Molecular, Endocrine, and Genetic Mechanisms of Arterial Calcification

Abstract

Pathologists have recognized arterial calcification for over a century. Recent years have witnessed a strong resurgence of interest in atherosclerotic plaque calcification because it: 1) can be easily detected noninvasively; 2) closely correlates with the amount of atherosclerotic plaque; 3) serves as a surrogate measure for atherosclerosis, allowing preclinical detection of the disease; and 4) is associated with heightened risk of adverse cardiovascular events. There are two major types of calcification in arteries: calcification of the media tunica layer (sometimes called Mönckeberg's sclerosis), and calcification within subdomains of atherosclerotic plaque within the intimal layer of the artery. There are important similarities and differences between these two entities. Of particular interest are increasing parallels between cellular and molecular features of arterial calcification and bone biology, and this has led to accelerating interest in understanding how and why bone-like mineral deposits may form in arteries. Here, we review the two major pathological types of arterial calcification, the proposed models of calcification, and endocrine and genetic determinants that affect arterial calcification. In addition, we highlight areas requiring further investigation.

Association of Thoracic Aorta Calcium Score With Exercise Blood Pressure Response and Clinical Outcomes in Elderly Individuals: Differential Impact of Aorta Calcification Compared With Coronary Artery Calcification

“…Aortic calcification reflects calcification in both the intimal and medial tunica layers of the artery, in contrast to coronary artery calcification, which generally occurs in the intimal layer of an atherosclerotic plaque 27. Medial calcification is not associated with atherosclerotic plaque, but is strongly associated with aging, diabetes, and end‐stage renal disease 28. Interestingly, in the current study, TACS and CACS demonstrated different prognostic roles in the elderly without obstructive CAD.…”

Imaging Cardiovascular Calcification

“…Ten‐year Framingham risk scores for CVD and death are related to 18 F‐NaF uptake 64. Other retrospective studies have shown positive correlations between arterial 18 F‐NaF uptake and CVD risk factors, including age, sex, hypertension, hypercholesterolemia, and diabetes mellitus, further supporting the notion that 18 F‐NaF PET imaging may improve CVD risk stratification 98, 100, 101, 102, 104, 111, 112, 113, 114…”

“…The exposed hydroxyapatite crystal surface area in the arterial wall and early active vascular calcification is below the resolution of CT, but the evolving powdery microcalcification is readily identified by 18 F‐NaF (Figure 3). 22, 98, 106 Dweck et al106 investigated histological markers of active calcification (ie, tissue nonspecific alkaline phosphatase and osteocalcin) in aortic stenosis and found a strong correlation between 18 F‐NaF uptake and these markers, thus confirming that 18 F‐NaF PET imaging provides information about the activity of calcification and might differentiate biologically active calcification from stable calcification. Alizarin Red staining also confirmed 18 F‐NaF uptake in areas of microcalcification17 (Figure 4).…”

“…Additionally, Jeziorska et al observed that the arterial calcification microenvironment has a histochemical resemblance to areas of osteogenesis and bone remodeling (eg, the foci of osteoid matrix, osteocytes, and thin bone trabeculae) 96. Modern histopathologic research further confirmed this hypothesis and demonstrated that cells in areas of vascular calcification are derived from osteoclastic and osteoblastic cells 97, 98…”

“…The results demonstrated that baseline 18 F‐fluoride uptake correlated strongly with the subsequent rate of progression in aortic valve calcium score and independently predicts cardiovascular death and aortic valve replacement after age and sex adjustments (hazard ratio: 1.55; 95% CI, 1.33–1.81; P <0.001). Furthermore, Beheshti et al98 found that 18 F‐NaF PET/CT allowed the detection of early molecular and cellular calcification in atherosclerotic plaque and may provide highly relevant information about the state of calcified plaque before macroscopic calcification can be detectable by standard CT techniques. These findings suggest that this modality may allow earlier risk stratification and therapeutic intervention in patients with asymptomatic atherosclerosis.…”