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(Circulation. 1998;97:2511-2518.)
© 1998 American Heart Association, Inc.

Clinical Investigation and Reports

Lower Expression of Neutrophil Adhesion Molecule Indicates Less Vessel Wall Injury and Might Explain Lower Restenosis Rate After Cutting Balloon Angioplasty

Teruo Inoue, MD; Yoshihiko Sakai, MD; Kazuhiro Hoshi, MD; Isao Yaguchi, MD; Tsuneo Fujito, MD; ; Shigenori Morooka, MD

From the Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, Saitama, Japan.

Correspondence to Teruo Inoue, MD, Department of Cardiology, Koshigaya Hospital, Dokkyo University School of Medicine, 2–1-50 Minamikoshigaya, Koshigaya City, Saitama 343–8555, Japan.

	Abstract

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Background—The Cutting Balloon is a novel dilatation catheter for coronary angioplasty (InterVentional Technologies Inc). It produces longitudinal, microsurgical incisions in the vessel wall before the actual dilatation. It is assumed that these controlled surgical incisions relieve hoop stress and reduce vessel wall injury and eventually restenosis. However, no clinical indicator to support the theory of reduced injury has been described. Certain clusters of differentiation (eg, CD11, CD18 on the leukocytes) are implicated in leukocyte adhesion, increased permeability, and opsonization. Therefore, they might serve as clinical indicators of the injury level of the vessels after angioplasty.

Methods and Results—We randomly selected 64 patients with isolated left anterior descending coronary artery disease for either Cutting Balloon angioplasty or conventional balloon angioplasty. The expression of CD18 and CD11b on the surface of neutrophils was determined by flow cytometric analysis. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) were also measured. The expression of both the CD18 and CD11b in the coronary sinus blood gradually increased and reached its maximum at 48 hours after angioplasty. The sICAM-1 levels in the coronary sinus serum also increased after angioplasty. Percentage increases of CD18 and CD11b expression and the increase of the sICAM-1 levels at 48 hours after angioplasty (as ratios to baseline values before angioplasty) were less in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group (CD18, 1.10±0.05 versus 1.31±0.05, P<0.05; CD11b, 1.23±0.06 versus 1.72±0.10, P<0.001; sICAM-1, 1.12±0.05 versus 1.25±0.02, P<0.05). In all patients, the late lumen loss at follow-up angiogram positively correlated with the increased levels of CD11b (R=0.59, P<0.001) and sICAM-1 (R=0.38, P<0.05) at 48 hours after angioplasty.

Conclusions—Balloon angioplasty upregulated Mac-1 (CD11b/CD18) on the surface of the neutrophils and increased sICAM-1 levels in association with late loss increase. These changes were significantly smaller in the Cutting Balloon angioplasty group than in the conventional balloon angioplasty group. This suggests that Cutting Balloon angioplasty may produce less vessel wall injury and, consequently, less neutrophil activation, which may account for the lower rate of restenosis.

Key Words: angioplasty • vasculature • cell adhesion molecules • restenosis

	Introduction

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Cutting Balloon (InterVentional Technologies Inc) is a new balloon angioplasty device with 3 or 4 microtome sharp metal blades (0.25 mm high) mounted longitudinally on the surface of the balloon.¹ During dilation, the device produces 3 or 4 endovascular surgical incisions. As a result, the elastic recoil may be reduced.^{1 2 3} In addition, intravascular ultrasound study demonstrated that the longitudinal incisions of plaque and vessel wall reduce true dissection rates as well as nominal vessel area decrease.⁴ Thus, Cutting Balloon angioplasty may limit the degree of traumatic vessel wall injury, typically encountered in conventional balloon angioplasty. However, the mechanism by which the trauma is beneficial and whether the trauma reduction leads to decreased restenosis rate are still to be clinically established.

We previously reported the role of an adhesion molecule, Mac-1 (CD11b/CD18), which is one of the ligands of ICAM-1 located primarily at surfaces of activated vascular endothelial cells.⁵ This molecule is upregulated on the surface of neutrophils after coronary angioplasty and may serve as an indicator of vessel wall injury or as a predictor of restenosis.⁶

The goal of this study was to clinically demonstrate the assumed injury reduction after Cutting Balloon angioplasty. We compared the Cutting Balloon and conventional balloon angioplasty–induced vessel wall injury/inflammatory reaction by examining the expression of Mac-1 on the neutrophil surface and, in addition, the circulating form of sICAM-1.⁷ Also, we assessed the angioplasty results quantitatively.

	Methods

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Patients
We enrolled into the study 64 consecutive patients with isolated proximal left anterior descending coronary artery disease undergoing initial elective coronary angioplasty. All patients had effort angina without previous myocardial infarction. Target lesions were all type A or type B lesions in the nomenclature of the American College of Cardiology/American Heart Association Task Force.⁸ All of the patients had previously received the standard medications for angina, including 40 mg of isosorbide dinitrate, 40 mg of nifedipine, 81 mg of aspirin, and 75 mg of dipyridamole daily. None of these were discontinued or exchanged during the angioplasty procedure or the postangioplasty follow-up period. Exclusion criteria included use of other cardioactive drugs and the presence of other cardiac or noncardiac conditions that could affect our analysis. The study protocol was approved by the Dokkyo University Institutional Review Board, and written informed consent was obtained from each patient.

Angioplasty Procedure
Patients were randomly selected to receive either Cutting Balloon angioplasty (with or without adjunctive conventional balloon angioplasty) or conventional balloon angioplasty alone. Baseline clinical characteristics were similar in the Cutting Balloon angioplasty group and the conventional balloon angioplasty group (Table 1). The angioplasty was performed with the standard Judkins technique and a movable guidewire system. Before angioplasty, 5000 U heparin IV and 0.3 mg nitroglycerin IC were administered. Cutting Balloon angioplasty was performed with either single or multiple inflations. If single inflation was used, in some cases, adjunctive conventional balloon angioplasty was applied. Conventional balloon angioplasty was also performed with either single or multiple inflations. A nonionic iodinated contrast agent (Iopamidole, Schering AG) was used in all patients. After the angioplasty, all patients received 500 U/h heparin IV for 24 hours. Primary success of angioplasty was defined as 20% increase in luminal diameter and residual diameter stenosis <50%. All patients underwent follow-up angiography at 6 months or earlier, if there was a clinical indication. Restenosis was defined as >50% diameter stenosis of the treated lesion.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics

QCA Analysis
We used a computer-based CAM-1000 system (PSP Corp) for QCA. The measurements were performed on the end-diastolic frames by a single investigator who was unaware of the study design. Reference diameter, lesion length, and MLD were measured before and after angioplasty and at the time of follow-up angiography. We determined the acute gain (MLD after angioplasty minus MLD before angioplasty), the late loss (MLD after angioplasty minus MLD at follow-up angiography), and the late loss index (the average ratio of late loss to acute gain) for each lesion.^{9 10} The balloon-to-artery ratio (the ratio of balloon size to reference diameter) was also calculated.

Blood Collection
A heparin-coated catheter was inserted through a right jugular venous sheath and was positioned in the mid to high coronary sinus before the angioplasty procedure. The catheter was left in the coronary sinus for 48 hours after the procedure. Coronary sinus blood and peripheral blood were taken through the coronary sinus catheter and through the jugular sheath, respectively, before angioplasty, and immediately after, 24 hours after, and 48 hours after angioplasty.

Assessment of Expression of Neutrophil Adhesion Molecule, Mac-1
The expression of adhesion molecules, Mac-1 (CD11b/CD18), on the surface of neutrophils was examined with two-color dual laser flow cytometry using monoclonal antibodies: FITC¹¹-conjugated anti-CD18 (IOT18, Immunotech, Inc) and PE¹²-conjugated anti-CD11b (Leu15, Becton Dickinson). The isotype controls were FITC-conjugated mouse immunoglobulin IgG1 (MsIgG1, Becton Dickinson) and PE-conjugated IgG2a (MsIgG2a, Becton Dickinson).

The two-color immunofluorescence staining¹³ was performed according to the following steps. (1) A 3.5-mL specimen of blood was immediately collected in a tube containing 1 mL of acid citrate dextrose and kept at room temperature. (2) Pairs of FITC-conjugated IOT18 and PE-conjugated Leu15 and of FITC-conjugated MsIgG1 and PE-conjugated MsIgG2a (as negative control) were added to each sample tube containing 100 µL of well-mixed whole blood. The amounts used were 20 µL of each antibody. (3) The mixture was incubated for 30 minutes at 4°C. (4) PBS solution (3 mL) containing 0.1% BSA and 0.1% sodium azide was added, and the specimen was mixed gently. (5) After centrifugation at 200g for 5 minutes, the supernatant was removed, leaving 100 µL of fluid. (6) Lysing solution (3 mL) was added to the specimen for hemolysis. The pH of the lysing solution containing 8.26 g NH₄Cl, 1.00 g KHCO₃, and 0.04 g EDTA-4Na in 1 L of distilled water was adjusted to 7.3. The lysing solution was stored at 4°C in a tightly closed bottle. The specimen was mixed and incubated immediately at room temperature for 5 minutes until the hemolysis was completed. (7) After centrifugation at 200g for an additional 5 minutes, the supernatant was removed, leaving 100 µL of fluid. (8) Steps 4 and 5 were repeated. (9) The solution was fixed in 3 mL of PBS containing 1.0% paraformaldehyde for 15 minutes at 4°C. (10) Step 5 was repeated. (11) Finally, after 0.7 mL of PBS was added, the specimen was mixed gently and stored at 4°C. CD-Chex (Streck Laboratories, Inc) was used to confirm the stability of antibodies as well as the staining process. This confirmation could rule out the in vitro modulation of antigen expression. The staining process was performed according to the guidelines for flow cytometry set by the National Committee for Clinical Laboratory Standards.¹⁴

The flow cytometric analysis was performed within 2 hours with a FACScan dual laser flow cytometer (Becton Dickinson). Briefly, cells were hydrodynamically focused and traveled in suspension, one by one, through a quartz flow channel. The cells were illuminated by a focused argon laser beam operated at 488 nm. Green fluorescence of the FITC-labeled cells was measured through a 530-nm band-pass filter, and red fluorescence of the PE-labeled compounds was measured through a 585-nm band-pass filter. After compensation with control beads, the scatter signals (linear scale) and the fluorescence intensity (log scale, 4 decade) were analyzed. Light scattered by the cells was collected in the forward and side directions. Cell size was detected by forward scatter and inner structure of the cell by side scatter. These light-scattering properties were projected on a scattered cytogram. Thus, a neutrophil cluster, of small size and complex inner structure, could be distinguished from other leukocyte clusters of larger size and simpler inner structure.¹⁵ The fluorescence intensity in both the FITC-conjugated IOT18 and PE-conjugated Leu15 was expressed on a cytohistogram in which the region of interest was limited to the neutrophil cluster. Furthermore, the MFI¹⁶ was calculated as an expression index of CD18 and CD11b on the surface of the neutrophils (Figure 1).

View larger version (18K): [in this window] [in a new window]   Figure 1. Scattered cytogram (left) and cytohistogram (right). On scattered cytogram, side scatter detects cell size, and forward scatter, inner structure of cells. Light-scattering properties can distinguish neutrophil cluster from other leukocyte clusters. Fluorescence intensity was expressed on a cytohistogram with log scale. MFI indicates integrated average of histogram.

Measurement of sICAM-1 Levels
Serum levels of sICAM-1 were measured by ELISA with a human ICAM-1 immunoassay kit (R&D Systems Europe, Inc). Blood was allowed to clot at 4°C for 1 hour and was centrifuged at 1500g for 15 minutes. Serum was frozen at -80°C until it was used. Serum samples were diluted 1:20 with sample diluent. Microtiter ELISA plates were precoated with murine antibody to human ICAM-1 (14C11) at a final concentration of 10 µg/mL in 0.1 mol/L bicarbonate buffer, pH 8.9. Wells were washed twice with PBS with Tween and blocked with 1.0% casein PBS with Tween at room temperature for 2 hours. Then 100 µL of sICAM-1 standard or diluted sample was added to each well and incubated for 1.5 hours at room temperature. The bound antigen was detected by sequential incubation with a specific biotin-labeled monoclonal antibody to ICAM-1 (BBIG-I1) followed by horseradish peroxidase–conjugated streptavidin and finally tetramethylbenzidine. The reaction was stopped by 1.0 mol/L hydrochloride, and the optical density at 450 nm (reference, 630 nm) was measured with an Emax precision microplate reader (Molecular Devices, Inc). The assay was performed in duplicate for each sample.

Statistical Analysis
Data are expressed as mean±SEM. Comparisons between the two groups were performed with unpaired t tests for continuous variables and ² tests for categorical variables. Serial changes in variables were evaluated by repeated measures ANOVA for intragroup and intergroup comparison. Correlations were evaluated by multiple linear regression. Values of P<0.05 were considered to be significant.

	Results

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Results of Angioplasty
Angioplasty was initially successful in all patients of both the Cutting Balloon and conventional balloon angioplasty groups. Neither abrupt coronary closure nor major coronary dissection requiring bailout stent implantation occurred. Minimal dissections (type B or type C in the National Heart, Lung, and Blood Institute PTCA Registry)¹⁷ were all successfully repaired by subsequent conventional balloon inflations. The lesion characteristics and angioplasty procedural variables were similar in both groups (Table 2). The QCA variables were also similar in both groups except for the late loss index, which was less (P<0.05) in the Cutting Balloon group than in the conventional balloon group. Restenosis was found in 22% of the Cutting Balloon group but in 41% of the conventional balloon group (P<0.05). Target lesion revascularization rate was 19% in the Cutting Balloon group and 31% in the conventional balloon group (Table 3).

View this table: [in this window] [in a new window]   Table 2. Lesion Characteristics and Procedural Variables

View this table: [in this window] [in a new window]   Table 3. QCA Analysis

Expression of Mac-1 on Neutrophils and Serum Levels of sICAM-1
Figure 2 shows the serial changes in MFI of CD18- and CD11b-positive neutrophils from the coronary sinus blood samples in the Cutting Balloon and conventional balloon angioplasty groups. The MFIs of both CD18 and CD11b gradually increased after angioplasty compared with preangioplasty baseline. The highest values occurred at 48 hours after angioplasty in both the Cutting Balloon (CD18, 43.2±1.8 to 48.2±3.9, P<0.05; CD11b, 726±68 to 892±98, P<0.01) and the conventional balloon (CD18, 43.3±2.2 to 56.9±3.6, P<0.01; CD11b, 727±62 to 1235±102, P<0.001) angioplasty groups. However, the values were lower in the Cutting Balloon angioplasty group. The percentage increase of the MFI for CD18 and CD11b in the coronary sinus blood samples at 48 hours after angioplasty over the baseline value before angioplasty (expressed as a ratio) was significantly less (CD18, P<0.01; CD11b, P<0.001) in the Cutting Balloon group than in the conventional balloon group (Table 4). Figure 3 shows the differences between the MFI of the coronary sinus blood samples and that of the peripheral blood samples (MFI of coronary sinus samples minus MFI of peripheral blood samples). Compared with baseline values, the difference was greater at 48 hours after angioplasty for both CD18 (P<0.01) and CD11b (P<0.01) in the conventional balloon angioplasty group. However, the difference did not change in the Cutting Balloon angioplasty group.

View larger version (19K): [in this window] [in a new window]   Figure 2. Serial changes in expression of CD18 and CD11b in coronary sinus samples after angioplasty. MFIs for both CD18 and CD11b were gradually increased after angioplasty from baseline values before angioplasty. Maximal increases were seen at 48 hours after angioplasty. These changes were lower in Cutting Balloon angioplasty group than in conventional balloon angioplasty group.

View this table: [in this window] [in a new window]   Table 4. Study End-Point Analysis

View larger version (16K): [in this window] [in a new window]   Figure 3. Differences between MFI of coronary sinus samples and that of peripheral blood samples (MFI of coronary sinus samples minus MFI of peripheral blood samples [MFI(CS-P)]). Compared with baseline values, difference was greater at 48 hours after angioplasty for both CD18 and CD11b in conventional balloon angioplasty group. However, difference did not change in Cutting Balloon angioplasty group.

The serum level of sICAM-1 in the coronary sinus samples increased immediately after angioplasty (194±13 to 220±12 ng/mL, P<0.05), and the maximum was reached at 48 hours after angioplasty (to 242±15 ng/mL, P<0.01) in the conventional balloon angioplasty group. In the Cutting Balloon angioplasty group, however, the level did not change immediately after angioplasty but was slightly elevated at 48 hours after angioplasty (192±11 to 217±13 ng/mL, P<0.05) (Figure 4). The percentage increase of the sICAM-1 levels in the coronary sinus serum at 48 hours after angioplasty was less (P<0.05) in the Cutting Balloon group than in the conventional balloon group (Table 4).

View larger version (16K): [in this window] [in a new window]   Figure 4. Serial changes in serum levels of sICAM-1 in coronary sinus samples after angioplasty. sICAM-1 levels increased immediately after angioplasty, then increased further, and maximum increase was seen at 48 hours after angioplasty in conventional balloon angioplasty group. In Cutting Balloon angioplasty group, however, levels did not change immediately after angioplasty and slightly increased at 48 hours after angioplasty.

Multiple regression analysis in all patients showed that the late loss index was not correlated with any procedural variables or other QCA variables but correlated strongly with the percentage increase of the MFI of CD11b on the coronary sinus neutrophils at 48 hours after angioplasty (R=0.59, P<0.001) and slightly with the increase of the sICAM-1 level in the coronary sinus serum at 48 hours after angioplasty (R=0.38, P<0.05) (Table 5). Figure 5 shows the correlation between the late loss index and the CD11b increase in all patients. This relationship also indicates that the late loss index and the CD11b increase were less prominent in the patients undergoing Cutting Balloon angioplasty.

View this table: [in this window] [in a new window]   Table 5. Multiple Regression Analysis in All Patients for Late Loss Index

View larger version (16K): [in this window] [in a new window]   Figure 5. Correlation between percentage increase of MFI for CD11b in coronary sinus blood samples at 48 hours after angioplasty over baseline value before angioplasty (expressed as ratio) and late loss index in all patients. Both were positively correlated. This relationship also indicated that late loss index and CD11b increase were less prominent in patients undergoing Cutting Balloon angioplasty.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The major finding of this pilot study is that the CD18 and CD11b expression on the surface of the neutrophils increased to a significantly smaller extent after Cutting Balloon angioplasty than after conventional balloon angioplasty. This result suggests that Cutting Balloon angioplasty induces less neutrophil activation, which might be a clinical indicator of smaller vascular injury and inflammatory reaction. Less injury and inflammatory reaction might be the explanation for the strikingly lower restenosis rate after Cutting Balloon angioplasty.

Mac-1 Is an Indicator of Vascular Injury and Inflammation After Angioplasty
It has been suggested that coronary angioplasty produces neutrophil activation.^{18 19 20 21} The activated neutrophils can release a variety of inflammatory mediators, which can aggravate the endothelial damage and further stimulate platelets.^{21 22} This process has potential implications in the subsequent development of intimal hyperplasia or smooth muscle cell proliferation and resulting restenosis. In the process of neutrophil activation, serial interactions with vascular endothelial cells, such as selectin-mediated "rolling," integrin-mediated "tight adhesion," and "transmigration" have been emphasized.²³

Mac-1 is an adhesion molecule classified as a member of the ß₂-integrin family, the structure of which includes heterodynamic glycoproteins possessing a ß-subunit of CD18 associated with an -subunit of CD11b.^{24 25} Although Mac-1 exists on the surface of inactive neutrophils, its activity is not sufficient to induce tight adhesion to vascular endothelial surface. However, cytokine-induced inflammatory stimuli or injury increases Mac-1 expression on the cell surface.²⁴ Endothelial cell surface molecules, including iC3b derived from the activation of the complement system, and ICAM-1 interact with the neutrophil CD18 adhesion-promoting receptor.^{5 26 27 28} Neutrophils adhering to vascular endothelial cells and activated can release a variety of mediators capable of promoting tissue injury.^{18 20 29}

We previously described that CD18 and CD11b (components of Mac-1) were significantly upregulated after angioplasty,⁶ whereas other integrin components (CD11a and CD11c) were only minimally upregulated. We have also found a correlation between the upregulation of Mac-1 and restenosis. These findings suggested that Mac-1 level is an indicator of the extent of vascular injury and will provide a means to substantiate the hypothesis that use of the Cutting Balloon is less traumatic. In addition to Mac-1 upregulation, a downregulation of L-selectin (CD62L) has also been demonstrated after coronary angioplasty.^{21 30 31} This might be due to "shedding." However, the change of L-selectin was smaller than that of Mac-1. Thus, we think that Mac-1 is a more attractive indicator of vessel wall injury and inflammation than L-selectin.

In the present study, the increase of the expression of CD18 and CD11b on the surface of neutrophils after angioplasty might indicate that the angioplasty upregulates Mac-1. CD11b is a Mac-1–specific subunit, whereas CD18 is a common subunit of all of the integrin family.^{24 25} Therefore, the change in the expression for CD11b might be equivalent to the change of Mac-1 expression. In addition, the differences of neutrophil surface expression of CD18 and CD11b between coronary sinus blood and peripheral blood were higher at 48 hours after the procedure in the patients undergoing angioplasty with conventional balloon only, whereas those differences did not change in the patients undergoing Cutting Balloon angioplasty. This indicates that the upregulation of Mac-1 after conventional balloon angioplasty occurred within the coronary circulation and that the intracoronary neutrophil activation was less with Cutting Balloon angioplasty.

In this study, we also demonstrated that serum levels of sICAM-1 in the coronary sinus samples increased after coronary angioplasty and that the increase was less with the Cutting Balloon angioplasty than with the conventional balloon angioplasty. Increased levels of sICAM-1 in the coronary sinus samples immediately after coronary angioplasty have also been shown by other investigators.³² Recent studies have demonstrated expression of ICAM-1 on human atherosclerotic plaque.³³ Circulating sICAM-1 appears to be slowly released from activated vascular endothelial cells.⁷ Thus, we speculate that the increase in sICAM-1 levels immediately after the conventional balloon angioplasty is due to endothelial cell injury, whereas the increase at 24 to 48 hours is due to endothelial cell activation. In addition, both the endothelial cell injury and activation might be less prominent after Cutting Balloon angioplasty. These findings may support the concept that neutrophils, activated and interacting with vascular endothelial cells by binding Mac-1 with ICAM-1, play a significant role in the process of vessel wall injury and inflammation. The Cutting Balloon might reduce this cell-to-cell interaction.

Our Findings Support the Theory of Cutting Balloon Angioplasty
The Cutting Balloon was designed by Barath et al.¹ The concept of the Cutting Balloon is to cut first and dilate next. The 3 or 4 radially directed microsurgical blades create longitudinal vascular incisions before the balloon inflation is completed, and balloon pressure serves primarily to propagate these incisions.¹ The hypothesis is that the unavoidable vascular injury is controlled and localized to the area of incisions and that interincisional segments are spared.^{1 2 3} In animal experiments, with the sharp surgical incision, medial smooth muscle cells were less stretched, and the vascular injury was localized to the incision sites.² In addition, platelet-derived growth factor A mRNA expression and DNA synthesis were localized to the incisional segments after Cutting Balloon dilatation but were observed circumferentially after conventional balloon dilatation.³ These experiments indicate that Cutting Balloon can minimize the traumatic vessel wall injury that is associated with balloon dilatation and that probably triggers a series of cellular and subcellular events leading to myointimal proliferation and consequently to restenosis.^{34 35 36} However, the mechanism of these beneficial effects of the Cutting Balloon has not been evaluated clinically.

Clinical experience with Cutting Balloon angioplasty has been reported previously.^{37 38 39} The safety and efficacy of Cutting Balloon angioplasty and the early angiographic and clinical outcome data were reviewed and evaluated.^{38 39} The Cutting Balloon International Pilot Trial⁴⁰ showed an 25% restenosis rate for the stand-alone Cutting Balloon cases and a 28% restenosis rate if adjunctive conventional balloon angioplasty was also used. In the present study, initial results, including acute gain, were similar in patients undergoing Cutting Balloon angioplasty and patients undergoing conventional balloon angioplasty. However, the late loss index was less and the restenosis rate was correspondingly lower in Cutting Balloon angioplasty than conventional balloon angioplasty. In addition, the late loss index was correlated not with the angioplasty procedure or initial angiographic results but rather with the changes of Mac-1 expression on the neutrophil surface as well as with the changes of sICAM-1 levels at 48 hours after the angioplasty in all patients. These results indicate that the activation of neutrophils after the procedure might be more closely related to the occurrence of restenosis than to the angioplasty procedure or the initial results. Cutting Balloon angioplasty may have a potential advantage in this context.

Potential Limitations
Our study included a limited number of patients with isolated left anterior descending coronary artery disease and only type A or type B lesions, although recently, the Cutting Balloon has been used for more complex lesions. Further investigations with larger numbers of patients and with more complex lesions are necessary.

The Cutting Balloon angioplasty group included patients in whom adjunctive conventional balloon dilatation was also used. We hypothesize that the initial incisions with the Cutting Balloon prepare the vessel for subsequent conventional balloon inflations, decreasing the vascular damage even in the adjunctive balloon cases. However, previous study data indicated that the restenosis rate was lower with the Cutting Balloon alone than with a combination of the Cutting Balloon and adjunctive conventional balloon. Therefore, a study should compare the two procedures vis-à-vis the neutrophil adhesion molecule expression.

As we mentioned above, the selection of Mac-1 and sICAM-1 as sole representatives of a complex process was based on our previous observations and on theoretical considerations.

Conclusions
The upregulation of Mac-1 on the surface of neutrophils in the coronary circulation was lower after Cutting Balloon angioplasty than after conventional balloon angioplasty. This fact may indicate that Cutting Balloon angioplasty produces less neutrophil activation and less balloon-induced vessel wall injury than conventional balloon angioplasty. The beneficial effect of Cutting Balloon angioplasty on restenosis may be related to a reduced activation of the neutrophil adhesion system, but this reduced activation is certainly an indicator of reduced vascular injury after Cutting Balloon dilatation.

	Selected Abbreviations and Acronyms

 

FITC = fluorescein isothiocyanate ICAM-1 = intercellular adhesion molecule-1 MFI = mean channel fluorescence intensity MLD = minimal lumen diameter PE = phycoerythrin QCA = quantitative coronary angiography sICAM-1 = soluble intercellular adhesion molecule-1

	Acknowledgments

 
This study was supported in part by grants from Kyowa Hakko Kogyo Co, Ltd, Tokyo, Japan, and the Vehicle Racing Commemorative Foundation, Japan. We gratefully acknowledge the technical support services of Kyowa Hakko Kogyo Co, Ltd. We thank Toshiyasu Miyazaki, PhD, Ohtsuka Tokyo Assay Laboratory, Japan, for flow cytometric analysis; Peter Barath, MD, PhD, Loyola University Medical School, Maywood, Ill, for his critical review of the manuscript; and John Urquhart, MD, Universiteit Maastricht, Netherlands, for helpful suggestions.

	Footnotes

 
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and published in abstract form (Circulation. 1996;94[suppl I]:I-87).

Received November 14, 1997; revision received February 5, 1998; accepted February 13, 1998.

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