Giving Calcification Its Due: Recognition of a Diverse Disease

Abstract

Cardiovascular calcification is a growing burden and a leading predictor of and contributor to acute cardiovascular events. Arterial calcification associates with a 4-fold increase in cardiovascular events, and patients with aortic valve calcification have a 5-year event-free survival rate of only 26%,1,2 worse than that of many cancers. Despite massive healthcare costs and extensive research efforts, effective therapeutic strategies remain elusive. Cardiovascular calcification, often generalized as one disease, is in reality a multifaceted disorder that occurs in diverse milieus as a result of multiple, interacting pathogenic processes. Herein, we explore these variables and propose a set of guidelines for studying cardiovascular calcification. Although vascular and valvular calcification share several risk factors, only ≈25% to 50% of patients with aortic valve calcification also present with significant coronary artery disease,3 suggesting that common risk factors initiate divergent disease processes. ### Vascular Versus Valvular Calcification Differences in prevalence are not unexpected, particularly when these 2 tissues are closely examined. Unlike the collagen and elastin-rich medial layer of the vasculature, the aortic valve has a complex trilayered architecture consisting of collagen, elastin, and proteoglycans. Calcific nodules occur almost exclusively on the stiffer, collagen-rich aortic side of the valve. Calcification takes the form of either hyperphosphatemic medial mineralization or inflammatory-driven intimal calcification, and although these discrete forms may coexist, they tend to be mechanistically distinct. Only 10% to 13% of valves and vasculature exhibit mature bone formation, while the remainder is dystrophic mineralization.4 The resident cell populations responsible for maintaining these tissue structures are also dissimilar: instead of vascular smooth muscle cells, valve interstitial cells populate the aortic valve. Valve interstitial cells are normally a quiescent fibroblastic population that may undergo myofibrogenesis, osteogenesis, and chondrogenesis during disease, thereby adding complexity to valvular calcification. The valve is particularly sensitive to biomechanical stimuli—calcific nodule formation occurs in …