Matrix Metalloproteinase-9 (MMP-9) and Myeloperoxidase (MPO) Levels in Patients with Nonobstructive Coronary Artery Disease Detected by Coronary Computed Tomographic Angiography

Rationale and Objectives

The aim of this study was to evaluate whether matrix metalloproteinase–9 (MMP-9) and myeloperoxidase (MPO) are elevated in patients with nonobstructive coronary artery disease.

Materials and Methods

Eighty-four patients with nonobstructive coronary artery disease (group A) and 90 patients with no coronary plaques (group B) were enrolled. MMP-9 and MPO levels were compared between the two groups. The relationships between these biomarkers and Framingham risk score were analyzed. Receiver-operating characteristic curves were used to evaluate the ability of these biomarkers to predict the presence of coronary artery plaques.

Results

The MMP-9 and MPO values in group A were significantly higher than in group B ( P < .001). The levels of MMP-9 and MPO showed significant correlations with Framingham risk score ( r = 0.796, P < .001, and r = 0.409, P < .001, respectively). The areas under the receiver-operating characteristic curves for MMP-9 and MPO were 0.80 (95% confidence interval, 0.74–0.87) and 0.74 (95% confidence interval, 0.66–0.81), respectively.

Conclusions

Levels of MMP-9 and MPO are positively correlated with Framingham risk score. Additionally, in patients with nonobstructive coronary artery disease, elevated levels of MMP-9 and MPO may identify patients at risk for future myocardial infarction or sudden cardiac death.

Early reports have revealed that obstructive coronary artery disease (CAD), as identified by coronary computed tomographic angiography (cCTA) and defined by coronary plaques causing ≥50% reductions in luminal diameter, is valuable for the prognosis of individuals at risk for major adverse cardiovascular events . Nevertheless, individuals undergoing cCTA commonly exhibit nonobstructive plaques. Prior invasive ultrasound and autopsy studies have implicated nonobstructive plaques as central to the pathophysiologic processes of sudden cardiac death and myocardial infarction . But percutaneous or surgical revascularization is performed only in patients with >50% luminal stenosis. Nonobstructive plaques cannot be detected by traditional coronary angiography and may be considered normal.

Matrix metalloproteinases (MMPs), a family of structurally and functionally related zinc endopeptidases, degrade extracellular matrix proteins and have been implicated in connective tissue destruction and remodeling . MMP-9, a significant member of the MMP family, has been found to degrade a wide range of extracellular matrix proteins, including gelatin, type IV collagen, and other basement membrane proteins . Increased levels of MMP-9 have been found in human atherosclerotic plaques involved in plaque rupture . Myeloperoxidase (MPO) is the most abundant component of primary azurophilic granules in neutrophils and is promptly discharged after activation by different agonists . First identified within human atherosclerotic plaques nearly a decade ago, MPO has emerged as an important factor in the development and progression of atherosclerotic disease . In clinical studies conducted in patients with acute coronary syndromes, an elevated level of MPO was associated with an adverse prognosis and the occurrence of major cardiovascular events .

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Materials and methods

Patient Recruitment

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Data Acquisition

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Image Analysis

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CAD Risk Assessment

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Biochemical Analysis

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Statistical Analysis

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Results

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Table 1

Baseline Characteristics of the Two Groups

Characteristic Group A Group B_P_ Men 64.3% (54) 63.3% (57) .90 Age (y) 52.68 ± 8.69 53.43 ± 11.29 .44 Body mass index (kg/m 2 ) 25.11 ± 3.68 25.18 ± 3.14 .84 Systolic blood pressure (mm Hg) 144 ± 19 140 ± 17 <.001 Diastolic blood pressure (mm Hg) 86 ± 12 84 ± 10 <.001 Total cholesterol (mmol/L) 6.7 ± 1.2 6.3 ± 1.0 <.001 Low-density lipoprotein cholesterol (mmol/L) 4.3 ± 1.0 3.9 ± 1.0 <.001 High-density lipoprotein cholesterol (mmol/L) 1.5 ± 0.3 1.5 ± 0.4 .93 Diabetes mellitus 13.1% (11) 3.3% (3) <.001 Smoking 44.1% (37) 51.1% (46) .351 Framingham risk score Low risk 14.3% (12) 20.0% (18) .319 Intermediate risk 34.5% (29) 43.3% (39) .234 High risk 51.2% (43) 36.7% (33) .038

Data are expressed as percentage (number) or as mean ± standard deviation.

Table 2

Nonobstructive Plaques in Group A Patients

Location Subjects Percentage Left main coronary artery 0 0 Left anterior descending coronary artery 52 40.6% Proximal 36 28.1% Mid 16 12.5% Distal 0 0 Diagonal branch 0 0 Left circumflex coronary artery 33 25.8% Proximal 20 15.6% Mid 9 7.0% Distal 0 0 Obtuse marginal branch 4 3.2% Right coronary artery 43 33.6% Proximal 30 23.4% Mid 13 10.2% Distal 0 0 Posterior left ventricular branch 0 0 Posterior descending 0 0

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Table 3

Serum Levels of Biomarkers in the Two Groups

Biomarker Minimum 25th Percentile Median 75th Percentile Maximum_P_ Matrix metalloproteinase–9 (ng/mL) Group A 206.10 486.30 592.10 802.20 1178.90 <.001 Group B 142.70 270.20 394.30 490.10 655.30 Myeloperoxidase (ng/mL) Group A 511.30 715.50 953.00 1220.70 1750.70 <.001 Group B 181.95 409.60 554.70 811.40 975.80

Table 4

Serum Levels of Biomarkers in the Two Groups after Adjustment for FRS

Biomarker FRS Group A Group B_P_ Matrix metalloproteinase–9 (ng/mL) Low risk 385.20 ± 104.30 152.50 ± 60.40 <.001 Intermediate risk 575.30 ± 198.90 301.20 ± 113.70 <.001 High risk 969.40 ± 287.30 562.10 ± 201.30 <.001 Myeloperoxidase (ng/mL) Low risk 651.10 ± 274.50 288.20 ± 94.30 <.001 Intermediate risk 1102.30 ± 334.30 683.60 ± 234.80 <.001 High risk 1484.40 ± 446.70 884.20 ± 301.60 <.001

FRS, Framingham risk score.

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Discussion

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Conclusions

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Acknowledgments

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References

• 1. Matsumoto N., Sato Y., Yoda S., et. al.: Prognostic value of nonobstructive CT low-dense coronary artery plaques detected by multislice computed tomography. Circ J 2007; 71: pp. 1898-1903.

• 2. Min J.K., Lin F.Y., Dunning A.M., et. al.: Incremental prognostic significance of left ventricular dysfunction to coronary artery disease detection by 64-detector row coronary computed tomographic angiography for the prediction of all-cause mortality: results from a two centre study of 5330 patients. Eur Heart J 2010; 31: pp. 1212-1219.

• 3. Virmani R., Burke A.P., Farb A., et. al.: Pathology of the vulnerable plaque. J Am Coll Cardiol 2006; 47: pp. C13-C18.

• 4. Ehara S., Kobayashi Y., Yoshiyama M., et. al.: Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation 2004; 110: pp. 3424-3429.

• 5. Visse R., Nagase H.: Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: pp. 827-839.

• 6. Newby A.C.: Dual role of matrix metalloproteinases (matrixes) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85: pp. 1-31.

• 7. Brown D.L., Hibbs M.S., Kearney M., et. al.: Identification of 92-kD gelatinase in human coronary atherosclerotic lesions. Association of active enzyme synthesis with unstable angina. Circulation 1995; 91: pp. 2125-2131.

• 8. Arnhord J.: Properties, functions, and secretion of human myeloperoxidase. Biochemistry (Mosc) 2004; 69: pp. 4-9.

• 9. Daugherty A., Dunn J.L., Rateri D.L., et. al.: Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 1994; 94: pp. 437-444.

• 10. Brennan M.L., Penn M.S., Van Lente F., et. al.: Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349: pp. 1595-1604.

• 11. Lin Fay Y., Shaw Leslee J., Dunning Allison M., et. al.: Mortality risk in symptomatic patients with nonobstructive coronary artery disease. J Am Coll Cardiol 2011; 58: pp. 510-519.

• 12. Cheng V.Y., Wolak A., Gutstein A., et. al.: Low-density lipoprotein and noncalcified coronary plaque composition in patients with newly diagnosed coronary artery disease on computed tomographic angiography. Am J Cardiol 2010; 105: pp. 761-766.

• 13. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults : Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: pp. 2486-2497.

• 14. Ambrose J.A., Tannenbaum M.A., Alexopoulos D., et. al.: Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988; 12: pp. 56-62.

• 15. Corrales-Medina V.F., Madjid M., Musher D.M.: Role of acute infection in triggering acute coronary syndromes. Lancet Infect Dis 2010; 10: pp. 83-92.

• 16. Muller J.E., Tawakol A., Kathiresan S., et. al.: New opportunities for identification and reduction of coronary risk: treatment of vulnerable patients, arteries, and plaques. J Am Coll Cardiol 2006; 47: pp. C2-C6.

• 17. Luttun A., Lutgens E., Manderveld A., et. al.: Loss of matrix metalloproteinase-9 or matrixmetalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation 2004; 109: pp. 1408-1414.

• 18. Loftus I.M., Naylor A.R., Goodall S., et. al.: Increased matrix metalloproteinase-9 activity in unstable carotid plaques. A potential role in acute plaque disruption. Stroke 2000; 31: pp. 40-47.

• 19. Hazen S.L.: Myeloperoxidase and plaque vulnerability. Arterioscler Thromb Vasc Biol 2004; 24: pp. 1143-1146.

• 20. Sugiyama S., Okada Y., Sukhova G.K., et. al.: Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating-factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol 2001; 158: pp. 879-891.

• 21. Fu X., Kassim S.Y., Parks W.C., et. al.: Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7): a mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 2001; 276: pp. 41279-41287.

• 22. Falk E., Shah P.K., Fuster V.: Coronary plaque disruption. Circulation 1995; 92: pp. 657-671.

• 23. Derosa G., D’Angelo A., Ciccarelli L., et. al.: Matrix metalloproteinase-2, -9, and tissue inhibitor of metalloproteinase-1 in patients with hypertension. Endothelium 2006; 13: pp. 227-231.

• 24. Tayebjee M.H., Nadar S., Blann A.D., et. al.: Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo- Scandinavian Cardiac Outcomes Trial ASCOT. Am J Hypertens 2004; 17: pp. 764-769.

• 25. Sundstrom J., Evans J.C., Benjamin E.J., et. al.: Relations of plasma matrix metalloproteinase-9 to clinical cardiovascular risk factors and echocardiographic left ventricular measures: the Framingham Heart Study. Circulation 2004; 109: pp. 2850-2856.

• 26. Noji Y., Kajinami K., Kawashiri M.A., et. al.: Circulating matrix metalloproteinases and their inhibitors in premature coronary atherosclerosis. Clin Chem Lab Med 2001; 39: pp. 380-384.