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Education in Heart
1
Department of Cardiology and
Angiology, University Hospital
Münster, Münster, Germany
2
Division of Cardiology,
Robert-Bosch-Krankenhaus,
Stuttgart, Germany
Correspondence to
Professor Ali Yilmaz,
Department of Cardiology and
Angiology, University Hospital
Münster, Albert-Schweitzer-
Campus 1, Gebäude A1,
Münster 48149, Germany;
ali.yilmaz@ukmuenster.de
Published Online First
3 April 2014
To cite: Yilmaz A,
Sechtem U. Heart
2014;100:1886–1896.
1886
ISCHAEMIC HEART DISEASE
Ischaemia testing in patients with stable angina:
which test for whom?
Ali Yilmaz,1 Udo Sechtem2
Coronary artery stenoses frequently cause chest
pain and/or dyspnoea. The clinical challenge for a
physician taking care of patients presenting for the
first time with such symptoms is to find out the
underlying cause by applying a straightforward and
accurate diagnostic approach—which minimises use
of personal and financial resources while achieving
a conclusive and clinically helpful diagnosis. Since
(1) the clinical picture of patients presenting with
symptoms of chest pain and/or dyspnoea is multifa-
ceted, and (2) the diagnostic armamentarium for
work-up of suspected coronary artery disease
(CAD) is steadily growing, an evidence based and
profound knowledge of the diagnostic value and
specific features/requirements of diagnostic tests is
mandatory in order to choose the appropriate
modality for the individual patient. Therefore, this
article will focus of the pre-test assessment of clin-
ical symptoms in patients with suspected CAD, and
the subsequent selection of the most appropriate
diagnostic modality for work-up of CAD.
DEFINITION OF CLINICAL SYMPTOMS
In simple terms, the symptom ‘angina pectoris’
(AP)—and/or the possible equivalent ‘dyspnoea’—
occurs as the result of a mismatch between myocar-
dial oxygen demand and supply; for example, it
may be caused by an epicardial coronary artery
stenosis leading to myocardial ischaemia in the
respective myocardial territory distal to the sten-
osis. In a patient with ‘typical’ symptoms of AP, the
discomfort is located retrosternally and occurs
during exercise, since the aforementioned mismatch
in oxygen demand/supply is increased in response
to physical activity and is relieved either by stop-
ping exercise or by administering vasodilating sub-
stances such as glyceryl trinitrate (nitroglycerine).1
In contrast, ‘atypical’ AP is defined as chest discom-
fort fulfilling two out of three conditions associated
with ‘typical’ angina. If only one or none of these
conditions is met, this is termed ‘non-anginal’ chest
pain. ‘Atypical’ angina comprises retrosternal chest
pain which occurs at rest and responds to acute
nitrates. The clinical differentiation between typical
and atypical AP is important since the pattern of
AP symptoms is not only a parameter for determin-
ing the probability of the presence of a significant
coronary artery stenosis, but may also provide a
valuable clue to the underlying pathomechanism
causing the chest pain (figure 1) and enable a more
straightforward diagnostic work-up (as will be dis-
cussed in the following sections). Many patients
with typical exercise related angina also report
occasional attacks of resting angina. This mixture
Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
of symptoms does not necessarily indicate that the
patient is unstable and suffers from intracoronary
thrombosis—but rather that there is an element of
vasospasm modulating the angina threshold (eg,
more angina in cold weather, occasional angina at
rest).
In the past, the occurrence of AP usually indi-
cated the presence of obstructive CAD defined as
narrowing of the left main coronary artery of
≥50% or of other major coronary arteries of
≥70%. However, it has recently become evident
that coronary microvascular disease is another fre-
quent cause of stable AP.2 Thus, angina during exer-
cise (due to a mismatch in oxygen demand/supply)
may be caused by (1) obstructing plaques in epicar-
dial coronary segments, (2) a dynamic stenosis
which becomes more severe during exercise3 or (3)
morphological and/or functional abnormalities in
the myocardial microvasculature. These patho-
mechanisms may not only occur alone but also in
combination and make interpretation of the clinical
picture of the patient even more challenging.
In contrast, resting angina in an otherwise stable
angina patient points to the presence of coronary
spasm. Clinically and angiographically, three types
of spasm can be distinguished4: (1) the Prinzmetal
type of occlusive focal epicardial spasm associated
with variant angina, (2) diffuse distally pronounced
epicardial spasm, and (3) microvascular spasm. As
illustrated in figure 1, obstructive epicardial disease
and microvascular disease are mostly associated
with symptoms of typical exercise related AP,
whereas epicardial and microvascular spasm lead to
atypical (resting) AP. If superimposed elements of
coronary spasm are present, atypical (resting) and
typical angina are reported by patients with ana-
tomical and/or functional obstruction.
INITIAL ASSESSMENT OF PATIENTS WITH
ANGINA PECTORIS
First of all, well known risk factors that accelerate the
development of CAD and are associated with a worse
prognosis need to be assessed. They comprise
(among others) hypertension, hypercholesterolaemia,
diabetes, smoking, obesity, and a positive family
history for CAD. After a thorough history taking and
physical examination, the following tests should be
applied to all patients with stable AP: biochemical
tests, resting ECG, and resting echocardiography.1
Biochemical tests should comprise a full blood
count, including haemoglobin and white cell count,
in addition to thyroid hormone measurement in
order to assess the presence of anaemia,
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Figure 1 Association between the type of angina and the possible underlying
mechanism. AP, angina pectoris; CAD, coronary artery disease.
inflammatory constellations and thyroid disorders,
since such disorders can cause and/or aggravate
myocardial ischaemia. Glycated haemoglobin
(HbA1c) should be measured to identify the pres-
ence of diabetes mellitus since cardiovascular
outcome is worse in diabetes patients—independ-
ent of other conventional risk factors. Moreover, a
lipid profile with measurement of low density lipo-
protein cholesterol as well as renal function para-
meters should be obtained, and B-type natriuretic
peptide (BNP)/N terminal proBNP (NT-proBNP)
measurements should be performed in those
patients with additionally suspected heart failure.
Obviously, the risk for the presence of (obstructive)
CAD increases with an increasing number of such
risk factors.
Moreover, a 12-lead resting ECG should be
recorded in every patient with suspected CAD.
Figure 2 Approach to the patient
with chest pain and/or dyspnoea
before choosing non-invasive imaging
modalities. AP, angina pectoris; CA,
coronary angiography; CAD, coronary
artery disease; LV-EF, left ventricular
ejection fraction. Modified with
permission from Montalescot et al.1
Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
Education in Heart
Such a resting ECG may not only show pre-existing
signs of CAD (such as deep Q waves, ST segment
or T wave abnormalities), but is also helpful in
selecting additional testing modalities for work-up
of suspected CAD. The diagnostic value of a subse-
quent exercise ECG is (further) limited; therefore
its use is not suggested if ECG abnormalities such
as a bundle branch block or ST segment abnormal-
ities are already observed in the resting ECG.
A resting echocardiogram enables assessment of
global and regional left ventricular (LV) function
and the presence of valvular disorders, thereby
either substantiating the suspicion of CAD (eg, in
the presence of regional wall motion abnormalities)
or making CAD more unlikely (eg, in the case of
severe valve disease). Moreover, the measurement
of resting LV systolic function is of decisive value in
selecting additional testing modalities for work-up
of suspected CAD. If the measured LV ejection frac-
tion (LVEF) is <50% and the patient is presenting
with typical AP, then straightforward invasive cor-
onary angiography (ICA) can be performed
without additional preceding non-invasive ischae-
mia testing. However, if differential diagnoses com-
prise non-ischaemic cardiomyopathies, then
non-invasive imaging allowing myocardial tissue
characterisation (such as cardiac MRI) should be
considered before ICA, even in patients with an
LVEF <50%, since such an approach will enable
the combination of ICA with subsequent endomyo-
cardial biopsy if obstructive CAD is ruled out.2 5
However, if the patient is presenting with atypical
chest pain or LVEF ≥50%, then non-invasive
imaging modalities have to be considered before
any invasive procedure (figure 2).
CALCULATION OF PRE-TEST PROBABILITIES
As recently outlined by Montalescot et al1 in the
2013 European Society of Cardiology (ESC) guide-
lines on the management of stable CAD, the
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Education in Heart

positive (assumingly pathological) diagnostic test

Table 1 Determination of the pre-test probability (PTP) for coronary artery
results will be ‘false’ positive (due to the test
disease
specificity of 85%). If such a diagnostic test is
Typical angina Atypical angina Non-anginal pain applied to a group of patients with a PTP of
Age Men Women Men Women Men Women only 10%, for example, then this test may cause
more harm than benefit since the number of
30–39 59 28 29 10 18 5 ‘false’ positive results (up to 15%) can be higher
40–49 69 37 38 14 25 8 than the likelihood of pre-existing CAD
50–59 77 47 49 20 34 12 (=10%). Hence, it is better to assume that all
60–69 84 58 59 28 44 17 patients are healthy and not to apply such a test
70–79 89 68 69 37 54 24 method in patients with a PTP <15%, since the
>80 93 76 78 47 65 32 clinical likelihood of CAD is lower (<15%)
White boxes have a PTP <15%, blue boxes a PTP of 15–65%, pink boxes a PTP of 66–85%, and red boxes than the likelihood of a false positive test result.
a PTP >85%. Reproduced with permission from Montalescot et al. Eur Heart J 2013;34:2949–3003.1 ▸ In contrast, if such a test is applied to a group of
‘diseased’ patients, then again exactly 15% of
the negative (assumingly healthy) diagnostic test
results will be ‘false’ negative (due to the test
‘pre-test probability’ (PTP) should be calculated sensitivity of 85%). If such a diagnostic test is
and assessed for a given patient before selecting a applied to a group of patients with a PTP of
specific non-invasive ischaemia testing modality for 90%, for example, then again this test may
(further) work-up of suspected CAD—since there cause more harm than benefit since the number
exists a clear interdependence between the PTP of ‘false’ negative results (up to 15%) can be
value and the diagnostic performance of an individ- higher than the true number of healthy patients
ual testing method. The PTP value is determined (100% − PTP=10%). Hence, it is better to
by age, gender, and the type of chest pain symp- assume that all patients are diseased and not to
toms (table 1), and reflects the clinical likelihood of perform such a test method in patients with a
a given patient having obstructive CAD. The PTP PTP >85%, since the clinical likelihood of over-
numbers given in table 1 are based on the most looking CAD is lower (<15%) than the likeli-
recent estimates of CAD prevalence (that were hood of getting false negative test results.
obtained prospectively by analysing data from 2260 ▸ For each test one can calculate the upper bound
patients from 14 different hospitals).6 It is note- of PTP above which false negative responses
worthy that the presence of coronary spasm and/or exceed true negative responses.8 9 If one inserts
microvascular disease was not evaluated in this pro- sensitivity of the exercise ECG (for detecting
spective analysis. Hence, the PTP value is import- CAD) of about 50% and specificity of about
ant in assessing the clinical likelihood of 90% (both values corrected for referral bias) in
‘obstructive’ atherosclerotic CAD as one possible the equation ‘PTP <[specificity/(1 − sensitivity)
reason for chest pain—but not appropriate regard- +specificity]’, an upper PTP cut-off value of
ing the presence of other pathomechanisms such as about 65% will result. The use of an exercise
coronary spasm or microvascular disease.2 Hence, ECG is thus only useful in patients with a PTP
other diagnostic approaches have to be considered ≤65%, but not helpful in those with a PTP
if obstructive CAD is unlikely to be the underlying >65%, since the likelihood of getting a false
cause of symptoms.2 4 7 negative test result is more likely than the clin-
The interdependence between the PTP value and ical likelihood of overlooking CAD (<35%) in
the diagnostic performance of an individual testing such patients (if one assumes all patients to be
method needs to be addressed in more detail in diseased).
order to understand the new diagnostic algorithm In order to optimally use the resources available
that was suggested in the 2013 ESC guidelines on for work-up of patients with AP and suspected
the management of stable CAD.1 Briefly, a Bayesian CAD, PTP values should be used following a thor-
approach starts from the so-called PTP which is, ough history taking and physical examination.
for example, the prevalence of coronary artery Considering the aforementioned Bayesian approach
stenoses in a cohort of persons defined by age, sex, and the current diagnostic sensitivities and specifici-
and type of angina. This probability is subsequently ties for each diagnostic modality, the respective
updated in the light of the test result and this is ESC guidelines established a new diagnostic algo-
called the post-test probability. Importantly, the use rithm for patients with suspected CAD (figure 3).
of a diagnostic test method only makes sense in a The major suggestions can be summarised as
low prevalence (low PTP) cohort (and hence is follows:
only suggested under this circumstance) if the ▸ No ischaemia testing is required in patients with
number of ‘false negative’ results after the test is a PTP <15% due to the low likelihood of CAD.
lower than the number of false negative results However, other diagnostic approaches to dem-
based on the PTP. onstrate coronary vasospasm and/or microvascu-
▸ For example, if a diagnostic test method has a lar disease as underlying causes have to be
sensitivity and specificity of around 85%, considered.1
respectively, and is applied to a group of ▸ Exercise ECG can be performed (if feasible) in
‘healthy’ patients, then exactly 15% of the patients with a PTP of 15–65%, provided the LV
1888 Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
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Figure 3 Diagnostic approach to the
patient with chest pain and/or
dyspnoea dependent on the pre-test
probability (PTP) of obstructive
coronary artery disease (CAD). AP,
angina pectoris; CA, coronary
angiography; LV-EF, left ventricular
ejection fraction. Modified with
permission from Montalescot et al.1
systolic function is not impaired (LVEF ≥50%).
The diagnostic value of exercise ECG is further
limited in the presence of left bundle branch
block (LBBB), paced rhythm, LV hypertrophy,
Wolff-Parkinson-White (WPW) syndrome, digi-
talis treatment, and electrolyte disturbances.
▸ Non-invasive stress imaging modalities such as
stress echocardiography, cardiovascular MR
(CMR), single photon emission CT (SPECT) or
positron emission tomography (PET) are sug-
gested in patients with a PTP of 15–85%—par-
ticularly in those patients with a PTP between
65–85% or an impaired LV systolic function
(LVEF <50%)—except in patients with typical
angina in whom ICA is suggested.
ADVANTAGES AND LIMITATIONS OF
NON-INVASIVE IMAGING MODALITIES
Stress echocardiography
Stress echocardiography allows the (indirect) evalu-
ation of inducible ischaemia following an inotropic
stimulus such as physical exercise (eg, bicycle;
figure 4) or a pharmacological agent such as dobu-
tamine (dobutamine stress echocardiography
(DSE)). Both stimuli lead to an increased myocar-
dial workload and an increased myocardial oxygen
demand. DSE is based on the stepwise intravenous
administration of 5/10/20/40 mg/kg/min dobuta-
mine (each step lasting 2–3 min). Additional atro-
pine administration is performed if the targeted
increase in heart rate is not achieved by dobuta-
mine alone. Second harmonic imaging is performed
at each step (in different views) in order to detect
either new segmental wall motion abnormalities
(WMA), worsening of pre-existing WMA, or
increasing contractility using a 16- or 17-segment
model. A good acoustic window allowing a clear
endocardial contour detection is essential for a
good diagnostic result. Contrast enhanced endocar-
dial contour detection can improve the diagnostic
Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
Education in Heart
yield and is advocated in patients with a limited
acoustic window. Occurrence of a regional WMA
in response to increasing stress suggests that this
region is supplied by a stenosed artery.
Improvement of contractile function in a region
with WMA at rest in response to stress is suggestive
of preserved myocardial viability, despite the pres-
ence of myocardial damage (infarction) or func-
tional abnormalities (stunning/hibernation).
Absence of any improvement in contractile func-
tion is indicative of severe structural abnormalities
such as (chronic) fibrosis following myocardial
infarction.
Previous studies primarily based on DSE showed a
mean sensitivity of 80–85% and a specificity of 80–
88% for detection of obstructive CAD.10 Hence, the
diagnostic accuracy—in particular the high negative
predictive value—of stress echocardiography is
remarkable considering the simplicity, wide availabil-
ity, and low costs of this method. However, limita-
tions of stress echocardiography comprise, in
particular, technical challenges such as a poor acous-
tic window in, for example, adipose patients, a quite
difficult assessment of WMA in segments with previ-
ous myocardial infarction due to a passive tethering
motion, and a non-neglectable degree of intra- and
inter-observer variability of test results.
Appropriateness criteria that should help to select
those patients who are most likely to have a correct
indication and subsequent clinical benefit from a
stress echocardiography study were published in
2008,11 although they did not really change the real-
world implementation of the method. Moreover, the
diagnostic accuracy of SonoVue enhanced myocardial
contrast echocardiography (MCE)—a promising
technique that enables myocardial perfusion imaging
following the administration of a vasodilator sub-
stance—was compared to SPECT for assessment of
CAD.13 Disappointingly, in spite of a surprisingly
higher sensitivity of MCE (75%) compared to
SPECT (49%), its specificity was extremely low
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Education in Heart

Figure 4 Example of stress echocardiography (bicycle exercise) with respective ECG recordings. At rest, the ECG was normal, and
echocardiography demonstrated normal wall motion (A). At 50 W of stress exposure, minor ECG changes were observed (subtle ST segment
elevation in leads V1 through V2 and ST segment depression in leads II, III, and aVF), whereas echocardiography revealed hypokinesis in the
anteroseptal wall (B, arrow). At 100 W of stress exposure, ECG changes increased, and echocardiography demonstrated akinesis of the anteroseptal
wall (C, arrow). After exercise was stopped, the ECG changes disappeared, and wall motion in the anteroseptal segments returned to normal (D).
Reproduced with permission from Yilmaz et al. Circulation 2010;122:e570–4.3

(52%). Therefore, MCE cannot be recommended for
routine clinical use.
Another difficulty—and this relates to all imaging
techniques used for the detection of coronary artery
stenoses—is that only a few of the published
studies14 corrected for ‘referral bias’. As recently
illustrated by Ladapo et al,15 the term ‘referral bias’
is used to describe the referral pattern of clinicians
by considering that patients with a pathological
stress test result are more frequently referred for
subsequent cardiac catheterisation compared to
those with normal test results. Obviously, this behav-
iour is understandable from a clinical point of view.
However, referral bias needs to be appropriately
considered when assessing the diagnostic perform-
ance of a test, because it usually leads to overesti-
mation of the sensitivity and underestimation of the
specificity of a technique.15 For example, suppose
all patients with a pathologic stress echocardiog-
raphy were referred for ICA, but not those with a
normal stress echocardiography. The observed sensi-
tivity of stress echocardiography for obstructive
1890 Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
CAD would be 100% because all patients with a
stenosis would—by the inclusion criterion—have a
pathologic stress echocardiography. In contrast, spe-
cificity of stress echocardiography would be 0%
because all patients without a stenosis at ICA would
also have a pathologic stress echocardiography. If
the precise referral pattern (eg, 15-fold higher refer-
ral after a pathologic test result) is known, one can
adjust for the bias.15 For example, with correction
for referral bias, exercise echocardiography sensitiv-
ity falls from 84% to 34%, and specificity rises from
69% to 99%. In addition, adjusting for referral bias
increases the positive predictive value but reduces
the negative predictive value.15 The practical impli-
cations of considering referral bias for the practising
clinician are challenging since the individual referral
pattern needs to be assessed, and appropriate data
on this issue are limited.
SPECT
The most frequently performed SPECT tracers
used today are technetium-99m (99mTc) based
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compounds. There are different SPECT protocols
combining rest and stress imaging scans—either on
the same day or on different days. The uptake of
99m
Tc is dependent on the mitochondrial mem-
brane integrity and on myocardial perfusion. The
degree of radiotracer uptake is mainly determined
by myocardial perfusion. In the case of myocardial
ischaemia/hypoxia and or myocardial damage (eg,
infarction), radiotracer uptake is decreased or com-
pletely absent. Scans performed at resting condi-
tions allow the assessment of (regional) myocardial
viability, whereas those additionally performed
during exercise (eg, adenosine perfusion) enable
the assessment of both myocardial ischaemia and
viability (figure 5). Moreover, gated SPECT studies
allow the assessment of (global) LV systolic func-
tion and help to limit attenuation artefacts (eg,
caused by the diaphragm).
While stress echocardiography is mainly used for
(indirect) assessment of inducible ischaemia (apart
from MCE), SPECT allows the direct visualisation of
perfusion abnormalities which occur earlier in the
ischaemic cascade compared to (regional) WMA.
Hence, compared to stress echocardiography, SPECT
imaging allows a more sensitive and accurate assess-
ment (and quantification) of ischaemic, viable, and
non-viable myocardium.16
Previous SPECT studies suggested a high sensitiv-
ity of 90–91%, but a lower specificity of 75–84%,
for detection of obstructive CAD.10 The limitations
of these studies, which did not correct for referral
bias, are discussed above. The recent CE-MARC
study14 17 was designed to send all patients to ICA
irrespective of the result of the stress tests applied.
Figure 5 Example of a single photon emission CT (SPECT) study. Pure inducible ischaemia on stress (A) and rest (B) imaging and polar plots (C).
Reduction of tracer uptake was observed on stress imaging (arrows), severe at the apex and mild in the anterior wall, which returned to normal at
rest. Reproduced with permission from Zamorano et al. The ESC Textbook of Cardiovascular Imaging. Springer, 2012.26
Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
Education in Heart
In this study, which thus corrected for referral bias,
the sensitivity of SPECT was 51% for women and
71% for men.
SPECT as a nuclear imaging technique has a non-
negligible burden of radiation for the patient and
adverse long term effects are possible. Radiation
burden is up to 8.5 mSv if 99mTc based radiotracers
are used.18 The radiation associated with the use of
thallium-201 (201Th) radiotracers is even higher.18
This is why 201Th radiotracers are less commonly used
today for diagnosing myocardial ischaemia. However,
new SPECT cameras reduce radiation and/or acquisi-
tion time significantly.19 Nevertheless, for radiation
safety, SPECT studies should be avoided in young
patients and should not be repeated for regular or
close follow-up. On the other hand, SPECT imaging
has some unique advantages compared to other
imaging modalities. It can be easily, rapidly and suc-
cessfully performed not only in patients with severe
dyspnoea, but also in those with arrhythmias,
implanted devices, and/or advanced renal disease—
which is not possible with other imaging techniques.
PET
Similar to SPECT, PET studies allow the evaluation of
LV systolic function and myocardial ischaemia.
Following pharmacological stressing with, for
example, intravenous adenosine administration, myo-
cardial perfusion is assessed using radiotracers such as
13
N ammonia, 15O labelled water or rubidium-82
82
( Ru). PET imaging shows a higher spatial resolution
than SPECT imaging (2–3 mm vs 4–6 mm) and is
more sensitive than SPECT. Previous PET studies sug-
gested a high sensitivity of up to 97%, but a specificity
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Education in Heart
Figure 6 Example of cardiovascular MR (CMR) perfusion study. Perfusion sequences obtained during adenosine infusion revealed a septal
perfusion defect (A, arrows) which was not seen at rest. Corresponding invasive coronary angiography revealed a significant stenosis in the left
anterior descending coronary artery (arrow). Reproduced with permission from Yilmaz and Sechtem. Dtsch Med Wochenschr 2008;133:644–9.27
as low as 74% for the detection of obstructive CAD.
Radiation burden is approximately 5 mSv in PET
using 82Ru. Unfortunately, the availability of this cost
intensive modality and its radiotracers is limited.
Therefore, PET is less often used as compared to
SPECT. However, the most accurate quantitative
assessment of myocardial perfusion is obtained by
PET imaging and this is helpful for identifying patients
with microvascular disease as the cause of angina.
Hybrid imaging modalities such as PET-CTare gaining
increasing clinical interest and importance.20
CMR
Today, 1.5 T MRI scanners are commonly available,
even in tertiary care centres, and represent a sine qua
non diagnostic tool for numerous, mostly non-
cardiac, diseases. CMR has gained worldwide accept-
ance in the diagnosis and therapy surveillance of
cardiac diseases due to several advantages21: (1)
CMR achieves a highly accurate evaluation of struc-
tural (anatomic) as well as functional cardiac para-
meters at the same time; (2) CMR is free of some
major limitations of other cardiac imaging modalities
such as a poor acoustic window in echocardiography
or radiation burden in SPECT, PET or CT; (3) CMR
enables different forms of stress testing (such as
adenosine perfusion imaging or dobutamine stress
cine imaging).
Similar to stress echocardiography, stress CMR
can be performed based on increasing steps of
dobutamine infusion followed by the application of
cine sequences for accurate detection of WMA.
This technique has a diagnostic accuracy similar to
DSE in patients with a good acoustic window;
however, as expected, it is superior to DSE in
patients with limited acoustic windows.22 However,
stress CMR is more frequently performed using
adenosine infusion followed by a first-pass perfu-
sion sequence (after administration of a gadolinium
based compound) that enables the detection of
ischaemic myocardial areas characterised by perfu-
sion deficits (figure 6)—similar to SPECT or PET.
Previous studies were mostly performed on 1.5 T
MR scanners and showed a high sensitivity of up
to 94%, but a specificity as low as 61%, for
1892 Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
detection of obstructive CAD. The lower specificity
of this method regarding the detection of CAD is
partly explained by the presence of microvascular
disease—which may also cause myocardial ischae-
mia in the absence of obstructive CAD—in some
patients with clinically suspected CAD.23
Recent studies performed on 3.0 T MR scanners
resulted in an even higher diagnostic accuracy.24 The
CE-MARC study obtained sensitivity and specificity
values in a cohort of patients without referral bias.14
17
This study employed a multi-parametric approach
using information from LV function imaging, MR
coronary angiography, and contrast and perfusion
imaging. For this approach, the sensitivity was 89%
in women and 86% in men, whereas the specificity
was 84% and 83%, respectively. When considering
the information obtained from perfusion imaging
alone, sensitivity was 75% for women and 81% for
men at specificities of 93% and 89%, respectively.17
In this particular study, sensitivities were the same for
SPECT and MR perfusion in men. However, for
women both sensitivity and specificity were higher
for MR perfusion than for SPECT, and this was also
true for the specificity in men.17
It should be noted that, apart from local expertise
in performing CMR studies, correct patient selection
is of the utmost importance for a high yield CMR
study. Patients with dyspnoea unable to hold their
breath or those with arrhythmia (atrial fibrillation,
recurrent extrasystole) are not well suited for under-
going CMR. Moreover, implanted cardiac devices
and advanced renal disease represent (relative) con-
traindications that have to be considered. Cost, avail-
ability, and local expertise are other obvious aspects
that need to be taken into account.
Coronary CT
In contrast to the above modalities, the main appli-
cation of cardiac CT is the non-invasive assessment
of coronary anatomy with an intriguing spatial
resolution (0.25×0.25 mm in-plane with modern
scanners). Following the intravenous administration
of a ( potentially nephrotoxic) contrast agent, cor-
onary CT angiography (CCTA) is used to visualise
the coronary lumen and wall in order to assess the
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Education in Heart

Figure 7 Coronary CT angiography and invasive angiography of a female patient with suspected coronary artery disease. (A–C) Curved multiplanar
reconstructions of the left main and left anterior descending coronary arteries, left circumflex artery, and right coronary artery. (D, E) Invasive
coronary angiography of the left and right coronary arteries. There was no coronary artery stenosis. Reproduced with permission from Achenbach
et al. JACC Cardiovasc Imaging 2011;4:328–37.28

Table 2 Comparison of non-invasive imaging modalities

Stress echocardiography SPECT/PET Stress-CMR Coronary CT

Time to perform 30–45 min
the test
Special No (apart from an
equipment appropriate ultrasound
system)
Sensitivity vs 80–85% vs 80–88% (not
specificity corrected for referral bias)
Operator Highly important for high
experience diagnostic yield
Major ▸ Wide availability
advantages ▸ Low costs
▸ High spatial and
temporal resolution
▸ No radiation burden
▸ Feasible in case of
advanced renal disease
▸ Feasible in patients with
devices
▸ High diagnostic
specificity and functional
predictive value
Major ▸ Pour acoustic window in
disadvantages some patients
▸ High intra- and
inter-observer variability
▸ Difficult assessment of
infarcted segments
▸ Possible side effects of
dobutamine in DSE
CMR, cardiovascular magnetic resonance; DSE, dobutamine stress echocardiography; LV, left ventricular; MR, magnetic resonance; PET, positron emission tomography; SPECT, single
photon emission CT.
Image acquisition 5–8 min with new cameras 40–50 min (including functional and <1 min
(1d protocol at 6 mSv total effective dose); morphological imaging)
total time ∼45 min
Yes (SPECT/PET camera+specific tracer) Yes (MR scanner+contrast agent) Yes (appropriate CT
scanner+contrast agent)
90–91%/81–97% vs 75–84%/74–91% 67–94% vs 61–85% (sensitivity 89% and 95–99% vs 64–83%
(sensitivity 51% and 71% in women and 86% in woman and men, respectively, in
men, respectively, in study without referral study without referral bias)
bias)
Important in performing the test (although Important in assessing ischaemic regions Important in assessing
automated analysis is feasible) and excluding artefacts stenoses and excluding
artefacts
▸ Wide availability (SPECT) ▸ High spatial and temporal resolution ▸ Wide availability
▸ Feasible in patients with dyspnoea ▸ Images in all axes possible ▸ Highest spatial and
▸ Feasible in case of advanced renal ▸ No windowing limitation temporal resolution
disease ▸ No radiation burden ▸ Direct visualisation of
▸ Feasible in patients with devices ▸ Multi-parametric imaging with plaques and stenoses
▸ High diagnostic sensitivity (particularly acquirement of functional and ▸ Feasible in patients
PET) structural parameters with devices
▸ High diagnostic sensitivity and ▸ High diagnostic
specificity sensitivity and high
negative predictive
value
▸ Radiation burden ▸ Cost intensive ▸ Radiation burden
▸ Cost intensive ▸ Restricted in case of advanced renal ▸ Cost intensive
▸ Low spatial resolution disease ▸ Restricted in case of
▸ Lower specificity than DSE or stress CMR ▸ Not feasible in patients with devices advanced renal
▸ Possible side effects/contraindications of ▸ Patient breath-hold required disease
adenosine ▸ Possible side effects/contraindications ▸ Only anatomic data,
▸ Diaphragmatic attenuation artefacts in of adenosine/dobutamine limited functional data
the inferior LV wall ▸ Sinus rhythm helpful ▸ Not helpful in case of
severe coronary
calcification
▸ Sinus rhythm and low
heart frequency
required

Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255 1893

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Education in Heart

calcifications of the coronary wall lead to an exag-

Ischaemia testing in patients with stable angina: key points gerated bright signal and prevent a meaningful
assessment of the degree of lumen narrowing in
this area. Therefore, the diagnostic sensitivity of
▸ The clinical differentiation between typical and atypical angina pectoris
CCTA for the detection of obstructive CAD is far
(AP) is important since the pattern of AP symptoms determines the
higher than its specificity (95–99% vs 64–83%).10
probability of the presence of a significant coronary artery stenosis and
Based on Bayesian principles, the upper cut-off
gives valuable clues to the underlying pathomechanism.
for using CCTA for excluding/making the diagnosis
▸ Apart from obstructive coronary artery disease (CAD), other
of obstructive CAD would be at a PTP of 99%.
pathomechanisms such as coronary vasospasm or microvascular disease
There would be only a few false negatives up to
have to be considered as possible underlying reasons for chest pain and/or
this high PTP due to the reported high sensitivity
dyspnoea, and require different diagnostic approaches.
of the technique. However, in older patients (the
▸ The ‘pre-test probability’ (PTP) value should be calculated and assessed for
main factor to increase PTP) calcifications become
a given patient before selecting a specific, non-invasive, ischaemia testing
more prevalent, leading to many false positives
modality for work-up of suspected CAD.
which limit the use of CCTA in this important sub-
▸ No ischaemia testing is required in patients with a PTP <15% due to the
population. Consequently, the 2013 ESC guidelines
low likelihood of CAD.
on the management of stable CAD1 suggest the use
▸ Exercise ECG can be performed (if feasible) in patients with a PTP of 15–
of CCTA only in those (symptomatic) patients with
65%, provided the LV systolic function is not impaired (LVEF ≥50%).
a PTP value of 15–50%. As with all the other
▸ Non-invasive stress imaging modalities such as stress echocardiography,
imaging modalities, appropriate patient selection is
CMR, SPECT or PET are suggested in patients with a PTP of 15–85%—
crucial in order to achieve high quality CCTA
particularly in those patients with a PTP between 65–85% or an impaired
images. Patients should be in sinus rhythm and
LV systolic function (LVEF <50%)—except in those with typical angina in
resting heart rate should be <65/min; there should
whom invasive coronary angiography is suggested.
be no arrhythmias or advanced renal disease.
▸ Coronary CT is suggested only in those patients with a low to intermediate
PTP of 1–50%.
▸ Patient characteristics and local expertise in non-invasive imaging
APPROACH TO PATIENTS WITH
modalities is of paramount importance when choosing the most
MICROVASCULAR DISEASE OR CORONARY
appropriate imaging technique.
SPASM
If obstructive CAD is rather unlikely as the under-
lying cause of symptoms (such as in women with
presence of lumen narrowings and plaque forma- atypical symptoms and a low PTP for obstructive
tion in the vessel wall (figure 7). Radiation dose CAD), or symptoms are unchanged in spite of suc-
has decreased over the past decade and high quality cessful percutaneous coronary intervention and
images can be acquired at doses <1 mSV and even stenting of epicardial stenoses, other diagnostic
lower with new reconstruction algorithms.25 approaches have to be considered, with a major
However, the presence of severe coronary wall cal- focus on microvascular disease and/or coronary
cification (defined as an Agatston score >400) spasm. For more detailed information on this issue,
limits the diagnostic accuracy/yield of CCTA due to several reviews are suggested.2 4 7 Briefly, micro-
the so-called ‘blooming’ effect—severe vascular disease should be suspected in patients
presenting with typical (exercise induced) AP but
who have normal coronary arteries or only minor
irregularities (<50%). Ischaemia testing using
You can get CPD/CME credits for Education in Heart CMR, SPECT or PET may demonstrate the pres-
ence of inducible (rather diffuse) myocardial ischae-
mia—in the absence of obstructive CAD. Stress
Education in Heart articles are accredited by both the UK Royal College of
echocardiography may be helpful as the initial test
Physicians (London) and the European Board for Accreditation in Cardiology—
since inducible wall motion abnormalities are
you need to answer the accompanying multiple choice questions (MCQs). To
uncommon in patients with microvascular disease,
access the questions, click on BMJ Learning: Take this module on BMJ
despite the presence of angina and/or ischaemic ST
Learning from the content box at the top right and bottom left of the online
changes. Provocation testing by intracoronary injec-
article. For more information please go to: http://heart.bmj.com/misc/education.dtl
tion of acetylcholine may lead to rather diffuse and
▸ RCP credits: Log your activity in your CPD diary online (http://www.
distally pronounced coronary vasoconstriction (sup-
rcplondon.ac.uk/members/CPDdiary/index.asp)—pass mark is 80%.
posedly extending into the microvasculature) in
▸ EBAC credits: Print out and retain the BMJ Learning certificate once you
some patients with microvascular disease. In con-
have completed the MCQs—pass mark is 60%. EBAC/ EACCME Credits can
trast, resting chest pain ( predominantly occurring
now be converted to AMA PRA Category 1 CME Credits and are recognised
at night or in the early morning hours) in patients
by all National Accreditation Authorities in Europe (http://www.ebac-cme.
without obstructive CAD is rather suggestive of
org/newsite/?hit=men02).
coronary (epicardial) spasm. ECG recordings with
Please note: The MCQs are hosted on BMJ Learning—the best available learning
demonstration of ischaemic ST changes (elevation
website for medical professionals from the BMJ Group. If prompted, subscribers
or depression) at the time of angina may allow the
must sign into Heart with their journal’s username and password. All users must
diagnosis. Moreover, intracoronary provocation
also complete a one-time registration on BMJ Learning and subsequently log in
tests may be used to demonstrate not only the pres-
(with a BMJ Learning username and password) on every visit.
ence but also the type of coronary spasm, which in
1894 Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255
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turn is important regarding therapeutic decision
making.1 4
CONCLUSIONS
In order to determine the underlying cause in a
patient with symptoms of chest pain and/or dys-
pnoea, one has to consider both patient specific as
well as technical/local factors before choosing the
most appropriate non-invasive imaging modality
(table 2). Apart from obstructive CAD, other
pathomechanisms such as coronary vasospasm or
microvascular disease have to be considered as pos-
sible underlying reasons for chest pain and/or dys-
pnoea, and require different diagnostic approaches.
In the case of suspected CAD, determination of the
PTP value is crucial to decide which diagnostic
modality is required and clinically helpful in order
to substantiate or rule out the suspicion of obstruct-
ive CAD. Patient characteristics and the local
expertise in non-invasive imaging modalities is of
paramount importance for choosing the most
appropriate imaging technique.
Competing interests In compliance with EBAC/EACCME
guidelines, all authors participating in Education in Heart have
disclosed potential conflicts of interest that might cause a bias in
the article. AY is financially supported by a grant from the
Robert-Bosch-Foundation.
Provenance and peer review Commissioned; externally peer
reviewed.
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1896 Yilmaz A, et al. Heart 2014;100:1886–1896. doi:10.1136/heartjnl-2013-304255

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Ischaemia testing in patients with stable

angina: which test for whom?
Ali Yilmaz and Udo Sechtem

Heart 2014 100: 1886-1896 originally published online April 3, 2014

doi: 10.1136/heartjnl-2013-304255

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