STATE-OF-THE-ART PAPER
Myocardial Contrast Echocardiography Evolving as a Clinically Feasible Technique for Accurate, Rapid, and Safe Assessment of Myocardial Perfusion
The Evidence So Far
Pieter A. Dijkmans, MD*,*,
Roxy Senior, MD, PhD
,
Harald Becher, MD, PhD
,
Thomas R. Porter, MD, PhD
,
Kevin Wei, MD||,
Cees A. Visser, MD, PhD* and
Otto Kamp, MD, PhD*
* Department of Cardiology, VU University Medical Center, Amsterdam, the Netherlands
Department of Cardiovascular Medicine, Northwick Park Hospital, Harrow, United Kingdom
Department of Cardiology, John Radcliffe Hospital, Headington, Oxford, United Kingdom
Section of Cardiology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
|| Oregon Health and Science University, Portland, Oregon.
Manuscript received February 28, 2006;
revised manuscript received April 21, 2006,
accepted May 15, 2006.
* Reprint requests and correspondence: Dr. Pieter A. Dijkmans, Department of Cardiology 6D-120, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, the Netherlands. (Email: pa.dijkmans{at}vumc.nl).
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Abstract
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Intravenous myocardial contrast echocardiography (MCE) is a recently developed technique for assessment of myocardial perfusion. Up to now, many studies have demonstrated that the sensitivity and specificity of qualitative assessment of myocardial perfusion by MCE in patients with acute and chronic ischemic heart disease are comparable with other techniques such as cardiac scintigraphy and dobutamine stress echocardiography. Furthermore, quantitative parameters of myocardial perfusion derived from MCE correlate well with the current clinical standard for this purpose, positron emission tomography. Myocardial contrast echocardiography provides a promising and valuable tool for assessment of myocardial perfusion. Although MCE has been primarily performed for medical research, its implementation in routine clinical care is evolving. This article is intended to give an overview of the current status of MCE.
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Abbreviations and Acronyms
| | ACS = acute coronary syndrome | | AMI = acute myocardial infarction | | CAD = coronary artery disease | | DSE = dobutamine stress echocardiography | | MBF = myocardial blood flow | | MBV = myocardial blood volume | | MCE = myocardial contrast echocardiography | | VI = video intensity |
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The use of ultrasound contrast agents for left ventricular opacification and myocardial perfusion in echocardiography has significantly improved the diagnostic accuracy of stress echocardiography. In the last decade, the clinical value of intravenous myocardial contrast echocardiography (MCE) in patients with both acute and chronic ischemic heart disease has been demonstrated. At the same time, experimental and clinical studies have demonstrated the physiologic basis for quantification of myocardial perfusion with MCE. In comparison with other imaging techniques, MCE is a rapid, easy-to-perform, and safe bedside technique for the assessment of myocardial perfusion. This article provides a review of the current status of MCE with respect to clinical value, practical issues, and conditions that need to be fulfilled for clinical implementation.
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MCE protocols
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Ultrasound contrast agents.
Since 1968, when the existence of ultrasound contrast was established, the development of ultrasound contrast agents has undergone significant advances. Initially, contrast agents were air-filled microbubbles, that were relatively unstable in the blood and could not pass the pulmonary capillary bed, rendering them unsuitable for the assessment of the left side of the heart during intravenous injection. Second-generation contrast agents were developed for this reason, containing a gas with low solubility and diffusibility and a shell of lipids, albumin, or galactose to prolong their life span. The microbubbles have a diameter less than that of a red blood cell, resist arterial pressure, and remain intravascular in the intact circulation. These properties allow passage of the pulmonary vasculature, opacification of the left ventricular cavity, and imaging of myocardial perfusion. Currently, the most used second-generation contrast agents are Sonovue (Bracco, Milan, Italy), Optison (Amersham Health AS, Oslo, Norway), and Definity (Bristol-Myers Squibb, Billerica, Massachusetts). These agents are licensed for left ventricular opacification only. These agents differ in terms of their shell constituents and gas content, that influence shell-stiffness and stability of the microbubble, and determine physical properties. All are suitable for MCE.
Physical principles.
The mechanism by which microbubbles enhance echocardiographic images, depends on their behavior under acoustic pressure. Low-energy ultrasound causes microbubbles to oscillate linearly, reflecting ultrasound at the insonation (fundamental or f
0) frequency. Ultrasound with an intermediate energy level induces nonlinear oscillations of microbubbles, resulting in generation of frequencies other than the fundamental frequency (multiples of the fundamental frequency) which are called harmonic frequencies (e.g., 2f
0). Finally, high-intensity ultrasound (within the energy levels used for diagnostic imaging) destroys microbubbles. In contrast to microbubbles, cardiac tissue produces much fewer harmonic frequencies, so selective reception of harmonic echos will preferentially detect signals emanating from contrast agent rather than the myocardium.
Imaging modalities.
Initial contrast imaging modalities relied mainly on harmonic imaging techniques, where fundamental frequencies were eliminated and harmonic frequencies were selectively detected. Although these methods improved the signal-to-noise ratio, off-line image processing was frequently required to evaluate myocardial perfusion, because tissue signals were still present. Harmonic imaging also used high acoustic powers that destroyed microbubbles—consequently, the imaging frame rate had to be reduced substantially with electrocardiographic triggering to allow microbubbles to replenish the myocardial microcirculation between pulses. Recently, several novel approaches to imaging microbubbles were developed: These include high-power modalities with superior tissue noise suppression that allow on-line assessment of myocardial perfusion and low-power modalities that permit imaging with high frame rates. These modalities specifically take advantage of the nonlinear behavior of microbubbles in an acoustic field. Many techniques use multiple transmitted pulses that are, e.g., full and half amplitude (power modulation (Fig. 1) to distinguish nonlinear microbubble signals from tissue (1). Reflected echos are scaled and subtracted. Because tissue responds linearly (especially at low acoustic powers), subtraction and scaling results in zero signal. Microbubbles reflect nonlinearly, so received echos will not be canceled out, enabling selective microbubble detection. Most of these multipulse techniques additionally use power Doppler, and the resulting signal is color coded and displayed (2).
Because high-power imaging destroys microbubbles, imaging of myocardial perfusion cannot be performed in real time. Low-power imaging (mechanical index <0.2) increases signal-to-noise ratio and because of minimal bubble destruction continuous imaging may be performed. Both high- and low-power MCE have their advantages and disadvantages. High-power imaging precludes continuous imaging owing to destruction of contrast, and therefore wall motion cannot be assessed simultaneously. On the other hand, signal-to-noise ratio is good. Low-power imaging allows simultaneous assessment of perfusion and contraction but has a lower sensitivity for the detection of microbubbles.
Stress agent.
The most commonly used stress agents are adenosine, dipyridamole, and dobutamine. All 3 agents have been used widely for pharmacologic stress during MCE. Although the working mechanism of these agents differ, all agents have a high diagnostic value for detection of coronary artery disease (CAD) (Tables 1 and 2).
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Table 1. Concordance of MCE and SPECT for Detection of Significant Coronary Artery Stenosis in Patients With Suspected Coronary Artery Disease
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Table 2. Sensitivity and Specificity of MCE and SPECT/DSE to Detect Stable Coronary Artery Disease: Gold Standard Angiography
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Assessment of myocardial perfusion
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Qualitative assessment.
During continuous infusion of microbubbles in a patient with intact coronary microvasculature and normal myocardial blood flow (MBF), destruction of microbubbles in the microcirculation by ultrasound is followed by relatively uniform contrast appearance in the coronary microcirculation, and homogenous opacification of the myocardium. In case of diminished epicardial flow, e.g., in significant CAD during stress, or after AMI, when microvascular integrity is affected, the speed and amount of contrast replenishment will be decreased. Earliest studies assessing MCE mainly used qualitative analysis in which contrast replenishment after microbubble destruction was scored as normal, reduced, or severely reduced. With such a scoring system, irreversible and reversible contrast defects in patients with flow-limiting CAD could be detected. Also, in patients with acute coronary syndrome (ACS), these scoring systems have proven their value in determining infarct size, viability, and prediction of functional recovery.
Quantitative assessment.
Because the microvascular rheology of microbubbles is similar to that of red blood cells, assessment of the transit of microbubbles through the coronary microcirculation with MCE should allow quantification of MBF (3). The first in vivo studies assessing quantification of MBF with MCE used bolus injections of microbubbles (4–6). The ratio of video intensity (VI) in diseased/nondiseased vascular territories correlated well with radiolabeled microsphere-derived blood flow ratios. The use of bolus injections of microbubbles, however, allows assessment of only relative differences in MBF and not absolute MBF. This limitation was overcome with continuous microbubble infusions, which allow a steady-state microbubble concentration to be reached in the blood. At this time, after microbubbles are destroyed by ultrasound, the subsequent replenishment of microbubbles into the ultrasound beam elevation will reflect MBF. The replenishment of contrast can be characterized by a time-intensity curve (Figs. 2 and 3), which can be fitted to a monoexponential function: y = A(1 – eßt). The reappearance rate of microbubbles, reflected by the slope of the replenishment curve (ß), provides a measure of mean myocardial microbubble velocity, and the plateau value (A) of the replenishment curve reflects the microvascular cross-sectional area (7). The product of A and ß therefore represents MBF. Animal studies using a coronary stenosis model demonstrated that the MCE estimate of MBF correlates very well with absolute MBF as measured with radiolabeled fluorescent microspheres (8–10). During pharmacologic stress, impaired hyperemic flow in the presence of coronary stenosis was associated with decreases in both A and ß. Thus, abnormalities in either MBF velocity or MBV during stress can be used to detect and quantify stenosis severity. In dogs, quantification by triggered MCE appeared to be accurate enough to make a distinction between endo- and epicardial flow (11). In humans, similar results were found (12). Myocardial blood flow reserve decreased in a step-wise manner in mild, moderate, and severe stenosis. Quantitative measures of MCE can not only be used to estimate stenosis severity, they can also be used to assess perfusion defect after AMI or to predict recovery of hibernating myocardium (13,14).
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Figure 2 Example of adenosine stress myocardial contrast echocardiography (subsequent end-systolic frames) with region of interest for quantification the apical 3-chamber view. (A) Baseline; (B) contrast destruction; (C to H) contrast replenishment.
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Absolute MBF in ml/min/g of tissue can be derived using MCE (14). Vogel et al. (15) have shown that myocardial blood volume (MBV) fraction can be derived from the ratio of myocardial video intensity and that of the adjacent left ventricular cavity. This method adjusts for inhomogeneous contrast enhancement of the myocardium due to technical factors such as attenuation. The MBV fraction can then be used to derive absolute MBF (MBF = relative blood volume x ß/tissue density, where the relative blood volume is Amyocardium/Acavity). In that study, MCE-derived absolute MBF was compared with positron emission tomography and showed excellent correlations.
A new application of quantitative MCE is generation of parametric images derived from contrast-enhanced images (16). These images contain information about the quality of acquisition, the maximal intensity of contrast in the myocardium, and the speed of contrast replenishment (Fig. 4) and allows fast visual interpretation of myocardial perfusion.
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Figure 4 Parametric image of apical 4-chamber view, containing information about (A) peak intensity, (B) slope of replenishment curve, (C) estimate of myocardial blood flow, and (D) quality of data.
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MCE in detecting stable coronary artery disease
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In normally perfused myocardium, the rate of capillary blood flow is 1 mm/s. Saturation of the coronary microvasculature by microbubbles therefore takes about 5 s (because the thickness of the ultrasound beam is approximately 5 mm). When there is no flow limiting stenosis, MBF increases 5 times during hyperemia (stress testing), and therefore the myocardium replenishes in 1 s. In addition, a flow-limiting stenosis leads to a reduction in capillary blood volume in the distal microvasculature, with an accompanying decrease in signal intensity during MCE. These 2 features (slowed contrast appearance and decreased capillary blood volume) form the basis for detecting CAD using MCE.
One of the first studies assessing MCE with triggered imaging in stable CAD patients showed that MCE can define the presence of abnormal perfusion at rest and during pharmacologic stress, with a high concordance between MCE and 99mTc-sestamibi single photon emission computerized tomography (SPECT) (17). Also, comparison of accelerated intermittent imaging at rest and with exercise to 99mTc-sestamibi-SPECT demonstrated a concordance of 76% to 92% (18). Several other studies assessed the accuracy of MCE and SPECT/dobutamine stress echocardiography (DSE) for detection of stable CAD. In general, agreements are high, ranging from 65% to 92% (19–27) (Table 1).
A number of these studies employed angiography as the gold standard (Table 2). Most reported a sensitivity of MCE for CAD detection that is similar to or higher than SPECT/DSE, ranging from 64% to 97%, compared with 33% to 100% for the latter (18,19,21,22,24,27–31). Furthermore, the addition of MCE may improve sensitivity for detection of CAD over wall motion analysis during DSE (18,29,31,32). We performed a meta-analysis of these studies and determined that the sensitivity and specificity of MCE for detection of CAD are at least not inferior to SPECT/DSE (Table 2, Fig. 5).
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Figure 5 We conducted a meta-analysis of 8 studies (PubMed reference lists, restricted to English-language literature) assessing the sensitivity and specificity of myocardial contrast echocardiography (MCE) and single-photon emission computed tomography (SPECT)/dobutamine stress echocardiography (DSE) for detection of significant coronary artery disease (CAD) that were published before January 2006. The text words used were "myocardial contrast echocardiography," "single-photon emission computerized tomography," "dobutamine stress echocardiography," and "stress echocardiography." Studies were included when coronary angiography was used as gold standard and if results were analyzed on a patient-based analysis. RevMan 4.2 of the Cochrane Collaboration Group was used to calculate variance-weighted pooled difference of proportions for the differences in sensitivity and specificity between MCE and SPECT/DSE according to a random effect meta-analysis. The pooled estimates of the differences in sensitivity and specificity were 0.14 (95% confidence interval [CI] 0.09 to 0.20) and 0.03 (95% CI –0.14 to 0.21), respectively, indicating a higher sensitivity for MCE than for SPECT/DSE. No difference was found for the specificity. n/N = number of patients with CAD detected by MCE or SPECT/DSE divided by the total number of patients with CAD; RD = risk difference. * indicates DSE.
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Myocardial contrast echocardiography also provides prognostic value in patients with stable CAD (33). Patients with normal perfusion have a better outcome than patients with normal wall motion. This underscores the value of incorporating MCE in stress echocardiography. An example of a perfusion defect with real-time perfusion during DSE is shown in Figure 6.
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Figure 6 Example of dobutamine stress contrast echocardiography. Reversible posterior/apical (apical 3-cv, A3C) and inferior/apical (apical 2-cv, A2C) perfusion defect during peak stress (arrows). Coronary angiography (angio) demonstrates corresponding significant stenoses in the left anterior descending, left circumflex (posteroapical defect), and right coronary arteries (inferoapical defect).
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MCE in acute coronary syndromes
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Currently, the diagnosis of ACS is based on the triad of clinical history, electrocardiography, and laboratory investigation. These methods, although useful, can often be nondiagnostic in this setting. Because MCE is the only technique that permits immediate assessment of wall motion and perfusion, it has a unique role in the diagnosis of ACS. Myocardial contrast echocardiography allows quick evaluation of myocardial perfusion in the emergency department and may be used to triage patients into a low- or high-risk category. The value of MCE in acute coronary syndromes has been studied experimentally using coronary balloon occlusions in pigs. Myocardial contrast echocardiography accurately reflects the decrease in myocardial perfusion during balloon occlusion compared with microsphere-derived MBF (1). Studies have also shown that during coronary occlusion the area at risk correlates closely with the contrast defect early after contrast flash destruction and that the plateau contrast defect identifies infarct size (34). Kamp et al. (35) were the first to report the sensitivity of MCE to detect perfusion defects in patients suspected of having AMI. With 1:1 end-systolic–triggered imaging, MCE perfusion defects were detected in 19 of 32 patients (59%) with Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 before percutaneous transluminal coronary angioplasty (35). The sensitivity of MCE tended to decrease when patients had better TIMI flow and inferior infarctions (20%), whereas the sensitivity of MCE in patients with an anterior coronary artery occlusion was high (88%). Other studies assessing the potential of MCE to acute coronary syndromes also reported high sensitivities, comparable with those of standard echocardiography and SPECT (35–43) (Table 3). In addition, MCE appears to have important prognostic value in patients presenting to the emergency department with acute chest pain (38–43).
Besides detection of acute ischemic heart disease, MCE may play a pivotal role in prediction of functional recovery in patients after ST-segment elevation myocardial infarction. The severity of myocardial damage is currently mainly estimated by enzymatic damage and wall motion score, whereas recovery of myocardial function is importantly dependent on reflow of blood to the risk area. The presence of reflow after coronary angioplasty is suggested by resolution of chest pain and the degree of resolution of ST-segment elevation but can be visualized by MCE (Fig. 7). Kloner (44) was the first to demonstrate the deleterious effect of no-reflow on clinical outcome. Later, it was shown that the presence of no-reflow on MCE after AMI related to absence of pre-infarction angina, number of Q waves, wall motion score at presentation, TIMI flow grade 0, the size of the area at risk, and the occlusion status of the culprit artery (45). Conversely, intact microvasculature after AMI (reflow), is a positive predictor of functional recovery (46). Patients without microvascular dysfunction on MCE have less enzymatic elevation, better functional performance, better recovery of global and regional wall motion, less remodeling, and better survival independent of other predictors (47–49). The ability of MCE to predict functional recovery is summarized in Table 4
(50–63) and is comparable to that of cardiovascular magnetic resonance imaging (64,65) (Fig. 8). Thus the existing literature suggests that MCE has important additional value for diagnosis and risk stratification in patients with acute ischemic heart disease.
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Table 4. Prediction of Recovery of Regional and Global Function and Prediction of Events by MCE in Patients After Acute Myocardial Infarction
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Figure 8 Fixed septal/apical perfusion defect (arrows) with myocardial contrast echocardiography (left), single photon emission computed tomography (middle), and delayed enhancement with magnetic resonance imaging (right) after myocardial infarction.
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Targeted imaging with ultrasound contrast
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Recently, "targeted microbubbles" have been developed by incorporating ligands in the microbubble shell. Experimental studies demonstrated that specific ligands to intercellular adhesion molecule 1 (ICAM-1) and glycoprotein IIb/IIIa enabled these targeted agents to bind selectively to ICAM-1–expressing tissue and thrombus, respectively (66,67). Because expression of ICAM-1 is associated with early atherosclerosis, targeted imaging could possibly play a role in diagnosis of preclinical atherosclerosis. Imaging of thrombus enables us to localize vascular clots in humans noninvasively. Furthermore, lipid microbubbles with phosphatidylserine in the microbubble shell appear to attach to inflamed tissue (68). Localized attachment of targeted ultrasound contrast to specific tissue creates great opportunities for development of new diagnostic tools and treatment modalities (targeted drug delivery).
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Safety
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The most important study assessing the safety of MCE was performed by Tsutsui et al. (69). More than 1,500 patients underwent dobutamine stress MCE with low-mechanical-index real-time perfusion, during which no major adverse events were seen. Myocardial contrast echocardiography has a similar safety profile as dobutamine stress echocardiography. In patients with heart failure, intravenous contrast did not show any deleterious hemodynamic effects compared with placebo (70). The occurrence of premature ventricular contractions, especially during end-systolic high-mechanical-index imaging, has been a matter of concern. However, data regarding this aspect are conflicting, and, because significant arrhythmias during MCE are observed rarely, the clinical significance is doubtful (71).
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Practical issues
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Myocardial contrast echocardiography is a relatively simple technique for imaging of myocardial perfusion. However, there is a learning curve as with all noninvasive techniques. Because perfusion of the myocardium is assessed in 1 specific region, it is important to keep the transducer still to minimize movement of the heart. In contrast to real-time imaging, triggered imaging does not allow continuous visualization of the heart (unless the system is equipped with monitoring mode). Especially with this technique, the quality of the images improves with more experience. Training is also required for interpretation.
When performing MCE, infusion pump, blood pressure, and heart rate monitoring must be available. Stress testing with the stressors mentioned in the preceding is safe, and the excellent safety profile is not expected to change when used in contrast echocardiography. However, a physician needs to be present to monitor the well-being of the patient (72). Emergency medication and facilities should be present in case of adverse events, which occur rarely.
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Future perspectives
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Real-time 3-dimensional myocardial perfusion echocardiography.
A promising tool within MCE is the development of real-time 3-dimensional perfusion echocardiography (73). The current matrix transducers use a more homogeneous ultrasound field, which improves image quality, and acquire a full volume instead of 1 scanning plane. Image interpretation is favored by slicing the myocardium in the appropriate view, by which perfusion defects can be visualized in any chosen myocardial region.
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Conclusions
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In the past 10 years, MCE has developed from a research tool to a clinically valuable technique in patients with known or suspected CAD. It is a rapid, safe, and accurate method for imaging of myocardial perfusion and can be used for qualitative and quantitative assessment of MBF. Large prospective multicenter trials would probably facilitate formal approval and more widespread acceptance of MCE.
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