Novel approaches to the non-invasive diagnosis of coronary-artery disease
Werner Moshage,
Stephan Achenbach and
Werner G. Daniel
Department of Internal Medicine II, University of Erlangen-Nürnberg, Erlangen, Germany
Keywords: computed tomography; coronary angiography; coronary artery disease; diagnosis; electron beam tomography; magnetic resonance imaging
Do we need novel approaches to the non-invasive diagnosis of coronary-artery disease?
The arsenal of non-invasive diagnostic tools for the workup of suspected coronary-artery disease seems well stocked: electrocardiography and echocardiography during rest and stress as well as nuclear cardiology are widely available. However, all of these techniques have an important limitation: they do not permit direct visualization and quantification of coronary-artery stenoses, but rather rely on the detection of functional consequences caused by flow-limiting lesions. Haemodynamically insignificant stenoses cannot be detected.
Cardiac catheterization with selective coronary angiography remains the gold standard for the assessment of the presence and severity of coronary-artery disease. This very frequently performed procedure, even though invasive, has a low procedure-related morbidity and mortality: severe adverse events such as acute myocardial infarction, stroke, or malignant arrhythmias are reported in less than 1%, death in less than 0.15% [1]. In the context of cardiac catheterization, intravascular ultrasound (IVUS) can be used to investigate precisely the coronary vessels concerning the presence of early atherosclerotic lesions not detectable by angiography and to analyse the composition of plaques [2]. In addition, invasive diagnostic procedures can immediately be followed by interventional revascularization, thus combining diagnosis and therapy in one session.
All the same, there has long been a quest for direct, non-invasive visualization of the coronary arteries and stenoses. This is justified by the relatively high cost of catheterization and coronary angiography as well as the small, but nevertheless not negligible risk of the invasive procedure, and last but not least by the fact that a substantial fraction of all invasive coronary angiographies are not followed by revascularization procedures (angioplasty or bypass surgery).
An even more important motivation to explore novel approaches to the non-invasive diagnosis of coronary-artery disease is the fact that all currently established non-invasive methods depend on the presence of haemodynamically relevant stenoses (exceeding 70% luminal narrowing) for detection of coronary-artery disease. This usually implies a relatively late detection and therefore also late therapy of this disease, which typically develops over decades: it is not until the occurrence of high-grade coronary-artery stenoses that the patient experiences chest pain and current diagnostic methods can detect the presence of coronary-artery disease. Acute occlusion of a coronary artery and subsequent myocardial infarction, however, is not usually caused by a high-grade coronary-artery stenosis but rather by rupture or erosion of an unstable atherosclerotic lesion which was previously not associated with a significant luminal narrowing [3,4]. Consequently, in approximately 50% of cases, acute myocardial infarction is not preceded by angina pectoris [5,6]. Non-invasive diagnosis of coronary-artery disease in its early stages, possibly including the identification of unstable plaques prone to rupture, and subsequent initiation of stringent prevention measures may therefore be a useful and cost-effective strategy in the management of coronary artery disease.
Magnetic resonance imaging (MRI)
MRI, a cross-sectional imaging technique without X-ray exposure and usually without application of contrast agent, is a tool that permits the addressing of a wide range of diagnostic questions in coronary artery disease (one-stop shop'). Theoretically, the diagnostic potential of MRI includes cardiac morphology, ventricular geometry, mass, and function at rest and under stress [7,8], myocardial perfusion [9], and visualization of the coronary arteries up to the analysis of flow in aorto-coronary bypass grafts [10] and coronary arteries [11]. MRI may therefore play an increasingly important role in the non-invasive diagnosis of coronary artery disease.
However, the holy grail of cardiac imagingthe reliable visualization of the coronary arteries and detection of coronary artery stenoseshas so far not been achieved by MRI. In 1993, Manning et al. [12] published an initial study in 37 patients that reported a sensitivity of 90% and specificity of 92% for the detection of significant coronary-artery stenoses by MRI using a two-dimensional breathhold technique. Until today, however, these results could neither be reproduced by MRI nor achieved by other non-invasive imaging methods.
While initially, coronary artery imaging by MRI had been attempted using two-dimensional techniques in oblique or double-oblique planes which required skillful positioning to cover the tortuous course of the coronary arteries [1216], modern MRI techniques permit the acquisition of continuous volume data sets [1725]. Image acquisition can be performed in relatively short breathholds [2426] or using navigator-echo techniques which permit continuous breathing of the patient [1723]. Image analysis can be performed based on the acquired cross-sectional images or after post-processing and generation of two-dimensional or three-dimensional image reconstructions [22,27,28]. In numerous trials, MRI has been compared to invasive coronary angiography (see Fig. 1
). In spite of continuously decreasing image acquisition times and increasing spatial resolution these trials could so far not justify a clinical role of MRI for the detection of coronary artery disease (see Table 1
).

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Fig. 1. Stenosis of the right coronary artery (arrow) visualized by (a) navigator-echo magnetic resonance imaging and (b) corresponding invasive coronary angiogram.
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Table 1. Detection of coronary artery stenoses: comparison of the sensitivity and specificity of navigator-echo based respiratory gated or single-breath-hold 3-dimensional magnetic resonance coronary angiography to conventional invasive coronary angiography
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On the other hand, MRI is a diagnostic imaging modality with excellent soft tissue contrast and therefore permits to visualize and analyse the components of atherosclerotic plaque. This has been shown to be applicable to atherosclerotic lesions in vitro [29] as well as in vivo in large, peripheral arteries such as the carotid arteries [30] and the thoracic aorta (Figure 2
) [31]. Coronary plaque imaging, even though shown to be feasible in selected cases [32] is currently not possible in a clinical setting due to the high temporal and spatial resolution that would be necessary to investigate the small and rapidly moving coronary arteries. Non-invasive coronary plaque characterization, however, would be a highly relevant clinical application of MRI, since it may allow the differentiation between stable and unstable lesions with the opportunity to initiate timely preventive interventions.

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Fig. 2. Visualization of an atherosclerotic plaque in the descending aorta (arrow) by magnetic resonance imaging (with permission from [31]).
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Electron-beam tomography (EBT)
Similar to MRI, electron-beam tomography (EBT), a cross-sectional X-ray imaging technology, permits prospectively electrocardiograph (ECG)-triggered imaging of the heart and has been shown to provide excellent visualization of morphology and function of the heart as well as perfusion imaging. The main advantage of the methodthe combination of high temporal resolution (50100 ms) with high spatial resolution (below 0.5 mm2)makes it particularly well suited for coronary-artery visualization. EBT with intravenous injection of contrast agent was the first non-invasive imaging modality that permitted robust imaging of coronary-artery stenoses (Figure 3
) [33]. In comparisons to invasive coronary angiography, the sensitivity for the visualization of significant coronary-artery stenoses has been shown to be between 74 and 92%, with a specificity between 79 and 94% (Figure 4
, Table 2
). Differences between the results in various centres are explained by slightly varying imaging protocols, the definition of significant stenosis (>50% diameter reduction or >75% diameter reduction), and the number of vessel segments that were excluded from analysis in EBT because of reduced image quality. The relatively high number of unevaluable coronary segments (approximately 2025%) currently constitutes the main drawback of contrast-enhanced EBT coronary angiography. Reduced image quality is in most cases caused by extensive calcifications of the coronary-artery wall and movement or breathhold artefacts. Contrast-enhanced EBT is not and will not be a substitute for invasive coronary angiography. However, contrast-enhanced EBT coronary angiography has a very high negative predictive value for the presence of coronary artery stenoses (9598%) [3440] and therefore has the potential to be used clinically to rule out coronary stenoses with low pre-test likelihood for the presence of significant coronary artery disease. Other possible clinical applications include the follow-up after coronary angioplasty (PTCA) [41], the assessment of coronary-artery bypass grafts [42], and the investigation of anomalous coronary arteries.

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Fig. 3. Cross-sectional image obtained by electron-beam tomography after intravenous injection of contrast agent. (a) The origin of the left main coronary artery from the aortic root and the proximal course of the left anterior descending coronary artery (arrow) can be seen. (b) Three-dimensional reconstruction of the coronary arteries in the same patient. Large arrow, left anterior descending coronary artery; small arrow, left circumflex coronary artery.
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Fig. 4. (a) High-grade stenosis (arrow) of the right coronary artery in electron-beam tomography, and (b) invasive coronary angiography (with permission from [38]).
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Table 2. Summary of trials comparing the visualization of significant coronary artery stenoses by contrast-enhanced electron-beam tomography to invasive coronary angiography
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Without injection of intravenous contrast agent, EBT permits the sensitive detection and quantification of coronary-artery calcifications in a rapid, widely standardized investigation (Figure 5
). Detection of coronary calcification by EBT is significantly more sensitive than fluoroscopic examinations, even if very skilfully performed [43]. The use of EBT to visualize coronary calcifications, which is currently not without controversy, does not permit the detection of non-calcified plaques or a distinction between stable and unstable coronary-artery lesions, but it does allow the detection of coronary atherosclerosis even in very early and asymptomatic stages [44]. In pathological studies, it has been well proven that coronary-artery calcifications are always due to atherosclerotic lesions [45,46]. Atherosclerotic lesions in the coronary arteries need not always be calcified, but there is a correlation between the quantity of coronary calcium detected by EBT and both the angiographic severity of coronary-artery disease (degree of worst coronary-artery stenosis, number of vessels with significant stenoses) [47] as well as the overall plaque burden in the coronary arteries [48]. However, the interindividual variations especially concerning the degree of worst stenosis are considerable, so that in general it is not possible to draw conclusions on the presence of significant stenosis based on the amount of calcification in an individual patient. Complete absence of coronary-artery calcifications, however, implies a very low likelihood of significant coronary-artery disease [47,49]. Concurrent with the fact that cardiovascular events are very frequent in patients with end-stage renal disease, it has been demonstrated that coronary calcification in EBT is much more frequent and severe in these patients as compared to the normal population [50,51].

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Fig. 5. Detection of coronary calcifications by EBT. Calcifications in the proximal left anterior descending coronary artery (arrow) as well as in the proximal left circumflex coronary artery and at the ostium of the left main coronary artery can be seen (image acquisition time, 100 ms).
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Concerning the clinical application of EBT for the detection of coronary calcifications, an issue that has been debated publicly with much controversy and emotion, the key question is whether or not the investigation results in therapeutic measures that alter the patient's prognosis. Large trials with long observation periods are necessary to answer this question, and even though several such studies are currently ongoing, this issue has not been definitely answered yet [52]. However, there are numerous studies which could prove that the presence of coronary calcifications detected by EBT has a higher predictive power concerning the occurrence of coronary events in symptomatic and especially in asymptomatic patients than conventional risk factor assessment [5355]. In a recent study, asymptomatic patients in the upper quartile of coronary calcium had a risk of suffering coronary events which was 21.5-fold higher than for patients in the lowest quartile of coronary calcium. For conventional risk factors, the odds ratio was only 7.0. One other investigation, performed in high-risk subjects, however, did not find an additive value of EBT calcium assessment when compared to conventional risk factor analysis [56]. The use of age-adjusted percentiles in the evaluation of calcium quantity seems important [55]. Patients without any coronary calcifications have a very low likelihood for the occurrence of coronary events [49].
The possibility of detecting non-invasively small amounts of coronary calcification offers the potential to diagnose coronary atherosclerosis in early, asymptomatic, and haemodynamically not yet relevant stages. In light of the prognostic relevance of coronary calcium and the possibility of improving prognosis by medical intervention (e.g. lipid-lowering therapy), the use of EBT to detect or rule out coronary calcification may be clinically meaningful. The presence of coronary calcification in EBT alone should not be a reason to perform an invasive coronary angiogram, since extensive plaque burden can be present without luminal stenosis. However, the detection of calcium is proof of the presence of coronary atherosclerosis and may justify intensive risk modification to lower the risk for future coronary events [57]. The test should be ordered by a physician who can assess the patient's clinical situation and take into account the individual history and risk factors. General screening of unselected, asymptomatic populations is neither clinically relevant nor cost-effective and is thus not justified. However, the assessment of coronary calcifications may contribute especially to the clinical management of patients who, based on traditional risk factor evaluation, are estimated to be at intermediate risk of coronary events [58]. In a joint consensus document of the American College of Cardiology and American Heart Association, the writing group states that a positive calcium score might be valuable in determining whether a patient who appears to be at intermediate coronary heart disease risk is actually at high risk. However, the expert group concludes that current data is not yet sufficient to clearly define which asymptomatic people require or will benefit from EBT calcium imaging, and strongly encourages additional studies [52].
Mechanical CT, helical CT, multirow helical CT
The detection of sufficiently large coronary calcium deposits is also possible with conventional and helical CT scanners. Since these scanners require at least 500 ms, usually more than 1000 ms, for one rotation, visualization of the heart and coronary arteries free of motion artefact is impossible. These systems are therefore not suited for exact quantification of coronary calcifications or visualization of the coronary-artery lumen with diagnostic image quality. The latest generation of helical CT scanners, however, offers the possibility to acquire data in up to four parallel slices simultaneously. Using retrospective ECG gating and sophisticated image reconstruction algorithms on dedicated workstations, it is possible to reconstruct cross-sectional images based on data collected during about 200 ms [59]. The significant reduction of motion artefacts that can be achieved in this way permits the quantification of coronary calcifications (Figure 6
) [60]. Due to very sensitive detectors and higher X-ray energy, spatial resolution and signal-to-noise ratio exceed those in EBT. It is important, however, to note that the very large amount of clinical data concerning the extent of coronary calcification and the associated risk of coronary events that has been collected so far for EBT can only with great caution be expanded to other imaging modalities such as mechanical computed tomography (CT). Large reference databases remain to be established for mechanical CT scanners and future studies will have to investigate the comparability of calcium detection by EBT to that by various mechanical CT scanners, including the issue of radiation exposure. Above all, image acquisition and evaluation protocols need to be standardized for mechanical CT scanners in the way it has been done for EBT. Prospective ECG triggering algorithms must be developed and evaluated, since retrospective ECG triggering subjects the patient to a significantly higher radiation dose than EBT because only part of the collected data is used for image reconstruction. Should these issues be resolved, however, the greater availability of modern spiral CT scanners as compared to the more expensive EBT scanners may help promote a more widespread and cost-effective clinical use of coronary calcium imaging in selected patient populations.

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Fig. 6. Calcifications in the left main and proximal left anterior descending coronary artery (arrows) detected by multirow spiral CT using retrospectively ECG-gated image reconstruction (data acquisition window, 215 ms).
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First results have shown that multirow spiral CT with retrospective ECG gating may also be used to visualize the coronary-artery lumen after intravenous injection of contrast agent (Figure 7
) [59,61,62] and due to the high signal-to-noise ratio of spiral CT scanners, high-resolution images can be obtained. However, the overall quality of images acquired in this fashion strongly depends on the patient's heart rate. If there is an unfavourable relationship between the heart rate and the filter function used for retrospective cardiac gating [59], significant motion artefacts persist and may render the images impossible to evaluate.

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Fig. 7. Three-dimensional reconstruction of the heart and coronary arteries obtained by retrospectively ECG-gated multirow spiral CT (large arrow, left anterior descending coronary artery; small arrow, right coronary artery).
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Conclusion and future prospects
Non-invasive cardiac imaging, especially in the diagnosis of coronary-artery disease, today permits investigators to go beyond examination of gross morphology, ventricular function, and myocardial perfusion; it allows them to visualize the coronary arteries themselves with high image quality. This, on one hand, concerns the detection of coronary-artery stenoses which has been shown to be possible by EBT and, with limitations, MRI and multirow spiral CT. While there are potentially useful clinical applications, for example to rule out coronary stenoses in patients with low likelihood of disease, current limitations of all of these techniques include their relatively low spatial resolution that does not allow the evaluation of small vessels such as side branches and peripheral segments of the large epicardial arteries. Furthermore, non-invasive cardiac imaging can of course not be used to guide coronary interventions. Further improvements in image quality will lead to a more widespread applicability of these imaging modalities and non-invasive coronary angiography will most probably be a clinical method available for the workup of coronary-artery disease in the not-too-distant future. Invasive coronary angiography, however, will remain the gold standard and cannot be replaced by non-invasive techniques within a predictable time frame.
On the other hand, ultrafast CT methods permit the detection of coronary calcifications which document the presence of coronary atherosclerosis even in asymptomatic patients. While it would be desirable, of course, to visualize the vulnerable plaque itself, the indirect assessment of plaque burden via quantification of coronary calcium is the best tool currently available. The absence of calcium rules out coronary stenoses with 95% accuracy [48]. The occurrence of coronary events in patients without calcium is possible, albeit much less likely than in patients who have coronary calcium [5456]. The assessment of coronary calcifications permits the identification of the at-risk patient in an early, still asymptomatic stage. This early detection of coronary disease may be timely enough to initiate effective risk modification which may otherwise not be justified. The visualization of coronary calcium, proof of the presence of atherosclerotic plaque, but only indirectly a sign of the presence of unstable plaque, has been demonstrated to have higher predictive power than conventional risk factors in two large studies [54,55].
For the ultimate goal, the direct imaging of coronary atherosclerotic plaques and analysis of their structure to detect lesions prone to rupture, MRI seems to be the most promising candidate, even though substantial further improvements in temporal, spatial, and contrast resolution remain necessary.
Notes
Correspondence and offprint requests to: Werner G. Daniel MD, Department of Internal Medicine II, University of Erlangen-Nürnberg, Östliche Stadtmauerstr. 29, D-91054 Erlangen, Germany. 
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