There is a wide variation in literature on the subject owing to different methodologies involved, different prevalence of disease in the populations studied and different definitions of significant CAD. Most studies define significant stenosis as 50% or more based on the original study by Gould [21
]. However, 70% or more stenosis is considered severe stenosis in day-to-day practice [28
] and this cut-off has been used in some studies to define significant stenosis. Invasive coronary angiogram is still considered to be a gold standard. This, in itself, is a flaw as an anatomical yardstick is used to validate the diagnostic accuracy of functional assessment. The rest of the article looks at the role of different imaging modalities, with particular reference to their accuracy in the diagnosis of CAD, prognostication and assessment of viability.
Single photon emission CT
SPECT imaging has been available since the 1970s and has given us a large body of evidence confirming its diagnostic and prognostic value. The commonly used radio-isotopes are thallium-201 and technetium-based agents such as 99Tcm sestamibi and 99Tcm tetrofosmin. Ischaemia is suspected when there is reduced tracer uptake on the stress acquisition which is reversible on the rest acquisition (). A fixed defect, i.e. a defect present on both stress and rest acquisitions, is suggestive of an infarct provided attenuation artefacts are ruled out ().
(a) Reversible ischaemia on myocardial scintigraphy scan in the anterior wall (arrows). (b) An occluded diagonal artery (arrow) on invasive coronary angiogram.
Infarct in the inferior wall identified by the fixed defect on stress and rest acquisitions on myocardial perfusion scintigraphy scan (arrows). Courtesy of Dr A Kelion, Consultant Cardiologist, Harefield Hospital, UK.
The sensitivity and specificity for the diagnosis of significant coronary stenosis (defined as ≥50% stenosis) were 86% and 74%, respectively [29
A false negative study may be a feature of three-vessel and left main stem disease because SPECT assesses relative perfusion. Normal perfusion is seen in up to 13–15% of patients with left main stem disease on account of balanced ischaemia in multivessel disease [30
False positive tests due to attenuation artefacts lower the specificity. For example, an elevated diaphragm results in an apparent fixed defect in the inferior wall in men, and breast artefact gives rise to an apparent defect in the anterior wall in women. Implementing gated studies [32
], attenuation correction algorithm [33
] and prone imaging [34
] help improve the specificity by reducing the number of equivocal scans in such cases.
Referral bias, introduced by the fact that only patients with a positive test will undergo an invasive angiogram, also falsely lowers the specificity.
A negative study confers an annualised risk of less than 1% of adverse cardiac events [35
An abnormal study is associated with an annual event rate of 6.7–7% [29
]. The annual event rate increases with increasing severity of the perfusion defect.
The warranty period refers to the frequency of follow-up testing following a negative study. The warranty period is approximately 5 years in a clinically stable patient with no new symptoms or signs. The individual risk and the warranty period are dependent on the age and sex of the patient, stress-induced ECG changes and associated comorbidities such as diabetes and renal dysfunction. The annual risk varies from 1.4% to 1.8%. The risk is highest for an 80-year-old female diabetic patient, in whom the warranty period is only 1–2 years [20
Assessment of viability
Viability assessment on SPECT is based on demonstration of the integrity of the cell membrane following an injection of a perfusion tracer. Pooled meta-analysis of thallium and tetrofosmin studies suggests good sensitivity of 83–88% and a modest specificity of 49–69% for prediction of regional functional recovery after revascularisation [36
]. This suggests that it has a good negative predictive value. The poor positive predictive value is due to the poor spatial resolution of the technique. Subendocardial infarcts are beyond the spatial resolution of SPECT and are likely to be missed leading to overestimation of viability [37
Assessment of cardiac function
Analysis of LVF on gated studies correlated well with MRI in a meta-analysis of nine studies. However, the margin of error was higher in women with smaller left ventricular volumes, with dilated cardiomyopathy and in the presence of global subendocardial perfusion defects [38
Role of perfusion scintigraphy scan
The European and American guidelines recommend the stress electrocardiography test as a first-line of investigation in patients with an intermediate pre-test probability owing to its wide availability [39
]. A perfusion scintigraphy scan is recommended for the diagnosis of CAD in the following conditions:
- contra-indications to performing stress ECG, e.g. severe arterial hypertension, left ventricular hypertrophy
- inability to perform stress ECG
- equivocal stress ECG
- abnormal resting ECG which would make interpretation of stress ECG difficult.
In patients with known CAD, it assesses the haemodynamic significance of a coronary lesion and is involved in risk stratification and prognosis.
Positron emission tomography
PET consists of perfusion imaging with a perfusion tracer (rubidium-82, nitrogen-13 ammonia or oxygen-15 water) and functional metabolic imaging with 18F-fluorodeoxyglucose (FDG).
Mismatch between flow and metabolism, i.e. reduced flow with normal or increased FDG uptake, suggests reversible ischaemia. Matched reduction in blood flow and metabolism suggests an infarct.
In a meta-analysis of 19 studies, PET had a sensitivity of 92% and a specificity of 85% for diagnosing significant CAD (defined as ≥50%) [41
A study of 1441 patients who underwent rubidium PET study confirmed that the all-cause mortality increased with increasing severity of perfusion defect and with decreasing left ventricular ejection fraction (LVEF) over a follow-up period of 2.7 years [42
]. The annualised cardiac event rate was 0.4% in patients with normal studies. It increased to 2.3% with mild perfusion abnormalities and 7% with moderate to severe perfusion defects [43
Assessment of viability
As with SPECT, PET has good sensitivity and moderate specificity for predicting functional recovery post-revascularisation [44
Comparison with SPECT
In a study looking at age-, gender- and body mass-matched patients who had PET (n
= 112) or SPECT (n
= 112), PET was superior to SPECT in many aspects [45
]. PET had higher diagnostic accuracy than SPECT (87% vs
71%) for stenosis of more than 50%. It correctly diagnosed multivessel disease in more patients. There was less gut interference and fewer attenuation artefacts, resulting in superior quality images. It was quicker than SPECT because of the short half-life of the perfusion tracers. Rubidium-82 has a half life of 72 s, nitrogen-13 ammonia has 10 min and oxygen-15 water has 2 min.
Unlike SPECT, PET has the advantage of being able to measure myocardial blood flow in absolute units, which is important in the assessment of the distal coronary microcirculation [46
Despite its superiority over SPECT imaging, the widespread use of PET is hampered by the requirement for expensive PET cameras and for cyclotron or rubidium generators.
SE is a low-cost, widely available procedure which is based on assessment of regional wall motion abnormality induced by exercise or increasing doses of dobutamine. Stress-induced new or worsening regional or global wall motion abnormality is a reliable predictor of ischaemia.
The sensitivity and specificity of SE in the diagnosis of CAD varies with the technique used. The sensitivity is 80%, 85% and 78% and specificity is 86%, 76% and 91% for dobutamine, exercise and dipyridamole, respectively [47
]. The sensitivity and specificity are reduced in patients with severe left ventricular dysfunction.
A negative SE confers a 0.5–0.8% risk of cardiac death or non-fatal myocardial infarction [49
]. An abnormal SE is associated with an increased risk of adverse cardiac events. The risk is increased with resting left ventricular dysfunction, extensive ischaemia and extensive wall motion abnormality [48
Viability imaging is based on demonstration of contractile reserve, i.e.
the ability of dysfunctional myocardium to contract with low doses of an ionotropic agent. SE had a sensitivity of 84% and a specificity of 81% for prediction of functional recovery. False negatives may be due to the presence of fibrosis or the disruption of the contractile apparatus in viable tissue. Contractile response of the myocardium adjacent to an infarct can give rise to a false positive result [36
Assessment of cardiac function
LVF is mainly assessed by M mode and two-dimensional echocardiography [52
]. It is widely available, inexpensive and does not involve the use of radiation. However, it is unreliable in progressive ventricular dilatation as it relies on geometric assumptions regarding the left ventricular cavity [53
Comparison with SPECT imaging
Pooled meta-analyses show that SPECT is more sensitive and SE is more specific, both in the diagnosis of significant CAD and in the assessment of viability [54
Role of stress echocardiography
Indications for SE include:
- diagnosis of CAD
- risk stratification in patients with known CAD
- pre-operative risk assessment in patients undergoing non-cardiac surgery
- assessment of valvular dysfunction .
It is most useful in patients in whom stress ECG is contraindicated, not feasible, equivocal or submaximal [51
Stress is achieved by the same mechanisms as for other techniques, i.e. exercise or pharmacological. The myocardium is imaged during the first pass of a bolus of gadolinium during stress. The normally perfused myocardium enhances with contrast.
Reversible ischaemia is visually assessed as a reversible low-signal defect in the absence of delayed enhancement (). An infarct shows up as an enhancing area as opposed to normal myocardium, which is black or “nulled” on the delayed enhancement sequences with gadolinium ().
(a) A hypoperfusion defect in the inferior wall on stress MRI (arrow). (b) No hyperfusion defect in the inferior wall on rest images (arrow). (c) Occlusion in the mid-right coronary artery (arrows) on coronary angiogram.
Enhancement in an infarct involving the anterior and anteroseptal walls of the left ventricle on delayed enhancement images on MRI (arrows).
A recent meta-analysis confirmed a high sensitivity of 89% and a moderate specificity of 80% for the diagnosis of significant CAD in a population with a high prevalence of CAD of 57% [55
]. The value of stress CMR in low-prevalence populations is not clear. False positive tests can be attributed to the presence of artefacts due to susceptibility (called dark rim artefacts), poor gating and motion artefacts [56
A negative adenosine stress perfusion CMR conferred a low cardiac event rate of 1%, both in the low to intermediate risk population and in patients with known CAD [57–59]. An abnormal adenosine stress CMR was associated with a 12-fold increased risk of a cardiac event, and an abnormal dobutamine stress perfusion was associated with a 5-fold risk of a cardiac event over a follow up period of 2.3 years [60
Assessment of viability
Viability imaging on CMR relies on the demonstration of scar tissue 10–20 min after the administration of gadolinium on the delayed enhancement inversion gradient echo sequence. In a study involving 50 consecutive patients who were imaged before and after revascularisation, Kim et al [61
] showed that the extent of the infarct on delayed enhancement sequences predicted functional recovery after revascularisation (). The extent of the infarct was expressed as a percentage of the myocardium that enhanced with contrast.
Table 5 Extent of delayed enhancement and functional recovery after revascularisation 
Thus, absence of enhancement and enhancement of more than 75% of myocardium were the best predictors of functional recovery 79±36 days after revascularisation.
Assessment of cardiac function
This is considered to be the gold standard for global and regional left ventricular functional analysis. It is superior to echocardiography for the following reasons:
- the newer sequence, called the steady-state free-precession sequence, allows good demarcation of the endocardial border and blood pool contrast; and
- unlike echo, there is no geometric assumption and the LVEF can be calculated with reasonable accuracy even in distorted ventricles .
Comparison with SPECT
A comparison of stress CMR and SPECT in 234 patients in 18 centres worldwide was the basis of the MR-IMPACT (magnetic resonance imaging for myocardial perfusion assessment in coronary artery disease) trial. It showed that stress CMR using 0.1 mmol kg–1
gadolinium performed better than SPECT (area under the curve of 0.86 vs
0.67) and that stress MR performed better than SPECT in the diagnosis of multivessel disease [63
CMR also consistently detects more subendocardial defects than SPECT or PET imaging. Nearly half of the segments with subendocardial infarcts are missed on SPECT [64
] and PET [65
Comparison with stress echocardiography
Delayed enhancement CMR has a better negative predictive value than SE, particularly in segments with severe dysfunction [61
]. Dobutamine echocardiography has a low sensitivity of 26% in severe left ventricular dysfunction [66
], the very segments whose viability assessment needs to be accurate. This is because contractility depends on the delivery of adequate amount of oxygen to an intact contractile apparatus. In severely dysfunctional segments, ionotropic reserve is hampered owing to an exhausted coronary flow reserve to a possibly disrupted contractile apparatus.
Coronary artery calcium
This is a marker of subclinical atherosclerosis and reflects the total atherosclerotic burden including calcified and non-calcified plaques. The most widely used method for quantifying coronary calcium is the Agatston score [67
]. It is based on identifying calcium on the basis of its density (>130 Hounsfield units) (). It assigns a CT factor to the coronary calcium based on the Hounsfield unit in all the coronary arteries and compiles a total score based on age and gender [68
Calcification in the left anterior descending artery on a coronary calcium score study (arrow).
Prognostic role of coronary calcium in asymptomatic patients
Coronary calcium is an independent risk factor superior to and additive to traditional risk factors in patients without known CAD, irrespective of their ethnicity [69
Absent coronary calcium was associated with an event rate of less than 1.01% over 50 months. A coronary calcium score of zero was associated with a low incidence of significant coronary artery stenosis on invasive angiogram, a low likelihood of acute coronary syndrome and a low incidence of an abnormal myocardial perfusion scintigraphy scan [72
Prognostic role of coronary calcium in symptomatic patients
Although most of the prognostic data are derived from studies involving asymptomatic patients, the prognostic role also extends to the symptomatic population. In a meta-analysis of 7 studies involving 3924 patients, 1.8% of patients with no coronary calcium had a cardiovascular event compared with 8.99% of symptomatic patients with coronary calcium followed over 42 months [72
Role of coronary calcium in the diagnosis of obstructive CAD in patients presenting with stable chest pain
Coronary calcium has an important role to play in patients presenting with stable chest pain, with a pre-test probability of 10–29% as suggested by the NICE guideline () [4
]. The presence of coronary calcium is sensitive but not specific for the diagnosis of significant coronary artery stenosis [72
]. A clear relationship exists between increasing coronary calcium scores and the severity of coronary stenosis and the number of stenotic vessels [73
]. Absent coronary calcium is indicative of the absence of significant stenosis. However, this has to be interpreted with caution. Both the Multi-Ethnic Study of Atherosclerosis [73
] and a recent meta-analysis [72
] showed that absent coronary calcium may be associated with significant coronary artery stenosis in 2–4% of patients. These patients were younger, and hence absent coronary calcium should be interpreted with caution in patients under 50 years.
Role of coronary calcium in patients presenting with acute chest pain to the emergency department
A limited number of studies of patients presenting to the emergency department with acute chest pain show that in patients with negative cardiac enzymes and no electrocardiographic changes, absent coronary calcium excludes acute coronary syndrome with a high sensitivity of 99% and a negative predictive value of 99% [72
]. These patients can be discharged from the unit promptly and safely with a low risk of a cardiac event [74
Role of coronary calcium in renal disease
Coronary calcium is deposited in a non-atherosclerotic process in the tunica media as a consequence of altered calcium metabolism [75
]. It is high and progressive in renal patients, particularly in patients on dialysis [76
]. It is associated with a significantly increased cardiovascular risk [77
]. The role of coronary calcium is not clear because of limited studies on the subject. More prospective studies are required to clearly ascertain the relationship between increased cardiovascular risk and coronary calcium.
Role of coronary calcium in diabetic subjects
Several studies demonstrate that:
- Coronary calcium is an independent prognostic indicator in diabetic patients.
- Increasing coronary calcium is associated with an increased risk of cardiovascular events. For every increase in coronary calcium the risk is higher in diabetics than non-diabetic patients.
- Absent coronary calcium is associated with a lower risk of events, a lower incidence of myocardial perfusion abnormalities and a short-term survival rate similar to that of non-diabetic patients [78-80].
Comparison with other imaging modalities
Absent coronary calcium is associated with a low incidence of ischaemia on SPECT/PET. Only 6% of patients with absent coronary calcium had ischaemia compared with 20% of patients with a high coronary calcium score [81
]. Increasing coronary calcium is associated with an increased risk of an adverse cardiac event, both in patients with normal perfusion scans and in those with perfusion abnormalities on PET imaging [83
Technological advancements in hardware and software of newer generation CT scanners have improved spatial and temporal resolution and z-axis coverage while reducing the radiation dose. Faster gantry rotation times, wide detector designs, dual-source technology and newer reconstruction methods have resulted in improvements in image acquisition, reconstruction, work flow and analysis.
Diagnosis of CAD involves detection of stenosis and plaque analysis ().
CT appearances of mixed plaque (arrows) in the left anterior descending artery.
In the diagnosis of coronary stenosis
Multicentre prospective studies [28
] and a recent meta-analysis [86
] confirm an excellent sensitivity of 99% for 64 slice coronary CT. Coronary CT rules out coronary stenosis with a high degree of confidence in low-, intermediate- and high-risk populations [28
However, its specificity varies between 64% and 89% [84
]. The relatively modest specificity, particularly in high-risk patients, is due to a number of factors, including heavily calcified vessels [28
], smaller vessels [89
] and the presence of stents [90
]. Artefacts introduced by poor image quality due to high heart rates, arrhythmias and motion may be falsely interpreted as stenoses [86
]. Thus, there is a tendency to overestimate stenoses, particularly in high-risk patients.
In plaque assessment
Assessment of the atherosclerotic burden by CT is based on plaque volume assessment. There is a good correlation between plaque volume estimation on intravascular ultrasound and on CT [91
]. Plaque volume estimation has the potential for monitoring response to lipid-lowering therapy [92
]. However, it is affected by several variables including the image quality and interobserver variability [93
Plaques may also be implicated in the development of acute coronary syndrome. Low attenuation plaques (i.e.
non-calcified plaques), plaques with spotty calcification (mixed plaques) and those associated with constrictive remodelling are more likely to result in an acute coronary syndrome [94
There are few data regarding long-term prognostic information, particularly with the newer generation of CT scanners. In a recent meta-analysis, the annualised cardiac event rate was 0.17% for a normal coronary CT over a median follow-up of 20 months. The adverse annual event rate was 8.8% for an abnormal coronary CT and the risk rose with increasing severity of coronary stenosis [95
Role of coronary CT in a stable patient with suspected CAD
Most of the data regarding the diagnostic accuracy of coronary CT, as described above, relate to stable patients with suspected CAD. The high negative predictive value in intermediate-risk patients safely reduces unnecessary referrals for invasive angiograms [96
]. Its modest positive predictive value limits its diagnostic accuracy, particularly in high-risk patients [84
]. Thus, coronary CT is of most value in the intermediate-risk population.
Role of coronary CT in acute chest pain
Patients presenting to the emergency department with acute chest pain can be stratified on the basis of coronary CT provided they have no ECG changes and have normal cardiac enzymes [97
]. Small studies show that up to 50% of such patients do not have significant coronary stenosis [97
] and can be safely discharged with a low 1 year event rate [98
]. Coronary CT also has a role to play in a “triple rule-out” test, which aims to rule out important non-cardiac causes of chest pain such as an acute aortic syndrome and pulmonary embolism. There are issues such as increased radiation dose and difficulty in ensuring adequate contrast opacification in three vascular territories [90
]. More data, particularly from large randomised controlled trials, are needed to evaluate the clinical utility of the triple rule out test in day-to-day practice.
MRI of coronary arteries
This involves free breathing three-dimensional acquisition of the coronary artery with real-time assessment of the diaphragm using a navigator (). It has a sensitivity of 72% and a specificity of 87% for diagnosing coronary artery stenosis of 50% or more [99
]. Its predictive value is best for proximal and mid-segments [100
]. Its clinical utility is limited by the fact that it is time-consuming and 30–50% of segments cannot be evaluated [100
Three-dimensional navigator image of the left main stem (thin arrow), left anterior descending artery (thick arrow) and circumflex artery (double-headed arrow) on MRI.