Intimal Hyperplasia Area Research Articles

Comparison of the Neointima Inhibition Between Paclitaxel- and Sirolimus-Eluting Expanded Polytetrafluoroethylene Hemodialysis Grafts in a Porcine Model

Neointimal hyperplasia causes vascular access dysfunction in hemodialysis patients with synthetic arteriovenous (AV) grafts. Several studies have reported that paclitaxel- or sirolimus-eluting AV grafts inhibit neointimal hyperplasia and display lower rates of stenosis compared with control grafts. However, there have been few comparative studies of the efficacy of paclitaxel- and sirolimus-eluting grafts. We compared the neointimal hyperplasia of paclitaxel- and sirolimus-eluting grafts. AV grafts were implanted laterally between the common carotid artery and the external jugular vein in 12 female Landrace pigs. The animals were sacrificed six weeks after surgery. The neointimal hyperplasia at the anastomosis sites of the grafts was quantified using the ratio of the intragraft hyperplasia to the graft area (H/G ratio) at the graft–vessel interface. The area of intimal hyperplasia at the venous (paclitaxel 1.06 [0.72-1.56] vs sirolimus 2.40 [1.72-3.0] mm 2 , P = 0.04) and arterial anastomosis sites (paclitaxel 0.93 [0.57-1.48] vs sirolimus 2.40 [1.72-3.0] mm 2 , P = 0.04) was significantly different between the two groups. However, the H/G ratios for the venous anastomosis site (paclitaxel 0.25 (0.17-0.38) vs sirolimus 0.38 (0.2-0.66), P = 0.4) and the arterial anastomosis site (paclitaxel 0.19 (0.08-0.39) vs sirolimus 0.41 (0.34-0.50), P = 0.1) did not differ significantly between the groups. In conclusion, there was no significant difference in the inhibition of neointimal hyperplasia by sirolimus- and paclitaxel-eluting AV grafts.

Understanding Saphenous Vein Graft Patency

Saphenous vein was the conduit used in the first series of coronary surgery, and, with the exception of revascularization of the left anterior descending coronary artery, it remains the most commonly used conduit.1 There are several reasons for this. First, because of its relatively large diameter and wall characteristics, it is technically easy to use; second, it is plentiful, and therefore can be used to perform multiple grafts; third, it is long and can reach any coronary artery; and fourth, it is easily harvested. However, its durability and longevity are not ideal. One year after coronary surgery, 10% to 20% of saphenous vein grafts fail.2–4 From 1 to 5 years, an additional 5% to 10% fail, and from 6 to 10 years, an additional 20% to 25% fail.5 At 10 years, only about half of saphenous vein grafts are patent, and of those, only half are free of angiographic arteriosclerosis.6 Article see p 280 Saphenous vein graft failure during the first year of surgery is due to technical errors, thrombosis, and intimal hyperplasia. All saphenous vein grafts experience endothelial damage during harvesting and initial exposure to arterial pressure. This intimal injury leads to platelet adherence that may result in graft thrombosis and acute occlusion. Platelet adherence to the intimal surface is also the initial event in the development of intimal hyperplasia. After adhering to the intima, platelets release mitogenic proteins, stimulating smooth muscle cell migration, resulting in intimal proliferation and hyperplasia.7–11 After a year from surgery, arteriosclerosis is responsible for further saphenous vein graft failure.12,13 Mural thrombi and intimal hyperplasia are the early stages of vein graft arteriosclerosis.4,12 With time, lipid becomes incorporated in these areas of intimal hyperplasia, resulting in arteriosclerotic plaque, and eventual …

Differentiation profile of peripheral blood-derived vascular progenitor cell predicts intimal hyperplasia after coronary stenting

In-stent restenosis is largely due to intimal hyperplasia (IH). The number of vascular progenitor cells (VPCs) mobilized at the acute phase after stenting is associated with IH. This study sought to determine whether the differentiation profile of VPC predicts the development of IH. Peripheral blood was collected in 58 patients after bare-metal stenting to culture VPCs. Intravascular ultrasound was performed to estimate the area of IH 6 months after stenting. VPC differentiation was determined using flow cytometry. VE-cadherin (VE-Cad) and α-smooth muscle actin (α-SMA) were used to identify endothelial and smooth muscle cell lineages, respectively. After culturing, VPCs differentiated into four different phenotypes (α-SMA(-)VE-Cad(+), α-SMA(+)VE-cad(high), α-SMA(+)VE-cad(low), and α-SMA(+)VE-Cad(-)). IH was correlated with gender (P = 0.04), smoking status (P = 0.04), reference diameter (P = 0.03), minimal lumen diameter (P = 0.03), stent area (P < 0.0001), and parameters in the VPC differentiation profile (P < 0.05). Multivariate analysis controlling for stent area, smoking status, and gender revealed that IH was positively and independently associated with the number of differentiated α-SMA(+)VE-Cad (low/-) VPCs (P < 0.0001), and the ratio of α-SMA(+)VE-Cad (low/-) VPCs to α-SMA(-)VE-Cad(+) VPCs (P = 0.001). These parameters in the VPC differentiation profile independently predicted the IH and provided additive information to traditional risk factors. In conclusion, the profile of VPC differentiation predicts the severity of post-stent IH and may be a potential tool in the future for clinicians to identify patients at risk of post-stent restenosis.

Mechanisms of In-Stent Restenosis After Drug-Eluting Stent Implantation

Background— We used intravascular ultrasound (IVUS) to (1) clarify the mechanisms of luminal loss after drug-eluting stent (DES) implantation and (2) classify morphological patterns of in-stent restenosis (ISR). Methods and Results— On the basis of IVUS-identified luminal narrowing (in-stent minimum lumen area &lt;4 mm 2 ), IVUS-defined ISR was classified as focal (luminal narrowing ≤10 mm in length), multifocal (≥1 focal lesions), and diffuse (luminal narrowing &gt;10 mm in length) with or without stent edge involvement. Significant intimal hyperplasia (IH) was defined as IH area &gt;50% of stent. Overall, 76 lesions had IVUS-defined ISR; 32 (42%) had stent underexpansion (minimal stent area &lt;5 mm 2 ); and 71 (93%) had IH area &gt;50% of stent. Total stent length negatively correlated with minimal stent area ( r =−0.613, P &lt;0.001) as well as with stent area at the minimum lumen site ( r =−0.436, P &lt;0.001) but not with minimum lumen area ( r =−0.084, P =0.472). Underexpansion was present at the minimum lumen site in 15 of 43 (35%) lesions with stent length &gt;28 mm, even though there was significant IH in 34 (79%) lesions; conversely, in 32 of 33 (97%) lesions with stent length ≤28 mm, the minimum lumen site was not associated with stent underexpansion but significant IH. IVUS-defined focal ISR was most common (47%). Compared with focal ISR, normalized vessel, stent, lumen, and plaque volumes were smaller in diffuse and multifocal than focal ISR, with no difference in IH extent. Conclusions— In most DES restenosis, IH was the dominant mechanism of ISR. Nevertheless, underexpansion associated with longer stent length remained an important preventable mechanism of ISR.

Tissue Characterization of In-Stent Neointima Using Intravascular Ultrasound Radiofrequency Data Analysis

Using virtual histology and intravascular ultrasound (VH-IVUS), tissue characterization of restenotic in-stent neointima after drug-eluting stent (DES) and bare metal stent (BMS) implantation was assessed. VH-IVUS was performed in 117 lesions (70 treated with DESs and 47 treated with BMSs) with angiographic in-stent restenosis and intimal hyperplasia (IH) > 50% of the stent area. The region of interest was placed between the luminal border and the inner border of the struts and tissue composition was reported as percentages of IH area (percent fibrous, percent fibrofatty, percent necrotic core, percent dense calcium) at the 2 sites of maximal percent IH and maximal percent necrotic core. Mean follow-up times between stent implantation and VH-IVUS study were 43.5 ± 33.8 months for BMS-treated lesions and 11.1 ± 7.8 months for DES-treated lesions (p < 0.001). The 2 groups had greater percent necrotic core and percent dense calcium at maximal percent IH and maximal percent necrotic core sites, especially in stents that had been implanted for longer periods. In conclusion, this VH-IVUS analysis showed that BMS- and DES-treated lesions develop in-stent necrotic core and dense calcium, suggesting the development of in-stent neoatherosclerosis.

Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes

BackgroundProteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.The aim of the current study was to investigate whether human macrophage foam cells degrade the extracellular matrix (ECM) of atherosclerotic plaques by cathepsin K mediated processes.MethodsWe 1) cultured human macrophages on ECM and measured cathepsin K generated fragments of type I collagen (C-terminal fragments of Type I collagen (CTX-I) 2) investigated the presence of CTX-I in human coronary arteries and 3) finally investigated the clinical potential by measuring circulating CTX-I in women with and without radiographic evidence of aortic calcified atherosclerosis.ResultsImmune-histochemistry of early and advanced lesions of coronary arteries demonstrated co-localization of Cathepsin-K and CTX-I in areas of intimal hyperplasia and in shoulder regions of advanced plaques. Treatment of human monocytes with M-CSF or M-CSF+LDL generated macrophages and foam cells producing CTX-I when cultured on type I collagen enriched matrix. Circulating levels of CTX-I were not significantly different in women with aortic calcifications compared to those without.ConclusionsHuman macrophage foam cells degrade the atherosclerotic plaques though cathepsin K mediated processes, resulting in increase in levels of CTX-I. Serum CTX-I was not elevated in women with aortic calcification, likely due to the contribution of CTX-I from osteoclastic bone resorption which involves Cathepsin-K. The human macrophage model system may be used to identify important pathway leading to excessive proteolytic plaque remodeling and plaque rupture.

Local Hemodynamics and Intimal Hyperplasia at the Venous Side of a Porcine Arteriovenous Shunt

Venous anastomotic intimal hyperplasia (IH) observed in the arteriovenous shunt (AVS) has been associated with disturbed hemodynamics. This study aims to correlate hemodynamics with wall histology and wall mechanics by examining the flow field in AVS with computational fluid dynamics using experimental data taken from in vivo experiments. Input data to the computational model were obtained in vivo one month after AVS creation; adjacent vessels were submitted to histological and mechanical examination. The 3-D shunt geometry was determined using biplane angiography. Ultrasound measurements of flow rates were performed with perivascular flow probes and pressures were recorded through intravascular catheters. These data were considered as boundary conditions for calculation of the unsteady flow field. Numerical findings are suggestive of strong Dean vortices toward both vein flow exits, verified by color Doppler. The high wall shear stresses (WSSs) and their gradients appear to be related to areas of IH and vessel wall stiffening, as evidenced in preliminary histological and mechanical studies of the venous wall. Additionally, suture line hyperplasia seems to be aggravated by the high WSS gradients noted at the transition line from graft to vein.

Pathogenesis of primary varicose veins

Valvular incompetence and reflux are common features of primary varicose veins, and have long been thought to be their cause. Recent evidence, however, suggests that changes in the vein wall may precede valvular dysfunction. A literature search was performed using PubMed and Ovid using the keywords 'varicose vein wall changes', 'pathogenesis', 'aetiology' and 'valvular dysfunction'. Articles discussing the pathophysiology of complications of varicose veins, such as ulceration, recurrence, thrombophlebitis and lipodermatosclerosis, were excluded. Positive family history, age, sex and pregnancy are important risk factors for varicose vein formation. Areas of intimal hyperplasia and smooth muscle cell proliferation are often noted in varicose veins, although regions of atrophy are also present. The total elastin content in varicose as opposed to non-varicose veins is reduced; changes in overall collagen content are uncertain. Matrix metalloproteinases (MMPs), including MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, and tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP-3 are upregulated in varicose veins. Activation of the endothelium stimulates the recruitment of leucocytes and the release of growth factors, leading to smooth muscle cell proliferation and migration. Dysregulated apoptosis has also been demonstrated in varicose veins. An understanding of the pathophysiology of varicose veins is important in the identification of potential therapeutic targets and treatment strategies.

Serial Intravascular Ultrasound Analysis of Bifurcation Lesions Treated Using the Novel Self-Expanding Sideguard Side Branch Stent

We used intravascular ultrasound (IVUS) to assess the efficacy of the Cappella Sideguard stent system for treating coronary bifurcation lesions. Treatment of bifurcation lesions is associated with restenosis at the side branch (SB) ostium, presumably due to inadequate coverage or stent-vessel wall malapposition. To address these limitations, the Sideguard stent was developed. It includes a balloon-deployed, self-expanding, thin-strut, low-stress, nitinol bare metal stent with anatomic funnel-shaped flaring at the SB ostium. Of 25 patients enrolled in the Sideguard I First-In-Man study, complete serial (after intervention and 6-month follow-up) IVUS images were available in 11 patients. All patients were treated with (1) predilation of the SB, (2) Sideguard stenting in the SB, (3) Cypher stenting in the main vessel, and (4) kissing balloon inflations. The Sideguard stent area at the SB carina increased from 3.9 +/- 1.2 to 4.6 +/- 1.1 mm(2) (p = 0.04), resulting in no change in lumen area (3.9 +/- 1.3 vs 4.0 +/- 1.3 mm(2), p = 0.77) despite an intimal hyperplasia (IH) area of 0.6 +/- 0.7 mm(2). Six patients had minimal IH; the increase in stent area translated into an increase in lumen area of 0.4 +/- 0.6 mm(2); 5 patients had relatively more IH (1.3 +/- 0.4 mm(2)), but the increase in stent area of 1.3 +/- 0.3 mm(2) compensated for the IH, resulting in no lumen decrease. In contrast, the main vessel stent area at the carina did not change (5.9 +/- 1.1 vs 6.0 +/- 1.2 mm(2), p = 0.35). In conclusion, serial IVUS analyses of the self-expanding bare metal Sideguard stent indicate preserved SB ostial lumen dimensions at follow-up due to additional increases in stent area that more than compensated for IH.

Alcohol Pretreatment of Small‐diameter Expanded Polytetrafluoroethylene Grafts: Quantitative Analysis of Graft Healing Characteristics in the Rat Abdominal Aorta Interposition Model

Long-term patency rates of small-diameter expanded polytetrafluoroethylene (ePTFE) vascular prostheses are unsatisfactory. Treatment of ePTFE grafts by alcohol before implantation was reported to increase hydrophilic properties, yielding better endothelialization and cellular in-growth, thus improving graft healing. The effect of alcohol pretreatment on ePTFE grafts and postoperative healing characteristics of wet ePTFE grafts were evaluated in this study. Ten sterile ePTFE grafts (2 mm ID, 30 micro thru-pore, 12 mm long) were implanted in the infrarenal aorta of male Sprague-Dawley rats (324-380 g). Five grafts were treated with ethanol 70% and soaked with saline solution before implantation (wet); five nontreated grafts served as control. All rats were sacrificed after digital subtraction angiography and sampling of the graft for histological investigation after 3 weeks. Histomorphometric analysis was performed for endothelial coverage, cellular in-growth, and intimal hyperplasia. All grafts were patent at the end of 3 weeks in both groups. Histological evaluation revealed significantly better endothelial coverage and prominent infiltration by fibroblasts and lymphocytes in the wet group. Endothelial coverage (31.03 +/- 10.61% vs. 13.03 +/- 9.46%, P = 0.03) and cellular infiltration of grafts (50.91 +/- 8.55% vs. 39.29 +/- 10.70%, P = 0.11) were higher in the wet group. Area of intimal hyperplasia per graft length was also higher in the wet group (5.32 +/- 4.75 microm(2)/microm vs. 2.69 +/- 3.41 microm(2)/microm, P = 0.36). Wetting of ePTFE grafts with ethanol 70% pretreatment before implantation might have a beneficial effect on long-term patency of small-diameter vascular grafts due to facilitated graft healing.

Effects of granulocyte-colony stimulating factor on the repair of balloon-injured arteries

The dysfunction of vascular endothelial cells plays a key role in starting arterial restenosis. The circulating endothelial progenitor cells (EPCs) can be mobilised by cytokines and are recruited to sites of injury, where they may participate in intima repair and the recovery of endothelial function. In the present study, we examined the hypothesis that mobilisation of EPCs by exogenous recombinant human granulocyte-colony stimulating factor (rhG-CSF) can promote vascular proliferation, reduce vascular inflammation and decrease the rate of restenosis. Male rats were randomly divided into the rhG-CSF and control groups. The animals were injected daily with 30 microg/kg rhG-CSF or 0.9% NaCl subcutaneously for 7 days, then the animals underwent balloon angioplasty of the common carotid artery. The animals were euthanased at 2 or 4 weeks after injury, and the carotid arteries were harvested and processed for immunohistochemistry, scanning electron microscopy (SEM), morphometric analysis of endothelialisation and neointimal formation at 1 hour, and 3, 7, 14 and 28 days after injury. Immunohistochemistry for proliferation cell nuclear antigen (PCNA) and reverse transcriptase polymerase chain reaction (RT-PCR) for endothelial nitric oxide synthase (eNOS) mRNA were also conducted for evaluating the proliferation of cells of the vessel wall and the possible mechanism of the repairing. Four weeks after balloon damage, SEM showed increased re-endothelialisation of the denuded vessels in the G-CSF treated animals compared with the control animals [(60.6 +/- 7.3)% versus (41.6 +/- 3.3)%, p < 0.01]. Re-endothelialisation was paralleled by a decrease in inflammation in the vessel wall. Histological examination showed that neointimal formation, vascular smooth muscle cells and fibrous tissue of the G-CSF group were less than those of the control group. Morphometry showed the lumen area of the G-CSF group was larger than that of the control group, and the neointimal area and percent of intimal hyperplasia were significantly smaller than those of the control group. Immunohistochemical staining for PCNA positive cells was less in the G-CSF treated animals compared with the control animals (42.9% versus 72.8%, p < 0.01). rhG-CSF-induced mobilisation of EPCs regenerated endothelium and inhibited neointimal hyperplasia after vascular injury. This cytokine therapy may be a feasible strategy for the promotion of re-endothelialisation after angioplasty.

Meta-analysis of the Effects of Paclitaxel-Eluting Stents Versus Bare Metal Stents on Volumetric Intravascular Ultrasound in Patients With Versus Without Diabetes Mellitus

Diabetes mellitus is a strong predictor of in-stent restenosis after bare-metal stent placement because of exaggerated intimal hyperplasia (IH). In this study, serial intravascular ultrasound was used to evaluate the effects of polymer-based, paclitaxel-eluting stents (PES) on in-stent neointima formation in patients with and without diabetes. A volumetric IVUS meta-analysis of 956 patients randomized to PES or bare-metal stents in the TAXUS IV (n=268), TAXUS V (n=509), and TAXUS VI (n=179) trials was performed. Diabetes was present in 273 of the 956 patients (28.6%). Stent, luminal, and IH areas were measured every millimeter within the stent, and volumes, percentage IH (%IH), and neointima-free stent length were calculated. Patients with diabetes treated with bare-metal stents had greater IH volumes (78.9 vs 61.2 mm3, p=0.0095) and %IH (34.9% vs 30.1%, p=0.0186) compared with those without diabetes. However, patients with diabetes treated with PES had similar median IH volume (22.8 vs 16.3 mm3, p=0.35) and median %IH (9.1% vs 9.2%, p=0.27) compared with those without diabetes and significantly less IH volume and %IH than after bare-metal stent implantation (p<0.0001 for the 2 comparisons). In conclusion, serial volumetric IVUS analysis showed that treatment with PES neutralizes the propensity of patients with diabetes to develop greater IH, such that patients with and without diabetes treated with PES have similar vascular responses and restenosis rates.

Photodynamic Therapy Reduces Intimal Hyperplasia in Prosthetic Vascular Bypass Grafts in a Pig Model

Bypass surgery has a failing frequency of 30% during the first year, mainly due to intimal hyperplasia (IH). This negative effect is most pronounced in artificial grafts. Photodynamic therapy (PDT) is a technique in which light activates photosensitizer dyes to produce free-radicals resulting in an eradication of cells in the vascular wall. The aim of this study was to determine the effectiveness of PDT to reduce IH in a preclinical porcine PTFE bypass model. Ten pigs were used. After a pilot PDT dosimetry study (n=3) PTFE grafts were bilaterally placed into the circulation as bypasses from the common to the external iliac arteries (n=7). The right sides served as controls (C). Before implantation of the left grafts, the arterial connecting sites of the left distal anastomoses were PDT-treated. The arteries were pressurized at 180 mmHg for 5 minutes with the photosensitizer Methylene Blue (330 microg/ml), and thereafter endoluminally irradiated with laser light (lambda = 660 nm, 100 mW/cm(2), 150 J/cm(2)). After 4 weeks the specimens were retrieved and formalin fixed. Cross sections through the midportions of the distal anastomoses and the grafts were used for histology, immunohistochemistry to identify inflammatory cells and morphometric evaluation (n=7). No systemic side effects and no graft occlusions were noted. PDT-treated anastomoses showed reduced IH in the mid-portions of the anastomoses (Area of IH: microm(2)/microm graft: C: 6970+/-1536, PDT: 2734+/-2560; P<0.005) as well as in the grafts (C: 5391+/-4031, PDT: 777+/-1331; P<0.02). The number of inflammatory cells per microscopic field was increased after PDT (C: 24+/-16, PDT: 37+/-15; P<0.009). Adjuvant PDT, performed in an endovascular fashion, was a safe method to reduce prosthetic graftstenosis in a preclinical setting. This study underscores the clinical potential of PDT to inhibit the development of clinical bypass graftstenosis.

Catheter-based infrared light scanner as a tool to assess conduit quality in coronary artery bypass surgery

Endothelial disruption within saphenous vein and radial artery grafts increases thrombosis risk. However, no clinically applicable method for imaging the intima currently exists. We used a novel infrared imaging technology, optical coherence tomography (OCT; LightLab Imaging, Inc, Westford, Mass), to visualize the intima within harvested conduits. Conduits were procured endoscopically (37 saphenous vein grafts and 8 radial artery grafts) or with the open technique (9 radial artery grafts) from 50 patients. Surplus segments were analyzed by means of OCT for evidence of preexisting pathology or traumatic injury. Focal plaques in radial artery grafts and the intimal hyperplasia area in saphenous vein grafts were quantified as having an intimal/medial thickness ratio of greater than 0.5. Biopsy specimens were obtained for histologic confirmation and to analyze matrix metalloproteinase 2 levels (saphenous vein grafts) and prostacyclin/nitric oxide metabolites (radial artery grafts). Interobserver kappa coefficients and a Bland-Altman analysis were used to determine the reproducibility and accuracy of OCT interpretations. Radial artery imaging revealed plaque in 76%. Endoscopically harvested vessels showed intraluminal clot (38%) and intimal tears ranging from severe (6%) to mild (88%). In saphenous vein grafts intimal thickening was detected in 86% and intraluminal clotting in 68%. The intimal/medial thickness ratio determined by means of OCT correlated directly with matrix metalloproteinase 2 levels (R = 0.6804) in saphenous vein grafts and inversely with metabolites of prostacyclin (R = -0.55) and nitric oxide (R = -0.58) in radial artery grafts. OCT imaging was reproducible (interobserver kappa coefficients of >0.81 for the characterization of plaque types) and showed a strong correlation with histology (R = 0.8, P < .001). OCT imaging provides an accurate, real-time, and reproducible means for assessing saphenous vein graft and radial artery graft bypass conduits. As a quality assurance tool, this technology might afford a more objective basis for conduit selection.

Sirolimus-eluting stent implantation and β-irradiation for the treatment of in-stent restenotic lesions: Comparison of underlying mechanisms of acute gain and late loss as assessed by volumetric intravascular ultrasound

The aim of the study was to compare the angioplasty mechanisms of drug (sirolimus)-eluting stent (DES) implantation and vascular brachytherapy (VBT) for the treatment of in-stent restenosis (ISR) as assessed by intravascular ultrasound (IVUS). We performed IVUS in 53 patients (28 DES, 25 VBT) before and after angioplasty of ISR and at 6-month follow-up. Cross-sectional areas of the external elastic membrane, the stent, and the lumen were measured. Plaque + media, peristent plaque, and intimal hyperplasia areas were calculated, respectively. Clinical and IVUS baseline characteristics did not differ between groups at baseline. After the index procedure, the lumen at the stent site was smaller in the DES group (DES 6.7 +/- 2.0 mm2 vs VBT 7.5 +/- 2.2 mm2, P = .042). Because of less intimal hyperplasia (DES 0.2 +/- 0.5 mm2 vs VBT 0.7 +/- 0.7 mm2, P = .043), the lumen dimensions revealed no difference between groups at follow-up (DES 6.5 +/- 2.3 mm2 vs VBT 6.8 +/- 2.2 mm2, P = .374). At the reference site, the index procedure led to a similar increase of plaque + media (DES 0.9 +/- 0.9 mm2 vs VBT 0.6 +/- 1.2 mm2, P = .150). At follow-up, the plaque + media was significantly smaller in the DES group (DES 8.0 +/- 6.6 mm2 vs VBT 9.9 +/- 7.8 mm2, P = .013). Drug-eluting stent for the treatment of ISR more effectively inhibits neointima formation when compared with VBT. Yet insufficient stent expansion might be a reason for device failure and should be avoided. At the reference site, lumen loss by an increased plaque burden, as has been well recognized following VBT, is not present with DES.

Angiogenesis Occurs Within the Intimal Proliferation That Characterizes Transplant Coronary Artery Vasculopathy

Vascular remodeling is central to the development of transplant coronary artery vasculopathy (CAV). For remodeling to occur, a sustained blood and nutrient supply is essential. Here we report on the presence of angiogenesis within the neointima of coronary arteries from cardiac transplant recipients. Coronary arteries from 57 cardiac transplant recipients with CAV were analyzed. Immunocytochemistry with antibodies raised against endothelial cells (CD31, CD34, and vWF), vascular smooth muscle cells (SmA), and activated endothelial cells (MHC 2, P-SEL, E-SEL, and VCAM-1) was performed. A total of 89% of patients had significant angiogenesis. These vessels appeared as endothelial lined channels and were present in a concentric circumferential pattern within the mid portion of the neointima. These new vessels were present at an interface between an area of intimal hyperplasia and below an area of fibrous regeneration. These 2 distinct zones were present in 64% of the cases, and were clearly demonstrated with an elastic van Gieson (EVG) stain and are distinctly different from that seen in native atherosclerosis. Endothelial activation markers were strongly expressed by the endothelial cells lining new vessels, suggesting that they are functional and may aid in the recruitment of inflammatory cells. These data suggest that angiogenesis is present within the intima of CAV lesions and may contribute to the continued obliteration of the vessel lumen. The vessels appear to originate in the intima and may represent the location of the donor endothelium before transplantation. Inhibition of endothelial damage may provide therapeutic options to prevent the progression of CAV.

Two‐year follow‐up intravascular ultrasound analysis after bare metal stent implantation in 120 lesions

The objective of this study was to examine long-term changes after bare metal stent implantation in a relatively large number of patients. There are few reports of intravascular ultrasound (IVUS) studies performed on stented and nonstented (reference) segments beyond 6 months after bare metal stenting. Using IVUS, we evaluated serial changes in stented and reference segments between 6 and 24 months after stent implantation in 110 patients with 120 lesions. Serial IVUS images were acquired at five equidistant intrastent sites and at two different reference segment sites. Measurements were made of the external elastic membrane (EEM), stent, lumen, and intimal hyperplasia (IH = stent - lumen) area. For the whole patient group, between 6 and 24 months, the mean IH area in stented segments decreased from 2.6 +/- 1.0 to 2.3 36+/- 0.9 mm2 (P < 0.001), and the mean lumen area increased from 6.2 +/- 2.0 to 6.5 +/- 1.9 mm2 (P < 0.001). The mean IH area decreased in 91 lesions (76%) and increased in 29 lesions (24%) between 6 and 24 months. There were no significant changes in EEM or lumen area in the reference segments. Late angiographic restenosis (diameter stenosis > or = 50%) occurred in three lesions between 6 and 24 months. A late target lesion revascularization was performed for one lesion. In the period of time between 6 and 24 months after stenting, IH regression occurred in most (76%) stent lesions, resulting in late lumen increase. However, IH progression was observed in 24% of in-stent lesions. No significant changes of EEM or lumen area occurred in the reference segments.

Nonuniform Strut Distribution Correlates With More Neointimal Hyperplasia After Sirolimus-Eluting Stent Implantation

Little is known about causes of intimal hyperplasia (IH) after sirolimus-eluting stent (SES) implantation. Intravascular ultrasound was performed in 24 lesions with intra-SES restenosis and a comparison group of 25 nonrestenotic SESs. To assess stent strut distribution, the maximum interstrut angle was measured with a protractor centered on the stent, and the visible struts were counted and normalized for the number of stent cells. In SES restenosis patients, minimum lumen site was compared with image slices 2.5, 5.0, 7.5, and 10.0 mm proximal and distal to this site. The minimum lumen site had a smaller IVUS lumen area at follow-up (2.7+/-0.9 versus 6.2+/-1.9 mm2; P<0.01), larger maximum interstrut angle (135+/-39 degrees versus 72+/-23 degrees; P<0.01), larger IH area (3.4+/-1.5 versus 0.6+/-1.1 mm2; P<0.01) and thickness (0.7+/-0.3 versus 0.1+/-0.2 mm; P<0.01) at maximum interstrut angle, and fewer stent struts (4.9+/-1.0 versus 6.0+/-0.5; P<0.01) even when normalized for the number of stent cells (0.78+/-0.15 versus 0.97+/-0.07; P<0.01). Compared with nonrestenotic SES, the restenosis lesions also had a smaller minimal lumen area, larger IH area, thicker IH at maximum interstrut angle, fewer stent struts, and larger maximum interstrut angle. Multivariate analysis identified the number of visualized stent struts normalized for the number of stent cells and maximum interstrut angle as the only independent IVUS predictor of IH cross-sectional area (P<0.01 and P<0.01), minimum lumen area (P<0.01 and P<0.01), and IH thickness (P<0.01 and P<0.01). The number and distribution of stent struts affect the amount of neointima after SES implantation.

Late intravascular ultrasound findings of patients treated with brachytherapy for diffuse in-stent restenosis.

This study aimed at evaluating long-term (24-month) effects of beta-irradiation (188Re-MAG3-filled balloon) using intravascular ultrasound (IVUS) in patients with in-stent restenosis (ISR). Long-term effects of beta-irradiation on intimal hyperplasia (IH) within the stented segment and vessel and lumen dimensions of nonstented adjacent segments in patients with ISR have not been sufficiently evaluated. Two-year follow-up IVUS was performed in 30 patients with patent ISR segments at 6-month follow-up angiography. Serial IVUS images were acquired at five equidistant intrastent sites and at three different reference segment sites. IH burden (%) was defined as 100 x (IH/stent area). Mean intrastent IH area and IH burden significantly increased between 6 and 24 months, from 2.1 +/- 1.1 to 2.6 +/- 1.4 mm2 (P < 0.001) and from 26% +/- 10% to 33% +/- 14% (P < 0.001), respectively. There was a significant decrease of mean external elastic membrane (from 10.1 +/- 3.9 to 9.7 +/- 3.9 mm2; P = 0.015) and lumen area (from 5.6 +/- 2.3 to 5.1 +/- 2.3 mm2; P = 0.021) within distal reference segments between 6 and 24 months. Target lesion revascularization (TLR) was performed in six patients (20%) between 6 and 24 months after beta-irradiation therapy. There were no significant differences between TLR and non-TLR groups except for a smaller minimum lumen area at 24 months in the TLR group. Because of a small amount of late loss between 6 and 24 months, most irradiated ISR vessel segments remained stable for up to 2 years. However, quantitative evidence of late catch-up was evident in most patients and was significantly associated with 24-month TLR in some patients.

Evaluation of a high-dose dexamethasone-eluting stent

This study evaluated the safety and efficacy of a dexamethasone-eluting stent with a special high dexamethasone-loading dose for treatment of de novo coronary lesions in 30 patients. Eight patients had in-stent restenosis (restenosis rate 31%) at 6-month follow-up, and the in-stent late lumen loss was 0.96 ± 0.63 mm due to an average intimal hyperplasia area obstruction of 32 ± 21%, indicating that high-dose dexamethasone-loaded stents do not significantly reduce neointimal proliferation.