Myocardial revascularisation can improve or relieve angina pectoris in symptomatic patients and also improve prognosis in patients with severe left main stem disease, severe proximal left anterior descending (LAD) coronary disease or multi-vessel coronary artery disease (CAD).1–2 However, it is also widely accepted that the visual estimation of stenosis severity at the time of cardiac catheterisation frequently does not correlate with the haemodynamic importance of a stenosis (i.e. an anatomical lesion does not necessarily imply a functional abnormality).3–4 Several studies have shown the benefit of treating only those stenoses which are flow-limiting and the safety behind not treating lesions which may appear significant but do not, in fact, induce ischaemia.5–6
There is, therefore, a major drive in contemporary cardiological practice to identify and treat coronary disease that can produce ischaemia rather than simply stenoses which appear important to the naked eye. Accordingly, there has been a very significant expansion in the use of non-invasive cardiac imaging procedures over the past decade. These ‘functional tests’ – which classically include stress echocardiography, myocardial perfusion scintigraphy (MPS) and stress cardiovascular magnetic resonance (CMR) – assess inducible ischaemia (new wall motion abnormality or perfusion defect). These tests are now frequently used to evaluate patients with chest pain of uncertain origin and have largely replaced diagnostic angiography as the first-line investigation for identification of CAD in patients with low or intermediate probability of disease.7 These tests are all superior to exercise electrocardiography (treadmill testing), which relies on the development of electrocardiogram (ECG) changes or symptoms – events known to occur late in the ischaemic cascade8 (see Figure 1) and this accounts for the test’s relatively poor sensitivity.
Myocardial contrast echocardiography (MCE) is an ultrasound-based technique for assessing myocardial perfusion. It is a test that can be performed at the patient’s bedside and is free from ionising radiation. MCE has accumulated a very large evidence base over the past 25 years, which has informed us of its ability to detect and assess severity of CAD, assess myocardial viability and predict LV remodelling following acute myocardial infarction (AMI). The purpose of this article is to give a brief overview of the principles that underpin the use of ultrasound contrast agents (UCAs) and then review the evidence base for MCE in patients with CAD.
Physiological Principles Behind Stress Testing
An increase in myocardial oxygen demand can only be met by coronary vasodilation, given that oxygen extraction from blood is virtually maximal at rest.9 The normal coronary arteries can increase their blood flow four- to sixfold to meet higher metabolic demands.10 The ratio between basal (resting) and maximal coronary blood flow is known as the coronary flow reserve (CFR).11 If a stenosis develops within a coronary artery, resting blood flow can be maintained if the vessel vasodilates to permit increased flow. However, this means that a portion of the CFR is utilised at rest and thus, under stress, there may be insufficient reserve to meet the increased oxygen demands and this will produce ischaemia. Previous experiments have shown that CFR remains normal for stenoses up to 40 % severity, is borderline normal for 40–70 % stenoses, abnormal for severe stenoses (70–90 %) and virtually abolished in critical (>90 %) stenoses.11 Stress testing aims to unmask this reduction in CFR, either by increasing myocardial oxygen demand through increased inotropy and chronotropy (exercise or dobutamine) or inducing a ‘steal’ phenomenon via maximal hyperaemia (using vasodilators such as dipyridamole or adenosine). MCE can be performed with dobutamine, dipyridamole or adenosine.
Physiological Principles of Contrast Agents
Contrast bubbles resonate when exposed to an ultrasound wave. This is predominantly a non-linear oscillation (i.e. expansion and contraction of the bubble are not equal) at the ultrasound frequencies used in diagnostic imaging. Microbubbles are several million times more effective at scattering sound than red blood cells, resulting in a greatly enhanced ‘blood pool’ signal.12 The blood pool agents developed consist of a gaseous material encapsulated within a stabilising outer shell. These microbubbles are typically slightly smaller than erythrocytes, allowing free passage within the circulation and effectively acting as red cell ‘tracers’.13
The first generation UCAs consisted of air surrounded by an albumin shell.14 Unfortunately, these agents had a very short lifespan in vivo and thus had limited utility in diagnostic tests. The second generation of UCAs addressed this issue by changing both components of microbubbles – the air was replaced by inert gases with high molecular weight, high density and low solubility, such as sulphur hexafluorane (Sonovue®, Bracco Diagnostics, Milan, Italy) or perfluorocarbons (e.g. Optison® or Definity®). The outer shell is now made using phospholipids, which also confer greater stability (see Table 1).
Physiological Principles of Myocardial Contrast Echocardiography
The majority (90 %) of the blood within the myocardial walls resides within capillaries.15 The intensity of the contrast signal, when the myocardium is fully saturated during a continuous infusion of UCA, therefore reflects the concentration of microbubbles within myocardial capillaries16 and consequently, capillary or myocardial blood volume (denoted A). A high intensity (high mechanical index) ‘flash’ or impulse is used to destroy the microbubbles and their rate of replenishment (microbubble velocity – denoted β) represents red cell velocity and is directly and proportionately related to blood flow (i.e. a stenosis will limit blood flow and thus result in longer replenishment time). The product of microbubble velocity and capillary (or myocardial) blood volume (A x β) is myocardial blood flow (MBF – see Figure 2).17
Specialist software, which allows calculation of A, β and their product Aβ, permits quantification of myocardial blood flow during MCE by placing regions of interest in LV myocardial segments.18 The difference between maximal and basal MBF gives the coronary flow reserve. This quantitative approach can be time-consuming and so semi-qualitative MCE has also been developed, which involves assigning a numerical contrast score to each segment (e.g. 0 = minimal or absent contrast opacification, 1 = reduced or heterogeneous opacification, 2 = homogenous opacification). A perfusion score index (PSI) can then be calculated, which is the sum of the scores divided by the number of segments analysed.19 The PSI at rest subtracted from the PSI at stress gives the ischaemic burden of myocardium.
MCE protocols have evolved significantly over the years, but the most common technique performed at present involves imaging at rest and at stress using conventional apical four-chamber, two-chamber and three-chamber views. Once a steady state of microbubbles has been achieved (usually using a continuous intravenous UCA infusion), a high intensity (high mechanical index) pulse or ‘flash’ of ultrasound is used to destroy the bubbles on screen. The replenishment of these bubbles in the myocardium is then studied either qualitatively (see Figure 3) or quantitatively, as described above.
The Evidence for Using Myocardial Contrast Echocardiography in Coronary Artery Disease
Detection of Coronary Artery Disease
MCE can be used as a first-line investigation to confirm or refute the possibility of underlying CAD. This has been proven in high-risk20 and intermediate-risk21 patient cohorts, using dipyridamole,21 adenosine22 and dobutamine.23 A recent meta-analysis24 which examined 13 studies (627 patients) that performed quantitative MCE supports the use of MCE for screening for CAD in patients with chest pain of unknown cause. Additionally, given that quantitative MCE can detect decreasing CFR, it has been shown that MCE can be used to predict not just the presence but also the severity of coronary disease.25
In a unique study, Senior et al. used MCE to predict whether patients presenting for the first time with heart failure had an underlying ischaemic aetiology or not.26 Fifty-two patients with no prior history of heart failure and no clinical evidence of infarction underwent dipyridamole MCE prior to cardiac catheterisation. Sensitivity, specificity, positive predictive value and negative predictive value for the detection of CAD by MCE were 82, 97, 95 and 88 %, respectively. MCE was also the only independent predictor of CAD.
Incremental Diagnostic and Prognostic Benefit of Myocardial Contrast Echocardiography
Vasodilator MCE has previously been compared to conventional stress echocardiography for detection of CAD. The addition of qualitative MCE improved sensitivity for the detection of CAD (91 versus 74 %, p=0.02) and accurate recognition of disease extent (87 versus 65 % of territories, p=0.003), with a non-significant reduction in specificity.27 The study showed that the addition of low-mechanical-index MCE to standard imaging during stress echocardiography improves detection of CAD and enables a more accurate determination of disease extent.
There is considerable evidence attesting to the prognostic value of MCE. Tsutsui et al. retrospectively analysed data of 788 real-time dobutamine-MCE studies.28 They found that evaluation of myocardial perfusion (MP) gave incremental prognostic information compared to wall motion (WM) alone – the three-year event-free survival was 95 % for patients with normal WM and MP, 82 % for normal WM and abnormal MP and 68 % for abnormal WM and MP.
The same group also demonstrated the incremental prognostic benefit of MCE over dobutamine echocardiography in patients presenting with chest pain but negative cardiac biomarkers.29 Similarly, stress MCE has been found superior to thrombolysis in myocardial infarction (TIMI) risk score and exercise electrocardiogram (ECG) in the assessment of risk in patients with suspected acute coronary syndrome, non-diagnostic ECG and negative troponin.30 Cardiac events in patients with abnormal MCE findings (59 %) were significantly higher than in patients with high-risk TIMI scores (39 %) or high-risk exercise ECG results (57 %).
In another study, MP using dipyridamole MCE was compared to WM alone – results were compared with 99 mTc-sestamibi SPECT. Prognosis was worst in those with abnormal WM and MP and best in those in whom both WM and MP were normal.31 Finally, Miszalski-Jamka and colleagues determined the incremental prognostic value of MCE over two-dimensional echocardiography (2DE) in patients undergoing supine bicycle stress.32 On multivariate analysis, the only independent follow-up event predictor was ischaemia on MCE. Among patients with normal results on 2DE, those with normal results on MCE had greater 4.5-year event-free survival than those with abnormal results on MCE (93 versus 69 %, p=0.01). They thus concluded that MCE enhances the predictive power of supine bicycle stress 2DE and allows the risk stratification of patients with normal results on 2DE.
Myocardial Contrast Echocardiography Following Myocardial Infarction
Adverse ventricular remodelling – including cardiac chamber dilatation – is frequently seen following myocardial infarction and carries a poorer prognosis than those in whom LV geometry is preserved. MCE has been utilised in numerous studies that have confirmed its potential clinical utility in this setting. Low-power MCE has been shown to be superior to harmonic echocardiography for estimating degree of LV remodelling.33 The success of reperfusion therapy (i.e. thrombolysis) has been assessed using MCE – Janardhanan and colleagues showed that low-power MCE early after acute MI could identify microvascular perfusion, which, in turn, reliably predicted late recovery of dysfunctional (stunned) myocardium.19 The same group also found that MCE could predict adequacy of collateral blood flow in the presence of a persistently occluded infarct-related coronary artery.
Such patients underwent MCE within one week of acute MI and low-dose dobutamine echocardiography 12 weeks later to look for contractile reserve (CR). CR was present in 83 % of segments with homogenous contrast opacification and absent in 82 % segments with reduced/absent opacification. Multivariate logistic regression analysis showed that MCE was the only independent predictor of collateral blood flow, as demonstrated by the presence of CR.34
Additionally, in an elegant study utilising MCE and CMR, it was shown that MCE can detect the transmural extent of myocardial necrosis accurately and can predict CR.35 It has also been proven that the degree of viability post-MI, as determined by MCE, predicts the degree of future LV remodelling.36 The results of each of these single-centre studies were confirmed in the multicentre prospective Acute myocardial infarction contrast imaging (AMICI) trial, which found that the extent of microvascular damage, detected and quantitated by MCE, was the most powerful independent predictor of LV remodelling after STEMI (compared with persistent ST-segment elevation on ECG and myocardial blush grade during angiography).37
Myocardial Contrast Echocardiography in the Emergency Department
Chest pain is one of the most frequent presentations to the Emergency Department (ED), with a costly evaluation pathway given that many patients require admission in order to exclude serious pathology such as acute coronary syndrome, pulmonary embolism or aortic dissection. MCE has been performed in such patients, who have chest pain and a non-diagnostic ECG. MCE was able to safely and speedily provide short-, intermediate- and long-term prognostic information in such patients and proved superior to the TIMI score.38 The cost efficiency of this approach was also shown, given that patients with normal MCE in the ED could be safely discharged home, thus removing the need for (and costs of) hospital admission and further investigations.39
Myocardial Contrast Echocardiography and Viability
A full discussion on the use of MCE to detect viable myocardium is beyond the scope of this article. However, in brief, contrast intensity in the myocardium reflects the concentration of microbubbles within the myocardial capillaries. The basis by which MCE could detect viability is that viable myocardium requires an intact microvasculature.40
It has been shown that in areas of infarcted myocardium, myocyte loss is accompanied by loss of microvasculature.41 Thus, absence of contrast on MCE should define areas of non-viable myocardium – and this has also been proven in a key paper in which MCE findings were correlated with histological findings from corresponding myocardial biopsy results.42
Studies have been published demonstrating the ability of MCE – performed following AMI – to predict recovery of function of dyssynergic myocardium.43 MCE has also been shown to have incremental benefit over low-dose dobutamine echocardiography for predicting myocardial viability.44 Shimoni et al.45 published the first study in humans utilising intravenous quantitative MCE to detect hibernating myocardium and reported an excellent sensitivity of 90 %. Further studies in larger numbers of patients are required to confirm the clinical reproducibility of MCE for detecting myocardial viability but the technique shows much promise in this field.
A Note on Safety
Millions of patients worldwide have received intravenous UCAs without adverse effects. However, safety concerns have been raised in the past regarding contrast agents which merit brief discussion. In May 2004, the European Medicines Agency (EMEA) recommended discontinuing the use of Sonovue® for cardiac ultrasound applications.46 This followed the reports of three deaths, though all three patients were found to have severe ‘unstable’ coronary disease. In November 2004, following a detailed review of these cases and appraisal of Sonovue’s® overall safety record, the EMEA allowed its use once more in cardiac patients but with caveats – to this day, Sonovue® is contraindicated in patients within seven days of a myocardial infarction or cardiac chest pain and in patients with New York Heart Association (NYHA) class III–IV heart failure.
In October 2007, the US Food and Drug Administration (FDA) placed a black box warning on the two UCA agents licensed in the US – Optison® and Definity® – after reports of four deaths temporally related to (though not necessarily causally related to) UCA administration.47 There were also almost two hundred reports of severe cardiopulmonary reactions. This resulted in a sudden and significant decrease in utilisation of UCAs in the US.
However, there is a wealth of data to support the excellent safety profile of these agents. A retrospective analysis of over four million patients who received UCAs showed no increase in mortality – in fact, patients receiving UCA for echocardiographic examinations had a 24 % lower mortality (presumably due to an accurate diagnosis being established with UCA use).48 In 2008, after intense lobbying from physicians and UCA advocates, the FDA eased its cautions surrounding the use of UCAs. Further large registry and retrospective analyses have also been published49–53 confirming the safety of UCA use in a broad spectrum of patient groups and have helped lay the issue of safety to rest.
MCE is a reproducible technique – which can be performed at the bedside, does not expose the patient to ionising radiation and does not involve the use of radioactive pharmaceutical agents. It has been demonstrated to be as accurate as – if not more accurate than – currently employed functional imaging tests in the evaluation of patients with both suspected and known coronary artery disease. There is a large evidence base supporting its use in routine clinical practice. The challenge now among the echocardiographic community is to use this enormous potential and evidence in the research arena to integrate this technique with existing tests in the clinical arena.54