Jurnal CT Cardiac 3

Int J Cardiovasc Imaging (2008) 24:645–671
DOI 10.1007/s10554-008-9319-z
ORIGINAL PAPER
Coronary artery calcium screening: current status

and recommendations from the European Society
of Cardiac Radiology and North American Society
for Cardiovascular Imaging
Matthijs Oudkerk Æ Arthur E. Stillman Æ Sandra S. Halliburton Æ
Willi A. Kalender Æ Stefan Möhlenkamp Æ Cynthia H. McCollough Æ
Rozemarijn Vliegenthart Æ Leslee J. Shaw Æ William Stanford Æ
Allen J. Taylor Æ Peter M. A. van Ooijen Æ Lewis Wexler Æ Paolo Raggi
Received: 12 February 2008 / Accepted: 6 May 2008 / Published online: 27 May 2008
The Author(s) 2008
Abstract Current guidelines and literature on Keywords Coronary artery calcium

screening for coronary artery calcium for cardiac risk Coronary artery atherosclerosis
assessment are reviewed for both general and special Coronary risk assessment Coronary artery CT
populations. It is shown that for both general and
special populations a zero score excludes most clini-
cally relevant coronary artery disease. The importance
of standardization of coronary artery calcium mea- Introduction
surements by multi-detector CT is discussed.
In 1996 and 2000, the American Heart Association
(AHA) issued statements on coronary artery calcium
This consensus article is being published concurrently in the

Springer journal European Radiology.
M. Oudkerk (&) R. Vliegenthart P. M. A. van Ooijen S. Möhlenkamp

Department of Radiology, University Medical Center West German Heart Center Essen, University Duisburg-
Groningen, University of Groningen, Essen, Essen, Germany
Hanzeplein 1, 9700 RB Groningen,
The Netherlands C. H. McCollough
e-mail: M.Oudkerk@rad.umcg.nl Department of Radiology, Mayo Clinic, Rochester, MN,
USA
A. E. Stillman L. J. Shaw P. Raggi
Department of Radiology, Emory University, Atlanta, W. Stanford
GA, USA Department of Radiology, University of Iowa, Iowa City,
IA, USA
S. S. Halliburton
Imaging Institute, Cardiovascular Imaging Laboratory, A. J. Taylor
Cleveland Clinic Foundation, Cleveland, Division of Cardiology, Walter Reed Army Medical
OH, USA Center, Washington, DC, USA
W. A. Kalender L. Wexler
Institute of Medical Physics, Friedrich-Alexander- Department of Radiology, Stanford University School of
University, Erlangen-Nurnberg, Germany Medicine, Stanford, CA, USA
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646 Int J Cardiovasc Imaging (2008) 24:645–671
(CAC) quantification [1, 2]. In 2006 and 2007, several Coronary artery calcium as a predictor
professional societies updated these statements of cardiac events
describing new evidence related to CAC imaging [3–
5]. The purpose of the present work is to summarize Most published studies addressing the issue of coro-
the rationale and content of those recommendations nary artery calcium as a predictor of cardiac events are
with regard to CAC quantification, to address differ- based on EBT data. In the ACCF/AHA Consensus
ences among them and to point out controversial areas Document on Coronary Artery Calcium Scoring 6
of CAC research of high clinical relevance among both such studies were selected for review because they
asymptomatic and symptomatic persons. fulfilled sufficient criteria for outcome analysis [18–
Nearly all of the published clinical outcome data 23]. From the data presented in these studies, it was
from CAC are based on results obtained with electron concluded that coronary artery calcium scores add
beam tomography (EBT) systems. However, these CT incremental prognostic value in the evaluation of
systems are largely no longer available and are being patients at intermediate risk for a coronary event.
widely replaced with multi-detector CT (MDCT) Other studies further support this conclusion. Raggi
systems. EBT, produced by one manufacturer, pro- et al. [24] screened 632 asymptomatic patients with
vided much more standardization than exists for all the EBT and followed them for 32 months to determine
various generations of MDCT systems from different the incidence of hard cardiac events (myocardial
manufacturers. Standardization guidelines have been infarction, MI and death). The majority of events
proposed for MDCT [6], but are rarely used. Studies occurred in individuals with high calcium scores and
with earlier MDCT technology (4–16 slice) have in individuals with scores [ 75th percentile compared
demonstrated that similar mean CAC scores can be with age and sex matched controls. Arad et al. [19]
obtained with EBT and MDCT [7–12]. Nevertheless screened 1,172 asymptomatic patients with EBT and
systematic differences exist which can likely affect followed them for a mean of 3.6 years to determine
serial measurements [6, 13, 14]. the incidence of cardiovascular end points (MI, death
While large numbers of patients were included in and the need for revascularization). The authors
the EBT outcome studies, most of these suffered from concluded that in asymptomatic adults EBT calcium
selection biases related to ethnicity, patient self- scores are highly predictive of events. Pletcher et al.
referral or referral by physicians concerned about [25] conducted a meta-analysis of studies performed
subclinical coronary artery disease (CAD) due to the between 1980 and 2003 in * 13,000 asymptomatic
presence of risk factors. The Dallas Heart Study [15], patients screened with EBT and followed for 3.6 years
Multi-Ethnic Study of Atherosclerosis (MESA) [16], or less to determine the odd ratios (OR) of hard
and Rotterdam Study [17, 18] have attempted to coronary events. OR for Agatston CAC scpres \ 100,
address some of these issues. The results from 100–400 and [ 400 were 2.1, 4.2 and 7.2, respec-
general populations cannot reliably be applied to tively. The authors concluded that the EBT derived
special populations. Nevertheless it is clear from Agatston calcium score is an independent predictor of
many studies that in all kinds of populations, even in coronary events in asymptomatic subjects.
high-risk populations such as diabetic patients, and in
both symptomatic and asymptomatic patients, the
absence of coronary artery calcium (zero calcium CAC as an indicator of coronary artery
score) excludes most clinically relevant CAD. This luminal stenosis
information is highly relevant since many individuals
of subjects among the general as well as special Only studies based on EBT data have addressed the
populations have a zero calcium score. issue of CAC as an indicator of coronary artery luminal
In this paper, we review the evidence in support of stenosis. Haberl et al. [26] analyzed the value of EBT
the use of CAC for cardiac risk assessment in the derived calcium CAC scores as an indicator of
general population as well as special populations with coronary luminal stenoses in 1,764 patients undergo-
particular focus on the importance of a zero score. ing conventional coronary angiography. The authors
The need for standardization of CAC measurements concluded that EBT CAC scores are highly sensitive
with MDCT is also discussed. but moderately specific determinants of stenosis. The
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Int J Cardiovasc Imaging (2008) 24:645–671 647
ACC/AHA Expert Consensus Document on Electron- EBT and 4-slice MDCT (prospective triggering, Sie-
Beam CT for the diagnosis and prognosis of CAD [1] mens Volume Zoom) in 68 patients. EBT and MDCT
reported a pooled sensitivity of 91.8% and specificity scores correlated well (r = 0.98–0.99) with a median
of 55% for detection of a coronary artery stenosis [ variability between EBT and MDCT for the Agatston
50% after reviewing 16 selected studies comparing score of * 25% and * 16% for CVS. Scores were
CAC scores and invasive angiography. Knez et al. [27] higher for EBT than MDCT in approximately half of
compared EBT derived Agatston CAC scores with the cases, with little systematic difference between the
calcium volume scores (CVS) as a predictor of two (median EBT-MDCT difference: Agatston score,
coronary luminal stenoses in 2,115 patients undergo- -0.55; volume score, 3.4 mm3).
ing conventional coronary angiography. The authors
reported overall results similar to those already
reported by others, but also concluded that the CVS Review of current guidelines on coronary artery
are as accurate as the Agatston score for stenosis calcification
prediction. Indeed, Budoff et al. [28] utilized CVS
obtained by EBT to predict the presence of coronary Risk assessment in asymptomatic persons
artery stenoses in 1,851 patients undergoing conven-
tional coronary angiography and concluded that CVS Risk stratification algorithms such as the Framingham
provide incremental value in predicting the severity risk score (FRS) [29], the PROCAM score [30] or the
and extent of angiographically significant CAD. European SCORE-system [31, 32] are used to assess
an individual’s global 10-year risk. Risk factors are
measured and weighed and attributed to an empiri-
Clinical comparison of MDCT and EBT for cally determined absolute risk of cardiovascular
coronary artery calcium score measurement events, i.e. cardiac death and MI [33]:
– low risk B 1% per year or \ 10% in 10 years
Knez et al. [12] studied 99 symptomatic men (mean
– intermediate risk = 1 - 2% per year or 10–20%
age: 60 years) with both MDCT (prospective trigger-
in 10 years
ing, Siemens Volume Zoom) and EBT imaging and
– high risk C 2% per year or [ 20% in 10 years.
found a correlation coefficient of 0.99 for CVS and 0.98
for the mass score (MS) with a mean overall variability This classification was slightly modified by the
of 17%. No significant differences for scores 1–100, 2004 update of NCEP guidelines (Table 1) [34].
101–400, 401–1000, [ 1000 were found. The authors It is argued that persons at high risk will most
concluded that MDCT is equivalent to EBT for CAC likely benefit from intensive risk modification, while
scoring. Becker et al. [7] compared a 4-slice MDCT persons at low risk are generally recommended to
(Siemens Volume Zoom) with EBT (prospective trig- adhere to a healthy lifestyle and guideline-based
gering) in 100 patients and calculated the Agatston treatment of individual risk factors when present. In
score, CVS and MS. The authors concluded that the persons at intermediate risk, however, there remains a
score variability is highest for the Agatston score (32%) diagnostic gap and further tests, such as CAC scoring,
and the correlation between MSCT and EBT is measuring intima-media thickness (IMT), the ankle
excellent for CVS and MS. Carr et al. [8] performed arm index, or exercise stress testing may be useful in
CT examinations with both GE Lightspeed LX/i distinguishing individuals who indeed have a high
4-slice MDCT (retrospective gating) and EBT in 36 risk from those at low risk, leaving hopefully few that
patients and calculated the Agatston score in all of them. remain at intermediate risk [33]. It should be
The authors reported excellent correlation between recognized, though, that the Framingham score does
scores obtained on the 2 CT systems. Horiguchi et al. not take into account life-style factors such as diet,
[11] performed EBT and 16-MDCT with retrospective exercise and body mass index. Neither does the score
gating in 100 patients and reported a high degree of reflect a positive family history of cardiovascular
correlation between the 2 CT systems for the Agatston disease. The extent of atherosclerotic disease burden,
score (r2 = 0.955), CVS (r2 = 0.952) and MS autonomic dysfunction, chronic inflammation, lipo-
(r2 = 0.977). Daniell et al. [9] compared the results of protein subfractions, blood thrombogenicity, the
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Table 1 Absolute risk categories ‘‘NCEP-Update 2004’’, modified from [34]

Ten-year risk categories Definition of risk category
High risk CADa, CAD-risk equivalentsb, C 2 major risk factorsc, 10-year-risk [ 20%
Moderately high risk C2 major risk factors but 10-year CAD risk 10–20%
Moderate risk C2 major risk factors but 10-year CAD risk \ 10%
Low risk 0–1 major risk factor and 10-year CAD risk \ 10%
CAD: coronary artery disease
a
History of myocardial infarction, coronary revascularisations or myocardial ischemia
b
Includes diabetes mellitus, stroke, TIA or carotid artery stenosis [ 50%, symptomatic peripheral artery disease or abdominal
aortic aneurysm
c
Smoking, hypertension, high LDL-cholesterol/low HDL-cholesterol, age (men [ 45 years., women [ 55 years), and premature
family history of CAD (first grade family member, i.e. men \ 55 years., women \ 65 years)
myocardial propensity to develop life-threatening cost-effectiveness of CAC CT, and clinical implica-
arrhythmias, and immeasurable genetic factors are tions of incidental findings were also addressed.
also not part of conventional risk assessment. Mea- The purpose of the 2006 Appropriateness Criteria
suring the atherosclerotic sequelae of life-long global Statement [5] was to create, review and categorize
exposure to all risk factors by virtue of measuring the appropriateness criteria for cardiac CT and also
extent of the disease in its early subclinical stages cardiac magnetic resonance imaging (MRI) with
may overcome this limitation. The detection of regard to detection of CAD, cardiovascular risk
calcified atherosclerosis is a general surrogate of stratification, as well as cardiac structure and function
total atheroma burden. It is noted however, that the assessment. Members of the expert group assessed
extent of coronary calcification systematically differs the risks and benefits of the imaging tests for several
among ethnic populations and by gender. indications and clinical scenarios and scored them
based on a scale of 1–9:
The focus of current guidelines on CAC scoring
7–9 = appropriate: the test is generally acceptable
and is a reasonable approach
The AHA Scientific Statement on ‘‘Assessment of
4–6 = uncertain: uncertain indication or clinical
Coronary Artery Disease (CAD) by Cardiac Computed
setting
Tomography’’ [3] reviewed scientific data for cardiac
1–3 = inappropriate: the test is generally not
CT related to imaging of CAD and atherosclerosis in
acceptable/is not a reasonable approach
symptomatic and asymptomatic subjects, including a
detailed description of technical aspects and radiation Indications in the latter statement were derived from
exposure of CAC CT and non-invasive CT angiogra- common applications or anticipated uses of cardiac CT
phy using EBT and MDCT. According to AHA and MRI. Working group panelists rated each indica-
standards, recommendations were classified (Class I, tion based on the ACC Methodology for Evaluating the
IIa, IIb and III) and the level of evidence (A, B, or C) Appropriateness of Cardiovascular Imaging [35].
was provided (see http://circ.ahajournals.org/manual/
manual_IIstep6.shtml).
The ACC/AHA 2007 Clinical Expert Consensus Indications for CAC scoring in asymptomatic
Document [4] discussed the role of CAC quantification individuals
with respect to (1) identifying and modifying coronary
event risk in asymptomatic subjects, (2) modifying In the past several years, numerous publications have
clinical care and outcomes of symptomatic patients reported on the incremental prognostic value of CAC
with suspected CAD and (3) understanding the role of over measured conventional risk factors in large series
CAC CT in selected patient sub-groups, including of patients including asymptomatic population-based
women, ethnic groups, and patients with renal disease cohorts [18, 20–23, 36]. The relative risk of coronary
or diabetes. (4) The clinical value of serial CAC CT, events increased with increasing CAC burden (Fig. 1).
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recommended: in low risk individuals, even a high

CAC score does not generally elevate this person’s risk
above the threshold to initiate therapy [4]. Yet, life-time
risk may be elevated in 18% and 20% of asymptomatic
men and women, respectively, who have a high CAC
score, i.e. CAC [ 400 or [ 75th percentile, despite a
low FRS [37]. Persons with a high 10-year risk are
candidates for intensive risk modification based on
current NCEP guidelines [34], and there is no evidence
Fig. 1 Increase in relative risk (RR) with increasing CAC that a low CAC score substantially reduces this risk.
scores in asymptomatic persons in comparison to asymptom- This also holds for persons with risk equivalents. The
atic persons without CAC (modified from [20]) performance of serial (follow-up) calcium scoring
examinations was not recommended.
The majority of the expert writing committees agree that
it may be reasonable to consider use of CAC measure-
ment in asymptomatic intermediate risk patients, i.e. Atherosclerotic disease quantification in patients
10–20% coronary events in 10 years. These patients with chest pain
might be reclassified to a higher risk status based on a
high CAC score, and subsequent patient management In symptomatic patients, diagnostic tests may be used
may be modified (Fig. 2). In the ACC Appropriateness for risk stratification, but the primary initial objective
Criteria Document, notably published prior to the most is to identify or rule out obstructive CAD. Especially
recent AHA and ACC statements and additional in young persons with atypical chest pain, non-
prospective CAC scoring studies, CAC scoring was atherosclerotic non-obstructive coronary disease such
considered appropriate only for very few indications. as myocardial bridging, coronary anomalies, coro-
However, all of them were given a rating of ‘‘uncertain’’, nary vasospasm, intramyocardial small vessel
most notably CAC scoring for risk assessment in the disease, or non-coronary heart disease (CHD) such
general population at moderate (score 6) or high (score as cardiomyopathy, valvular heart disease, pericardial
5) CAD Framingham risk. In patients with a low or a disease, aortic disease, pulmonary disease, etc. must
high 10 year risk of coronary events, i.e. \ 10% be considered as differential diagnoses. Persons with
or [ 20% in 10 years, CAC quantification is not an intermediate pretest-likelihood of obstructive
CAD, i.e. between 20 and 80%, are most likely to
benefit from additional testing [38].
Functional tests such as treadmill, exercise or
pharmacological nuclear stress tests or stress-echo-
cardiography are used to induce myocardial ischemia
in patients with flow limiting coronary obstruction. In
contrast, CAC CT is aimed at estimating coronary
plaque severity and the associated likelihood of a
flow-limiting lesion. These two approaches, the
former functional and the latter morphological, are
distinctly different and have inherently different
reasons for false positive and false negative results.
The presence of CAC is almost 100% sensitive for
Fig. 2 Annual rate of myocardial infarction or cardiac death in the presence of atherosclerotic coronary plaque but not
categories of CAC burden in persons at intermediate risk based specific for flow limiting plaque, as both obstructive
on convention risk factor assessment. In persons with a high and non-obstructive lesions can contain calcific depos-
CAC score ([ 400), the annual event rate exceeds the threshold
for intensive risk factor modification, i.e. [2% per year (black its in the vessel wall. However, increasing calcium
line). A CAC score [400 in intermediate risk persons may scores are associated with an increasing likelihood of
therefore be considered as a risk equivalent (modified from [20]) both obstructive disease, and an increased severity
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(number of vessels involved) of CAD. Moderately high treatment intensity: ‘‘Measurement of coronary cal-
coronary calcium scores (approximately 150) in cium is an option for advanced risk assessment in
symptomatic patients are associated with a roughly appropriately selected persons. In persons with
80% sensitivity and specificity for the presence of an multiple risk factors, high coronary calcium scores
obstructive coronary artery lesion (among patients (e.g., [ 75th percentile for age and sex) denote
referred to coronary angiography) [26, 28] an accuracy advanced coronary atherosclerosis and provide a
that is similar in magnitude to conventional stress tests rationale for intensified LDL-lowering therapy.
[38, 39]. Consistent with these data are findings from Moreover, measurement of coronary calcium is
myocardial perfusion scintigraphy in which only 2% of promising for older persons in whom the traditional
patients with a CAC score \ 100 were shown to have a risk factors lose some of their predictive power [34].
positive nuclear stress test [40]. A clinical application The use of CAC percentile ranks, as advocated in the
of these relationships has been demonstrated among NCEP guidelines, is especially important in young
emergency department patients with chest pain, in individuals whose absolute scores may be low, yet
whom a zero calcium score was associated with a very ‘‘high-for-age’’, indicating a high life-long risk, even
low risk of cardiovascular events [41]. Caution in the though short-term risk over the next 5–10 years may
interpretation of zero calcium scores is warranted be low. As risk factor modification in high-risk
among individuals with a high pretest probability for subjects should be initiated as early as possible, such
CAD (e.g., young smokers) in whom false negative persons are likely appropriate candidates for intensive
studies may be observed [42]. risk modification—a notion that needs to be further
In summary, the majority of expert writing com- confirmed by prospectively collected outcome data.
mittee members agreed that patients at low risk of
CAD by virtue of atypical cardiac symptoms may Limitations
benefit from CAC testing to help exclude the
presence of obstructive CAD. CAC scoring may be There is currently little evidence that CAC CT and
a useful filter prior to invasive angiography or further knowledge of CAC score severity has an impact on
stress testing [43, 44]. However, more data on direct the advice physicians give to patients or on patients’
comparisons with established forms of stress testing adherence to prescribed risk factor modification
are needed. Currently, additional non-invasive testing efforts [45]. Further, CAC CT may improve risk
in persons with a very high CAC score, e.g. [ 400 is stratification in selected populations, but currently the
not recommended as there is no evidence that such data are limited that CAC CT improves outcome.
additional testing will improve appropriate selection Accordingly, current evidence does not support
of candidates for therapy. CAC CT was classified as lowering treatment intensity in intermediate risk
‘‘Class IIb, Level of Evidence: B’’ when used to rule subjects even if the CAC score is zero [4].
out obstructive CAD in patients with chest pain with
equivocal or normal ECGs and negative cardiac Summary
enzymes, and in symptomatic patients in the setting
of equivocal exercise stress tests [3]. Current guidelines propose the use of CAC CT to
Other clinical scenarios: Serial imaging of CAC to improve risk stratification in subjects at intermediate
assess disease progression is currently not indicated 10-year risk of incident coronary events. The present
by the existing guidelines [3]; this issue is discussed writing committee agrees with this general
later herein. Existing evidence on CAC CT has recommendation.
mostly been gathered from studies in Caucasian men
and caution is warranted in extrapolating existing
data to other ethnic groups or women. Race and calcium score
Implications for therapy There is still limited knowledge of the predictive

value of CAC in non-Caucasians. It has been well
The NCEP/ATP III Guidelines have incorporated documented that there is a notable difference in CAC
CAC CT as a complementary test to modify accumulation not only between men and women, but
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also between subjects of different ethnicities and Whites, the relative risk of death was 2.97 (CI: 1.87–
races. Doherty et al. [46] using subtraction fluoros- 4.72) in Blacks, 1.58 (CI: 0.92–2.71) in Hispanics and
copy first noted a significantly lower prevalence of 0.85 (CI: 0.47–1.54) in Chinese individuals. A 50-year-
CAC in Blacks than Whites (35.5 vs. 59.9%, old black patient with a CAC score [ 400 had an
P = 0.0001) and warned of the different prognostic estimated loss of 7 years of life, as opposed to
significance of CAC in these races. Indeed, during a 2.5 years of life for a white patient with the same score.
follow up of 70 ± 13 months, 23.7% of the black and Therefore, it would appear appropriate to consider
14.8% of the white screened population suffered an CAC a good marker of risk in all races so far
incident cardiovascular event (odds ratio: 2.16, 95% investigated, although the prognostic significance of
CI: 1.34–3.48). The significant difference in preva- score categories varies between racial groups. This
lence and distribution of CAC assessed by CT in 4 underscores the importance of racial specific risk
races in the US, was recently confirmed by the Multi- categories defined according to CAC score thresh-
Ethnic Study of Atherosclerosis. Bild et al. [16] olds. An attempt at defining such categories was
showed that the prevalence of CAC on cardiac CT recently published by Sirineni et al. [50]. In their
(score [ 0) was highest in Whites followed by publication the authors suggested substituting the
Chinese, Hispanics and finally Blacks. Santos et al. chronological age of a patient undergoing CAC
[47] showed that North American Caucasian subjects screening for his vascular age. The vascular age can
have more CAC than Caucasian subjects from Brazil be assessed according to the median CAC score for a
and Portugal despite the higher prevalence of risk subject of the same age, race and sex. For example a
factors in the latter two ethnic groups. Interestingly, 50-year-old black man with a CAC score of 40 should
despite a substantial genetic similarity between be considered * 20 years older than his chronolog-
Brazilian and Portuguese patients, and the presence ical age, since 40 is the median score of a 70-year-old
of more smokers among the latter, Brazilians had a black man in MESA. On the other hand, a score of 40
greater extent of coronary artery calcium than adds only 11 years of age to a 50-year-old white man.
Portuguese subjects. These findings mirrored the The prognostic validity of this novel approach is still
national mortality and morbidity statistics indicating awaiting confirmation in prospective studies.
a greater cardiovascular event rate in the North
American, followed by the Brazilian and finally the
Portuguese population. The value of coronary artery calcium
Despite the noted differences in CAC scores, there in the elderly population
is currently limited evidence of the prognostic
significance of CAC in different races. Detrano et al. The assessment of coronary calcification may have
[48] showed that CAC is a strong predictor of particular value in the elderly population. The
cardiovascular death, non-fatal MI, angina and potential for prevention of CHD in older adults is
revascularization (total events = 162) in all 6,722 large, since even a small reduction in risk factor
MESA patients independent of race. Furthermore, levels results in a considerable reduction in event
CAC added incremental prognostic value beyond rates. However, to identify asymptomatic elderly in
traditional risk factors for the prediction of events. the population at the highest risk of CHD is
Recently, Nasir et al. [49] evaluated the use of CAC challenging. Office-based risk score algorithms like
to predict all-cause mortality in 14,812 patients the FRS [29] and the European SCORE [31] have an
belonging to the same four races considered in MESA upper age threshold that limits their applicability to
(505 deaths in 10 years of follow-up). Once again the older adults. Furthermore, the predictive power of
prevalence of CAC was highest in Whites, although risk factors diminishes with increasing age [51–53].
Blacks and Hispanics had a greater clustering of risk Finally, age becomes the predominant factor in the
factors for CAD. Despite a lower prevalence of CAC algorithm in older adults, despite the fact that a fixed
and lower scores compared to the other races, black weight attributed to age does not take into account the
patients had the highest mortality rates even after individual variation in coronary plaque burden. On
multivariable adjustment for clinical risk factors and the basis of risk factors and age, the true CHD risk
baseline CAC score (P \ 0.0001). Compared with may be miscalculated, and this may lead to inaccurate
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selection of elderly for aggressive risk factor and C 400 (7.1 and 8.2 per 1000 person-years,
modification. respectively). Conversely, absence of CAC was
CAC reflects the life-time impact of all athero- associated with a very low event rate (0.9 per 1,000
sclerosis risk factors, both known and unknown, on person-years).
the arterial wall [54]. Thus, this non-invasive mea-
surement can provide a more accurate estimate of the Summary
accumulated plaque burden and CHD risk. So far, one
population-based study has focused on the predictive These data support the notion that CAC screening
value of CAC in the elderly: the Rotterdam Coronary may be used in all age groups to adjust the relative
Calcification Study (mean age, 71 years) [18]. During risk level. They must, however, be considered
a mean follow-up period of 3.3 years, 50 of the 1,795 preliminary; more research will be needed to dem-
initially asymptomatic subjects had a coronary event. onstrate that expensive medical therapies can be
Increasing CAC score categories showed relative withheld in the elderly with risk factors in the
risks for CHD up to 8.2 (95% CI: 3.3–20.5) for a absence of CAC and to establish the best approach to
CAC score above 1,000, compared to absent or low managing older, asymptomatic patients with exten-
CAC score (0–100). Similar relative risks were found sive CAC.
after adjustment for risk factors and in asymptomatic
individuals over 70 years of age. Of interest, there
was a very low probability of events in subjects with Diabetes mellitus and coronary artery calcium
a low CAC score (0–100). Furthermore, irrespective
of the Framingham risk category (low-to-intermedi- Patients suffering from diabetes type–2 have been
ate or high risk), increasing CAC score categories shown to harbor larger amounts of CAC than non-
were strongly associated with the risk of events. diabetic patients with the metabolic syndrome [58]
Thus, a low CAC score in elderly may be as valuable and subjects of similar age and otherwise similar risk
a finding as in younger subjects. These results factor profile [58, 59]. The extent of CAC in patients
indicate that the CAC score is a very promising with type-2 diabetes is similar to that of patients with
measurement to improve cardiovascular risk stratifi- established CAD but without diabetes, diabetic
cation in the elderly. In a recent publication, Abbott women harbor as much CAC as diabetic men [60,
et al. [55] reported on 224 very old (age 84–96) 61], and younger diabetic individuals have a plaque
Japanese men living in Hawaii followed for an burden comparable to that of older non-diabetic
average of 2.5 years after CAC imaging. A total of 17 individuals [62]. All of this confirms the clinical
deaths occurred during 2.5 years of follow-up and no evidence that diabetes mellitus is associated with a
death occurred in patients with a CAC score \ 10. As very high prevalence of CAD; it negates the advan-
shown in the study by Vliegenthart et al. [18], the tage of women over men and of youth over older age
death rate increased significantly as the CAC score in prevalence and extent of atherosclerosis. Hoff
increased (P \ 0.001). Finally, Newman et al. [56] et al. utilized a large database to calculate the age and
measured CAC and carotid IMT in 559 patients (336 gender normative (percentile) distribution of calcium
women) age 70–99 years. The top quartile of each scores in asymptomatic (self-reported) diabetic indi-
measurement was associated with * 2-fold viduals [62].
increased risk of a combined cardiovascular disease Olson et al. [63] investigated the presence of CAC
end-point. and prior CAD in 302 patients with diabetes mellitus
Other population prospective studies have been type-1 and a history of MI, angina, or evidence of
conducted in a wide age range [20–22, 24, 36, 57]. ischemia on stress testing or surface electrocardio-
Most of these studies did not specifically address the grams. Among the subjects free of clinical CAD, 5%
predictive value of CAC in older age. In a study by had a CAC score C 400 (large atherosclerosis bur-
LaMonte et al. [22], CHD event rates adjusted for den), as opposed to 25% of the subjects with prior
gender were presented in different age groups. In angina or objective evidence of myocardial ischemia
subjects over 65 years of age, a graded increase in and 80% of the patients with MI or luminal stenoses
event rates was seen for CAC scores C 100 on invasive angiography. CAC showed a sensitivity
123
of 84% and 71% for clinical CAD in men and end-point of the study was all-cause mortality. The
women, respectively, and 100% sensitivity for MI authors showed that the risk of all-cause mortality
and obstructive CAD. was higher in diabetic patients than non-diabetic
Limited data exist on outcome related to CAC in subjects for any degree of CAC and the risk increased
diabetic patients. Wong et al. [64] performed CAC as the score increased. Additionally, the absence of
screening and stress myocardial perfusion imaging CAC predicted a low short-term risk of death (* 1%
(MPI) in 1043 patients, 313 of whom were affected at 5 years) for both diabetic patients and non-diabetic
by either diabetes mellitus (N = 140) or the meta- subjects [67]. Hence, both the presence and absence
bolic syndrome (N = 173). In patients with a CAC of CAC were important modifiers of risk even in the
score \ 100, the prevalence of stress induced MPI presence of established risk factors for atherosclerosis
abnormalities was very low (* 2%). However, in the such as diabetes mellitus. This suggests that there is a
presence of a metabolic disorder (diabetes mellitus or great heterogeneity among diabetes mellitus patients
the metabolic syndrome) a CAC score between 100 and that risk stratification may be of benefit even in
and 399 or greater than 400 was associated with a patients considered to be at high-risk of atheroscle-
greater incidence of ischemia than in patients without rosis complications.
a metabolic disorder (13% vs. 3.6%, P \ 0.02, and
23.4% vs. 13.6%, P = 0.03, respectively). Similarly, Summary
Anand et al. [65] performed sequential CAC screen-
ing and MPI in 180 type-2 diabetic patients. The The preceding discussion suggests that CAC imaging
incidence of myocardial ischemia was directly pro- techniques may be very helpful to the practicing
portional to the CAC score. For type-2 diabetic physician faced with the dilemma of accurate risk
patients with a CAC score of 0, 11–100, 101–400, assessment even in diabetic patients at high risk.
401–1,000, and [ 1,000, the incidence of myocardial However, as is the case with other subsets of patients,
ischemia on stress MPI was 0%, 18%, 23%, 48%, and further research will be needed to confirm the
71%, respectively. In summary, based on the Wong prognostic role of CAC in diabetes mellitus.
[64] and Anand data [65], type-2 diabetic patients
with a CAC score [ 100 are expected to have an
increased frequency of ischemia on MPI. Renal failure and coronary artery calcium
Two outcome studies addressed the question of
whether CAC constitutes a risk for events in asymp- Both EBCT and MSCT have been utilized in the
tomatic patients but came to opposite conclusions. recent past to investigate the natural history and
The South Bay Heart Watch (SBHW) was a pathogenesis of CAC, as well as the impact of
prospective cohort study designed to determine the different therapeutic strategies in chronic kidney
relation between radiographically detectable CAC disease (CKD). Evidence indicates that as the
and cardiovascular outcome in high-risk asymptom- estimated glomerular filtration rate (eGFR) declines
atic adults [66]. Thirteen hundred and twelve the prevalence of CAC increases. In fact, the
asymptomatic subjects C 45 years old with cardiac prevalence of CAC was reported to be 40% in 85
risk factors were recruited via mass-mailing adver- pre-dialysis patients as opposed to 13% in controls
tisement in the Los Angeles area; of these 19% were with normal renal function [68]. In a prospective
diabetic patients. In a sub-analysis of the main study of 313 high-risk hypertensive patients a
database after a mean follow-up of 6 years, Qu et al. reduced eGFR was shown to be the major determi-
[66] found an increased risk of cardiovascular events nant of the rate of progression of CAC (ORs for
(death, MI, stroke and revascularizations) in diabetic calcium progression in the group with
patients compared to non-diabetic subjects in the eGFR B 60 ml/min: 2.1; 95% CI: 1.2–3.7) [69].
presence of CAC. However, the risk did not increase Consistent with these findings, Sigrist et al. [70]
significantly as the CAC score increased. Raggi et al. reported a prevalence of CAC of 46% in 46 pre-
[67] utilized a database of 10,377 asymptomatic dialysis patients compared to 70% and 73% respec-
individuals (903 diabetic patients), followed for an tively in 60 hemodialysis and 28 peritoneal dialysis
average of 5 years after CAC screening. The primary patients (P = 0.02). Hence, it appears that the
123
prevalence of CAC increases with declining renal followed 104 chronic hemodialysis patients for an
function and after initiation of dialysis. Of note, CAC average of 43 months after a screening EBT. Patients
was reported in * 60% of patients new to hemod- were divided in two groups according to a baseline
ialysis [71] and in as many as 80–85% of adult CAC score falling below or above the median for the
prevalent hemodialysis patients [72] in two prospec- group (score = 200). The 5-year cumulative survival
tive, randomized studies. In a small longitudinal was significantly lower for patients with a CAC
study, the baseline CAC score measured by EBT in score [ 200 than for those with a score \ 200
49 prevalent hemodialysis patients was on average 2- (67.9% vs. 84.2% P = 0.0003).
to 5-fold higher than in age and sex matched
individuals with established CAD. A repeat CT after Summary
an interval of 12 months showed significant progres-
sion of CAC (P \ 0.05) [73]. CAC appears to be predictive of an adverse outcome
A number of factors have been associated with in CKD patients and its absence has been linked with
progression of CAC in dialysis patients. Associations a very low event rate.
with age and duration of dialysis [72, 74], diabetes
mellitus [72] abnormalities of mineral metabolism
[75–77] as well as use and dose of calcium based The value of the ZERO calcium
phosphate binders [78, 79] have all been reported. To score—ASYMPTOMATIC PATIENTS
investigate the impact of therapy for hyperphosphate-
mia on the progression of CAC a randomized clinical The presence of coronary calcification is, especially
trial compared the effect of Sevelamer (Genzyme, with advancing age, a sensitive but unspecific finding.
Cambridge, MA USA—a non-absorbable polymer As discussed above, many studies have emphasized
with gut phosphate binding ability) and calcium-based the graded increase in CHD risk with increasing
phosphate binders in 200 hemodialysis patients for calcium scores. However, an even more clinically
1 year [78]. Throughout the study both drugs provided relevant finding may be the absence of CAC. In a
a comparable phosphate control (mean phos- large population of over 10,000 individuals screened
phate = 5.1 mg/dl), although a significantly higher for CAC, all-cause mortality was assessed during a 5-
serum calcium concentration (P = 0.002) was noted in year follow-up period. With a zero or very low (\ 10)
the calcium-salts treated arm. At study completion calcium score, the investigators reported a very low
Sevelamer treated subjects were less likely to experi- probability of mortality, * 1.0% at the end of
ence CAC progression (median absolute progression follow-up [82]. This finding was confirmed in a
of CAC score 0 vs. 36.6, P = 0.03 and aorta 0 vs. 75.1, study by Budoff in 25,253 individuals, in which only
P = 0.01, respectively) [78]. 0.4% of the individuals with a negative calcium score
In a smaller series of 129 patients new to died during almost 7 years of follow-up, compared to
hemodialysis [80], subjects treated with calcium- 3.3% of individuals with a positive CAC score [57].
containing phosphate binders showed a more rapid In prospective studies in which CHD was used as
and more severe increase in CAC score compared outcome measure, a zero or very low calcium score
with those receiving Sevelamer (P = 0.056 at was associated with a very low probability of events
12 months, P = 0.01 at 18 months) [80]. In the same during follow-up [21, 23, 24, 36, 83]. Church et al.
series, all cause mortality was strongly associated reported a relative risk of coronary events in subjects
with the baseline CAC score, and was significantly without CAC compared to those with a positive
lower in the Sevelamer arm after 4.5 years of follow calcium score of 0.13 (95% CI, 0.06–0.30) [83].
up (P = 0.02) [71]. Even more surprisingly mortality Cumulative incidences in studies with a follow-up
was extremely low (3.9%/year) in patients with 0 period of 3–5 years ranged between 0.1% and 0.7%
calcium score. This stands in contrast with a reported (Table 2). One study showed a somewhat higher
mortality of * 20–25%/year in patients undergoing cumulative incidence of 4.4% during more than
hemodialysis. CAC scores were also shown to be 6 years [20]. This may be partly explained by the
predictive of an unfavorable outcome in dialysis different CT protocol (6 mm slicing) which may have
patients by Matsuoka et al. [81]. The authors resulted in missing calcified lesions.
123
Table 2 Absent or very low calcium score and events in asymptomatic populations
Author Year N total N subgroups Mean Lowest Percentage in Mean follow- Outcome Cumulative
age ± SD calcium lowest up ± SD incidence
(years) score category (%) (years) (%)
category
Raggi et al. [24] 2000 632 52 ± 9 0 46 2.7 ± 0.6 MI/cardiac death 0.3
Shaw et al. [82]a 2003 10,377 53 ± 10 0–10 57 5.0 ± 3.5 All cause mortality 1.0
Raggi et al. [84]a 2004 10,377 4,191 Women 55 ± 11 0–10 68 5.0 ± 3.5 All cause mortality 1.6
6,186 Men 52 ± 11 50 1.5
Raggi et al. [67]a 2004 10,377 903 Diabetics 57 ± 10 0 30 5.0 ± 3.5 All cause mortality 1.2
9,474 Non- 53 ± 10 51 0.6
diabetics
Int J Cardiovasc Imaging (2008) 24:645–671
Shaw et al. [42]a 2006 10,377 4,113 Smokers 53 ± 10 0–10 About 49 5.0 ± 3.5 All cause mortality 0.5
6,264 Non- 54 ± 11 About 63 0.3
smokers
Kondos et al. [21] 2003 5,635 1,484 Women 54 ± 9 0 49 3.0 ± 1.0 MI/CHD death 0.3
4,151 Men 50 ± 9 26 0.3
Greenland et al. 2004 1,029 66 ± 8 0 31 6.3 ± 1.5 MI/CHD death 4.4
[20]
Arad et al. [36] 2005 4,613 59 ± 6 0 33 4.3 MI/CHD death/ 0.5
revascularizations
Vliegenthart et al. 2005 1,795 71 ± 6 0–100 50 3.3 ± 0.8 MI/CHD death 0.7
[18]
Taylor et al. [23] 2005 1,983 356 Women 43 ± 3 0 92 3.0 ± 1.4 MI/CHD death/ 0.0
1,627 Men 78 unstable 0.2
angina
Church et al. [83]b 2007 10,746 54 ± 10 0 53 3.5 ± 1.4 MI/CHD death 0.1
LaMonte et al. 2005 10,746 3,911 Women 54 ± 10 0 71 3.5 ± 1.4 MI/CHD death 0.1
[22]b 6,835 Men 53 ± 10 39 0.1
Budoff et al. [57] 2007 25,253 56 ± 11 0 44 6.8 ± 3.0 All cause mortality 0.4
CHD: coronary heart disease; MI: myocardial infarction; SD: standard deviation
a
Same study, analysis in different subgroups
b
Same study, analysis in different subgroups
Cumulative incidence derived from published data or calculated
655
123
Four studies have specifically compared the prog- and cholesterol-lowering medications. Although the
nosis for men and women in the absence of CAC. current evidence is substantial, such a notion
Raggi et al. found no difference in all-cause mortality cannot be endorsed at this time in the absence of
after 5 years of follow-up in over 4,000 women and prospective, randomized trials.
over 6,000 men with a very low CAC score (\ 10):
1.6% vs. 1.5% [84]. Recently, the results from three
studies in which CHD was the outcome [21–23], were The value of ZERO calcium
used in a meta-analysis [85]. In total, the analysis score—SYMPTOMATIC PATIENTS
included 3,862 women and 5,548 men with absent or
minimal CAC. The annual CHD event rate was very Calcium score and prediction of obstructive
similar in women and men: 0.2% vs. 0.3%. When coronary artery disease on angiography
only women and men with no CAC were studied,
rates were somewhat lower (0.16% vs. 0.27%) but As outlined above, a negative CAC score has a
again not significantly different. Thus, absent or very high negative predictive value in asymptomatic
low CAC score carries the same prognostic value in patients of both genders and even in patients with
both genders. risk factors such as smoking, diabetes or renal
Interestingly, even in the presence of cardiovas- failure. In symptomatic patients where CAD is
cular risk factors, the negative predictive value of suspected, can a zero or a minimal CAC score
absent or minimal CAC appears to be very high. In (e.g., \ 10) be used as a filter to rule out obstruc-
the aforementioned study in which all cause mortality tive CAD? Several investigators have addressed
was the outcome [82], further investigations were this point. Becker et al. studied 1,347 symptomatic
performed according to smoking status and diabetes subjects with suspected CAD [86]. Sensitivity,
status of the participants [42, 67]. Absence of CAC specificity and predictive accuracy were calculated
was noted in about 30% of individuals with diabetes, for different calcium thresholds for prediction of
and in 50% of smokers. Little or no CAC was CAD. In 720 (53%) subjects, invasive angiography
associated with a near 100% survival in non-smokers revealed a lumen diameter stenosis greater than
as well as smokers, and non-diabetic as well as 50%. Patients with obstructive CAD had signifi-
diabetic subjects. cantly higher total calcium scores than patients
As discussed in the previous section, Block et al. without CAD (P = 0.001). The overall sensitivity
[71] reported a very low mortality rate for hemod- of any CAC score to predict stenosis was 99%,
ialysis patients without evidence of CAC (3.9%/ with a specificity of 32%. An absolute score
year); this is in contrast with the extremely high cutoff C 100 and an age and sex specific scor-
mortality rate (* 25–30%/yearly), typically quoted e [ 75th percentile were identified as the cutoff
for this category of patients. Thus, the absence of levels with the highest sensitivities (86–89%) and
CAC may be an important modifier of the risk of lowest false positive rates (20–22%). Absence of
events even in the presence of cardiovascular risk CAC was highly accurate for exclusion of CAD in
factors. The high negative predictive value of a subjects older than 50 years (negative predictive
zero CAC score is extremely valuable, considering value = 98%). The authors concluded that the
that a large number of asymptomatic individuals presence of CAC on MDCT in symptomatic
have no CAC. In various studies, absence of CAC patients is accurate for prediction of obstructive
was noted in 26–92% of individuals, depending on CAD and that its absence is associated with a high
the age of the individuals. Hence, a zero CAC negative predictive value for exclusion of CAD.
score may have important implications in daily Several other studies investigated the presence of
clinical practice and on a population level. The non-calcified plaques and obstructive lesions in
most important question from a population and patients with a low or zero CAC score. Cheng et al.
societal point of view is whether individuals assessed the presence and severity of non-calcified
without CAC should be considered at low risk, coronary plaques on 64-MDCT coronary angiography
even in the presence of cardiovascular risk factors, in 554 symptomatic patients with low to intermediate
and therefore be spared therapies such as aspirin pre-test likelihood for CAD and zero or low CAC
123
score (low score: men, score \ 50; women, The value of zero calcium score to rule out CAD
score \ 10) [87]. The authors intended to elucidate in symptomatic patients: comparison to treadmill
how well absence of CAC predicts the absence of stress testing and nuclear stress tests
obstructive non-calcified coronary artery plaque
(NCAP). Compared with patients with absent CAC, In discussing the potential value of a zero CAC score in
those with a low CAC score had markedly increased symptomatic patients for a reliable exclusion of CAD,
rates of critical luminal stenoses (8.7% vs. 0.5%, other non-invasive tests like ECG stress testing or
P \ 0.001). The authors concluded that in symptom- nuclear stress testing have to be considered. Exercise
atic patients with low to intermediate pre-test stress testing is often used as the initial non-invasive
probability of CAD, absence of CAC predicts very diagnostic test in symptomatic patients with suspected
low prevalence of occlusive NCAP. Nonetheless, low obstructive CAD. Positive standard ECG criteria are
but detectable CAC scores were significantly less quite specific for obstructive CAD, but there may be a
reliable in excluding the presence of plaque that at substantial number of false negative tests, including
times could be obstructive. patients with severe disease. Also, exercise stress tests
Leschka et al. recently studied the potential of frequently yield equivocal results. Lamont et al.
using the CAC score to improve the diagnostic assessed the value of combining CAC screening with
accuracy of MDCT angiography [88]. They evaluated a stress test to reduce the high false-positive rate seen
74 consecutive patients who underwent CAC scoring, with treadmill stress test (TMST) alone [90]. A CAC
MDCT angiography and invasive angiography. Seg- score was obtained by EBT in 153 symptomatic
ments that were not evaluable on MDCT angiography patients who underwent coronary angiography because
were considered to be false-positive. When using of a positive TMST. The TMST false-positive rate was
CAC scores of 0 to exclude stenoses and C 400 to 27% (41 of 153). In these patients, a CAC score of zero
predict stenosis for segments with non-evaluative resulted in a negative predictive value of 93%. The
segments, the per-patient sensitivity and specificity authors concluded that the absence of CAC reliably
improved from 98% and 87% to 98% and 100%, identified patients with a false-positive TMST result.
respectively. Only the 0 CAC score was found to be Raggi et al. [44] showed that in symptomatic patients
helpful to exclude stenoses as a high CAC score often with low to intermediate pretest probability of disease
corresponds to more than one stenosis in the coronary (5-50%), a CAC score of zero can be reliably used to
artery tree. exclude obstructive CAD and that calcium scoring as
In a study by Rubinshtein et al. [89], the severity the initial test to investigate presence of CAD provides
of CAD was examined using 64-MDCT angiography a substantial cost benefit over a pathway based on
in patients who underwent testing due to chest pain exercise stress testing. Berman et al. [40] described the
syndromes and had a zero or low CAC score. Of 668 relationship between stress-induced myocardial ische-
consecutive patients, 231 had a low score (\ 100) or mia on single-photon emission computed tomography
absent CAC. Obstructive CAD was present in 9 of (SPECT) perfusion studies and CAC. Including a total
125 patients (7%) with a 0 CAC score, and in 18 of of 1,195 patients without known CAD, 51% asymp-
106 (17%) with a low score (CAC: 1–100). tomatic, the frequency of ischemia by SPECT was
compared to the magnitude of CAC. The frequency of
Summary ischemic SPECT was \ 2% with CAC scores \ 100
and increased progressively with CAC [ 100 (P for
In conclusion, absent CAC seems to be an excellent trend \ 0.0001). Patients with symptoms and CAC
filter for exclusion of obstructive CAD in symptom- scores [ 400 had higher likelihood of myocardial
atic patients with intermediate to high pre-test ischemia versus those without symptoms (P \ 0.025).
likelihood of obstructive CAD. A low CAC score, The authors concluded that ischemic SPECT is asso-
however, is more controversial as a number of studies ciated with a high likelihood of subclinical
showed that the presence of non-calcified and poten- atherosclerosis by CAC, but it is rarely seen for CAC
tially obstructive lesions is higher in patients with scores \ 100. In most patients, low CAC scores appear
low CAC scores and symptoms compared to patients to obviate the need for subsequent non-invasive
with a score of zero. testing. Patients with normal perfusion studies,
123
however, frequently had extensive non-obstructive cardiac enzymes and found that the presence of any
atherosclerosis by CAC criteria. CAC is a strong predictor for future cardiac events.
Geluk et al. determined the efficiency of a screening Conversely, patients without CAC may safely be
protocol based on CAC scores compared with exercise discharged from the ED given the extremely low rate
testing in patients with suspected CAD, a normal ECG of future events (* 0.1%/year) [41]. Nonetheless,
and troponin levels [43]. A total of 304 patients were after reviewing the available evidence, Andrews
enrolled in a screening protocol that included CAC concluded that currently existing data do not suffi-
scoring by EBT, and exercise testing. Decision-making ciently support the widespread use of CAC CT in
was based on CAC scores. When the CAC score patients with acute chest pain syndromes [95]. Even
was C 400, coronary angiography was recommended. so, in patients at low pre-test likelihood of CAD
When the CAC was \ 10, patients were discharged. presenting with angina-like symptoms to the ED, a
Exercise tests were graded as positive, negative or non- negative CAC score can possibly be used to rule out
diagnostic. The combined endpoint was defined as an acute coronary syndrome. In conclusion, the
coronary event or obstructive CAD at coronary agiog- available single center studies based on a limited
raphy. During 12 ± 4 months, CAC C 400, 10–399 number of patients indicate that the negative predic-
and \ 10 were found in 42, 103 and 159 patients and tive value of a zero CAC is high ([ 90%). However,
the combined endpoint occurred in 24 (57%), 14 (14%) the positive predictive value is somewhat lower,
and 0 patients (0%), respectively. In 22 patients (7%), rendering CAC screening a highly sensitive, but
myocardial perfusion scintigraphy was performed poorly specific modality for the diagnosis of acute
instead of exercise testing due to the inability to coronary syndromes.
perform an exercise test. A positive, non-diagnostic
and negative exercise test result was found in 37, 76
and 191 patients, and the combined endpoint occurred Calcium score progression: interpretation
in 11 (30%), 15 (20%) and 12 patients (6%), respec-
tively. Receiver–operator characteristics curves Serial changes in CAC score may have important
showed that the area under the curve of 0.89 (95% implications for monitoring the response of athero-
CI: 0.85–0.93) for CAC was superior to 0.69 (95% CI: sclerotic disease to the initiation of or changes in
0.61–0.78) for exercise testing (P \ 0.0001). The plaque-altering medical therapy as well as for iden-
authors concluded that measurement of CAC is an tifying patients with more aggressive disease who are
appropriate initial screening test in a well-defined low- at high risk for incident CAD [4]. In this section, we
risk population with suspected CAD. will discuss the methodological approaches to calcu-
lating CAC progression as well as provide a synopsis
The value of zero calcium score in patients of the available literature on the utility of sequential
presenting with acute chest pain to the emergency CT imaging to evaluate atherosclerotic disease
department progression.
The use of CAC assessment was briefly discussed in a

recent consensus paper on the use of MDCT for acute Serial testing paradigm
chest pain [91, 92]. The use of CAC screening has
been described in patients with angina-like symptoms Serial testing is based on the concept that changes in
and negative cardiac enzymes presenting to the CAC are valid markers of varying atherosclerotic
emergency department (ED). Laudon et al. per- disease states [96]. Furthermore, a change in CAC
formed CAC scoring in the emergency department may serve as a surrogate for clinical outcomes or
in 104 patients, and noted a negative predictive value disease activity and, as such, provides clinically
for CAD of 100% for a CAC score of zero [93]. useful information to guide further patient manage-
McLaughlin et al. reported a negative predictive ment [97–102]. The paradigm of using imaging as a
value of 98% in 134 patients in a similar ED setting surrogate outcome has been advanced in the onco-
[94]. Georgiou et al. followed 198 patients presenting logic PET literature [103]. The response evaluation
to the ED with chest pain and normal ECG and criteria in solid tumors (RECIST) provide definable
123
criteria for partial or complete response to therapies 64-slice MDCT systems. The variability is best with
of target and non-target lesions. thinner slices, higher calcium scores and with retro-
Using this type of sequential monitoring, a positive spective acquisition mode, although this is associated
change in CAC score above a given threshold with a higher radiation dose for the patient. Currently,
signifies progressive disease, minimal or no changes the reported variability of the Agatston, volume and
in CAC score identify patients with stable disease, mass score on 16–64-slice MDCT ranges between 8
while a reduction in CAC score beyond a given limit and 18% (lower end of the range with 64 slice
defines patients exhibiting regression in their under- MDCT) on sequential examinations performed within
lying disease. With regards to the latter, it is still very minutes of each other [109–111]. Given the radiation
controversial whether CAC truly regresses. As such, exposure, especially with MDCT systems, the bene-
this document will focus on defining rapidly and fit-risk ratio and time intervals of repeat CT must be
slowly progressive disease states. considered individually, especially when women and
young men are examined.
Reproducibility of CAC CT and its determinants Clinical thresholds of coronary artery calcium
progression
A major consideration for interpretation of changes in
CAC between serial CT examinations is the variabil- Progression of CAC is generally calculated as a
ity of repeat imaging. Inter-examination variability is percent or absolute change from the baseline score
affected by image artifacts including motion, noise, using either the Agatston score, CVS, or MS [99, 104,
and partial volume averaging that are highly depen- 112–119]. Raggi et al. defined a change [ 15% as
dent on the specific imaging protocol as well as the true progression [98], while Hokanson et al. sug-
extent of CAC burden. Optimal timing of ECG gested a CAC progression C 2.5 mm3 of the square
triggering can reduce variability of Agatston root of the initial volume score as a useful threshold
scores [ 30 to \ 15% with EBT [104–106]. The of progression [108].
correlation coefficients across CAC measurements, The absolute change in CAC is expected to be
including Agatston score (AU), CVS, or MS, are greater in patients with a higher baseline score
excellent (r C 0.96, N = 161) [11, 107]. CVS’s (Figs. 3 and 4) [98, 115, 116], although the absolute
improve reproducibility only marginally compared differences reflect minor changes compared to base-
to Agatston scores. The square root of the CVS has, line. Larger percent score changes are expected in
however, been suggested to reduce inter-examination patients with a low index CAC score (e.g., index
variability [108]. CAC score of 10 to repeat score of 20 = progression
Differences between types of CT systems are very of 100%) and do not necessarily reflect a clinically
small after adjustment for body mass index and CAC relevant change.
burden [10]. In the MESA study, mean relative
differences between CT examinations at different
times were 20.1% for the Agatston score, and 18.3% Clinical interpretation of changes in coronary
for the interpolated CVS (P \ 0.01) [10], which are artery calcium
in line with previous reports. Of note these data were
obtained from CT performed at 80% of the RR- For most patients within the various risk groups in
interval, which is associated with a lower reproduc- Fig. 5, the error in score reproducibility would not
ibility as compared to earlier triggering. affect their clinical management, unless scores are
Data acquired with 4-slice CT systems were close to adjacent risk groups. Variability increases
reported to have higher rates of mis-registration with CAC score and may be as much as 200–380
compared with EBT [10]. Motion artifacts were also units for scores of 400 or higher (Fig. 5) [120]. As
higher in these CT systems compared to EBT scores of 100 or 400 may trigger more aggressive
machines, while image noise was lower [10]. The post-screening management or follow-up ischemia
reproducibility of the calcium score has improved testing, clinicians should rely less on the absolute
with the introduction of 16-slice and more recently thresholds and more on a combination of CAC score
123
80 1400
Absolute Change
Repeatability Limits (units)

70 1200
Percent Change
Change in Agatston Score
Very High Risk Score

1000
60
800
50
600
40 High Risk Score
400
30
200
Significant Score
20 0
0 5 10 20 50 100 200 300 400 500 600 700 800 900 1000
10
Agatston Score (units)
0
Low Risk Mild Risk Moderate Risk High Risk
Fig. 5 95% confidence intervals for repeatability of coronary
Baseline CAC Score
CAC Scores <10 10-99 52-399 ≥194
artery calcium scores from 0 to C1,000
Fig. 3 The absolute and percent change in baseline Agatston change [117]. However, the absolute change will be
score on serial CT imaging greater but the relative change may be smaller. The
248
score does not continue to grow exponentially and the
400 (118, 379)
rate of growth eventually tapers off. Most patients
Yearly Rate of Change
350
exhibit a positive change in CAC scores over time
300
250
[99, 112–114, 116, 118] although some patients (29–
200
34%) exhibit no change if they are at low Framing-
150 66
(16, 117)
ham risk, including women, or have a baseline score
100 41 of 0 (38%) [114]. In patients with an initial 0 score, a
11 (31, 50)
50 0.2 5.0
(2, 7)
(5, 17) repeat CT \ 5 years after the initial examination may
(0.0, 0.4)
0
0 1-10 11-100 101-400 401-1,000 >1.000
not be useful for clinical purposes [114].
Baseline CAC Score (AU)
Fig. 4 Expected yearly rate of change (95% Confidence Results of randomized clinical trials on effect
Intervals) from baseline for coronary artery calcium scores of statin therapy on coronary artery calcium
ranging from 0 to C1,000 Agatston Units (AU) progression
with the patient’s clinical presentation and cardiac
A number of observational studies (Table 3) and
risk factor profile. Aggressive management is indi-
randomized clinical trials (Fig. 6) have evaluated
cated for scores of 1,000 or higher (very high risk
change in CAC following treatment with statin
CAC) and it is unlikely that the expected variability
therapy. In four observational reports untreated
about this point estimate will change clinical care
patients had an average CAC score progression of
[99, 104, 112–119].
36% [98, 126–128]. By comparison, statin therapy
attenuated changes in CAC scores averaging 13%
Rates of coronary artery calcium progression and (Table 3) [98, 126–128].
its determinants However, these promising observational data were
contradicted by large randomized clinical trials
In subjects at average Framingham risk the annual showing similar changes in CAC scores following
CAC progression rates typically range from 20% to placebo and/or moderate-intensive statin therapy
24% per year using either the Agatston or the CVS (Fig. 6). Except for a preliminary pilot trial [129],
[99, 104, 112–119]. Factors that may significantly all other randomized trials have failed to confirm the
modify rate of change include the patient’s baseline preliminary observational findings (Fig. 6). Compar-
CAC score, gender, age, family history of premature ison of intensive versus moderate statin therapy
CAD, ethnicity, diabetes and glycemic control, body showed no difference in CAC progression (Fig. 6)
mass index, hypertension, and renal insufficiency [98, [100, 130]. The lack of an effect in these clinical
121–125]. Further, the longer the interval from trials suggests that a longer observational time period
baseline to repeat CAC CT, the greater the expected may be warranted and that statins may reduce cardiac
123
Table 3 Percent yearly progression from observational cohorts of consecutive patient series, with average framingham risk, and
evidence of coronary artery calcium (CAC) on baseline CT
Author Year N Entry criteria Score Testing period Percent change
(in years) CAC score/yeara
Budoff et al. [126] 2000 299 Consecutive pts. AU C1 33%

Shemesh et al. [117] 2001 116 Asymptomatic AU 1, 2, 3 Yr. 1: 18%
hypertensive pts. Yr 2: 31%
Yr 3: 41%
Sutton-Tyrrell et al. [118] 2001 80 Middle-aged women AU 1.5 11%
Yoon et al. [119] 2002 217 Consecutive subjects AU 2.1 34%
CVS 29%
Raggi et al. [99] 2003 772 Consecutive pts. CVS 2.2 26%
Hsia et al. [115] 2004 94 Healthy post-menopausal AU 3.3 27%
women CAC C 10
Budoff et al. [113] 2005 177 Post-menopausal pts. AU C1 15%–22%
Rasouli et al. [116] 2005 133 Asymptomatic pts. AU 1.7 17%–22%
Gopal et al. [114] 2006 710 Consecutive pts. w/CAC = 0 AU C1 Mean ± sd: 1 ± 3
Median (IQR): 0 (0–0.8)
Becker et al. [112] 2007 277 Post-menopausal women CVS 3.3 18%
Summary data 2,875 AU 20%
CVS 24%
a
Mean ± standard deviation (s.d.), Median, interquartile range (IQR) in the Gopal series
Abbreviations: CAC = Coronary Artery Calcium, year = year, AU = Agatston units, CVS = calcium volume score,
s.d. = standard deviation
Fig. 6 Summary meta- RCTs of Statin Therapy vs. Placebo

Baseline CAC Change / yr Rate Difference (95% CI)
analysis of randomized
control trials (RCT) on the Studies: N Control:Active-1.0 -0.50
CAC Control:Active 0.0 0.50 1.0
rffect of Statin therapy (Rx) 66 CVS 155*
Achenbach [129] 25:11 relative p=0.016
on CAC progression Arad [19] 1,005 AU 563:527 240:192 p=0.39
abs
*Achenbach – Patients had a Treated and Untreated Time Period. Thus, Favors
there is no RCT of Favors
Statin vs. Placebo and no summary effect was calculated.
Rx Control
RCTs of Moderate vs. Intensive Statin Therapy
Baseline CAC Change / yr Rate Difference (95% CI)
Studies: N CAC Moderate:Intensive

Moderate:Intensive
-1.0 -0.50 0.0 0.50 1.0
Raggi100 614 CVS 371:434 23:38 p=0.36
relative p=0.85
Schmermund130 366 CVS 267:205 31:28 relative
Summary Effect
5.4% (-7.2% to 17.9%) p=0.40
Favors Favors
Abbreviations: CAC=Coronary Artery Calcium, CVS=Calcium Volume Score, Intensive Rx Moderate Rx
AU=Agatston Units, RCT=Randomized Clinical Trial, Yr=Year,
events independent of an effect on calcified plaque serial imaging [131, 132]. Finally, other treatments
[4]. Further, these trials often did not consider or plan have been tested as far as an effect on CAC
the management of other CV risk factors that may progression. In the Women’s Health Initiative
confound the lack of therapeutic benefit [4]. There are (WHI), menopausal women between the ages of
ongoing trials using CAC as a surrogate where 50–59 years were randomized to treatment with
additional evidence may be put forth on the benefit in conjugated estrogens or placebo [133]. In a sub-study
123
of the WHI, 1,064 women were submitted to CAC scoring in every patient that has undergone a baseline
screening after 8.7 years from trial initiation. Women CT and is receiving treatment for factors related to
receiving estrogens showed a lower CAC score atherosclerosis. An individualized approach to assess
compared those receiving placebo (83.1 vs. 123.1, rate of progression in specific situations may be taken
P = 0.02). into consideration.
Cardiovascular prognosis related to coronary Standardization of the calcium score measured

artery calcium progression using different CT systems
Despite the lack of an effect of statins on CAC The utilization of CAC scores for outcomes data, risk
progression, several reports have noted that a rapid stratification, and particularly, the serial assessment
change in CAC score is associated with worse clinical of patients over time demands accurate measure-
outcomes including incident MI [97, 99]. In one ments. Accurate measurement of MDCT derived
report of 495 patients, subjects who experienced an CAC scores requires implementation of standardized
acute MI experienced greater degrees of CAC imaging and quantification methods on many differ-
progression compared to event-free survivors ent types of commercially available MDCT systems.
(42% ± 23% vs. 17% ± 25%, P \ 0.0001) [97]. This formidable goal can be achieved by selecting CT
Patients with and without [ 15%/year change in parameters that fulfill minimum requirements for
CAC score had 66% and 97% MI-free survival, temporal resolution, spatial resolution, and noise and
respectively, at 6 years (P \ 0.0001). Patients who by applying a physically meaningful, calibration-
exhibited significant progression from their index CT based calcium quantification algorithm.
(C 15%/year) and those with baseline CAC A standard for CAC quantification was recently
score C 400 had a more rapid presentation to acute proposed by the Physics Task Group of the Interna-
MI occurring at 2–4 years post-testing as compared tional Consortium on Standardization in Cardiac CT
to those with CAC scores B 100 with incident MI’s and is reviewed here [6]. Standardized CT protocols
at over 5 years from baseline testing (P \ 0.0001). were developed for six CT models from five manufac-
Thus, the baseline CAC score provides an insight into turers (Aquilion, Toshiba Medical Systems, Nasu,
not only the expected rate of progression but also the Japan; Imatron, Imatron San Francisco, CA; Light-
timeline of conversion to symptomatic CAD. Speed Plus, General Electric Healthcare, Milwaukee,
Wisconsin; MX8000, Philips Medical Systems, Best,
Summary The Netherlands; Volume Zoom, Siemens Medical
Solutions, Erlangen, Germany; Sensation 64, Siemens)
The evidence is inconclusive as to what is the most using an anthropomorphic cardiac phantom containing
accurate method to define CAC progression (percent water and calcium inserts and capable of simulating
versus absolute versus square root change). Further three patient sizes. Manufacturer recommended pro-
research is indicated as to documenting meaningful tocols met the minimum requirements for imaging
changes in the various scores. For the patient with an coronary calcium with MDCT: (1) acquisition of at
average FRS, the yearly increase in CAC score is least four slices per rotation, (2) rotation time less than
approximately 15–20%. Absolute changes are greater or equal to 0.5 s, (3) ability to reference data acqui-
in patients whose baseline score exceeds 100. To date, sition or reconstruction to the ECG signal. Most
published randomized trials have failed to demonstrate protocols were, however, modified to achieve a target
a benefit of statin therapy to attenuate CAC progres- noise level (20–23 HU) in the water insert for each
sion. Despite this, rapidly increasing CAC scores may phantom size. This primarily required determination of
be used to define higher risk patients. Further insight CT model- and size-specific values for the tube current
into the prognostic implications of serial CT examin- (mA) or tube-current time product (mAs). Small,
ations is warranted to further guide optimal patient medium, and large anthropomorphic phantoms were
management. This writing committee does not recom- then examined on a total of 10 different CT machines
mend the systematic performance of serial CAC using these standardized CT protocols.
123
All image sets were scored using a single software mathematical construct and as such cannot be com-
package because, although not explicitly evaluated by pared to a physical reference standard. However,
the Consortium, differences among scoring packages calcium volume and mass scores could be compared
are assumed to be non-negligible (but low compared to known values from the cardiac phantom. For the
to other sources of error; see next section). To address five MDCT systems, the total calcium mass score was
this issue, software manufacturers were asked to within ± 5 mg of the total known mass of calcium
modify existing algorithms according to recommen- HA within the phantom (168.2 mg). The accuracy of
dations of the Consortium. Software packages will EBT measurement was considerably worse (mean
then be validated as they become available (at least mass score equaled 182.7 mg). Therefore, the
three manufacturers have incorporated the Consor- increased precision of the mass score as compared
tium recommendations into their software at this with the volume score and the ability to compare the
writing). measured mass score with a known physical standard
To quantify CAC, voxels containing calcium were motivated the Consortium to endorse the mass score
first isolated from other tissue and image noise approach as the preferred method of quantifying
primarily by applying a standard 130 HU attenuation CAC.
threshold to the reconstructed images. Agatston, Additional data have been collected by the Physics
volume, and mass scores were then calculated using group towards optimization of the mass score.
standard quantification algorithms [6]. To obtain Specifically, the requirements for calculation of a
absolute values for calcium mass, a calibration calibration factor were examined. Variation in the
measurement of a calcification with known hydroxy- measured calibration factor from three sizes of the
apatite (HA) density was carried out and a calibration anthropomorphic cardiac phantom was assessed
factor determined. Because the CT number of all across CT machines, time, and patient sizes. Assess-
materials except water depends on the X-ray spec- ment across CT machines, revealed the coefficient of
trum, a specific calibration factor exists for each variation in the calibration factor was small for a
machine and each CT protocol. Work by the Physics specific CT manufacturer and CT model (0.13–
Group of the Consortium also showed that patient 1.6%). Subsequent data analysis from the same CT
size changes the X-ray spectrum and impacts the systems over time has shown slightly higher variation
value of the calibration factor significantly. There- for measurements made quarterly over a 4-year
fore, a unique calibration factor was determined for period from a single 16-slice CT machine (2.8–
each of three broad categories of patient sizes for 3.2%) and over a 2-year period from a single 64-slice
each CT model and each CT protocol using the CT machine (2.5–3.1). The change in phantom (i.e.,
cardiac phantom’s water and calcium inserts. patient size), however, caused a much larger change
The mass score (mij) was then computed as the in calibration factor both across CT systems (3.8–
product of the appropriate calibration factor (cHA), the 5.1%) and over time (3.4–5.0%). Therefore, determi-
number of voxels containing calcium (Nvoxel), the nation of a calibration factor for a given CT machine
volume of one voxel (Vvoxel), and the mean CT and patient size from quarterly CT of an anthropo-
number for each lesion (CTij ): morphic phantom should be sufficiently stable over
time to permit 3% or less variation in the measure-
mij ¼ cHA Nvoxel Vvoxel CTij
ment. It has been suggested that inclusion of a
The total mass score is the sum of the mass of all calibration insert with each patient is necessary for
individual lesions. precise measurement of a calibration factor. How-
Analysis of the mean and standard deviation of the ever, this seems unnecessary based on the low
calcium scores measured under ideal conditions from variability in calibration estimation with quarterly
EBCT and MDCT systems demonstrated a coefficient anthropomorphic CT.
of variation of 4.0% for Agatston scores, 7.9% for Because of the variation in calibration measure-
volume scores, and 4.9% for mass scores. The ments, particularly across patient sizes, the consortium
accuracy, or exact correspondence between measured recommended identifying voxels containing calcium
and true values, could not be assessed for Agatston by applying a threshold based on a fixed density or
scores because this score represents only a concentration of calcium HA (100 mg/cc of calcium
123
HA) rather than the traditional fixed attenuation (130 developed through the efforts of the Consortium to
HU) that may not provide a consistent cutoff value allow collection of standardized MDCT patient risk
for calcium across examinations. factor and CAC data (https://clinapps.bio.ri.ccf.org/
In summary, the Physics Group demonstrated that cascore/). A sufficient number of patients must be
standardized protocols and algorithms can provide entered before assignment of a precise percentile
accurate and precise calcium mass scores in phan- ranking can be provided to an individual patient. Based
toms independent of MDCT model and phantom on early data, it was determined that a total registry size
(patient) size through the use of appropriate calibra- of 4,000 would be sufficient to estimate the percentile
tion factors. Implementation of these protocols ranking of future patients in the age range of 45–
should move the field of CAC scoring closer to the 70 years. To date, data from over 1,000 patients have
realization of meaningful quantitative comparisons of been collected. The Writing Group supports this stan-
CAC scores measured over time within a patient and dardization procedure and recommends that this
across patients even when imaging is performed registry be supported.
using different MDCT models. An obvious output of
the implementation of such standards should be
reduced variability in CAC measurements although Influence of scoring parameter settings of
this remains a point of investigation. underlying software algorithms on calcium
The recommendations of the Consortium have scoring
largely been implemented by the CT manufacturers
making adherence to these standardization proce- All scoring methods used for the determination of
dures in clinical CT straightforward. Additional CAC have a common denominator. This is the
relatively tasks beyond current practice will, how- algorithm used to determine which areas above the
ever, be required including measurement of lateral threshold HU value are calcified lesions and which can
skin-to-skin width at mid-liver from an anteroposte- be discarded as noise. To determine this very impor-
rior CT radiograph (‘‘scout’’ image) to assess patient tant distinction, common algorithms are used that are
size, selection of appropriate patient-size specific influenced by a number of different parameter settings
mA/mAs to achieve the noise target, and selection of which, as shown by van Ooijen et al. in 50 patients
appropriate patient-size specific calibration factor to imaged with EBT, influence the resulting CAC score
determine a density-based attenuation threshold and [134]. The most common parameters are the HU
calculate absolute calcium mass. threshold value, the connectivity, the lesion size
The biggest obstacle to widespread use of the mass threshold and the use of interpolation. Some commer-
score is the paucity of data available for clinical cially available software packages provide the user
decision-making. The CAC score is most clinically with the parameter settings and even allow changing
meaningful in the context of risk-stratification which these parameters. Others hide the default settings and
requires referencing a patient’s total CAC score to determining the settings used can be very difficult.
age- and sex-matched data. A patient is assigned to a Mean variability can be up to 15–16 points for the
percentile range of risk on the basis of his or her total Agatston score with the largest influence coming from
CAC score; the percentile range is defined by flexible changing the lesion size threshold between 2 and 4
thresholds that take into account the independent pixels. For the CVS, mean variability can be up to 20–
effects of age and sex on the amount of total CAC. 30 points largely due to the effect of changing the
Most currently available databases, particularly those lesion size threshold between 2 and 4 pixels and from
with a significant number of patients, contain only turning interpolation on and off. It could well be that
Agatston scores. An MDCT database founded upon the effect of interpolation will be less prominent when
standard protocols using the mass score is therefore using MDCT instead of EBT because of the use of slice
necessary. overlap. There are no published data for the mass
Implementation of a standardization procedure for scoring method, but since this method also relies on
the acquisition and analysis of CAC images permits the algorithms to determine what regions are lesions and
accumulation of scores from various MDCT systems in what regions are not, it is likely that similar results will
a single database. A web-based database has been be found.
123
In conclusion, when performing CAC scoring because of the higher radiation sensitivity and the
based on the volume or Agatston score, software longer available time for cancer development after
parameter settings affect the outcome. Furthermore, exposure. Using the linear non-threshold model of
the use of new software versions or other software radiation induced risk and the organ specific risk from
packages and the use of data acquired in other Biological Effects of Ionizing Radiation (BEIR VII)
institutes in the follow-up of patients could also affect [139], the data presented by Einstein et al. [140] can
the measured progression or regression of CAC be linearly scaled to predict the lifetime risk of
because of different parameter settings. These data cancer. Assuming a factor of 10 reduction of dose
show, therefore, that not only standardization of CT from a coronary CTA exam, the lifetime risk of
protocols is obligatory, but CAC scoring parameters cancer for a CAC CT in a 50-year-old individual is
also need to be standardized. Further research is 0.04% for a man and 0.12% for a woman. To
required to determine whether using phantom data or properly interpret these data, the individual’s com-
test patient datasets can help standardizing settings plete risk profile must be considered, including the
across software and help selecting the appropriate background risk of cancer incidence in the general
settings of a certain software package when they are population and any individual-specific risks such as
unclear. diabetes, high blood pressure or a family history of
cancer or heart disease. According to statistics from
the American Cancer Society, the lifetime risk of
Radiation exposure cancer at any site is 45% for men and 38% for
women; the respective death rates are 23 and 20%
A broad implementation of CAC screening may be [141]. Thus, taking into account the patient’s specific
limited by factors such as cost, patient access and medical risks, particularly of CAD, and the back-
demonstration of altered medical outcomes. In addi- ground population risks, the additive cancer risk from
tion, risks associated with the use of ionizing a CAC exam is negligible, provided that some benefit
radiation must be taken into account, especially for may be gained from the examination. Thus, this
younger or female patients or when considering committee of experts does not support the application
additional radiological tests such as CT and MPI. of CAC screening to individuals at low risk of CAD,
CAC screening delivers a relatively low radiation where medical benefit is not expected. For individ-
dose (effective dose of 0.7 mSv with EBT and 1.0– uals at intermediate risk of CAD, the small statistical
4.1 mSv with MDCT) [135], while coronary CT risk of cancer induction and death is very low relative
angiography (outside of the scope of this writing) to the patient’s complete risk profile. In these
delivers somewhat increased levels of radiation dose patients, the potential benefit to the patient from
(effective dose of 9.4 to 14.8 mSv) [136]. The dose to knowledge obtained in the CAC exam greatly
any one individual depends both on the imaging exceeds the small potential risk of cancer and the
protocol used and the patient’s body habitus. The use of CAC screening is recommended in several
radiation exposure provided by CAC screening is clinical scenarios.
substantially lower than that of MPI studies (effective Further, in contrast to alarming media reports
dose range of 13–16 mSv), especially those con- regarding the risks associated with ionizing radiation,
ducted using Thallium–201 or dual isotope the radiation biology and epidemiology community is
techniques (effective dose of 27.3 mSv) [137] or divided as to the actual degree of risk at the low doses
invasive diagnostic coronary catheterization (effec- associated with medical imaging examinations. Con-
tive dose of 3–10 mSv) [138]. sidering the error bars associated with the data from
Much of our knowledge on the carcinogenic the Japanese bomb survivors, the difficultly in
effects of low doses of radiation (whole body transferring risk estimates between population
exposures of 5–150 mSv) derives from follow-up cohorts and irradiation dose rates and types (high
data on the survivors of the atomic bombings in versus low dose rates, whole body versus partial body
Japan. Although quite small, there appears to be an exposures, etc.), and the conflicting reports from
increase in incidence of cancer in subjects exposed to medically exposed populations that show no increase
low doses of radiation, especially in children— in risk at medical imaging dose levels, it is the official
123
position of the Health Physics Society that meaning- Finally, standardized procedures for both image
ful risk estimates are not possible below effective acquisition and CAC scoring should be followed so that
doses of 100 mSv [142]. Thus, CAC exams, with we might best advance our knowledge using MDCT.
effective doses of 1–4 mSv, may be in fact be
associated with no additional risk and hence should Disclosure of support SSH—None; WAK—Siemens
Medical Solutions; CHM—Bayer Healthcare, Siemens
not be avoided when information important to the
Medical Solutions; RTI Electronics, Inc; SM—None; MO—
patient’s medical management may be obtained. None; PMAO—None; PR—None; AES—Astellas, Siemens
Medical Solutions; LJS—None; WS—None; AJT—None;
RV—None; LW—None.
Conclusions Open Access This article is distributed under the terms of the
Creative Commons Attribution Noncommercial License which
The writing committee would like to summarize in a permits any noncommercial use, distribution, and reproduction
series of conceptual points the evidence discussed in any medium, provided the original author(s) and source are
credited.
herein as follows.
We know and support the conclusion that:
• CAC is a good predictor of events in Caucasians References
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Int J Cardiovasc Imaging (2008) 24:645–671

Coronary artery calcium screening: current status

Abstract Current guidelines and literature on Keywords Coronary artery calcium

This consensus article is being published concurrently in the

M. Oudkerk (&) R. Vliegenthart P. M. A. van Ooijen S. Möhlenkamp

Table 1 Absolute risk categories ‘‘NCEP-Update 2004’’, modified from [34]

recommended: in low risk individuals, even a high

Implications for therapy There is still limited knowledge of the predictive

The use of CAC assessment was briefly discussed in a

Repeatability Limits (units)

Very High Risk Score

Budoff et al. [126] 2000 299 Consecutive pts. AU C1 33%

Fig. 6 Summary meta- RCTs of Statin Therapy vs. Placebo

RCTs of Moderate vs. Intensive Statin Therapy

Baseline CAC Change / yr Rate Difference (95% CI)

Studies: N CAC Moderate:Intensive

Cardiovascular prognosis related to coronary Standardization of the calcium score measured

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