Coronary artery disease (CAD) remains a diagnostic challenge, even though there are several diagnostic techniques available for the detection of ischaemia – assessed either as function or perfusion abnormalities or directly by demonstrating anatomical coronary stenoses.1 An overview of different non-invasive modalities used in the diagnosis of myocardial ischaemia and their average sensitivity and specificity is presented in Figure 1. In CAD, in addition to coronary anatomy the evaluation of regional myocardial function and perfusion is important for both diagnosis and, in particular, the choice of treatment. Thus, a combination of different imaging modalities is often necessary to make a definite diagnosis and choose the optimal treatment strategy. This article will discuss the current status of contrast stress echocardiography as a novel non-invasive method for diagnosing myocardial ischaemia.2,3
Stress Echocardiography
In stress echocardiography, CAD is diagnosed by demonstrating stress-induced reduction of regional myocardial contractility secondary to ischaemia.4 Since stress echocardiography was first introduced 25 years ago, it has been recognised as a sensitive and specific non-invasive method in diagnosis and risk stratification in CAD.5 Clinical use in the diagnosis of CAD has been established through numerous studies reporting an average sensitivity of 88% and an average specificity of 83% in detecting significant angiographic CAD.5
However, stress echocardiography allows only an indirect diagnosis of CAD based on reduced regional myocardial contractility. The results vary with the experience of examiners, and as quantification is not possible the inter-observer variability is high. The method is critically dependent on the image quality, and in 10–15% of patients suboptimal image quality makes stress echocardiography unsuitable. In addition, the ability to detect CAD is highly dependent on achieving a high stress level, which is defined as >85% age-predicted maximal heart rate. Left ventricular concentric remodelling and conduction abnormalities such as bundle branch block may also interfere with the diagnostic accuracy of the methods.5 To overcome these limitations, adding ultrasound contrast to the stress protocol has been suggested.
Ultrasound Contrast Agents and Contrast-specific Ultrasound Modalities
Ultrasound contrast agents consist of microbubbles – an inert gas surrounded by a phospholipid shell – that have special acoustic properties when exposed to ultrasound.3,6 In contrast to tissue, ultrasound contrast microbubbles oscillate in a low-energy ultrasound field and are destroyed in a high-energy ultrasound field. Contrast-specific ultrasound modalities utilise and combine these properties to provide a realtime assessment of contrast-agent enhancement in the left ventricular cavity and myocardium. Contrast microbubbles are the same size as red blood cells, and are exclusively intravascular tracers reflecting myocardial microcirculation independently of metabolic processes and the extravascular compartment. By virtue of the destruction–replenishment imaging modality, both regional wall motion – expressed as wall contractility and thickening – and myocardial contrast enhancement can be assessed in realtime (see Figure 2).3 Contrast refilling can be scored as normal, delayed or reduced, distinguishing between ischaemia and myocardial scarring. Due to the high spatial resolution of ultrasound, not only transmural but also subendocardial perfusion defects can be detected and the size of the hypoperfused area can be estimated as an indicator of the area at risk. In addition, parametric imaging expresses the contrast signal intensity over time, thus allowing the quantification of myocardial perfusion.7
Clinical Use of Contrast Stress Echocardiography
SonoVue® and Luminity® are contrast agents approved for left ventricular opacification in Europe,8 and current indications for contrast echocardiography were recently published in a previous edition of this publication by Becher and Olszewski.8 In clinical practice, the introduction of contrast-enhanced stress echocardiography has several advantages in the detection of CAD. It is an easily available, non-invasive method for bedside evaluation of both myocardial function and perfusion. It is less time-consuming than other methods, the results are immediately available to the examiner and it is not associated with radiation or radioactivity. There is no interference with renal function and there are few contraindications. In addition, contrast agents have few adverse events, mostly mild and passing, but allergic and anaphylactic reactions have been reported. Although rare, we recommend continuous surveillance of blood pressure and heart rhythm during contrast administration, and adrenalin, steroids and antihistamines should be available in the laboratory in case of an emergency. 9
Assessment of Regional Wall Motion in Contrast Stress Echocardiography
The evaluation of myocardial function by regional/segmental wall motion scoring of contractility and wall thickening is highly dependent on image quality and optimal visualisation of the endocardial border. The introduction of ultrasound contrast for left ventricular opacification during stress echocardiography to improve endocardial border delineation was tested in the Randomized Cross-Over Study for Evaluation of the Effect of Image Optimization With Contrast on the Diagnostic Accuracy of Dobutamine Echocardiography in Coronary Artery Disease (OPTIMIZE) trial,10 which demonstrated that improvement of endocardial border visualisation by contrast resulted in higher confidence of interpretation and greater accuracy in evaluating CAD at rest, and even more so during stress. Contrast also increased the number of left ventricular wall segments interpretable at rest and especially during stress, and it markedly reduced the number of patients who could not be properly evaluated by stress echocardiography due to suboptimal image quality. Contrast in stress echocardiography has also been shown to reduce inter-observer variability. Furthermore, improved visualisation of the left ventricular segments by the introduction of contrast in echocardiography was also demonstrated in a multicentre study evaluating contrast for left ventricular opacification and perfusion against 2D echocardiography, demonstrating higher accuracy in the detection of regional myocardial abnormalities when contrast was used.11
Administration of ultrasound contrast agent is routinely used in many advanced echocardiography laboratories for the assessment of myocardial wall motion abnormalities during stress echocardiography. Use of ultrasound contrast in left ventricular opacification to improve endocardial border delineation is implemented in the current indications for contrast echocardiography.5 In stress echocardiography, ultrasound contrast is well established to improve assessment of myocardial wall motion abnormalities,12 and according to the American Society of Echocardiography (ASE) guidelines for performance, interpretation and application of stress echocardiography, contrast is indicated during stress echocardiography when two or more segments are not well visualised.5
Assessment of Myocardial Perfusion in Contrast Stress Echocardiography
Contrast stress echocardiography in the assessment of regional myocardial perfusion, which focuses on contrast enhancement in the myocardium, has so far not been included in the stress echocardiography guidelines.5 However, several studies suggest that adding perfusion analysis to wall motion analysis during contrast stress echocardiography increases the sensitivity to diagnose CAD.2,13
In a meta-analysis by Dijkmans, the accuracy of myocardial perfusion assessment by myocardial contrast stress echocardiography was compared with wall motion analysis in the detection of chronic angiographic coronary artery stenoses.2 The meta-analysis included 12 studies and 674 patients, and demonstrated a statistically significant increase in sensitivity in detecting angiographic CAD by perfusion analysis. The increase in sensitivity was demonstrated for all coronary territories, showing the highest sensitivity in the left anterior descending (LAD) territory, followed by the circumflex and right coronary arteries. The difference in sensitivity was particularly high at intermediate stress levels. This is in accordance with results in a recent study from our laboratory examining patients scheduled for percutaneous coronary intervention due to significant coronary artery stenoses diagnosed by quantitative coronary angiography.14 In this study, 95% of patients did not reach the target heart rate during stress, a common problem in patients on beta-blockade where withdrawal before testing is not desirable. However, perfusion analysis was significantly more sensitive in detecting coronary artery stenoses than wall motion analysis, especially in detecting prognostically important CAD as multivessel disease or proximal LAD stenoses even at the intermediate stress level.14
Thus, regional myocardial perfusion is more sensitive for detecting CAD than wall motion analysis, especially at lower stress levels. This may be explained by several factors, including the fact that in the ischaemic cascade abnormal perfusion precedes contractile abnormality when ischaemia is induced,15 and in chronic ischaemia capillary de-recruitment occurred distally to coronary stenosis to maintain perfusion pressure. This capillary de-recruitment explains a common finding in contrast stress echocardiography: hypoperfusion without wall motion abnormality is often referred to as mechanically silent ischaemia.16,17
Compared with coronary angiography, perfusion imaging is less specific than wall motion scoring in detecting CAD. Possible explanations could be the development of collateral circulation due to chronic ischaemia, small-vessel disease only affecting myocardial microcirculation that cannot be detected by coronary angiography, which is recognised as a gold standard in the diagnosis of CAD, and individual variation in coronary artery anatomy significantly influences the relation between perfusion defects and anatomical stenoses in epicardial coronary arteries.
Quantification of Regional Myocardial Perfusion in Contrast Stress Echocardiography
The additional value of using quantification of regional myocardial perfusion in the evaluation of CAD compared with simple perfusion scoring has yet to be demonstrated in larger studies. As previously published, regional myocardial perfusion can be calculated using parametric imaging.7 Myocardial perfusion may be assessed by a measurement of the myocardial contrast signal intensity plotted against time, obtaining contrast replenishment curves fitting the exponential function: y(t) = A(1-e-βt) + C, where y is signal intensity at any time during contrast replenishment and equalling regional myocardial perfusion (see Figure 3). As demonstrated in Figure 3, A is the plateau signal intensity corresponding to the total blood volume, β is the rate of signal intensity rise representing the myocardial blood flow velocity and C represents the background intensity level. With the quantification of contrast enhancement being expressed as contrast replenishment curves and the regional perfusion parameters as myocardial blood flow velocity, the total blood volume, perfusion rate and refilling time can be expressed as numbers. In graded coronary artery stenoses,18 quantification has been shown to reflect the degree of stenosis; however, measurement of myocardial perfusion has not been established as a useful tool in clinical practice and needs further investigation.
Conclusions
CAD remains a diagnostic challenge warranting the development of new diagnostic tests. The introduction of contrast in stress echocardiography to improve endocardial border delineation for more accurate wall motion scoring is implemented in the ASE guidelines for stress echocardiography performance. Adding myocardial perfusion analysis to contrast stress echocardiography may improve diagnosis of prognostically important CAD such as proximal LAD stenosis or multivessel disease, and may overcome some of today’s limitations in non-invasive diagnosis of myocardial ischaemia. However, evidence from larger trials is needed before perfusion assessment during contrast stress echocardiography is ready for implementation in guideline recommendations.