- Email: [email protected]
Detection of Subendocardial Ischemia in the Left Anterior Descending Coronary Artery Territory With Real-Time Myocardial Contrast Echocardiography During Dobutamine Stress Echocardiography
JACC: CARDIOVASCULAR IMAGING
VOL. 1, NO. 3, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 1936-878X/08/$34.00 DOI:10.1016/j.jcmg.2008.02.004
CLINICAL RESEARCH
Detection of Subendocardial Ischemia in the Left Anterior Descending Coronary Artery Territory With Real-Time Myocardial Contrast Echocardiography During Dobutamine Stress Echocardiography Feng Xie, MD, Saritha Dodla, MD, Edward O’Leary, MD, FACC, Thomas R. Porter, MD, FACC Omaha, Nebraska
O B J E C T I V E S 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. B A C K G R O U N D 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. M E T H O D S 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. R E S U L T S 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). C O N C L U S I O N S 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. (J Am Coll Cardiol Img 2008;1:271– 8) © 2008 by the American College of Cardiology Foundation
From the Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska. This work was supported by the Theodore Hubbard Foundation, Omaha, Nebraska. 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. Dr. Xie has served as consultant to Acusphere Inc. Manuscript received December 21, 2007; revised manuscript received February 20, 2008, accepted February 28, 2008.
272
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
R
eal-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 ABBREVIATIONS subendocardial ischemia despite normal AND ACRONYMS transmural thickening. This hypothesis CI ⴝ confidence interval was tested in patients with known left DSE ⴝ dobutamine stress anterior descending stenoses, by examinechocardiography ing transmural and subendocardial apical LAD ⴝ left anterior descending WT with RTMCE during dobutamine coronary artery stress. MCR ⴝ myocardial contrast replenishment
See page 279
MI ⴝ mechanical index RTMCE ⴝ real-time myocardial contrast echocardiography
METHODS
WT ⴝ wall thickening
Study population. 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. RTMCE. 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 ⱕ0.25, 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. Dobutamine stress. 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 g/kg/min, followed by increasing doses of 10, 20, 30, 40, up to a maximal dose of 50 g/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 ⱖ2 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 ⱖ20 mm Hg from baseline. A hypertensive response was defined as blood pressure ⱖ230/120 mm Hg. Image analysis. 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
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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. Transmural WT (%) ⫽ End-systolic thickness 共mm兲 ⫺ End-diastolic wall thickness 共mm兲 ⫻ 100% End-systolic defect thickness 共mm兲
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:
273
Table 1. Clinical Characteristics of Patients With Known LAD Stenoses
Variables n
Patients Without LAD Disease
Patients With LAD Disease
39
Age (yrs) Male
p Value
55
60 ⫾ 13
61 ⫾ 14
17
30
0.669 0.402
History of smoking
12 (31%)
24 (44%)
0.294
Hypertension
33 (85%)
50 (91%)
0.516
Hyperlipidemia
30 (77%)
42 (76%)
0.854
Diabetes
22 (56%)
30 (55%)
0.975
No. of patients achieving 85% PMHR
34 (87%)
46 (84%)
0.856
Rate-pressure product (mm Hg/min)
22,794 ⫾ 5996
21,343 ⫾ 5911
0.273
1 (3%)
4 (7%)
0.399
17 (44%)
16 (29%)
0.218
3
5
Previous MI outside LAD territory Previous PCI or CABG Previous PCI to LAD Previous CABG to LAD No. of patients with RCA/LCX disease Also with LAD stenosis Concentric remodeling
5
3
13 (33%)
35 (64%)
0.007
16 (29%)
0.679
0 9 (23%)
CABG ⫽ coronary artery bypass graft; LAD ⫽ left anterior descending coronary artery; MI ⫽ mechanical index; PCI ⫽ percutaneous coronary intervention; PMHR ⫽ predicted maximum heart rate; RCA ⫽ right coronary artery.
Figure 1. Example of Measurements for Subendocardial WT Apical 4-chamber view of real-time myocardial contrast echocardiography with contrast pulse sequencing (Siemens Acuson Sequoia, Mountain View, California) was obtained from a patient with significant left anterior descending coronary artery disease during dobutamine stress. Subendocardial wall thickening (WT) within the apex was measured off-line with commercially available software. The end-diastolic and -systolic wall thickness for transmural WT was measured on the pre-MCR images (the first cardiac cycle after the high mechanical index impulse; left panels) as the distance between the endocardial border (arrow) delineated with left ventricular cavity contrast and the epicardial border (arrow). Subendocardial WT was measurable only if a subendocardial perfusion defect was present (arrows) during the replenishment period (MCR; right panels). See the text for calculation formula. ED ⫽ end-diastole; ES ⫽ end-systole; MCR⫽ myocardial contrast replenishment.
274
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
Table 2. Sensitivity, Specificity, and Accuracy of Visual WMA During the Pre-MCR and MCR Time Periods in Detecting a Significant Coronary Stenosis WMA Pre-MCR
WMA During MCR
Sensitivity
27%
59%*
Myocardial Perfusion 91%†
Specificity
87%
74%
49%‡
Accuracy
52%
65%
73%*
Myocardial perfusion analysis is also shown. *p ⬍ 0.02 compared with pre-MCR; †p ⬍ 0.001 compared with other groups; ‡p ⬍ 0.05 compared with other groups. MCR ⫽ myocardial contrast replenishment; WMA ⫽ wall motion analysis.
Subendocardial WT (%) ⫽ End-systolic defect thickness 共mm兲 ⫺ End-diastolic defect thickness 共mm兲 ⫻ 100% End-systolic defect thickness 共mm兲
End-diastole was defined as the largest left ventricular cavity size and end-systole was defined as the smallest left ventricular cavity size. Statistical analysis. 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. RESULTS Patient characteristics. The LAD stenoses ⬎50%
diameter were present in 55 of the patients (32 with multi-vessel coronary artery disease, 23 with singlevessel 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, spec-
ificity, 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
Figure 2. Dynamic Changes of Subendocardial WT on Apical 4-Chamber View With RTMCE A 65-year-old woman presented with shortness of breath. Apical 40-chamber view of real-time myocardial contrast echocardiography (RTMCE) with contrast pulse sequencing was obtained during dobutamine stress. On the pre-MCR images, WT was normal, whereas during MCR an apical subendocardial WT abnormality was evident, because of the subendocardial perfusion defect. Subendocardial WT measured 20%, whereas transmural WT was measured to be 50%. At complete replenishment (4 s after high MI impulse), the defect disappeared. Abbreviations as in Figure 1.
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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 subendocar-
dial 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) DISCUSSION
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 myo-
Xie et al. Detection of Subendocardial Ischemia
Figure 3. Example of Subendocardial Defects With Normal Transmural WT on Apical 3-Chamber View With RTMCE Apical 3-chamber view of RTMCE with power modulation (iE33, Philips Medical Systems, Bothell, Washington) during peak dobutamine stress in a patient with a significant left anterior descending coronary artery stenosis. Pre-MCR (left panels) WT was normal, as delineated by the blue arrows in the left panels. On the MCR images (right panels), a subendocardial perfusion defect is evident and subendocardial WT appeared abnormal (red arrows). Abbreviations as in Figures 1 and 2.
cardial 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 ab-
275
276
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
Table 3. Pertinent Variables in Patients With LAD Stenoses
Abnormal TM WT (n ⴝ 10) 75 ⫾ 18%
% LAD diameter stenosis (range)
Normal TM WT, Abnormal SE WT (n ⴝ 18)
Normal TM WT, Normal SE WT (n ⴝ 17)
73 ⫾ 18%
74 ⫾ 17%
p Value 0.967
22,620 ⫾ 5,788
20,653 ⫾ 6,750
21,533 ⫾ 6,261
0.745
No. of patients reaching 85% predicted maximal heart rate
9 (90%)
15 (83%)
13 (76%)
0.666
No. of patients with RCA/LCX stenosis
6 (60%)
11 (61%)
12 (71%)
0.797
Rate-pressure product (mm Hg/min)
Pertinent variables in patients with left anterior descending coronary artery (LAD) stenoses who had subendocardial (SE) perfusion defects and: 1) abnormal transmural (TM) wall thickening (WT); 2) normal TM WT but abnormal subendocardial WT and perfusion; or 3) normal TM WT and abnormal subendocardial perfusion but normal subendocardial WT. LCX ⫽ left circumflex coronary artery; RCA ⫽ right coronary artery.
normality 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. Study limitations. The ability of WT on the preMCR 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
Table 4. WT Measurements in Patients With Subendocardial Perfusion Defects and Normal TM WT TM WT at Rest
Subendocardial WT at Peak
TM WT at Peak
Subendocardial perfusion defects with normal WT
42 ⫾ 11% (23%–69%)
25 ⫾ 10% (8%–48%)
36 ⫾ 14% (20%–63%)*
Subendocardial perfusion defects with abnormal WT
39 ⫾ 11% (27%–55%)
17 ⫾ 8% (0%–30%)†
TM perfusion defects
43 ⫾ 7% (33%–53%)
—
30 ⫾ 27% (7%–76%)
Patients without LAD disease
39 ⫾ 11% (20%–57%)
—
44 ⫾ 13% (22%–65%)
33 ⫾ 15% (14%–63%)*
*p ⬍ 0.05 compared with patients without left anterior descending coronary artery (LAD) disease; †p ⬍ 0.01 compared with subendocardial perfusion defects with normal wall thickening (WT). TM ⫽ transmural.
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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
REFERENCES
1. Porter TR, Xie F, Silver M, Kricsfeld D, O’Leary E. Real-time perfusion imaging with low mechanical index pulse inversion Doppler imaging. J Am Coll Cardiol 2001;37: 748 –53. 2. Leong-Poi H, Rim SJ, Le DE, Fisher NG, Wei K, Kaul S. Perfusion versus function: the ischemic cascade in demand ischemia: implications of single-vessel versus multivessel stenosis. Circulation 2002;105:987–92. 3. Elhendy A, O’Leary E, Xie F, McGrain AC, Anderson J, Porter TR. Comparative accuracy of real-time myocardial contrast perfusion imaging and wall motion analysis during dobutamine stress echocardiography for the diagnosis of coronary artery dis-
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 underestimated 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. CONCLUSIONS
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. Acknowledgments
The authors thank Stephanie Lyons and Stacey Kearney for their help in the preparation of the manuscript. Reprint requests and correspondence: Dr. Thomas R. Porter, University of Nebraska Medical Center, 981165 Nebraska Medical Center, Omaha Nebraska 681981165. E-mail: [email protected].
ease. J Am Coll Cardiol 2004;44: 2185–91. 4. Jeetley P, Hickman M, Kamp O, et al. Myocardial contrast echocardiography for the detecting of coronary artery stenosis. J Am Coll Cardiol 2006;47: 141–5 5. Peltier M, Vancraeynest D, Pasquet A, et al. Assessment of the physiologic significance of coronary disease with dipyridamole teal-time myocardial contrast echocardiography: Comparison with technetium-99m sestamibi single-photon emission computed tomography and quantitative coronary angiography. J Am Coll Cardiol 2004; 43:257– 64. 6. Tsutsui JM, Elhendy A, Anderson JR, Xie F, McGrain AC, Porter TR. Prognostic value of dobutamine stress
myocardial contrast perfusion echocardiography. Circulation 2005;112: 1444 –50. 7. Elhendy A, Geleijnse ML, Roelandt JR, et al. Dobutamine-induced hypoperfusion without transient wall motion abnormalities: less severe ischemia or less severe stress? J Am Coll Cardiol 1996;27:323–9. 8. McGillem MJ, DeBoe SF, Friedman HZ, Mancini GBJ. The effects of dopamine and dobutamine on regional function in the presence of rigid coronary stenoses and subcritical impairments of reactive hyperemia. Am Heart J 1988;115:970 –7. 9. Gong G, Ugurbil K, Zhang J. Transmural metabolic heterogeneity at high cardiac work states. Am J Physiol 1999;46:H236 – 42.
277
278
Xie et al. Detection of Subendocardial Ischemia
10. Bin J-P, Pelberg RA, Wei K, Le E, Goodman NC, Kaul S. Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis. J Am Coll Cardiol 2002;40: 167–74. 11. Bin JP, Le E, Jayaweera AR, Coggins MP, Wei K, Kaul S. Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography. J Am Soc Echocardiogr 2003;16:871–9. 12. Sklenar J, Ismail S, Villaneuva FS, Goodman C, Glasheen WP, Kaul S. Dobutamine echocardiography for determining the extent of myocardial salvage after reperfusion. An experimental evaluation. Circulation 1994; 90:1502–12. 13. Clark NR, Reichek N, Bergey P, et al. Circumferential myocardial shorten-
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
ing in the normal human left ventricle. Assessment by magnetic resonance imaging using spatial modulation of magnetization. Circulation 1991;84: 67–74. 14. Linka AZ. Assessment of transmural distribution of myocardial perfusion with contrast echocardiography. Circulation 1998;98:1912–20. 15. Masugate H, Lafitte S, Peters B, Strachan GM, DeMaria AN. Comparison of real-time and intermittent myocardial contrast echocardiography for quantification of coronary stenosis severity and transmural perfusion gradient. Circulation 2001;104:1550 – 6. 16. Lewis JF, Lin L, McGorray S, et al. Dobutamine stress echocardiography in women with chest pain. Pilot phase data from the National Heart, Lung and Blood Institute Women’s Ischemia Syndrome Evaluation (WISE). J Am Coll Cardiol 1999;33:1462– 8.
17. Segar DS, Brown SE, Sawada SG, Ryan T, Feigenbaum H. Dobutamine stress echocardiography: correlation with coronary lesion severity as determined by quantitative angiography. J Am Coll Cardiol 1992;19:1197–202. 18. Yuda S Khoury V, Marwick TH. Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 2002;40: 1311–9. 19. Mir-Avi V, Collins KA, Korcarz CE, Shah M, Spencer KT, Lang RM. Detection of regional temporal abnormalities in left ventricular function during acute myocardial ischemia. Am J Physiol Heart Circ Physiol 2001;280:H1770 – 81. APPENDIX For supplementary videos, please see the online version of this article.
VOL. 1, NO. 3, 2008
© 2008 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 1936-878X/08/$34.00 DOI:10.1016/j.jcmg.2008.02.004
CLINICAL RESEARCH
Detection of Subendocardial Ischemia in the Left Anterior Descending Coronary Artery Territory With Real-Time Myocardial Contrast Echocardiography During Dobutamine Stress Echocardiography Feng Xie, MD, Saritha Dodla, MD, Edward O’Leary, MD, FACC, Thomas R. Porter, MD, FACC Omaha, Nebraska
O B J E C T I V E S 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. B A C K G R O U N D 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. M E T H O D S 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. R E S U L T S 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). C O N C L U S I O N S 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. (J Am Coll Cardiol Img 2008;1:271– 8) © 2008 by the American College of Cardiology Foundation
From the Department of Internal Medicine, Section of Cardiology, University of Nebraska Medical Center, Omaha, Nebraska. This work was supported by the Theodore Hubbard Foundation, Omaha, Nebraska. 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. Dr. Xie has served as consultant to Acusphere Inc. Manuscript received December 21, 2007; revised manuscript received February 20, 2008, accepted February 28, 2008.
272
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
R
eal-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 ABBREVIATIONS subendocardial ischemia despite normal AND ACRONYMS transmural thickening. This hypothesis CI ⴝ confidence interval was tested in patients with known left DSE ⴝ dobutamine stress anterior descending stenoses, by examinechocardiography ing transmural and subendocardial apical LAD ⴝ left anterior descending WT with RTMCE during dobutamine coronary artery stress. MCR ⴝ myocardial contrast replenishment
See page 279
MI ⴝ mechanical index RTMCE ⴝ real-time myocardial contrast echocardiography
METHODS
WT ⴝ wall thickening
Study population. 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. RTMCE. 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 ⱕ0.25, 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. Dobutamine stress. 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 g/kg/min, followed by increasing doses of 10, 20, 30, 40, up to a maximal dose of 50 g/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 ⱖ2 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 ⱖ20 mm Hg from baseline. A hypertensive response was defined as blood pressure ⱖ230/120 mm Hg. Image analysis. 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
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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. Transmural WT (%) ⫽ End-systolic thickness 共mm兲 ⫺ End-diastolic wall thickness 共mm兲 ⫻ 100% End-systolic defect thickness 共mm兲
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:
273
Table 1. Clinical Characteristics of Patients With Known LAD Stenoses
Variables n
Patients Without LAD Disease
Patients With LAD Disease
39
Age (yrs) Male
p Value
55
60 ⫾ 13
61 ⫾ 14
17
30
0.669 0.402
History of smoking
12 (31%)
24 (44%)
0.294
Hypertension
33 (85%)
50 (91%)
0.516
Hyperlipidemia
30 (77%)
42 (76%)
0.854
Diabetes
22 (56%)
30 (55%)
0.975
No. of patients achieving 85% PMHR
34 (87%)
46 (84%)
0.856
Rate-pressure product (mm Hg/min)
22,794 ⫾ 5996
21,343 ⫾ 5911
0.273
1 (3%)
4 (7%)
0.399
17 (44%)
16 (29%)
0.218
3
5
Previous MI outside LAD territory Previous PCI or CABG Previous PCI to LAD Previous CABG to LAD No. of patients with RCA/LCX disease Also with LAD stenosis Concentric remodeling
5
3
13 (33%)
35 (64%)
0.007
16 (29%)
0.679
0 9 (23%)
CABG ⫽ coronary artery bypass graft; LAD ⫽ left anterior descending coronary artery; MI ⫽ mechanical index; PCI ⫽ percutaneous coronary intervention; PMHR ⫽ predicted maximum heart rate; RCA ⫽ right coronary artery.
Figure 1. Example of Measurements for Subendocardial WT Apical 4-chamber view of real-time myocardial contrast echocardiography with contrast pulse sequencing (Siemens Acuson Sequoia, Mountain View, California) was obtained from a patient with significant left anterior descending coronary artery disease during dobutamine stress. Subendocardial wall thickening (WT) within the apex was measured off-line with commercially available software. The end-diastolic and -systolic wall thickness for transmural WT was measured on the pre-MCR images (the first cardiac cycle after the high mechanical index impulse; left panels) as the distance between the endocardial border (arrow) delineated with left ventricular cavity contrast and the epicardial border (arrow). Subendocardial WT was measurable only if a subendocardial perfusion defect was present (arrows) during the replenishment period (MCR; right panels). See the text for calculation formula. ED ⫽ end-diastole; ES ⫽ end-systole; MCR⫽ myocardial contrast replenishment.
274
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
Table 2. Sensitivity, Specificity, and Accuracy of Visual WMA During the Pre-MCR and MCR Time Periods in Detecting a Significant Coronary Stenosis WMA Pre-MCR
WMA During MCR
Sensitivity
27%
59%*
Myocardial Perfusion 91%†
Specificity
87%
74%
49%‡
Accuracy
52%
65%
73%*
Myocardial perfusion analysis is also shown. *p ⬍ 0.02 compared with pre-MCR; †p ⬍ 0.001 compared with other groups; ‡p ⬍ 0.05 compared with other groups. MCR ⫽ myocardial contrast replenishment; WMA ⫽ wall motion analysis.
Subendocardial WT (%) ⫽ End-systolic defect thickness 共mm兲 ⫺ End-diastolic defect thickness 共mm兲 ⫻ 100% End-systolic defect thickness 共mm兲
End-diastole was defined as the largest left ventricular cavity size and end-systole was defined as the smallest left ventricular cavity size. Statistical analysis. 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. RESULTS Patient characteristics. The LAD stenoses ⬎50%
diameter were present in 55 of the patients (32 with multi-vessel coronary artery disease, 23 with singlevessel 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, spec-
ificity, 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
Figure 2. Dynamic Changes of Subendocardial WT on Apical 4-Chamber View With RTMCE A 65-year-old woman presented with shortness of breath. Apical 40-chamber view of real-time myocardial contrast echocardiography (RTMCE) with contrast pulse sequencing was obtained during dobutamine stress. On the pre-MCR images, WT was normal, whereas during MCR an apical subendocardial WT abnormality was evident, because of the subendocardial perfusion defect. Subendocardial WT measured 20%, whereas transmural WT was measured to be 50%. At complete replenishment (4 s after high MI impulse), the defect disappeared. Abbreviations as in Figure 1.
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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 subendocar-
dial 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) DISCUSSION
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 myo-
Xie et al. Detection of Subendocardial Ischemia
Figure 3. Example of Subendocardial Defects With Normal Transmural WT on Apical 3-Chamber View With RTMCE Apical 3-chamber view of RTMCE with power modulation (iE33, Philips Medical Systems, Bothell, Washington) during peak dobutamine stress in a patient with a significant left anterior descending coronary artery stenosis. Pre-MCR (left panels) WT was normal, as delineated by the blue arrows in the left panels. On the MCR images (right panels), a subendocardial perfusion defect is evident and subendocardial WT appeared abnormal (red arrows). Abbreviations as in Figures 1 and 2.
cardial 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 ab-
275
276
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
Table 3. Pertinent Variables in Patients With LAD Stenoses
Abnormal TM WT (n ⴝ 10) 75 ⫾ 18%
% LAD diameter stenosis (range)
Normal TM WT, Abnormal SE WT (n ⴝ 18)
Normal TM WT, Normal SE WT (n ⴝ 17)
73 ⫾ 18%
74 ⫾ 17%
p Value 0.967
22,620 ⫾ 5,788
20,653 ⫾ 6,750
21,533 ⫾ 6,261
0.745
No. of patients reaching 85% predicted maximal heart rate
9 (90%)
15 (83%)
13 (76%)
0.666
No. of patients with RCA/LCX stenosis
6 (60%)
11 (61%)
12 (71%)
0.797
Rate-pressure product (mm Hg/min)
Pertinent variables in patients with left anterior descending coronary artery (LAD) stenoses who had subendocardial (SE) perfusion defects and: 1) abnormal transmural (TM) wall thickening (WT); 2) normal TM WT but abnormal subendocardial WT and perfusion; or 3) normal TM WT and abnormal subendocardial perfusion but normal subendocardial WT. LCX ⫽ left circumflex coronary artery; RCA ⫽ right coronary artery.
normality 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. Study limitations. The ability of WT on the preMCR 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
Table 4. WT Measurements in Patients With Subendocardial Perfusion Defects and Normal TM WT TM WT at Rest
Subendocardial WT at Peak
TM WT at Peak
Subendocardial perfusion defects with normal WT
42 ⫾ 11% (23%–69%)
25 ⫾ 10% (8%–48%)
36 ⫾ 14% (20%–63%)*
Subendocardial perfusion defects with abnormal WT
39 ⫾ 11% (27%–55%)
17 ⫾ 8% (0%–30%)†
TM perfusion defects
43 ⫾ 7% (33%–53%)
—
30 ⫾ 27% (7%–76%)
Patients without LAD disease
39 ⫾ 11% (20%–57%)
—
44 ⫾ 13% (22%–65%)
33 ⫾ 15% (14%–63%)*
*p ⬍ 0.05 compared with patients without left anterior descending coronary artery (LAD) disease; †p ⬍ 0.01 compared with subendocardial perfusion defects with normal wall thickening (WT). TM ⫽ transmural.
Xie et al. Detection of Subendocardial Ischemia
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
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
REFERENCES
1. Porter TR, Xie F, Silver M, Kricsfeld D, O’Leary E. Real-time perfusion imaging with low mechanical index pulse inversion Doppler imaging. J Am Coll Cardiol 2001;37: 748 –53. 2. Leong-Poi H, Rim SJ, Le DE, Fisher NG, Wei K, Kaul S. Perfusion versus function: the ischemic cascade in demand ischemia: implications of single-vessel versus multivessel stenosis. Circulation 2002;105:987–92. 3. Elhendy A, O’Leary E, Xie F, McGrain AC, Anderson J, Porter TR. Comparative accuracy of real-time myocardial contrast perfusion imaging and wall motion analysis during dobutamine stress echocardiography for the diagnosis of coronary artery dis-
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 underestimated 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. CONCLUSIONS
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. Acknowledgments
The authors thank Stephanie Lyons and Stacey Kearney for their help in the preparation of the manuscript. Reprint requests and correspondence: Dr. Thomas R. Porter, University of Nebraska Medical Center, 981165 Nebraska Medical Center, Omaha Nebraska 681981165. E-mail: [email protected].
ease. J Am Coll Cardiol 2004;44: 2185–91. 4. Jeetley P, Hickman M, Kamp O, et al. Myocardial contrast echocardiography for the detecting of coronary artery stenosis. J Am Coll Cardiol 2006;47: 141–5 5. Peltier M, Vancraeynest D, Pasquet A, et al. Assessment of the physiologic significance of coronary disease with dipyridamole teal-time myocardial contrast echocardiography: Comparison with technetium-99m sestamibi single-photon emission computed tomography and quantitative coronary angiography. J Am Coll Cardiol 2004; 43:257– 64. 6. Tsutsui JM, Elhendy A, Anderson JR, Xie F, McGrain AC, Porter TR. Prognostic value of dobutamine stress
myocardial contrast perfusion echocardiography. Circulation 2005;112: 1444 –50. 7. Elhendy A, Geleijnse ML, Roelandt JR, et al. Dobutamine-induced hypoperfusion without transient wall motion abnormalities: less severe ischemia or less severe stress? J Am Coll Cardiol 1996;27:323–9. 8. McGillem MJ, DeBoe SF, Friedman HZ, Mancini GBJ. The effects of dopamine and dobutamine on regional function in the presence of rigid coronary stenoses and subcritical impairments of reactive hyperemia. Am Heart J 1988;115:970 –7. 9. Gong G, Ugurbil K, Zhang J. Transmural metabolic heterogeneity at high cardiac work states. Am J Physiol 1999;46:H236 – 42.
277
278
Xie et al. Detection of Subendocardial Ischemia
10. Bin J-P, Pelberg RA, Wei K, Le E, Goodman NC, Kaul S. Dobutamine versus dipyridamole for inducing reversible perfusion defects in chronic multivessel coronary artery stenosis. J Am Coll Cardiol 2002;40: 167–74. 11. Bin JP, Le E, Jayaweera AR, Coggins MP, Wei K, Kaul S. Direct effects of dobutamine on the coronary microcirculation: comparison with adenosine using myocardial contrast echocardiography. J Am Soc Echocardiogr 2003;16:871–9. 12. Sklenar J, Ismail S, Villaneuva FS, Goodman C, Glasheen WP, Kaul S. Dobutamine echocardiography for determining the extent of myocardial salvage after reperfusion. An experimental evaluation. Circulation 1994; 90:1502–12. 13. Clark NR, Reichek N, Bergey P, et al. Circumferential myocardial shorten-
JACC: CARDIOVASCULAR IMAGING, VOL. 1, NO. 3, 2008 MAY 2008:271– 8
ing in the normal human left ventricle. Assessment by magnetic resonance imaging using spatial modulation of magnetization. Circulation 1991;84: 67–74. 14. Linka AZ. Assessment of transmural distribution of myocardial perfusion with contrast echocardiography. Circulation 1998;98:1912–20. 15. Masugate H, Lafitte S, Peters B, Strachan GM, DeMaria AN. Comparison of real-time and intermittent myocardial contrast echocardiography for quantification of coronary stenosis severity and transmural perfusion gradient. Circulation 2001;104:1550 – 6. 16. Lewis JF, Lin L, McGorray S, et al. Dobutamine stress echocardiography in women with chest pain. Pilot phase data from the National Heart, Lung and Blood Institute Women’s Ischemia Syndrome Evaluation (WISE). J Am Coll Cardiol 1999;33:1462– 8.
17. Segar DS, Brown SE, Sawada SG, Ryan T, Feigenbaum H. Dobutamine stress echocardiography: correlation with coronary lesion severity as determined by quantitative angiography. J Am Coll Cardiol 1992;19:1197–202. 18. Yuda S Khoury V, Marwick TH. Influence of wall stress and left ventricular geometry on the accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 2002;40: 1311–9. 19. Mir-Avi V, Collins KA, Korcarz CE, Shah M, Spencer KT, Lang RM. Detection of regional temporal abnormalities in left ventricular function during acute myocardial ischemia. Am J Physiol Heart Circ Physiol 2001;280:H1770 – 81. APPENDIX For supplementary videos, please see the online version of this article.