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(Circulation. 1996;94:3098-3102.)
© 1996 American Heart Association, Inc.

Articles

Macrophage Infiltration Predicts Restenosis After Coronary Intervention in Patients With Unstable Angina

Pedro R. Moreno, MD; Victor H. Bernardi, MD; Julio Lopez-Cuellar, MD; John B. Newell, BA; Charles McMellon, BA; Herman K. Gold, MD; Igor F. Palacios, MD; Valentin Fuster, MD, PhD; John T. Fallon, MD, PhD

the Cardiac Unit, Massachusetts General Hospital, Harvard Medical School, Boston, and the Cardiovascular Institute (V.F., J.T.F.), Mount Sinai School of Medicine, New York, NY.

Correspondence to Pedro R. Moreno, MD, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail prmoreno@bics.bwh.harvard.edu.

	Abstract

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Background Restenosis remains the major limitation of percutaneous coronary revascularization. Macrophages release cytokines, metalloproteinases, and growth factors that may induce smooth muscle cell migration and proliferation. We tested the hypothesis that primary lesions that develop restenosis after coronary atherectomy have more macrophages and smooth muscle cells than primary lesions that do not develop restenosis.

Methods and Results Fifty patients with unstable angina were identified. Total and segmental areas were quantified on trichrome-stained sections of coronary atherectomy tissue. Macrophages and smooth muscle cells were identified by immunohistochemical staining. Restenosis, defined as >50% stenosis diameter by quantitative cineangiography, was present in 30 patients. The other 20 patients (<50% stenosis) constitute the "no restenosis" group. The percentages of smooth muscle cell areas were similar in specimens from patients with and without restenosis (57±5% and 52±6%) (P=NS). However, macrophage-rich areas were larger in plaque tissue from patients with restenosis (20.4±2%) than in tissue from patients without restenosis (9.3±2%) (P=.0007). Multiple stepwise logistic regression analysis identified macrophages as the only independent predictor for restenosis (P=.006).

Conclusions Macrophages are increased in coronary atherectomy tissue from primary lesions that develop restenosis, suggesting a possible role for macrophages in the restenotic process after percutaneous coronary intervention.

Key Words: atherosclerosis • angioplasty • coronary disease • leukocytes

	Introduction

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Restenosis remains a major limitation of percutaneous revascularization. The mechanisms involved in the process of restenosis are postulated to include elastic recoil, SMC proliferation with extracellular matrix production, and remodeling.^{1 2 3} Macrophages and SMCs play a prominent role in atherosclerotic plaque formation, progression, and rupture responsible for the majority of acute coronary syndromes.^{4 5 6} Macrophages are increased in coronary plaque tissue from patients with unstable angina compared with plaque tissue from patients with stable angina.⁷ Restenosis after percutaneous revascularization is more frequently seen in patients with unstable angina in comparison with patients with chronic stable angina.^{8 9} Macrophages may be involved in the process of restenosis because of their capacity to express numerous growth factors, cytokines, and metalloproteinases.^{10 11 12 13 14 15} In addition, restenosis after coronary angioplasty is associated with activated monocytes at the time of intervention.¹⁶

To test the hypothesis that macrophage content is increased in coronary lesions predisposed to restenosis after coronary intervention, we quantified plaque tissue components and correlated with angiographic restenosis after DCA in patients with unstable angina.

	Methods

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Patient Population
From October 1991 to November 1994, 724 consecutive DCA procedures were performed in the Cardiac Catheterization Laboratory of the Massachusetts General Hospital. We identified 106 patients with unstable angina¹⁷ who also underwent follow-up angiography. Patients were required to meet the following criteria: (1) successful DCA of the culprit lesion (>20% reduction in diameter stenosis and residual diameter stenosis <50%), (2) follow-up angiography 1 to 12 months after DCA, (3) no previous coronary intervention at the site of the culprit lesion, and (4) pathology specimen area >1.5 mm². Fifty patients met the inclusion criteria and constitute the study population. There were 38 men and 12 women, with a mean age of 61±15 years (range, 41 to 80 years). Restenosis, defined as >50% stenosis diameter by quantitative cineangiography, was present in 30 patients. The other 20 patients (<50% stenosis) constitute the "no restenosis" group. The remainder of the 106 patients were excluded because of previous procedure at the site of the culprit lesion (44 patients), follow-up angiography >12 months (4 patients), or atherectomy sample area <1.5 mm² (8 patients).

Atherectomy Specimen
Tissue obtained from each lesion at atherectomy was immediately immersion-fixed in 10% buffered formalin and routinely processed for paraffin embedding. Sections were cut at 5 µm, mounted on lysine-coated slides, and stained by a trichrome method.

Immunocytochemistry
Antibody staining was performed with 5-µm-thick sections deparaffinized and rehydrated with PBS. Macrophages were identified with an anti–human CD-68 panmacrophage antibodyKP-1, M851, Dako) at a concentration of 7.6 µg/mL. Identification of SMCs was performed with 0.1 µg/mL of anti–smooth muscle -actin antibody (1A4, M851, Dako). Sections were blocked with normal goat serum and 3% H₂O₂ in water, washed in PBS, and incubated with appropriate primary antibody for 1 hour at 37°C. Sections were washed in PBS, and primary antibodies were detected with a biotin-streptavidin amplified detection system (SuperSensitive Kit, Biogenex) developed with diaminobenzidine. Sections were dehydrated, coverslipped, and examined. Positive control slides (spleen for KP-1 and intact arteries for -actin), nonimmune negative controls, and processing controls were performed for each antigen stain.

Morphometry
The trichrome-stained tissue sections were used to identify and quantify the following five components: (1) sclerotic tissue, composed of tissue with few cells and densely stained collagen; (2) fibrocellular tissue composed of tissue with abundant SMCs and densely stained collagen; (3) hypercellular tissue, composed of a loose connective tissue matrix containing numerous stellate cells; (4) atheromatous gruel, composed of acellular debris with cholesterol clefts and without preserved connective tissue matrix; and (5) thrombus, which stained red. Each specimen was outlined manually at x40 magnification without knowledge of the group assignment. Total and segmental areas were quantified by computer-aided planimetry. Macrophage and SMC areas (-actin positive) were measured by use of the KP-1 and -actin–stained sections, respectively. Since -actin immunostaining may underestimate SMCs,² planimetric colocalization analysis was performed with the immunostained and the trichrome-stained slides. KP-1–negative and -actin–negative areas of hypercellular and fibrocellular tissue were classified as SMC areas.

Quantitative Measurement of Coronary Stenosis
Angiography was performed before and immediately after DCA and at follow-up with the same single-view projections and angulation. The reference diameter, percent diameter stenosis, and MLD were determined by quantitative coronary analysis after intracoronary administration of 100 µg of nitroglycerin by the MEDIS Reiber system.¹⁸ The angiographic catheter was used for calibration. Late loss, defined as the decrease in absolute MLD of the treated segment from the postprocedure to the follow-up angiogram, was calculated according to the following equation: Late loss equals post-DCA MLD minus follow-up MLD.

Statistical Analysis
Results are expressed as mean±SEM. Values of P<.05 were considered significant. For comparison of discrete variables (clinical and demographic data), a Fisher's test was used. For comparison of two gaussian samples (angiographic data), a two-tailed Student's t test was used. For comparison of data not compatible with a normal frequency distribution (morphometric data), the two-tailed Student's t test was performed with the logarithmic transformation of individual values. For multiple comparisons, a correction for the level of significance was performed according to the Bonferroni formula. Multiple stepwise logistic regression analysis was performed with the BMDP LR program with clinical (age, sex, risk factors for coronary artery disease), angiographic (reference diameter, pre-DCA MLD), and component (macrophages, -actin–positive and -actin–negative SMCs, sclerotic tissue, atheromatous gruel, and thrombus) areas included as independent variables. Restenosis was the outcome variable. Finally, linear regression analysis was performed between independent predictors for restenosis and late loss.

	Results

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Clinical and Demographic Characteristics
The clinical and demographic characteristics of the population were similar for the two groups (Table 1). There were no significant differences between the two groups with regard to age, sex, total plasma cholesterol, LDL, or HDL. The incidence of other risk factors for coronary artery disease, including hypertension, diabetes, cigarette smoking, and family history of coronary artery disease, was also similar in the two groups.

View this table: [in this window] [in a new window]   Table 1. Clinical and Demographic Data

Angiography
The artery containing the culprit lesion was similar in both groups. Culprit lesions were in the left anterior descending coronary artery in 17 patients with restenosis and 10 patients without restenosis. The right coronary artery contained the culprit lesion in 7 patients with restenosis and 7 patients without restenosis, and the left circumflex artery in 6 patients with restenosis and 3 patients without restenosis. The time interval between the initial DCA procedure and the follow-up angiogram was 17±2 weeks in the restenosis group and 15±2 weeks in the no restenosis group (P=NS). Reference diameter, percent diameter stenosis, and MLD before DCA and acute gain after DCA were similar for both groups (Table 2). At follow-up angiography, MLD was lower and percent diameter stenosis and late loss were significantly larger in patients with restenosis than in patients without restenosis (P<.0001).

View this table: [in this window] [in a new window]   Table 2. Quantitative Angiographic Data of the Culprit Lesion

Morphometry
The total and segmental areas for each of the plaque components are given in Table 3. A total of 823 pieces of tissue were stained and quantified. The percentages of total area occupied by sclerotic, fibrocellular, and hypercellular tissue and atheromatous gruel were similar for both groups (P=NS). Thrombus was present in 14 of 30 samples from patients with restenosis and 10 of 20 samples from patients without restenosis (P=NS). The percentage of total area occupied by SMCs (-actin–positive and -actin–negative) was not significantly different in coronary tissue from patients with restenosis from coronary tissue from patients without restenosis (P=NS).

View this table: [in this window] [in a new window]   Table 3. Total, Segmental, and Percent Areas of Plaque Tissue Components

The percentage of total area occupied by macrophages was larger in coronary samples from patients with restenosis (20.4±2%) than in samples from patients without restenosis (9.3±2%) (P=.0007) (Figs 1 and 2). Macrophages were identified by both univariate and multivariate analysis as the only predictor for restenosis after DCA (P=.006). Reference diameter showed a tendency to predict restenosis (P=.08). Linear regression analysis did not demonstrate a correlation between reference diameter and macrophages (r=.0016, P=.78). Finally, the percentage of total area occupied by macrophages correlated with late luminal loss after DCA, as shown in Fig 3.

View larger version (15K): [in this window] [in a new window]   Figure 1. Increased percent area (mean±SEM) of macrophages in tissue from primary coronary lesions of patients who developed restenosis versus tissue from patients without restenosis at follow-up angiography 4 months after successful DCA.

View larger version (663K): [in this window] [in a new window]   Figure 2. Photomicrographs of atherectomy tissue from a lesion that developed restenosis (A and B) and from a lesion that did not develop restenosis (C and D). A and C, Trichrome connective tissue stain. B and D, Immunostained with anti–human panmacrophage antibody (immunoperoxidase). Larger macrophage content in plaques prone to restenosis after coronary intervention.

View larger version (19K): [in this window] [in a new window]   Figure 3. Association of percent area of macrophages identified by immunostaining in coronary samples from patients with restenosis () and without restenosis () versus late loss measured by quantitative coronary analysis, which can be described by the equation y=0.52112x+0.095477 (r=.39, P=.005).

	Discussion

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This study demonstrates a significantly larger content of macrophages in primary coronary plaque tissue from patients with unstable angina who developed restenosis after DCA. Furthermore, macrophage content was an independent predictor for restenosis at follow-up angiography 4 months after DCA.

We have performed morphometric correlation of tissue from coronary culprit lesions showing similar contents of hypercellular tissue, fibrocellular tissue, sclerotic tissue, atheromatous gruel, thrombus, and SMCs from lesions that developed restenosis versus those that did not develop restenosis at follow-up angiography. This finding suggests that the severity of vascular renarrowing after coronary atherectomy is not related to the initial SMC content in the culprit lesion. However, macrophage content was significantly larger in lesions that underwent restenosis, suggesting that a larger macrophage content of culprit lesions may be a marker for restenosis after coronary intervention. Coronary restenosis is increased in patients with unstable angina and presents with a more aggressive clinical syndrome than in patients with chronic stable angina.^{8 9} Histopathologically, culprit plaques from patients with unstable angina have an increased content of macrophages and SMCs.^{7 19 20 21} We showed previously that macrophage-rich areas are more frequently found in plaque tissue from patients with the acute coronary syndromes of unstable angina and non–Q-wave myocardial infarction than in plaque tissue from patients with chronic stable angina.⁷ Consequently, macrophage-rich coronary atherosclerotic plaques may have both a higher risk of rupture with thrombosis and a higher propensity for restenosis after coronary intervention. The macrophage content of plaques may be a link between both phenomena, ie, acute coronary syndromes and restenosis.

Macrophages and SMCs are the principal cellular components of the atherosclerotic plaque.²² Coronary atherosclerotic plaques may evolve from fatty streaks to lipid-rich plaques (high macrophage content) to sclerotic lesions and may undergo calcification.⁴ The role of macrophages in SMC migration and proliferation is unclear and remains to be elucidated. Activated monocytes at the time of coronary angioplasty have been correlated with restenosis after balloon angioplasty,¹⁶ and we demonstrated an increased amount of macrophages in coronary lesions that underwent restenosis after DCA. This suggests that vascular injury may influence the state of activation of mononuclear phagocytes. Libby et al¹⁰ postulated that angioplasty may induce a change in macrophage phenotype from a resting to an activated state that could be involved in the restenosis process, but further studies should be done to prove this hypothesis.

The mechanisms of macrophage involvement in restenosis may include thrombus organization, SMC migration and proliferation, and constrictive scarring of the adventitia. Wilensky et al²³ studied the cellular mechanisms of vascular repair and restenosis in a rabbit atherosclerotic model. Macrophages exhibit an early and sustained DNA synthesis in both the intima and the media layers over the first 2 weeks. Monocyte inhibition reduced intimal SMC accumulation by 70% in the rabbit carotid model.²⁴ Macrophage-derived metalloproteinases correlated with SMC migration from the media into the intima after angioplasty in the rat.^{12 13 14 15} Most importantly, administration of metalloproteinase inhibitor after balloon injury resulted in a 97% reduction in the number of SMCs migrating into the intima. Macrophage tissue factor expression has been identified in coronary tissue from patients with unstable angina²⁵ and may be responsible for a prolonged luminal surface thrombogenicity after balloon injury.^{26 27} Blockage of factor VIIa binding to tissue factor as well as the use of recombinant tissue factor pathway inhibitor reduced angiographic restenosis and decreased neointimal hyperplasia in the rabbit atherosclerotic model.²⁸ Furthermore, Galis and Libby (unpublished data, 1996) have identified macrophage-derived metalloproteinases in the adventitia after balloon injury, suggesting that macrophages are involved in the adventitial constrictive response after percutaneous transluminal coronary angioplasty.

Limitations
Several limitations must be addressed. First, it is known that immunohistochemistry underestimates the content of SMCs in atherosclerotic plaques. Loss of expression of -actin in SMCs is associated with a phenotypic change from a contractile to a "synthetic" phenotype,² and specific markers of activated SMCs were not evaluated in this study. This limitation applies to all samples examined. Second, planimetry may overestimate cellular areas mixed with extracellular tissue. Nevertheless, only positive KP-1–immunostained cellular areas were included as macrophage areas. In addition, the method was applied blindly for all samples, so this potential error is distributed randomly in both groups. Third, reference diameters and MLDs were larger in the no restenosis group, and "bigger is better" may apply in this situation. This study was not designed to identify angiographic predictors of restenosis. For completeness, however, we included these variables in the multiple logistic regression analysis. The relatively small number of patients may explain the lack of statistical significance. Fourth, DCA is a limited method to remove atherosclerotic lesions.²⁹ Recent intravascular ultrasound studies have shown that DCA is able to remove 33% to 67% of the lesion,^{30 31} and macrophage areas may be limited to small areas that could or could not be removed by this technique. We selected lesions with areas >1.5 cm² to diminish this sample error. Again, this limitation applies equally for both groups.

Conclusions
The results of the present study indicate that macrophage content of coronary plaque tissue is significantly higher in patients who undergo restenosis after DCA. Furthermore, macrophage content is an independent predictor for the degree of vascular renarrowing after successful coronary intervention. However, this is primarily an observational study. Further studies, including tissue expression of metalloproteinases, will be necessary to establish mechanistic relationships and completely define the role of macrophages in coronary restenosis after percutaneous revascularization.

	Selected Abbreviations and Acronyms

 

DCA = directional coronary atherectomy MLD = minimal luminal diameter SMC = smooth muscle cell

	Acknowledgments

 
Dr Bernardi was supported in part by the Anchorena Hospital in Buenos Aires, Argentina. We thank Veronica Gulle, Michelle Forrestall, and Mark J. Semigran, MD, for expert technical assistance and Robert H. Holt for editorial assistance. We also thank Drs Erling Falk and Alfredo Rodriguez for their constructive criticism.

	Footnotes

 
Presented in part at the 68th Annual Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13-16, 1995, and published in abstract form (Circulation. 1995[suppl I]:I-161).

Received March 27, 1996; revision received July 15, 1996; accepted July 30, 1996.

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