Noninvasive cardiac imaging in suspected acute coronary syndrome

Pankaj Garg1, S. Richard Underwood2,3, Roxy Senior4, John P. Greenwood1and Sven Plein1

Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Clarendon Way, Leeds

LS2 9JT, UK.

Imperial College London, London SW7 2AZ, UK.

Royal Brompton & Harefield NHS Trust, Sydney St, London SW3 6NP, UK.

Royal Brompton Hospital and Cardiovascular Biomedical Unit, National Heart and

Lung Institute, Imperial College London, Sydney St, London SW3 6NP, UK.

Correspondence to S.P.
[email protected]

Abstract | Noninvasive cardiac imaging has an important role in the assessment of patients with acuteonset chest pain. In patients with suspected acute coronary syndrome (ACS), cardiac imaging offers
incremental value over routine clinical assessment, the electrocardiogram, and blood biomarkers of
myocardial injury, to confirm or refute the diagnosis of coronary artery disease and to assess future
cardiovascular risk. This Review covers the current guidelines and clinical use of the common
noninvasive imaging techniques, including echocardiography and stress echocardiography, computed
tomography coronary angiography, myocardial perfusion scintigraphy, positron emission tomography, and
cardiovascular magnetic resonance imaging, in patients with suspected ACS, and provides an update on
the developments in noninvasive imaging techniques in the past 5 years.

Chest pain suggestive of acute coronary syndrome (ACS) is a common cause of presentation to
emergency departments in developed countries and contributes to 2037% of medical admissions

1,2

. In

up to 90% of patients presenting with suspected ACS, the diagnosis is subsequently ruled out, generally
after a period of observation and a series of investigations that lead to substantial health-care costs

3,4

Diagnostic pathways based on the 12-lead electrocardiogram (ECG) and on older-generation blood
biomarkers missed ACS in 25% of patients, potentially resulting in inappropriate discharge

57

. Modern

blood biomarkers, such as fifth-generation troponins measured with a highly sensitive assay, improve the
detection of ACS, but can have low specificity, which leads to unnecessary further investigations 8. Hearttype fatty acid-binding protein is a novel biomarker of myocardial ischaemia that provides incremental
value when used in combination with troponins measured with a highly sensitive assay 9. However, even
with modern biomarkers, ACS cannot reliably be ruled out from a single early blood sample, and current
guidelines recommend serial sampling that necessitates prolonged observation 10. Furthermore, evidence
of the diagnostic value of novel cardiac biomarkers in patients with unstable angina is insufficient; these
patients, by definition, have no elevation of conventional serum markers 10,11.
Cardiac imaging can complement history, ECG, and cardiac biomarkers for a timely identification and
exclusion of ACS (FIG. 1). When appropriately used, imaging can reduce the rate of missed diagnoses
and guide the management of those patients with confirmed ACS. The most commonly used noninvasive
techniques are discussed in this Review, including echocardiography and stress echocardiography,
computed tomography coronary angiography (CTCA), myocardial perfusion scintigraphy (MPS), and
cardiovascular magnetic resonance (CMR) imaging. An overview of the relative strengths and
weaknesses of each of these modalities in the assessment of patients with acute chest pain is given in
Table 1.

Transthoracic echocardiography
The European Society of Cardiology (ESC) guidelines for the management of suspected ACS endorse
bedside standard 2D transthoracic echocardiography (2D-TTE) as the first-line imaging technique (class

1C evidence) for patients with acute chest pain (TABLE 2) 12. In the ESC guidelines for the management
of ST-segment elevation myocardial infarction (STEMI), 2D-TTE is recommended for the diagnosis of
other causes of chest pain, such as pulmonary embolus, dissection of the ascending aorta, or pericardial
effusion 13. Similarly, the American College of Cardiology Foundation (ACCF) Appropriate use criteria
for echocardiography, published in 2011, rate the role of 2D-TTE in suspected ACS as appropriate 14.
In clinical practice, 2D-TTE can be helpful in patients with suspected STEMI if a diagnosis cannot be
made from the patients history and ECG. In these circumstances, early 2D-TTE can detect regional wallmotion abnormalities and assist the decision for invasive assessment and primary percutaneous coronary
intervention (FIG. 2). Several studies have demonstrated the incremental value of 2D-TTE over the ECG
in the assessment of patients with suspected ACS 1522. In a study of 280 patients with suspected ACS on
the role of echocardiography in patients with equivocal ECG, echocardiography demonstrated a
sensitivity of 71%, a specificity 91%, and a negative predictive value of 73% for diagnosing ACS 7. In the
ischaemic cascade, regional wall-motion abnormalities precede ECG changes and can be detected even if
the patient presents many hours after an event (FIG. 3) 18,23. However, the presence of regional wallmotion abnormalities is not only associated with myocardial ischaemia, but also with previous myocardial
infarction (MI), focal myocarditis, left bundle branch block, and several cardiomyopathies, posing
diagnostic challenges. In some patients, a poor acoustic window because of body habitus or lung diseases
might limit the acquisition of diagnostically useful images 24.
Novel 2D-TTE methods offer additional information over regional wall-motion abnormalities alone.
Before contracting during the ejection phase, the ischaemic myocardial segments tend to stretch as the
intraventricular pressure rises steeply during the isovolumetric contraction phase
identify this process in patients with suspected ACS

2729

25,26

. Strain imaging can

. In a study that used a cut-off value for global

peak systolic longitudinal strain of 20%, strain imaging demonstrated sensitivity of 93% and specificity
of 78% for the diagnosis of myocardial ischaemia 27. Another study showed a strong correlation of
segmental strain imaging with coronary stenosis on invasive coronary angiography in patients with no
apparent regional wall-motion abnormality 28. Furthermore, absence, or a shorter duration, of early
systolic lengthening on strain imaging accurately identified patients with non-ST-segment elevation
myocardial infarction (NSTEMI) even in those with minimal myocardial damage 30. In this study, the
duration of early systolic lengthening was more prolonged in patients with coronary occlusions than in
those without occlusions (86 45 versus 63 31 ms, P <0.01), and showed good correlation with final
infarct size (r = 0.67, P <0.001).

Contrast echocardiography
Contrast agents can improve endocardial detection for the assessment of regional wall-motion
abnormalities in TTE. Real-time myocardial contrast echocardiography extends the evaluation of wallmotion abnormalities by assessing myocardial perfusion. Importantly, initial concerns over the safety of
ultrasound contrast agents (SonoVue, Bracco Imaging SpA, Italy, and Luminity, Lantheus Medical
Imaging, USA) proved to be unfounded and the agents are now considered safe in patients with chest pain
and suspected ACS 31. Several studies have shown that contrast echocardiography can accurately identify
patients with ACS and contribute to prognostication. In a study of 957 patients presenting to the
emergency department with chest pain, normal wall thickening on contrast echocardiography was
associated with a low incidence of future adverse events, whereas both abnormal wall thickening and a
myocardial perfusion defect suggestive of ischaemia were associated with a high incidence of events 23. In
this study, the negative predictive value for contrast echocardiography was extremely high, at 99100%.
However, the positive predictive value was very poor in the presence of previous MI (in the range of 2.9
14.0% between the four quartiles, which were assigned on the basis of the time interval between the last
episode of chest pain and contrast echocardiography). In another study of multivariate logistic regression
analysis, in which myocardial contrast echocardiography, Thrombolysis In Myocardial Infarction (TIMI)
risk score, abnormal ECG, and troponin T levels were compared in 100 patients, myocardial contrast
echocardiography was the strongest predictor of ACS, and the measured perfusion defect size correlated
with the ejection fraction at the 4-week follow-up (r = 0.79, P <0.001) 32. Two other studies have also
shown that myocardial contrast echocardiography can provide incremental mid-term (30 days) and longterm (2 years) prognostic information over a modified TIMI score 33,34. Myocardial contrast
echocardiography in the emergency room can be cost-effective, with a saving of $900 per patient
compared with usual care 35.
Echocardiography methods under development include antibody-coated microbubbles to image selectins,
which are adhesion molecules that are expressed by the injured endothelium in acute ischaemia and
persist for several hours after the acute event, providing an ischaemic memory. However, these
antibody-coated microbubbles have only been evaluated in animal models 36.
Stress echocardiography
The role of exercise and pharmacological stress echocardiography in the assessment of suspected ACS
(FIG. 4) has been studied extensively 31,3743. The use of stress echocardiography is advocated in the ESC
guidelines on suspected ACS (class I, level A evidence) and is categorized as appropriate in suspected
ACS in North American guidelines 12,14. In both guidelines , the use of stress echocardiography is mainly

recommended for patients with no resting chest pain, normal ECG findings, negative troponin, and a low
risk score.
The diagnostic accuracy of stress echocardiography was evaluated in a study of 503 patients with acute
chest pain who underwent exercise stress echocardiography and exercise MPS for the detection of
coronary artery disease (CAD) 38. Stress echocardiography had similar sensitivity to stress MPS (85%
versus 86%), with slightly, but significantly, greater specificity (95% versus 90%). The sensitivity of
exercise-tolerance testing was significantly lower (43%) than that of stress echocardiography, although
the specificity was similar (95%). In a real-world study of stress echocardiography assessing the
feasibility and safety of the examination in 839 consecutive patients presenting to chest pain units, 811
(96.7%) patients had technically successful stress echocardiography with no major complications 41. At
1- year follow-up, hard event rates (all-cause mortality and acute MI) were 0.5% in the normal stress
echocardiography group versus 6.6% in the abnormal stress echocardiography group. In multivariate
regression analysis, only abnormal stress echocardiography (HR 4.08, 95% CI 2.157.72, P <0.001) and
advancing age (HR 1.78, 95% CI 1.392.37, P <0.001) predicted MI and death. A prospective, doubleblind, multicentre, dobutamine stress study in 377 low-risk patients presenting to the emergency
department with acute chest pain showed a 6-month risk of composite cardiac events of 14/351 (4%) in
patients with a negative dobutamine stress echocardiography and 8/26 (30.8%) in patients with positive
dobutamine stress echocardiography (P <0.0001) 42. In a head-to-head comparison of stress
echocardiography and ECG-based exercise-tolerance testing, stress echocardiography was superior to
exercise-tolerance testing in stratifying patients as low risk (77% versus 33%, P <0.0001). In addition,
fewer of the patients who underwent stress echocardiography required further tests than those who
underwent exercise-tolerance testing (3% versus 47%, P <0.0001), and stress echocardiography was more
cost-effective than exercise-tolerance testing (366.63 versus 515.48, P = 0.004) 39 In another study of
199 patients with acute-onset chest pain presenting to the emergency department and randomized to
exercise-tolerance testing or stress echocardiography, the cost-effectiveness was similar, but the event rate
in patients who underwent exercise-tolerance testing was significantly higher than in those who
underwent stress echocardiography (0% versus 11%, P = 0.004) 43.

Computed tomography coronary angiography

The use of CTCA is rapidly expanding and recommendations for the use of this imaging test are included
in several relevant guidelines. The ACCF Appropriate use criteria for cardiac computed tomography
have endorsed CTCA as an appropriate test in the context of acute chest pain with normal or

nondiagnostic ECG, and normal or equivocal biomarkers in the groups determined pretest to have low- or
intermediate likelihood of an ACS 44. CTCA is also endorsed by the ACCF for the evaluation of
suspected coronary anomalies in this setting. Similarly, the ESC guidelines on suspected ACS recommend
CTCA (class IIa, level B evidence) as an alternative to invasive coronary angiography to exclude ACS or
other causes of chest pain in low- to intermediate likelihood groups in whom ECG and troponin are
inconclusive (TABLE 2) 12.
High quality CTCA is feasible with multidetector CT scanners acquiring 64 slices, and these scanners
are now widely available, including in many emergency departments 45. In a meta-analysis of 9 studies 46
54

involving 1,559 patients with symptoms suggestive of ACS and an initial nondiagnostic ECG, the

pooled sensitivity, specificity, and positive and negative predictive values for 64-slice CTCA for major
cardiovascular events at 30 days were 93.3%, 89.9%, 48.1%, and 99.3%, respectively 55. Four
randomized, controlled clinical trials have incorporated CTCA into an early evaluation strategy in patients
with suspected ACS presenting to the emergency department and have compared this test with usual care
5659

. A meta-analysis of these trials involving 3,266 patients determined pretest to have a low- to

intermediate-likelihood of ACS showed that incorporating CTCA shortened the hospital stay. However,
the pooled weighted incidence of invasive coronary angiography was 8.4% in the CTCA group versus
6.3% in the standard investigation group (P = 0.03) a relative increase of invasive coronary
angiography rates of 33% 60. Whether the observed increase in invasive procedures leads to improved
patient outcome or decreases the need for future testing is unknown. A long-term outcome study
published in 2014 assessing the use of CTCA in 196 patients with suspected ACS and a median follow-up
of 47.4 months showed an excellent prognosis if CTCA was negative (1% readmitted with chest pain; 0%
revascularization, ACS, or death) 61.
In addition to coronary imaging, coronary artery calcium scoring has also demonstrated high negative
predictive value of 99% in patients presenting with acute chest pain 62. However, coronary artery calcium
scoring alone in this study missed two patients (1.5%) with obstructive coronary artery disease. In another
study of 1,049 patients, addition of coronary artery calcium scoring analysis to CTCA did not help predict
30-day cardiovascular events 63. Contrast-enhanced CT can be used to assess myocardial perfusion. A
retrospective study of 158 consecutive patients who underwent ungated contrast-enhanced CT in the
emergency department to rule out other causes of chest pain (mainly pulmonary embolus) showed high
sensitivity (93%) and specificity (87%) of perfusion CT to detect acute MI (defined by a rise in troponin)
64

. Similarly, a subgroup analysis of the ROMICAT trial 65 that evaluated the role of CTCA in acute chest

pain showed that the assessment of myocardial perfusion and regional wall-motion abnormalities by CT
improved the detection of ACS (area under the curve 0.88 versus 0.79, P=0.02). In patients with a

nondiagnostic ECG and equivocal cardiac biomarkers, current evidence thus shows that CTCA has a high
negative predictive value for excluding ACS in low- to intermediate- likelihood groups, can facilitate
triage decisions and reduce lengths of stay in patients with suspected ACS. In a multicentre, randomized,
control trial of 749 patients, costs of care were 38% lower using CTCA compared with the standard care
[57]. Also, in the same study, time to diagnosis was significantly lower for CTCA versus MPS (2.9 h,
95% CI 2.14.0 h versus 6.3 h, 95% CI 4.219.0 h, P <0.0001) [57].

Radionuclide imaging
MPS is the most established method for assessment of ischaemia and viability 66,67. A full MPS study
consists of imaging after both stress and rest injections of thallium-201 or technetium-99m labelled
tracers, with the resting study showing myocardial scar and the stress-induced defects indicating inducible
hypoperfusion commonly, but incorrectly, referred to as ischaemia.
Among the currently available techniques in the acute setting, MPS has the strongest prognostic data.
MPS is endorsed by the North American Appropriate use criteria for cardiac radionuclide imaging and
the ESC guidelines as an appropriate test in suspected ACS where diagnosis was not confirmed by ECG
and biomarkers (TABLE 2) 12,68. Many observational studies have assessed the diagnostic and prognostic
performance of rest MPS in the acute setting 6977. In a pooled analysis of 2,465 patients presenting with
recent (<6 h) pain, the sensitivity for detecting MI by rest MPS was 90%, with a specificity of 80% and a
negative predictive value of 99% 78. The ERASE trial

79

was a large (n=2,475) multi-centre, randomized

trial that compared MPS with usual care and showed a 14% reduction in hospital admission and an
estimated cost-saving of $60 to $72 per patient with the incorporation of MPS . Several prospective,
randomized trials have also shown that resting MPS is cost-effective, and that the use of resting MPS
improves the triage of patients presenting with acute chest pain 8083. In the short term, 30-day cardiac
event rates (acute MI, death, or revascularization) are 3% with normal MPS compared with 1030% with
abnormal MPS 75,80. Finally, an observational study of 1,187 consecutive patients showed excellent 1-year
outcome in patients with normal MPS compared with those with abnormal MPS (0% MI/death versus
11% MI and 8% cardiac death, P< 0.001)73.
Although rest MPS is an excellent rule-out test, the sensitivity of this test in patients who no longer have
chest pain is low 84. Another limitation is the inability of rest MPS to distinguish acute from chronic MI 85,
as both appear as hypoperfused areas. After the initial chest pain has settled, stressrest MPS to detect
inducible hypoperfusion is more accurate and has greater prognostic value than rest MPS

8688

. The stress

study is normally performed after a normal resting study, which can delay the discharge; however, the
stress study can be performed after discharge in otherwise low-risk patients. Initial stress MPS in low-risk
patients is safe and has similar performance to rest MPS alone 89.
MPS techniques developed in the past 5-10 years allow myocardial metabolism to be imaged. In
ischaemic memory imaging, prolonged functional and/or biochemical alterations following an episode of
severe myocardial ischaemia are detected. Myocardial ischaemia leads to a shift from aerobic fatty acid to
anaerobic glucose metabolism 90. Even when myocardial perfusion is restored and ischaemia has resolved,
the return to fatty acid metabolism can take 12h or longer 91. This metabolism shift can be imaged using
the fatty acid analogue -methyl-p-[123I] iodophenylpentadecanoic acid92. This form of ischaemic memory
imaging has similar sensitivity (90%) and specificity (80%) to resting MPS for detecting ACS within 12 h
of the cessation of chest pain 93 (FIG. 3 and 4), with no difference between early (012 h) and late (12
13 h) imaging. 18F-fluorodeoxyglucose (FDG) is a glucose analogue tracer that is used in positron
emission tomography (PET) imaging to measure glucose utilization. The tracer accumulates in normal
and ischaemic (viable) myocardium; however, under fasting conditions, FDG uptake is suppressed in
normal myocardium and is accumulated in the ischaemic region 91. Hence, for FDG-PET ischaemic
memory imaging, FDG is administered after a fast of at least 6 h or after an overnight fast. Flurpiridaz F18 is a novel tracer in phase III clinical trials that has demonstrated increased image quality, with higher
contrast and resolution than current PET tracers 94. However, the value of flurpiridaz F-18 in patients with
suspected ACS remains unknown.
Hybrid imaging classically involves the combination (or fusion) of an anatomical (CTCA) and a
functional test (SPECT, PET, CMR). Hybrid imaging is superior in determining the presence of
functionally significant CAD (stenosis 70% with 10% myocardial ischaemic burden) compared with
either of the individual techniques 95. The first reports of PET-CT 9698 and SPECT-CT 99101 have suggested
a role for hybrid imaging in detecting functionally significant CAD, but further evaluation in patients with
ACS is required. In addition, the availability of hybrid imaging is currently limited to a small number of
centres with appropriate expertise and equipment.

Cardiovascular Magnetic Resonance

CMR has an emerging role in the assessment and management of patients with ACS, in particular those
who are clinically stable. CMR provides structural and functional assessment of regional myocardial
motion and thickening, rest and stress perfusion, myocardial oedema, microvascular obstruction, and

intramyocardial haemorrhage 102. The 2006 North American Appropriateness criteria for cardiac
computed tomography and cardiac magnetic resonance imaging recommends stress CMR as appropriate
for the evaluation of patients deemed to have intermediate- likelihood of ACS when the ECG is
uninterpretable or the patient is unable to exercise 103. MR coronary angiography, where available, might
be appropriate to detect coronary anomalies. Current ESC guidelines highlight in particular the ability of
CMR to detect myocarditis and assess viability and perfusion defects in patients with suspected ACS 12.
The ESC guidelines on the management of suspected NSTEMI also recommend stress CMR (class I,
level A evidence) in patients without recurrent pain, normal ECG, negative troponin and a low (108)
Global Registry of Acute Coronary Events (GRACE) risk score (TABLE 2) 12.
A study published in 2004 showed that CMR was feasible and safe in 72 patients with recent non-STsegment elevation ACS 104. CMR within 3 days of the event had 96% sensitivity and 83% specificity for
significant CAD (stenosis 70%) defined by invasive angiography. CMR was also more accurate than the
TIMI risk score (P <0.001). In a study of 161 patients presenting to the emergency department within
12 h of symptoms suggestive of ACS, but without ST-segment elevation on initial ECG, the diagnostic
performance of CMR was evaluated using cine imaging for LV function, resting first-pass perfusion, and
late gadolinium enhancement

105

. Total imaging time was 38 minutes and patients were absent from the

emergency department for less than 1 h. Although the sensitivity and specificity for the diagnosis of ACS
as defined by troponin I and invasive angiography for this CMR protocol was only 84% and 85%,
respectively, CMR added incremental value over clinical parameters.
Myocardial oedema develops before ischaemic necrosis or even troponin release
persist even when ECG changes and myocardial dysfunction have resolved
to 1 month

107

106

. The oedema can

(FIG 3), and can persist up

108

. A study in which oedema-sensitive T2-weighted imaging (T2W-imaging) was added to the

CMR protocol used in previous reports showed increased specificity, positive predictive value, and
overall accuracy (96%, 85%, and 93%, respectively) compared with the conventional CMR protocol
while sensitivity remained at 85% 109. In addition, in this study, oedema-sensitive T2W-imaging
accurately identified all patients with acute MI, often before cardiac biomarkers were elevated. A study of
135 low-risk patients presenting to the emergency department with chest pain showed that none of the
patients with a normal adenosine CMR study had a subsequent diagnosis of CAD or an adverse outcome
after 1 year 110. In the same study, the sensitivity of stress CMR was 100%, with a specificity of 93% for
predicting adverse outcomes during a 1-year follow-up period. In two similar separate studies evaluating
192 patients who received adenosine stress and rest CMR, none of the patients with normal CMR had
clinical events during 9 months of follow-up 111,112. Finally, in a randomized trial evaluating the costeffectiveness of stress CMR in 110 intermediate- and high-risk patients with ACS, stress CMR led to a

cost-saving of >20% compared with standard inpatient care ($3,101 versus $4,742, P = 0.004). The
decrease of medical-care costs was a result of the reductions in coronary artery revascularization,
readmissions, and further cardiac testing, without an increase in post-discharge ACS at 90 days 113.
Emerging CMR methods for ACS imaging include in particular parametric mapping techniques. T1mapping can quantify the extent and severity of acute ischaemic injury (FIG. 5). In an early study,
noncontrast T1-maps had 96% sensitivity and 91% specificity for detecting acute MI 114. In a study
published in 2012, T1-mapping was superior to T2W-imaging in detecting NSTEMI (area under the curve
0.910.02 versus 0.810.04, P=0.004) 115. T1-mapping is also superior to T2W and late gadolinium
enhancement imaging in detecting acute myocarditis, which is one of the main differential diagnoses in
patients with acute chest pain 116,117.
Value of noninvasive imaging tests
Whether noninvasive imaging improves clinical outcome in patients presenting with possible ACS, and
which imaging strategy provides the best results, remains unknown. In a retrospective analysis of
privately insured patients in the USA who presented with chest pain but no evidence of MI by 24 h, early
testing by CTCA, stress echocardiography, MPS, and exercise ECG led to higher rates of cardiac
catheterisation and revascularisation, but no reduction in cardiac events compared with conservative
management 118. Notably, stress echocardiography did not lead to a rise in invasive downstream
investigation. CMR was not included in this study, highlighting the need for further large, prospective
trials that include all contemporary imaging modalities 118.

Conclusions
Bedside echocardiography is the first-line imaging test in patients with acute chest pain to assist in the
diagnosis and management of patients presenting with suspected ACS. The advanced imaging techniques
(stress echocardiography, CTCA, MPS, and CMR) add additional diagnostic and prognostic value,
particularly when history, ECGs, and early cardiac biomarkers results are equivocal. Negative predictive
values for all the advanced imaging techniques are comparable, and are higher than routine bedside
echocardiography. Advanced imaging techniques are cost-effective, can reduce length of hospital stay,
provide information on alternative diagnoses, and, if appropriately used, can improve patient flow in the
emergency department. However, the optimal use and comparative value of these imaging techniques
remain to be defined.

10

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1.

Goodacre, S. The health care burden of acute chest pain. Heart 91, 229230 (2005).

2.

Knockaert, D. C., Buntinx, F., Stoens, N., Bruyninckx, R. & Delooz, H. Chest pain in the
emergency department: the broad spectrum of causes. Eur. J. Emerg. Med. 9, 2530 (2002).

3.

Ekelund, U., Nilsson, H.-J., Frigyesi, A. & Torffvit, O. Patients with suspected acute coronary
syndrome in a university hospital emergency department: an observational study. BMC Emerg.
Med. 2, 1 (2002).

4.

Goodacre, S. W. et al. The Randomised Assessment of Treatment using Panel Assay of Cardiac
Markers (RATPAC) trial: a randomised controlled trial of point-of-care cardiac markers in the
emergency department. Heart 97, 1906 (2011).

5.

Solinas, L. et al. Prevalence, clinical characteristics, resource utilization and outcome of patients
with acute chest pain in the emergency department. A multicenter, prospective, observational study
in north-eastern Italy. Ital. Heart J. 4, 31824 (2003).

6.

Pope, J. H. et al. Missed diagnoses of acute cardiac ischemia in the emergency department. N.
Engl. J. Med. 342, 116370 (2000).

7.

Di Pasquale, P. et al. Sensitivity, specificity and predictive value of the echocardiography and
troponin-T test combination in patients with non-ST elevation acute coronary syndromes. Int. J.
Cardiovasc. Imaging 20, 3746 (2004).

8.

Hammarsten, O. et al. Troponin T percentiles from a random population sample, emergency room
patients and patients with myocardial infarction. Clin. Chem. 58, 62837 (2012).

9.

Gami, B. N. et al. Utility of Heart-type Fatty Acid Binding Protein as a New Biochemical Marker
for the Early Diagnosis of Acute Coronary Syndrome. J. Clin. Diagn. Res. 9, BC224 (2015).

10.

Thygesen, K. et al. Third universal definition of myocardial infarction. Eur. Heart J. 33, 2551
2567 (2012).

11.

OGara, P. T. et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial
infarction: a report of the American College of Cardiology Foundation/American Heart
Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 61, e78140 (2013).

12.

Hamm, C. W. et al. ESC Guidelines for the management of acute coronary syndromes in patients
presenting without persistent ST-segment elevation: The Task Force for the management of acute
coronary syndromes (ACS) in patients presenting without persistent ST-segment elevatio. Eur.
Heart J. 32, 29993054 (2011).

13.

Steg, P. G. et al. ESC Guidelines for the management of acute myocardial infarction in patients
presenting with ST-segment elevation. Eur. Heart J. 33, 2569619 (2012).

14.

Douglas, P. S. et al. ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/SCCT/SCMR 2011

Appropriate Use Criteria for Echocardiography. A Report of the American College of Cardiology
Foundation Appropriate Use Criteria Task Force, American Society of Echocardiography,
American Heart Associat. J. Am. Coll. Cardiol. 57, 112666 (2011).

15.

Horowitz, R. S. et al. Immediate diagnosis of acute myocardial infarction by two-dimensional

echocardiography. Circulation 65, 323329 (1982).
12

16.

Sasaki, H., Charuzi, Y., Beeder, C., Sugiki, Y. & Lew, A. S. Utility of echocardiography for the
early assessment of patients with nondiagnostic chest pain. Am. Heart J. 112, 4947 (1986).

17.

Peels, C. H., Visser, C. A., Kupper, A. J., Visser, F. C. & Roos, J. P. Usefulness of two-dimensional
echocardiography for immediate detection of myocardial ischemia in the emergency room. Am. J.
Cardiol. 65, 68791 (1990).

18.

Sabia, P. et al. Value of regional wall motion abnormality in the emergency room diagnosis of
acute myocardial infarction. A prospective study using two-dimensional echocardiography.
Circulation 84, I8592 (1991).

19.

Saeian, K., Rhyne, T. L. & Sagar, K. B. Ultrasonic tissue characterization for diagnosis of acute
myocardial infarction in the coronary care unit. Am. J. Cardiol. 74, 12115 (1994).

20.

Kontos, M. C. et al. Comparison between 2-dimensional echocardiography and myocardial

perfusion imaging in the emergency department in patients with possible myocardial ischemia.
Am. Heart J. 136, 72433 (1998).

21.

Kontos, M. C., Arrowood, J. A., Paulsen, W. H. & Nixon, J. V. Early echocardiography can predict
cardiac events in emergency department patients with chest pain. Ann. Emerg. Med. 31, 5507
(1998).

22.

Mohler, E. R. et al. Clinical utility of troponin T levels and echocardiography in the emergency
department. Am. Heart J. 135, 25360 (1998).

23.

Kalvaitis, S. et al. Effect of time delay on the diagnostic use of contrast echocardiography in
patients presenting to the emergency department with chest pain and no S-T segment elevation. J.
Am. Soc. Echocardiogr. 19, 148893 (2006).

24.

Senior, R. et al. Contrast echocardiography: evidence-based recommendations by European

Association of Echocardiography. Eur. J. Echocardiogr. 10, 194212 (2008).

25.

Lyseggen, E. et al. Myocardial strain analysis in acute coronary occlusion: a tool to assess
myocardial viability and reperfusion. Circulation 112, 39013910 (2005).

26.

Smedsrud, M. K. et al. Duration of myocardial early systolic lengthening predicts the presence of
significant coronary artery disease. J. Am. Coll. Cardiol. 60, 108693 (2012).

27.

Dahlslett, T. et al. Early assessment of strain echocardiography can accurately exclude significant
coronary artery stenosis in suspected non-ST-segment elevation acute coronary syndrome. J. Am.
Soc. Echocardiogr. 27, 5129 (2014).

28.

Choi, S. W. et al. Diagnostic Value of Ultrasound-Based Strain Imaging in Patients With

Suspected Coronary Artery Disease. Korean Circ. J. 38, 398 (2008).

29.

Sarvari, S. I. et al. Layer-specific quantification of myocardial deformation by strain

echocardiography may reveal significant CAD in patients with non-ST-segment elevation acute
coronary syndrome. JACC. Cardiovasc. Imaging 6, 53544 (2013).

30.

Zahid, W. et al. Early systolic lengthening may identify minimal myocardial damage in patients
with non-ST-elevation acute coronary syndrome. Eur. Heart J. Cardiovasc. Imaging 15, 115260
(2014).
13

31.

Anantharam, B. et al. Safety of contrast in stress echocardiography in stable patients and in

patients with suspected acute coronary syndrome but negative 12-hour troponin. Am. J. Cardiol.
104, 148 (2009).

32.

Korosoglou, G. et al. Usefulness of real-time myocardial perfusion imaging in the evaluation of

patients with first time chest pain. Am. J. Cardiol. 94, 122531 (2004).

33.

Tong, K. L. et al. Myocardial contrast echocardiography versus Thrombolysis In Myocardial

Infarction score in patients presenting to the emergency department with chest pain and a
nondiagnostic electrocardiogram. J. Am. Coll. Cardiol. 46, 9207 (2005).

34.

Rinkevich, D. et al. Regional left ventricular perfusion and function in patients presenting to the
emergency department with chest pain and no ST-segment elevation. Eur. Heart J. 26, 160611
(2005).

35.

Wyrick, J. J. et al. Cost-efficiency of myocardial contrast echocardiography in patients presenting

to the emergency department with chest pain of suspected cardiac origin and a nondiagnostic
electrocardiogram. Am. J. Cardiol. 102, 64952 (2008).

36.

Villanueva, F. S. et al. Myocardial ischemic memory imaging with molecular echocardiography.

Circulation 115, 34552 (2007).

37.

Tsutsui, J. M. et al. Diagnostic accuracy and prognostic value of dobutamine stress myocardial
contrast echocardiography in patients with suspected acute coronary syndromes.
Echocardiography 22, 48795 (2005).

38.

Conti, A. et al. Assessment of patients with low-risk chest pain in the emergency department:
Head-to-head comparison of exercise stress echocardiography and exercise myocardial SPECT.
Am. Heart J. 149, 894901 (2005).

39.

Jeetley, P., Burden, L., Stoykova, B. & Senior, R. Clinical and economic impact of stress
echocardiography compared with exercise electrocardiography in patients with suspected acute
coronary syndrome but negative troponin: a prospective randomized controlled study. Eur. Heart
J. 28, 20411 (2007).

40.

Gaibazzi, N. et al. Contrast stress-echocardiography predicts cardiac events in patients with

suspected acute coronary syndrome but nondiagnostic electrocardiogram and normal 12-hour
troponin. J. Am. Soc. Echocardiogr. 24, 133341 (2011).

41.

Shah, B. N. et al. Incremental diagnostic and prognostic value of contemporary stress

echocardiography in a chest pain unit: mortality and morbidity outcomes from a real-world setting.
Circ. Cardiovasc. Imaging 6, 2029 (2013).

42.

Bholasingh, R. et al. Prognostic value of predischarge dobutamine stress echocardiography in

chest pain patients with a negative cardiac troponin T. J. Am. Coll. Cardiol. 41, 596602 (2003).

43.

Nucifora, G. et al. Comparison of early dobutamine stress echocardiography and exercise

electrocardiographic testing for management of patients presenting to the emergency department
with chest pain. Am. J. Cardiol. 100, 106873 (2007).

44.

Taylor, A. J. et al. ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate

14

use criteria for cardiac computed tomography. A report of the American College of Cardiology
Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed
Tomography, the. J. Am. Coll. Cardiol. 56, 186494 (2010).
45.

Hoffmann, U. & Bamberg, F. Is computed tomography coronary angiography the most accurate
and effective noninvasive imaging tool to evaluate patients with acute chest pain in the emergency
department?: CT coronary angiography is the most accurate and effective noninvasive imaging to.
Circ. Cardiovasc. Imaging 2, 25163; discussion 263 (2009).

46.

Johnson, T. R. et al. ECG-gated 64-MDCT angiography in the differential diagnosis of acute chest
pain. AJR Am J Roentgenol 188, 7682 (2007).

47.

Gallagher, M. J. et al. The Diagnostic Accuracy of 64-Slice Computed Tomography Coronary

Angiography Compared With Stress Nuclear Imaging in Emergency Department Low-Risk Chest
Pain Patients. Ann. Emerg. Med. 49, 125136 (2007).

48.

Rubinshtein, R. et al. Usefulness of 64-slice cardiac computed tomographic angiography for

diagnosing acute coronary syndromes and predicting clinical outcome in emergency department
patients with chest pain of uncertain origin. Circulation 115, 17628 (2007).

49.

Johnson, T. R. C. et al. Dual-source CT for chest pain assessment. Eur. Radiol. 18, 773780
(2008).

50.

Takakuwa, K. M. & Halpern, E. J. Evaluation of a triple rule-out coronary CT angiography

protocol: use of 64-Section CT in low-to-moderate risk emergency department patients suspected
of having acute coronary syndrome. Radiology 248, 438446 (2008).

51.

Ueno, K. et al. Diagnostic capacity of 64-slice multidetector computed tomography for acute
coronary syndrome in patients presenting with acute chest pain. Cardiology 112, 211218 (2009).

52.

Hollander, J. E. et al. Coronary Computed Tomographic Angiography for Rapid Discharge of

Low-Risk Patients With Potential Acute Coronary Syndromes. Ann. Emerg. Med. 53, 295304
(2009).

53.

Hoffmann, U. et al. Coronary computed tomography angiography for early triage of patients with
acute chest pain: the ROMICAT (Rule Out Myocardial Infarction using Computer Assisted
Tomography) trial. J. Am. Coll. Cardiol. 53, 164250 (2009).

54.

Hansen, M. et al. The value of dual-source 64-slice CT coronary angiography in the assessment of
patients presenting to an acute chest pain service. Heart. Lung Circ. 19, 213218 (2010).

55.

Takakuwa, K. M., Keith, S. W., Estepa, A. T. & Shofer, F. S. A meta-analysis of 64-section

coronary CT angiography findings for predicting 30-day major adverse cardiac events in patients
presenting with symptoms suggestive of acute coronary syndrome. Acad. Radiol. 18, 15228
(2011).

56.

Goldstein, J. A. et al. A randomized controlled trial of multi-slice coronary computed tomography

for evaluation of acute chest pain. J. Am. Coll. Cardiol. 49, 86371 (2007).

57.

Goldstein, J. A. et al. The CT-STAT (Coronary Computed Tomographic Angiography for

Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J. Am. Coll. Cardiol. 58, 1414

15

22 (2011).
58.

Litt, H. I. et al. CT angiography for safe discharge of patients with possible acute coronary
syndromes. N. Engl. J. Med. 366, 1393403 (2012).

59.

Hoffmann, U. et al. Coronary CT angiography versus standard evaluation in acute chest pain. The
New England journal of medicine 367, 299308 (2012).

60.

Hulten, E. et al. Outcomes after coronary computed tomography angiography in the emergency
department: a systematic review and meta-analysis of randomized, controlled trials. J. Am. Coll.
Cardiol. 61, 88092 (2013).

61.

Nasis, A. et al. Long-term outcome after CT angiography in patients with possible acute coronary
syndrome. Radiology 272, 67482 (2014).

62.

Fernandez-Friera, L. et al. Diagnostic value of coronary artery calcium scoring in lowintermediate risk patients evaluated in the emergency department for acute coronary syndrome.
Am. J. Cardiol. 107, 1723 (2011).

63.

Chang, A. M., Le, J., Matsuura, A. C., Litt, H. I. & Hollander, J. E. Does coronary artery calcium
scoring add to the predictive value of coronary computed tomography angiography for adverse
cardiovascular events in low-risk chest pain patients? Acad. Emerg. Med. 18, 106571 (2011).

64.

Mano, Y., Anzai, T., Yoshizawa, A., Itabashi, Y. & Ohki, T. Role of non-electrocardiogram-gated
contrast-enhanced computed tomography in the diagnosis of acute coronary syndrome. Heart
Vessels (2013). doi:10.1007/s00380-013-0437-8

65.

Bezerra, H. G. et al. Incremental value of myocardial perfusion over regional left ventricular
function and coronary stenosis by cardiac CT for the detection of acute coronary syndromes in
high-risk patients: a subgroup analysis of the ROMICAT trial. J. Cardiovasc. Comput. Tomogr. 5,
38291

66.

Kontos, M. C. et al. Sensitivity of acute rest myocardial perfusion imaging for identifying patients
with myocardial infarction based on a troponin definition. J. Nucl. Cardiol. 11, 129

67.

Zaman, M. M. et al. Correlation between severity of coronary artery stenosis and perfusion defect
assessed by SPECT myocardial perfusion imaging. Mymensingh Med. J. 19, 60813 (2010).

68.

Hendel, R. C. et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 Appropriate Use

Criteria for Cardiac Radionuclide Imaging: A Report of the American College of Cardiology
Foundation Appropriate Use Criteria Task Force, the American Society of Nuclear Cardiology, the
American Col. J. Am. Coll. Cardiol. 53, 220129 (2009).

69.

Wackers, F. J. et al. Value and limitations of thallium-201 scintigraphy in the acute phase of
myocardial infarction. N. Engl. J. Med. 295, 15 (1976).

70.

Bilodeau, L., Throux, P., Grgoire, J., Gagnon, D. & Arsenault, A. Technetium-99m sestamibi
tomography in patients with spontaneous chest pain: correlations with clinical,
electrocardiographic and angiographic findings. J. Am. Coll. Cardiol. 18, 168491 (1991).

71.

Varetto, T., Cantalupi, D., Altieri, A. & Orlandi, C. Emergency room technetium-99m sestamibi
imaging to rule out acute myocardial ischemic events in patients with nondiagnostic
16

electrocardiograms. J. Am. Coll. Cardiol. 22, 18048 (1993).

72.

Hilton, T. C. et al. Technetium-99m sestamibi myocardial perfusion imaging in the emergency

room evaluation of chest pain. J. Am. Coll. Cardiol. 23, 101622 (1994).

73.

Tatum, J. L. et al. Comprehensive strategy for the evaluation and triage of the chest pain patient.
Ann. Emerg. Med. 29, 11625 (1997).

74.

Kontos, M. C., Jesse, R. L., Schmidt, K. L., Ornato, J. P. & Tatum, J. L. Value of acute rest
sestamibi perfusion imaging for evaluation of patients admitted to the emergency department with
chest pain. J. Am. Coll. Cardiol. 30, 97682 (1997).

75.

Heller, G. V et al. Clinical value of acute rest technetium-99m tetrofosmin tomographic

myocardial perfusion imaging in patients with acute chest pain and nondiagnostic
electrocardiograms. J. Am. Coll. Cardiol. 31, 10117 (1998).

76.

Duca, M. D. et al. Comparison of acute rest myocardial perfusion imaging and serum markers of
myocardial injury in patients with chest pain syndromes. J. Nucl. Cardiol. 6, 5706

77.

Kosnik, J. W. et al. Resting sestamibi imaging for the prognosis of low-risk chest pain. Acad.
Emerg. Med. 6, 9981004 (1999).

78.

Sechtem, U., Achenbach, S., Friedrich, M., Wackers, F. & Zamorano, J. L. Non-invasive imaging
in acute chest pain syndromes. Eur. Heart J. Cardiovasc. Imaging 13, 6978 (2012).

79.

Udelson, J. E. & Spiegler, E. J. Emergency department perfusion imaging for suspected coronary
artery disease: the ERASE Chest Pain Trial. Md. Med. Suppl, 904 (2001).

80.

Udelson, J. E. et al. Myocardial Perfusion Imaging for Evaluation and Triage of Patients With
Suspected Acute Cardiac Ischemia. JAMA 288, 2693 (2002).

81.

Stowers, S. A. et al. An economic analysis of an aggressive diagnostic strategy with single photon
emission computed tomography myocardial perfusion imaging and early exercise stress testing in
emergency department patients who present with chest pain but nondiagnostic electro. Ann.
Emerg. Med. 35, 1725 (2000).

82.

Radensky, P. W., Hilton, T. C., Fulmer, H., McLaughlin, B. A. & Stowers, S. A. Potential cost
effectiveness of initial myocardial perfusion imaging for assessment of emergency department
patients with chest pain. Am. J. Cardiol. 79, 5959 (1997).

83.

Forberg, J. L. et al. Negative predictive value and potential cost savings of acute nuclear
myocardial perfusion imaging in low risk patients with suspected acute coronary syndrome: a
prospective single blinded study. BMC Emerg. Med. 9, 12 (2009).

84.

Fram, D. B. et al. Duration of abnormal SPECT myocardial perfusion imaging following

resolution of acute ischemia: an angioplasty model. J. Am. Coll. Cardiol. 41, 4529 (2003).

85.

Harrison, S. D., Harrison, M. A. & Duvall, W. L. Stress myocardial perfusion imaging in the
emergency department--new techniques for speed and diagnostic accuracy. Curr. Cardiol. Rev. 8,
11622 (2012).

86.

Nerenberg, R. H., Shofer, F. S., Robey, J. L., Brown, A. M. & Hollander, J. E. Impact of a negative

17

prior stress test on emergency physician disposition decision in ED patients with chest pain
syndromes. Am. J. Emerg. Med. 25, 3944 (2007).
87.

Shoyeb, A. et al. Value of definitive diagnostic testing in the evaluation of patients presenting to
the emergency department with chest pain. Am. J. Cardiol. 91, 14104 (2003).

88.

Fesmire, F. M. et al. The Erlanger chest pain evaluation protocol: a one-year experience with serial
12-lead ECG monitoring, two-hour delta serum marker measurements, and selective nuclear stress
testing to identify and exclude acute coronary syndromes. Ann. Emerg. Med. 40, 58494 (2002).

89.

Duvall, W. L. et al. Stress-only Tc-99m myocardial perfusion imaging in an emergency

department chest pain unit. J. Emerg. Med. 42, 64250 (2012).

90.

Depre, C., Vanoverschelde, J.-L. J. & Taegtmeyer, H. Glucose for the Heart. Circulation 99, 578
588 (1999).

91.

Yoshinaga, K., Naya, M., Shiga, T., Suzuki, E. & Tamaki, N. Ischaemic memory imaging using
metabolic radiopharmaceuticals: overview of clinical settings and ongoing investigations. Eur. J.
Nucl. Med. Mol. Imaging 41, 38493 (2014).

92.

Inaba, Y. & Bergmann, S. R. Prognostic value of myocardial metabolic imaging with BMIPP in
the spectrum of coronary artery disease: a systematic review. J. Nucl. Cardiol. 17, 6170

93.

Kontos, M. C. et al. Iodofiltic acid I 123 (BMIPP) fatty acid imaging improves initial diagnosis in
emergency department patients with suspected acute coronary syndromes: a multicenter trial. J.
Am. Coll. Cardiol. 56, 2909 (2010).

94.

Li, Y., Zhang, W., Wu, H. & Liu, G. Advanced tracers in PET imaging of cardiovascular disease.
Biomed Res. Int. 2014, 504532 (2014).

95.

Gaemperli, O., Bengel, F. M. & Kaufmann, P. A. Cardiac hybrid imaging. Eur. Heart J. 32, 2100
8 (2011).

96.

Namdar, M. et al. Integrated PET/CT for the assessment of coronary artery disease: a feasibility
study. J. Nucl. Med. 46, 9305 (2005).

97.

Groves, A. M. et al. First experience of combined cardiac PET/64-detector CT angiography with

invasive angiographic validation. Eur. J. Nucl. Med. Mol. Imaging 36, 202733 (2009).

98.

Kajander, S. et al. Cardiac positron emission tomography/computed tomography imaging

accurately detects anatomically and functionally significant coronary artery disease. Circulation
122, 60313 (2010).

99.

Rispler, S. et al. Integrated single-photon emission computed tomography and computed

tomography coronary angiography for the assessment of hemodynamically significant coronary
artery lesions. J. Am. Coll. Cardiol. 49, 105967 (2007).

100.

Sato, A. et al. Incremental value of combining 64-slice computed tomography angiography with
stress nuclear myocardial perfusion imaging to improve noninvasive detection of coronary artery
disease. J. Nucl. Cardiol. 17, 1926

101.

Schaap, J. et al. Incremental diagnostic accuracy of hybrid SPECT/CT coronary angiography in a

18

population with an intermediate to high pre-test likelihood of coronary artery disease. Eur. Heart
J. Cardiovasc. Imaging 14, 6429 (2013).
102.

Lockie, T., Nagel, E., Redwood, S. & Plein, S. Use of cardiovascular magnetic resonance imaging
in acute coronary syndromes. Circulation 119, 167181 (2009).

103.

Hendel, R. C. et al. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness

criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the
American College of Cardiology Foundation Quality Strategic Directions Committee
Appropriateness C. J. Am. Coll. Cardiol. 48, 147597 (2006).

104.

Plein, S. et al. Assessment of non-ST-segment elevation acute coronary syndromes with cardiac
magnetic resonance imaging. J. Am. Coll. Cardiol. 44, 217381 (2004).

105.

Kwong, R. Y. et al. Detecting acute coronary syndrome in the emergency department with cardiac
magnetic resonance imaging. Circulation 107, 5317 (2003).

106.

Abdel-Aty, H., Cocker, M., Meek, C., Tyberg, J. V & Friedrich, M. G. Edema as a very early
marker for acute myocardial ischemia: a cardiovascular magnetic resonance study. J. Am. Coll.
Cardiol. 53, 1194201 (2009).

107.

h-Ici, D. O. et al. T1 mapping in ischaemic heart disease. Eur. Heart J. Cardiovasc. Imaging 15,
597602 (2014).

108.

Fishbein, M. C., Maclean, D. & Maroko, P. R. The histopathologic evolution of myocardial

infarction. Chest 73, 8439 (1978).

109.

Cury, R. C. et al. Cardiac magnetic resonance with T2-weighted imaging improves detection of
patients with acute coronary syndrome in the emergency department. Circulation 118, 83744
(2008).

110.

Ingkanisorn, W. P. et al. Prognosis of negative adenosine stress magnetic resonance in patients

presenting to an emergency department with chest pain. J. Am. Coll. Cardiol. 47, 142732 (2006).

111.

Lerakis, S. et al. Prognostic value of adenosine stress cardiovascular magnetic resonance in

patients with low-risk chest pain. J. Cardiovasc. Magn. Reson. 11, 37 (2009).

112.

Hartlage, G. et al. Prognostic value of adenosine stress cardiovascular magnetic resonance and
dobutamine stress echocardiography in patients with low-risk chest pain. The international
journal of cardiovascular imaging 28, 80312 (2012).

113.

Miller, C. D. et al. Stress CMR imaging observation unit in the emergency department reduces 1year medical care costs in patients with acute chest pain: a randomized study for comparison with
inpatient care. JACC. Cardiovasc. Imaging 4, 86270 (2011).

114.

Messroghli, D. R. et al. Myocardial T1 mapping: application to patients with acute and chronic
myocardial infarction. Magn. Reson. Med. 58, 3440 (2007).

115.

DallArmellina, E. et al. Cardiovascular magnetic resonance by non contrast T1-mapping allows

assessment of severity of injury in acute myocardial infarction. J. Cardiovasc. Magn. Reson. 14,
15 (2012).

19

116.

Ferreira, V. M. et al. T(1) mapping for the diagnosis of acute myocarditis using CMR: comparison
to T2-weighted and late gadolinium enhanced imaging. JACC. Cardiovasc. Imaging 6, 104858
(2013).

117.

Garg, P., Greenwood, J. P. & Plein, S. Multiparametric relaxometry by cardiac magnetic resonance
imaging in Takotsubo cardiomyopathy. Eur. Heart J. Cardiovasc. Imaging (2015).
doi:10.1093/ehjci/jev167

118.

Foy, A. J., Liu, G., Davidson, W. R., Sciamanna, C. & Leslie, D. L. Comparative effectiveness of
diagnostic testing strategies in emergency department patients with chest pain: an analysis of
downstream testing, interventions, and outcomes. JAMA Intern. Med. 175, 42836 (2015).

Author contributions
P.G. researched data for the article and wrote the manuscript. P.G., S.R.U., R.S., J.P.G.
and S.P. reviewed and edited the manuscript before submission. P.G. and S.P.
provided substantial contribution to the discussion of content.
Competing interests statement
The authors declare no competing interests.

Figure 1 | Algorithm for the management of suspected acute coronary syndrome (ACS). Use of
cardiac imaging is dependent on resting electrocardiogram (ECG) and a highly sensitive troponin (hs-Tn)
assay (adapted from ESC guidelines). STEMI, ST-segment elevation myocardial infarction; CTCA,
computed tomography coronary angiography; CMR, cardiovascular magnetic resonance; Echo,
echocardiography; MPS, myocardial perfusion scintigraphy; PPCI, primary percutaneous coronary
intervention.

Figure 2 | Transthoracic echocardiography in a patient with suspected ACS. a | Apical four-chamber

view in end-diastole. b | Apical four-chamber view in end-systole demonstrating reduced thickening in the
mid-to-apical septum and apex (yellow arrows) suggestive of left anterior descending artery ischaemia. c |
Colour Doppler in apical four-chamber view demonstrating moderate-to-severe ischaemic mitral
regurgitation. d | Continuous wave Doppler across the mitral valve demonstrated dense spectrum of the

20

mitral regurgitation.

Figure 3 | Timeline of pathophysiological changes in ischaemic myocardium and imaging techniques

used to study the associated changes. a | Computed tomography coronary angiography (CTCA). b |
Myocardial contrast echocardiography for the assessment of perfusion defects. c | Rest myocardial
perfusion scintigraphy (MPS). d | Contrast-enhanced magnetic resonance angiography for the detection of
proximal coronary anomaly. e | Stress cardiovascular magnetic resonance (CMR). f | Myocardial
ischaemic memory imaging with -methyl-p-[123I] iodophenylpentadecanoic acid. g | Strain imaging on
echocardiography (Echo) for heterogeneity of strain curves. h | Myocardial tagging with CMR for
regional strain variations in ischaemic myocardium. i | Echocardiography to detect regional wall motion
abnormality. j | Cine CMR imaging to detect regional wall motion abnormality. k | Ratio of peak mitral
inflow velocity (E) and mitral valve propagation velocity (Vp) for estimating left atrial pressure (E/Vp). l
| Native T1-maps on CMR imaging for the quantification of myocardial oedema. m | T2-weighted CMR
imaging for myocardial oedema. n | Late gadolinium enhancement (LGE) imaging on CMR for scarred
myocardium. o | LGE for microvascular obstruction. p | T2-weigthed imaging on CMR for
intramyocardial haemorrhage. Panel f is reprinted with permission obtained from Elsevier Ltd 93.CP,
chest pain; IMH, intramyocardial haemorrhage; LV, left ventricular MVO: microvascular obstruction.

Figure 4 | Imaging in patients with suspected ACS. a | Rest (upper panel) and stress (lower panel)
myocardial perfusion scintigraphy (MPS) in a patient with inferior wall ischaemia at stress. b | Rest
(upper panel) and stress (lower panel) contrast-enhanced stress echocardiography demonstrating apical
ballooning at peak stress suggestive of significant ischaemia (involving more than 3 segments and hence
10% myocardial ischaemic burden) in the left anterior descending artery (LAD). c | Computed
tomography coronary angiography in a patient with crescendo angina and negative serial troponin tests
demonstrating significant proximal right coronary artery soft plaque lesion and two nonsignificant LAD
lesions (inset; through-plane imaging for plaque characterization).

Figure 5 | Multiparametric cardiovascular magnetic resonance imaging in a patient with suspected

ACS. a | 3D wall-motion colourmap showing an area of hypokinesia and akinesia (yellow arrow). b |
Short-axis native T1-map demonstrating high inflammation in the peri-infarct anterior wall (green arrow).
c | Nonquantitative T2-weighted imaging demonstrating myocardial oedema in the same segment (yellow

21

arrow). d | Early gadolinium enhancement imaging demonstrating absence of microvascular obstruction. e

| Late gadolinium enhancement imaging confirms small subendocardial scar in the anterior wall (yellow
arrow). f | Extracellular volume from the pre/post-contrast T1-maps shows that the area of myocardial
oedema and the infarct are in the same segments (yellow arrow).

22

Table 1. Overview of noninvasive cardiac imaging for the assessment of acute chest
pain.
Modality

Advantages

Disadvantages

2D-TTE

Bedside
Widely available
Relatively low cost to other imaging modolities
RCT and observational data support the use of
2D-TTE
Standard reporting approach
Strain related techniques might add to the
diagnostic accuracy

Might not be available 24/7

Poor endocardial definition that reduces the
diagnostic yield
Quantification is not as reliable as for other
techniques
Reliability is questionable when symptoms
subside

Contrast
Echo (CE)
or

CE increases the diagnostic yield of 2D-TTE

RCT and observational data support use of CE
and MCE
For MCE, large studies suggests incremental
diagnostic and prognostic information

Reporting approach for MCE is not

standardized
MCE is mostly used in research centres

Stress
Echo (SE)

SE (exercise) is superior to EET (and similar to

exercise MPS) in risk stratification
RCT and observational data support the use of
SE (mainly exercise with/without contrast)
Contrast is safe to use in SE
Can be used even when symptoms have
subsided
Provides incremental prognostic information

Probably not available 24/7

Available only in centres with local
expertise in SE

CTCA

Widely available
Can be reported remotely by on-call
radiologist/cardiologist
Standard acquisition and reporting approach
RCT and observational data support the use of
CTCA
Perfusion CT might add to the diagnostic value
Other causes of chest pain can be diagnosed
using triple rule-out CT

Probably not available 24/7

Coronary calcium could interfere with the
interpretation
Functionally nonsignificant lesions
(moderate stenosis) can lead to increased
invasive assessments
Patients with fast heart rates, atrial
fibrillation and abnormal renal functions
might not be eligible
Radiation exposure
Adequate renal function is required (eGFR
>30ml/min/1.73m2), otherwise the risk of
contrast induced nephropathy increases

Rest MPS

Widely available
Standard acquisition and reporting approach
RCT and observational data support the use of
rest MPS
Quantitative assessment is possible and is widely
used
Provides prognostic information

Probably not available 24/7

Radiation exposure

CMR

Comprehensive structural and functional

assessment

Most probably not available 24/7

Expertise for comprehensive imaging in

MCE
(Perfusion
)

23

Tissue characterization myocardial oedema

assessment, EGE for thrombus, LGE for scar
and MVO, IMH
Well validated for the quantification of LV
functional parameters
RCT and observational data support use of stress
CMR
Provides several clinical parameters of prognosis
No radiation exposure

this setting is not widely available

Reporting approaches are not standardized
Patients with claustrophobia, fast heart
rates, severe renal impairment, high burden
of ventricular ectopics, and ferromagnetic
implants might not be eligible for stress
CMR
Adequate renal function is required (eGFR
>30ml/min/1.73m2), otherwise there is a
potential risk of nephrogenic systemic
fibrosis

CMR, cardiovascular magnetic resonance; CTCA, computed tomography coronary angiography; Echo,
echocardiography; EET, exercise electrocardiography test ; EGE, early gadolinium
enhancement; IMH, intramyocardial haemorrhage; LGE, late gadolinium enhancement; LV, left
ventricular; MCE, myocardial contrast echocardiography ; MOV, microvascular
obstruction; MPS, myocardial perfusion scintigraphy; RCT, randomized controlled trial ; TTE,
transthoracic echocardiography.

24

Table 2 | Guideline endorsement of advanced imaging when ACS is suspected but ECG and
biomarkers are inconclusive
Modality
2D-TTE

Guidelines
ESC guidelines for NSTE-ACS 2011
ACCF/ASE/AHA Appropriate Use Criteria for

Endorsed for
Primary bedside modality
For resting RWMA

Echocardiography 2011

Stress
Echo

ESC Guidelines for NSTE-ACS 2011

ACCF/ASE/AHA Appropriate Use Criteria for

In all suspected ACS for RWMA

Echocardiography 2011
CTCA

ESC Guidelines for NSTE-ACS 2011

ACCF/ASE/AHA Appropriate Use Criteria for
Cardiac Computed Tomography 2010

In low/intermediate CAD likelihood

for coronary anatomy
In patients with suspected coronary
anomalies

Rest MPS

ESC Guidelines for NSTE-ACS 2011

Appropriate Use Criteria for Cardiac Radionuclide

In all suspected ACS for myocardial

scar

Imaging 2009
CMR

ESC Guidelines for NSTE-ACS 2011

Appropriateness Criteria for Cardiac Computed

In intermediate CAD likelihood for

Tomography and Cardiac Magnetic Resonance

myocardial scar or RWMA

In patients with suspected coronary

Imaging 2006

anomalies using MR coronary

angiography

ACCF, American College of Cardiology Foundation; ACS, acute coronary syndrome; ASE, American
Society of Echocardiography ; CAD, coronary artery disease; CMR, cardiovascular magnetic resonance;
CTCA, computed tomography coronary angiography; Echo, echocardiography; MPS, myocardial
perfusion scintigraphy; NSTE, non-ST-segment elevation; MR, magnetic resonance; RWMA, regional
wall motion abnormalities

25

Author biographies

Pankaj Garg obtained his medical degree with honours in 2003 from the Moscow Medical Academy,
Russia. Dr Garg currently works as a research fellow in cardiac MRI at the University of Leeds, UK. He
is honorary cardiology registrar for the Sheffield Teaching Hospitals NHS Foundation Trust and Leeds
Teaching Hospitals NHS Trust, UK. His research focus is on tissue characterization and the role of 3D
phase contrast acquisition for the assessment of intracardiac flow on cardiac MRI.
Stephen Richard Underwood is Professor of Cardiac Imaging at the Imperial College London (National
Heart and Lung Institute), UK, and Honorary Consultant to the Royal Brompton Hospital, London, UK. A
cardiologist by initial training, Professor Underwood now has dual specialization in cardiology and
nuclear medicine. His principal interest is noninvasive imaging of the cardiovascular system, in particular
nuclear cardiology, X-ray CT, and magnetic resonance imaging. He has been involved in the pioneering
work at the Royal Brompton Hospital, where many of the techniques for cardiac imaging have been
developed. His research interests include myocardial hibernation, the cost-effectiveness of imaging
techniques, and pharmacological stress.
Roxy Senior is Professor of Clinical Cardiology at the National Heart and Lung Institute,
Imperial College London, UK. Professor Senior graduated and obtained a Masters degree in
medicine and cardiology from the University of Calcutta, India. He became a Consultant Cardiologist and
Director of Cardiac Research at the Northwick Park Hospital, Harrow, UK, in 1995, and was then
appointed Consultant Cardiologist and Director of Echocardiography at the Royal Brompton Hospital in
2010. His research interests include echocardiography and he has published >250 original papers in this
field.
John P. Greenwood obtained his medical degree from Leeds University, UK, in 1991, and his PhD in
cardiovascular disease in 1999 (Leeds University, UK). Professor Greenwood trained in cardiac MR at the

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Royal Brompton Hospital, London, UK, and in coronary intervention in Toulouse, France. His research
interests include optimizing the diagnosis and treatment of stable and unstable coronary artery disease.
Sven Plein graduated from Phillips University Marburg, Germany, in 1996. He obtained a PhD in
Cardiology from the University of Leeds, UK, in 2003, and has been a Professor of Cardiology in Leeds
since 2013. Professor Plein has published >140 papers in cardiac imaging with a focus on cardiovascular
magnetic resonance.

Key Points

Cardiac imaging can complement history, electrocardiogram, and cardiac biomarkers for a timely
identification and ruling out of acute coronary syndrome (ACS)
Bedside echocardiography is the first-line imaging test in patients with suspected ACS
The advanced imaging techniques (stress echocardiography, computed tomography coronary
angiography, myocardial perfusion scintigraphy, and cardiovascular magnetic resonance) add
diagnostic and prognostic value in patients with suspected ACS
Novel radionuclides, such as -methyl-p-[123I] iodophenylpentadecanoic acid, enable imaging of
metabolic disturbances in glucose metabolism that result from myocardial ischaemia (which can
last >12h), thereby allowing late detection of ischaemia
Multiparametric tissue characterization on cardiovascular magnetic resonance enables the
detection of myocardial oedema in ischaemic injury, which can be detected very early and can
last up to a few weeks

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