Coronary artery atherosclerosis is approaching epidemic proportions in the United States and worldwide. Based on data from the Framingham Heart Study, a person’s lifetime risk of developing symptomatic coronary artery disease (CAD) after the age of 40 is 49% in men and 32% in women. Each year, approximately 1.8 million Americans will experience an acute myocardial infarction (AMI), or sudden cardiac death will be their ﬁrst clinical manifestation of CAD.
is currently a Fellow in Cardiovascular Disease in the Division of
Cardiology at Washington University School of Medicine in St.
Louis, MO. In 2001, he received his MD from Indiana University
School of Medicine, Indianapolis, IN. At Duke University, Durham,
NC, he completed his Internal Medicine Residency in 2004 and his
Cardiovascular Magnetic Resonance Imaging Fellowship in 2005. Dr.
Todoran has received the American Society of Nuclear Cardiology
Imaging Award and currently has research support from American
Society of Nuclear Cardiology Research Foundation. In 2008, Dr.
Todoran will begin interventional training at Brigham and Women's
Hospital, Harvard Medical School, Boston, MA
Despite current methods of identifying patients with coronary
artery atherosclerosis, many individuals suffer cardiovascular
events in the absence of established risk factors. Thus, current
diagnostic paradigms for the detection of coronary artery
atherosclerosis are inadequate. Consequently, there is an impetus
to develop improved noninvasive imaging modalities to better
detect coronary artery disease (CAD) and determine the prognosis
of future cardiovascular events. Cardiac computed tomography (CT)
has the capacity to directly visualize the coronary arteries.
Cardiac CT can be performed to detect coronary artery stenoses
and assess nonobstructive stages of coronary atherosclerosis
either through calcium measurement or the analysis of calcified
and noncalcified plaque. There are some clinical recommendations
for the use of coronary CT angiography (CTA) for symptomatic
patients, as well as for the use of coronary artery calcium (CAC)
measurement in patients who are asymptomatic but are at
intermediate risk for CAD events based on the Framingham risk
assessment. There are currently no clinical indications for
coronary CTA in asymptomatic individuals for stenosis detection
or assessment of coronary artery plaque.
Coronary artery atherosclerosis is approaching epidemic
proportions in the United States and worldwide. Based on data from
the Framingham Heart Study, a person's lifetime risk of developing
symptomatic coronary artery disease (CAD) after the age of 40 is
49% in men and 32% in women. Each year, approximately 1.8 million
Americans will experience an acute myocardial infarction (AMI), or
sudden cardiac death will be their first clinical manifestation of
Finally, despite scientific advances in diagnosis and treatment,
CAD is the leading cause of death in the United States, accounting
for 1 in 5 deaths in men and women.
Current diagnostic paradigms are failing to adequately identify
asymptomatic individuals with subclincal CAD. Additionally, the
work-up of symptomatic individuals is frequently cumbersome,
requiring multiple tests. Consequently, a need exists for better
diagnostic paradigms for the detection of CAD. One way the current
approach can be improved is by the use of noninvasive imaging
modalities that, ideally, can be applied to both asymptomatic and
symptomatic persons. There are two issues, however. First,
subclinical atherosclerosis must be detected among asymptomatic
individuals earlier for the purpose of risk stratification. Second,
the approach needs to identify symptomatic individuals with CAD
efficiently, and more importantly, identify those with
flow-limiting disease in whom the treatment paradigms differ from
those with non- flow-limiting disease.
With the exception of cardiac CT, no single noninvasive imaging
technology currently detects both subclinical atherosclerosis and
flow-limiting CAD. As such, cardiac CT coronary artery calcium
(CAC) detection and coronary CT angiography (CTA) are well
positioned to identify these 2 groups of individuals.
Evolution of cardiac CT
Imaging the coronary arteries is difficult because of their
small diameters and the motion during the cardiac cycle.
Visualizing the lumen of coronary arteries using contrast-enhanced
CTA requires maximal temporal and spatial resolution. There has
been rapid advancement in cardiac CT technology. In particular,
greater X-ray tube currents, faster gantry rotation times, and
decreasing collimation size while increasing detector length have
resulted in significant improvement of image quality. The advent of
4-slice multidetector CT (MDCT) in 2000, 16-slice in 2002, and,
more recently, 64-slice has allowed for progressively higher
accuracy for the detection of coronary artery stenoses.
Greater X-ray tube currents allow for thinner collimation and
thinner slice reconstruction, resulting in improved spatial
resolution. Faster gantry rotation time, as high as 330 msec for
dual-source CT (DSCT), has resulted in an improved temporal
resolution of 83 msec. Finally, a higher number of detector rows
have led to shorter overall acquisition time, as short as 5 to 8
seconds with 64-slice CT and 1.5 sec with 256slice CT. These
shorter acquisition times also make it possible to obtain images
with a smaller volume of contrast. All of these advancements have
led to significantly improved resolution and the reduction of image
CAC detection of subclinical coronary artery
atherosclerosis in asymptomatic individuals
Little data and no current recommendations exist regarding the
use of coronary CTA in the assessment of occult CAD. Therefore,
this section will focus on CAC detection.
The presence of calcium in the coronary arteries occurs almost
exclusively in the context of atherosclerotic changes. Thus, CAC
has become a surrogate marker for coronary artery atherosclerotic
Detection of latent CAD in asymptomatic individuals is important
since many individuals suffer cardiovascular events in the absence
of established risk factors.
Cardiac CT can accurately detect and quantify CAC, allowing for
noninvasive assessment of subclinical coronary artery
atherosclerosis. As a result, CAC measurement has been proposed as
a way to improve risk assessment compared with the use of
traditional risk factors.
Diagnostic accuracy of CAC measurement in asymptomatic
The presence of CAC is highly specific for coronary artery
atherosclerosis but does not allow for determining the level of
stenosis since both flow-limiting and non-flow-limiting lesions
have calcification present within the intima.
CAC and prognosis in asymptomatic individuals
Coronary artery calcium increases with age
and differs based on gender and race.
Additionally, age- and gender-adjusted CAC scores have been shown
to be more predictive of cardiovascular events than an absolute CAC
Several studies have found that CAC scoring provides prognostic
information either alone or in combination with traditional risk
factors. A recent metaanalysis reported a summary relative risk
ratio of 4:3 for any measurable CAC, suggesting that a person with
measurable CAC is 4 times more likely to have a cardiovascular
event than an individual with a CAC score of 0.
Furthermore, studies have shown an incremental relationship where
higher CAC scores are associated with higher relative risk ratios
for cardiovascular events, and more recently, independent
prediction of outcomes beyond traditional risk factors or
Framingham Risk Score (FRS).
Additionally, CAC scoring has been shown to predict all-cause
mortality more accurately than risk factors alone. A recent large
observational study that evaluated long-term prognosis reported an
age- and risk-factor-adjusted 10year survival of 99% for a CAC
score of 0 compared with 89% for a CAC score >1000.
Table 1 summarizes recent published prognostic studies based on CAC
Diagnostic impact of CAC in asymptomatic individuals
The current guidelines in primary prevention of cardiovascular
events recommend initial assessment and risk stratification based
on traditional risk factors. Validated analysis from the Framingham
Heart Study provides algorithms projecting the 10-year risk of
having a cardiovascular event. In an effort to better identify
patients at risk, governing bodies such as the American Heart
Association (AHA) have proposed prevention paradigms that include
diagnostic tests for atherosclerosis, such as CAC measurement. For
example, the Executive Summary of Screening for Heart Attack
Prevention and Education (SHAPE) Task Force
and the recent
Guidelines for Cardiovascular Prevention in Women: 2007
recommend further risk stratification of individuals based on the
results of CAC measurement by cardiac CT in addition to their FRS.
Patients with a CAC score of 0 and no risk factors are at "very
low" risk, while a CAC score of 0 in the presence of traditional
risk factors places a patient in the "moderate" risk category.
Those who test positive for coronary artery atherosclerosis are
further stratified into groups of "moderately high," ''high," and
"very high" risk.
Therapeutic impact of CAC in asymptomatic individuals
Based on recommendations from multiple guidelines, individuals
identified to be at risk either by FRS or the presence of
subclinical coronary artery atherosclerosis are treated with
goal-directed lipid-lowering therapy based on recommendations from
the National Cholesterol Education Program.
Observational studies have shown that CAC progression is the
strongest predictor of future cardiac events.
Small observational studies have shown that lowering low-density
lipoprotein cholesterol with statins also results in the reduction
However, the St. Francis Heart Study, comparing atorvastatin to
placebo in otherwise healthy asymptomatic men and women with a CAC
score above the 80th percentile for their age and gender did not
confirm these findings and was unable to show a statistically
different reduction in events or mortality between the 2 groups.
Applications of cardiac CT in symptomatic
Although the presence of CAC is synonymous with coronary artery
atherosclerosis, it does not imply stenosis. The disease process
begins decades prior to causing obstruction of blood flow and
symptoms. This is best explained by positive remodeling, where in
its early stages, plaque accumulation produces a compensatory
outward expansion while maintaining a constant luminal diameter.
Currently, invasive coronary angiography (ICA) is the reference
standard for the detection of coronary artery atherosclerosis in
patients with known or suspected CAD. Nearly 4 million ICA
procedures are performed annually in the United States for the
purpose of detecting CAD.
The procedure-related major complication rate for death, AMI, and
stroke is <1%.
Because of the small but nonnegligible risk of morbidity and
mortality, there has been an impetus to develop a noninvasive
modality of coronary artery imaging. Furthermore, ICA is limited by
its inability to see beyond the vessel lumen. In contrast, coronary
CTA allows for the assessment of both luminal stenoses and
identification of the extent of the plaque burden through the
visualization of the vessel wall (Figure 1).
Diagnostic accuracy of coronary CTA in stable angina
Native coronary arteries-
Numerous studies have compared the diagnostic accuracy of detecting
coronary artery stenosis by MDCT to ICA. The diagnostic performance
of MDCT varies depending on the type of analysis
performed-per-segment versus the more clinically relevant
per-patient analysis. Many of the early studies performed a
per-segment analysis and excluded uninterpretable segments, leading
to overestimation of sensitivity and specificity. Comparison of
pooled per-segment accuracy with per-patient accuracy reveals an
increased sensitivity from 81% to 96% at the expense of a reduced
specificity from 93% to 74%.
There has been an overall decrease in the number of uninterpretable
segments with recent technological advances; however, this still
remains a problem. The diagnostic accuracy of MDCT has improved
dramatically when moving from 4- to 64-slice MDCT with
sensitivities and specificities in interpretable segments
approaching 100% in the latter.
Figure 2 shows an example of a patient with flow-limiting CAD seen
on coronary CTA and confirmed by ICA. Table 2 shows the diagnostic
accuracy for the detection of coronary artery stenosis using
64-slice MDCT angiography compared with ICA from recent published
In 2004, an estimated 1,471,000 inpatient diagnostic cardiac
catheterizations were performed, with roughly 427,000 referred for
coronary artery bypass graft (CABG) surgery and 1,285,000 for
Patency of bypass grafts and coronary artery stents is limited,
thus follow-up examinations are inevitable.
Coronary artery bypass grafts-
The development of 16-slice MDCT allowed for excellent accuracy for
graft patency with sensitivities and specificities between 95% and
100%, but the accuracy for detection of graft stenosis remains
suboptimal, owing to the inability to detect stenosis in the distal
graft anastomosis. A recent meta-analysis compared the accuracy of
distinguishing between graft occlusion and graft stenosis with
16-slice MDCT or ICA. The authors found that the number of
adequately visualized vessels were much lower in the graft stenosis
group compared with the graft occlusion group, 88% and 96%,
When compared with previous-generation scanners, recent studies
using 64-slice MDCT have shown superior accuracy and higher
evaluability rates of both native coronary arteries and bypass
grafts, with reported sensitivities and specificities of 97%.
Much of the improved accuracy of imaging grafts is due to their
larger diameter, minimal calcification, and reduced motion.
However, for MDCT to play a significant role in the evaluation of
the symptomatic post-CABG patient, a complete angiographic
assessment of grafts, nongrafted arteries, and distal runoff
arteries is required (Figure 3). This can prove to be a challenge
in cases of advanced atherosclerosis with heavily calcified,
diffusely diseased vessels.
A limited number of studies have examined the diagnostic
accuracy of coexisting native CAD. First reports using 16-slice
MDCT showed sensitivities and specificities of 83% and 59% with all
segments compared with 100% and 93% with grafts only.
Recently, 2 small studies used 64-slice MDCT to evaluate bypass
grafts, native (nongrafted) arteries, and distal runoff coronary
arteries. The accuracy for detecting graft stenosis was similar to
previous reports, but the reported accuracy for native and distal
runoff coronary arteries was much worse, with sensitivities and
specificities as low as 86% and 76%, respectively.
Table 3 summarizes the diagnostic accuracy in the detection of
stenosis in bypass grafts versus native and distal runoff coronary
arteries. The inability to adequately assess native coronary
arteries severely limits the clinical utility of coronary CTA in
patients after CABG surgery.
Coronary artery stents-
Prior to the development of 64-slice MDCT, CT scanners lacked
sufficient spatial and temporal resolution to adequately detect
in-stent restenosis with reported sensitivities and specificities
of 78% and 73%, respectively, using 16-slice MDCT.
Improved image quality with newer-generation scanners has permitted
better visualization of the lumen within the coronary artery stent,
as shown in Figure 4, resulting in an overall reduction in the
number of uninterpretable segments from 32% to 7%.
A recent study using 64-slice MDCT reported a sensitivity of 95%,
specificity of 93%, positive predictive value (PPV) of 63%, and a
negative predictive value (NPV) of 99%.
Table 4 shows the diagnostic accuracy of MDCT angiography in the
detection of in-stent stenosis from recent published studies.
Factors that influence the evaluation of in-stent restenosis
include stent diameter, strut thickness, and stent material.
Stents <3 mm in diameter with thick struts are the most
challenging to evaluate.
Acute chest pain-
Chest pain accounts for nearly 6 million visits to U.S. emergency
departments annually; >50% of patients admitted to the hospital
are admitted for noncardiac causes. This results in an enormous
economic burden on the healthcare system. Despite conservative
approaches, 2% to 10% of cases of acute coronary syndrome (ACS) are
As a result, there is a movement to efficiently triage patients
presenting to the emergency department with chest pain to avoid
unnecessary hospital admission while delivering appropriate care to
patients with ACS.
Diagnostic accuracy of coronary CTA in the setting of acute
Multiple observational studies have shown that MDCT is highly
accurate in detecting coronary artery stenosis and in predicting
ACS in low-to-intermediate risk and high-risk patients presenting
to the emergency department with chest pain.
A small randomized trial comparing MDCT to the standard of care in
low-risk patients found that MDCT effectively triaged >75% of
the patients either to discharge (68%) or to undergo ICA (8%).
Additionally, MDCT has been shown to have similar accuracy to
nuclear stress testing in this setting.
One advantage of using cardiac CTA over stress imaging in the
emergency department is that cardiac CTA can exclude extracardiac
causes of chest pain, such as pulmonary embolus or aortic
Prognostic implications of cardiac CT in symptomatic
Annual cardiac event rates in patients with a CAC score of 0 are
extremely low. In contrast, patients with an age- and
gender-adjusted CAC score >400 had annualized event rates of
13.9% for future cardiovascular events compared with 0.6% in
patients with a CAC score of 0.
In individuals being evaluated for acute chest pain, outcome data
from a few small studies with follow-up ranging from 30 days to 15
months reported no deaths or myocardial infarctions in any of the
patients who were discharged directly from the emergency department
with normal coronary CTA.
One study reported a late major adverse cardiovascular event (MACE)
rate of 2.8%. From this, the authors calculated a sensitivity of
92%, specificity of 76%, PPV of 52%, and NPV of 97% for MDCT
performed in the acute setting to predict overall risk of MACE.
One small outcome study of individuals with stable angina with a
mean follow-up of 16 months has been published. Patients with a
normal coronary CTA had a 1-year event rate of 0% compared with 30%
in patients with any evidence of CAD on coronary CTA. Additionally,
patients with flow-limiting CAD had an event rate of 63% compared
with 8% in those with non-flow-limiting CAD.
This study further illustrates the importance of not only detecting
CAD but also differentiating between flow-limiting and
Diagnostic and therapeutic impact of cardiac CT in
The use of coronary CTA in low-to-intermediate risk symptomatic
patients would prevent ICA in patients with a normal coronary CTA.
In the setting of acute chest pain in the emergency department,
patients can be rapidly and effectively triaged in addition to
excluding extracardiac causes of chest pain. It is conceivable,
however, that coronary CTA may result in an increase in the number
of unnecessary ICA procedures and subsequent revascularizations.
This was seen in a recent study in which more patients in the
coronary CTA arm underwent ICA and subsequent revascularization
than did those treated with the standard of care.
Although requiring further validation, the diagnosis of flow-
limiting CAD by coronary CTA may identify patients who warrant
intensified risk factor modification and goal-directed medical
therapy. Additionally, individuals with flow-limiting CAD by
coronary CTA will likely be referred for additional diagnostic
testing, possibly ICA with revascularization, especially in the
setting of left main coronary artery or multivessel disease.
Cost-effectiveness of cardiac CT in symptomatic
There are limited data that suggest that coronary CTA appears to
be a time- and cost-effective strategy in patients presenting with
acute chest pain to the emergency room. Coronary CTA has been shown
to significantly reduce the median diagnostic time in patients
undergoing MDCT angiography (3.4 versus 15 hours) compared with
patients treated with the standard of care. Reduced cost is
primarily a result of reduced length of stay.
Although this study does not show cost-effectiveness, it suggests a
potential cost-effective approach if applied across large numbers
of patients presenting to emergency departments annually for acute
In symptomatic persons with stable chest pain, CTA has been
shown to be cost-effective in individuals with low-to-intermediate
pretest likelihood of CAD (<50%) as compared with traditional
diagnostic modalities, such as ICA, stress echocardiography, and
exercise treadmill tests. In individuals with higher pretest
likelihood, ICA was more cost-effective.
Contraindications and limitations of cardiac CT
Multiple contraindications to performing cardiac CT exist
relating to patient safety and potential artifacts. Because of the
need for iodinated contrast agents, cardiac CT should be avoided in
individuals with intravenous contrast allergies and renal
insufficiency. There is a small but non-negligible risk of
contrast-induced nephropathy; however, it is associated with high
in-hospital morbidity and mortality.
Radiation exposure has been linked to malignancy and birth defects.
Consequently, women who are pregnant or breastfeeding should not
undergo cardiac CT. With the widespread use of cardiac CT for the
detection of subclinical coronary artery atherosclerosis, this has
become an issue, especially in young women because of the risk of
breast cancer. A recent study reported the estimated lifetime risk
attributable to a single coronary CTA to be as high as 1 in 143 for
a 20-year-old woman.
Additionally, obese patients require increased X-ray tube current
output for adequate tissue penetration and spatial resolution and
thus receive a higher radiation dose.
Factors that lead to artifact include arrhythmias (atrial
fibrillation or flutter and premature ventricular or arterial
contractions), heart rate >65 beats per minute that is
refractory to beta-blockade,
metallic structures (vascular clips, bypass graft anastomosis
markers, and metallic valves), dense calcium, coronary artery
stents, body mass index (BMI) >40 kg/m
, and poor opacification.
As a result of blooming artifacts (caused by partial-volume
effect resulting in a brighter appearance adjacent to the calcium),
calcium in the vessel wall obscures the lumen and reduces the
ability to detect stenosis. Multiple studies have shown the
deleterious effects of CAC on diagnostic accuracy as a result of
increasing the percent of unevaluable segments, resulting in lower
sensitivities and specificities.
Metal objects, such as vascular clips, are also susceptible to
X-ray scatter, resulting in streak artifacts. Extreme obesity
results in excessive radiation attenuation with subsequent
reduction in signal-to-noise ratio. Examples of these artifacts are
illustrated in Figure 5. Newer technology using DSCT has been shown
to reduce the effect of calcification on image quality.
Cardiac motion artifacts are a major cause of image degradation.
Heart rate irregularity results in slice misregistration.
Similarly, poor gating can result in slice misregistration
artifact. This artifact can be minimized through image
reconstruction techniques. Figure 6 shows an example of a patient
before and after correction for inappropriate gating. Typical
reconstruction intervals are at 60% of diastole, although the
optimal reconstruction interval providing the least amount of
motion may vary by patient and vessel. An example of optimizing
image quality by changing the reconstruction interval is
illustrated in Figure 7. Initial feasibility studies using
256-slice CT have shown the ability to perform the entire study in
1 cardiac cycle without electrocardiographic gating, thus
potentially eliminating artifacts from heart rate variability.
Fast heart rates cause image blurring (Figure 8). Beta-blockers are
typically given to achieve an optimal heart rate <65 bpm. With
improved technology, such as DSCT, higher heart rates may be
acceptable, thereby eliminating the need for heart rate control.
In addition to potential artifacts, a significant limitation of
this technology is that cardiac CT provides only the presence and
extent of atherosclerosis but does not assess for myocardial
ischemia. Nor at the present time does cardiac CT provide
prognostic information regarding long-term cardiovascular morbidity
and mortality. In contrast, stress testing (such as myocardial
perfusion imaging) offers both evaluation for ischemic burden as
well as the associated prognostic implications. Current efforts to
use hybrid-imaging techniques, such as single-photon emission CT
(SPECT)/CT and positron emission tomography (PET)/ CT are being
developed and potentially could provide near-simultaneous anatomic
and physiologic information. An initial feasibility study has shown
improved diagnostic accuracy with hybrid SPECT/CT when compared
with MDCT alone.
Professional society recommendations
The exact role of cardiac CT has not been fully elucidated, and
the guidelines are evolving. A recent scientific statement
published by the AHA suggests that there is conflicting evidence
and diverging opinions about the usefulness of cardiac CT for the
detection of coronary artery atherosclerosis. According to the AHA
guidelines, CAC assessment is useful for the detection of
subclinical CAD in intermediate-risk asymptomatic individuals. For
symptomatic persons, coronary CTA is useful in those with
low-to-intermediate pretest likelihood of CAD.
Additionally, several imaging societies have collaborated on the
2006 Appropriateness Criteria for Cardiac CT Imaging.
According to this consensus statement, the usefulness of CAC
measurement is uncertain in asymptomatic individuals. Coronary CTA
is considered to be appropriate for the evaluation of both stable
angina and acute chest pain in individuals with intermediate
pretest probability of CAD.
The usefulness of coronary CTA in patients following
revascularization is uncertain in symptomatic individuals and is
considered to be inappropriate in asymptomatic individuals.
Although promising, cardiac CT still has limitations that
prevent a broad clinical application in the detection of coronary
artery atherosclerosis. In addition, it is a problem that no large
trials have firmly established its clinical utility,
cost-effectiveness, or the best way to integrate cardiac CT in the
work-up of patients with suspected CAD. Multiple technologic
advancements on the horizon (including DSCT, 256slice MDCT, and
hybrid imaging with PET-CT or SPECT-CT) will offer the potential
for reduced artifacts and for an overall improvement in diagnostic
accuracy. On-going randomized trials are evaluating the potential
applications of coronary CTA in the evaluation of acute chest pain.
The future is bright for cardiac CT as a potential mainstay of
noninvasive imaging of coronary arteries.
I would like to thank Drs. Pamela Woodard and Robert Gropler for
their mentorship and Drs. Santosh Mathews, Suraj Kurup, Michael
Barry, Brian Seeck, and Peter Rao for their constructive criticism
of the manuscript.