Author + information
- Received December 21, 2007
- Revision received February 20, 2008
- Accepted February 28, 2008
- Published online May 1, 2008.
Reprint requests and correspondence:
Dr. Thomas R. Porter, University of Nebraska Medical Center, 981165 Nebraska Medical Center, Omaha Nebraska 68198-1165.
Objectives The purpose of this study was to test whether the transmural delineation of myocardial perfusion during dobutamine stress imaging with real-time myocardial contrast echocardiography (RTMCE) might permit visualization of dobutamine-induced subendocardial ischemia.
Background Significant coronary artery disease can be present despite normal transmural wall thickening (WT) responses during dobutamine stress echocardiography (DSE). One potential reason is dobutamine-induced recruitment of epicardial WT in the presence of subendocardial ischemia.
Methods Myocardial perfusion and WT were examined with RTMCE during DSE with a continuous infusion of ultrasound contrast in 94 patients with normal resting WT. Fifty-five of the patients had a >50% diameter stenosis in the left anterior descending coronary artery (LAD). The WT was visually assessed by a blinded reviewer at 2 time periods: initially after a high mechanical index impulse before myocardial contrast replenishment (MCR), and again during MCR. Subendocardial %WT was measured during MCR, if a subendocardial perfusion defect was visually evident, whereas transmural WT was quantified on the pre-MCR images.
Results Fifty patients (91%) with LAD stenoses exhibited a myocardial contrast defect at peak stress, with 45 defects being subendocardial. Transmural WT pre-MCR appeared normal in 35 of the 45 patients with subendocardial perfusion defects (78%). However, a subendocardial WT abnormality was apparent during MCR in 18 of these 35 patients, even though transmural WT was not different from the 17 patients with normal subendocardial WT (33 ± 15% vs. 36 ± 14%). Quantitative measurements of WT within the subendocardium were significantly less in the patients with visually evident subendocardial WT abnormalities, when compared with those who seemed to have normal WT during MCR (17 ± 8% vs. 25 ± 10%, p < 0.01).
Conclusions In patients with significant LAD disease, RTMCE during DSE detects subendocardial ischemia even when transmural WT appears normal. Real-time myocardial contrast echocardiography should be the preferred ultrasound imaging method when using contrast to detect coronary artery disease during DSE.
Real-time myocardial contrast echocardiography (RTMCE) has become a useful tool to detect coronary artery disease during dobutamine and dipyridamole stress echocardiography (1–5). The low mechanical index (MI) pulse sequence scheme significantly reduces microbubble destruction, allowing the examination of myocardial perfusion while simultaneously improving endocardial border delineation. This can be especially helpful during dobutamine stress echocardiography (DSE), where the assessment of perfusion might add to the value of wall motion analysis in detecting significant coronary artery disease (6). Detection of ischemia (i.e., wall thickening [WT] abnormalities) during dobutamine stress might be made more difficult, because of the ability of dobutamine to recruit the epicardial layers to contract (7). This might mask WT abnormalities that are confined to the subendocardial layers. We hypothesized that a subendocardial perfusion defect delineated with RTMCE might permit one to detect subendocardial ischemia despite normal transmural thickening. This hypothesis was tested in patients with known left anterior descending stenoses, by examining transmural and subendocardial apical WT with RTMCE during dobutamine stress.
Fifty-five patients with normal resting wall motion and normal resting myocardial contrast enhancement underwent DSE with RTMCE and had quantitative angiography performed at a mean of 2.4 ± 2.8 weeks of the stress test documenting the presence of a >50% diameter stenosis in the left anterior descending coronary artery (LAD). Thirty nine patients without significant LAD stenoses (or with bypassed LAD arteries) who underwent dobutamine stress with RTMCE over the same time period served as control subjects. Mean age of the patients was 61 ± 13 years (47 women). Other demographic characteristics are listed in Table 1.
The contrast agent used for RTMCE was the commercially available lipid-encapsulated microbubble Definity (Bristol-Myers Squibb Medical Imaging, Inc., North Billerica, Massachusetts). This agent was administered as a 3% intravenous continuous infusion at 4 to 6 ml/min under resting conditions and during dobutamine stress. The infusion was adjusted to optimize myocardial opacification while minimizing attenuation from left ventricular cavity contrast.
The RTMCE was performed with ultrasound scanners equipped with low-MI real-time pulse sequence schemes, which use either interpulse amplitude modulation (Power Modulation; Sonos 5500, Philips Medical Systems, Bothell, Washington) or interpulse phase and amplitude modulation (Contrast Pulse Sequencing; Siemens Acuson Sequoia, Mountain View, California). The MI was kept at ≤0.25, and frame rate was kept at 25 to 30 Hz during dobutamine stress imaging. Time gain compensation and 2-dimensional gain settings were adjusted to suppress any nonlinear signals from tissue before contrast injection and remained unchanged throughout the study. Contrast-enhanced images from apical views (4-, 2-, and 3-chamber) were obtained and digitized at rest and at maximal stress after the patients had achieved a test end point.
Patients were instructed to discontinue beta-blocker drugs at least 24 h before the stress test. Intravenous dobutamine was infused at a starting dose of 5 μg/kg/min, followed by increasing doses of 10, 20, 30, 40, up to a maximal dose of 50 μg/kg/min, in 3- to 5-min stages. Atropine (up to 2.0 mg) was injected in patients not achieving 85% of the predicted maximal heart rate (220 − age in years). The end points of stress tests were: achievement of the target heart rate (85% of predicted maximal heart rate), maximal dobutamine/atropine doses, ST-segment elevation ≥2 mm at an interval of 80 ms after the J point in non–Q-wave leads, sustained arrhythmias, severe chest pain, or intolerable adverse effects considered to be due to dobutamine or atropine. Hypotension was defined as a fall of systolic blood pressure below 80 mm Hg or a reduction ≥20 mm Hg from baseline. A hypertensive response was defined as blood pressure ≥230/120 mm Hg.
Apical WT and contrast enhancement was analyzed on the first cardiac cycle after a brief (5 to 25 frames for the Philips Sonos 5500 or 1 to 3 cardiac cycles for Siemens Acuson Sequoia) high (1.4 to 1.9) MI impulse before any myocardial contrast replenishment (MCR). These were referred to as pre-MCR images. The second analysis of WT occurred during a cardiac cycle 1 to 2 s after the high MI impulse (referred to as MCR images). Digitized loops of these images were examined in the apical windows. A subendocardial perfusion defect was defined as one in which an evident decrease in contrast enhancement within the inner one-half of the myocardial wall was visualized during the replenishment phase of contrast (Online Video 1). A transmural perfusion defect was one in which decreased contrast enhancement was observed through the entire wall of the segment during the replenishment phase in the apical segments despite normal myocardial contrast enhancement in other segments (Online Video 2).
For each patient, 2 separate files were digitized and created for blinded analysis (total of 188 image loop files in the 94 patients). The images were randomly mixed with other studies and analyzed separately from one another. One file was the immediate post–high-MI impulse pre-MCR, in which the reviewer analyzed transmural WT when no contrast was present in the myocardium and only contrast-enhanced endocardial border delineation was present. The second analysis, done at a separate time from a separate independent file, was the examination of WT during MCR. At this time, if a subendocardial perfusion defect was present, the reviewer determined whether WT within the region defined by the perfusion defect was abnormal, with both the contrast-enhanced endocardial and transmural border. Subendocardial WT was graded as normal when it appeared to be thickened beyond approximately 30% of its end-diastolic thickness during systole and abnormal when no or reduced thickening within the subendocardial defect was perceived.
Quantitative measurements of WT
The end diastolic and end systolic wall thickness for transmural WT was measured on the pre-MCR images (the first cardiac cycle after the high MI impulse) by using the endocardial border delineated with left ventricular cavity contrast and the epicardial border.
The subendocardial WT measurement was only possible if a subendocardial perfusion defect was present during MCR images. This was measured with the endocardial border delineated with cavity contrast and the transmural border delineated by the subendocardial perfusion defect. (see example in Fig. 1). The formula for subendocardial WT was then determined as follows:
End-diastole was defined as the largest left ventricular cavity size and end-systole was defined as the smallest left ventricular cavity size.
All data are expressed as mean values ± SD. For clinical characteristics of patients, 2-tailed unpaired Student t tests were used for inter-group comparison. A chi-square test was used for comparisons of proportions, unless proportions were low, in which case a Fisher exact test was used. The sensitivity, specificity, and accuracy of WT analysis (transmural and subendocardial) as well as perfusion analysis were computed for detecting a >50% diameter stenosis in the LAD. Proportional differences between the visual analysis of WT and perfusion were compared with McNemar tests or Fisher exact tests if expected cell frequencies were low. Multi-group means were compared by analysis of variance (ANOVA). One-way ANOVA was used for comparisons of quantitative WT measurements. The inter-observer agreement on both transmural and subendocardial WT analysis was compared by analyzing the agreement with a second reviewer in 25 patients randomly selected from the study group. Kappa values were used to determine interobserver agreement. A p value < 0.05 was considered significant.
The LAD stenoses >50% diameter were present in 55 of the patients (32 with multi-vessel coronary artery disease, 23 with single-vessel LAD disease). The range of stenosis diameters was 50% to 100%. Table 1 lists the demographic data of the patients examined, comparing those with and without LAD disease. There were no differences in these 2 groups in cardiac risk factors, prior revascularizations, or rate pressure product achieved. Four patients with LAD stenosis had a history of a previous myocardial infarction in a non-LAD territory, 12 (22%) patients had previous percutaneous coronary intervention (5 of the LAD), and 4 (7%) patients had previous coronary artery bypass grafting surgery (3 of the LAD).
Visual subendocardial and transmural myocardial perfusion analysis
Table 2 depicts the sensitivity, specificity, and accuracy of perfusion imaging versus WT analysis (pre-MCR and during MCR). Of the 55 patients with a significant LAD stenosis, 45 exhibited a subendocardial perfusion defect and 5 exhibited a transmural perfusion defect. Diagnostic accuracy of visual analysis of perfusion imaging with RTMCE was 73% (95% confidence interval [CI] 65% to 79%); sensitivity was 91% (95% CI 84% to 96%); and specificity was 49% (95% CI 39% to 56%). Figure 2 demonstrates an example of a subendocardial perfusion defect seen during MCR in the apical 4-chamber view (Online Video 3).
Of the 45 patients with subendocardial apical defects, 10 (22%) exhibited abnormal WT on the pre-MCR images. Of the 35 remaining patients, 18 exhibited a subendocardial WT abnormality on the MCR image, whereas 17 seemed to have normal subendocardial WT during MCR. Figures 2 and 3⇓ demonstrate examples in 2 patients where subendocardial WT appeared abnormal during MCR, whereas transmural WT on the pre-MCR images appeared normal (Online Videos 4 and 5). Interobserver agreement for visual subendocardial and transmural myocardial WT analysis was 88%, Kappa values 0.76.
Table 3 demonstrates the rate pressure product, mean and range of % diameter stenoses in the LAD, and frequency of left circumflex or right coronary stenoses in the patients who had >50% diameter LAD stenoses and had 1) abnormal transmural WT on the pre-MCR images, 2) normal transmural WT but abnormal subendocardial WT and abnormal subendocardial perfusion, and 3) normal transmural and subendocardial WT but abnormal subendocardial perfusion. Note that there were no differences in any of these variables between the 3 groups.
Quantitative subendocardial and transmural myocardium analysis
Table 4 summarizes the subendocardial and transmural WT measurements in the patients who had subendocardial perfusion defects at peak stress without transmural WT abnormalities on the pre-MCR images. Measured WT within the subendocardium was significantly less in the patients with visually evident subendocardial WT abnormalities, when compared with those who seemed to have normal WT during MCR (17 ± 8% vs. 25 ± 10%, p < 0.01). However, these 2 groups did not show any differences in transmural WT measured on the pre-MCR images (33 ± 15% vs. 36 ± 14%, p = 0.30)
Chronotropic doses of dobutamine have been shown to increase transmural WT, even in perfusion beds subtended by coronary stenoses that range from 30% to 80% in diameter (8). If the stenosis is more severe or if higher doses of dobutamine are used, WT becomes abnormal (2). Transmural myocardial blood flow responses, however, are different, with decreases in myocardial blood flow observed even in milder non-flow limiting stenoses (2). As the stenosis becomes more severe, a marked decrease in subendocardial blood flow has been observed (9–11), with a marked decrease in endocardial/epicardial flow ratios. In this study, RTMCE detected this decrease in endocardial to epicardial blood flow abnormality in 45 of the 55 patients with LAD stenoses >50%.
Another pertinent pharmacologic property of dobutamine is its ability to recruit the subepicardial layers to thicken. The subendocardium is responsible for over 40% of WT under resting conditions (12,13), and thus resting WT might be abnormal even when only a subendocardial infarction is present. Dobutamine, in this setting, will nearly normalize WT due to recruitment of the epicardial layers (12). This finding has served as the basis for the use of dobutamine to identify viable myocardium. In this study, however, we observed that this recruitment of subepicardial layers might mask the detection of subendocardial ischemia. Because RTMCE is capable of delineating transmural perfusion abnormalities (14,15), the transmural border created by the subendocardial perfusion defect was able to delineate when a subendocardial WT abnormality was present. Of the 35 patients with LAD stenoses who seemed to have normal transmural WT on the pre-MCR images, 18 exhibited evidence of subendocardial ischemia when the MCR images were examined.
We did not see differences between those with subendocardial perfusion defects and visually abnormal subendocardial WT and those with visually normal WT in terms of severity of the LAD stenosis subtending the affected perfusion bed or the rate pressure product achieved during dobutamine stress (Table 3). Furthermore, we did not see any differences between these 2 groups in the number of cases in which the collateral perfusion beds were subtended by a significant stenosis. One potential explanation is that the “ischemic cascade” played a role (2), in that if we had prolonged the duration of stress further in the patients with normal subendocardial WT it would have eventually become abnormal. However, we did not attempt in this study to prolong the duration of infusion, once we had achieved maximum dobutamine/atropine doses or >85% of the predicted maximum heart rate.
These findings have 2 important clinical implications. Conventional DSE relies on the induction of a transient wall motion abnormality to detect significant coronary artery disease. However, these wall motion abnormalities might not occur in up to 40% of patients with significant coronary artery disease (7,16). Although radionuclide imaging has detected perfusion abnormalities in patients with normal wall motion during dobutamine stress (7), it is unable to delineate transmural differences in myocardial blood flow and thus will not be able to identify when subendocardial ischemia might be present in those normal transmural WT at peak stress. Real-time myocardial contrast echocardiography has sufficient resolution to identify transmural differences in myocardial blood flow during stress imaging and thus might improve the detection of ischemia during dobutamine stress testing. Secondly, current ultrasound contrast agents are approved only for enhancing endocardial border delineation. This study indicates that enhancing border delineation might not be sufficient to improve the detection of coronary artery disease during dobutamine stress testing. Real-time myocardial contrast echocardiography can be used to improve both the endocardial and transmural border and thus should be the preferred ultrasound imaging method when clinically using contrast during dobutamine stress testing.
The ability of WT on the pre-MCR images (where only an enhanced endocardial border is present) to detect significant LAD stenoses had lower sensitivity than what has been reported in published reports. There are several potential explanations for this. One is that we only included patients with normal resting WT in this study, whereas other studies looking at the ability of dobutamine stress WT to detect LAD disease have included patients with resting WT abnormalities (17). Secondly, it is possible that the ultrasound contrast on some of our pre-MCR images (which were obtained immediately after the high MI impulse) might have inadequately filled the endocardial border and prevented the detection of a transmural WT abnormality. Thirdly, we had a high percentage of patients with concentric remodeling, which might have reduced wall stress and the frequency of inducible transmural WT abnormalities (18). In these patients, it is possible that WT might have become abnormal during the recovery phase, which was not analyzed in our study. Fourthly, the use of real-time perfusion usually requires frame rates that are 22 to 25 Hz. This lower frame rate might have prevented the detection of tardokinesis in zones supplied by >50% diameter stenoses, which requires frame rates of 60 Hz using color kinesis (19). Finally, although we reached 85% of predicted maximum heart rate in nearly all patients, the rate pressure product achieved might have been insufficient to induce a WT abnormality (Table 3).
Although there was visually no detectable WT abnormality in a large percentage of pre-MCR images in the patients with subendocardial perfusion defects, quantitative measurements of transmural WT were not augmented when compared with baseline WT (Table 4). We did note that there was a trend toward worsening quantitative measurements of WT in patients with visually normal subendocardial WT to those with visually abnormal subendocardial WT to those with transmural WT abnormalities. Augmentation of WT would not be expected in patients with inducible subendocardial perfusion defects. However, we have found in this study that the recruitment of subepicardial WT by dobutamine might be sufficient to prevent the visual detection of abnormal WT in these patients during dobutamine stress imaging.
We defined the subendocardial thickness as the layer within the wall defined by the subendocardial perfusion defect. This might have over- or under-estimated the actual subendocardial thickness. Myocardial tagging techniques, such as those available with cine magnetic resonance imaging (13), might assist in better defining how much epicardial recruitment occurs during dobutamine stress in the setting of coronary artery disease.
Real-time myocardial contrast echocardiography with a continuous infusion of ultrasound contrast permits the detection of subendocardial ischemia in a significant number of patients that have apparent normal transmural WT during dobutamine stress. Because this technique can detect subendocardial perfusion abnormalities, it improves the detection of ischemia by creating both a transmural and endocardial border and thus should be the preferred ultrasound imaging method when using contrast during DSE.
The authors thank Stephanie Lyons and Stacey Kearney for their help in the preparation of the manuscript.
For supplementary videos, please see the online version of this article.
↵1 Dr. Porter has received grant support from Bristol-Myers Squibb Medical Imaging, ImaRx Therapeutics, Inc., and Siemens Medical Solutions and has served as consultant to ImaRx Therapeutics, Inc., Acusphere Inc., and Point BioMedical.
↵2 Dr. Xie has served as consultant to Acusphere Inc.
This work was supported by the Theodore Hubbard Foundation, Omaha, Nebraska.
- Abbreviations and acronyms
- confidence interval
- dobutamine stress echocardiography
- left anterior descending coronary artery
- myocardial contrast replenishment
- mechanical index
- real-time myocardial contrast echocardiography
- wall thickening
- Received December 21, 2007.
- Revision received February 20, 2008.
- Accepted February 28, 2008.
- American College of Cardiology Foundation
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