Prognostic Utility Of Novel Biomarkers in Aortic Valve Stenosis

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The aim of the present study was to evaluate plasma levels of chemerin, myeloperoxidase (MPO), fibroblast growth factor-21 (FGF-21), thioredoxin reductase-1 (TrxR1), and matrix metallopeptidase-9 (MMP-9) in acquired aortic valve (AoV) stenosis patients to determine correlations between the studied cellular factors, and also clarify the predictive values of these factors as biomarkers in AoV stenosis. AoV stenosis patients were classified into three groups: 17 patients with mild AoV stenosis; 19 with moderate and 15 with severe AoV stenosis. Twenty-four subjects without AoV stenosis were selected as a control group. Our findings suggest that AoV stenosis might be associated with increased chemerin, TrxR1, MPO, and FGF-21 levels in plasma. Moreover, these factors and also MMP-9 already reached statistically significantly elevated levels in the early stages of AoV stenosis, but MPO levels were more pronounced in patients with moderate and severe AoV stenosis. Chemerin was correlated with all of the studied cytokines; TrxR1 and MMP-9 were correlated with several other cellular factors. Our findings (by ROC analysis) suggest that MPO and chemerin might serve as specific and sensitive biomarkers for AoV stenosis without grading the severity, but, in relation to mild AoV stenosis, TrxR1, FGF-21, and MMP-9 also reached good or moderate levels as biomarkers. The cellular factors might serve as novel diagnostic and prognostic biomarkers in AoV stenosis patients, while chemerin and MPO may be more powerful.

Akahori, H., Tsujino, T., Masuyama, T., Ishihara, M. (2018). Mechanisms of aortic stenosis. J. Cardiol., 71 (3), 215–220.

Ali, O. A., Chapman, M., Nguyen, T. H., Chirkov, Y. Y., Heresztyn, T., Mundisugih, J., Horowitz, J. D. (2014). Interactions between inflammatory activation and endothelial dysfunction selectively modulate valve disease progression in patients with bicuspid aortic valve. Heart, 100 (10), 800–805.

Chen, B., Meng, L., Shen, T., Gong, H., Qi, R., Zhao, Y., Sun, J., Bao, L., Zhao, G. (2017). Thioredoxin attenuates oxidized low-density lipoprotein induced oxidative stress in human umbilical vein endothelial cells by reducing NADPH oxidase activity. Biochem. Biophys. Res. Commun., 490 (4), 1326–1333.

Cheng, P., Zhang, F., Yu, L., Lin, X., He, L., Li, X., Lu, X., Yan, X., Tan, Y., Zhang, C. (2016). Physiological and pharmacological roles of FGF21 in cardiovascular diseases. J. Diabetes Res., 2016, 1540267.

Couchie, D., Vaisman, B., Abderrazak, A., Mahmood, D. F. D., Hamza, M. M., Canesi, F., Diderot, V., El Hadri, K., Nègre-Salvayre, A., Le Page, A., Fulop, T., Remaley, A. T., Rouis, M. (2017). Human plasma thioredoxin-80 increases with age and in ApoE-/-mice induces inflammation, angiogenesis, and atherosclerosis. Circulation, 136 (5), 464–475.

El Hadri, K., Mahmood, D. F., Couchie, D., Jguirim-Souissi, I., Genze, F., Diderot, V., Syrovets, T., Lunov, O., Simmet, T., Rouis, M. (2012). Thioredoxin-1 promotes anti-inflammatory macrophages of the M2 phenotype and antagonizes atherosclerosis. Arterioscler. Thromb. Vasc. Biol., 32 (6), 1445–1452.

Fondard, O., Detaint, D., Iung, B., Choqueux, C., Adle-Biassette, H., Jarraya, M., Hvass, U., Couetil, J. P., Henin, D., Michel, J. B., Vahanian, A., Jacob, M. P. (2005). Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. Eur. Heart J., 26 (13), 1333–1341.

Heymans, S., Schroen, B., Vermeersch, P., Milting, H., Gao, F., Kassner, A., Gillijns, H., Herijgers, P., Flameng, W., Carmeliet, P., Van de Werf, F., Pinto, Y. M., Janssens, S. (2005). Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart. Circulation, 112 (8), 1136–1144.

Ji, Q., Lin, Y., Liang, Z., Yu, K., Liu, Y., Fang, Z., Liu, L., Shi, Y., Zeng, Q., Chang, C., Chai, M., Zhou, Y. (2014). Chemerin is a novel biomarker of acute coronary syndrome but not of stable angina pectoris. Cardiovasc. Diabetol., 13, 145.

Kammerer, A., Staab, H., Herberg, M., Kerner, C., Klöting, N., Aust, G. (2018). Increased circulating chemerin in patients with advanced carotid stenosis. BMC Cardiovasc. Disord., 18 (1), 65.

Kaur, J. L., Mattu, H. S., Chatha, K., Randeva, H. S. (2018). Chemerin in human cardiovascular disease. Vascul. Pharmacol., 110, 1–6.

Khan, A. A., Alsahli, M. A., Rahmani, A. H. (2018). Myeloperoxidase as an active disease biomarker: Recent biochemical and pathological perspectives. Med. Sci. (Basel), 6 (2). pii: E33.

Kim, J. B., Kobayashi, Y., Kuznetsova, T., Moneghetti, K. J., Brenner, D. A., O’Malley, R., Dao, C., Wu, J. C., Fischbein, M., Craig Miller, D., Yeung, A. C., Liang, D., Haddad, F., Fearon, W. F. (2018). Int. J. Cardiol., 270, 83–88.

Kunimoto, H., Kazama, K., Takai, M., Oda, M., Okada, M., Yamawaki, H. (2015). Chemerin promotes the proliferation and migration of vascular smooth muscle and increases mouse blood pressure. Amer. J. Physiol. Heart Circ. Physiol., 309 (5), H1017–H1028.

Lenart-Lipińska, M., Duma, D., Hałabiś, M., Dziedzic, M., Solski, J. (2016). Fibroblast growth factor 21 — a key player in cardiovascular disorders? Horm. Mol. Biol. Clin. Investig., 30 (2).

Lurins, J., Lurina, D., Tretjakovs, P., Mackevics,V., Lejnieks, A., Rapisarda, V., Baylon, V. (2018). Increased serum chemerin level to predict early onset of aortic valve stenosis. Biomed. Rep., 8 (1), 31–36.

Münch, J., Avanesov, M., Bannas, P., Säring, D., Krämer, E., Mearini, G., Carrier, L., Suling, A., Lund, G., Patten, M. (2016). Serum matrix metalloproteinases as quantitative biomarkers for myocardial fibrosis and sudden cardiac death risk stratification in patients with hypertrophic cardiomyopathy. J. Card. Fail., 22 (10), 845–850.

Nussbaum, C., Klinke, A., Adam, M., Baldus, S., Sperandio, M. (2013). Myeloperoxidase: A leukocyte-derived protagonist of inflammation and cardiovascular disease. Antioxid. Redox Signal, 18 (6), 692–713.

Perrotta, I., Sciangula, A., Aquila, S., Mazzulla, S. (2016). Matrix metalloproteinase-9 expression in calcified human aortic valves: A histopathologic, immunohistochemical, and ultrastructural study. Appl. Immunohistochem. Mol. Morphol., 24 (2), 128–137.

Planavila, A., Redondo-Angulo, I., Ribas, F., Garrabou, G., Casademont, J., Giralt, M., Villarroya, F. (2015a). Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc. Res., 106 (1), 19–31.

Planavila, A., Redondo-Angulo, I., Villarroya, F. (2015b). FGF21 and cardiac physiopathology. Front. Endocrinol. (Lausanne), 6, 133.

Savic-Radojevic, A., Pljesa-Ercegovac, M., Matic, M., Simic, D., Radovanovic, S., Simic, T. (2017). Novel biomarkers of heart failure. Adv. Clin. Chem., 79, 93–152.

Spiroglou, S. G., Kostopoulos, C. G., Varakis, J. N., Papadaki, H. H. (2010). Adipokines in periaortic and epicardial adipose tissue: Differential expression and relation to atherosclerosis. J. Atheroscler. Thromb., 17 (2), 115–130.

Stein, J. H, Korcarz, C. E., Hurst, R. T., Lonn, E., Kendall, C. B., Mohler, E. R., Najjar, S. S., Rembold, C. M., Post, W. S.; American Society of Echocardiography Carotid Intima-Media Thickness Task Force (2008). Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. J. Amer. Soc. Echocardiogr., 21, 93–111.

Vahanian, A., Iung, B. (2012). The new ESC/EACTS guidelines on the management of valvular heart disease. Arch. Cardiovasc. Dis., 105, 465–467.

van der Veen, B. S., de Winther, M. P., Heeringa, P. (2009). Myeloperoxidase: Molecular mechanisms of action and their relevance to human health and disease. Antioxid. Redox Signal, 11 (11), 2899–2937.

Wada, S., Sugioka, K., Naruko, T., Kato, Y., Shibata, T., Inoue, T., Inaba, M., Ohsawa, M., Yoshiyama, M., Ueda, M. (2013). Myeloperoxidase and progression of aortic valve stenosis in patients undergoing hemodialysis. J. Heart Valve Dis., 22 (5), 640–647.

Yamawaki, H., Kameshima, S., Usui, T., Okada, M., Hara. Y. (2012). A novel adipocytokine, chemerin exerts anti-inflammatory roles in human vascular endothelial cells. Biochem. Biophys. Res. Commun., 423 (1), 152–157.

Yao, Q., Song, R., Ao, L., Cleveland, J. C Jr., Fullerton, D. A., Meng, X. (2017). Neurotrophin 3 upregulates proliferation and collagen production in human aortic valve interstitial cells: a potential role in aortic valve sclerosis. Amer. J. Physiol. Cell Physiol., 312 (6), C697–C706.

Zhang, H., Liu, Q., Lin, J. L., Wang, Y., Zhang, R. X., Hou, J. B., Yu, B. (2018). Recombinant human thioredoxin-1 protects macrophages from oxidized low-density lipoprotein-induced foam cell formation and cell apoptosis. Biomol. Ther. (Seoul), 26 (2), 121–129.

Journal Information

CiteScore 2017: 0.22

SCImago Journal Rank (SJR) 2017: 0.127
Source Normalized Impact per Paper (SNIP) 2017: 0.211


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