Features of The Dynamics of Profibrotic Markers and Regression of Left Ventricular Hypertrophy After Renal Denervation in Patients With Resistant Hypertension and Stenosing Atherosclerosis of the Coronary Arteries

Aim. To compare the changes in serum concentrations of matrix metalloproteinases (MMPs) and their tissue inhibitor (TIMP) to the dynamics of blood pressure (BP) and parameters of left ventricular hypertrophy (LVH) 6 months after renal denervation (RD) in patients with resistant arterial hypertension (RAH) and complicated coronary atherosclerosis.
Material and methods. In 22 RAH patients with complicated coronary atherosclerosis (revascularization and/or history of myocardial infarction (MI)), 24-hour BP monitoring, echocardiography, and measurement of blood MMPs and TIMP were performed at baseline and six months after RD. The comparison group consisted of 48 RAH patients without a history of coronary revascularization or MI.
Results. In 6 months after RD, BP was decreased comparably in both groups. In the group of complicated atherosclerosis, there were no significant changes in profibrotic markers or LVH parameters. Thus, at baseline and after 6 months, the values of the studied indicators were the following: left ventricular myocardial mass (LVMM) 233.1±48.1 and 243.0±52.0 g, LVMM index 60.6±14.5 and 62.8±10 .9 g/m2.7, proMMP-1 4.9 [2.1; 7.7] and 3.6 [2.0; 9.4]  ng/ml, MMP-2 290.4 [233.1; 352.5] and 352.2 [277.4; 402.9] ng/ml, MMP-9 220.6 [126.9; 476.7] and 263.5 [82.9; 726.2] ng/ml, TIMP-1 395.7 [124.7; 591.4] and 424.2 [118.2; 572.0] ng/ml, respectively. In the comparison group, on the contrary, there was a significant decrease in LVMM from 273.6±83.3 g to 254.1±70.4 g, LVMM index from 67.1±12.3 to 64.0±14.4 g/m2.7, proMMP-1 from 7.2 [3.6; 11.7] to 5.9 [3.5; 10.9] ng/ml, MMP-2 from 328.9 [257.1; 378.1] to 272.8 [230.2; 343.2] ng/ml, MMP-9 from 277.9 [137.0; 524.0] to 85.5 [34.2; 225.9] ng/ml, and the MMP-9/TIMP-1 ratio from 0.80 [0.31; 1.30] to 0.24 [0.07; 0.76]. The BP dynamics in this group was inversely correlated with MMP-2 at 6 months (r=-0.38), and the MMP-9/TIMP-1 ratio was correlated with LVMM and the LVMM index at baseline (r=0.39 and r=0.39) and at 6 months (r=0.37 and r=0.32). The change in TIMP-1 from 543.9 [277.5; 674.1] to 469.8 [289.7; 643.6] ng/ml was not significant (p=0.060).
Conclusion. In RAH patients with complicated coronary atherosclerosis, the dynamics of profibrotic biomarkers and LVH parameters after RD was absent despite the pronounced antihypertensive effect, probably due to the low reversibility of cardiovascular remodeling processes or more complex regulatory mechanisms of the MMP system.

1. Bassiouni W, Ali MAM, Schulz R. Multifunctional intracellular matrix metalloproteinases: implications in disease. The FEBS Journal. 2021;288(24):7162–82. DOI: 10.1111/febs.15701

2. Fontana V, Silva PS, Gerlach RF, Tanus-Santos JE. Circulating matrix metalloproteinases and their inhibitors in hypertension. Clinica Chimica Acta. 2012;413(7–8):656–62. DOI: 10.1016/j.cca.2011.12.021

3. Patrichi G, Patrichi A, Satala C-B, Sin AI. Matrix Metalloproteinases and Heart Transplantation—A Pathophysiological and Clinical View. Medicina. 2023;59(7):1295. DOI: 10.3390/medicina59071295

4. Euler G, Locquet F, Kociszewska J, Osygus Y, Heger J, Schreckenberg R et al. Matrix Metalloproteinases Repress Hypertrophic Growth in Cardiac Myocytes. Cardiovascular Drugs and Therapy. 2021;35(2):353–65. DOI: 10.1007/s10557-020-07138-y

5. Cui N, Hu M, Khalil RA. Biochemical and Biological Attributes of Matrix Metalloproteinases. Progress in Molecular Biology and Translational Science. 2017;147:1–73. DOI: 10.1016/bs.pmbts.2017.02.005

6. Ricard-Blum S. The Collagen Family. Cold Spring Harbor Perspectives in Biology. 2011;3(1):a004978. DOI: 10.1101/cshperspect.a004978

7. Wang X, Khalil RA. Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease. Advances in Pharmacology. 2018;81:241–330. DOI: 10.1016/bs.apha.2017.08.002

8. Hayashidani S, Tsutsui H, Ikeuchi M, Shiomi T, Matsusaka H, Kubota T et al. Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. American Journal of Physiology-Heart and Circulatory Physiology. 2003;285(3):H1229–35. DOI: 10.1152/ajpheart.00207.2003

9. López B, Ravassa S, González A, Zubillaga E, Bonavila C, Bergés M et al. Myocardial Collagen Cross-Linking Is Associated With Heart Failure Hospitalization in Patients With Hypertensive Heart Failure. Journal of the American College of Cardiology. 2016;67(3):251–60. DOI: 10.1016/j.jacc.2015.10.063

10. Gao Y, Bai X, Lu J, Zhang L, Yan X, Huang X et al. Prognostic Value of Multiple Circulating Biomarkers for 2-Year Death in Acute Heart Failure With Preserved Ejection Fraction. Frontiers in Cardiovascular Medicine. 2021;8:779282. DOI: 10.3389/fcvm.2021.779282

11. Falkovskaya A.Yu., Mordovin V.F., Pekarskiy S.E., Ripp T.M., Zyubanova I.V., Sitkova E.S. et al. Matrix metalloproteinases in patients with resistant hypertension and type 2 diabetes mellitus: relation with renal blood flow and kidney function. Arterial Hypertension. 2019;25(1):34–45. DOI: 10.18705/1607-419X-2019-25-1-34-45

12. Stakos DA, Tziakas DN, Chalikias GK, Mitrousi K, Tsigalou C, Boudoulas H. Associations Between Collagen Synthesis and Degradation and Aortic Function in Arterial Hypertension. American Journal of Hypertension. 2010;23(5):488–94. DOI: 10.1038/ajh.2010.2

13. Vacek T, Rahman S, Yu S, Neamtu D, Givimani S, Tyagi S. Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms. Vascular Health and Risk Management. 2015;11:173–83. DOI: 10.2147/VHRM.S68415

14. Lee JS, Basalyga DM, Simionescu A, Isenburg JC, Simionescu DT, Vya vahare NR. Elastin Calcification in the Rat Subdermal Model Is Accompanied by Up-Regulation of Degradative and Osteogenic Cellular Responses. The American Journal of Pathology. 2006;168(2):490–8. DOI: 10.2353/ajpath.2006.050338

15. Hopps E, Caimi G. Matrix metalloproteases as a pharmacological target in cardiovascular diseases. European Review for Medical and Pharmacological Sciences. 2015;19(14):2583–9. PMID: 26221886

16. Hansson J, Vasan RS, Ärnlöv J, Ingelsson E, Lind L, Larsson A et al. Biomarkers of Extracellular Matrix Metabolism (MMP-9 and TIMP-1) and Risk of Stroke, Myocardial Infarction, and Cause-Specific Mortality: Cohort Study. PLoS ONE. 2011;6(1):e16185. DOI: 10.1371/journal.pone.0016185

17. Schmieder RE, Mahfoud F, Mancia G, Azizi M, Böhm M, Dimitriadis K et al. European Society of Hypertension position paper on renal denervation 2021. Journal of Hypertension. 2021;39(9):1733–41. DOI: 10.1097/HJH.0000000000002933

18. Ionov M.V., Emelyanov I.V., Yudina Yu.S., Panarina S.A., Zverev D.A., Avdonina N.G. et al. Renal sympathetic denervation in patients with resistant hypertension. Results of long-term prospective follow-up. Arterial Hypertension. 2021;27(3):318–32. DOI: 10.18705/1607-419X-2021-27-3-318-332

19. Glybochko P.V., Svetankova A.A., Rodionov A.V., Maltseva A.S., Sulimov V.A., Fomin V.V. Renal denervation with a resistant arterial hypertension: the results of a five-year follow-up. Therapeutic Archive. 2018;90(9):88–91. DOI: 10.26442/terarkh201890988-91

20. Chichkova T.Yu., Mamchur S.E., Romanova M.P., Khomenko E.A. Renal denervation: a new life of the technology. Fundamental and Clinical Medicine. 2020;5(4):117–25. DOI: 10.23946/2500-0764-2020-5-4-117-125

21. Zyubanova I.V., Mordovin V.F., Falkovskaja A.Yu., Pekarsky S.E. Changes in ambulatory blood pressure monitoring data after renal denervation: 12-month follow-up. Siberian Medical Journal (Tomsk). 2015;30(3):41–4.

22. Gapon L.I., Mikova E.V., Krinochkin D.V., Savelyeva N.Yu., Zherzhova A.Yu., Aleksandrovich E.L. Renal artery denervation in patients with resistant arterial hypertension: clinical and organ-protective effect. Systemic Hypertension. 2021;18(3):153–60. DOI: 10.26442/2075082X.2021.3.201090

23. Falkovskaya A.Yu., Mordovin V.F., Pekarskiy S.E., Ripp T.M., Manukyan M.A., Lichikaki V.A. et al. Renal denervation as a new nephroprotective strategy in diabetic patients with resistant hypertension. Siberian Medical Journal (Tomsk). 2020;35(1):80–92. DOI: 10.29001/2073-8552-2020-35-1-80-92

24. Dörr O, Liebetrau C, Möllmann H, Mahfoud F, Ewen S, Gaede L et al. Beneficial effects of renal sympathetic denervation on cardiovascular inflammation and remodeling in essential hypertension. Clinical Research in Cardiology. 2015;104(2):175–84. DOI: 10.1007/s00392-014-0773-4

25. Zyubanova I.V., Mordovin V.F., Falkovskaya A.Yu., Pekarsky S.E., Ripp T.M., Lichikaki V.A. et al. The effects of renal denervation on dynamics of biochemical indicators of vascular fibrosis in patients with resistant hypertension. Siberian Medical Journal (Tomsk). 2016;31(2):18–22.

26. Kobalava Zh.D., Konradi A.O., Nedogoda S.V., Shlyakhto E.V., Arutyunov G.P., Baranova E.I. et al. Arterial hypertension in adults. Clinical guidelines 2020. Russian Journal of Cardiology. 2020;25(3):149–218. DOI: 10.15829/1560-4071-2020-3-3786

27. Schulz R. Intracellular Targets of Matrix Metalloproteinase-2 in Cardiac Disease: Rationale and Therapeutic Approaches. Annual Review of Pharmacology and Toxicology. 2007;47(1):211–42. DOI: 10.1146/annurev.pharmtox.47.120505.105230

28. Fletcher EK, Wang Y, Flynn LK, Turner SE, Rade JJ, Kimmelstiel CD et al. Deficiency of MMP1a (Matrix Metalloprotease 1a) Collagenase Suppresses Development of Atherosclerosis in Mice: Translational Implications for Human Coronary Artery Disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2021;41(5):e265–79. DOI: 10.1161/ATVBAHA.120.315837

29. Wang H, Wang J, Guo C, Luo W, Kleiman K, Eitzman DT. Renal Denervation Attenuates Progression of Atherosclerosis in Apolipoprotein E–Deficient Mice Independent of Blood Pressure Lowering. Hypertension. 2015;65(4):758–65. DOI: 10.1161/HYPERTENSIONAHA.114.04648

30. Wang Y, Dinh TN, Nield A, Krishna SM, Denton K, Golledge J. Renal Denervation Promotes Atherosclerosis in Hypertensive Apolipoprotein E-Deficient Mice Infused with Angiotensin II. Frontiers in Physiology. 2017;8:215. DOI: 10.3389/fphys.2017.00215

31. Su Y, Li H, Yan Z, Li M, Wei J, Zheng W et al. Renin-angiotensin system activation and imbalance of matrix metalloproteinase-9/tissue inhibitor of matrix metalloproteinase-1 in cold-induced stroke. Life Sciences. 2019;231:116563. DOI: 10.1016/j.lfs.2019.116563

32. Koike H, Katsuno M. Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights. Biomedicines. 2019;7(1):11. DOI: 10.3390/biomedicines7010011

33. Lopez B, Gonzalez A, Diez J. Role of matrix metalloproteinases in hypertension-associated cardiac fibrosis: Current Opinion in Nephrology and Hypertension. 2004;13(2):197–204. DOI: 10.1097/00041552-200403000-00008

34. Mordovin V, Falkovskaya A, Pekarskyi S, Semke G, Ripp T, Zyubanova I et al. Relationship between matrix metalloproteinases with cardiac structural and functional impairments in patients with resistant hypertension and type 2 diabetes mellitus. Journal of Hypertension. 2016;34(Suppl 1):e117. DOI: 10.1097/01.hjh.0000500175.00199.a8

35. Odenbach J, Wang X, Cooper S, Chow FL, Oka T, Lopaschuk G et al. MMP-2 Mediates Angiotensin II–Induced Hypertension Under the Transcriptional Control of MMP-7 and TACE. Hypertension. 2011;57(1):123–30. DOI: 10.1161/HYPERTENSIONAHA.110.159525

36. Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K et al. Targeted Deletion of Matrix Metalloproteinase 2 Ameliorates Myocardial Remodeling in Mice With Chronic Pressure Overload. Hypertension. 2006;47(4):711–7. DOI: 10.1161/01.HYP.0000208840.30778.00

37. Zyubanova I.V., Mordovin V.F., Pekarskiy S.E., Ripp T.M., Falkovskaya A.Yu., Lichikaki V.A. et al. Possible mechanisms of renal denervation long-term cardiac effects. Arterial Hypertension. 2019;25(4):423–32. DOI: 10.18705/1607-419X-2019-25-4-423-432

38. Ripp T.M., Pekarskiy S.E., Baev A.E., Ryabova T.R., Yaroslavskaya E.I., Falkovskaya A.Yu. et al. Comparative analysis of cardioprotective effects of two renal denervation techniques. Russian Journal of Cardiology. 2020;25(12):103–10. DOI: 10.15829/1560-4071-2020-3994