How does atherosclerotic plaque become calcified, and why?

Vascular calcification involves the crystallization of calcium/phosphate in the form of hydroxyapatoite in the extracellular matrix of the arterial wall. Vascular calcification is categorized into 3 main etiologies: (1) inflammatory/atherosclerotic (mostly intimal), (2) metabolic (mostly medial), and (3) genetic background (mostly medial). Several overlapping mechanisms trigger all three types of calcifications. Intimal coronary artery calcification simultaneously develops with the progression of atherosclerosis and has been recognized as a surrogate marker of atherosclerotic inflammatory vascular disease. Pathologically, atherosclerotic calcification initially occurs as microcalcifications (0.5 to 15 µm) and results in larger dense calcification, eventually forming sheet calcifications (>3 mm). Among the plaque types, the degree of calcification is the highest in fibrocalcific plaques, followed by healed plaque ruptures, and is the lowest in pathologic intimal thickening. Recent pathologic and imaging-based studies suggest that massive dense calcifications are usually associated with stable plaques, whereas microcalcifications are indicative of vulnerable plaques which may cause acute thrombotic events. Although the mechanisms of calcification are not fully elucidated, apoptotic inflammatory cells and smooth muscle cells, along with the induction of bone formation, play crucial roles in its initiation and progression. A deeper understanding of vascular calcification will improve the risk stratification and patient outcomes through the development of new therapies.