Vol 1, No 1 (2013)

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Correlation between coronary and valve

calcification: Review of current evidence

Rachel Nicoll Bsc

Department of Public Health and Clinical Medicine and Heart Centre, umeå

university. umeå, sweden

Introduction

Coronary artery calcification (CAC) has become known as

sub-clinical atherosclerosis and is widely used as a marker for

coronary artery disease (CAD) and is an independent predictor

of cardiovascular (CV) events and all-cause mortality

1

_{. CAC}

has been much studied as an entity in itself, while calcification

of other arteries and cardiac valves has been considered

of less direct clinical value, despite potential relationships

between them. Aortic valve calcification (AVC) is the most

frequent cause of aortic stenosis in the west and is an actively

regulated process

2

_{, while mitral annular calcification (MAC)}

is a degenerative process that can occasionally have serious

clinical consequences, such as mitral stenosis, cerebral emboli,

arrhythmia and bacterial endocarditis

3

_.

this article examines the pattern of relationships between CAC

and calcification of other arteries and the aortic and mitral

valves. We also looked at the potential relationships between

calcification locations and risk factors, although we did not

conduct a rigorous analysis of the individual risk factors from

these studies.

Multiple arterial beds

In two studies of asymptomatic patients, the presence of

calcification in one artery correlated with presence in other

arteries, although with respect to the coronary artery the

correlation was only modest

4,5

_{. Calcification appeared first in}

the coronary artery but was widespread in the elderly with the

highest prevalence in the aorta

6

_{. Male gender, hypertension}

and age were risk factors for systemic calcification

7,8

_{, while in}

postmenopausal women the premenopausal LDL concentration

may also be a risk factor.

The aorta

A number of studies comparing calcification of the aorta and

other arteries show an association between prevalence, extent

or progression of aortic calcification and CAC

9,10,11,12,13,14,15,16,17 ,18,19,20,21,22,23

_{, irrespective of symptoms or the area of the aorta}

that was scanned. there was also a correlation between the

prevalence of aortic and carotid calcification

24

_{. the prevalence}

and extent of aortic calcification generally appears to be higher

than the prevalence and extent of CAC

25

_{and a substantial}

proportion of those with abdominal aortic calcification had zero

CAC

26,27

_{; nevertheless, one study found that in symptomatic}

patients CAC was more prevalent than thoracic aorta

calcification (tAC)

28

_{. In symptomatic Chinese, the abdominal}

aorta and aortic arch displayed the highest prevalence and

extent of calcium deposition, followed by the descending and

ascending aortas

29

_{, while in asymptomatic subjects calcification}

progression may be faster in the abdominal than in the thoracic

aorta

30

_{. Aortic baseline values of zero tended to remain at zero}

at follow-up

31

_{, suggesting that calcium begets calcium in the}

aorta as well as the coronary artery.

Although age was more strongly associated with aortic

calcification than CAC in some studies

32,33

_{, Wong et al found}

that in asymptomatic subjects CAC prevalence was higher

than tAC prevalence until age 50, when there was a rapid

increase in tAC to coincide with CAC prevalence by the 8th

decade (>80%)

34

_{. Although some studies show no gender}

prevalence with respect to calcification of the aorta as a

whole, the prevalence of abdominal aortic calcification (AAC)

was significantly higher among women, although they had a

substantially lower prevalence of CAC at all age groups

35,36

and indeed two studies found the severity of tAC was more

Abstract

We carried out a review of the correlation between calcification of different arteries and valves and their risk factors to determine

the extent of the association. We found a strong correlation between calcification presence, extent and progression between

different arterial beds and the aortic valve, suggesting that calcification is a systemic diffuse disease, affecting the arterial tree as a

whole. Despite this strong association, a comparison between coronary artery calcification (CAC) and calcification of other arteries

may not be strictly valid, since only intimal calcification is seen in the coronary artery while other arteries may also contain medial

calcification, with current scanning modalities being incapable of detecting the difference. Furthermore the pathogenesis of each

type may be different.

Calcification seems to appear first in the coronary artery in younger adults but may be more prevalent in the aorta in the elderly,

although the incidence is notably higher in the abdominal aorta among women. Mitral annulus calcification (MAC) occurs less

frequently than aortic valve calcification (AVC) in asymptomatic subjects only. MAC is correlated with calcification of the aorta and

advanced MAC is found with higher CAC but there is little relationship with AVC and calcification of other arterial beds. As with the

coronary artery, in the aorta and aortic valve, calcium begets calcium. Although age, male gender and possibly systolic hypertension

are most frequently associated with arterial calcification, there is little consistency for other conventional risk factors and MAC and

abdominal aortic calcification may be more prevalent among postmenopausal women. When the presence of CAC is factored in as a

risk factor for calcification of the other arteries, multivariate analysis shows no additional significant risk factors except age.

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strongly associated with CAC presence in women than men

37,38

_.

Nevertheless, a score of >2000 for calcification of the aortic

arch in asymptomatic subjects was seen twice as often in

men as in women and the correlation with CAC was stronger

in men

39

_{. the correspondence of conventional CV risk factors}

between CAC and aortic calcification was not generally

assessed, although there was little consistency in risk factors

for aortic calcification between studies, with only systolic

hypertension occurring regularly (although curiously diastolic

pressure

40

_{and smoking}

41

_{showed an inverse association in two}

studies).

Other arteries

Irrespective of symptoms, good correlation has been found

between calcification prevalence in the carotid, subclavian, renal

and peripheral arteries and that of the coronary artery

42,43,44

_and

aorta

45,46,47

_{, although a large study investigating the subclavian}

artery in asymptomatic subjects found that correlation with CAC

was only borderline

48

_{. In asymptomatic subjects, the presence}

of calcium in the abdominal aorta had the highest sensitivity for

any renal artery calcification (94.5%)

49

_{. Risk factors were rarely}

assessed and generally it is only age and male gender, possibly

with hypertension, that are consistently associated

50,51,52

_,

although, curiously, low body mass index and low diastolic

blood pressure were risk factors for presence and extent

respectively of subclavian artery calcification

53

_.

Arterial calcification - Discussion

there appears to be a consistent correlation between CAC

prevalence, extent and progression and calcification in other

vascular beds, although the strength of the association

varies. In the few studies investigating calcification in

non-coronary beds, there are also correlations between the aorta,

carotid and renal arteries. From the undoubted association

between calcification prevalence at various sites, it is clear

that calcification is a systemic diffuse disease, affecting the

arterial tree as a whole. In most studies, calcification seems to

appear first in the coronary artery in younger adults but could

be more prevalent in the aorta in the elderly, suggesting that

age is a stronger risk factor for aortic calcification. Nevertheless,

a higher prevalence of early aortic and carotid calcification

in asymptomatic women has been reported, suggesting that

in younger women the measurement of aortic, particularly

abdominal aortic, rather than coronary calcium may provide

the earliest and most accurate evaluation of the underlying

atherosclerotic burden

54,55

_.

In general, age and male gender were fairly consistent risk

factors for calcification, although this was not the case for

the aorta, where there was either no gender prevalence or

in specific areas of calcification one gender predominated.

However, there appears to be little uniformity with respect to

other conventional risk factors, although systolic hypertension

was among the most common. Furthermore, CAC was such a

strong marker of aortic calcification that in multivariate analyses

it eliminated all conventional risk factors except age

56

_.

Because the contributors to calcification in each artery may be

different

57

_{, it has been suggested that an index of measures}

may provide a more consistent association with risk factors

than any individual measure of calcification

58

_{. Nevertheless,}

several authors have pointed out that since CAC is almost

always found in the intima, while calcification in other arteries

may be found in either the intima or the media, the summation

of the calcium scores may not be a fair comparison of extent of

calcification between arteries since intimal calcification cannot

be differentiated from medial calcification on any scanning

modality. Furthermore, while CAC is commonly described

as a form of subclinical atherosclerosis, this may not be an

appropriate description for medial calcification in the other

arteries, since this is more a reflection of the oxidative damage

and uraemia of type 2 diabetes and chronic kidney disease.

59,60,61

_{Moreover, others have speculated that it is the different}

geometries and various local tensile and shear stresses which

might contribute to different susceptibilities between arteries for

calcium deposition

62

_.

Combined valve calcification

there is little correlation between calcification presence in the

two valves; in symptomatic patients and Japanese women

with osteoporosis there was no correlation

63,64

_although

in asymptomatic subjects there was moderate correlation

between calcification of the two annuli

65

_{. Nevertheless, studies}

of asymptomatic subjects show a good correlation between

calcification of the combined annuli and most vascular beds

66,67

_,

with calcification of the thoracic aorta being the strongest

correlation

68

_{, while renal artery calcification presence appears}

to be associated with AVC but not with MAC

69

_{. In asymptomatic}

subjects, aortic valve calcification is more prevalent than

MAC, with incidence up to three times higher

70,71

_{, while in}

symptomatic patients there were almost equal numbers with

MAC and AVC

73

_{. Coronary artery calcified and mixed plaques}

(but not non-calcified plaques) were found to be more extensive

in those with combined valve calcification than those with no

valve calcification or isolated AVC . extensive CAC does not

always imply valve calcification, however; in a small study

5% of patients with a CAC score of >400 had no cardiac

calcification

74

_{. Few of these studies looked at conventional CV}

risk factors, although there was always a positive correlation

between age and cardiac calcium scores

75,76,77,78

_{; only}

hypertension was significantly associated with calcification of

both annuli in asymptomatic subjects

79

_{, while in symptomatic}

patients, diabetes and hypertension were associated with

combined valve calcification

80

_.

Aortic valve

Most studies of asymptomatic subjects show that AVC

prevalence and progression is independently associated with

prevalence and increasing severity of CAC, with 38% of those

with CAC >/=400 also having AVC

81,82,83,84

_{, with higher}

follow-up CAC scores also predicting de novo AVC

85

_{. With respect to}

calcification of the aortic root, one study found that CAC was

a weak predictor, with tAC presence having the highest odds

ratio

86

_{. AVC scores increased faster with higher baseline AVC}

score, showing that calcium begets calcium in the aortic valve

as well as arteries

87

_{. similar results were seen in symptomatic}

patients, with a significant association between prevalence of

AVC and prevalence of aortic calcification and CAC and extent

of CAC

88,89,90,91

_{. A smaller study found no correlation between}

baseline AVC and CAC although there was a significant

correlation between the extent of annual progression of CAC

and AVC

92

_{. In high risk hypertensives, AVC was an independent}

predictor of CAC>300 and triple vessel coronary calcification

93

_.

Age is an independent predictor of AVC presence in most

studies

94,95,96,97,98,99,100,101

_{, but does not appear to be predictive}

of progression , . Prevalence rates between AVC and CAC

grew more similar with age in asymptomatic subjects, with

CAC appearing around seven years before AVC . studies

are divided over whether male gender is also a risk factor

for AVC

105,106,107,108,109

_{. Although there are associations}

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symptomatic and asymptomatic subjects, there is no

consistency among studies.

Mitral valve

studies of asymptomatic subjects by Allison et al found that

calcification of all arterial beds was a significant predictor of

MAC with the exception of the coronary, iliac and renal arteries,

while the presence of abdominal aorta calcification gave the

highest odds for MAC

110,111

_{. Nevertheless, other studies have}

found a strong association between the presence and extent of

MAC and presence and progression of CAC

112,113

_{, although the}

prevalence of CAC appears to be much higher than prevalence

of MAC (50% vs 9%)

114

_{. In symptomatic patients, MAC showed}

a sensitivity and specificity 71% and 56% respectively for

detecting a CAC score >/=400, although advanced MAC

(>/=5mm) had markedly reduced sensitivity but improved

specificity

115

_{. studies of hypertensives with additional risk}

factors show mixed results but all agree that advanced MAC

was an independent predictor of a CAC score >300

116,117,118

_and

presence of MAC is associated with tAC

119

_.

In the few studies that considered gender, there was no

difference between men and women in the association of MAC

with CAC in asymptomatic subjects

120

_{, or as a risk factor for}

MAC

121,122

_{, although in symptomatic patients MAC, particularly}

advanced MAC, was more prevalent among postmenopausal

women

123,124

_{. Age, hypertension and diabetes were fairly}

consistent risk factors, irrespective of symptoms

125,126

_,

although some studies found no associated conventional risk

factors

127,128

_.

Valvular Calcification - Discussion

there is a clear association between the prevalence, extent and

progression of aortic valve and arterial calcification in multiple

arterial beds but the association with CAC, although significant,

is only modest, and symptomatic patients with high CAC may

not necessarily have valve calcification. some studies show no

relationship between MAC and CAC, while only in symptomatic

patients is advanced MAC predictive of higher CAC, although

the association between MAC and calcification of other arterial

beds, particularly the aorta, appears stronger. there is negligible

relationship between calcification of the two valves and in

asymptomatic subjects, MAC occurs much less frequently than

AVC but this difference may disappear as symptoms develop.

AVC scores increased faster with higher baseline AVC, showing

that in the aortic valve, calcification also begets calcification.

CAC appears before AVC in asymptomatic subjects but the

prevalence is similar in the elderly. studies appear divided on

whether there is a gender prevalence for AVC, while MAC tends

to be more prevalent among postmenopausal women. In the

few studies considering predictors of valve calcification, age

and possibly hypertension were risk factors for prevalence but

not necessarily for progression; there was no consistency with

respect to other conventional risk factors for AVC or MAC.

A number of authors have linked the development of valvular

calcification to atherosclerosis, citing the fact that both are

actively regulated processes with histological, risk factor

and CV outcome similarities

129,130,131,132,133,134,135,136,137,138,139

_.

Furthermore, takasu et al noted that all patients with

progression of AVC had progression of CAC, while 80% of

those with stabilisation of AVC also had stable CAC, indicating

parallel development

140

_{. the aortic valve contains cells similar}

to myofibroblasts that have been shown to differentiate into

osteoblast-like cells which form calcific nodules in vitro; these

myofibroblasts are phenotypically analogous to vascular

smooth muscle cells, which can also undergo differentiation

into calcifying cells

141

_{. supporting this, Adler et al noted that}

foam cells (representing early atherosclerotic lesions) are

present on the ventricular surface of the posterior mitral leaflet

and on the aortic aspect of each aortic valve cusp, as well

as on the endothelium of the epicardial coronary arteries

142

_.

Nevertheless, because some patients have AVC without

atherosclerosis and statins cannot prevent calcium deposition

in advanced AVC, other mechanisms for valvular calcification

may also exist independently

143,144

_{. Although histology and CV}

outcome is beyond the scope of this article, our review found

no consistent evidence of any conventional CV risk factor for

valvular calcification other than age and possibly hypertension,

indicating that one of the pillars of the association of valvular

calcification with atherosclerosis may not hold.

Conclusions

there appears to be a consistent correlation between the

prevalence, extent and progression of arterial and valvular

calcification, although the strength of the association varies

and may only be modest for associations with CAC. From the

unequivocal association between calcification prevalence at

various sites, it is clear that calcification is a systemic diffuse

disease, affecting the arterial tree as a whole as well as the

cardiac valves. Despite this, some patients with severe CAC

may have zero calcification elsewhere. MAC is much less

prevalent than AVC and there is little correlation of calcification

between the two valves. the correlation between MAC and

CAC is frequently weak or non-existent, suggesting that MAC

may have little to do with atherosclerosis. AVC and aortic

calcification scores increase faster with higher baseline values,

showing that, as in the coronary artery, calcification also begets

calcification in these locations. In general, age, possibly male

gender, and systolic hypertension were fairly consistent risk

factors for calcification, although MAC and AAC were more

prevalent in postmenopausal women. there appears to be little

uniformity with respect to other risk factors, and, curiously,

on more than one occasion, BMI and diastolic blood pressure

proved to be inversely associated. Despite other similarities,

this inconsistency of conventional risk factors between studies

might cast doubt over the association of valvular calcification

with atherosclerosis and there is little additional evidence to

support the view that MAC is a manifestation of atherosclerosis.

Nevertheless, our review suggests that calcification of one area

of the CV system is indicative of the likelihood of calcification

elsewhere and since it tends to be initiated in the coronary

artery, this can be used as a guide to later calcification in other

arteries and valves.

Corresponding Author

Michael Henein MD PhD Msc FRCP

Professor of Cardiology

Department of Public Health and Clinical Medicine and

Heart Centre, umeå university, umeå, sweden

[email protected]

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