1887
Volume 2015, Issue 4
  • ISSN: 2305-7823
  • E-ISSN:

Abstract

Calcific aortic valve stenosis (CAVS) is seen in a large proportion of individuals over 60 years. It is an active process, influenced by lipid accumulation, mechanical stress, inflammation, and abnormal extracellular matrix turnover. Various biomarkers (BMs) are studied, as regards mechanisms, diagnosis and prognosis. In the calcified valves calcium deposition, elastin fragmentation and disorganization of cellular matrix were assessed, together with expression of OPN, OPG, osteocalcin (OCN) and RL2.

We prospectively studied the following serum BMs in 60 patients with CAVS and compared them to 20 healthy controls, free from any cardiac disease: Matrix metalloproteinases (MMP) 2 and 9 and tissue inhibitor of metalloproteinase 1 (TIMP1), which regulate collagen turnover, inflammatory factors, i.e. tumor necrosis factor a (TNFa), interleukin 2 (IL2), transforming growth factor β1 (TGF-β1) which regulates fibrosis, fetuin-A (fet-A), osteopontin (OPN), osteoprotegerin (OPG), sclerostin (SOST), and relaxin-2 (RL2) which positively or negatively regulate calcification. Monocyte chemoattractant protein 1 (MCP-1) which regulates migration and infiltration of monocytes/macrophages was also studied as well as malondialdehyde (MDA) an oxidative marker. Extent of tissue valve calcification (Alizarin Red stain) was negatively correlated with tissue elastin, and RL2, and positively correlated with tissue OCN and serum TIMP1 and MCP-1 and negatively with MMP9.

Tissue OCN was positively correlated with OPN and negatively with the elastin. Tissue OPN was negatively correlated with elastin and OPG. Tissue OPN OPG and RL2 were not correlated with serum levels In the serum we found in patients statistically lower TIMP1, fet-A and RL2 levels, while all other BMs were higher compared to the healthy group. Positive correlations between SOST and IL2, OPG and MDA but negative with TNFa and OPN were found; also MMP9 was negatively correlated with TNFa and MCP-1 was negatively correlated with TIMP1. We found that many BMs expressing calcification, collagen breakdown, or formation, and inflammation are increased in the valve tissue and in the serum of patients with CAVS as compared with healthy group. Our findings may give new insights towards diagnosis but also therapy. Thus antisclerostin, and antiflammatory agents could be tried for preventing aortic calcification progression.

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2015-11-13
2020-02-17
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References

  1. Towler DA. Molecular and cellular aspects of calcific aortic valve disease. Circ Res. 2013 Jul 5; 113:2:198208.
    [Google Scholar]
  2. Chester AH, El-Hamamsy I, Butcher JT, Latif N, Bertazzo S, Yacoub MH. The living aortic valve: From molecules to function. Glob Cardiol Sci Pract. 2014 Jan 29; 2014:1:5277.
    [Google Scholar]
  3. Sainger R, Grau JB, Branchetti E, Poggio P, Lai E, Koka E, Vernick WJ, Gorman RC, Bavaria JE, Ferrari G. Comparison of transesophageal echocardiographic analysis and circulating biomarker expression profile in calcific aortic valve disease. J Heart Valve Dis. 2013 Mar; 22:2:156165.
    [Google Scholar]
  4. Stewart BF, Siscovick D, Lind BK, Gardin JM, Gottdiener JS, Smith VE, Kitzman DW, Otto CM. Clinical factors associated with aortic valve calcification. J Am Col Card. 1997 Mar 1; 29:3:630634.
    [Google Scholar]
  5. Lindroos M, Kupari M, Heikkilä J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly. J Am Coll Card. 1993 Apr; 21:5:12201225.
    [Google Scholar]
  6. Mohler ER 3rd, Gannon F, Reynolds C, Zimmerman R, Keane MG, Kaplan FS. Bone formation and inflammation in cardiac valves. Circulation. 2001 Mar 20; 103:11:15221528.
    [Google Scholar]
  7. Olsson M, Dalsgaard CJ, Haegerstrand A, Rosenqvist M, Rydén L, Nilsson J. Accumulation of T-lymphocytes and expression of IL-2 receptors in nonrheumatic aortic valve stenosis. J Am Coll Card. 1994 Apr; 23:5:11621170.
    [Google Scholar]
  8. Wallby L, Janerot-Sjöberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in nonrheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspidaortic valves. Heart. 2002 Oct; 88:4:348351.
    [Google Scholar]
  9. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of degenerative aortic stenosis. Histological and immunohistochemical studies. Circulation. 1994 Aug; 90:2:844853.
    [Google Scholar]
  10. Helske S, Kupari M, Lindstedt KA, Kovanen PT. Aortic valve stenosis: an active atheroinflammatory process. Curr Opin Lipidol. 2007 Oct; 18:5:483491.
    [Google Scholar]
  11. Jian B, Narula N, Li QY, Mohler ER 3rd, Levy RJ. Progression of aortic valve stenosis:TGF-beta1 is present in calcified aortic valve cusps and promotes aortic valve interstitial cell calcification via apoptosis. Ann Thorac Surg. 2003 Feb; 75:2:465466, discussion 465-6.
    [Google Scholar]
  12. Kaden JJ, Dempfle CE, Grobholz R, Tran HT, Kiliç R, Sarikoç A, Brueckmann M, Vahl C, Hagl S, Haase KK, Borggrefe M. IL-1 beta promotes matrixmetalloproteinase expression and cell proliferation in calcific aortic valve stenosis. Atherosclerosis. 2003 Oct; 170:2:205211.
    [Google Scholar]
  13. Villar AV, Llano M, Cobo M, Expósito V, Merino R, Martín-Durán R, Hurlé MA, Nistal JF. Gender differences of echocardiographic and gene expression patterns in human pressure overload left ventricular hypertrophy. J Mol Cell Cardiol. 2009 Apr; 46:4:526535.
    [Google Scholar]
  14. Ix JH, Chertow GM, Shlipak MG, Brandenburg VM, Ketteler M, Whooley MA. Fetuin-A and kidney function in persons with coronary artery disease: data from the Heart and Soul Study. Nephrol DialTransplant. 2006 Aug; 21:8:21442151.
    [Google Scholar]
  15. Weikert C, Stefan N, Schulze MB, Pischon T, Berger K, Joost HG, Häring HU, Boeing H, Fritsche A. Plasma fetuin-a levels and the risk of myocardial infarction and ischemic stroke. Circulation. 2008 Dec 9; 118:24:25552562.
    [Google Scholar]
  16. Mukhopadhyay S, Pandit BN, Saran RK, Mazumdar K, Yusuf J, Minhas HS, Trehan V, Tyagi S. Systemic and local levels of fetuin-a in calcified mitral valves of rheumatic heart disease. J Heart Valve Dis. 2014 Jan; 23:1:5565.
    [Google Scholar]
  17. Wang AY, Woo J, Lam CW, Wang M, Chan IH, Gao P, Lui SF, Li PK, Sanderson JE. Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol Dial Transplant. 2005 Aug; 20:8:16761685.
    [Google Scholar]
  18. Mohty D, Côté N, Pibarot P, Fournier D, Pépin A, Audet A, Després JP, Mathieu P. Reduced Fetuin A serum levels is associated with faster stenosis progression and increased valvular calcification in elderly patients with aortic stenosis. J Clinic Experiment Cardiol. 2011; 11::8.
    [Google Scholar]
  19. Cho HJ, Cho HJ, Kim HS. Osteopontin: a multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep. 2009 May; 11:3:206213.
    [Google Scholar]
  20. Yu PJ, Skolnick A, Ferrari G, Heretis K, Mignatti P, Pintucci G, Rosenzweig B, Diaz-Cartelle J, Kronzon I, Perk G, Pass HI, Galloway AC, Grossi EA, Grau JB. Correlation between plasma osteopontin levels and aortic valve calcification: potential insights into the pathogenesis of aortic valve calcification and stenosis. J Thorac Cardiovasc Surg. 2009 Jul; 138:1:196199.
    [Google Scholar]
  21. Gössl M, Mödder UI, Atkinson EJ, Lerman A, Khosla S. Osteocalcin expression by circulating endothelial progenitor cells in patients with coronary atherosclerosis. J Am Coll Cardiol. 2008 Oct; 52:16:13141325.
    [Google Scholar]
  22. Bjerre M. Osteoprotegerin (OPG) as a biomarker for diabetic cardiovascular complications. Springerplus. 2013 Dec 6; 2::658.
    [Google Scholar]
  23. D'Amelio P, Isaia G, Isaia GC. The osteoprotegerin/rank/Rankl system: A bone key to vascular disease. J Endocrinol Invest. 2009; 32:4 Suppl:69.
    [Google Scholar]
  24. Lind M, Schumacker B, Søballe K, Keller J, Melsen F, Bünger C. Transforming growth factor-beta enhances fracture healing in rabbit tibiae. Acta Orthop Scand. 1993 Oct; 64:5:553556.
    [Google Scholar]
  25. Sefat F, Denyer MC, Youseffi M. Imaging via widefield surface plasmon resonance microscope for studying bone cell interactions with micropatterned ECM proteins. J Microsc. 2011 Mar; 241:3:282290.
    [Google Scholar]
  26. Jian B, Jones PL, Li Q, Mohler ER 3rd, Schoen FJ, Levy RJ. MMPs-2 is associated with tenacin-C in calcific aortic valve. Am J Path. 2001 Jul; 159:1:321327.
    [Google Scholar]
  27. Satta J, Melkko J, Pöllänen R, Tuukkanen J, Pääkkö P, Ohtonen P, Mennander A, Soini Y. Progression of human aortic valve stenosis is associated with tenascin-C expression. J Am Coll Cardiol. 2002 Jan; 39:1:96101.
    [Google Scholar]
  28. Jones PL, Crack J, Rabinovitch M. Regulation of tenascin-C, a vascular smooth muscle cell survival factor that interacts with the alpha v beta 3 integrin to promote epidermal growth factor receptor phosphorylation and growth. J Cell Biol. 1997 Oct 6; 139:1:279293.
    [Google Scholar]
  29. Cowan KN, Jones PL, Rabinovitch M. Regression of hypertrophied rat pulmonary arteries in organ culture is associated with suppression of proteolytic activity, inhibition of tenascin-C, and smooth muscle cell apoptosis. Circ Res. 1999 May 28; 84:10:12231233.
    [Google Scholar]
  30. Galis ZS, Muszynski M, Sukhova GK, Simon-Morrissey E, Unemori EN, Lark MW, Amento E, Libby P. Cytokine-stimulated human vascular smooth muscle cells synthesize a complement of enzymes required for extracellular matrix digestion. Circ Res. 1994 Jul; 75:1:181189.
    [Google Scholar]
  31. Fondard O, Detaint D, Iung B, Choqueux C, Adle-Biassette H, Jarraya M, Hvass U, Couetil JP, Henin D, Michel JB, Vahanian A, Jacob MP. Extracellular matrix remodelling in human aortic valve disease: the role of matrix metalloproteinases and their tissue inhibitors. Eur Heart J. 2005 Jul; 26:13:13331341.
    [Google Scholar]
  32. Edep ME, Shirani J, Wolf P, Brown DL. Matrix metalloproteinase expression in nonrheumatic aortic stenosis. Cardiovasc Pathol. 2000 Sep–Oct; 9:5:281286.
    [Google Scholar]
  33. Brandenburg VM1 , Kramann R, Koos R, Krüger T, Schurgers L, Mühlenbruch G, Hübner S, Gladziwa U, Drechsler C, Ketteler M. Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study. BMC Nephrol. 2013 Oct 10; 14::219.
    [Google Scholar]
  34. Koos R, Brandenburg V, Mahnken AH, Schneider R, Dohmen G, Autschbach R, Marx N, Kramann R. Sclerostin as a potential novel biomarker for aortic valve calcification: an in-vivo and ex-vivo study. J Heart Valve Dis. 2013 May; 22:3:317325.
    [Google Scholar]
  35. Kastellanos SS, Toumpoulis IK, Aggeli C, Zezas S, Chlapoutakis E, Kastellanos S, Stefanadis CI. Time course of C-reactive protein, tumour necrosis factor-alpha and monocyte chemoattractant protein-1 following the surgical treatment of patients with aortic valve stenosis. Hellenic J Cardiol. 2007 Jan–Feb; 48:1:514.
    [Google Scholar]
  36. Gonzalez-Quesada C, Frangogiannis NG. Monocyte chemoattractant protein-1/CCL2 as a biomarker in acute coronary syndromes. Curr Atheroscler Rep. 2009 Mar; 11:2:131138.
    [Google Scholar]
  37. Wallby L, Janerot-Sjöberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart. 2002 Oct; 88:4:348351.
    [Google Scholar]
  38. Moreno PR, Astudillo L, Elmariah S, Purushothaman KR, Purushothaman M, Lento PA, Sharma SK, Fuster V, Adams DH. Increased macrophage infiltration and neovascularization in congenital bicuspid aortic valve stenosis. Thorac Cardiovasc Surg. 2011 Oct; 142:4:895901.
    [Google Scholar]
  39. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation. 2007 Feb 27; 115:8:949952.
    [Google Scholar]
  40. Braunwald E. Biomarkers in heart failure. N Engl J Med. 2008 May 15; 358:20:21482159.
    [Google Scholar]
  41. Beckmann E, Grau JB, Sainger R, Poggio P, Ferrari G. Insights into the use of biomarkers in calcific aortic valve disease. J Heart Valve Dis. 2010 Jul; 19:4:441452.
    [Google Scholar]
  42. Parenica J, Nemec P, Tomandl J, Ondrasek J, Pavkova-Goldbergova M, Tretina M, Jarkovsky J, Littnerova S, Poloczek M, Pokorny P, Spinar J, Cermakova Z, Miklik R, Malik P, Pes O, Lipkova J, Tomandlova M, Kala P. Prognostic utility of biomarkers in predicting of one-year outcomes in patients with aortic stenosis treated with transcatheter or surgical aortic valve implantation. Plos one. 2012 Dec; 7:12:e48851.
    [Google Scholar]
  43. Kaden JJ, Bickelhaupt S, Grobholz R, Haase KK, Sarikoç A, Kiliç R, Brueckmann M, Lang S, Zahn I, Vahl C, Hagl S, Dempfle CE, Borggrefe M. Receptor activator of nuclear factor kappa B ligand and osteoprotegerin regulate aortic valve calcification. J Mol Cell Cardiol. 2004 Jan; 36:1:5766.
    [Google Scholar]
  44. Brecht A, Bartsch C, Baumann G, Stangl K, Dschietzig T. Relaxin inhibits early steps in vascular inflammation. Regul Pept. 2011 Jan 17; 166:1–3:7682.
    [Google Scholar]
  45. Mu X, Urso ML, Murray K, Fu F, Li Y. Relaxin regulates MMP expression and promotes satellite cell mobilization during muscle healing in both young and aged mice. Am J Pathol. 2010 Nov; 177:5:23992410.
    [Google Scholar]
  46. Lee KW, Everett TH 4th, Rahmutula D, Guerra JM, Wilson E, Ding C, Olgin JE. Pirfenidone prevents the development of a vulnerable substrate for atrial fibrillation in a canine model of heart failure. Circulation. 2006 Oct 17; 114:16:17031712.
    [Google Scholar]
  47. Cardin S, Pelletier P, Libby E, Le Bouter S, Xiao L, Kääb S, Demolombe S, Glass L, Nattel S. Marked differences between atrial and ventricular gene-expression remodeling in dogs with experimental heart failure. J Mol Cell Cardiol. 2008 Dec; 45:6:821831.
    [Google Scholar]
  48. Hoit BD, Takeishi Y, Cox MJ, Gabel M, Kirkpatrick D, Walsh RA, Tyagi SC. Remodeling of the left atrium in pacing-induced atrial cardiomyopathy. Mol Cell Biochem. 2002 Sep; 238:1–2:145150.
    [Google Scholar]
  49. LeMaire SA, Wang X, Wilks JA, Carter SA, Wen S, Won T, Leonardelli D, Anand G, Conklin LD, Wang XL, Thompson RW, Coselli JS. Matrix metalloproteinase in ascending aortic aneurysms: bicuspid versus trileaflet aortic valves. J Surg Res. 2005 Jan; 123:1:4048.
    [Google Scholar]
  50. Arasu A, Cawthon PM, Lui LY, Do TP, Arora PS, Cauley JA, Ensrud KE, Cummings SR. Study of Osteoporotic Fractures Research Group. Serum sclerostin and risk of hip fracture in older Caucasian women. J Clin Endocrinol Metab. 2012 Jun; 97:6:20272032.
    [Google Scholar]
  51. Claes KJ, Viaene L, Heye S, Meijers B, d'Haese P, Evenepoel P. Sclerostin: Another vascular calcification inhibitor? J Clin Endocrinol Metab. 2013 Aug; 98:8:32213228.
    [Google Scholar]
  52. Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, Stolina M, Kostenuik PJ, Demer LL. Osteoprotegerin inhibits vascular calcification without affecting atherosclerosis in ldlr(-/-) mice. Circulation. 2008 Jan 22; 117:3:411420.
    [Google Scholar]
  53. Miller JD, Weiss RM, Heistad DD. Calcific aortic valve stenosis: methods, models, and mechanisms. Circ Res. 2011 May 27; 108:11:13921412.
    [Google Scholar]
  54. Warburton DE, Nicol CW, Gatto SN, Bredin SS. Cardiovascular disease and osteoporosis: balancing risk management. Vasc Health Risk Manag. 2007; 3:5:673689.
    [Google Scholar]
  55. Nokhbehsaim M1, Eick S, Nogueira AV, Hoffmann P, Herms S, Fröhlich H, Jepsen S, Jäger A, Cirelli JA, Deschner J. Stimulation of MMP-1 and CCL2 by NAMPT in PDL cells. Mediators Inflamm. 2013; 2013::437123.
    [Google Scholar]
  56. Ueland T, Aukrust P, Dahl CP, Husebye T, Solberg OG, Tønnessen T, Aakhus S, Gullestad L. Osteoprotegerin levels predict mortality in patients with symptomatic aortic stenosis. J Intern Med. 2011 Nov; 270:5:452460.
    [Google Scholar]
  57. Isoda K, Matsuki T, Kondo H, Iwakura Y, Ohsuzu F. Deficiency of interleukin-1 receptor antagonist induces aortic valve disease in BALB/c mice. Arterioscler Thromb Vasc Biol. 2010 Apr; 30:4:708715.
    [Google Scholar]
  58. Lewiecki EM. Role of sclerostin in bone and cartilage and its potential as a therapeutic target in bone diseases. Ther Adv Musculoskelet Dis. 2014 Apr; 6:2:4857.
    [Google Scholar]
  59. Quemerais-Durieu MA1 , Kerlan V, Chabre O. [Therapeutic innovation in osteoporosis (antisclerostin antibody and denosumab)]. Ann Endocrinol (Paris). 2011 Oct; 72:Suppl 1:S15S22.
    [Google Scholar]
  60. Filippatos G, Teerlink JR, Farmakis D, Cotter G, Davison BA, Felker GM, Greenberg BH, Hua T, Ponikowski P, Severin T, Unemori E, Voors AA, Metra M. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J. 2014 Apr; 35:16:10411050.
    [Google Scholar]
  61. Khanna D, Clements PJ, Furst DE, Korn JH, Ellman M, Rothfield N, Wigley FM, Moreland LW, Silver R, Kim YH, Steen VD, Firestein GS, Kavanaugh AF, Weisman M, Mayes MD, Collier D, Csuka ME, Simms R, Merkel PA, Medsger TA, Sanders ME Jr, Maranian P, Seibold JR. A Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Relaxin in the Treatment of Systemic Sclerosis with Diffuse Scleroderma. Arthritis Rheum. 2009 April; 60:4:11021111.
    [Google Scholar]
  62. Shetty R, Girerd N, Côté N, Arsenault B, Després JP, Pibarot P, Mathieu P. Elevated proportion of small, dense low-density lipoprotein particles and lower adiponectin blood levels predict early structural valve degeneration of bioprostheses. Cardiology. 2012; 121:1:2026.
    [Google Scholar]
  63. Yeghiazaryan K, Skowasch D, Bauriedel G, Schild HH, Golubnitschaja O. Degenerative valve disease and bioprostheses: risk assessment, predictive diagnosis, personalised treatments. EPMA J. 2011 Mar; 2:1:91105.
    [Google Scholar]
  64. Ferrari G, Sainger R, Beckmann E, Keller G, Yu PJ, Monti MC, Galloway AC, Weiss RL, Vernick W, Grau JB. Validation of plasma biomarkers in degenerative calcific aortic stenosis. J Surg Res. 2010 Sep; 163:1:1217.
    [Google Scholar]
  65. Nigam V, Sievers HH, Jensen BC, Sier HA, Simpson PC, Srivastava D, Mohamed SA. Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves. J Heart Valve Dis. 2010 Jul; 19:4:459465.
    [Google Scholar]
  66. Yanagawa B, Lovren F, Pan Y, Garg V, Quan A, Tang G, Singh KK, Shukla PC, Kalra NP, Peterson MD, Verma S. miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis. J Thorac Cardiovasc Surg. 2012 Jul; 144:1:256262.
    [Google Scholar]
  67. Gerber IL, Stewart RA, Hammett CJ, Legget ME, Oxenham H, West TM, French JK, White HD. Effect of aortic valve replacement on c-reactive protein in nonrheumatic aortic stenosis. Am J Cardiol. 2003 Nov 1; 92:9:11291132.
    [Google Scholar]
  68. Askevold ET, Gullestad L, Aakhus S, Ranheim T, Tønnessen T, Solberg OG, Aukrust P, Ueland T. Secreted Wnt modulators in symptomatic aortic stenosis. J Am Heart Assoc. 2012 Dec; 1:6:e002261.
    [Google Scholar]
  69. Mathieu P, Després JP, Pibarot P. The ‘valvulo-metabolic’ risk in calcific aortic valve disease. Can J Cardiol. 2007 Oct; 23:Suppl B:32B39B.
    [Google Scholar]
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  • Article Type: Research Article
Keyword(s): aortic valve stenosis , biomarkers , calcification , relaxin-2 and Sclerostin
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