Myocardial contrast echocardiography in acute coronary syndromes

Cardiol Clin 22 (2004) 253–267

Myocardial contrast echocardiography in acute coronary syndromes Roxy Senior, MD, DM, FRCP, FESC, FACCa, Flordeliza Villanueva, MD, FACCb, Mani A. Vannan, MBBS, FACCc a Northwick Park Hospital, Watford Road, Harrow, HA1 3UJ, UK University of Pittsburgh Cardiovascular Institute, 200 Lothrop Street, Pittsburgh, PA 15213, USA c University of California, Irvine, 101 The City Drive, Building 53, Route 81, Orange, CA 92868-4080, USA b

Patients presenting to the emergency department with chest pain of probable cardiac origin may be broadly classified into two groups: acute myocardial infarction with ST elevation (STEMI) and acute myocardial infarction without ST elevation (non-STEMI). The approach and the type of management in these two groups differ. Acute myocardial infarction with ST elevation The ultimate goal of therapy in acute myocardial infarction (AMI) is to salvage as much myocardium as possible with the least possible risk to the patient. In the immediate aftermath of thrombolytic therapy, the clinician must determine whether the infarct-related artery (IRA) is patent and, if so, whether successful myocardial reperfusion has been achieved. Addressing these questions expeditiously is important for subsequent treatment strategies (eg, if thrombolytic therapy has failed, the patient may be transferred for rescue coronary intervention). Furthermore, even when the patency of the IRA is restored either by percutaneous coronary intervention (PCI) or thrombolytic therapy, one must determine whether microvascular perfusion is present. It is also important to identify the presence and extent of residual myocardial viability following AMI, especially after thrombolysis, because subsequent revascularization may not benefit patients with predominant myocardial necrosis, whereas those

E-mail address: [email protected] (R. Senior).

with significant myocardial viability are likely to benefit from revascularization. Myocardial contrast echocardiography Myocardial contrast echocardiography (MCE) is a technique that uses microbubbles during echocardiography [1]. These microbubbles remain entirely within the intravascular space, and their presence within any myocardial region denotes the status of microvascular perfusion within that region [2,3]. The volume of blood present in the entire coronary circulation (arteries, arterioles, capillaries, venules, and veins) is approximately 12 mL/100 g of cardiac muscle [4]. Approximately one third of this blood is present within the myocardium itself and is termed myocardial blood volume [5]. The predominant (90%) component of the myocardial blood volume resides in the capillaries [6]. The myocardial signal is assessed visually because contrast intensity reflects the concentration of microbubbles within the myocardium. When the entire myocardium is fully replenished during the continuous infusion of microbubbles, the signal intensity denotes the capillary blood volume [6–8]. Any alteration of signal in this situation must, therefore, occur principally from change in capillary blood volume. Furthermore, it has been shown that, after destruction of microbubbles in the myocardium during high-power imaging, the replenishment of the myocardium takes approximately 5 seconds at rest [8]. A decrease in myocardial blood flow prolongs replenishment time proportionately to the reduction of myocardial blood flow [6].

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Myocardial perfusion is defined as tissue blood flow at the capillary level. The two components of tissue blood flow are capillary blood volume and microbubble velocity (ie, rate of microbubble replenishment following destruction of microbubbles). The product of these two components denotes myocardial blood flow at the tissue level [9]. Thus, MCE can detect capillary blood volume and, by virtue of its temporal resolution, can also assess myocardial blood flow. The technique by which myocardial blood flow may be assessed is described elsewhere in this issue. Briefly, a series of high-energy ultrasound pulses is delivered to destroy microbubbles in the myocardium. Ultrasound imaging is then continued either intermittently (during high-power imag-

ing) [6,7] or continuously (during low-power imaging) [10] to observe contrast intensity and microbubble velocity. The product of peak contrast intensity and microbubble velocity gives the measure of myocardial blood flow [8]. Pathophysiology of ST elevation and relevance to myocardial contrast echocardiography The extent of myocardial necrosis after AMI is directly related to (1) the total duration of coronary occlusion, (2) the extent of myocardium subtended by the occluded artery, and (3) the quality of collateral circulation. Thus, following AMI the progression of myocardial necrosis may

Fig. 1. Examples of successful reperfusion with no infarction and, hence, complete myocardial salvage in a dog receiving left atrial injection of contrast and dipyridamole infusion. An anterior perfusion defect is noted on myocardial contrast echocardiography during left anterior descending coronary artery occlusion (A), with a corresponding defect on Technetium autoradiography (B). After reperfusion, no defect is noted on myocardial contrast echocardiography (C), and no infarction is noted on postmortem triphenyl tetrazolium chloride staining of the heart (D). (From Villanueva FS, Glasheen WD, Sklenar J, et al. Characterization of spatial patterns of flow within the reperfused myocardium using myocardial contrast echocardiography: implications in determining the extent of myocardial salvage. Circulation 1993;88:2596–606; with permission.)

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be halted if the IRA opens either spontaneously or after reperfusion therapy or if there is sufficient collateral circulation supplying the jeopardized region despite occluded artery. Prolonged ischemia may result in the failure to establish microvascular reperfusion (low-reflow or no-reflow states) despite restoration of epicardial coronary patency [11]. The no-reflow state is a marker of myocyte necrosis and hence lack of residual myocardial viability [11]. In the immediate reperfusion period, however, coronary hyperemia may occur and may result in underestimation of myocardial necrosis by any technique that uses intravascular tracers such as MCE [9]. Finally, the magnitude and spatial extent of the no-reflow phenomenon varies over time [9]. This dynamic feature of postischemic flow must be taken into account in determining the appropriate timing and interpretation of MCE following AMI.

Application of myocardial contrast echocardiography in acute myocardial infarction with ST elevation Determination of ultimate infarct size at the time of acute myocardial infarction Patients presenting with on-going chest pain and ST elevation in the ECG need emergent reperfusion therapy. There are, however, patients who present in the emergency room in whom chest pain has resolved despite persistent ST elevation. Under these circumstances it is important to determine whether the myocardium is at risk of necrosis. If so, emergent perfusion therapy is required. Coggins et al [12] found that the size of the defect visualized by MCE late after the destruction-replenishment sequence corresponded to the ultimate infarct size and that myocardial blood flow assessed by MCE accurately predicted collateral blood flow during acute coronary occlusion [5]. Thus it may be speculated that those with extensive collateral myocardial blood flow need not undergo emergent revascularization as long as they are hemodynamically stable. Assessment of infarct-related artery patency IRA patency may not be achieved in approximately 30% of patients after thrombolytic therapy. Clinical predictors (eg, resolution of chest pain, resolution of ST elevation, and amount of cardiac enzyme release) for detecting IRA patency immediately after thrombolysis have limited accuracy [13]. IRA patency can be determined with MCE

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based on the physiologic considerations described previously. During acute total coronary occlusion in the absence of collateral flow, a transmural contrast perfusion defect occurs as shown in Fig. 1 [14]. After reperfusion the defect will no longer be transmural. Whether infarction is absent (Fig. 1) or present (Fig. 2), the contrast defect will be smaller than that seen during occlusion as a result of regions of postischemic hyperemia, sparing of an epicardial rim of viable tissue, or both [14]. Thus, if MCE is performed before and after reperfusion therapy, the IRA patency can be determined by comparing the transmural extent of the defects in each image. If the IRA patency is not restored after thrombolysis, the patient may be referred urgently for rescue PCI. This approach will result in appropriate triaging of patients who would benefit most from rescue PCI. On the other hand, if the IRA patency is restored, one can predict the extent of myocardial necrosis. In an experimental model, MCE performed late (3 hours) but not early after restoration of IRA (after abatement of coronary hyperemia) showed the best predictive value for ultimate infarct size [15]. In a study performed by Greaves et al [16], MCE, performed 24 hours after restoration of IRA patency with PCI was found to be superior to clinical and angiographic predictors of myocardial perfusion. The identification and quantification of these areas of tissue viability allows clinicians to risk stratifying patients and target those likely to benefit from aggressive medical treatment. On the other hand, if no microvascular reflow can be demonstrated, treatment to improve microvascular flow may be necessary (Fig. 3). Such treatments are being investigated. Assessment of myocardial viability after acute myocardial infarction Ragosta et al [17] noted that patients with patent IRA and good contrast intensity (microvascular volume) demonstrated improvement in contractile function compared with those patients with poor contrast score 1 month after AMI [17]. Janardhanan et al [18] similarly showed that the extent and severity of contrast defects after AMI showed a strong inverse correlation with recovery of function at 3 months after revascularization (Fig. 4). Ito et al [19] noted that in the 25% of their patient cohort with no myocardial opacification, despite a patent IRA, regional and global function were worse 1 month later than in those

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Fig. 2. Successful reperfusion with partial myocardial salvage in a dog receiving left atrial injection of contrast during dipyridamole infusion. An anterior perfusion defect is noted on myocardial contrast echocardiography during left anterior descending coronary artery occlusion (A), with a corresponding defect on Technetium autoradiography (B). After reperfusion, an endocardial defect is noted on myocardial contrast echocardiography (C), and a subendocardial infarction is noted on postmortem triphenyl tetrazolium chloride staining of the heart (D). (From Villanueva FS, Glasheen WD, Sklenar J, et al. Characterization of spatial patterns of flow within the reperfused myocardium using myocardial contrast echocardiography: implications in determining the extent of myocardial salvage. Circulation 1993;88:2596–606; with permission.)

showing opacification of the infarct bed. These studies established the value of intact microvasculature after AMI as assessed by MCE to predict myocardial viability. Indeed Shimoni et al [20] confirmed that MCE indices of myocardial blood velocity and flow correlate with histologically determined microvascular density, capillary area, and collagen content in patients with coronary artery disease and chronic left ventricular (LV) dysfunction. Myocardial blood flow may be normal or reduced in predominantly viable myocardium, however, if there is a severe flow-limiting stenosis of the IRA, partial microembolization to distal vessels despite a patent IRA and in the presence of collateral blood flow to the infarct bed [20,21].

Thus, when myocardial blood flow is reduced but is sufficient to maintain microvascular integrity, one should allow enough time for contrast microbubbles to transit to the capillaries after the initial phase of microbubble destruction (Fig. 4). In a study of 98 patients after AMI, Swinburn et al [22], found contrast intensity assessed early after microbubble destruction is a poor predictor of microvascular integrity compared with contrast intensity assessed late after microbubble destruction. This was also shown by both Coggins et al [12] and Laffitte et al [15] found that, for optimal assessment of microvascular integrity, assessment of contrast intensity should be continued for up to 15 cardiac cycles following the destructive phase because of variability in myocardial blood flow in the infarct-

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Fig. 3. (Upper panel ) (A) Apical four-chamber view in systole showing akinetic septum and apex (arrows) 12 hours after successful primary transluminal coronary angioplasty (PTCA). (B) Homogeneous contrast opacification of the akinetic segments. (C) Follow-up echocardiography at 1 month, showing recovery of function of these segments (arrows) with reduction of left ventricular end systolic value. (Lower panel ) (A) Apical four-chamber view in systole showing akinetic mid-septum and apex (arrows) 12 hours after successful PTCA. (B) No contrast opacification seen in mid-septum and apex. (C) Follow-up echocardiography at 1 month, showing lack of recovery of function of these segments (arrows) with no change in left ventricular end systolic volume. (From Greaves K, Dixon SR, Fejka M, et al. Myocardial contrast echocardiography is superior to other known modalities for assessing myocardial perfusion after acute myocardial infarction. Heart 2003;89:139–44; with permission.)

related region. In a clinical study of 50 patients with AMI, Janardhanan et al [18] assessed myocardial contrast intensity for 15 cardiac cycles after destructive imaging. They showed that absence of contrast opacification virtually rules out subsequent recovery of function. Fig. 5 shows an example of two patients with AMI, with and without contrast opacification in akinetic segments at 15 cardiac cycles after destruction imaging. The former patient recovered function; the latter remained akinetic. Although such assessment of microvascular integrity is a reliable indicator of myocardial viability, it may not be able to discriminate normal tissue from minor tissue damage. In a study by Coggins et al [12], the authors assessed final infarct size during AMI with MCE. They performed quantitative analysis using peak contrast intensity, rate of microbubble replenishment (b) following

destruction, and MCE-derived myocardial blood flow. They found that the most significant parameter that predicted mild versus moderate reduction of myocardial blood flow assessed by radiolabeled microspheres was the rate of microbubble replenishment and myocardial blood flow derived from the product of peak contrast intensity and the b value. In another study, Janardhanan et al [23] also showed that microbubble velocity was the strongest predictor of contractile reserve in patients after AMI. This finding is not surprising, because the b value has a stronger relationship with myocardial blood flow than peak contrast intensity. Also, the threshold effect and indistinguishable background noise may result in the failure of contrast intensity to detect differences between normal and mildly reduced microvascular volume in small infarctions. Because myocardial blood flow is

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Fig. 4. The importance of imaging intervals to determine the extent of perfusion defect in reperfused acute MI: end-systolic frames of intravenous contrast infusion MCE (MI 0.2) in the parasternal short-axis views, 3 days after primary transluminal coronary angioplasty of the left anterior descending coronary artery (LAD) with TIMI 3 flow are shown. (A) the frame immediately before bubble destruction. (B) Bubble destruction (transient MI of 1.4). (C) the frame immediately after bubble destruction. Note the absence of myocardial bubbles in the LAD region. Subsequently, there is progressive filling of the LAD territory so that the perfusion defect that appears large and nearly transmural at 3 seconds is smaller and non-transmural at 8 seconds. (From Verjans JW, Narula N, Loyd A, et al. Myocardial contrast echocardiography in acute myocardial infarction. Curr Opin Cardiol 2003;18:346–50; with permission).

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Fig. 5. (Left panel) End-systolic (ES) frames of the apical three-chamber view showing (A) akinetic mid-anterior septum and apex (arrows); (B) Immediately after high mechanical index destruction frame on MCE; (C) Lack of contrast opacification of the dysynergic segments even at 15 cardiac cycles (arrows); (D) Lack of functional recovery at 12 weeks despite revascularization (arrows). (Right panel) ES frames of the apical four-chamber view showing (A) akinetic mid-septum, apex, and mid-lateral segments (arrows); (B) complete destruction of myocardial contrast immediately after a high mechanical index pulse on MCE; (C) homogenous contrast opacification of the dysynergic segments by 15 cardiac cycles (arrows); (D) functional recovery at 12 weeks after revascularization (arrows). (From Janardhanan R, Swinburn J, Greaves K, et al. Usefulness of myocardial contrast echocardiography using low-power continuous imaging early after acute myocardial infarction to predict late functional left ventricular recovery. Am J Cardiol 2003;92:493–7; with permission.)

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Fig. 6. Late, reversible no reflow and its impact on ventricular remodeling and function. This 62-year-old woman had a perioperative acute anterior MI during hip arthroplasty and underwent primary PTCA of the left descending coronary artery (LAD) with TIMI 3 flow. MCE with intravenous contrast in the apical four-chamber view is shown. The upper panel views (A, B, and C) are from day 5 after LAD intervention. Note the dilated and remodeled, spherical-shaped LV apex (arrows) in end-systolic frame A. Contrast in LV cavity in B further emphasizes the abnormal apex, and the MCE in C shows an area of nontransmural no reflow (arrows) at the apex. Note the rim of epicardial re-reflow. The lower panel (D, E, and F ) is from a study done 8 weeks after the LAD intervention. No further intervention was done in the intervening period except for usual post-MI pharmacotherapy. Note the significant reverse remodeling of the LV apex (conical shape) in end-systolic frame in A, which is further exemplified in contrast-LVO frame B. This remodeling was accompanied nearly normal perfusion of the LV apex (arrows). The LV systolic function also improved from an estimated ejection fraction of 30% on day 5 to normal at 8 weeks. (From Verjans JW, Narula N, Loyd A, et al. Myocardial contrast echocardiography in acute myocardial infarction. Curr Opin Cardiol 2003;18:346–50; with permission).

invariably reduced even in minor infarctions, microbubble velocity will be reduced and is more easily detectable. Furthermore, even as early as 1 week after AMI, a state of myocardial hibernation may ensue as the result of repetitive silent ischemia caused by the persistence of critical flow-limiting IRA stenosis. The result may be reduced resting myocardial blood flow and persistent myocardial dysfunction. Thus, despite similar microvascular volumes, higher myocardial blood velocity, which translates into higher myocardial blood flow, may maintain a higher degree of myocardial viability. Effect of timing of myocardial contrast echocardiography on accuracy to predict myocardial viability Restoration of epicardial coronary flow in the infarct-related region early after AMI may result

in coronary hyperemia that lasts for 3 to 6 hours [24]. Reactive coronary hyperemia results in underestimation of myocardial necrosis and hence in overestimation of myocardial viability. Reactive hyperemia disappears about 3 to 6 hours after primary coronary intervention. The addition of the pharmacologic stress of dipyridamole to MCE performed at 3 hours most accurately predicts infarct size, probably because even infracted areas with perfusion immediately after reflow have impaired flow reserve, resulting in a perfusion defect during pharmacologic hyperemia [25]. Furthermore, such assessments during pharmacologic stress can predict infarct size even earlier than 3 hours into reflow. The degree of coronary hyperemia is invariably related to the extent of myocardial necrosis and is directly related to the

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Accuracy of myocardial contrast echocardiography to predict myocardial viability after acute myocardial infarction Several studies using both intracoronary and intravenous MCE have demonstrated high sensitivity (75%–90%) but poorer specificity (50%– 60%) in identifying recovery of contractile function after AMI. Most of these studies consisted of patients studied early after reperfusion and assessed by resting function. The combination of reactive hyperemia, dynamic changes in the microcirculation early after AMI, and the fact that myocardial infarction involving more than 20% of the subendocardium can render the myocardium akinetic despite significant epicardial and midmyocardial viability [32] apparently tend to make MCE less specific for detection of myocardial viability if viability is defined in terms of recovery of systolic function. Technical factors such as inability to distinguish microbubble signature from the underlying tissue also contribute to the low specificity of MCE. Recent studies have shown that assessing patients 3 to 5 days after AMI and assessment of contractile reserve using background subtraction techniques, either on-line (low-power or highpower imaging) or off-line, considerably improved the specificity (80%–90%) and positive predictive value (85%–90%) of MCE [33,34]. Balcells et al [35] assessed grades of perfusion 3 to 5 days after PCI and correlated them with contractile reserve assessed 1 month later. Almost all segments with good perfusion demonstrated contractile reserve; conversely almost all segments with no perfusion failed to show contractile reserve (Fig. 7). The authors also observed a threshold myocardial perfusion beyond which there was strong correla-

100 % Segments with Contractile Reserve

degree of patency of the IRA [26]. Following this phase, however, microvascular stunning may persist for up to 48 hours [27,28]. Thus, the MCE defects seen may be caused by microvascular stunning, which is recoverable (reversible noreflow phenomenon) (Fig. 6). This stunning may especially be seen in the setting of coronary occlusion by thrombus followed by percutaneous angioplasty, where there is significant distal embolic plugging of capillaries [29]. A clinical study by Brochet et al [30] clearly showed that approximately 30% of MCE defects observed at 24 hours improved at 7 days after AMI. Others have also shown a similar phenomenon [25–27,31]. Assessment of microvasculature approximately 3 to 5 days after AMI may produce optimal accuracy.

80 60 40 20 0 0 (n=10)

1 (n=37)

2 (n=25)

Perfusion Score 3-5 days Fig 7. Percentage of segments demonstrating a positive inotropic response to dobutamine at 4 weeks according to perfusion score at 3 to 5 days. P < 0.01 for differences between all groups by v2 analysis.

tion between perfusion and contractile reserve. The key to improved accuracy for determining viability after myocardial infarction in an reperfused infarct is to perform MCE at least 24 hours after reperfusion, as shown in Fig. 8 [36,37]. Prognostic value of myocardial contrast echocardiography after acute myocardial infarction In addition to predicting recovery of regional systolic function, the presence of a no-reflow state on MCE predicts acute complications after AMI, most likely because the extent of no reflow tracks infract size. In 126 patients with first anterior MI undergoing after reflow [38], the 37% with no reflow on MCE were more likely to have pericardial effusion, as well as early and more protracted congestive heart failure, than patients with MCE reflow. Whereas there was no difference between groups in LV end-diastolic volume on day 1, at 1-month follow-up end-diastolic volume was significantly higher in the no-reflow group than in the reflow group. These data suggest that the presence of no reflow correlates with the occurrence of adverse LV remodeling. Adverse clinical outcome in patients with no reflow most likely results from more extensive myocardial damage. Iwakura et al [39] performed MCE in 199 patients undergoing primary angioplasty for AMI to determine the clinical predictors of the no-reflow phenomenon. On multivariate analysis, pre-infarction angina, thrombolysis in myocardial infarction (TIMI) grade 0 on the ECG, the number of abnormal Q-waves, and the

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Acute MI + Reperfusion Resting MCE ≥ 24hours

Transmural Defect

NonNon-Transmural Defect Epicardial Rim No Reflow

Patchy and/or Slow Filling LowLow-Flow

(near(near-)Absence of Filling NoNo-Reflow

Viability Likely

Necrosis Likely

Dipyramidole Dipyramidole MCE MCE

Defect ↓

No Change

Dipyramidole Dipyramidole MCE MCE

Defect ↑

Viability

No Change

Defect ↑

Necrosis

Fig. 8. A proposed schema for using MCE in acute reperfused MI. Even 24 hours after reperfusion a non-transmural perfusion defect on resting MCE may represent myocardial viability. A dipyramidole stress MCE may aid in the assessment of final infarct size as shown. The dotted line indicates a phenomenon seen in the early hours after reperfusion and usually with adenosine. It has not been described in the recovery phase with dipyramidole. A transmural defect on resting MCE is indicative of predominant myocardial necrosis. Dipyramidole MCE may help to establish the true size of final infarct size. (From Verjans JW, Narula N, Loyd A, et al. Myocardial contrast echocardiography in acute myocardial infarction. Curr Opin Cardiol 2003;18:346–50; with permission).

wall motion score on the echocardiogram obtained at hospital admission were independent predictors of MCE no reflow. These data indicate that no reflow on MCE is related to the extent of myocardial necrosis (number of Q-waves), the size of the risk area (wall motion score), and the occlusion status of infarct-related artery.

echocardiography or cardiac MRI [45–49]. Lately, gadolinium-based contrast agents with cardiovascular magnetic resonance (CMR) are used to assess late hyperenhancement of the myocardium, which reflects myocardial necrosis [50,51]. Gadolinium is an extracellular tracer that in essence measures the interstitial space associated with myocyte loss.

Comparison of myocardial contrast echocardiography with other imaging techniques

Comparison with dobutamine echocardiography

Techniques such as positron emission tomography and single photon emission computed tomography (SPECT) have been used to assess myocardial viability because of their ability either to demonstrate ongoing metabolic activity in dysfunctional myocardial cells (positron emission tomography) [40] or to indicate intact cell membrane (Thallium-201) [41,42] or mitochondrial function (Technitium-99m sestamibi) [43,44]. Contractile reserve, which is a marker of myocardial viability, may be assessed by low-dose dobutamine

Most of the studies so far performed compared dobutamine echocardiography with MCE. Numerous studies have indicated the value of dobutamine echocardiography in identifying viable myocardium. The major determinants of contractile response in dysfunctional myocardium during dobutamine echocardiography are the coronary flow reserve and the extent of myocardial necrosis. Thus, despite the presence of significant viable myocardium, limited coronary flow reserve (critical flow-limiting coronary artery stenosis or poor collateral circulation in presence

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of occluded artery) may result in demand-induced ischemia even during low-dose dobutamine testing and prevent contractile response [52]. Coronary artery studies in the post-thrombolytic era have clearly shown the existence of critical residual stenosis of the IRA in a significant number of patients. Furthermore, the contractile response diminishes with increasing extent of myocardial necrosis. Thus, dobutamine echocardiography has a potential to underestimate myocardial viability after AMI. In a study by Agati et al [53] 2 weeks after AMI dobutamine echocardiography showed a lower sensitivity (85%) and negative predictive value (93%) compared with MCE (100% and 100%, respectively) [53]. In 24 patients after AMI, Iliceto et al [54] compared MCE with low-dose dobutamine echocardiography. In this study, also, MCE was more sensitive than dobutamine echocardiography in detecting myocardial viability. It may be inferred that although dobutamine response suggests significant myocardial viability, absence of dobutamine response does not necessarily imply absence of viability. The presence of homogenous contrast opacification of these dobutamine-nonresponsive segments, however, is likely to suggest significant myocardial viability and therefore is likely to translate into recovery of function during follow-up. In a study by Senior et al [55], the sensitivity and negative predictive value of dobutamine echocardiography for the recovery of dysynergic segments during follow-up improved significantly, from 59% to 79%, and improved from 88% to 95% when contrast opacification was observed in the segments not responsive to dobutamine [55]. Indeed, dobutamine and myocardial contrast ECG data show

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that the combination of dobutamine and contrast provide the best independent predictor for the recovery of function. This result was also shown in an experimental study by Meza et al [57]. Shimoni et al [56] compared quantitative MCE with dobutamine stress echocardiography and rest-redistribution Technetium-201 (201TL) in patients with coronary artery disease and LV dysfunction undergoing CABG. Using recovery of function as an end point, sensitivity of MCE [9] was 90%, that of 201Tl was 92%, and contractile reserve was 80%. The specificity of MCE was higher than that of 201Tl and dobutamine stress echocardiography in this study [56]. Comparison with radionuclide imaging Radionuclide imaging has been used extensively to assess myocardial viability after AMI and in chronic coronary artery disease. Few studies, however, have compared radionuclide techniques and MCE to assess myocardial viability after AMI. Recent studies conducted with MCE in post-AMI patients demonstrated a good concordancewithradionuclidemyocardialperfusionimaging in detecting myocardial perfusion (Fig. 9). Using power Doppler imaging in a study of 15 patients after AMI, the agreement for presence or absence of myocardial perfusion was excellent. That study was followed by a larger study of 100 patients, in whom the concordances using harmonic B-mode and power Doppler imaging were 80% and 82%, respectively [58]. The partial volume effect caused by suboptimal spatial resolution and attenuation artifacts may result in underestimation of radiotracer uptake, however.

Fig. 9. (Left) Myocardial contrast echocardiography showing reduced opacification (perfusion) in distal septum and apex. (Right) Corresponding images on 99mTc-sestamibi scan showing identical perfusion defect. These images suggest nonviable myocardium. (From Krishnamani R, Senior R. Evaluation of myocardial viability after myocardial infarction. Eur Heart J 2002;4(Suppl C):C35–8; with permission.)

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Indeed, a recent study revealed significant underestimation of contractile reserve when radionuclide imaging was compared with MCE after AMI [59,60]. Comparison with cardiovascular MRI Gadolinium-enhanced MRI has been shown to detect the transmural extent of myocardial infarction accurately. In the only study to date comparing MCE with infarct transmurality using contrast-enhanced MRI following AMI, Janardhanan et al [23] showed that correlates of myocardial perfusion assessed by MCE clearly classify the transmural extent of myocardial infarction with a high degree of accuracy (Fig. 10) [23]. Acute myocardial infarction without ST elevation Despite advances in clinical, EKG, and serologic assessment of AMI [61–63], the diagnosis of non-STEMI remains problematic. ST-segment elevation is seen in only about one third of patients with AMI [64]. Other patients with AMI either have a normal EKG or exhibit nonspecific ST-T changes that are associated with other concomitant cardiac conditions, including hypertension, congestive heart failure, and digitalis use, making diagnosis of AMI difficult. Some of these patients may even have unstable angina, but there are no definite diagnostic criteria for this syndrome that can be used effectively in the emergency department. Therefore, these patients are either observed

in the emergency department or admitted to the hospital. The cost of evaluating these patients, including hospital admission, is in excess of $10 billion annually in the United States alone [64]. Although traditional serologic markers such as CPK-MB and the newer ones such as troponin and myoglobin ultimately become abnormal in these patients, it takes several hours before the results become available; meanwhile valuable time is lost in making a diagnosis and providing appropriate therapy. Recent studies showed that imaging of cardiac perfusion and function either by MCE or SPECT provides valuable diagnostic and prognostic information in these patients when they present to the emergency department. This information can potentially be used for either further evaluation (coronary angiography), rapid treatment with a bona fide acute coronary syndrome, or discharge with normal studies [65,66]. In terms of logistics, MCE is more attractive than SPECT. Ultrasound systems are portable, the ultrasound contrast agent does not require special preparation or a radiopharmacy, and the examination takes no more than 10 minutes. Most modern cardiologists are trained in the use of ultrasound, whereas SPECT requires special personnel. It also entails a waiting period of 1 to 2 hours after isotope injection for splanchnic and liver clearance. Placement of a gamma camera in or near the emergency department is not always possible. Therefore, for practical reasons, MCE

Fig. 10. A patient who sustained an anterior myocardial infarction. (A, top) Apical two-chamber view on MCE with absence of contrast opacification (solid arrows) at the apex and anterior wall, which were akinetic. The normal, remote segments (outlined arrows) show normal contrast intensity. (A, bottom). Replenishment curves in the akinetic segment (yellow) demonstrates very low microbubble velocity and myocardial blood flow remote, normal segment (red). (B) The corresponding image on CMR demonstrates transmural extent index >75% in the akinetic segments compared with remote normal remote segment.

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may be preferable to SPECT. Obviously, local expertise and infrastructure ultimately dictate which method is better in any particular setting.

Summary MCE is a reliable, bedside technique for assessment of a patient with acute coronary syndrome. It can be used to estimate the myocardial risk-area and infarct size and to establish periinfarct viability. This information is critical in both management decision-making and in assigning prognosis in the setting of acute coronary syndromes.

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