**5. Clinical implications**

Calcific aortic valve disease in individuals with severe aortic stenosis can progress quickly after presentation with symptoms, usually portending limited short-term survival (Turina et al., 1987). Clinical trials on medical therapy including statins have found little benefit and utility in forestalling disease progression, with no demonstrated impact on survival. Since the evidence suggests that inflammatory cells, particularly macrophages, play a crucial role in calcification, anti-inflammatory therapies may prevent development of arterial and valvular calcification. We and others have demonstrated that lipid lowering reduces inflammation (Aikawa et al., 1998; Aikawa et al., 2001; Chu et al., 2012; Libby and Aikawa, 2002; Libby et al., 2011). However, clinical trials (e.g. SALTIRE, SEAS, etc.) have failed to demonstrate that lipid lowering attenuates development of aortic stenosis. Preclinical findings suggest that macro‐ phage accumulation precedes calcific changes in arteries and valves while lesions with advanced calcification are often unassociated with macrophages (Aikawa et al., 2007a; Aikawa et al., 2007b). This may suggest that anti-inflammatory therapies need to be initiated early (Aikawa and Otto, 2012), and thus clinical trials involving patients who had been diagnosed with aortic stenosis due to advanced calcification did not show substantial benefits of lipid lowering therapy. To establish more effective therapies, it is crucial to better understand the complex mechanisms for aortic valve calcification. To identify individuals with subclinical aortic valve calcification and those with high probability or propensity of developing severe aortic valvular stenosis, methods for early detection of calcific changes (e.g., molecular imaging, biomarkers) need to be developed. National Institutes of Health of the United States of America has formed the Working Group of Calcific Aortic Valve Disease to facilitate basic research on this devastating global health threat and initiated federal funding (Rajamannan et al., 2011).

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