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(Circulation. 1997;95:2027-2031.)
© 1997 American Heart Association, Inc.

Articles

The White Blood Cell Adhesion Molecule E-Selectin Predicts Restenosis in Patients With Intermittent Claudication Undergoing Percutaneous Transluminal Angioplasty

J.J.F. Belch, MB, FRCP, MD (Hons); J.W. Shaw, FFRRCSI; G. Kirk, BSc; M. McLaren, BSc, PhD; R. Robb, RGN; C. Maple, MB, MRCP; P. Morse, BSc, DipStat, CStat

From the Section of Vascular Medicine, University Department of Medicine, Department of Radiology, Ninewells Hospital and Medical School, Dundee, Scotland (J.J.F.B., J.W.S., G.K., M.M., R.R., C.M.); and the Department of Clinical Statistics, Scotia Pharmaceuticals Ltd, Woodbridge Meadows, Guildford, England (P.M.).

Correspondence to Dr J.J.F. Belch, Department of Medicine, Ninewells Hospital and Medical School, Dundee DD1 9SY, Scotland.

	Abstract

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Background Experimental studies have shown that endothelial dysfunction is an early event preceding restenosis. Monocytes and neutrophils have been shown to bind to damaged endothelium via the cell adhesion molecules (CAMs). The selectins are involved in capturing the leukocytes and tethering them to the endothelium. E-selectin is a CAM that is only expressed on activated endothelial cells. Its ligands are expressed on monocytes and neutrophils and it has been found to exist in a soluble form. This soluble form may represent a marker for endothelial damage and may be a precursor of smooth muscle proliferation.

Methods and Results Fifty-four patients who were undergoing peripheral arterial balloon angioplasty had blood sampled before angioplasty. E-selectin was measured in plasma with the use of an ELISA. At follow-up angiogram, 30% (n=14) of the patients had restenosed at 1 year. There was a significant difference in baseline E-selectin levels in patients who restenosed compared with those who did not (65.3 ng/mL [58.25 to 78.05] versus 52.3 [34.2 to 62.1], Mann-Whitney U, P<.007). Endothelial activation with subsequent adherence of white blood cells is an important step in restenosis.

Conclusions We have shown an increased level of shed E-selectin in patients destined for restenosis and suggest that this work further supports a role for white blood cell/endothelial interaction in restenosis after angioplasty.

Key Words: restenosis • angioplasty • blood cells • endothelium • peripheral vascular disease

	Introduction

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Symptomatic peripheral arterial occlusive disease (PAOD) affects 5% of men over the age of 50 years.¹ Its commonest manifestation, intermittent claudication, can produce disabling leg pain on exercise resulting in severely limited mobility. Nevertheless, claudication symptoms seem to stabilize in the majority of patients² and few progress to limb-threatening ischemia.³ The initial enthusiasm for surgical intervention has thus been attenuated, and bypass surgery is usually reserved for patients with critical limb ischemia or very disabling short-distance claudication. In contrast, percutaneous transluminal angioplasty (PTA) has gained increased acceptance as a safe and effective therapy for PAOD.⁴ Nevertheless, the longer-term benefits of angioplasty have been limited in some patients by the recurrence of the stenotic lesions. The restenosis rate depends on many factors including the length of occlusion, occlusion versus stenosis,⁵ and distribution of the disease. In most series, the restenosis rate is between 30% and 60% between 6 months and 1 year after the initial angioplasty.^{6 7 8} Acute closure immediately after angioplasty is usually caused by dissection, spasm,⁹ or embolism and is frequently complicated by thrombosis.¹⁰ This occurs in between 1% to 4% of PTAs.^{11 12} More commonly, restenosis occurs between 1 or 2 months and between 9 months and 1 year after angioplasty and is an intimal proliferation response to the vascular injury induced by the procedure.¹³

Activated white blood cells (WBCs), platelets, and endothelial cells all produce growth factors either directly or indirectly. These include platelet-derived growth factor (PDGF)¹⁴ and fibroblast growth factor (FGF).¹⁵ These growth factors are strongly linked to the smooth muscle cell proliferation underlying most cases of restenosis.¹⁶ Blood cell adhesion to the vascular endothelium can be mediated via the platelet, the WBC, or the endothelial cell with changes brought about by stimulants acting on all three cell types. These changes are mediated by the regulation of the structure, or the surface exposure, of cell adhesion molecules (CAMs). On the endothelium the adhesive molecules of interest are of the selectin family, E-selectin, P-selectin, or of the immunoglobulin family. E-selectin is particularly interesting because it is found only on activated endothelium, in contrast to other adhesion molecules that have a wider tissue distribution. Endothelial cells have been shown to release E-selectin after in vitro activation.^{17 18} The demonstration of soluble E-selectin (sE-selectin) in the blood is therefore taken as conclusive evidence of endothelial activation. It is more sensitive than other more conventional markers of endothelial activation such as thrombomodulin, endothelin, and von Willebrand factor antigen as these are produced in cells other than the endothelial cell.^{19 20} The mechanism of release of sE-selectin has not been established but it is biologically active being able to activate the polymorphonuclear cell CD11b integrin receptor.²¹

We have previously shown evidence to suggest a role for the leukocyte in PAOD^{22 23} and have demonstrated increased WBC activation in this group of patients.²⁴ Increased endothelial E-selection expression could enhance leukocyte adhesion to the angioplasty site and promote the subsequent release of growth factors and free radicals known to be involved in the process of smooth muscle cell proliferation.¹⁶

The aim of our study therefore was to evaluate plasma sE-selectin levels in patients with intermittent claudication undergoing PTA. Subsequent restenosis was documented at 1 year by angiography and correlated with the preangioplasty sE-selectin levels.

	Methods

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Patients and Subjects
Patients with PAOD routinely referred for femoropopliteal angioplasty were considered for enrollment in the study. Patients were considered suitable for the trial if they had a stenotic segment 10 cm in length or an occlusive lesion of 5 cm in length. Exclusion was made of patients with a history of a previous balloon angioplasty of femoral or popliteal segments in the affected limb, severe and recurrent illness such as malignancy, liver failure, or severe cardiac failure or patients who were intolerant of aspirin. Patients with diabetes mellitus were also excluded. The study was approved by the local ethics committee, and written informed consent was obtained from all patients. Fifty-four patients were enrolled into the study (21 women, 33 men); median age was 64 years (range, 40 to 78 years). All patients received aspirin 75 mg per day. This medication was begun at least 1 week before angioplasty. Thirteen age- and sex-matched control subjects were also enrolled into the study to provide sE-selectin values.

Angioplasty
A standardized regime was used for PTA in this study, all treatments being performed by the same operator (J.W.S.). At least three balloon inflations of 45 seconds' duration were used. Heparin 3000 units intra-arterially (ia) and Isoket 400 µg ia were administered during the procedure. Angiographic assessment included groin to ankle views and localized views of the dilatation site in two projections. Stenosis was measured as a percentage degree of narrowing at the site of the lesion relative to the estimated diameter of adjacent normal patent vessel (Fig 1). Successful angioplasty was interpreted as a reduction of 20% in the degree of stenosis relative to the patent vessel. Follow-up angiography, again using two projections at the dilatation site, was performed after 12 months with the use of an outpatient intra-arterial digital technique.

View larger version (5K): [in this window] [in a new window]   Figure 1. Assessment of patency after angioplasty. Patency= x/yx100.

Arteriography was repeated earlier than planned if patients developed recurrent symptoms with a concomitant drop in ankle/brachial systolic pressure indices measured by Doppler ultrasound. Restenosis was regarded as either a recurrence of the original baseline stenosis or an increase in the postangioplasty stenosis of 25%. For the purpose of patency assessment, angiograms were magnified on a Sipro viewer.

sE-Selectin Assay
Blood samples were taken at the same time each visit (in the morning) after a standard light breakfast. We have previously shown a circadian variation in this CAM.²³ Blood was sampled from the antecubital fossa after minimal venous occlusion from both patients and controls. The blood samples were taken between 7 and 10 days before the angioplasty being carried out. The blood was anticoagulated with lithium heparin. The blood was centrifuged for 15 minutes at 4°C at 3500 rpm. Plasma was withdrawn and was stored at -70°C. Levels of sE-selectin were measured with a commercially available ELISA kit (R&D Systems). Each of the samples was tested in duplicate. The sampling area between duplicate samples is 3.57% (mean coefficient of variation for all samples). In this assay, a specific biotinylated antibody is added to murine anti-human E-selectin antibody–coated microtiter ELISA plates. Antibody to E-selectin conjugated to horseradish peroxidase is added to each well. Standards and samples are then added to the plate, which is then covered and incubated for 1.5 hours at room temperature. The plate is then washed and the substrate tetramethyl benzidine is added to each well and incubated for 30 minutes at room temperature. Finally, the stop solution (sodium azide) is added, and the optical density of each well is determined with the use of a plate reader. The results are calculated from a standard curve.

Statistical Analysis
The sE-selectin levels in those subjects experiencing restenosis were compared with those without through the use of the nonparametric Mann-Whitney U test. The same test was used to compare control values with those of the PAOD patients. The probability of avoiding restenosis was compared with sE-selectin levels through the use of logistic regression.²⁵ The sensitivity (proportion of predicted successes [vessel patent] that were correct) and selectivity (proportion of predicted failures [restenosis] that were correct) were also estimated.²⁶ We examined the homogeneity of the patient groups in terms of age, sex, demographic factors, history, and angiographic features by appropriate nonparametric and parametric tests. Probabilities were regarded as statistically significant at the .05 level. Unless otherwise indicated, values are given as median (range).

	Results

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Table 1 shows the clinical and angiographic characteristics of all patients divided by the presence or absence of restenosis by 1 year. There were no statistically significant differences between the two groups for these measures, nor were there any differences in presenting stenosis or occlusion length. All angioplasties were defined as being successful, and no patient experienced an acute thrombosis/embolism in the immediate postangioplasty period. All patients completed the study with none being lost to follow-up.

View this table: [in this window] [in a new window]   Table 1. Demographic Details of Study Subjects

The control group median sE-selectin levels were 38.2 (28.3 to 44.8) compared with 57.4 (37.7 to 73.1) in the PAOD group as a whole. The difference between these two groups is statistical significantly at P<.003 (Mann-Whitney U).

Fig 2 shows a whisker plot of the sE-selectin data for those with and without restenosis. In the restenosis group, the median sE-selectin levels were 65.3 ng/mL (58.25 to 78.05) compared with 52.3 (34.2 to 62.1) in the group with patent vessels. The difference between these two groups is statistically significant at P<.007 (Mann-Whitney U).

View larger version (15K): [in this window] [in a new window]   Figure 2. Preangioplasty soluble E-selectin (sE-selectin) levels in patients who experienced a restenotic event and in those who did not.

If it is assumed that the probability of success (ie, of not restenosing) is related to sE-selectin by an S-shaped curve, the logistic function is as follows.

where determines the probability of success at zero sE-selectin level and ß determines the general slope of the curve. Logistic regression then estimates the parameters and ß as displayed in Table 2. Both and ß are statistically significant, and Fig 3 shows a graph of the fitted curve with the observed probability of success demonstrated. Clearly, vessel patency is associated with low sE-selectin values.

View this table: [in this window] [in a new window]   Table 2. Logistic Regression to Estimate and ß

View larger version (10K): [in this window] [in a new window]   Figure 3. Observed probability of no restenosis for selected cohorts of patients. Solid circles show the observed probability (%) of no restenosis for cohorts of patients with mid values of 9.5, 29.5, 49.5, 69.5, 89.5, and 125 E-selectin (units). Solid line shows the filled curve from the logistic regression model.

Tables 3 and 4 show the positive predictive value (PPV) for sE-selectin values, ie, the proportion of patients correctly predicted to be free from restenosis when given the sE-selectin value. The negative predictive value (NPV) is similarly defined and is equal to 100-PPV%. Table 3 also shows the sensitivity and selectivity of the test, where sensitivity equals the proportion of predicted successes that are correct and selectivity, the proportion of predicted failures that are correct. The above data suggest that sE-selectin levels are statistically significant predictors of future restenosis.

View this table: [in this window] [in a new window]   Table 3. Probability of No Restenosis and Soluble E-Selectin Levels

View this table: [in this window] [in a new window]   Table 4. Predictive Values and Sensitivity/Selectivity of Data

	Discussion

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In this study we have shown for the first time a link between restenosis after PTA in PAOD patients and soluble E-selectin levels in plasma. This cell adhesion molecule has an important role in the adhesive interaction between neutrophils and endothelium.^{16 17} In the circulation, neutrophil adhesion depends on the balance between pairs of adhesion molecules, rate of bond formation, and the flow forces washing the cells away. Initially, the WBC flows centrally within the luminal vessel. To induce rolling of the leukocyte along the endothelial surface requires a relatively low-affinity CAM but with a fast-acting interaction. It is thought that L-selectin is important in this area.²⁷ Immobilization of the neutrophil probably needs a greater affinity of the CAMs for each other, but they are slower acting because the cell's flow speed has already been reduced by the rolling.²⁸ E-selectin and P-selectin are important endothelial CAMs, and antibodies to them inhibit leukocyte immobilization.²⁹ Monoclonal antibodies to ICAM-1 or CD 18 (neutrophil integrins) inhibit adhesion at low flow rates or in static conditions but not at higher, more physiological, flow rates. The final phase of leukocyte/endothelial interaction, that is, the neutrophil migration into the tissues, requires the ability to modulate adhesion, ie, turning it on and off. It is dependent on endothelial activation and is inhibited by monoclonal antibodies to ICAM-1, E-selectin, or CD 18.³⁰ Since no one knows where sE-selectin comes from normally or in PAOD, the relationship between its level and leukocyte infiltration at any specific vascular site remains unknown. Nevertheless, it is interesting to speculate that in patients with elevated sE-selectin, there may be increased endothelial/neutrophil adhesiveness. One can assume from these data that the elevation of sE-selectin is coming from the atherosclerotic vascular lesions. At the same time, the decreased perfusion pressure at the time of angioplasty will decrease the disruptive forces acting on the neutrophils. The end result will be increased WBC immobilization on the endothelial/subendothelial surface.

If a PNM becomes trapped in the circulation, it can then deliver a variety of insults to the blood vessel lining.³¹ These chemical substances would normally be utilized in the protection of the organism against microbial invaders within the normal process of tissue repair, but such defense mechanisms can be the trigger for smooth muscle cell proliferation and subsequent restenosis. Free radicals released from leukocytes and products of free radical reactions are increased during the reperfusion phase (balloon deflation) of angioplasty.³² Production of cytokines such as interleukin-1 and tumor necrosis factor is increased, and both of these enhance E-selectin expression on the endothelial surface.³⁰ Cytokines also enhance release of the various growth factors such as PDGF, FGF, and tumor growth factor-ß₁. These latter two have been closely linked in animal work to the recurrence of restenosis,^{14 15} which is attenuated by blocking antibodies.³³ These growth factors stimulate smooth muscle cell proliferation.¹⁶ There is thus a good theoretical rationale to link elevated sE-selectin levels and restenosis occurrence.

The importance of smooth muscle cell proliferation in restenosis is supported by the lack of correlation of platelet activity with restenosis³⁴ and the failure of antiplatelet drugs such as aspirin and dipyridamole² and ticlopidine³⁵ to prevent restenosis.

In the coronary arteries, there have been a number of well-designed studies that have suggested various predictors of restenosis. These include diabetes mellitus, multivessel coronary artery disease, eccentric narrowing, and residual stenosis 30%. In contrast, only a few studies have addressed the question of predictors of restenosis after PTA in PAOD. Some clinical indicators include length of occlusion >10 cm, popliteal and infrapopliteal vessels affected,⁵ older age of patient,⁶ occlusion versus stenosis,⁶ and length of time the patient is on the waiting list before receiving angioplasty. Laboratory markers have been studied infrequently. While platelet deposition has been evaluated and found to persist despite aspirin therapy,¹⁰ no one has studied the endothelial CAM E-selectin. We believe that our findings are important for two reasons. First, they further clarify mechanisms for restenosis suggesting an important role for endothelial/WBC adhesion. Second, these findings may be of therapeutic relevance. Although PTA for intermittent claudication has a certain complication rate, it is considered to be low and certainly less than that of surgical revascularization where failure of the bypass graft can lead to limb loss. Furthermore, with the newer techniques that are currently being introduced, it is also more cost-effective than surgery.³⁶ Nevertheless, the significant restenosis rate has implications on patient morbidity and cost effectiveness. Monoclonal antibodies to E-selectin are becoming available, and a therapeutic trial of such antibodies might be of interest in this indication.

	Acknowledgments

 
Gwen Kirk is a PhD student supported by Pfizer Ltd (UK). Other funding for this study was received through an award from the British Medical Association. The group receives core support funding from Scotia Pharmaceuticals Ltd (UK).

Received September 25, 1996; revision received November 18, 1996; accepted November 25, 1996.

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