Calcification of bicuspid aortic valves.

Over the past decade, our concept of the pathogenesis of calcific aortic valve disease has undergone a major transformation. We now recognise that calcific valve disease is the end stage of an active disease process and is not caused by “wear and tear” of the valve tissue. Immunohistochemical studies of trileaflet aortic valves with varying degrees of valve stenosis have demonstrated the presence of inflammation, lipid infiltration, and production of proteins that mediate tissue calcification. These studies have established the presence of T lymphocytes and macrophages both in the early stages of this disease process and in valves with severe stenosis removed at surgery. 2 The inflammatory cell infiltrate is located in areas of subendothelial lipid infiltration on the aortic side of the valve leaflet with extension into the adjacent fibrosa, the dense collagenous layer of the leaflet that provides tensile strength. The focal presence of neutral lipid can be demonstrated with oil-red-O staining with specific immunohistochemical markers being consistent with infiltration of low density lipoprotein and lipoprotein Lp(a). In addition, there is evidence of lipid oxidation, as is seen in atherosclerotic lesions. 4 The interrelations between lipid infiltration, oxidation, and inflammation appear to be similar to the process of atherosclerosis. In addition, several proteins associated with tissue calcification have been localised in sclerotic and stenotic trileaflet aortic valves. In vitro hybridisation has shown that osteopontin is produced by a subset of lesion macrophages, while bone morphogenetic proteins 2 and 4 are expressed by myofibroblasts, in areas adjacent to lymphocyte infiltration. 6 Other evidence of an active disease process in calcific aortic valve disease includes up-regulation of adhesion molecules, expression of matrix metalloproteinase, and production of the large extracellular matrix glycoprotein, tenascin-C.