This prospective study investigated whether the incorporation of myocardial contrast echocardiography (MCE) into a clinical stress echocardiography service reproduces the benefits of assessing myocardial perfusion proved previously in research studies.
MCE was performed during physiologic and pharmacologic clinical stress echocardiographic studies, and the value of myocardial perfusion to the reporting echocardiologists was categorized as of benefit (subclassified as incremental benefit over wall motion [WM] or greater confidence with WM) or of no added benefit. The presence and extent of inducible ischemia by WM and myocardial perfusion were documented and correlated with angiographic results in patients who underwent cardiac catheterization.
In total, 220 patients underwent simultaneous MCE during stress echocardiography by eight different operators. Overall, MCE was of benefit in 193 patients (88%), providing incremental benefit over WM in 25% and greater confidence with WM evaluation in 62%. MCE provided no added benefit in 27 patients (12%). MCE detected significantly more cases of ischemia than WM in the left anterior descending coronary artery territory (65% vs 53%, P = .02) and detected a greater ischemic burden than WM on a per patient basis (median, 5 [interquartile range, 3–8] vs 4 [interquartile range, 2–7] segments; P < .001) and across all coronary territories. MCE correctly identified a greater proportion of patients with multivessel disease than WM (76% vs 56%, P = .02) and a greater ischemic burden in patients with multivessel disease (median, 7 [interquartile range, 4–9] vs 5 [interquartile range, 1–8] segments; P < .001).
This prospective study is the first to demonstrate that the excellent feasibility and diagnostic utility of MCE, which have been documented in the research arena, are reproducible in the clinical arena.
Accurate detection of myocardial ischemia carries therapeutic and prognostic importance in symptomatic patients with suspected or known coronary artery disease (CAD). Stress echocardiography (SE) is a widely used technique for detecting myocardial ischemia, the hallmark of which is a new or worsening wall motion (WM) abnormality during stress imaging. Because myocardial perfusion (MP) defects manifest before the onset of WM abnormalities during demand ischemia, SE is considered less sensitive than techniques such as single-photon emission computed tomography (SPECT), which assess MP, for the detection of CAD.
Contrast echocardiography uses microbubbles (gas-filled microspheres) that enhance image quality and are approved for clinical use for improved accuracy of WM assessment, by improving endocardial border delineation, during rest and SE. However, because these microbubbles have a rheology similar to that of erythrocytes and remain exclusively within the intravascular space, their presence within the myocardium (i.e., within myocardial capillaries) depicts MP. Consequently, the use of such contrast agents during SE permits not just accurate WM assessment but also the simultaneous evaluation of MP during myocardial contrast echocardiography (MCE). MCE was recently shown to be more sensitive than SPECT for the detection of CAD in a large multicenter study. Indeed, many research reports have previously described the excellent sensitivity of MCE for the detection of CAD, in single-center and multicenter studies. MCE has been used for the assessment of myocardial ischemia and myocardial viability and also in patients without CAD, for example, those with hypertrophic cardiomyopathy.
However, MCE is perceived by some as a time-consuming technique with a requirement for extensive training, thus making it less suitable for use in day-to-day practice within clinical time constraints and using multiple operators. This perspective is strengthened by the observation that although many research studies have shown improved sensitivity over WM for the detection of CAD, to the best of our knowledge, no prior publications have reported the feasibility and clinical utility of MCE when performed as part of routine clinical care within a clinical SE service. Therefore, we designed this prospective study, the Incorporation of Myocardial Perfusion Assessment into Clinical Testing with Stress Echocardiography (IMPACT-SE) Study, to determine the role of MCE in the clinical arena.
Patient Selection and Characteristics
Our hospital, a large tertiary referral center, performs SE daily for the evaluation of CAD (ischemia and viability studies) as well as for “noncoronary” indications, such as dynamic assessment of valvular heart disease (particularly in patients with aortic stenosis and mitral regurgitation), hypertrophic cardiomyopathy, and certain patients with adult congenital heart disease. Only patients undergoing SE for CAD assessment were considered for MCE.
All adult cardiology patients referred for SE for the evaluation of CAD were assessed at the beginning of the test as to whether MCE would be used in addition to WM analysis. We performed MCE in all patients receiving pharmacologic stress and patients performing treadmill exercise stress in whom the cardiologist was not certain that a high workload or target heart rate would be achieved (and thus in whom it was anticipated that additional MP data would be helpful in addition to WM). This was a judgment made at the time of the stress echocardiographic study on the basis of the patient’s general level of fitness and any theoretical limitations to exercise, such as orthopedic or respiratory disorders or significant obesity (which may cause premature cessation of exercise because of dyspnea). We decided not to perform MCE in patients who seemed clearly able to exercise to a high workload (i.e., those otherwise free from other comorbidities), because in these patients, we hypothesized that MP would be less likely to show incremental benefit over WM.
Patient demographics and stress echocardiographic test results were collected prospectively when the patient attended for SE. Patients were deemed to have preexisting ischemic heart disease if there was a history of acute myocardial infarction or coronary revascularization, either by percutaneous coronary intervention or coronary artery bypass grafting. Approval to undertake this study was granted by the local institutional review board.
Images of the left ventricle (parasternal long-axis, short-axis, and apical four-chamber, two-chamber, and three-chamber views) were obtained with the patient in the left lateral decubitus position (iE33; Philips Medical Systems, Eindhoven, The Netherlands) by two-dimensional echocardiography. A real-time low–mechanical index (0.10) perfusion setting was used for WM and myocardial contrast echocardiographic imaging. Standard symptom-limited treadmill exercise was the preferred stress modality (with imaging performed at rest and at peak stress), but in patients unsuitable for treadmill exercise (e.g., general frailty, severe arthritis, pulmonary disease), dobutamine SE was performed.
For assessment of ischemia only, dobutamine was infused peripherally in 3-min dose increments, starting from 10 μg/kg/min and increasing to 20, 30, and 40 μg/kg/min. In patients with resting WM abnormalities, both ischemia and viability were assessed, commencing dobutamine at 5 μg/kg/min and increasing to 10, 15, and 20 μg/kg/min in 5-min intervals. Thereafter, the dose was increased to 30 and 40 μg/kg/min in 3-min intervals, per the ischemia protocol. If no end point was reached, atropine was added to the continuing 40 μg/kg/min dobutamine infusion in bolus doses of 0.3 mg (up to a maximum of 1.2 mg). For ischemia-protocol studies, imaging was performed at rest and with low-dose and peak-dose dobutamine, whereas for viability studies, images were acquired at the rest, low-dose, intermediate-dose, and peak-dose stages of the dobutamine infusion.
For the minority of patients unable to exercise and in whom dobutamine was contraindicated, vasodilator stress using dipyridamole was used. WM and MP assessment were performed at rest and after slow intravenous injection, over 4 min, of dipyridamole (0.56 mg/kg body weight). If there was no change in heart rate and the patient had not experienced any symptoms after this dose, a further 0.28 mg/kg of dipyridamole was administered over 2 min. All patients were given aminophylline (50–75 mg) at the end of the test.
Resting left ventricular (LV) systolic function was deemed normal if all 17 segments had normal contractility and abnormal if any segment exhibited a WM abnormality. The presence of ischemia was defined as a new or worsening WM abnormality at peak stress, including a biphasic response during viability studies, in any segment.
MCE was performed in the apical four-chamber, two-chamber, and three-chamber views using both low-power real-time and triggered (end-systolic) imaging. Time-gain compensation and background gain settings were optimized so that minimal tissue signal was seen. The focus was set at the mitral valve level, and the frame rate was 40 frames/sec. All patients received intravenous infusion of SonoVue at 0.8 to 1.0 mL/min using VueJect (BR-INF 100; Bracco, Milan, Italy), an infusion syringe pump that rotates gently to maintain the microbubbles in suspension. The infusion rate was adjusted to optimize myocardial opacification with minimal attenuation. Additionally, for those patients performing exercise, an intravenous bolus injection (0.5 mL) of contrast was given 10 sec before terminating exercise. Nonstandard apical views (e.g., bringing the lateral wall into the sector field) were used, if required, to overcome basal attenuation artifacts. In dilated hearts, each myocardial wall (e.g., the inferior and anterior walls in the apical two-chamber view) was imaged separately.
Flash echocardiography at a high mechanical index (0.50–1.0) was performed to clear microbubbles in the myocardium and permit evaluation of the rate of microbubble replenishment. Real-time and end-systolic triggered images were acquired digitally up to 15 cardiac cycles after microbubble destruction in each view. If patients have normal resting LV function, then MP by definition must be normal also. In these patients, MCE was performed only at rest in one view (usually apical four-chamber) to optimize settings (flash frames, flash mechanical index, gain, and time-gain compensation) for performing MCE at peak stress, which was done immediately after WM cine loops had been acquired. We perform MCE after WM cine loops have been acquired because we believe the side-by-side comparison of rest and stress WM loops, in the quad-screen format, facilitates the accurate identification of WM abnormalities. This viewing format is not possible if individual cine loops are acquired. However, as contrast is being given by continuous intravenous infusion in these patients, we can assess myocardial signal intensity (i.e., myocardial blood volume) on the WM loops, with subsequent MCE also permitting flash-replenishment imaging.
A perfusion defect was deemed to be present at rest if, in the presence of a WM abnormality, there was patchy or absent contrast uptake or delayed perfusion beyond 5 sec after microbubble destruction. Ischemia was deemed present when subendocardial or transmural defects appeared that replenished beyond 1 sec after flash. Worsening of resting perfusion was also deemed indicative of ischemia. This was performed on a segmental basis using the same 17-segment LV model used for WM analysis.
The value of assessing MP to the reporting cardiologist, in addition to WM, was determined at the time of image interpretation, immediately after completion of the test, and assigned to predefined categories. MP data from MCE were deemed beneficial if they yielded “incremental benefit” over WM analysis or gave “greater confidence” with WM assessment, or were “nonbeneficial.” Incremental benefit over WM analysis was defined as follows: WM is normal but MP is abnormal; WM and MP are abnormal, but more segments are ischemic by MP than by WM; and patients do not attain 85% of the target heart rate (i.e., submaximal stress), but MP is normal. Greater confidence with WM assessment was defined as follows: segments with equivocal WM (in these patients, normal MP would be used to label WM as normal, whereas abnormal MP would lead us to label WM as abnormal also); patients with WM abnormality in just one segment; and WM and MP are both normal (because MP is more sensitive for the detection of CAD than WM, the finding of both normal WM and normal MP gives the reporting echocardiologist greater confidence that inducible ischemia has not been “missed”). No added benefit over WM analysis was defined as follows: WM is unequivocally abnormal and MP is correspondingly abnormal (i.e. matching perfusion defect), and myocardial contrast echocardiographic images are uninterpretable.
Submaximal stress, particularly during exercise SE, can be a problem and affect a test’s feasibility by producing inconclusive results, which often then require additional investigations at further cost and further delay to diagnosis. However, per the ischemic cascade, MP is more sensitive than WM for the detection of ischemia, and prior research has indeed shown that MP assessment at submaximal stress (65%–75% of target heart rate) is significantly more accurate than WM for the detection of ischemia (84% vs 20%). Furthermore, and crucially, in that study, the sensitivity of MP at intermediate stress for the detection of flow-limiting CAD (84%) was superior to the sensitivity of WM (70%) at peak stress (>85% of target heart rate). It is for this reason that we accepted such scans and categorized MP assessment as of incremental benefit.
MCE was performed by staff echocardiologists at our institution, most of whom were doctors in training. All were familiar with and independent operators for conventional stress echocardiographic techniques (i.e., acquisition and interpretation of WM cine loops). There was an initial period of 2 to 4 weeks (minimum, 4 studies/wk) during which an experienced operator was observed performing MCE, followed by a further period of 2 to 4 weeks in which the novice was supervised performing MCE. Thereafter, stress and myocardial contrast echocardiographic studies were performed independently but coreported with the expert reader, who decided the final assessment by WM and MP.
Patients were referred for coronary angiography (CA) at the discretion of their responsible cardiologists, and WM and MP results were available to help inform this decision-making process. Coronary angiographic studies within 3 months of SE were included in the results, providing patients did not have any cardiac events in the intervening time period. Results of CA were not considered if CA was performed >3 months after SE. CAD was defined as the presence of a ≥50% stenosis in an epicardial coronary artery or major branch vessel, as determined by the interventional cardiologist performing the procedure. Analyses were then performed to determine the relative accuracy of WM and MP for detecting CAD overall, by coronary territory (left anterior descending coronary artery [LAD], left circumflex coronary artery, and right coronary artery territories) and by grouped coronary territory (i.e., anterior [LAD] vs posterior [left circumflex or right coronary artery] coronary circulation). Multivessel disease (MVD) was defined as ≥50% stenosis in the LAD plus one or more other (non-LAD) epicardial coronary vessel.
Categorical variables are expressed as percentages and continuous variables as mean ± SD. Ischemic burden is expressed as median (interquartile range [IQR]). Wilcoxon’s matched-pairs test was used to compare the burden of ischemia between WM and MCE (ischemia considered as a continuous variable), while paired exact tests were used to compare the presence or absence of ischemia between WM and MCE (ischemia considered as a categorical variable). For all tests, P values < .05 were considered statistically significant. All statistical analyses were performed using both Stata version 12.1 (StataCorp LP, College Station, TX) and SPSS version 19.0 (SPSS Inc, Chicago, IL).
Over the study period of December 2010 to August 2012 inclusive, 875 patients underwent SE at our center. Approximately two thirds of these studies were for CAD assessment, and one third were for assessment of other conditions (i.e., valvular heart disease, hypertrophic obstructive cardiomyopathy and adult congenital heart disease). Of the patients undergoing SE for evaluation of known or suspected CAD, 220 underwent simultaneous MCE during SE. The mean age was 66 ± 11 years, and 74% were men. Of note, almost two thirds of patients had known CAD, and almost half had previously undergone myocardial revascularization ( Table 1 ).
|Age (y), mean ± SD||66 ± 11|
|Current smokers||57 (26%)|
|Known CAD||144 (65%)|
|Indication for referral to SE|
|Exertional chest pain||88 (40%)|
|Exertional dyspnea||52 (24%)|
|Assess ischemia (known CAD)||47 (21%)|
|Assess viability (known CAD)||33 (15%)|
|Resting LV function|
|Contrast needed for LV opacification||165 (75%)|
SE and MCE were performed by eight different doctors, who coreported WM and MP together with an expert reader ( Table 2 ). The most frequent reason for referral to SE was exertional chest pain, and more than half of the group underwent dobutamine stress. Ultrasound contrast was indicated in three quarters of patients to ensure optimal endocardial border definition. There were no major complications; specifically, no patients had acute myocardial infarctions, ventricular arrhythmias, or cardiac arrest or had major adverse reactions (including anaphylaxis) to SonoVue. The addition of MCE did not alter departmental work patterns, as the number of stress studies scheduled per clinical session (four patients, one per hour) was unaffected.
|Stress test characteristic||n|
|Benefit from MP imaging||193 (88%)|
|Incremental benefit over WM|
|Normal WM but abnormal MP ∗||16|
|Segments with MP abnormality > segments with WM abnormality||31|
|Patients with normal MP but submaximal (<85% of target heart rate) stress||10|
|Greater confidence with WM|
|For segments with equivocal WM||44|
|Patients with minor (one segment) WM abnormality only||5|
|Normal WM with normal MP also||87|
|No benefit from MP imaging||27 (12%)|
|WM unequivocally abnormal with corresponding abnormal MP also||14|
|Uninterpretable myocardial contrast echocardiographic images||13|
Utility of Myocardial Contrast Echocardiographic Data to Reporting Cardiologists
The results of the prospective assignment of the benefit of MP assessment, by MCE, to the predefined categories are shown in Table 2 . Overall, MP data were of benefit to the reporting echocardiologists in 193 of 220 patients (88%) and not of benefit in 27 patients (12%), including 13 uninterpretable studies (6%).
Within the “benefit” group ( n = 193), there were 15 patients in whom MP was abnormal though WM was normal (see Figure 1 Videos 1 and 2 ; available at www.onlinejase.com ). There was also one patient with grossly abnormal WM (a biphasic response) at peak stress but with normal MP. This patient was reported as having no inducible ischemia on the basis of MP, and indeed, subsequent angiography showed normal coronary arteries. There were 31 patients in whom we reported greater numbers of segments with MP defects than WM (e.g., two segments by WM vs four segments by MP; see Figure 2 , Videos 3 and 4 ; available at www.onlinejase.com ). There were also 10 patients in whom, despite maximal exertion, ≥85% maximum heart rate was not attained (range, 79%–84%), which by WM alone would usually be deemed “inconclusive” because of suboptimal stress. However, given that both WM and MP were normal, at near maximal target heart rate, a diagnostic report could be issued, which would not otherwise have been possible.
In the “greater confidence” group, there were 49 patients with equivocal WM abnormalities (including five patients with WM abnormality in just one segment), in whom the added information of normal or abnormal MP helped decide whether to report the segments as normal or abnormal ( Figure 3 , Videos 5 and 6 ; available at www.onlinejase.com ). Of those in whom we used MP data to report inducible ischemia, the majority who proceeded to angiography did indeed have significant CAD, whereas in those patients in whom we used MP findings to report no ischemia, those who did proceed to angiography all had normal coronary arteries (see Figure 4 ). Thus, the use of MP results to decide on the presence or absence of ischemia improved the accuracy of the test in this cohort of patients also. Figure 5 illustrates an example in which MP was not of benefit, as WM was unequivocally abnormal in all three apical views with matching perfusion defects.
We explored whether the additional benefits gained from MCE varied with gender and with the presence or absence of resting WM abnormalities, and these results are presented in Tables 3 and 4 , respectively. Regarding gender, there were no significant differences in baseline characteristics, indication for SE, and stress modality. Inducible ischemia was more frequent in men. There were no significant differences between any of the MCE categories and, overall, no difference between men and women in the proportion of scans in which MCE was beneficial (87% vs 89%, P = .64). Regarding LV function, patients with resting WM abnormalities, as expected, were more likely to have histories of CAD and were more likely to undergo dobutamine stress. Inducible ischemia was also more common in this group. Again, overall, there was no difference in proportion of scans in which MCE was beneficial (also 87% vs 89%, P = .65).
( n = 163)
( n = 57)
|Age (y), mean ± SD||65.8 ± 11.4||66.1 ± 11.9||.88|
|Known CAD||112 (69%)||32 (56%)||.09|
|Normal left ventricle at rest||99 (61%)||39 (68%)||.30|
|SE and MCE|
|Indication chest pain||64 (39%)||24 (42%)||.71|
|Indication breathlessness||35 (21%)||17 (30%)||.20|
|Exercise stress||69 (42%)||19 (33%)||.23|
|Inducible ischemia||76 (47%)||17 (30%)||.03|
|MCE category: incremental benefit over WM|
|Normal WM, abnormal MP||13 (8%)||3 (5%)||.50|
|MP >WM abnormality||26 (16%)||5 (9%)||.18|
|Submaximal stress||6 (4%)||4 (7%)||.30|
|MCE category: greater confidence with WM|
|Equivocal WM||31 (19%)||13 (23%)||.54|
|Minor (one segment) WM abnormality||4 (3%)||1 (2%)||.76|
|Unequivocally normal WM and MP||62 (38%)||25 (44%)||.44|
|MCE category: no added benefit over WM|
|Matching WM and MP abnormality||11 (7%)||3 (5%)||.69|
|Uninterpretable myocardial contrast echocardiographic images||10 (6%)||3 (5%)||.81|
|Overall benefit from MP assessment||142 (87%)||51 (89%)||.64|