Evaluation of Fibrosis Markers as a Potential Method for Diagnosing Non-Obstructive Coronary Artery Disease in Patients with Stable Coronary Artery Disease
https://doi.org/10.20996/1819-6446-2022-11-01
Abstract
Aim. To study the levels of fibrosis markers in patients with stable coronary artery disease (CAD) and various types of coronary artery (CA) lesions (obstructive and non-obstructive), to identify possible differences for diagnosing the types of coronary obstruction.
Material and methods. The observational study included three groups of patients: with non-obstructive (main group, coronary artery stenosis <50%; n=20) and obstructive (comparison group, hemodynamically significant coronary artery stenosis according to the results of coronary angiography; n=20) CAD and healthy volunteers (control group; n=40). Transforming growth factor beta 1 (TGF-β1) and matrix metalloproteinase 9 (MMP-9) levels were measured in plasma by enzyme immunoassay. According to the results of echocardiography, all patients included in the study were divided into four groups depending on the type of myocardial remodeling.
Results. TGF-β1 levels were significantly higher in patients with obstructive CAD (p=0.008) than in patients with non-obstructive CAD and healthy volunteers (p <0.001). There were no significant differences between the main and control groups (p>0.05). There were no statistically significant differences in TGF-β1 levels depending on the type of left ventricular remodeling (p=0.139). The maximum level of MMP-9 was in the group with obstructive coronary disease and significantly differed from the main group (p <0.001) and the control group (p=0.04).
Conclusio. The maximum levels of TGF-β1 and MMP-9 were found in the group with obstructive coronary artery disease. The levels of these biomarkers in the main group were statistically different from the values obtained in the control group. Thus, considering the pathogenesis of the development of non-obstructive CAD, the use of fibrosis markers TGF-β1 and MMP-9 may be promising for diagnosing the severity of CA obstruction.
About the Authors
N. N. PakhtusovRussian Federation
Nikolay N. Pakhtusov
Moscow
A. O. Yusupova
Russian Federation
Alfia O. Yusupova
Moscow
K. A. Zhbanov
Russian Federation
Konstantin A. Zhbanov
Moscow
A. A. Shchedrygina
Russian Federation
Anastasia A. Shchendrygina
Moscow
E. V. Privalova
Russian Federation
Elena V. Privalova
Moscow
Yu. N. Belenkov
Russian Federation
Yuri N. Belenkov
Moscow
References
1. The top 10 causes of death [cited 2022 Jan 12]. Available from: https://www.who.int/newsroom/fact-sheets/detail/the-top-10-causes-of-death.
2. Gibbs RA. The Human Genome Project changed everything. Nat Rev Genet. 2020;21(10):575-6. DOI:10.1038/s41576-020-0275-3.
3. Low EL, Baker AH, Bradshaw AC. TGFβ smooth muscle cells and coronary artery disease: a review. Cell Signal. 2019;53:90-101. DOI:10.1016/j.cellsig.2018.09.004
4. Hata A, Chen YG. TGF-β signaling from receptors to smads. Cold Spring Harb Perspect Biol. 2016;8(9):a022061. DOI:10.1101/cshperspect.a022061.
5. Morikawa M, Derynck R, Miyazono K. TGF-β and the TGF-β family: Context-dependent roles in cell and tissue physiology. Cold Spring Harb Perspect Biol. 2016;8(5):a021873. DOI:10.1101/cshperspect.a021873.
6. Dobaczewski M, Chen W, Frangogiannis NG. Transforming growth factor (TGF)-β signaling in cardiac remodeling. J Mol Cell Cardiol. 2011;51(4):600-6. DOI:10.1016/j.yjmcc.2010.10.033.
7. Wang JH, Zhao L, Pan X, et al. Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-β1 signaling pathway. Lab Investig [Internet]. 2016;96(8):839-52. DOI:10.1038/labinvest.2016.65.
8. Hu HH, Chen DQ, Wang YN, et al. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018;292:76-83. DOI:10.1016/j.cbi.2018.07.008.
9. Knuuti J, Wijns W, Achenbach S, et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41(3):407-77. DOI:10.1093/eurheartj/ehz425.
10. Jespersen L, Hvelplund A, Abildstrøm SZ, et al. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012;33(6):734-44. DOI:10.1093/eurheartj/ehr331.
11. Safdar B, Spatz ES, Dreyer RP, et al. Presentation, clinical profile, and prognosis of young patients with myocardial infarction with nonobstructive coronary arteries (MINOCA): Results from the VIRGO study. J Am Heart Assoc. 2018;7(13):e009174. DOI:10.1161/JAHA.118.009174.
12. Faul F, Erdfelder E, Buchner A, Lang AG. Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav Res Methods. 2009;41(4):1149-60. DOI:10.3758/BRM.41.4.1149.
13. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification. Eur J Echocardiogr. 2006;7(2):79-108. DOI:10.1016/j.euje.2005.12.014.
14. Grainger DJ, Kemp PR, Metcalfe JC, et al. The serum concentration of active transforming growth factor-beta is severely depressed in advanced atherosclerosis. Nat Med. 1995;1(1):74-9. DOI:10.1038/nm0195-74.
15. Erren M, Reinecke H, Junker R, et al. Systemic inflammatory parameters in patients with atherosclerosis of the coronary and peripheral arteries. Arterioscler Thromb Vasc Biol. 1999;19(10):2355-63. DOI:10.1161/01.atv.19.10.2355.
16. Wang XL, Liu SX, Wilcken DEL. Circulating transforming growth factor beta1 and coronary artery disease. Cardiovasc Res. 1997;34(2):404-10. DOI:10.1016/s0008-6363(97)00033-3.
17. van Dijk RA, Engels CC, Schaapherder AF, et al. Visualizing TGF-β and BMP signaling in human atherosclerosis: a histological evaluation based on Smad activation. Histol Histopathol. 2012;27(3):387- 96. DOI:10.14670/HH-27.387.
18. Grainger DJ. TGF-beta and atherosclerosis in man. Cardiovasc Res. 2007;74(2):213-22. DOI:10.1016/j.cardiores.2007.02.022.
19. Rodríguez-Vita J, Sánchez-Galán E, Santamaría B, et al. Essential role of TGF-β/Smad pathway on statin dependent vascular smooth muscle cell regulation. PLoS One. 2008;3(12):e3959. DOI:10.1371/journal.pone.0003959.
20. Lefer AM, Tsao P, Aoki N, Palladino MA. Mediation of cardioprotection by transforming growth factor-beta. Science.1990;249(4964):61-4. DOI:10.1126/science.2164258.
21. Border WA, Noble NA. Transformation growth factor β in tissue fibrosis. N Engl J Med. 1994;331(19):153-8. DOI:10.1056/NEJM199411103311907.
22. Kuwahara F, Kai H, Tokuda K, et al. Transforming growth factor-β function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats. Circulation. 2002;106(1):130- 5. DOI:10.1161/01.CIR.0000020689.12472.E0.
23. Li JM, Brooks G. Differential protein expression and subcellular distribution of TGFβ1, β2, and β3 in cardiomyocytes during pressure overload-induced hypertrophy. J Mol Cell Cardiol. 1997;29(8):2213- 24. DOI:10.1006/jmcc.1997.0457.
24. Bujak M, Ren G, Kweon HJ, et al. Essential role of Smad3 in infarct healing and in the pathogenesis of cardiac remodeling. Circulation. 2007;116(19):2127-38. DOI:10.1161/CIRCULATIONAHA.107.704197.
25. Xia Y, Lee K, Li N, D. et al. Characterization of the inflammatory and fibrotic response in a mouse model of cardiac pressure overload. Histochem Cell Biol. 2009;131(4):471-81. DOI:10.1007/s00418-008-0541-5.
26. Ali M, Girgis S, Hassan A, et al. Inflammation and coronary artery disease: From pathophysiology to Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Coron Artery Dis. 2018;29(5):429-37. DOI:10.1097/MCA.0000000000000625.
27. Nidorf SM, Fiolet ATL, Eikelboom JW, et al. The effect of low-dose colchicine in patients with stable coronary artery disease: The LoDoCo2 trial rationale, design, and baseline characteristics. Am Heart J. 2019;218:46-56. DOI:10.1016/j.ahj.2019.09.011.
28. Bagi Z, Feher A, Cassuto J, Microvascular responsiveness in obesity: Implications for therapeutic intervention. Br J Pharmacol. 2012;165(3):544-60. DOI:10.1111/j.1476-5381.2011.01606.x.
29. Pasqualetto MC, Tuttolomondo D, Cutruzzolà A, et al. Human coronary inflammation by computed tomography: Relationship with coronary microvascular dysfunction. Int J Cardiol. 2021;336:8-13. DOI:10.1016/j.ijcard.2021.05.040.
Review
For citations:
Pakhtusov N.N., Yusupova A.O., Zhbanov K.A., Shchedrygina A.A., Privalova E.V., Belenkov Yu.N. Evaluation of Fibrosis Markers as a Potential Method for Diagnosing Non-Obstructive Coronary Artery Disease in Patients with Stable Coronary Artery Disease. Rational Pharmacotherapy in Cardiology. 2022;18(6):630-637. (In Russ.) https://doi.org/10.20996/1819-6446-2022-11-01