Constrictive Remodeling Research Articles

Genetic risk factors and restenosis after percutaneous coronary interventions.

Restenosis is the major limitation of percutaneous coronary interventions. Depending on the form of intervention and patients' characteristics, 20 to 50% of the treated patients incur significant restenosis. Restenosis is caused by a complex and only partially understood cascade of events. Thrombus formation at the injury site, formation of the neointima as a result of the migration and proliferation of smooth muscle cells (SMC) and extracellular matrix production, as well as constrictive remodeling of the vessel wall contribute by a variable degree to restenosis. Restenosis is not a random event but it affects selectively a certain subset of patients. These patients have some peculiar characteristics that help to identify the presence of a higher risk for restenosis. Conventional patient-related factors account only for a relatively small portion of the predictive power, much more contribution comes from lesion and procedural characteristics. There is increasing evidence that inherited factors may explain at least part of the excessive risk for restenosis observed in certain patients. Evidence exists that gene polymorphisms may lead to quantitative or functional alterations of the respective gene products. Recent studies have also found significant associations between several polymorphic alleles encoding for proteins with a relevant role in the process of lumen renarrowing and restenosis after percutaneous coronary interventions. The best studied polymorphisms in this regard are those of the genes encoding for angiotensin-converting enzyme and platelet glycoprotein-IIIa. Completed or ongoing studies have focused on polymorphisms of genes encoding for proteins interfering with lipid metabolism, hemostasis, nitric oxide production, inflammatory mechanisms, SMC proliferation and matrix production. The results of this research will have considerable pathophysiological and therapeutical implications for the battle against restenosis.

Plaque Characteristics and Clinical Presentation Associated with Coronary Artery Remodeling: An Intravascular Ultrasound Study

Background: : : :Factors leading to coronary remodeling and relationship between remodeling patterns and clinical presentation remain unclear. Methods: : : :Seventy-five culprit lesions of 75 patients with acute coronary syndro- me (ACS(n=49 and stable angina (SA(n=26(60 men and 15 women;mean age 56±10 years were studied by intravascular ultrasound. Remodeling index (RI was calculated as culprit lesion vessel area (VA/ proximal reference VA. We defined:1 compensatory remodeling (CpR as RI≥1.1;2 constrictive remodeling (CsR as RI≤0.9;3 no remodeling (NR as 0.9<RI<1.1. Results:Twenty-three (31% lesions had CpR, 37 (49% had CsR and 15 (20% had NR. No significant differences in remodeling patterns were noted with respect to coranary risk factors. Soft plaques were more prevalent in lesions with CpR, whereas hard plaques were more prevalent in lesions with CsR (p<0.001. Lesions with CpR had significantly smaller proximal ref- erence VA than those with NR or CsR (p<0.05. Plaque characteristics were similar in ACS and SA patients. However, more culprit lesions with CpR were present in patients with ACS (21/49 vs 3/26, p<0.01, whereas more culprit lesions with CsR were noted in patients with SA (18/26 vs 19/49, p<0.05. Conclusion:Local factors such as plaque characteristics and vessel size appear to be associated with remodeling patterns. The type of remodeling is more related to clinical presentation than plaque characteristics. ( ( ( (Korean Circulation J 2000;30( ( ( (8 :911-920

Pentoxifylline inhibits neointimal formation and stimulates constrictive vascular remodeling after arterial injury.

Pentoxifylline (PTX) is a phosphodiesterase inhibitor used in the treatment of peripheral vascular disease, and this agent can suppress inflammatory vascular damage. Inflammation has been implicated in vascular lesion formation, and we examined the effects of PTX in a model of arterial injury. Sprague-Dawley rats were treated with intraperitoneal PTX (75 mg/kg/day) or saline starting 3 days before carotid balloon injury, and killed 24 h or 14 days later. Carotid arteries were analyzed by cross-sectional morphometry, immunostaining for proliferating cell nuclear antigen (PCNA) and subjected to terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL). Moreover, the effects of PTX on vascular smooth-muscle cell (VSMC) migration and production of collagen types I, IV, and VI were examined in vitro. At 14 days after balloon injury, PTX reduced the neointimal area (0.074+/-0.001 vs. 0.172+/-0.003 mm2; p<0.001), media area (0.143+/-0.001 vs. 0.176+/-0.001 mm2; p<0.01), intima/media ratio (0.50+/-0.02 vs. 0.99+/-0.12; p<0.001), and total vessel area (0.601+/-0.010 vs. 0.744+/-0.011 mm2; p<0.01). The lumen area, PCNA expression, and TUNEL were similar in the two treatment groups, whereas the neointimal cell density was increased by PTX (3,476+/-504 cells/mm2 vs. 2,215+/-232 cells/mm2; p<0.05). In vitro, PTX inhibited VSMC production of collagen type I in a concentration-dependent manner and did not influence VSMC migration. We conclude that PTX inhibits neointimal formation and induces constrictive vascular remodeling in the rat model of balloon injury by mechanisms involving decreased VSMC collagen type I production.

Histopathology of postpercutaneous transluminal coronary angioplasty remodeling in human coronary arteries

Background We studied the histomorphometric correlates of long-term successful coronary balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA]). Restenosis after PTCA may occur secondary to the failure of compensatory arterial enlargement or post-PTCA arterial constriction. The histopathology of this process in human subjects remains poorly defined. Methods Forty-two coronary segments from 41 patients treated with PTCA 60 ± 58 weeks before death were studied. The histomorphometric findings at the PTCA site were compared with those obtained at a proximal reference site. Results Histologic long-term success was seen in 18 (43%) of 42 arteries. Histologically successful PTCA arteries (PTCA site lumen of ≥50% of the reference lumen) demonstrated a larger acute lumen, smaller plaque size (normalized to the internal elastic lamina area), and thinner adventitia compared with histologic failures. Relative to the reference sites, histologically successful PTCA showed expansion of the external elastic lamina. In contrast, histologic failures showed a reduced external elastic lamina area, suggesting constrictive remodeling. Neointimal area correlated with the extent of internal elastic lamina disruption, but neither variable was related to histologic PTCA success or failure. Conclusions These data provide histomorphometric confirmation of the hypothesis that constrictive remodeling, not neointimal formation, determines the long-term outcome of PTCA. (Am Heart J 1999;138:681-7.)

Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty.

Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling. Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study. These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Arterial remodelling of native human coronary arteries in patients with unstable angina pectoris: a prospective intravascular ultrasound study

OBJECTIVETo investigate the use of intravascular ultrasound (IVUS) in detecting the presence of arterial remodelling in patients with unstable angina.DESIGNProspective case study.PATIENTS60 of 95 consecutively admitted patients with unstable angina...

Prevention of coronary restenosis.

Percutaneous transluminal coronary angioplasty (PTCA) was introduced 22 years ago as a nonsurgical catheter-based treatment for obstructive coronary artery disease. Over the following 2 decades, major advances in equipment and techniques led to tremendous growth in the use of PTCA to treat coronary artery disease and angina. Restenosis persists as the limiting factor in the maintenance of vessel patency after PTCA, occurring in 30% to 50% of patients and accounting for significant morbidity and health care expenditures. Plaque persistence and vessel recoil, thrombus formation, constrictive remodeling, and neointimal proliferation are the primary contributors to the development of restenosis after PTCA. Early clinical trials in restenosis prevention using various revascularization devices, antiplatelet drugs, antithrombotic drugs, and antiinflammatory drugs were uniformly negative. Coronary stents are the only devices that have shown a reduction in the incidence of restenosis. Recently, novel therapies, such as intracoronary radiation, antioxidant drugs, and platelet-derived growth factor antagonists, have shown reductions in the incidence of restenosis in small randomized trials. This review focuses on the etiology and pathophysiology of restenosis and discusses current and future therapies that may reduce the incidence of restenosis.

Aminoguanidine induces constrictive vascular remodeling and inhibits smooth muscle cell death after balloon injury

We examined the effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, in the rat model of balloon injury. Arteries were assessed by histomorphometry, and vascular smooth muscle cell death and proliferation were examined 24 h and 14 days after balloon injury by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA and expression of proliferating cell nuclear antigen, respectively. Aminoguanidine decreased the luminal area 14 days after balloon injury (0.19±0.04 mm 2 vs. 0.35±0.02 mm 2; P<0.005), and this effect was attributable to reduction of the total vessel area, i.e., constrictive vascular remodeling (0.42±0.03 mm 2 vs. 0.55±0.03 mm 2; P<0.005). At 24 h after injury, the percentage of TUNEL-positive cells in the medial layer was reduced by aminoguanidine (2.0±1.0% vs. 17.3±5.4%; P<0.05), and the percentage of proliferating cells was increased (18.4±5.5% vs. 4.9±2.2%; P<0.05). Aminoguanidine did not influence the density of VSMC nuclei in the injured artery wall, systemic blood pressure or endothelium-dependent vasorelaxation. We conclude, that in the rat model of balloon injury, aminoguanidine induces luminal loss by constrictive vascular remodeling in association with reduced early VSMC death and increased proliferation.

Endovascular brachytherapy for the prevention of recurrence after PTA

Recurrent stenosis after PTA is caused by intimal hyperplasia and constrictive arterial remodeling. In experimental and first clinical studies, ionizing radiation has demonstrated its potential to control excessive intimal proliferation. We wanted to evaluate the safety, feasibility and efficacy of endoluminal irradiation after PTA and/or stent implantation. From September 1996, 24 patients (24 lesions) who had a stenosis or occlusion measuring more than 5 cm in length in the superficial femoral artery or a restenosis after PTA underwent endoluminal irradiation. An isodose of 14 Gy was applied to the vessel wall using an Ir-192-HDR afterloading unit. The radiation was tolerated well; the additional time needed for the procedure was 30-45 min. In a mean follow-up time of 15 months we found a cumulative patency rate of 60%. No side effects were observed. Endovascular brachytherapy is a safe and brief procedure. In our selection of patients, a patency rate of approx. 40% after 1 year has to be expected. Thus, these first results are promising, although first published studies of endoluminal irradiation in peripheral vessels with stent implantation showed higher patency rates. No randomized data are currently available. We conclude that endovascular irradiation should be performed together with stent implantation in long lesions or recurrent stenosis after PTA, in order to control not only excessive intimal proliferation but also constrictive arterial remodeling.

Coronary risk factors influence plaque morphology in patients with unstable angina.

The risk of plaque disruption and subsequent thrombosis in patients with unstable angina depends on the plaque type and size. Intravascular ultrasound (IVUS) was employed to illustrate the correlation between risk factors and plaque morphology in patients with unstable angina. In a prospective study of 60 of 95 patients consecutively admitted with unstable angina [41 men, aged 61.2 +/- 8.1 years (mean +/- SD)], qualitative (soft and hard plaque, thrombus, calcification, eccentricity, adaptive and constrictive remodeling) and quantitative [lumen, external elastic membrane (EEM) and plaque cross-sectional area (CSA) and plaque burden] IVUS data relating to the target lesion, and proximal and distal reference segments were analyzed and correlated with risk factors. Univariate and multivariate nominal logistic regression analyses and analyses of variance were used to determine the independent predictors for IVUS morphology. For plaque composition univariate analysis showed a younger age (< 60 years) to be a predictor for adaptive remodeling (P = 0.019), and an older age to be a predictor for constrictive remodeling (P = 0.021). Hypercholesterolemia, smoking and sex were associated with a higher frequency of thrombus (P = 0.044, 0.038 and 0.043, respectively). Multivariate analyses revealed that only younger and older ages were independent predictors for adaptive and constrictive remodeling (P = 0.039 and P = 0.045). For plaque size, univariate and multivariate analyses demonstrated that diabetes mellitus and hypercholesterolemia were independent predictors for greater plaque (13.5 +/- 5.72 versus 10.17 +/- 4.6 mm2, P = 0.015, for diabetic versus non-diabetic patients; 12.0 +/- 5.35 versus 9.03 +/- 3.76 mm2, P = 0.010, for hypercholesterolemic versus normocholesterolemic patients) and EEM CSA (17.16 +/- 5.81 versus 14.3 +/- 5.1 mm2, P = 0.033, for diabetic versus non-diabetic patients; 16.57 +/- 5.49 versus 12.25 +/- 3.8 mm2, P = 0.001, for hypercholesterolemic versus normocholesterolemic patients) at the target lesion. Hypercholesterolemia was associated with significantly greater plaque and EEM CSA in both proximal and distal reference segments. Multivariate analyses indicated that age, diabetes and hypercholesterolemia are independent predictors for plaque morphology in patients with unstable angina.

Endothelial Dysfunction and Accumulation of Collagen are Associated With Restenosis and Constrictive Remodeling After Experimental Angioplasty

Endothelial Dysfunction and Accumulation of Collagen are Associated With Restenosis and Constrictive Remodeling After Experimental Angioplasty

Arterial response to mild balloon injury in the normal rabbit: evidence for low proliferation rate in the adventitia.

The role of constrictive remodeling, spasm and proliferation (particularly in the adventitia) in the genesis of chronic lumen narrowing after balloon injury remains under debate. This study analyzed the time course of these components following mild injury in normal arteries. Iliac injury was induced by balloon overstretch in 32 rabbits, sacrificed at timed intervals from day 3 to 28. Angiographic response to nitrates, morphometric, immunohistochemical and biochemical analysis were performed at each time point. Quantitative angiography showed a decrease in lumen diameter and no change in response to nitrates over time. On morphometric analysis, remodeling was usually constrictive, appeared as early as day 3 and was responsible for 69+/-14% of the histologic lumen area stenosis at day 28. Constrictive remodeling was correlated negatively to intimal hyperplasia (r= 0.51, P< 0.002) and positively to the lumen area stenosis (r= 0.92, P< 0.0001). Macrophages (labeled by anti-RAM 11 antibodies) were very rare at all time points. Immunohistochemistry identified a high rate of proliferating smooth muscle cells in the media (13+/-7%) and intima (49+/-8%) at day 7, which decreased rapidly. Proliferating cells in the adventitia were rare (3+/-2% at day 7). The number of proliferating cells was time-dependent (r= 0.82, P< 0.0001) and related to cyclin A mRNA measured by reverse transcription-polymerase chain reaction (r= 0.84, P< 0.0001). In this model, luminal loss was mainly caused by constrictive remodeling rather than intimal hyperplasia. Constrictive remodeling appeared early and was not time-dependent. Macrophages, spasm and adventitial proliferation did not contribute to this constrictive remodeling.

Endothelial dysfunction and accumulation of collagen are associated with restenosis and constrictive remodeling after experimental angioplasty

Endothelial dysfunction and accumulation of collagen are associated with restenosis and constrictive remodeling after experimental angioplasty

Psoralen and long wavelength ultraviolet radiation as an adjuvant therapy for prevention of intimal hyperplasia and constrictive remodeling after balloon dilation: A study in the rabbit iliac artery

Restenosis after balloon angioplasty is the summated effect of intimal hyperplasia and arterial shrinkage, both caused by hyperproliferation. In the present study, the potential of a photochemotherapeutic modality (Psoralen + UVA: PUVA) for the prevention of angioplasty induced proliferation was explored. In rabbit iliac arteries, balloon dilation followed by PUVA-therapy (H = 1 J/cm2) was performed (n = 15). Contralateral arteries served as control. After 2 and 28 days of survival, the contribution of intimal hyperplasia and remodeling to lumen loss was determined by means of angiography and histological analysis. After 2 days, large parts of the media had become acellular, while proliferation was occurring predominantly in the adventitia in both groups. After 28 days, late loss, arterial shrinkage, but not intimal hyperplasia were larger in the PUVA group (P < 0.05). PUVA-therapy did not prevent intimal hyperplasia following balloon dilation but enhanced luminal narrowing by augmented constrictive remodeling.

Predictors of Coronary Arterial Remodeling Patterns in Patients With Myocardial Ischemia

Preangioplasty intravascular ultrasound in 81 patients showed that adaptive remodeling occurred in 35% and constrictive remodeling in 34%. Multivariate analysis showed that smoking and fibrocalcific plaques were associated with constrictive remodeling, whereas small vessel size and hypercholesterolemia were associated with adaptive remodeling.

The biology of restenosis

Recent studies have allowed a better understanding of the biology of restenosis. Neointimal thickening--also referred to as neointimal hyperplasia--occurs in response to experimental arterial injury. This process involves different steps which include smooth muscle cell activation, proliferation, and migration, and the production of extracellular matrix. Neointimal thickening has been identified as one of the mechanisms of restenosis after balloon angioplasty in humans. The factors which control neointimal thickening include growth factors, hormonal factors, and mechanical factors. Delinquent reendothelialization has been shown to have a permissive impact on smooth muscle cell proliferation. In addition to neointimal thickening, arterial remodeling also plays a major role in restenosis. Studies performed on animals and in human subjects have established the potential for "constrictive remodeling" to reduce the vessel lumen after angioplasty. Restenosis thus appears as a multifactorial entity that may be addressed in the future by a combined mechanical and pharmacological approach.

Mechanisms of Neointima Formation—Lessons from Experimental Models

The lamina intima of an artery is the region between the endothelial cell surface and the internal elastic lamina, which forms the luminal margin of the media. In humans the intima of atherosclerosis-prone arteries becomes thicker due to accumulation of smooth muscle cells, which originate from the media. The introduction of percutaneous transluminal coronary angioplasty (PTCA) boosted scientific interest in intimal thickening, because restenosis remains an unresolved problem of this intervention. In order to unravel the mechanisms of intimal thickening there is a need for appropriate animal models. A brief overview of these models is given together with factors that control proliferation and/or migration. Despite intensive research on neointima formation, an effective therapy for restenosis has not emerged to date. This may be due to the fact that other processes, such as acute elastic recoil and chronic constrictive remodeling may contribute to lumen narrowing as well. Other limitations of neointima models are related to species and anatomical differences. Most studies are performed in arteries that are either lesion-free, or contain relatively mild plaques, in contrast to the complicated, stenotic lesions that are the substrate for human PTCA. Other differences are the severity of the injury and incorporation of a mural fibrin-rich thrombus. Nevertheless, studies based on superficial injury, like the frequently used balloon denudation model, are useful. There are similarities with angioplasty, such as endothelial cell damage and proliferation of medial and intimal smooth muscle cells. The use of techniques such as differential display, gene transfer and application of antisense oligonucleotides may provide new therapeutic approaches to reduce neointima formation.

Coronary AVE micro stents: serial quantitative angiography and histology in a canine model.

The AVE Micro Stent (AVE Inc., Santa Rosa, CA) is composed of helically welded 3 mm long, zigzag crowns with stent lengths from 6 to 39 mm and diameters from 2.5 to 4.5 mm. Quantitative coronary angiography and histologic analyses of acute and chronic implantation were obtained in 52 stented coronary segments of 18 dogs. Three hearts with 8 stented coronary segments were harvested after 24 hr, 3 hearts with 9 stented segments were harvested after 2 weeks, 6 hearts with 15 stented segments were harvested at 8 weeks, and 6 hearts with 20 stented segments were harvested at 24 weeks post-deployment. There were no procedural complications, deaths, or acute vessel closures. The average lumen diameter of the stented segment was largest at 2 weeks (3.3 +/- 0.3 mm). The smallest average diameters were observed at 8 weeks after the stent deployment (2.7 +/- 0.4, P < 0.05) with an increase again at 24 weeks (2.9 +/- 0.6). The pre-explant percent of stenosis was <30% in all animals. Histologically, a peak of inflammation was visible at 2 weeks; however, the extent of luminal narrowing reached its peak at 8 weeks and the lumen dimension increased somewhat at 24 weeks. The degree of intimal thickening remained relatively constant throughout the different time points (<200 microm). Overall, these data suggest that constrictive remodeling within the stented segment occurs at 8 weeks in this animal model. The later increase of the stented segment dimensions as well as higher net gain at 24 weeks compared to 8 weeks after deployment suggests that this constriction is a transitory phenomenon.

Perspectives of arterial gene therapy for the prevention of restenosis.

Restenosis remains the main limitation of interventional cardiology. Restenosis is an important target for gene therapy since it is frequent (30% of patients), costly (estimated $2 billion annually), refractory to all pharmacological therapies, and related, at least in part, to smooth muscle cell proliferation which is an inviting target for antiproliferative molecular strategies. Because cell division is ultimately controlled by intranuclear events, the protein product of genes selected for their antiproliferative effects usually remains inside the cells. Consequently, the transfer of growth-inhibitory genes needs to be efficient-i.e., involve a large proportion of smooth muscle cells populating the angioplasty site. To date, adenoviral vectors are, by far, the most efficient vectors to perform in vivo arterial gene delivery. These vectors, as well as others, have been recently used to demonstrate that therapeutic genes encoding cytolytic (thymidine kinase) or cytostatic (hypophosphorylatable retinoblastoma protein, endothelial nitric oxide synthase, gax, etc.) products successfully inhibit smooth muscle cell proliferation and related intimal hyperplasia. Despite substantial progress, major technical issues remain to be addressed before gene therapy is applied to clinical restenosis. First-generation recombinant adenoviruses evoke both cellular and humoral immune responses leading to local toxicity and transient gene expression. Moreover, the low efficiency of gene transfer to atherosclerotic arteries may further impair the biological effect of antiproliferative genes. Finally, restenosis is a multifactorial phenomenon in which intimal hyperplasia plays an important but not exclusive role. Prevention of constrictive remodeling should also be taken into account in an integrated genetic strategy to prevent restenosis.

Coronary stenting with a novel stainless steel balloon-expandable stent: Determinants of neointimal formation and changes in arterial geometry after placement in an atherosclerotic model

This study evaluated the delivery characteristics and vascular response to placement of a novel balloon-expandable stent in swine with experimentally induced atherosclerosis. The Multi-Link stent is a balloon-expandable stainless steel stent with an interconnected ring structure designed to provide a high degree of compressive resistance while preserving longitudinal flexibility. The placement characteristics and vascular response to this stent in atherosclerotic coronary arteries have not been characterized. We tested the delivery characteristics and vascular response to the Multi-Link stent in 19 miniature swine with experimentally induced coronary atherosclerosis created in 37 coronary artery segments by overstretch balloon injury and high cholesterol diet. Quantitative coronary angiography was used to define stent performance characteristics, such as lesion dilation and compressive resistance. Pathologic assessment of the stented arteries was used to evaluate the immediate and long-term vascular response to stent placement. Nineteen (95%) of 20 stents were successfully implanted in the left anterior descending (n = 11), left circumflex (n = 7) or right (n = 1) coronary artery. The baseline angiographic minimal lumen diameter of the stented coronary segment was 2.48 +/- 0.09 mm (reference diameter 2.87 +/- 0.06 mm, mean +/- SE) and increased to 2.82 +/- 0.05 mm (p < 0.001) after stent placement. The balloon-inflated stent diameter was 2.98 +/- 0.06 mm with minimal recoil to a final minimal lumen diameter of 2.82 +/- 0.06 mm at 15 min after implantation (p = 0.001). Angiographic and histologic follow-up at 72 h (n = 7), 14 days (n = 4) and 56 days (n = 8) demonstrated that all stents were patent, without evidence of migration, intraluminal filling defects or side branch occlusion. At 56 days, mean neointimal thickness was significantly greater at the stent wire sites in the region of the plaque where the media was absent than the stent wire sites, where the internal elastic lamina was intact with underlying normal media (0.48 +/- 0.01 vs. 0.27 +/- 0.02 mm, p < 0.0001). Compared with the nonstented atherosclerotic lesions, after 56 days the stented vessels had a mildly reduced lumen area when normalized to the proximal reference vessel (2.81 +/- 0.27 vs. 2.68 +/- 0.30 mm2, p = 0.07). The mean change in the area within the external elastic lamina relative to a normal proximal reference segment was significantly greater in stented vessels (1.45 +/- 0.34 mm2) than nonstented atherosclerotic vessels (0.44 +/- 0.28 mm2, p = 0.033). Morphologic data confirm that the principal beneficial effect of stent placement is vessel expansion and attenuation of constrictive remodeling. In vessels with eccentric atherosclerotic fibrocellular plaques, the presence of normal media underlying the stent determines the degree of neointimal formation. These data may be useful in understanding the mechanism of stent restenosis in patients with prior percutaneous transluminal coronary angioplasty.