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. 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. 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 high-resolution 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 μg 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. 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. 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 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], β) were derived. MBF was then calculated by multiplying A by β.

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 μg/kg/min and increased in 3-minute intervals to 10 and then 15 μg/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. Contrast for LV opacification was administered to patients in whom ≥2 contiguous segments were inadequately visualized.

Statistical Analysis

Continuous variables are expressed as mean ± SD and categorical variables as percentages. Logistic regression analysis was used to assess the quantitative and qualitative parameters on MCE and 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).

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.

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), β (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 , β, 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 , β, and RMBF were 5.0 (sensitivity, 88%; specificity, 61%), 0.28 (sensitivity, 84%; specificity, 31%), and 1.34 (sensitivity, 88%; specificity, 50%).

Quantitative MCE in segments with and without HM.

ROC curves for the various quantitative parameters on MCE and SPECT for the prediction of recovery of segmental LV function. AUCs for A, β, and RMBF were 0.80, 0.66, and 0.78, respectively; AUC for single photon-emission computed tomographic score was 0.60.

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.

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 0.60. 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%).

Single photon-emission computed tomographic counts in HM versus necrotic myocardium.

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%).

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 ).

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	1.06	0.95-1.20	.30
Sex	0.36	0.039-3.26	.36
BMI	0.96	0.82-1.14	.67
Medical history
Previous MI	1.5	0.22-10.3	.68
Diabetes mellitus	0.61	0.09-3.78	.59
Hypertension	3.6	0.34-37.6	.28
Smoking	1.25	0.21-7.62	.22
Hyperlipidemia	0.19	0.02-1.57	.12
Echocardiographic parameters
LVEF	1.07	0.97-1.19	.10
RWMSI	0.16	0.01-1.51	.12
MCE
Qualitative	0.065	0.006-0.72	.02	0.04	0.002-0.7	.03
SPECT
Qualitative	0.34	0.047-2.46	.29

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