SERIAL CHANGES IN THE LEVELS OF MATRIX METALLOPROTEINASE-3, -9, THEIR INHIBITORS AND INDICATORS OF MYOCARDIAL REMODELING IN PATIENTS WITH ACQUIRED HEART DISEASE UNDERGOING MITRAL VALVE REPLACEMENT

Background. The matrix metalloproteinase (MMP) system and their tissue inhibitors (TIMPs) act to control myocardial remodeling processes.

Aim. To evaluate serum levels of MMP-3, -9, TIMP-1,     -2 and their relationships with instrumental parameters of myocardial remodeling after isolated mitral valve replacement.

Methods. All patients enrolled into the mitral stenosis group (n = 24) and the mitral insufficiency group (n=24) underwent measurements of serum levels of MMP-3, -9, TIMP-1, -2 by solid-phase enzyme immunoassay before mitral valve replacement and 1 year after it.

Results. Initial elevated levels of MMP-9 correlated with the left ventricular ejection fraction and the integrated systolic remodeling index. One year after mitral valve replacement, MMP-9 levels decreased by 18.54% in the mitral insufficiency group and by 17.17% in the mitral stenosis group (p -0.05). The decrease was more pronounced with a significant increase in exercise tolerance.

Conclusion. The activation of MMP-9 is closely as-sociated with structural cardiac remodeling and severe changes in exercise tolerance in patients with isolated mitral valve disease.

1. Сторожанов Г.И., Тронина О.А., Гендлин Г.Е. Приобретенные пороки сердца. Некоторые особенности клинической картины и лечения в XXI веке. Сердечная недостаточность. 2009; Т. 10, 6: 335-341 [Storozhamv G.I., Tromm O.A., Gendlin G.E. Priobretennye poroki serdca. Nekotorye osobennosti klimcheskoj kartmy i lechenija v XXI veke. Serdechrnja nedostatochnost. 2009; T. 10, 6: 335-341. (Гп Russ)]

2. Briasoulis A., Tousoulis D., Papageorgiou N., Kampoli A.M., Androulakis E., Antoniades C., Tsiam is E., Latsios G., S tefarnd is C. Novel therapeu tic approaches targe tm g in atrix in etallopro tem ases in cardiovascular disease. Curr Top Med Chem. 2012; 12 (10): 1214-1221.

3. Abu El-Asrar A.M., Ahmad A., Bittoun E., Siddiquei M.M., Mohammad G., Mousa A., De Hertogh G., Opdenakker G. Differential expression and localization of human tissue mhibitors of metalloproteinases in proliferative diabetic retmopathy. Acta Ophthalmol. 2017. doi: 10.1111/aos.13451.

4. Masciantonio M.G., Lee C.K.S., Arpmo V., Mehta S., Gill S.E. The balaMe between metalloproteinases and TIMPs: critical regulator of microvascular endotheial cell function in health and disease. Prog Mol Biol Trarnl Sci. 2017; 147: 101-131. doi: 10.1016/bs.pmbts.2017.01.001.

5. Lurz J.A., Luecke C., Lang D., Besler C., Rommel K.P., Klmgel K., Kandolf R., Adams V., Schбne K., Hmdricks G., Schuler G., Linke A., Thiele H., Gutberlet M., Lurz P. CMR-Derived extracellular volume fraction as a marker for myocardial fibrosis: the importance of coexistmg myocardial. JACC Cardiovasc Imaging. 2017. doi: 10.1016/j.jcmg.2017.01.025.

6. Rao V.H., Karnal V., Stoupa S., Agrawal D.K. MMP-1 and MMP-9 regulate epidermal growth factor-dependent collagen loss in human carotid plaque smooth muscle cells. Physiol Rep. 2014; 2 (2): e00224. doi: 10.1002/phy2.224. eCollection 2014 Feb 1.

7. Печерина Т.Б., Груздева O.B., Кашталап B.B., Барбараш О.Л. Роль матриксных металлопротеиназ в оценке прогноза у больных инфарктом миокарда с подъемом сегмента ST в период пребывания в стационаре. Кардиология. 2013; 56 (6): 18-24 [Pecherma T.B., Gruzdeva O.V., Kashtalap V.V. Barbarash., O.L. The role of matrix metalloproteimses in assessmert: of progmsis in parients with ST-Elevation myocardial infarction during hospital stay. Kardiologija. 2013; 56 (6): 18-24. (Ш Russ)]

8. Garr R.J., Krasuski R.A., Eckart R.E., Wang A., Pierce C., Kisslo K.B., Harrison J.K., Bashore T.M. Peripheral blood levels of matrix metalloprotemases in patients referred for percutaneous balloon mitral valve commissurotomy. J Heart Valve Dis. 2006; 15 (3): 369-374.

9. Deschamps A.M., Spmale F.G. Matrix modulate and heart failure: raw concepts question old beliefs. Curr Opm Cardiol. 2005; 20 (3): 211-216.

10. Leong S.W., Soor G.S., Butany J., Herny J., Thangaroopan M., Leask R.L. Morphological imdmgs in 192 surgically excised native mitral valves. Can J Cardiol. 2006; 22 (12): 1055-1061.

11. BaMrjee T., Mukherjee S., Ghosh S., Biswas M., Dutta S., Pattari S., Chatterjee S., Bandyopadhyay A. Clmical significance of markers of collagen metabolism in rheumatic mitral valve disease. PLoS One. 2014; 9 (3): e90527. doi: 10.1371/joumal.pone.0090527. eCollection 2014.

12. Sivakumar P., Gupta S., Sarkar S., Sen S. Uregulate of lysyl oxidase and MMPs during cardiac remodeling in human dilatedcardiomyopathy. Mol Cell Biochem. 2008; 307 (1-2): 159-167. doi:10.1007/s11010-007-9595-2

13. Ducharme A., Frantz S., Aikawa M., Rabkin E., Lmdsey M., Rohde L.E., Schoen F.J., Kelly R.A., Werb Z., Libby P., Lee R.T. Targeted delete of matrix metalloproteimse-9 attenuates left ventricular enlargement and collagen accumulate after experimental myocardial infarction. J Clm Invest. 2000; 106: 55-62. doi: 10.1172/JCI8768

14. Zhu H., Zhang W., Guo C.H., Zhang G., Zhang W.D., Zhong M., Yang G.R., Ge Z.M., Zhang Y. Effects of matrix metalloprotemase-9 and tissue inhibitor-1 of metalloprotemase expression on atrial structural remodelmg during chronic atrial fibrillation. Zhonghua Yi Xue Za Zhi. 2005; 85 (1): 45-48.

15. Walther T., Schubert A., Falk V., Binnerr C., Kanev A., Bleiziffer S., Walther C., Doll N., Autschbach R., Mohr F.W. Regression of left ventricular hypertrophy after surgical therapy for aortic steMsis is associated with changes in extracellular matrix gene expression. Circulation 2001; 104 (12 Suppl 1): I54-158.

16. Jia Y., Hu D.N., Sun J., Zhou J. Correlations between MMPs and TIMPs levels in aqueous humor from high myopia and cataract parients. Curr Eye Res. 2017; 42 (4): 600-603. doi: 10.1080/02713683.2016.1223317.

17. Roten L., Nemoto S., Simsic J., Coker M.L., Rao V., Baicu S., Defreyte G., Soloway P.J., Zile M.R., Spinale F.G. Effects of geM deletion of the tissue mhibitor of the matrixmetalloprotemase-type 1 (TIMP-1) on left ventricular geometryand function in mice. J Mol Cell Cardiol. 2000; 32 (1): 109-120. doi:10.1006/jmcc.1999.1052

18. Jung K. Serum or plasma: what kmd of blood sample should be used to measure circulatmg matrix metalloprotemases and their mhibitors? J Neurotomunol 2005; 162: 1-2. doi:10.1016/j.jneuroim.2004.12.021

19. Schwartz G.G., Olsson A.G., Ezekowitz M.D., Gam P., Oliver M.F., Waters D., Zeiher A., Chaitman B.R., Leslie S., Stem T. Effects of atorvastatm on early recurred ischemic events in acute corornry syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285: 1711-1718.

20. Koh K., Son K.W., Ata J.Y., Jin D.K., Kim H.S., Choi Y.M., Kim D.S., Jeong E.M., Park G.S., Choi I.S., Shm E.K. Comparative effects of diet and statin on NO bioactivity and matrix metalloproteinases hypercholesterolemic patiert:s with coronary artery disease. Arterioscler Thromb Vasc Biol. 2002; 22: 9-23.