI, 0.15-2.50; P = .72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents (RR, 0.47; 95% CI, 0.30-0.71; P

The WISDOM Registry tracked clinical outcomes in patients receiving a slow-release, polymer-based, paclitaxel-eluting stent during the transition from randomized trials to commercial use in everyday interventional cardiology practice. Although randomized trials of drug-eluting stents have demonstrated the safety and effectiveness of these devices in less complicated, de novo lesions, observation of long-term clinical outcomes is required to monitor safety as use of this revolutionary technology expands to broader patient populations. In total, 778 patients were enrolled at 22 sites in 9 countries where the TAXUS paclitaxel-eluting stent first received market approval. Patients with de novo or restenotic coronary lesions eligible for stenting were enrolled. Clinical follow-up was conducted by telephone at 3, 6, 9, and 12 months after the procedure to capture reported stent thrombosis and major cardiac events (death, myocardial infarction, and reintervention on the target lesion). Clinical follow-up at 12 months was completed for 92% of patients. The 12-month rate of physician-reported major cardiac events was 5.2%, with a target lesion reintervention rate of 2.0%. The low overall stent thrombosis rate of 0.6% included no stent thromboses30 days after the index procedure. Low target lesion reintervention rates were also observed in the high-risk subgroups: patients with diabetes (4.0%), vessels2.5 mm (2.5%), lesions20 mm (3.6%), and multiple stents in a lesion (1.4%). In conclusion, the paclitaxel-eluting TAXUS slow-release stent exhibits long-term safety and efficacy in uncomplicated and higher risk patients and lesions seen in everyday clinical practice.