Calcific aortic valve stenosis, the most frequent heart valve disorder in developed countries, is an actively regulated process with similarities to bone formation. Fetuin-A has recently been identified as a potent circulating inhibitor of calcification. While several studies involving patients with end-stage renal disease have shown an association between low serum fetuin-A and cardiovascular calcification, nothing is known about fetuin-A serum levels in non-renal patients with calcific aortic valve stenosis. Furthermore, while fetuin-A has been localized in calcified areas of atherosclerotic arteries, data about fetuin-A deposition in stenotic aortic valves are unavailable at present. Serum fetuin-A levels were determined in patients with (n=31) and without (n=28) calcified aortic valve stenosis by ELISA. Creatinine and CRP levels were determined and glomerular filtration rate (GFR) was calculated by the MDRD formula. Immunohistochemistry for fetuin-A was performed on human calcified stenotic (n=14) and control (n=8) aortic valves using a monoclonal antibody. Serum fetuin-A levels were lower in patients with calcific aortic stenosis as compared to the control group (1.41+/-0.33 versus 1.57+/-0,27 mg/dl; p=0.046). This difference was particularly evident in individuals with a normal GFR >or=60 ml/min (1.36+/-0.24 versus 1.63+/-0.27 mg/dl; p=0.007). Furthermore, specific staining of fetuin-A was found in stenotic valves but not in healthy control valves. The data suggest a role of fetuin-A in the pathogenesis calcific aortic valve stenosis independently of the renal function and support the concept that mechanisms of calcium homeostasis are involved in the development of calcific aortic stenosis.