Rachel H. Mackey Lakshmi Venkitachalam Kim Sutton-Tyrrell
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pa., USA
Vascular calcification can occur in either the intimal or medial layers of the arterial wall. Intimal calcification is associated with atherosclerosis, which is characterized by lipid accumulation, inflammation, fibrosis and development of focal plaques. Medial calcification is associated with arteriosclerosis, i.e. age- and metabolic disease-related structural changes in the arterial wall which are related to increased arterial stiffness. It has been hypothesized that vascular calcification, either intimal or medial, may directly increase arterial stiffness. Alternatively, arterial stiffness may contribute to the development of calcification and focal plaque. Ample evidence (i.e. animal data and studies of diabetes and end-stage renal disease) has demonstrated that medial calcification of elastic fibers contributes to increased arterial stiffness. Evidence linking intimal calcification with arterial stiffness is less definitive, partly because it is very difficult to differentiate vascular calcification due to focal plaques (intimal) from medial calcification, and partly because the number of studies has been small. Conclusion: Current evidence supports that medial calcification is associated with increases in arterial stiffness. The association between intimal (atherosclerotic-associated) calcification and arterial stiffness is less definitive.
Copyright © 2007 S. Karger AG, Basel
The medium and large arteries are affected by two separate but related disease processes - atherosclerosis, which is characterized by lipid accumulation, inflammation, fibrosis and development of focal plaques, and arteriosclerosis, i.e. age- and metabolic disease-related structural changes in the arterial wall which are related to increased arterial stiffness. Vascular calcification can occur in the presence or absence of atherosclerosis. In the setting of atheroscle-
rosis, calcification of the intima occurs as a result of an inflammatory response to lipid accumulation and plaque formation. Medial calcification, as seen in arteriosclerosis, is driven by age-related changes in the vascular wall, elevated blood pressure (BP) and inflammation, among other factors. It has been hypothesized that vascular calcification of the medial layer, and possibly of the intimal layer, directly increases arterial stiffness. Conversely, stiffer arteries are less able to buffer the pulsatile blood flow, which increases the strain on arterial walls, contributing to injury and the development or progression of atheroma. These two processes of atherosclerosis (and intimal calcification) and arterial stiffening (arteriosclerosis and medial calcification) likely contribute to each other, accelerating the process of vascular damage. The purpose of this chapter is to review what is known about vascular calcification and its associations with arterial stiffness, to evaluate what conclusions are supported by current evidence.
Historically, vascular calcification was considered to be a passive degenerative process. However, recent human, animal and cell biological studies have demonstrated that vascular calcification is an actively regulated process similar to bone formation. For example, human vascular smooth muscle cells (VSMCs) have been shown to express many bone-regulating proteins, including osteopontin, matrix Gla protein, osteocalcin, osteonectin, collagen I and II, alkaline phosphatase, bone sialoprotein and bone morphogenic proteins . Intense interest in this evolving area has generated several comprehensive reviews [1-4], the details of which are beyond the scope of this chapter.
As previously noted, calcification of the arterial wall can occur either in the intima, as part of a focal atherosclerotic plaque, or in the medial layer in the absence of atherosclerotic plaque. These two forms of arterial calcifications differ in their morphological features and epidemiology and may differ in their clinical significance as discussed below.
Calcification of the medial layer of the arteries, which occurs in the absence of atheroma, has been recognized by pathologists for over a century, and has historically been referred to as 'Monckeberg's sclerosis'. Medial calcification typically occurs in lower limb arteries such as the femoral and tibial, but it is also a common finding in the aorta. Medial calcification is non-occlusive, but can occur in the same locations as calcification of focal plaques (intimal calcification.) Medial calcification increases with age, and is widespread in persons with metabolic disorders such as diabetes mellitus and end-stage renal disease (ESRD) [ 2]. Familial aggregation of medial artery calcification has been reported, suggesting a genetic component. Other risk factors include duration of dialysis, duration of diabetes, and diabetic nephropathy .
Medial calcification has a different morphology from that of intimal calcification, appearing first as linear deposits along elastic lamellae, and in more severe cases, forming a thick circumferential sheet of calcium apatite crystals (and even bone tissue) in the center of the medial layer, with VSMCs on both sides . On soft-tissue x-ray of the aorta and lower limbs, the appearance of medial calcification has been described as railroad tracks . Historically, medial artery calcification was believed to be clinically insignificant, but several large studies have now shown that it is associated with increased risk for CVD events, at least among diabetic and ESRD patients . In a recent study of ESRD patients by London et al. , patients with predominantly intimal (plaque-associated) calcification had the highest risk of CVD events; patients with only medial arterial calcification had an intermediate risk of events, and patients with no calcifications had the lowest CVD event risk. Those with in-timal calcification were older, and had higher levels of calcified common carotid artery (CCA) plaques, smoking, LDL cholesterol and CRP, more prevalent diabetes and atherosclerosis, and longer duration of dialysis. Patients with only medial artery calcification were similar in age to those with no calcifications, but had much longer duration of dialysis. Interestingly, medial artery calcification was less prevalent among black ESRD patients, similar to reported racial differences in coronary artery calcification.
As illustrated by London and colleagues , the epidemiology and clinical significance of intimal calcification, or calcification of focal plaques, may differ from that of medial calcification. Intimal calcium deposition in the context of atherosclerosis is mostly seen in the coronaries and large arteries like the aorta and is associated with lipids, macrophages (inflammation) and VSMCs . Intimal calcification occurs in at least two distinct patterns: (1) discrete or punctate in the basal portion of the intima, and (2) diffuse calcification throughout the intima. The discrete pattern is thought to reflect an active, organized and regulated process because hematopoietic marrow, osteo-clast-like cells, osteoblasts and other proteins normally associated with bone formation are seen . Histopathological techniques that avoid decalcification have revealed a second, more diffuse pattern of calcification. This type of calcification can be missed by imaging modalities because the overall tissue density is similar to the adjacent, non-calcified tissue. It has been speculated that in intimal calcification, the calcification process begins with a diffuse pattern which undergoes reorganization to form the more discrete pattern [1, 2].
Quantification of intimal calcification in the coronaries has been shown to be a good marker of atherosclerotic burden. To date, the strongest determinants identified are older age, male sex and race/ethnicity, with higher calcification levels among white compared to black individuals , Traditional risk factors such as LDL and total cholesterol have been predictors of coronary calcification burden, with smoking, BP and BMI showing slightly stronger relationships. Coronary calcification scores are much higher in men, but interestingly, this gender difference does not apply to the aorta, where autopsy studies have shown a more similar level of atheroma between men and women .
Coronary artery calcification is strongly indicative of atheroma; however, an absence of coronary calcification does not rule out the presence of non-calcified plaques. This has raised the question of whether calcification may be involved in the stabilization of plaques that would otherwise be vulnerable to rupture. The role of calcium deposition in this process is contradictory, depending on the stage of atherosclerosis. When calcium deposition occurs as superficial nodules in early stages of plaque formation, it can protrude, causing rupture , Studies have also shown that plaque rupture is most likely at interfaces between materials of different stiffness; however, as the lesion progresses, deposition of calcium is thought to impart resistance to stress in proportion to its quantity .
A number of imaging modalities, both invasive and non-invasive, are currently available to detect and quantify vascular calcification. These include plain radiographs (x-ray), ultrasound techniques (intravascular, transthoracic and transesophageal), computed tomography (CT) and magnetic resonance imaging. Of these modalities, x-ray and ultrasound have some ability to distinguish medial and intimal calcification, but provide only semiquantitative assessments ; moreover, intravascular ultrasound is invasive and transthoracic and transesophageal methods provide limited or no view of coronary arteries.
Intimal calcification has been studied in the aorta, carotid and femoral arteries using B-mode ultrasound to identify and semiquantify echogenic plaques. Some studies have also used x-rays and plain CT to identify extra-coronary calcification, but with these modalities, authors have usually as sumed that they were measuring atherosclerotic calcification and have not always specified that they used a method that would exclude medial calcification from their results. A method of distinguishing between medial and intimal (plaque-associated) calcification on soft-tissue x-ray has been described, but it is user-dependent and provides only semiquantitative assessments .
An explosion of interest in calcification of the coronary arteries has been initiated by the recent development of electron-beam CT (EBT). The rapid scanning time (100 ms) of EBT has made it possible to obtain clear images of the coronary arteries without motion artifact. Most of the existing literature on coronary calcification has used EBT, although newer multidetector row spiral CT can also be used. 30-40 adjacent axial images of the heart are typically obtained with a 3- to 6-mm thickness. Trained 'readers' use software to quantify calcium area and density (calcification is detected when pixels >130 Houn-sfield units are observed.) Most frequently, summary scores have been calculated using Agatston's method, although more recently some have advocated the determination of volumetric calcification scores . EBT is not currently able to distinguish between medial and intimal calcification. However, coronary calcification is believed to primarily represent intimal calcification of focal plaques, since medial calcification is rare in the coronary arteries [2, 7].
Potential Mechanisms for Association between Arterial Calcification and Stiffness
Medial calcification is believed to directly increase arterial stiffness. The walls of large arteries contain collagen fibers, ensheathing elastic lamellae and VSMCs, all embedded in a non-fibrous matrix. The mechanical properties of the artery are determined mainly by the elastin and collagen components in the media of the artery, with smooth muscle cells also playing a role in vascular tone. With age, structural changes (remodeling) occur in the arterial wall including fragmentation and degeneration of elastin, increases in collagen, dilation of the artery and a thickening of the arterial wall . Animal models have shown that various components of the media, especially elastin, and other components of elastic fibers are prone to calcification . The net effect of these arteriosclerotic changes, including calcification of the elastic components of the medial layer, increases the stiffness of the arterial wall. In contrast, the most intuitive mechanism for a causal relationship between arterial stiffness and intimal calcification is that increased stiffness increases stress on the arterial wall, which makes it more prone to atherosclerosis and calcification.
In summary, when evaluating studies relating arterial stiffness to vascular calcification, it should be recognized that medial calcification is a distinct en tity from intimal calcification (calcified atheroma). The current consensus is that coronary calcification represents primarily atherosclerotic intimal calcification. Aortic calcification and calcification of the lower extremities may be medial calcification or a combination of medial and intimal calcification. This is especially true for groups such as the elderly, diabetics, and ESRD patients, who are especially prone to medial calcification. However, current imaging methods generally do not distinguish medial from intimal calcification, and both medial and intimal calcification are associated with increased risk of CVD. In addition, both intimal and medial calcification may be associated with higher arterial stiffness, although for different reasons, as discussed above.
Ideally, the association between arterial stiffness and vascular calcification would be evaluated separately for medial calcification (arteriosclerosis) versus intimal calcification (atherosclerosis or calcified plaque.) Fortunately, experimental models have the advantage of being able to specifically induce medial calcification in the absence of atheroma. Two different rat models of experimentally induced calcification of the medial elastic fibers of the aorta [13, 14] have demonstrated that an increase in medial calcification increases aortic stiffness, in parallel with an increase in collagen and decrease in elastin. Other evidence that medial calcification stiffens arteries comes from studies of lower limb arteries in diabetic patients, which have demonstrated that calcified arteries are rigid and have reduced blood flow . However, most human studies of arterial stiffness and calcification have not differentiated between medial (arteriosclerosis) and intimal (atherosclerotic) calcification, primarily due to limitations of non-invasive imaging techniques to distinguish between them. Therefore, we will discuss them below according to arterial site (extra-coronary vs. coronary), since the current consensus holds that coronary calcification represents primarily intimal calcification, whereas extracoronary calcification may be a combination of medial and intimal calcification. For arterial stiffness, our review includes only well-validated measures of large and medium elastic arterial stiffness, specifically: carotid-femoral pulse wave velocity (cfPWV), pulse pressure (PP), carotid distensibility, and the carotid incremental elastic modulus (E inc).
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