European Journal of Echocardiography Advance Access published online on April 14, 2008
European Journal of Echocardiography, doi:10.1093/ejechocard/jen136
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Contrast-enhanced three-dimensional dobutamine stress echocardiography: between Scylla and Charybdis?
Department of Cardiology, Erasmus MC, Thoraxcenter, Room Ba 316, Dr Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
Received 21 October 2007; received in revised form 8 February 2008; accepted after revision 9 March 2008.
* Corresponding author. Tel: +31 10 7040704; fax: +31 10 4110419. E-mail address: b.krenning{at}erasmusmc.nl
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Abstract |
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Aims: Real-time three-dimensional echocardiography (RT3DE) allows quick volumetric scanning of the left ventricle (LV). We evaluated the diagnostic accuracy of contrast-enhanced stress RT3DE for the detection of coronary artery disease (CAD) in comparison with coronary arteriography as the reference technique.
Methods and results: Forty-five consecutive patients (age 59 ± 10, 31 males) referred for coronary angiography were examined by contrast-enhanced RT3DE. Wall motion analysis was performed off-line by dedicated software. New or worsening wall motion abnormalities were detected in 17 of 28 patients with significant CAD (sensitivity 61%), and in two of 17 patients without significant CAD (specificity 88%). The sensitivity for detection of single-vessel CAD was 8/15 patients (53%), for two-vessel CAD 4/6 (67%), and for three-vessel CAD 5/7 (71%). In 35 patients, comparison with conventional RT3DE was available. The image quality index at rest improved from 2.5 ± 1.2 to 3.2 ± 1.0 (P < 0.001) with contrast and at peak stress from 2.3 ± 1.2 to 3.1 ± 1.0 (P < 0.001). Interobserver agreement on the diagnosis of myocardial ischaemia improved from 26 of 35 studies (74%, 
= 0.44) with conventional stress RT3DE to 30 of 35 studies (86%, = 0.69) with contrast-enhanced stress RT3DE. Sensitivity increased from 50 to 55% and specificity from 69 to 85% with contrast-enhanced stress RT3DE in this subset of patients.
Conclusion: Despite some important practical and theoretical benefits, contrast-enhanced stress RT3DE currently has only moderate diagnostic sensitivity due to several technical limitations as temporal and spatial resolution.
Keywords: Dobutamine; Stress; Three-dimensional echocardiography; Contrast
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Introduction |
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Dobutamine stress echocardiography (DSE) is a well-established method for the diagnosis of coronary artery disease (CAD).1 Although standard two-dimensional echocardiography (2DE) has acceptable temporal and spatial resolution for assessment of wall motion abnormalities, the technique is limited by the necessity of sequentially acquiring 2DE images from multiple precordial windows for analysis. This is overcome by real-time three-dimensional echocardiography (RT3DE), by obtaining quick volumetric data sets of the left ventricle (LV).2 Previously, we showed that the use of ultrasound contrast agent during stress RT3DE improves LV cavity border delineation and thus decreases interobserver variability for identifying wall motion abnormalities.3 The aim of this study was to evaluate the diagnostic accuracy of contrast-enhanced stress RT3DE for the detection of CAD in comparison with the results of coronary arteriography as the reference method.
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Methods |
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Study patients
We studied 45 consecutive patients in sinus rhythm with suspected CAD referred for diagnostic coronary arteriography. No selection based on image quality was made. Baseline clinical characteristics of the patients are listed in Table 1. Beta-blockers were used in 27 patients (60%). The institutional review board approved the study and all patients gave informed consent.
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Dobutamine–atropine stress protocol
Dobutamine was administered through a peripheral vein in 3 min stages of 10, 20, 30, and 40 µg/kg/min. The infusion was aborted when 85% of age-predicted heart rate was reached. Otherwise, dobutamine infusion was continued and supplemented by 0.25 mg doses of atropine (to a maximal dose of 1 mg). The infusion was stopped when severe angina, shortness of breath, a symptomatic decrease in systolic blood pressure (>40 mm Hg), arterial hypertension (>240/120 mmHg), severe arrhythmias, or other serious adverse effects occurred.1
Contrast examination
SonoVue (Bracco Imaging, Milan, Italy) was used at baseline conditions, low dose, and peak stress as a bolus of 0.5 ml with additional boluses of 0.25 ml when needed.4 A low mechanical index (0.3) was used. Care was taken to record the images at a phase when contrast flow was relatively stable, with absent or minimal swirling of contrast in the apex.
Dobutamine stress real-time three-dimensional echocardiography
The RT3DE images were acquired from an apical window with a Sonos 7500 echocardiographic system (Philips Medical Systems, Best, The Netherlands) with a X4 matrix-array transducer (n = 36) or iE33 system with a X3-1 transducer (n = 9), using second harmonic imaging. After visualizing the reference images (in the apical four-chamber and orthogonal views), a full-volume data set of the LV was acquired. With electrocardiographic gating, four (using the X4-transducer) or seven pyramidal subvolumes (using the X3-1 transducer) were acquired which were automatically integrated into a pyramidal data set incorporating full LV volume. All conventional images were acquired before contrast imaging and, if necessary, after ultrasound bubble destruction with short-lasting imaging with a high mechanical index.
Off-line data analysis
The RT3DE data sets were analysed off-line with the assistance of 4D TomTec Echoview 5.3 software (TomTec Inc., Unterschleissheim, Germany). Two-dimensional long-axis and short-axis cross-sections were reconstructed for analysis. These images were judged on the basis of the absence of artefacts throughout the cardiac cycle. All at peak stress available reconstructed segments were graded as optimal (4, excellent quality without possibility to improve); good (3, good quality without artefacts); moderate (2, sufficient quality without artefacts or good quality with artefacts); or poor (1, poor or moderate quality with artefacts). An image quality index was calculated by the summation of all scores of each analysed segment divided by the number of analysed segments. Wall motion was assessed using the standard 17-segment LV model of the three reconstructed apical views by two independent observers who were blinded to the patients’ clinical data.5 Wall motion was scored as normal, mild hypokinesia, severe hypokinesia, akinesia, or dyskinesia. Test results were considered positive in the case of new or worsening wall motion abnormalities at any stage during stress. Segmental wall motion abnormalities were assigned to coronary artery territories as previously described.5 Because of the known limitations of stress imaging in distinguishing the right coronary artery and the left circumflex artery territory, the data were analysed according to the anterior and common posterior circulation.1
Coronary arteriography
Coronary angiography was performed within 2 weeks in all patients. Significant CAD was defined as a diameter stenosis 
50% in a major epicardial artery including major side branches at quantitative angiography.
Statistical analysis
All values are expressed as mean ± SD. Continuous variables were compared by use of the paired Student's t-test. The coefficient was calculated to determine interobserver agreement. Sensitivity was defined as the number of true positive tests divided by the total number of patients with a positive angiogram. Specificity was defined as the number of true negative tests divided by the total number of patients with a negative angiogram. Data were analysed using standard statistical software (SPSS version 12.0; SPSS Inc., Chicago, IL, USA).
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Coronary angiography
Coronary angiography showed significant CAD in 28 (62%) patients, 15/28 (54%) patients had single-vessel CAD, 6/28 (21%) two-vessel CAD, and 7/28 (25%) three-vessel CAD. Coronary artery stenoses involved the left anterior descending artery in 17 (38%) patients, the right coronary artery in 17 (38%) patients, and the left circumflex artery in 14 (31%) patients. The posterior circulation was involved in 23 (51%) patients.
Dobutamine stress echocardiography results
DSE increased heart rate (from 73 ± 14 to 130 ± 21 bpm, P < 0.001) and systolic blood pressure (from 125 ± 19 to 143 ± 25 mmHg, P < 0.001). Atropine was administered in 13 patients (29%) at a mean dose of 0.6 ± 0.2 mg. Chest pain occurred in 10 patients (22%) and ST-segment depression (>0.1 mV horizontal or down sloping) in five (11%) patients. Reasons for termination of the test were target heart rate in 34 (76%), maximal dose of dobutamine–atropine in four (9%), angina in five (11%), and ST-segment changes in two (4%). New or worsening wall motion abnormalities during contrast-enhanced RT3DE occurred in 19 (42%) patients.
Diagnostic accuracy of contrast-enhanced real-time three-dimensional echocardiography
New or worsening wall motion abnormalities were detected in 17 of 28 patients with significant CAD (sensitivity 61%), and in two of 17 patients without significant CAD (specificity 88%). The sensitivity for detection of single-vessel CAD was 8/15 patients (53%), for two-vessel CAD 4/6 (67%), and for three-vessel CAD 5/7 (71%). The sensitivity and specificity for detection of significant CAD in the anterior circulation was 9/17 (53%) and 26/28 (93%), respectively. The sensitivity for detection of significant CAD in the posterior circulation was 10/23 (43%), with a specificity of 19/22 (86%).
Comparison between conventional and contrast-enhanced real-time three-dimensional echocardiography
In 35 (78%) patients, a comparison between acquisition using unenhanced second harmonic imaging and contrast-enhanced RT3DE was available. During conventional RT3DE, 532 segments (89%) could be analysed at rest and 472 segments (78%) at peak stress. With contrast-enhanced stress RT3DE, the number of available LV segments at peak stress increased to 535 (90%) (P < 0.001). The image quality index of the analysable segments is depicted in Table 2. The global LV myocardial segment visibility index at rest improved from 2.5 ± 1.2 to 3.2 ± 1.0 (P < 0.001) with contrast and at peak stress from 2.3 ± 1.2 to 3.1 ± 1.0 (P < 0.001). There were no regional differences in improvement with contrast.
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As shown in Figure 1, the two observers agreed on the diagnosis of myocardial ischaemia in 26 of 35 studies (74%,
= 0.44) with conventional stress RT3DE and in 30 of 35 studies (86%, = 0.69) with contrast-enhanced stress RT3DE. In these 35 patients, sensitivity increased from 50 to 55% and specificity from 69 to 85% with contrast-enhanced stress RT3DE.
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Discussion |
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Stress RT3DE has the potential to become the new standard in stress echocardiography, because of the shorter acquisition time, elimination of off-axis acquisition and/or analysis, the ability to obtain multiple cross-sections of any desired LV segment, and more precise comparison of identical segments.
In this study, we confirm our previous results on image quality improvement in regional endocardial wall delineation with contrast-enhanced imaging resulting in a better interobserver agreement for the diagnosis of myocardial ischaemia.3 Contrast-enhanced stress RT3DE also increased diagnostic accuracy, although non-significantly due to the relatively small number of patients. The sensitivity of 61% and specificity of 88% for contrast-enhanced stress RT3DE reported in our study is in the range of those reported in 2DE stress studies.1 However, it should be noted that in two earlier stress RT3DE studies, higher sensitivities of 78–84% were reported.6,7
Several patient and technical characteristics may explain the relatively low diagnostic sensitivity found in our study. Most of our patients with CAD had single-vessel disease and in particular left circumflex stenosis. Patients with such characteristics are very difficult to identify with any stress test.1,8,9 This is in agreement with the low sensitivity (65 and 63%, respectively) for stenosis in the left circumflex territory by Aggeli et al.7 and Matsumura et al.10 Also, the vast majority of our patients did not have a history of prior myocardial infarction or rest wall motion abnormalities. Such characteristics are also known to negatively affect the diagnostic sensitivity of DSE.11 Finally, some patients did not achieve target heart rate, partially caused by the relatively high number of patients using beta-blockers in our study.
Also, several technical issues limit the accuracy of stress RT3DE in its current form compared with 2DE. In earlier studies, others and us have shown that in particular anterior wall segments may be poorly visualized because of ribs interfering with the large foot print of the X4 transducer.3,12 Both Aggeli et al.7 and Matsumura et al.10 suggested that stress RT3DE identifies more readily wall motion abnormalities in the apical region compared with 2D imaging due to non-foreshortening acquisition and/or analysis. However, in our study, 
10% of the distal segments could not be visualized due to the earlier described interfering ribs and prominent near-field artefacts. It should be noted that all patients in the study of Aggeli et al. were studied with the smaller X3-1 transducer, whereas in our study only a minority were studied with this newer transducer. Moreover, different methods for data analysis are used. Aggeli et al. and Matsumura et al. used the integrated software of the ultrasound system to analyse cropped planes from apex to base along the long axis of the LV. We used TomTec off-line analysis software to visualize identical 2D cross-sections of the LV at baseline and peak stress. Both methods take advantage of the full volumetric data set, but quantify wall motion abnormalities only in a limited number of cropped planes. Further investigations are necessary to develop a semi-automated approach to endocardial border delineation and subsequent wall motion analysis. This may result in less observer dependent analysis and more quantitative determination of myocardial ischaemia.
Both spatial and temporal resolutions are still the Achilles heel of stress RT3DE. The spatial resolution of RT3DE is less compared with 2DE, which can partially be circumvented by contrast enhancement. Additionally, it is known from 2D stress echocardiography that lower frame rates negatively influence the identification of significant CAD.13 The number of available frames per heart cycle for analysis depends on several machine settings and the heart rate of the patient. When the heart rate of the patient increases, fewer volumes per heart cycle are available for analysis. Specific imaging methods may be used to improve the detection of ultrasound contrast agents, such as power modulation. In this multi-pulse technique, the acoustic amplitude of the transmitted pulses is changed. Although this method improves contrast-imaging quality, unfortunately, this technique significantly decreases frame rate. During a typical full-volume acquisition of the LV with second harmonic imaging, frame rate decreases from 30 to 9 Hz when power modulation is activated.14 Therefore, an improvement in image quality is followed by a lower temporal resolution, as in navigating between ‘Scylla and Charybdis’. This is an idiom from Greek mythology which has come to mean the necessity to choose between two unattractive choices. Scylla and Charybdis are two sea monsters who were situated on opposite sides of the Strait of Messina between Sicily and Italy. The two sides of the strait are within an arrow's range of each other, so that they posed an inescapable threat to passing sailors; avoiding Charybdis meant passing too close to Scylla and vice versa.
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Conclusions |
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Despite some important practical and theoretical benefits, contrast-enhanced stress RT3DE currently has only moderate diagnostic sensitivity due to several technical limitations. Further developments in transducer technology (e.g. with single crystal technology15) seem necessary to really profit from these benefits and bring (contrast-enhanced) stress RT3DE into clinical practice. Specific imaging functions to improve the detection of ultrasound contrast agents, such as power modulation, should not be used because of the negative effect on frame rate.
Conflict of interest: none declared.
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References |
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