BACKGROUND: The study aimed to assess serum RANKL:OPG ratio, Dkk-1 and deposition of calcium in aortic valve in relation to the presence of concomitant coronary atherosclerosis in patients with symptomatic calcified aortic stenosis (CAS). METHODS: OPG, soluble RANKL and Dkk-1 were measured in 218 consecutive patients who were undergoing cardiac catheterization because of symptomatic CAS. Values of studied compounds were compared between patients without (Group A) and with (Group B) coronary atherosclerosis. Computed tomography derived Agatston score was assessed by using 256-slice CT. RESULTS: Presence of coronary atherosclerosis was related to significantly (p = 0.007) higher OPG and to significantly (p = 0.004) lower Dkk-1. Coronary atherosclerosis was also associated with a trend towards a decrease of RANKL. RANKL/OPG Ratios (mean (95% C.I.)) were: 20.04 (16.58; 24.23) in Group A and 12.69 (9.96; 16.17) in Group B, resp., p = 0.018). After adjustment, the difference in RANKL:OPG ratios was no longer significant. Multivariable regression underscored the significance of difference in Dkk-1 (pafter adjustement = 0.020). Group A patients had significantly higher Dkk-1, significantly higher deposition of calcium in aortic valve and were symptomatic in significantly younger age (p < 0.001) as compared to group B patients: Agatston score (mean (95% C.I.)) 4069.9 (3211.8; 5134.5) and 2413.5 (1821.3; 3198.1), p = 0.007. CONCLUSIONS: Dkk-1 and deposition of calcium in aortic valve differ significantly in relation to the presence/absence of coronary atherosclerosis in patients with symptomatic CAS. A positive association was found between Dkk-1 and calcium load in aortic valve in patients with symptomatic CAS and angiographically normal coronary arteries.

Cardiocentre 3rd Medical Faculty Charles University and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Radiology University Hospital Kralovske Vinohrady Prague Czech Republic

National Institute of Public Health Prague Czech Republic

See more in PubMed

Rajamannan NM, Bonow RO, Rahimtoola SH. Calcific aortic stenosis: an update. Nat Clin Pract Cardiovasc Med. 2007;4:254–62. doi: 10.1038/ncpcardio0827. PubMed DOI

Towler D. Vascular calcification: a perspective on an imminent disease epidemic. IBMS BoneKEy. 2008;5:41–58. doi: 10.1138/20080298. DOI

Rosenhek R, Binder T, Porenta G, Lang I, Christ G, Schemper M, et al. Predictors of outcome in severe, asymptomatic aortic stenosis. N Engl J Med. 2000;343:611–7. doi: 10.1056/NEJM200008313430903. PubMed DOI

Parolari A, Loardi C, Mussoni L, Cavallotti L, Camera M, Biglioli P, et al. Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention. Eur J Cardiothorac Surg. 2009;35:493–504. doi: 10.1016/j.ejcts.2008.11.033. PubMed DOI

Towler DA. Molecular and cellular aspects of calcific aortic valve disease. Circ Res. 2013;113:198–208. doi: 10.1161/CIRCRESAHA.113.300155. PubMed DOI PMC

Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ, et al. The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood. 2009;113:517–25. doi: 10.1182/blood-2008-03-145169. PubMed DOI PMC

Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O’Brien KD. Characterization of the early lesion of ‘degenerative’ valvular aortic stenosis: histological and immunohistochemical studies. Circulation. 1994;90:844–53. doi: 10.1161/01.CIR.90.2.844. PubMed DOI

European Perspectives in Cardiology Centres of excellence: the cardiocentre prague, czech republic. Circulation. 2008;118:f13–8. doi: 10.1161/CIRCULATIONAHA.108.189692. DOI

Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M, et al. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107:2181–4. doi: 10.1161/01.CIR.0000070591.21548.69. PubMed DOI PMC

Diarra D, Stolina M, Polzer K, Zwerina J, Ominsky MS, Dwyer D, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med. 2007;13:156–63. doi: 10.1038/nm1538. PubMed DOI

Rajamannan NM. Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(−/−) null mice. J Cell Biochem. 2012;113:1623–34. PubMed PMC

Yasuda H, Shima N, Nakagawa N, Yamaguchi K, Kinosaki M, Mochizuki S, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A. 1998;95:3597–602. doi: 10.1073/pnas.95.7.3597. PubMed DOI PMC

Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine Wnt signals. J Clin Invest. 2005;115:1210–20. doi: 10.1172/JCI24140. PubMed DOI PMC

O’Brien KD. Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more) Arterioscler Thromb Vasc Biol. 2006;26:1721–8. doi: 10.1161/01.ATV.0000227513.13697.ac. PubMed DOI

Wierzbicki A, Shetty C. Aortic stenosis: an atherosclerotic disease? J Heart Valve Dis. 1999;8:416–23. PubMed

Agmon Y, Khandheria BK, Meissner I, Sicks JR, O’Fallon WM, Wiebers DO, et al. Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study. J Am Coll Cardiol. 2001;38:827–34. doi: 10.1016/S0735-1097(01)01422-X. PubMed DOI

Banks LM, Lees B, MacSweeney JE, Stevenson JC. Effect of degenerative spinal and aortic calcification on bone density measurements in post-menopausal women: links between osteoporosis and cardiovascular disease? Eur J Clin Invest. 1994;24:813–7. doi: 10.1111/j.1365-2362.1994.tb02024.x. PubMed DOI

Hak AE, Pols HA, van Hemert AM, Hofman A, Witteman JC. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol. 2000;20:1926–31. doi: 10.1161/01.ATV.20.8.1926. PubMed DOI

Hjortnaes J, Butcher J, Figueiredo JL, Riccio M, Kohler RH, Kozloff KM, et al. Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J. 2010;31:1975–84. doi: 10.1093/eurheartj/ehq237. PubMed DOI PMC

Aicher A, Kollet O, Heeschen C, Liebner S, Urbich C, Ihling C, et al. The Wnt antagonist Dickkopf-1 mobilizes vasculogenic progenitor cells via activation of the bone marrow endosteal stem cell niche. Circ Res. 2008;103:796–803. doi: 10.1161/CIRCRESAHA.107.172718. PubMed DOI

Tian E, Zhan F, Walker R, Rasmussen E, Ma Y, Barlogie B, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma. N Engl J Med. 2003;349:2483–94. doi: 10.1056/NEJMoa030847. PubMed DOI

Butler JS, Murray DW, Hurson CJ, O’Brien J, Doran PP, O’Byrne JM. The role of Dkk1 in bone mass regulation: correlating serum Dkk1 expression with bone mineral density. J Orthop Res. 2011;29:414–8. doi: 10.1002/jor.21260. PubMed DOI

Price PA, June HH, Buckley JR, Williamson MK. Osteoprotegerin inhibits artery calcification induced by warfarin and by vitamin D. Arterioscler Thromb Vasc Biol. 2001;21:1610–6. doi: 10.1161/hq1001.097102. PubMed DOI

Shao JS, Cheng SL, Charlton-Kachigian N, Loewy AP, Towler DA. Teriparatide (human parathyroid hormone (1–34)) inhibits osteogenic vascular calcification in diabetic low density lipoprotein receptor-deficient mice. J Biol Chem. 2003;278:50195–202. doi: 10.1074/jbc.M308825200. PubMed DOI

Baron R, Rawadi G. Targeting the Wnt/beta-catenin pathway to regulate bone formation in the adult skeleton. Endocrinology. 2007;148:2635–43. doi: 10.1210/en.2007-0270. PubMed DOI

Yaccoby S, Ling W, Zhan F, Walker R, Barlogie B, Shaughnessy JD. Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in-vivo. Blood. 2006;109:2906–11. PubMed PMC