Conclusion: MCE was superior to SPECT for the assessment of HM in ischemic cardiomyopathy. (J Am Soc Echocardiogr 2010;23:840-7.)

Transcription

1 Myocardial Contrast Echocardiography Versus Single Photon Emission Computed Tomography for Assessment of Hibernating Myocardium in Ischemic Cardiomyopathy: Preliminary Qualitative and Quantitative Results Rajesh K. Chelliah, MBChB, MRCP, Michael Hickman, MBBS, MRCP, Christopher Kinsey, HND, Leah Burden, BSc, and Roxy Senior, MBBS, MD, DM, FRCP, FESC, FACC, London, United Kingdom Background: Single photon-emission computed tomography (SPECT) is widely used for the assessment of hibernating myocardium (HM). The aim of this study was to test the hypothesis that myocardial contrast echocardiography (MCE), because of its better spatial and temporal resolution, would be superior to SPECT for the detection of HM. Methods: Thirty-nine consecutive patients with symptomatic ischemic cardiomyopathy underwent rest and vasodilator SPECT and MCE. Of these, 23 survived to undergo assessment 3 months after revascularization for the recovery of left ventricular (LV) function (spontaneous recovery or dobutamine induced), which is the definition of HM. Results: Of the 214 dysfunctional segments, 156 segments demonstrated HM in the 23 patients, of whom 16 showed significant improvement in LV function. Logistic regression analysis showed that both qualitative and quantitative MCE were independent predictors for the detection of HM (P <.0001 vs P =.06 for qualitative MCE vs qualitative SPECT, respectively, and P <.01 vs P =.25 for all quantitative myocardial contrast echocardiographic parameters vs quantitative SPECT, respectively). Using clinical and LV functional data, SPECT, and MCE for predicting the recovery of LV function, MCE was the only independent predictor (P =.03). Conclusion: MCE was superior to SPECT for the assessment of HM in ischemic cardiomyopathy. (J Am Soc Echocardiogr 2010;23:840-7.) Keywords: Myocardial contrast echocardiography, SPECT, Hibernating myocardium Hibernating myocardium (HM) is a phenomenon characterized by reduced or absent systolic contraction but persistent although reduced resting perfusion and preserved metabolism that is able to recover function following revascularization in patients with severe coronary artery disease (CAD). 1 Single photon-emission computed tomography (SPECT), using thallium or technetium radionuclide tracer, is commonly used for the assessment of HM. 2 However, problems with partial volume effects, tracer kinetics, and variable tracer extraction with SPECT have identified the need for newer imaging techniques to improve accuracy for the detection of HM. Recently, myocardial contrast echocardiography (MCE) has emerged as an From the Department of Cardiology and Cardiac Research, Northwick Park Hospital, London, United Kingdom. This work was supported by a grant from the Cardiac Research Fund, Institute of Postgraduate Medical Education and Research (London, United Kingdom). Reprint requests: Roxy Senior, MBBS, MD, DM, FRCP, FESC, FACC, Royal Brompton Hospital, London and Northwick Park Hospital, Department of Cardiology, Middlesex, HA1 3UJ, United Kingdom. ( roxysenior@cardiac-research.org) /$36.00 Copyright 2010 by the American Society of Echocardiography. doi: /j.echo imaging modality for the noninvasive assessment of myocardial perfusion. 3,4 Animal and human studies have shown that MCE reliably assesses infarct size and hence myocardial viability after acute myocardial infarction. 5-8 Advantages of MCE over SPECT include the lack of radiation exposure and its ability to be performed at the bedside. However, only one study compared MCE with SPECT for the detection of HM in ischemic cardiomyopathy, but it did not attempt to show whether MCE was superior to SPECT. 9 Furthermore, that study did not address the ability of MCE versus SPECT for the detection of reversible ischemia in HM, as the latter may influence the decision to proceed to revascularization in patients with ischemic cardiomyopathy. 10 Therefore, the aims of this study were to determine whether quantitative and qualitative resting myocardial contrast echocardiographic parameters are superior for the detection of HM, compared with qualitative and quantitative SPECT parameters, in patients with severe ischemic cardiomyopathy and whether MCE is more accurate than SPECT for the detection of reversible ischemia in HM. In this study, HM was defined as dysfunctional myocardium (presumed to be hypoperfused in the presence of severe chronic CAD) that improves spontaneously or demonstrates contractile function with low-dose dobutamine in persistently dysfunctional segments after

2 Journal of the American Society of Echocardiography Volume 23 Number 8 Chelliah et al 841 Abbreviations AUC = Area under the curves CAD = Coronary artery disease HM = Hibernating myocardium LV = Left ventricular MBF = Myocardial blood flow MCE = Myocardial contrast echocardiography RMBF = Resting MBF ROC = Receiver operating characteristic SPECT = Single photonemission computed tomography revascularization. Low-dose dobutamine in persistently dysfunctional segments was used to unmask viability in midsubepicardial myocardial segments with subendocardial infarction, which will prevent the spontaneous recovery of function after revascularization despite significant myocardial viability. 11 METHODS Patient Population This was a prospective study in which consecutive patients with symptomatic ischemic left ventricular (LV) systolic dysfunction (LV ejection fraction < 40%) were recruited. These patients had undergone recent coronary angiography, and the decision to revascularize or continue with medical therapy was based mainly on clinical presentation and coronary arteriographic data. However, the results of either dobutamine stress echocardiography or SPECT were available at the time of decision making. Patients were excluded if they were aged < 18 years, were unable to give informed consent, had significant valvular heart disease, had recent acute coronary syndromes within the preceding 3 months, or had known allergies to the contrast agent or vasodilator agent used. The study complied with the Declaration of Helsinki, and ethical approval was obtained. Informed consent was obtained from all patients. Study Protocol Patients had full histories taken and clinical examinations performed. Twelve-lead electrocardiography and standard resting transthoracic echocardiography were also undertaken. MCE was performed on the same day as 99m Tc sestamibi SPECT. Resting contrast images were acquired, and dipyridamole was administered (0.56 mg/kg), infused over 4 minutes. During peak hyperemia (2 minutes after the administration of dipyridamole), 99m Tc sestamibi was administered, following which the stress contrast images were acquired. The stress single photon-emission computed tomographic images were acquired 1 to 2 hours later. Resting single photon-emission computed tomographic images were obtained 48 hours later. Patients either proceeded to revascularization or were treated with medical therapy alone, as dictated by the managing physicians. Patients were followed up 3 to 6 months after their revascularization. During follow-up, a further history was taken, and resting transthoracic echocardiography was performed. If significant wall motion abnormalities persisted, low-dose dobutamine echocardiography was performed to assess for residual contractile reserve, as resting function may not improve because of subendocardial infarction despite significant HM, which, however, contributes to wall thickening during exercise and prevents LV remodeling. 10 Lack of improvement after revascularization during low-dose dobutamine suggests predominance of scar tissue. Two-Dimensional Transthoracic Echocardiography Two-dimensional echocardiography was performed in standard apical and parasternal views using tissue harmonic imaging (Sonos 5500 and HDI CV 5000; Philips Medical Systems, Andover, MA). Regional wall thickening abnormalities were graded as 1 = normal, 2 = mildly hypokinetic, 3 = moderately hypokinetic, or 4 = akinetic in a 17-segment LV model. 12 For each patient, a wall motion score index was derived by dividing the sum score of the segments by the total number of segments, which gives an estimate of LV function. Technetium-99m Sestamibi SPECT Scans were performed in accordance with our standard departmental protocol. Peak hyperemia was induced using an infusion of 0.56 mg/ kg of dipyridamole over 4 minutes. During peak hyperemia, 600 MBq of 99m Tc sestamibi was administered intravenously. Patients were encouraged to drink a single glass of full-fat milk to stimulate gallbladder emptying and then 500 ml of water to minimize artifacts of the inferior wall of the myocardium. Imaging was performed 1 to 2 hours after the tracer injection but delayed a short while if significant gut uptake was noticeable. A large-field dual-head gamma camera (DS7; Sopha Medical Vision International, Buc, France) with highresolution collimators was used. Thirty-two projections (20 s/projection) were acquired over a 180 arc from 45 right anterior oblique to 45 left posterior oblique. Images were reconstructed using a Butterworth filter and then reoriented into horizontal long-axis, vertical long-axis, and short axis planes. Values for LV dimensions and ejection fraction were derived using QGS software (Cedars- Sinai Medical Center, Los Angeles, CA). Resting SPECT was performed 48 hours after the acquisition of the stress images, following 400 mg of sublingual nitroglycerin spray 10 minutes prior to tracer injection. The left ventricle was divided into 17 segments, as described by imaging consensus. The standard qualitative 5-point scoring system (0 = normal tracer uptake, 1 = mildly reduced tracer uptake, 2 = moderately reduced tracer uptake, 3 = severely reduced tracer uptake, 4 = absent tracer uptake) was used. 2 Perfusion score index was then calculated by dividing the sum of the total perfusion score of analyzable by the number of segments analyzed. Reversible perfusion defect was defined as worsening of perfusion by $1 grade in dysfunctional segments with significant perfusion (scores 0-2). Myocardial quantification on SPECT was performed using MyoQuant software. 13 The software calculates and quantifies perfusion and perfusion deficits in myocardial single photon-emission computed tomographic data through the analysis of polar maps generated from the radial slices. Normalized perfusion values were displayed in the 17-segment grid model. All single photon-emission computed tomographic images were interpreted by an expert, blinded to clinical, myocardial contrast echocardiographic, and coronary angiographic data. MCE MCE was performed in the apical 4-chamber, 2-chamber, and 3-chamber views using low-power continuous power modulation MCE in color Doppler mode at a mechanical index of 0.1. Tissue signal was minimized by reducing background gain, and color gains were set so that Doppler signal was only seen at the mitral valve and proximal to the apex. SonoVue (Bracco, Milan, Italy) was administered via an intravenous cannula in the left arm. The contrast was infused at a rate of 50 to 70 ml/h using a VueJect (BR-INF 100; Bracco Diagnostics) infusion pump. The infusion rate was adjusted to ensure adequate myocardial opacification while minimizing attenuation. Destruction-replenishment imaging was used with a high mechanical index (1.7) pulse used to destroy the microbubbles. The number of frames for a high mechanical index burst varied from 8 to 12 frames

3 842 Chelliah et al Journal of the American Society of Echocardiography August 2010 to achieve adequate destruction of microbubbles within the myocardium. End-systolic frames were captured for a minimum of 15 seconds following microbubble destruction to record replenishment. Dipyridamole (0.56 mg/kg) was infused over 4 minutes with continuous blood pressure and electrocardiographic monitoring. A 4-point semiquantitative scoring system was used to assess transmural contrast intensity at 15 cardiac cycles following microbubble destruction in all 17 segments: 1 = normal contrast intensity, 2 = mild reduction, 3 = moderate to severe reduction, and 4 = absent contrast. Contrast score index was thus calculated by dividing the sum of the perfusion score of all analyzed segments by the number of segments analyzed. Reversible perfusion defect in a segment was defined as worsening of perfusion by $1 grade in the dysfunctional segments with significant perfusion (scores 1-3). Quantitative assessment of MCE was performed using QLab software (Philips Medical Systems). To minimize artifacts, the digitally acquired images were analyzed using the mid and apical portions of the 17-segment LV model, thus allowing for the analysis of 11 segments in each patient. A region of interest was drawn transmurally within each segment, avoiding the high-intensity epicardial and endocardial borders. Background subtracted plots of contrast intensity against time were created. Values for peak contrast intensity (representing relative myocardial capillary blood volume, A) and microbubble velocity (representing myocardial blood flow [MBF], b) were derived. MBF was then calculated by multiplying A by b. Coronary Angiography Coronary angiography was performed in all patients as part of their clinical workup for the management of LV dysfunction. Significant CAD was defined as a >50% luminal stenosis in $1 of the major epicardial coronary arteries assessed qualitatively, which is the standard practice in our hospital. Reporting of coronary angiograms was performed by the clinician undertaking the study. Patient Follow-Up Patients were followed up 3 to 6 months after revascularization for the assessment of improvement in resting LV function and, when appropriate, contractile reserve. Following resting transthoracic echocardiography, low-dose dobutamine echocardiography was performed to assess contractile reserve when significant wall motion abnormality persisted. Dobutamine infusion was started at 5 mg/kg/ min and increased in 3-minute intervals to 10 and then 15 mg/kg/ min. Images were digitally acquired in standard parasternal and apical views. Wall thickening was assessed in all 17 segments and analyzed with the same 4-point semiquantitative scoring system as at baseline. A previously dysfunctional segment was categorized as demonstrating HM if wall thickening had improved by $1 point between baseline and follow-up. Furthermore, segments that did not demonstrate improvement in resting function and did not improve following dobutamine were considered scar tissue. An improvement of wall motion score index of $30% after revascularization was defined as the presence of significant HM on per patient basis. 14,15 Contrast for LV opacification was administered to patients in whom $2 contiguous segments were inadequately visualized. Statistical Analysis Continuous variables are expressed as mean 6 SD and categorical variables as percentages. Logistic regression analysis was used to assess the quantitative and qualitative parameters on MCE and Table 1 Baseline patient demographics SPECT for the prediction of recovery of function. The effects of the various parameters were included in a multivariate model, in which factors with P values #.10 in the univariate analysis were included in the multivariate analysis to determine independent predictors of HM. Receiver operating characteristic (ROC) curves were plotted to determine the areas under the curves (AUCs) and the best cutoff values for parameters on MCE and SPECT for the prediction of recovery of function. Sensitivity and specificity for the detection of HM were obtained for each imaging modality on segmental and per patient bases. Statistical analysis was performed using SPSS version 14.0 (SPSS, Inc, Chicago, IL). RESULTS Entire cohort Revascularization cohort Variable (n = 39) (n = 23) Age (y) Men 35 (90%) 19 (82.6%) BMI (kg/m 2 ) Cardiac history Previous MI 26 (67%) 14 (61%) Previous CABG 4 (10%) Angina 17 (44%) 10 (43%) NYHA class Cardiac risk factors Hypertension 23 (59%) 16 (70%) Diabetes mellitus 20 (51%) 14 (61%) Smoking (previous or current) 14 (36%) 9 (39%) Hyperlipidemia 31 (79%) 18 (78%) Drug therapy Aspirin/clopidogrel 36 (92%) 23 (100%) ACE inhibitors/arbs 34 (87%) 21 (91%) b-blockers 23 (59%) 15 (65%) Statins 32 (82%) 19 (83%) Loop diuretics 35 (90%) 20 (87%) Spironolactone 14 (36%) 8 (35%) WMSI Baseline Follow-up ACE, Angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BMI, body mass index; CABG, coronary artery bypass grafting; MI, myocardial infarction; NYHA, New York Heart Association; WMSI, wall motion score index. Data are expressed as mean 6 SD or as number (percentage). Patient Demographics Of 39 patients with symptomatic ischemic cardiomyopathy, 27 underwent revascularization, and 12 continued on medical therapy alone. Of these 39 patients, 28 (72%) had severe 3-vessel disease, and 31 (80%) had $1 blocked major coronary artery. Of the 27 patients who underwent revascularization, 4 died prior to follow-up echocardiography (there were no periprocedural events). The demographics of all patients and the revascularized group are summarized in Table 1. These patients were recruited consecutively and hence represented the general ischemic cardiomyopathy population at our center.

4 Journal of the American Society of Echocardiography Volume 23 Number 8 Chelliah et al 843 Figure 2 ROC curves for the various quantitative parameters on MCE and SPECT for the prediction of recovery of segmental LV function. AUCs for A, b, and RMBF were 0.80, 0.66, and 0.78, respectively; AUC for single photon-emission computed tomographic score was Figure 1 Quantitative MCE in segments with and without HM. Of the 214 dysfunctional LV segments in the remaining 23 patients, 156 segments (73%) demonstrated HM. Sixteen of the 23 patients (70%) showed significant improvements in LV function. Quantitative and Qualitative MCE and HM A (peak contrast intensity), b (microbubble velocity), and resting MBF (RMBF) were significantly higher in HM compared with segments with scar (Figure 1). ROC curves were generated to assess the prediction of recovery of segmental LV function by the different myocardial contrast echocardiographic parameters. The AUCs for A, b, and RMBF were 0.80, 0.66, and 0.78, respectively (Figure 2). Using the ROC curves, the best cutoff points for the various myocardial contrast echocardiographic parameters were identified to give the best combination of sensitivity and specificity. The best cutoff values for A, b, and RMBF were 5.0 (sensitivity, 88%; specificity, 61%), 0.28 (sensitivity, 84%; specificity, 31%), and 1.34 (sensitivity, 88%; specificity, 50%). The qualitative myocardial contrast echocardiographic parameter of resting visual contrast score index was used to assess the prediction of recovery of global LV function, as defined above. ROC curve analysis showed an AUC of 0.82 (Figure 3). The best cu-off value to predict the recovery of LV function was a resting visual contrast score index of 2.26 (qualitative visual score # 3) (sensitivity, 94%; specificity, 58%). On a segmental basis, myocardial contrast echocardiographic scores of 1, 2, 3, and 4 predicted HM in 90%, 70%, 62%, and 30%, respectively, of the dysfunctional segments. Figure 3 ROC curves for qualitative resting myocardial contrast echocardiographic perfusion score index (AUC, 0.82) and qualitative single photon-emission computed tomographic perfusion score index (AUC, 0.63) for the prediction of recovery of LV function. Qualitative and Quantitative SPECT and HM Counts on SPECT were significantly higher in segments with HM than in segments with scar (Figure 4). An ROC curve was generated to assess the prediction of recovery of segmental LV function by quantitative SPECT (Figure 2). The AUC was The best cutoff value, determined on the basis of the best sensitivity and specificity, to predict the recovery of segmental LV function was a SPECT count score of 55% (sensitivity, 86%; specificity, 30%). Qualitative single photon-emission computed tomographic analysis using resting visual perfusion count index for the prediction of recovery of global LV function was performed. The AUC for the generated ROC was 0.63 (Figure 3). The best determined cutoff value to predict the recovery of global LV function was a visual perfusion count index of 1.08 (qualitative visual score $ 2) (sensitivity, 75%; specificity, 43%).

5 844 Chelliah et al Journal of the American Society of Echocardiography August 2010 Table 2 Predictors by MCE and SPECT for segmental detection of HM Variable HR (95% CI) P Qualitative analysis SPECT 0.79 ( ).06 MCE 0.55 ( ) <.0001 Quantitative analysis SPECT 1.01 ( ).25 MCE A 1.7 ( ) <.0001 b 4.13 ( ).004 RMBF 1.48 ( ) <.0001 Figure 4 Single photon-emission computed tomographic counts in HM versus necrotic myocardium. Comparison Between MCE and SPECT for the Prediction of HM Logistic regression analysis using MCE and SPECT showed that both qualitative and quantitative MCE but not SPECT were significant predictors for the segmental detection of HM (Table 2). Using clinical, LV functional, single photon-emission computed tomographic, and myocardial contrast echocardiographic data for predicting the recovery of global LV function (global HM) showed that MCE was the only significant univariate predictor and was the only independent predictor in a multivariate model (P =.03; Table 3). Reversible Defects Of the 449 dysfunctional segments in the 39 patients, vasodilator MCE demonstrated 380 segments (85%) with reversible defects, which was significantly higher compared with SPECT (P <.001), which detected 267 segments (59%). Among those revascularized, MCE demonstrated 169 reversible defects, of which 138 (82%) demonstrated recovery of segmental function, which was higher (P <.001) compared with SPECT, which demonstrated 42 reversible defects, of which 31 (73%) recovered function. The study results are summarized in a flow chart in Figure 5. Comparison Between Qualitative Single Photon-Emission Computed Tomographic Detection of HM and Quantitative Myocardial Contrast Echocardiographic Parameters A, b, and RMBF were significantly higher in segments with HM correctly predicted by SPECT (true positive) compared with segments with scar but SPECT-predicted HM (false positive). Similarly, A, b, and RMBF were significantly lower in segments with scarred segments that were correctly predicted by SPECT (true negative) compared with segments that demonstrated HM but SPECT deemed as scar (false-negative) (Table 4). DISCUSSION This is the first study to comprehensively compare both qualitative and quantitative MCE versus qualitative and quantitative SPECT for the detection of HM in patients with chronic ischemic cardiomyopathy. In this setting, MCE was superior to SPECT for the prediction CI, Confidence interval; HR, hazard ratio. of HM both at the segmental level and on a patient basis. Furthermore, our study showed that reversible ischemia detected by MCE was not only more prevalent compared with SPECT but also was more accurate in predicting HM compared with SPECT. This study further provided insights into the possible pathophysiologic mechanisms underlying the suboptimal detection of HM by SPECT. Mechanism of Detection of HM by MCE MCE detects contrast microbubbles at the capillary level within the myocardium, and capillary integrity is a marker of HM. 5 During a steady state of intravenous contrast infusion, signal intensity from contrast microbubbles represents relative capillary volume. 16 After a steady state is obtained, MBF derived from the time to peak contrast intensity curve correlates well with radiolabeled microsphere derived MBF and that obtained from positron emission tomography. 17,18 The degree of myocyte injury during myocardial ischemia is proportionally related to the degree of capillary damage. 19 Experimental and clinical studies have demonstrated that peak contrast intensity correlates well with the size and transmurality of infarction. 6,8 It has also been shown that in ischemic cardiomyopathy, peak contrast intensity detected by MCE is inversely proportional to fibrosis. 20 In our study, peak contrast intensity (capillary volume) and MBF were significantly higher in HM versus segments with fixed defects. The sensitivity and specificity of MCE for the detection of HM was similar to that obtained in a previous study. 9 Mechanism of Detection of HM by SPECT The detection of HM with SPECTrelies on the amount of radiotracer uptake. The quantity of radiotracer uptake by myocytes is related to capillary volume as well as mitochondrial activity (for 99m Tc) and the integrity of myocyte membrane (for 201 Tl), its extraction fraction, and MBF SPECT has extensive literature regarding the detection of HM Specificity for the detection of HM has been shown to be low in most studies. This was also demonstrated in our study. Furthermore, sensitivity for the prediction of improvement of global LV function has not always been shown to be high. Unlike MCE, nitrate needs to be preadministered to enhance the detection of HM, or in case of 201 Tl imaging, a late redistribution scan is required. Segments falsely identified as HM by SPECT (false positive) showed significantly lower capillary blood volume and MBF compared with true HM. Possible mechanisms for this include poor spatial

6 Journal of the American Society of Echocardiography Volume 23 Number 8 Chelliah et al 845 Figure 5 Flow diagram of analysis, per patient and per segment basis. Table 3 Univariate and multivariate predictors of improvement in LV function Univariate Multivariate Variable HR 95% CI P HR 95% CI P Clinical characteristics Age Sex BMI Medical history Previous MI Diabetes mellitus Hypertension Smoking Hyperlipidemia Echocardiographic parameters LVEF RWMSI MCE Qualitative SPECT Qualitative BMI, Body mass index; CI, confidence interval; HR, hazard ratio; LVEF, LV ejection fraction; MI, myocardial infarction; RWMSI, regional wall motion score index. resolution, resulting in overlapping regions of normal perfusion, and increased extraction rate of radiotracer due to decreased MBF. 29 Similarly, segments falsely identified as scar by SPECT (false negative) demonstrated significantly higher capillary blood volume and MBF Table 4 Detection of segmental HM by SPECT compared with quantitative myocardial contrast echocardiographic parameters True positive False positive False negative True negative Variable (n = 137) (n = 38) (n = 20) (n = 19) Peak contrast * value, A Microbubble * velocity, b MBF, A b * *P <.01 versus false positive. P <.01 versus true positive. compared with segments with true scar. The likely mechanism for this is partial volume effect due to the limited spatial resolution of the gamma cameras used (about mm). A previous study showed that an end-diastolic wall thickness < 10 mm produced significant perfusion defects despite the demonstration of normal myocardial perfusion by MCE. 30 In ischemic cardiomyopathy, akinetic but viable myocardium may have thinner than normal myocardium, which can result in partial volume effect. The spatial resolution of MCE is 2 to 4 mm. 30 Thus, a small subendocardial infarction may be detected by MCE but missed by SPECT. Wagner et al 31 clearly showed the inability of SPECT to detect subendocardial infarction compared with cardiac magnetic resonance imaging. Furthermore, because of a lack of temporal resolution, a resting single photonemission computed tomographic study, unlike MCE, is unable to assess MBF and hence may not accurately assess HM.

7 846 Chelliah et al Journal of the American Society of Echocardiography August 2010 Mechanism of Superior Detection of Reversible Ischemia by MCE Versus SPECT in HM MCE can detect capillary blood volume and by virtue of its temporal resolution can also assess MBF. During hyperemia, in the presence of flow-limiting stenosis, there is reduction of both capillary blood volume and blood velocity. Because of its superior spatial resolution, mild reductions in capillary blood volume are more readily detected by MCE compared with SPECT. 17,32 With SPECT, because of attenuation and Compton scatter, errors in count intensity during image acquisition are approximately 30%. This implies that a minimal perfusion defect of this magnitude must be present for its accurate detection by SPECT, when comparing stress and rest images. 32 This becomes even more apparent with already reduced single photon-emission computed tomographic counts at rest in thinner HM. Furthermore, blood velocity reduction is more severe than capillary volume change in mild to moderate coronary stenosis. 18 This allows MCE to detect ischemia even in the absence of significant capillary blood volume change because of its temporal resolution, which SPECT lacks. The accurate detection of ischemia is especially important in patients with LV dysfunction and moderate CAD, because these patients are more likely to demonstrate improved outcomes than those with no ischemia. The value of MCE for the diagnosis of ischemic versus nonischemic cardiomyopathy has recently been shown. 32,33 Limitations A limitation of this study is the relatively small number of patients involved, hence the possibility of type 2 error. This was more a proof of concept exercise than a definitive study trial. Therefore, larger studies are required to validate these results. These results also pertain to one single photon-emission computed tomographic radiotracer ( 99m Tc) and one ultrasound contrast agent (SonoVue), as well as one vasodilator agent (dipyridamole). Whether similar results are obtained with other agents remains to be seen. Also, the decision to revascularize or operate was based mainly on clinical grounds and coronary arteriographic data. However, the result of either dobutamine stress echocardiography or SPECT, but not both, was available at the time of decision making. Therefore, single photon-emission computed tomographic data may have been used in some patients. With regard to the definition of HM in our study, viable myocardium without flow-limiting coronary stenosis as opposed to reduced function associated with significant coronary stenosis could also have shown an improvement in function when stimulated with dobutamine. However, all those patients had severe CAD, and the dysfunctional myocardium is likely to be supplied by flow-limiting CAD. With regard to MCE, the analysis of the A value should be cautioned, because this value may vary with different machine settings, techniques, and flow rates of contrast infusion. CONCLUSION We have demonstrated that qualitative and quantitative MCE is superior to qualitative and quantitative SPECT in detecting HM in patients with ischemic cardiomyopathy and predicting the recovery of LV function. Revascularization of these segments resulted in an overall improvement in LV function. ACKNOWLEDGMENT We would like to thank all those involved in this study. REFERENCES 1. Rahimtoola SH. From coronary artery disease to heart failure: role of the hibernating myocardium. Am J Cardiol 1995;75(suppl):16E-22E. 2. Senior R, Raval U, Lahiri A. Technetium 99m-labelled sestamibi imaging reliably identifies retained contractile reserve in dyssynergic myocardial segments. J Nucl Cardiol 1995;2: Kaul S, Force T. Assessment of myocardial perfusion with contrast 2-dimensional echocardiography. In: Weyman A, editor. Principles and practice of echocardiography. Philadelphia, PA: Lea & Febiger; pp Janardhanan R, Swinburn JM, Greaves K, Senior R. Usefulness of myocardial contrast echocardiography using low power continuous imaging early after acute myocardial infarction to predict late functional recovery. Am J Cardiol 2003;92: Swinburn JM, Lahiri A, Senior R. Intravenous myocardial echocardiography predicts recovery of dyssynergic myocardium early after acute myocardial infarction. J Am Coll Cardiol 2001;38: Janardhanan R, Moon JC, Pennell DJ, Senior R. Myocardial contrast echocardiography accurately reflects transmurality of myocardial necrosis and predicts contractile reserve after acute myocardial infarction. Am Heart J 2005;149: Lafitte S, Higashiyama A, Masugata H, Peters B, Strachan M, Kwan OL, et al. Contrast echocardiography can assess risk area and infarct size during coronary occlusion and reperfusion: experimental validation. J Am Coll Cardiol 2002;39: Coggins MP, Sklenar J, Le DE, Wei K, Lindner JR, Kaul S. Noninvasive prediction of ultimate infarct size at the time of acute coronary occlusion based on the extent and magnitude of collateral-derived myocardial blood flow. Circulation 2001;104: Shimoni S, Frangogiannis N, Agelli C, Shan L, Verani MS, Quinones MA, et al. Identification of hibernating myocardium with quantitative intravenous myocardial contrast echocardiography. Comparison with dobutamine echocardiography and thallium-201 scintigraphy. Circulation 2003;107: Afridi I, Kleiman NS, Raizner AE, Zoghbi WA. Dobutamine echocardiography in myocardial hibernation. Optimal dose and accuracy in predicting recovery of ventricular function after coronary angioplasty. Circulation 1995;91: Lieberman AN, Weiss JL, Jugdutt BI, Bulkley LC, Bulkley BH, Garrison JG, et al. Two-dimensional echocardiography and infarct size: relationship of regional wall motion and thickening to the extent myocardial infarction in the dog. Circulation 1981;63: Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. AHA Writing Group on Myocardial Segmentation and Registration for Cardiac Imaging. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the cardiac imaging committee of the council on clinical cardiology of the AHA. Circulation 2002;105: Vivegnis BTD, Foulon J, Rigo P. Quantitative evaluation of myocardial single-photon emission computed tomographic imaging: application to the measurement of perfusion defect size and severity. Eur J Nucl Med 1996;23: Senior R, Kaul S, Lahiri A. Myocardial viability on echocardiography predicts long term survival after revascularization in patients with ischemic congestive heart failure. J Am Coll Cardiol 1999;33: Meluzín J, Cerný J, Frélich M, Stetka F, Spinarová L, Popelová J, et al. Prognostic value of the amount of dysfunctional but viable myocardium in revascularized patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 1998;32: Kassab GS, Lin DH, Fung YB. Topology and dimensions of pig coronary capillary network. Am J Physiol 1994;267(suppl):H

8 Journal of the American Society of Echocardiography Volume 23 Number 8 Chelliah et al Wei K, Firoozan S, Jayaweera AR, Skyba M, Linka A, Kaul S. Quantification of myocardial blood flow with ultrasound-induced destruction of microbubbles administered as a constant venous infusion. Circulation 1998; 97: Vogel R, Indermuhle A, Reinhardt J, Meier P, Siegrist PT, Namdar M, et al. The quantification of absolute myocardial perfusion in humans by contrast echocardiography. J Am Coll Cardiol 2005;45: Kloner RA, Rude RE, Carlson N, Maroko PR, DeBoer LW, Braunwald E. Ultrastructural evidence of microvascular damage and myocardial cell injury after coronary artery occlusion: which comes first? Circulation 1980; 62: Shimoni S, Frangogiannis NG, Agelli CJ, Shan K, Quinones MA, Espada R, et al. Microvascular structural correlates of myocardial contrast echocardiography in patients with coronary artery disease and left ventricular dysfunction. Circulation 2002;106: Glover DK, Beller GA, Cunningham M, Edwards NC, Ruiz M, Simanis JP, et al. Comparison between 201 Tl and 99m Tc sestamibi uptake during adenosine induced vasodilation as a function of coronary artery stenosis severity. Circulation 1995;91: Glover DK, Okada RD. Myocardial kinetics of Tc-MIBI in canine myocardium dipyridamole. Circulation 1990;81: Nielson AP, Bruno FP, Cobb FR, Morris KG, Murdock R. Linear relationship between the distribution of thallium-201 and blood flow in ischemic and nonischemic myocardium during exercise. Circulation 1980;61: Piwnica Worms D, Chiu ML, Kronauge JF. Uptake and retention of hexakis (2-methoxy-isobutyl isonitrile) technetium in cultured chick myocardial cell: mitochondrial and plasma membrane potential. Circulation 1974;82: Ragosta M, Beller GA, Watson DD, Kaul S, Gimple LW. Quantitative planar rest-redistribution 201 Tl imaging in detection of myocardial viability and prediction of improvement in left ventricular function after coronary bypass surgery in patients with severely depressed left ventricular function. Circulation 1993;87: Nagueh SF, Vaduganathan P, Ali N, Blaustein A, Verani MS, Winters WL, et al. Identification of hibernating myocardium: comparative accuracy of myocardial contrast echocardiography, rest-redistribution thallium-201 tomography and dobutamine echocardiography. J Am Coll Cardiol 1997;29: Qureshi U, Nagueh SF, Afridi I, Vaduganathan P, Blaustein A, Verani MS, et al. Dobutamine echocardiography and quantitative rest-redistribution 201 Tl tomography in myocardial hibernation: relation to contractile reserve to 201 Tl uptake and comparative prediction of recovery of function. Circulation 1997;95: Senior R, Kaul S, Raval U, Lahiri A. Impact of revascularization and myocardial viability determined by nitrate enhanced tc-99m sestamibi and Tl-201 imaging on mortality and functional outcome in ischemic cardiomyopathy. J Nucl Cardiol 2002;9: Mousa SA, Cooney JM, Williams SJ. Relationship between regional myocardial blood flow and the distribution of Tc-99-m-sestamibi in the presence of total coronary artery occlusion. Am Heart J 1990;119: Hayat SA, Dwivedi G, Jacobsen A, Lim TK, Kinsey C, Senior R. Effects of left bundle branch block on cardiac structure, function, perfusion and perfusion reserve. Implications for myocardial contrast echocardiography versus radionuclide perfusion imaging for the detection of coronary artery disease. Circulation 2008;117: Wei K, Le E, Bin JP, Coggins M, Jayawera, Kaul S. Mechanism of reversible 99m Tc-sestamibi perfusion defects during pharmacologically induced coronary vasodilation. Am J Physiol 2001;280:H Mor-Avi V, Koch R, Holper EM, Goonewardena S, Coon PD, Min JK, et al. Value of vasodilator stress myocardial contrast echocardiography and magnetic resonance imaging for the differential diagnosis of ischemic versus nonischemic cardiomyopathy. J Am Soc Echocardiogr 2008;21: Senior R, Janardhanan R, Jeetley P, Burden L. Myocardial contrast echocardiography for distinguishing ischemic from non-ischemic first-onset acute heart failure: insights into the mechanism of acute heart failure. Circulation 2005;112: