Calcification in atherosclerosis: bone biology and chronic inflammation at the arterial crossroads

Abstract

Dystrophic or ectopic mineral deposition occurs in many pathologic conditions, including atherosclerosis. Calcium mineral deposits that frequently accompany atherosclerosis are readily quantifiable radiographically, serve as a surrogate marker for the disease, and predict a higher risk of myocardial infarction and death. Accelerating research interest has been propelled by a clear need to understand how plaque structure, composition, and stability lead to devastating cardiovascular events. In atherosclerotic plaque, accumulating evidence is consistent with the notion that calcification involves the participation of arterial osteoblasts and osteoclasts. Here we summarize current models of intimal arterial plaque calcification and highlight intriguing questions that require further investigation. Because atherosclerosis is a chronic vascular inflammation, we propose that arterial plaque calcification is best conceptualized as a convergence of bone biology with vascular inflammatory pathobiology.

Figures

Fig. 1.

(A) Calcification (center circled region) in the proximal left anterior descending coronary artery shown on an electron beam computed tomography transverse section. Consecutive high-resolution non-contrast-enhanced computed tomography images are acquired from the top to the bottom of the heart to visualize arterial calcification. Regions of high computed tomography density representing calcium deposits are summed, and a calcium score is derived. This score is then used to ascertain the risk of future cardiac events. (B and C) Human coronary artery sections prepared by using undecalcified methylmethacrylate embedding and sectioning procedures and stained with Goldner–Masson trichrome stain. Two distinct patterns of calcification are evident: large focal mineral deposition (turquoise, black arrow in B and C) and a fine speckled pattern (purple arrow in B).

Fig. 2.

Interrelationships between development and stability of plaque and calcium deposition. There are significant uncertainties among three key plaque-related variables (presence, progression, and stability of plaque) and the variables that radiographic calcium scans measure (presence, quantity, and change in quantity of calcium deposits). The circle in the center represents possible sequences of events in the natural history of an individual plaque. Known risk factors and other injurious stimuli, such as infectious agents, initiate plaque formation. Plaque begins to grow and might proceed toward luminal obstruction and eventually cause a clinical event. The period of growth occurs at highly variable rates and tends to be episodic, with long periods of latency during which growth of the plaque may be minimal. At any point during the period of stable plaque growth, an individual lesion can become vulnerable, after which plaque rupture and thrombosis can result. Plaque rupture can lead directly to a clinical event but can also be silent and may itself be innocuous. Reorganization and remodeling may ensue with or without a supervening clinical event. Reorganization of ruptured plaque may proceed to a period of relatively rapid plaque progression but can also stabilize and remain stabilized indefinitely. From there, a period of dormancy may ensue, or, alternatively, further development of plaque can again take any of the pathways described above and result in a clinical event or remain clinically silent. This cycle repeats itself at each lesion site somewhat independently of what is occurring even at closely adjacent plaques. Calcification can begin at any point in this process. The sequence of events in plaque development does not seem to directly determine calcium deposition or progression of arterial calcification, in that there is no evidence that calcification develops episodically; instead, calcification appears to develop more linearly over time (large blue arrow on right). When an arterial tree such as the coronary arterial circulation is considered, overall plaque burden also proceeds roughly linearly and approximates the quantity of calcification. Time between and duration of individual stages of plaque development tend to be highly variable and more nonlinear than calcification.

Fig. 3.

Mechanism of osteogenesis, showing the major genes, growth factors, and signaling pathways culminating in fully mature chondrocytes, osteoblasts, and osteoclasts. Inhibitory influences are shown in red. Considerable ontogenetic plasticity is retained at each step but appears to diminish as terminally differentiated cellular phenotypes are approached. The proposed mechanism of arterial calcification appears to involve many of the same components.