Copyright © 2007, The European Society of Cardiology
The clinical applications of contrast echocardiography
aOxford University, John Radcliffe Hospital, Oxford, OX3 9DU, UK
bKing's College Hospital, London, UK
cNational Heart and Lung Institute, Hammersmith Hospital, London, W12 0HS, UK
dDepartment of Cardiology, Northwick Park Hospital, Harrow, HA1 3UJ, UK
* Corresponding author. Cardiac Investigation Annexe, John Radcliffe Hospital, Oxford, OX3 9DU, UK. Tel.: +44 1865 220 325; fax: +44 1865 740 409. harald.becher{at}orh.nhs.uk
Keywords: Contrast echocardiography; LV opacification; Stress echocardiography; LV ejection fraction; LV systolic function
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1 Available contrast agents and imaging techniques |
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At present three contrast agents are licensed for left ventricular (LV) opacification and endocardial definition: SonoVue (Bracco, Italy), Luminity (BMS, USA) and Optison (GE, USA). The latter is currently not available. All these agents provide intensive opacification of the left heart chambers when administered intravenously. All agents are suspensions of microspheres filled with a perfluorocarbon gas and have a similar size as red blood cells. The dosages of contrast needed for LV opacification are minimal (0.1–0.3ml) compared to those in other imaging modalities, such as X-ray for instance. These small dosages are possible because of very sensitive contrast specific imaging technologies, which have been implemented in all state of the art ultrasound systems.1
Harmonic imaging has been developed primarily as a contrast specific imaging modality that can be used with a lower transmit power (mechanical index <0.6) than used for non-contrast imaging (mechanical index >1.0). Harmonic imaging has become the standard imaging technique for native echocardiography. In order to use it for contrast studies one has to reduce the transmit power. However, the power is still relatively high and can cause destruction of the contrast in the nearfield of the transducer as well as tissue signals of the myocardium, which impair the delineation of the endocardium.
Latest developments, such as power modulation and power pulse inversion, which use very low non-destructive transmit power techniques (mechanical index <0.2), allow for real-time imaging without the limitations of harmonic imaging. As tissue returns are not displayed, unlike with high powered techniques, they are ideal for accurately delineating the left ventricular borders. Low power-contrast specific techniques display the contrast within the cavities and the myocardial blood within the intramyocardial vessels. The blood volume within the myocardial vessels makes up only 7% of the myocardial tissue. Therefore, the myocardial opacification is always much less intensive than the cavity opacification and provides an excellent contrast for endocardial delineation (Fig. 1). The myocardial contrast is also very useful for assessing thickening of the myocardium and myocardial perfusion. The settings of the ultrasound scanners and the contrast dosages are well standardized and make contrast echocardiography an easy to use technique. Whenever available, low power contrast specific imaging techniques should be the first choice.
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2 Is there enough evidence for using contrast agents? |
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High variability of measurements was one of the major criticisms of native echocardiography in the past, which led to a shift in patient referrals towards multiple gated acquisition (MUGA) scans or magnetic resonance imaging (MRI) studies. However, it is hardly justifiable to refer patients to these more invasive and more expensive studies just for assessing LV function!
Several multicentre and numerous single centre trials, as well as a series of case reports, have demonstrated the usefulness of contrast echocardiography in clinical practice (Tables 1–3
). The reproducibility of contrast-enhanced echocardiography is as good as that of MRI. For assessment of global and regional LV function there are controlled large trials, some including several hundred patients. Contrast echocardiography is probably one of the best validated techniques, because very strict protocols and a completely blinded reading had to be performed for approval of the agents. There are very few studies with other echocardiographic technologies, which had to follow protocols that were as tightly regulated. However, contrast echocardiography is still indicated in cases where the evidence is not as broad as for assessment of LV function. For these indications (LV thrombus, LV non-compaction, RV dysplasia, etc.) we can just take advantage of the improved border delineation proven in the large LV trials, while we wait for the results of further large trials.
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3 Contrast echo only in patients with suboptimal windows? |
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Improved accuracy of contrast-enhanced images is not restricted to patients with a poor baseline image quality.2 Even with an optimal baseline image quality the borders are not as well defined as after intensive LV opacification. Therefore, automatic boundary detection is still not completely successful even in visually satisfying images, whereas with contrast-enhanced images the complete border can usually be traced. However, it is likely that there are other benefits from using ultrasound contrast than just the improved border delineation. Contrast definitely improves image alignment and in particular it helps to avoid off-axis scanning. For instance, a suboptimal two chamber view can easily be identified by a rim of RV contrast lateral to the inferoseptum. Complete display of atrial and right ventricular cavities can be useful to align the LV in the four chamber view. Using the low power contrast specific modalities there is usually an opacification of the myocardium and the epicardial vessels. An experienced echocardiographer uses all these features to obtain the optimal alignment when dealing with contrast-enhanced images.
Most of the time ultrasound contrast is given to patients with poor acoustic windows. Even with high-end ultrasound equipment the percentage of so called suboptimal images can range from 10 to 15%. The success rate of contrast enhancement in rest and stress echocardiography is very high, as has been shown in many clinical studies (Tables 1–2
). To our knowledge there are no studies published on ultrasound contrast agents, which did not show a benefit in patients with suboptimal windows. The availability of contrast-presets on the ultrasound scanners has made this technique widely applicable. In most patients the default setting and a standard contrast dosage provide excellent results with a very good safety profile.3,4 This has resulted in the increased use of contrast over the last few years, but still many patients do not receive contrast despite having suboptimal acoustic windows.
However, there have been differences, in the definition and the percentage of poor images, between echo laboratories. The recent guidelines of the European Association of Echocardiography (EAE) and the American Society of Echocardiography (ASE) suggest that the delineation of the endocardium should be used as a selection criterion.5 Contrast agents should be considered when less than 80% of the circumference of the LV endocardium is not clearly seen. However, with stress echocardiography there is always the need for optimal image quality (see Section 4.8). In rest echocardiography, suboptimal acoustic windows are not necessarily an indication for contrast echocardiography. Before a contrast agent is used to improve image quality, the echocardiographer has to clarify, whether an improved image quality might alter the patient's management, compared to proceeding with a suboptimal study. There are several clinical situations in which one can make the right management decisions despite a suboptimal echocardiogram. For instance, in a 70year old symptomatic patient who has a peak or mean transaortic gradient of 90mm Hg, it does not matter whether the endocardium is not completely delineated or whether the calculated ejection fraction (EF) is 30 or 40%. But there are other patients in whom one has to aim for the most accurate measurement of LV volumes and function.
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4 Clinical practice of contrast echocardiography |
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4.1 Assessment of LV function to guide further treatment in heart failure: implantable cardioverter-defibrillators (ICDs), cardiac resynchronization therapy (CRT)
The LV ejection fraction is an essential parameter, which determines further diagnostic procedures and treatment. For instance prophylactic ICD implantation is approved for NYHA class II and III patients with an ejection fraction of less than 35%.6 The same threshold has been established for cardiac resynchronization therapy when there is a prolongation of the QRS and heart failure class III.7 The new therapeutic options make it clear that echocardiographic examination cannot provide only semiquantitative measurements of the EF. However, LV ejection fraction can vary considerably in weekly repeated measurements in an individual patient. The limits of agreement vary by as much as 8.5% below or above the mean calculated EF for an individual patient.8 There are also differences in the calculated EF depending on the method used.
Echocardiographic methods have been underestimating LV volumes and this may not necessarily affect endsystolic and enddiastolic volumes to the same extent. One reason is the limitation due to geometric factors, particularly when using only one plane for calculating the volume. But even with 3D echocardiography the calculated echocardiographic volumes are significantly smaller than those obtained in MRI studies.9 The LV walls are not smooth borders, but irregularly trabeculated. With contrast the small spaces between the trabeculations are filled and consequently the contour for border tracing will include a larger area than with native echocardiography, where the inner border of the trabeculated area is traced. In patients with non-compaction, the trabeculated layer becomes much thicker and it may be difficult to differentiate non-compacted myocardium from simple LV wall thickening. In this situation, contrast will help to display the true lumen and will enhance the spongiform thickened trabeculated layer.
Thus, contrast echocardiography makes measurements interchangeable with MRI results, in regards to both the reproducibility and absolute measurements.
4.2 Follow up of patients with moderate valvular disease and decision for surgical treatment
Accurate assessment of LV volumes and ejection fraction is necessary for follow-up in patients with moderate mitral or aortic regurgitation. An increase in LV volumes may prompt surgery even in the absence of symptoms. Such decisions should be based on findings obtained by using the most accurate echocardiographic method. Thus, whenever there are any myocardial segments that cannot be delineated properly, contrast echocardiography must be considered.
4.3 Selection and monitoring of patients undergoing chemotherapy with cardiotoxic drugs
Left ventricular function may be impaired by some therapeutic agents and a reduced systolic LV function is a contraindication for the use of these substances. Trastuzumab (Herceptin), used for the treatment of breast cancer, is one of these agents. Although local guidelines may vary, most guidelines state that patients should not be commenced on trastuzumab if their baseline ejection fraction (EF) is <55%. If the EF falls by more than 10% or to <50% cessation of treatment should be considered. These figures indicate that the most accurate method for ejection fraction should be used. The British Society of Echocardiography recommends (biplane) Simpson's method for 2D echocardiography or 3D echocardiography with the availability of contrast for LV opacification by appropriately skilled echocardiographers.10 The indication for the use of contrast is not specified in these chemotherapy guidelines. However, it is reasonable to apply the general ASE/EAE guidelines, which recommend contrast echocardiography in those patients in whom the endocardium is not well delineated in two or more segments. Echo laboratories that perform studies to monitor trastuzumab treatment, have to provide yearly evidence through audits or other quality control processes that they can reproducibly measure the LV ejection fraction. This means they can identify a 10% change in EF as a true change. Considering the variability of EF measurements in native echocardiograms, the widespread of use of contrast is strongly recommended.
4.4 Assessment of LV function in patients in intensive care and coronary care units
These patients generally need urgent assessment and often have suboptimal echocardiographic windows. Moreover, immediate management decisions tend to follow their echocardiographic assessment. Consecutive scans are frequently performed to follow a change in cardiac performance. In these patients it is therefore reasonable to use contrast agents routinely, as they will provide the best reproducibility and accuracy. Importantly, the new hand-held ultrasound devices are especially useful in these settings and this has led to the increased use of contrast imaging modes. However, the patients treated in intensive care units were not included in the clinical trials for the approval of the contrast agents. Consequently, the special warnings and absolute or relative contraindications have to be considered prior to the injection of these agents in intensive care or coronary care patients.
4.5 Left ventricular masses and thrombi
A left ventricular thrombus has to be excluded in patients with low ejection fraction or wall aneurysms. Currently transthoracic echocardiography is the standard diagnostic procedure for the diagnosis of LV thrombus and has a reported sensitivity and specificity of 95% and 86%, respectively.11 Native imaging suffers from near field artefacts, where apical left ventricular thrombi are usually located and can be seen in apical views. The use of contrast has been shown to improve the exclusion or display of LV clots (Fig. 2). Contrast is also useful in the differential diagnosis of masses: using contrast specific imaging modalities a thrombus typically shows up as a non-opacified structure. This may be important in those rare conditions when the mass is found in a ventricle with normal contractility and a tumour is suspected. Tumour opacification is usually related to their degree of vascularization.
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4.6 Left ventricular non-compaction/apical hypertrophy
A mass found in a left ventricle with normal or only mildly impaired systolic function, should lead to suspicion of underlying non-compaction (Fig. 3). This cardiomyopathy has been observed more frequently over the last few years. The non compact trabeculated myocardium becomes thicker and the compact layer gets thinner. It is easy to misdiagnose this disease, since the compacted layer often resembles a thickened myocardium,12 especially if the acoustic windows are not optimal and fine trabeculations are missed. With contrast, the two myocardial layers can be clearly displayed. There is a grey zone around how much of non-compaction can be regarded as normal. The ratio of 2:1 (measuring the thickness of the non-compacted to the compacted myocardium) has been proposed. For these measurements it appears to be sensible to use contrast irrespective of the image quality.
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4.7 Right ventricular dysplasia, right ventricular thrombus
An optimal display of the endocardial borders is also necessary when assessing right ventricle volumes, degree of dysplasia or presence of an intracavitary thrombus.13 Small apical aneurysms may be particularly difficult to display with non-contrast echocardiography. With intravenous contrast injection, it is easy to see the clear outline of the right ventricular endocardium together with the RV trabeculations. No controlled study has been performed yet to see whether contrast-enhanced ultrasound can match the findings of MRI. But considering the results with LV assessment, it is very likely that contrast-enhanced ultrasound could be a cheaper alternative to MRI. In patients, in whom there is a contraindication to MRI, contrast-enhanced ultrasound appears already to be the method of choice for assessing RV volumes. Although agitated saline often provides intensive RV and RA opacification, the use of a left heart contrast agent provides a prolonged effect and less artefacts, in particular if an infusion is used. This facilitates image alignment and multiple recordings. Fig. 3 shows an example of an RV mass, which was identified as a cyst by using contrast-enhanced 2D and 3D echocardiography. With increasing availability of 3D echocardiography the measurement of RV volumes becomes more feasible. This would be certainly further facilitated by adding contrast.
4.8 Stress echocardiography and regional wall motion assessment
At present ultrasound contrast agents are used for stress echocardiography. Stress echocardiography is recognized as one of the most demanding echocardiography techniques to learn, but it has been also been shown to have a high sensitivity and specificity for coronary heart disease.14 Currently it remains an entirely subjective assessment of regional wall motion and is dependent on the quality of the images recorded. Previous studies have shown that good endocardial visualization is required for reliable assessment of regional wall motion. Images are worse during stress because of cardiac movement and hyperventilation. In one study that looked at inter-institutional observer agreement during dobutamine stress echocardiography, agreement of the presence of an abnormality on stress echocardiography was 73% for all studies, but 100% when considering only images with the highest image quality and 43% for the lowest quality. Clinical studies have shown the benefit of contrast in improving image quality, percentage of wall segments visualized, and confidence of interpretation of regional function both at rest and at peak stress.15 With contrast-specific imaging modalities, the opacification of the myocardium provides additional important information on myocardial perfusion. Subtle wall motion abnormalities, for instance, are often found in conjunction with perfusion abnormalities, which facilitate detection of abnormal segments (personal communication.16). Therefore it appears to be reasonable to use contrast routinely in stress echocardiography.17
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5 Future echocardiography will still need cavity opacification |
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Future echocardiography will be more 3D and more quantitative than current echocardiography. Contrast echocardiography has already proven its value for both applications. With contrast, for the first time, automatic boundary detection becomes feasible in a clinical setting (Fig. 4). Automatic boundary detection, obviating the need for manual tracing, has been a goal for a number of years. However, with native images numerous techniques have failed to track the borders adequately.52 With contrast and low power techniques we have the ideal conditions for these automatic boundary detection algorithms to work. Acoustic quantification (AQ) is one technique for boundary detection. This was found to be more accurate for assessing regional function with contrast, compared to AQ on native images.53 Initial results from an automatic boundary detection algorithm that is currently in use at our centre, have shown their ability to improve interobserver and intraobserver variability in the assessment of left ventricular volumes compared to hand tracing.
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All the issues with 2D image quality also apply for 3D scans. The problem is more evident in 3D echocardiography, because, in principle, multiple slices have to be traced and there are few patients in whom a complete optimal display of the myocardium is possible. A special problem of 3D echocardiography is the amount of data for volume analysis, requiring tracing of multiple left ventricular slices.54 All these measurements are facilitated by automatic boundary detection. Therefore, the ideal imaging modality is the use of 3D echo synergistically with contrast agents. The accurate measurements provided by 3D techniques, coupled with the enhanced endocardial border identification provided by contrast agents, lead to a quick and effective method of assessing left ventricular function.55 The opportunity to perform automatic analysis of a 3D dataset is now available. Reliable automatic boundary detection has become a prerequisite for using 3D echocardiography as one of the most promising tools to assess LV asynchrony. Contrast has been shown to improve assessment of volumes in 3D echocardiography, but it is expected to be even more valuable, when every frame of the cardiac cycle has to be accurately traced.
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[56].
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Eur J Echocardiogr 2007 8: 308.[Extract] [FREE Full Text]
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