Histological analyses and imaging findings showed that asymptomatic carotid Vorinostat HDAC inhibitor lesions were significantly more calcified than symptomatic carotid lesions. Notably, they found a similar rate of bone formation in the most calcified lesions. Recent works have established the importance of microcalcifications in plaque stability, strongly suggesting that the presence of microcalcifications in the thin fibrous cap covering atherosclerotic lesions increase the risk of rupture. This is consistent with the present results: microcalcification may destabilize the lesions by introducing a mismatch at the interface between soft and hard calcified tissue, while highlyevolved large calcification could ultimately stabilize the lesion. Consequently, OM should not only be considered as a marker for highly-evolved lesions, but also as a qualitative and informative marker for plaque vulnerability. In contrast, OPG levels in humans correlate positively with the calcic Y-27632 dihydrochloride burden of the plaque and the severity of the cardiovascular disease. In bone tissue, OPG is secreted by osteoblasts and acts as a soluble decoy receptor for RANK-Ligand. As a result, osteoclast differentiation and activation and finally bone resorption are inhibited. Here, we consistently observed that asymptomatic carotid lesions, displaying OM, had the highest intraplaque OPG level. This high mineral presence within the plaque may ultimately result in a more stable phenotype. Taken together, these results suggest that an intense secretion of OPG in carotid plaques promotes the development of OM, which in turn stabilizes the lesion, leading to the asymptomatic phenotype. Previous works have shown different results. Straface et al. suggested that high serum OPG levels might be associated with plaque instability, however, if the plaques were histologicallyassessed regarding their vulnerability status, no information on the clinical symptoms of the patients were provided, limiting the clinical relevance of their conclusions. Similarly, Golledge et al. also observed elevated OPG levels in symptomatic carotid lesions, but no histological data regarding plaque vulnerability were provided. In contrast, we here provide both clinical and histological data of the carotid lesions as well as detailed imaging data analysis.