Document Type : Original Article

Authors

Cardiovascular Surgery Research Center, Okan University, Istanbul, Turkey

10.48305/arya.2025.43384.3019

Abstract

BACKGROUND: The role of matrix metalloproteinases in developing ischemic heart disease has been suggested. We investigated the effect of the MMP-9 gene polymorphism rs17576 on the severity of coronary artery disease and outcomes in affected individuals.
METHODS: A total of 654 patients suspected of having coronary artery disease were assessed. Real-time PCR was performed for MMP-9 (rs17576) genotyping, and ELISA was used to assess MMP-9 plasma levels. The patients were followed up for one year.
RESULTS: Coronary angiography showed coronary artery involvement in 28% of patients. The frequencies of AA, AG, and GG genotypes of rs17576 in the group without coronary artery involvement were 5.5%, 31.4%, and 63.1%, respectively, while in those with coronary artery disease, the frequencies were 55.2%, 29.5%, and 15.3%, respectively, showing a significant difference (p < 0.001). The frequency of the major allele (G allele) in the normal group and the groups with single-, two-, and three-coronary involvement was 21.1%, 65.4%, 61.8%, and 85.0%, respectively, indicating a significant difference (p < 0.001). The mean serum level of MMP-9 was 2,963 ± 1,077 pg/ml in the group with coronary artery disease and 2,145 ± 926 pg/ml in the group without coronary involvement, with a significant difference between the two groups (p = 0.008). The presence of the A allele of rs17576 was associated with an increased hazard of one-year mortality in the coronary artery disease group (HR = 5.764, p < 0.001). 
CONCLUSION: Tracking the rs17576 polymorphism of the MMP-9 gene can predict coronary artery disease severity and its long-term poorer outcome.

Keywords

1. Nowbar AN, Gitto M, Howard JP, Francis DP, Al-Lamee R. Mortality From Ischemic Heart Disease. Circ Cardiovasc Qual Outcomes. 2019 Jun;12(6):e005375. https://doi.org/10.1161/circoutcomes.118.005375
2. Menotti A, Puddu PE, Catasta G. Lifestyle behaviours predicting major cardiovascular diseases mortality in a practically extinct cohort of middle-aged men followed-up for 61 years. Acta Cardiol. 2023 Jul;78(5):578-85. https://doi.org/10.1080/00015385.2022.2101876
3. Kasargod Prabhakar CR, Stewart R. Physical activity and mortality in patients with stable coronary heart disease. Curr Opin Cardiol. 2018 Nov;33(6):653-9. https://doi.org/10.1097/hco.0000000000000563
4. Okere AN, Sanogo V, Alqhtani H, Diaby V. Identification of risk factors of 30-day readmission and 180-day in-hospital mortality, and its corresponding relative importance in patients with Ischemic heart disease: a machine learning approach. Expert Rev Pharmacoecon Outcomes Res. 2021 Oct;21(5):1043-8. https://doi.org/10.1080/14737167.2021.1842200
5. Henning RJ. Recognition and treatment of ischemic heart diseases in women. Future Cardiol. 2019 May;15(3):197-225. https://doi.org/10.2217/fca-2018-0079
6. Stone PH, Libby P, Boden WE. Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review. JAMA Cardiol. 2023 Feb 1;8(2):192-201. https://doi.org/10.1001/jamacardio.2022.3926
7. Boudoulas KD, Triposciadis F, Geleris P, Boudoulas H. Coronary Atherosclerosis: Pathophysiologic Basis for Diagnosis and Management. Prog Cardiovasc Dis. 2016 May-Jun;58(6):676-92. https://doi.org/10.1016/j.pcad.2016.04.003
8. Bräuninger H, Krüger S, Bacmeister L, Nyström A, Eyerich K, Westermann D, et al. Matrix metalloproteinases in coronary artery disease and myocardial infarction. Basic Res Cardiol. 2023 May 9;118(1):18. https://doi.org/10.1007/s00395-023-00987-2
9. Wang C, Li Q, Yang H, Gao C, Du Q, Zhang C, et al. MMP9, CXCR1, TLR6, and MPO participant in the progression of coronary artery disease. J Cell Physiol. 2020 Nov;235(11):8283-92. https://doi.org/10.1002/jcp.29485
10. Mittal B, Mishra A, Srivastava A, Kumar S, Garg N. Matrix metalloproteinases in coronary artery disease. Adv Clin Chem. 2014;64:1-72. https://doi.org/10.1016/b978-0-12-800263-6.00001-x
11. Theofilis P, Sagris M, Oikonomou E, Antonopoulos AS, Lazaros G, Theofilis A, et al. Extracellular Matrix Remodeling Biomarkers in Coronary Artery Disease. Curr Top Med Chem. 2022;22(28):2355-67. https://doi.org/10.2174/1568026623666221024091758
12. Kremastiotis G, Handa I, Jackson C, George S, Johnson J. Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis. Sci Rep. 2021 Nov 30;11(1):23081. https://doi.org/10.1038/s41598-021-02508-4
13. Li H, Yuan Z, Li S, Qi Q, Liu J, Zhou M, et al. Plasma levels of matrix metalloproteinase 9 in patients undergoing off-pump coronary artery bypass grafting. J Thorac Dis. 2017 Apr;9(4):1100-6. https://doi.org/10.21037/jtd.2017.03.156
14. Polonskaya YV, Kashtanova EV, Murashov IS, Striukova EV, Kurguzov AV, Stakhneva EM, et al. Association of Matrix Metalloproteinases with Coronary Artery Calcification in Patients with CHD. J Pers Med. 2021 Jun 3;11(6):506. https://doi.org/10.3390/jpm11060506
15. Pöllänen PJ, Karhunen PJ, Mikkelsson J, Laippala P, Perola M, Penttilä A, et al. Coronary artery complicated lesion area is related to functional polymorphism of matrix metalloproteinase 9 gene: an autopsy study. Arterioscler Thromb Vasc Biol. 2001 Sep;21(9):1446-50. https://doi.org/10.1161/hq0901.095545
16. Caselli C, Di Giorgi N, Ragusa R. Association of MMP9 with adverse features of plaque progression and residual inflammatory risk in patients with chronic coronary syndrome (CCS). Vascul Pharmacol. 2022 Oct;146:107098. https://doi.org/10.1016/j.vph.2022.107098
17. Guo C, Zhang S, Zhang J, Liu H, Li P, Liu H, Wang Y. Correlation between the severity of coronary artery lesions and levels of estrogen, hs-CRP and MMP-9. Exp Ther Med. 2014 May;7(5):1177-80. https://doi.org/10.3892/etm.2014.1565
18. Dong M, Mu N, Ren F, Li F, Zhang C, Yang J. Matrix Metalloproteinase-9 in the Culprit Coronary Artery and Myocardial No-Reflow. Am J Med Sci. 2015 Nov;350(5):352-6. https://doi.org/10.1097/maj.0000000000000559
19. Niu W, Qi Y. Matrix metalloproteinase family gene polymorphisms and risk for coronary artery disease: systematic review and meta-analysis. Heart. 2012 Oct;98(20):1483-91. https://doi.org/10.1136/heartjnl-2012-302085
20. Takase B, Matsushima Y, Uehata A, Ishihara M, Kurita A. Endothelial dysfunction, carotid artery plaque burden, and conventional exercise-induced myocardial ischemia as predictors of coronary artery disease prognosis. Cardiovasc Ultrasound. 2008 Dec 16;6:61. https://doi.org/10.1186/1476-7120-6-61
21. Pogorielova OS, Korniienko VV, Chumachenko YD, Obukhova OA, Martsovenko I, Harbuzova VY. Impact of MMP-9 Genetic Polymorphism and Concentration on the Development of Coronary Artery Disease in Ukrainian Population. Cardiol Res Pract. 2022 Apr 11;2022:2067632. https://doi.org/10.1155/2022/2067632
22. Charach L, Blatt A, Jonas M, Teodorovitz N, Haberman D, Gendelman G, Grosskopf I, George J, Charach G. Using the Gensini score to estimate severity of STEMI, NSTEMI, unstable angina, and anginal syndrome. Medicine (Baltimore). 2021 Oct 15;100(41):e27331. https://doi.org/10.1097/md.0000000000027331
23. Wu HD, Bai X, Chen DM, Cao HY, Qin L. Association of genetic polymorphisms in matrix metalloproteinase-9 and coronary artery disease in the Chinese Han population: a case-control study. Genet Test Mol Biomarkers. 2013 Sep;17(9):707-12. https://doi.org/10.1089/gtmb.2013.0109
24. Iwaki K, Hayashi Y. [Method for estimating the precision and detection limit for ELISA]. Nihon Yakurigaku Zasshi. 2009 Oct;134(4):207-11. https://doi.org/10.1254/fpj.134.207
25. Sheikhvatan M, Boroumand MA, Behmanesh M, Ziaee S. Association of R279Q and C1562T polymorphisms of matrix metalloproteinase 9 gene and increased risk for myocardial infarction in patients with premature coronary artery disease. J Clin Lab Anal. 2018 Jan;32(1):e22218. https://doi.org/10.1002/jcla.22218
26. Panayiotou AG, Griffin MB, Tyllis T, Georgiou N, Bond D, Humphries SE, et al. Association of genotypes at the matrix metalloproteinase (MMP) loci with carotid IMT and presence of carotid and femoral atherosclerotic plaques. Vasc Med. 2013 Oct;18(5):298-306. https://doi.org/10.1177/1358863x13502698
27. Horne BD, Camp NJ, Carlquist JF, Muhlestein JB, Kolek MJ, Nicholas ZP, et al. Multiple-polymorphism associations of 7 matrix metalloproteinase and tissue inhibitor metalloproteinase genes with myocardial infarction and angiographic coronary artery disease. Am Heart J. 2007 Oct;154(4):751-8. https://doi.org/10.1016/j.ahj.2007.06.030