Ex vivo and preclinical assessment of an endothelial progenitor cell capturing bioengineered stent.

Although drug-eluting stents (DES) have significantly reduced the rates of restenosis as compared to bare metal stents, late stent thrombosis remains a major drawback, especially for "off-label" use. Delayed arterial healing, characterized by persistent fibrin deposition and poor endothelialization, has been shown to correlate with late DES thrombosis. To overcome these limitations, a "pro-healing" approach has been developed to capture circulating endothelial progenitor cells (EPC) to enhance endothelialization of the stent surface. EPC have the ability to migrate to sites of vascular injury and aid the regeneration of damaged and dysfunctional endothelium. Clinically, the safety of EPC-capture stent has been proven in numerous clinical trials with low incidence of late stent thrombosis. The focus of this review is to demonstrate the efficacy of the Genous stent in preclinical studies, specifically to show the effectiveness of the anti-CD34+ coating in promoting endothelialization and reducing thrombogenicity.

Aortic endothelial cells regulate proliferation of human monocytes in vitro via a mechanism synergistic with macrophage colony-stimulating factor. Convergence at the cyclin E/p27(Kip1) regulatory checkpoint.

Monocyte-derived macrophages (Mphis) are pivotal participants in the pathogenesis of atherosclerosis. Evidence from both animal and human plaques indicates that local proliferation may contribute to accumulation of lesion Mphis, and the major Mphi growth factor, macrophage colony stimulating factor (MCSF), is present in atherosclerotic plaques. However, most in vitro studies have failed to demonstrate that human monocytes/Mphis possess significant proliferative capacity. We now report that, although human monocytes cultured in isolation showed only limited MCSF-induced proliferation, monocytes cocultured with aortic endothelial cells at identical MCSF concentrations underwent enhanced (up to 40-fold) and prolonged (21 d) proliferation. In contrast with monocytes in isolation, this was optimal at low seeding densities, required endothelial cell contact, and could not be reproduced by coculture with smooth muscle cells. Intimal Mphi isolated from human aortas likewise showed endothelial cell contact-dependent, MCSF-induced proliferation. Consistent with a two-signal mechanism governing Mphi proliferation, the cell cycle regulatory protein, cyclin E, was rapidly upregulated by endothelial cell contact in an MCSFindependent fashion, but MCSF was required for successful downregulation of the cell cycle inhibitory protein p27(Kip1) before cell cycling. Thus endothelial cells and MCSF differentially and synergistically regulate two Mphi genes critical for progression through the cell cycle.

Intravascular sonotherapy decreases neointimal hyperplasia after stent implantation in swine.

BACKGROUND: Intimal hyperplasia and subsequent in-stent restenosis remain a major limitation after stent implantation. In vitro cell culture studies show that low-frequency, noncavitational ultrasound energy may impact smooth muscle cell proliferation. Accordingly, we assessed the efficacy of intravascular sonotherapy treatment on intimal hyperplasia in a swine stent model. METHODS AND RESULTS: After balloon injury, biliary stents (Johnson & Johnson) were implanted in the femoral arteries of 14 swine. A total of 48 stented sites were randomized to sonotherapy or sham treatment using a custom-built, 8-French catheter intravascular sonotherapy system (URX, PharmaSonics Inc). After stent deployment, ultrasound energy (700 KHz) was applied to the treatment group for up to 5 minutes. Smooth muscle cell proliferation was assessed using bromodeoxyuridine histology preparation (BrdU) at 7 days in 28 stented sites. At 28 days, the neointimal thickness and the ratio of neointimal/stent area (percent stenosis) was calculated by histomorphometric quantification in 20 stented sites. At 7 days, percent of BrdU staining was significantly reduced in the sonotherapy group compared with the sham group (24.1+/-7.0% versus 31.2+/-3.0%, P<0.05). At 28 days, percent stenosis was significantly less in the sonotherapy group than in the sham group (36+/-24% versus 44+/-27%, P<0.05), and the mean neointimal thickness in the sonotherapy group was less than in the sham group (417+/-461 micrometer versus 643+/-869 micrometer, P=0.06). CONCLUSIONS: In this swine peripheral model, intravascular sonotherapy seemed to decelerate cellular proliferation and decrease in-stent hyperplasia. Therefore, intravascular sonotherapy may be an effective form of nonionizing energy to reduce in-stent restenosis.

Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression.

BACKGROUND: Subclinical episodes of plaque disruption followed by healing are considered a mechanism of increased plaque burden. Detailed pathological studies of healed ruptures, however, are lacking. METHODS AND RESULTS: We identified acute and healed ruptures from 142 men who died of sudden coronary death and performed morphometric measurements of plaque burden, luminal stenosis, and smooth muscle cell phenotype. Healed ruptures were found in 61% of hearts and were associated with healed myocardial infarction, increased heart weight, dyslipidemia, and diabetes. Multiple healed rupture sites with layering were frequently found in segments with acute and healed rupture; the percent area luminal narrowing increased with increased numbers of healed sites of previous rupture. The underlying percent luminal narrowing for acute ruptures (mean 79+/-15%) exceeded that for healed ruptures (mean 66+/-14%, P:=0.0001), and the area within the internal elastic lamina was significantly less in healed ruptures than in acute ruptures, when segments were grouped by distance from the ostium. Healed ruptures favored the accumulation of immature smooth muscle cells at repair sites, with a cellular proliferation index of 0.40+/-0.09%, significantly higher than the index at the sites of rupture (P:=0.008). CONCLUSIONS: These data provide evidence that silent plaque rupture is a form of wound healing that results in increased percent stenosis. Healed ruptures occur in arteries with less cross-sectional area luminal narrowing than acute ruptures and are a frequent finding in men who die suddenly with severe coronary atherosclerosis.

Pathological analysis of local delivery of paclitaxel via a polymer-coated stent.

BACKGROUND: Paclitaxel can inhibit vascular smooth muscle proliferation in vitro, and early studies suggest that paclitaxel may be useful in preventing restenosis. Early and late intimal growth and local vascular pathological changes associated with paclitaxel delivered via stents have not been fully explored. METHODS AND RESULTS: Localized drug delivery was accomplished with balloon-expandable stainless steel stents coated with a cross-linked biodegradable polymer, chondroitin sulfate and gelatin (CSG), containing various doses of paclitaxel. CSG-coated stents with paclitaxel (42.0, 20.2, 8.6, or 1.5 microgram of paclitaxel per stent), CSG-coated stents without paclitaxel, and uncoated stents (without paclitaxel or CSG) were deployed in the iliac arteries of New Zealand White rabbits, which were killed 28 days after implant. Mean neointimal thickness at stent strut sites was reduced 49% (P<0.0003) and 36% (P<0.007) with stents containing 42.0 and 20.2 microgram of paclitaxel per stent, respectively, versus CSG-coated stents without paclitaxel. However, histological findings suggested incomplete healing in the higher-dose (42.0 and 20.2 microgram) paclitaxel-containing stents consisting of persistent intimal fibrin deposition, intraintimal hemorrhage, and increased intimal and adventitial inflammation. Stents coated with CSG alone (without paclitaxel) had similar neointimal growth as uncoated stents. In a separate group of rabbits killed at 90 days, neointimal growth was no longer suppressed by CSG-coated stents containing 42.0 or 21.0 microgram of paclitaxel CONCLUSIONS: CSG coating appears to be a promising medium for localized drug delivery. Paclitaxel polymer-coated stents reduce neointima formation but are associated with evidence of incomplete healing at 28 days. However, neointimal suppression was not maintained at 90 days.

Limitation of no reflow injury by blood-free reperfusion with oxygenated perfluorochemical (Fluosol-DA 20%).

This study was designed to assess the effects of blood-free reperfusion with oxygenated or unoxygenated intracoronary perfluorochemical (Fluosol-DA 20%) on myocardial perfusion and to determine its mechanism or mechanisms of limiting no reflow. Twenty-four dogs underwent 90 min of coronary occlusion followed by 210 min of reperfusion and were randomized to either: 1) blood-free reperfusion with intracoronary oxygenated perfluorochemical (20 ml/kg per min) for 20 min followed by blood reperfusion (n = 8); 2) intracoronary unoxygenated perfluorochemical administered as in those treated with oxygenated perfluorochemical (n = 8); and 3) blood reperfusion alone (control) (n = 8). Regional myocardial blood flow was serially determined and global myocardial perfusion was assessed by an intravenous injection of the fluorescent dye (thioflavin-S). Quantitative studies were performed to determine neutrophil infiltration and extent of endothelial injury. Hemodynamic variables were similar in all groups. The zone of impaired perfusion (thioflavin negative), expressed as a percent of the left ventricle, averaged 10 +/- 2%, 6 +/- 2% and 3 +/- 1%, in control and unoxygenated and oxygenated perfluorochemical groups, respectively (control versus oxygenated perfluorochemical p less than 0.004). The reduction in thioflavin-negative area with oxygenated perfluorochemical was associated with a notable recovery of endocardial blood flow (0.97 +/- 0.22 vs. control 0.39 +/- 0.08 ml/min per g; p less than 0.04) at 210 min of reperfusion. The number of capillaries plugged by neutrophils (per 200 capillaries) in thioflavin-negative areas was similar with both oxygenated (5.9 +/- 1.4) and unoxygenated perfluorochemical (5.4 +/- 0.8) treatment and was significantly less than that with the control group (18.9 +/- 3.2, p less than 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial infarct extension during reperfusion after coronary artery occlusion: pathologic evidence.

OBJECTIVES: The goal of this study was to demonstrate myocardial infarct extension during reperfusion within the same animal. BACKGROUND: Whether myocardial reperfusion can result in the extension of myocardial necrosis remains controversial. The transformation of reversibly injured myocytes into irreversibly damaged cells after reperfusion has been difficult to demonstrate pathologically. METHODS: New Zealand White rabbits (Group I, n = 10) were subjected to 30 min of coronary artery occlusion and 180 min of reperfusion. Horseradish peroxidase, a tracer protein that permeates the sarcolemma of irreversibly injured myocytes, was used to quantitate myocyte necrosis at the beginning of reperfusion. Within the same heart, infarct size was measured after 180 min of reperfusion by triphenyltetrazolium chloride (TTC) staining. In separate experiments to demonstrate the validity of the model, rabbits were subjected to 30 min of coronary occlusion, followed by intravenous infusion of horseradish peroxidase and rapid induction of death (Group II) or 30 min of occlusion, 180 min of reperfusion with horseradish peroxidase administered after 180 min of reperfusion and TTC staining after induced death (Group III). RESULTS: In Group I, infarct size at the onset of reperfusion, delineated by horseradish peroxidase, measured 45.3 +/- 2.8% of the area of risk and was significantly less than TTC-delineated infarct size after 180 min of reperfusion (59.8 +/- 3.3%, p = 0.0002). By electron microscopy, border areas within the ischemic bed demonstrated irreversibly injured horseradish peroxidase-positive myocytes adjacent to irreversibly injured horseradish peroxidase-negative myocytes, suggesting that further cell death occurred during reperfusion. In Group II, infarcts delineated by horseradish peroxidase after 30 min of coronary occlusion were similar in size to infarcts measured by this tracer in Group I. In Group III, infarcts delineated by horseradish peroxidase at 180 min of reperfusion were similar in size to infarcts measured by TTC and similar to TTC-delineated infarcts measured at 180 min of reperfusion in Group I. CONCLUSIONS: These results provide evidence that there is a subset of myocytes in border areas within the ischemic region that are viable at the beginning of reperfusion but subsequently progress to irreversible injury during the reperfusion period.

Plaque morphology and pathologic changes in arteries from patients dying after coronary balloon angioplasty.

Morphologic correlates of pathologic success or failure were studied at autopsy in 28 patients with 40 coronary arteries that had been subjected to balloon angioplasty. The presence of the following histologic features was evaluated: plaque concentricity or eccentricity, calcification, fibrous or fibropultaceous plaque, medial disruption, luminal thrombus and inflammation. Angioplasty was considered successful (residual cross-sectional luminal area greater than 25%) on pathologic examination in 14 arteries and unsuccessful in 26 arteries. Eccentric plaques were more likely to be successfully dilated than were concentric lesions (p less than 0.05). Six (50%) of 12 fibropultaceous plaques were successfully dilated compared with only 8 (29%) of 28 fibrous plaques. Moderate to severe calcification did not preclude morphologic success. Medial stretching or dissection, or both, was more often associated with a successful result. Thus, plaque morphology may be an important determinant of pathologic outcome after coronary angioplasty.

Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaine-associated coronary vasospasm and thrombosis.

Coronary vasospasm has been implicated as a cause of myocardial ischemia and sudden cardiac death in cocaine abusers. However, the mechanism or mechanisms remain unknown. Autopsy records (n = 5,871) from the medical examiner's files at Baltimore, Maryland and northern Virginia were examined and 495 persons (8.4%) were identified with positive toxicologic findings for cocaine. Of these, six subjects (1.2%) had total thrombotic occlusion, involving primarily the left anterior descending coronary artery. The mean number of adventitial mast cells per coronary segment and the degree of atherosclerosis were determined. These observations were compared with findings in age- and gender-matched subjects who died from cocaine overdose and in patients who had sudden cardiac death (acute thrombosis) without a history of illicit drug abuse. There were significantly more mast cells in subjects with cocaine-associated thrombosis than in the other groups. The number of mast cells showed a significant correlation with the degree of cross-sectional luminal narrowing (r = 0.68) in subjects with cocaine-associated thrombosis but not in subjects with sudden death due to thrombosis (r = 0.34, p less than 0.03). Subjects with cocaine-associated thrombosis also had significant coronary atherosclerosis without plaque hemorrhage (five had one or more vessels with greater than 75% cross-sectional area luminal narrowing) despite a mean age of 29 +/- 2 years. These findings suggest that adventitial mast cells may potentiate atherosclerosis and vasospasm, thrombosis and premature sudden death in long-term cocaine abusers.

Hyperoxic reperfusion is required to reduce infarct size after intravenous therapy with perfluorochemical (Fluosol-DA 20%) or its detergent component (poloxamer 188) in a poorly collateralized animal model. Absence of a role of polymorphonuclear leukocytes.

OBJECTIVES: The aim of this study was to assess whether hyperoxic reperfusion contributes to the efficacy of Fluosol 20% or poloxamer 188 for infarct size reduction and whether suppression of polymorphonuclear leukocyte function is responsible for cardioprotection. BACKGROUND: The perfluorochemical Fluosol and its detergent component poloxamer 188 limit myocardial reperfusion-induced injury; however, the underlying mechanism(s) are uncertain. METHODS: A series of in vivo and ex vivo studies were performed in a 30-min temporary coronary occlusion rabbit model. Before reperfusion, rabbits received a 25-ml/kg infusion of 1) Fluosol; 2) poloxamer 188 (equivalent % w/v to Fluosol, 675 mg/kg body weight); or 3) 5% dextrose (control). In protocol A, animals were subjected to either normoxic or hyperoxic reperfusion; in protocols B and C, hyperoxic reperfusion was studied. In protocol B, myocardial blood flow was assessed. In protocol C, polymorphonuclear leukocyte function and myocardial myeloperoxidase were determined. RESULTS: In rabbits subjected to normoxic reperfusion, infarct size (normalized to risk region weight) was not significantly different among groups. In rabbits subjected to hyperoxic reperfusion, infarcts were significantly reduced with both poloxamer 188 and Fluosol treatment compared with control animals (p = 0.05 and p = 0.0004, respectively). Blood flow at 3 h of reperfusion within the ischemic endocardium was greater in the Fluosol and poloxamer 188 groups than in the control group (p = 0.001 and p = 0.08, respectively). Myeloperoxidase activity was not affected by treatment, nor was there suppression of polymorphonuclear leukocyte function. CONCLUSIONS: Fluosol and poloxamer 188 reduce infarct size in rabbits subjected to hyperoxic reperfusion. Suppression of polymorphonuclear leukocyte function was not demonstrated, suggesting a greater role for increased arterial oxygen delivery in salvaging ischemic myocardium.

Right ventricular myocardial infarction in patients with chronic lung disease: possible role of right ventricular hypertrophy.

To determine the relation between right ventricular hypertrophy and right ventricular myocardial infarction in patients with chronic lung disease, the records of 28 patients with chronic lung disease, inferior myocardial infarction and significant coronary artery disease (group I) and 20 patients with right ventricular hypertrophy, chronic lung disease without inferior myocardial infarction or significant coronary artery disease (group II) were reviewed. Chronic lung disease was diagnosed by clinical criteria, chest radiographs and pulmonary function tests. All patients had postmortem examinations. Patients in group I were classified into two subgroups: group Ia (without right ventricular hypertrophy) and group Ib (with right ventricular hypertrophy). Right ventricular wall thickness was 3.3 mm +/- 0.5 in group Ia, 6.0 mm +/- 1.1 in group Ib and 8.8 mm +/- 2.4 in group II (group Ia versus Ib, p less than 0.001; group Ia versus II, p less than 0.001; group Ib versus II, p less than 0.001). Eleven patients (78.6%) in group Ib (chronic lung disease with both right ventricular hypertrophy and inferior myocardial infarction) had right ventricular myocardial infarction compared with only 3 patients (21.9%) in group Ia (chronic lung disease without right ventricular hypertrophy and with inferior myocardial infarction) (p less than 0.008). Isolated right ventricular myocardial infarction occurred in four patients (20%) in group II (chronic lung disease with right ventricular hypertrophy, but without evidence of infarction of the left ventricle or significant coronary artery disease). There was no significant difference in the extent of anatomic coronary disease in groups Ia and Ib.(ABSTRACT TRUNCATED AT 250 WORDS)

Retrieval and analysis of particulate debris after saphenous vein graft intervention.

OBJECTIVES: This study was designed to evaluate the composition and quantity of particulate debris resulting from vein graft intervention. BACKGROUND: Distal embolization and "no reflow" are frequent and important complications resulting from angioplasty of diseased saphenous vein grafts. Little is known about the composition and quantity of embolic particulate debris associated with vein graft intervention, and no intervention has been shown to protect against its clinical consequences. METHODS: A catheter system, designed to contain, retrieve and protect against distal embolization of this material, was evaluated during 27 percutaneous interventional saphenous vein graft procedures. Clinical, angiographic and pathologic analyses were performed. RESULTS: The duration of distal graft occlusion required to allow intervention and subsequent debris removal was 150 +/- 54 s, decreasing as experience was gained. Thrombolysis in Myocardial Infarction trial (TIMI) flow grade increased from 2.6 +/- 0.8 to 3.0 +/- 0.0. Creatine kinase (CK) rose above normal in three patients (11.1%) exceeding 3x normal in one (3.7%) resulting in the diagnosis of non-Q-myocardial infarction. Particulate material was identified following 21 of 23 procedures suitable for analysis. Particle size was 204 +/- 57 microm in the major axis and 83 +/- 22 microm in the minor axis. Particles consisted predominantly of soft acellular atheromatous material, such as that typically found under a fibrous cap. Semiquantitative analysis suggested that the quantity of particulate material was less following stenting than following balloon dilation. CONCLUSIONS: Particulate matter is commonly present following routine angioplasty and stenting of saphenous vein grafts. Containment, retrieval and analysis of this particulate debris are all feasible. Comparison to prior clinical experience is limited by small sample size. However, to the extent that these particles may contribute to distal embolization, no-reflow and infarction, such a system may contribute to the reduction of complications following vein graft intervention.

A change in inflammatory footprint precedes plaque instability: a systematic evaluation of cellular aspects of the adaptive immune response in human atherosclerosis.

BACKGROUND: Experimental studies characterize adaptive immune response as a critical factor in the progression and complications of atherosclerosis. Yet, it is unclear whether these observations translate to the human situation. This study systematically evaluates cellular components of the adaptive immune response in a biobank of human aortas covering the full spectrum of atherosclerotic disease. METHODS AND RESULTS: A systematic analysis was performed on 114 well-characterized perirenal aortic specimens with immunostaining for T-cell subsets (CD3/4/8/45RA/45RO/FoxP3) and the Th1/non-Th1/Th17 ratio (CD4(+)T-bet(+)/CD4(+)T-bet(-)/CD4(+)/interleukin-17(+) double staining). CD20 and CD138 were used to identify B cells and plasma cells, while B-cell maturation was evaluated by AID/CD21 staining and expression of lymphoid homeostatic CXCL13. Scattered CD4 and CD8 cells with a T memory subtype were found in normal aorta and early, nonprogressive lesions. The total number of T cells increases in progressive atherosclerotic lesions (≈1:5 CD4/CD8 T-cell ratio). A further increase in medial and adventitial T cells is found upon progression to vulnerable lesions.This critical stage is further hallmarked by de novo formation of adventitial lymphoidlike structures containing B cells and plasma cells, a process accompanied by transient expression of CXCL13. A dramatic reduction of T-cell subsets, disappearance of lymphoid structures, and loss of CXCL13 expression characterize postruptured lesions. FoxP3 and Th17 T cells were minimally present throughout the atherosclerotic process. CONCLUSIONS: Transient CXCL13 expression, restricted presence of B cells in human atherosclerosis, along with formation of nonfunctional extranodal lymphoid structures in the phase preceding plaque rupture, indicates a "critical" change in the inflammatory footprint before and during plaque destabilization.

Cocaine: an independent risk factor for aortic sudanophilia. A preliminary report.

Several recent autopsy reports indicate an increased prevalence of coronary atherosclerosis in ischemic heart disease temporally associated with cocaine abuse. The objective of this study was to conduct a retrospective analysis of sudanophilic lesions in young asymptomatic individuals who abused cocaine. Twenty-six cases (15-34-year-old black males) were examined from the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study. Sixteen subjects (mean age 25 +/- 1 years) had a positive toxicologic screen for cocaine and/or its major metabolites at autopsy and were confirmed habitual cocaine abusers. The remaining 10 cases (mean age 24 +/- 2 years) were subjects with a negative toxicologic screen at autopsy and no history of illicit drug abuse. Post-mortem blood was collected for lipoprotein analysis and determination of smoking status. The aorta and right coronary arteries were stained with Sudan IV and the degree and extent of sudanophilia was quantitated by image analysis. Multiple linear regression analysis of cocaine, age, smoking status, VLDL+LDL-C/HDL-C ratio and HDL-C as predictor variables of percentage intimal surface involvement, revealed an association between cocaine abuse and the extent of sudanophilia in both the thoracic and abdominal aorta (P = 0.002 and 0.049, respectively). Analysis of risk factors or of cocaine abuse as predictors of sudanophilia did not achieve statistical significance in the right coronary artery. These preliminary results suggest that habitual use of cocaine, through unknown mechanism(s), increases aortic sudanophilia independent of traditional risk factors.

Reperfusion injury in the ischemic myocardium.

Myocardial reperfusion injury is defined as the conversion of reversibly injured myocytes to irreversibly injured cells following temporary coronary artery occlusion. Although not universally accepted, the concept of lethal reperfusion injury is strongly supported by studies that temporally link an interventional therapy administered in the perireperfusion period to myocardial salvage. Myocardial reperfusion may be due to the deleterious consequences of cellular edema, calcium overload, free-radical generation, neutrophil infiltration, and microvascular damage. Current studies suggest that perfluorochemicals and adenosine (agents that preserve endothelium and attenuate neutrophil chemotaxis) are the most promising compounds that reduce infarct size in experimental animal models and may warrant clinical trials in man.

Apoptosis in atherosclerosis. Does it contribute to plaque instability?

Several reports have demonstrated apoptosis in the advanced human atheroma. Most clinical events however, are precipitated by plaque rupture, to a lesser extent erosion, and the development of occlusive thrombi. Whether the extent of apoptosis can influence lesion stability is not precisely known, however, there is emerging data supporting this role. Obvious difficulties arise when studying apoptosis in atherosclerotic plaques because of the complex nature of the disease and lack of an experimental model of plaque instability. This article applies a systematic approach to discuss the issue of apoptosis in context of early disease to complex symptomatic lesions that may become fatal.

Pathophysiology of superficial femoral artery in-stent restenosis.

Peripheral artery disease (PAD) is an emerging problem especially with aging population and increase in the incidence of diabetes and metabolic syndrome. The disease is histologically characterized by the presence of moderate to severe calcification and fibrous plaques as compared to coronary and carotid atherosclerotic disease, which are richer in necrotic core. Endovascular therapy for the superficial femoral artery (SFA), at least in the United States, has been largely limited to balloon angioplasty and stenting and these are considered safe and relatively effective therapies. However, the patency rates remain low even at one year and restenosis is a growing and challenging problem. Recently the development of newer devices, i.e., drug-eluting stent, and drug coated balloon are showing greater efficacy and are being adopted into daily practice. In this review, we will present the morphologic characteristics of the underlying SFA atherosclerotic disease and discuss in-stent restenosis and the mechanisms that may be involved in the induction of excessive smooth muscle cell proliferation and deposition of proteoglycans and collagen, that lead to restenosis.

Unique demands of the femoral anatomy and pathology and the need for unique interventions.

With the aging of the population the incidence of peripheral artery disease (PAD) is increasing, which is histologically characterized by fibrocalcific intimal plaques as well as underlying Mönckeberg's medial calcinosis as compared to coronary and carotid artery disease. Superficial femoral artery (SFA) is one of the longest and most dynamically active vessels in the body undergoing torsion, compression, flexion, and extension from leg motion, and is known to be more susceptible to atherosclerosis because of low shear stress or spiral flow, best appreciated in the long segment in its lesser curvature. Endovascular interventions are now considered the first-line strategy for the treatment of PAD patients presenting with claudication or critical limb ischemia, where physiologic stresses on the arterial wall, anatomic considerations, and lesion characteristics impact on their success. Stent fracture and malapposition, are a common phenomenon in PAD which are attributed to severe calcification and fibrosis along with greater motion of the lower extremity, that result in the dampening of the efficacy of stenting and balloon angioplasty. Better designs of self-expanding stents have resulted in either reduction in stent fracture rates or its elimination at least in the short-term follow-up studies, to date. Although drug-eluting stents (DES) have reduced restenosis rates in the coronary circulation, this benefit has not been consistently observed in PAD. However, recent clinical studies utilizing novel Zilver-PTX self-expanding stent (DES) have demonstrated favorable patency rate. Also, in patients with critical limb ischemia, better outcomes have been reported for below-the-knee utilization of DES. Nevertheless, drawbacks of stent technology remain and interests in the greater use of drug-coated balloons (DCB) for PAD have emerged. Randomized controlled trials have consistently shown superiority of DCB over uncoated balloons in reducing neointimal formation in patients with SFA disease. Moreover, there is a growing interest in atherectomy as an alternative treatment strategy for PAD, thus decreasing plaque burden with possibly avoidance of barotrauma. The results from registries support the effectiveness of the atherectomy devices; however, prospective randomized controlled trials are needed to confirm their benefit.

Identification of intraplaque hemorrhage on MR angiography images: a comparison of contrast-enhanced mask and time-of-flight techniques.

BACKGROUND AND PURPOSE: MRA is widely used to measure carotid narrowing. Standard CE- and TOF-MRA techniques use highly T1-weighted gradient-echo sequences that can detect T1 short blood products, so they have the potential to identify IPH, an indicator of plaque rupture. We sought to determine the accuracy and reliability of these MRA sequences to detect IPH. MATERIALS AND METHODS: 3D TOF and CE carotid MRA scans were obtained at 3T on 15 patients (age range, 58-86 years; 13 men) scheduled for CEA. The source images from the precontrast (mask) CE-MRA and the TOF sequences were reviewed by 2 independent readers for IPH presence (identified as hyperintense signal intensity compared with adjacent muscle). CEA specimens were stained with antibody against glycophorin A and Mallory stain to detect IPH and were correlated with MR images. RESULTS: Nine of 15 CEA specimens (61 of 144 MR images) contained IPH confirmed by histology. Compared with TOF, CE-MRA mask demonstrated greater sensitivity, specificity, PPV, and NPV for IPH detection. The accuracy for correctly identifying IPH by using CE-MRA mask images and TOF images was 94% and 84%, respectively. Inter- and intraobserver agreement for IPH detection was excellent by mask images (κ = 0.91 and κ = 0.94, respectively) and TOF images (κ = 0.77 and κ = 0.84, respectively). CONCLUSIONS: CE-MRA mask images are highly accurate and reliable for identifying IPH, more so than the TOF sequence, and can potentially provide valuable information about risk for rupture.