How Far Have We Come?
Cardiac imaging using ultrasound (so-called ‘echocardiography’) was introduced more than 50 years ago. Resting echocardiographic detection of myocardial infarction was described as the reduction in regional contractile function,1 and the development of stress echocardiography in the early era was recognised after the introduction of 2D echocardiographic imaging. The initial report in 1979 by Wann et al. demonstrated the value of 2D echocardiography in identifying exercise-induced wall motion abnormalities.2 During the early days of stress echocardiography, problems included imaging quality and techniques. For evaluating patients with known or suspected coronary artery disease (CAD), there was also the need to establish equivalent accuracy and prognostic values to the well-established alternative imaging technique, stress radionuclide myocardial perfusion imaging. The acquisition of stress echocardiographic imaging initially involved continuous videotape recording for sequential evaluation of wall motion; the development of the digital acquisition system for the side-by- side comparison of rest and post-stress imaging was a major advance.
Early studies of stress echocardiography employed exercise as a stressor and were mostly feasibility studies.2–4 Any form of physical exercise that provides an appropriate increase in heart rate and cardiovascular workload can be used in the performance of exercise echocardiography. However, the technique of exercise echocardiography is challenging in terms of image acquisition during physical exercise (either on a treadmill or a bicycle). Furthermore, the feasibility of exercise echocardiography is limited in patients who are unable or unwilling to exercise, or when myocardial viability is an important issue. This led to the development of various forms of pharmacological and other non-exercise stressors (see Table 1).
The advent of offline digital handling for data acquisition, storage and display, further improvements in echocardiographic imaging techniques and the development of a wide variety of stressor modalities contributed to rapid growth in the field of stress echocardiography.
Images are acquired in multiple views at baseline and at varying stages during stress and/or recovery. Representative images are then displayed in a side-by-side format for the comparison of either various stages of the same echocardiographic view or individual views at each stage of stress. Regardless of the stressors, the echocardiographic detection of inducible ischaemia as new or worsening wall motion abnormalities remains the hallmark of the positive test result for the diagnosis of CAD. The wall motion abnormalities can be matched to the standardised multisegment left ventricular (LV) model, as recommended by the American Society of Echocardiography (ASE).5 Additional information, such as a change in LV volume during stress, provides additive value with respect to accuracy and prognosis.
Exercise remains the prototype for stress testing in the diagnosis of CAD. It was the first stress modality to be combined with echocardiography and remains popular in clinical practice. The very first reports of stress echocardiography dealt with the use of M-mode echocardiography with exercise in normal subjects6 and in patients with CAD.7 Subsequently, 2D echocardiography was introduced to detect exercise-induced ischaemic wall motion abnormalities.2 Exercise echocardiography can be performed using a treadmill or a bicycle. The most commonly employed form of exercise echocardiography involves immediate imaging after treadmill use. Images are acquired at rest as a baseline for comparison and either immediately after treadmill exercise or during various levels of bicycle exercise. It is possible to obtain additional Doppler data during bicycle exercise; this test may also be used for assessing valvular heart disease or exertional changes in diastolic function. Data regarding haemodynamic response to exercise, exercise capacity and arrhythmias have also added useful diagnostic and prognostic information and should be included in the report. Ischaemic threshold and the heart rate or percentage of target heart rate at which ischaemia first occurs can be obtained from bicycle exercise but not from treadmill exercise.
Pharmacological stress echocardiography is an alternative in patients who are unable to exercise or when assessment of viable myocardium is an issue. Among pharmacological stress agents, dobutamine and dipyridamole are popular. Dobutamine provides a balanced inotropic and chronotropic response, and has become the most commonly utilised pharmacological stressor. Images are acquired at baseline and during each sequential stage of dobutamine infusion. The protocol for dobutamine stress echocardiography varies, but most commonly dobutamine infusion starts at a dose of 5g/kg/minute and increases every three minutes to 10, 20, 30 and 40g/kg/minute. Atropine can be added in 0.25mg increments to a total dose of 1–2mg at peak or pre-peak dose to augment heart rate response. Variations on the protocol of dobutamine stress echocardiography include those for the detection of viable myocardium or true severe aortic stenosis in the setting of low-output, low-gradient aortic stenosis. The ability of dobutamine to mimic the cardiac effects of exercise and detect myocardial viability coupled with the safety and feasibility of the test has contributed to its popularity in clinical practice. Dipyridamole was the first pharmacological stress agent used in cardiac imaging.8 As a coronary vasodilator it provokes ischaemia through coronary steal effect, which results in flow mismatch and subsequent wall motion abnormalities. As with dobutamine stress protocol, atropine can be added if no end-point is reached. Dipyridamole stress echocardiography is widely performed in Europe based on cost considerations. Despite the different pathophysiological mechanisms of the induction of ischaemia, dobutamine and dipyridamole stress echocardiography show comparable diagnostic accuracy.9
Diagnostic Accuracy of Stress Echocardiography
The accuracy of stress echocardiography for the detection of CAD is expressed as the sensitivity and specificity of the test, as shown in Tables 2, 3 and 4. Limitations regarding the accuracy of studies include variations in the angiographic cut-off for significant CAD, the population studied, adequacy of stress and other echocardiographic factors. As with any form of stress testing, the sensitivity for detecting CAD is higher in patients with multivessel disease than in those with single-vessel disease. Inadequate heart rate response may reduce the sensitivity of the test. The accuracy of stress echocardiography has been shown to be comparable to that of radionuclide myocardial perfusion imaging. Post-test referral bias accounts for the apparent lower specificity and higher sensitivity when a test has become accepted in clinical practice. In clinical practice, it is generally patients with positive test results who are referred for coronary angiography. More recent studies have focused on the prognostic value of stress testing, as outcomes of all consecutive patients and not just the subset undergoing coronary angiography can be considered.
Prognostic Value of Stress Echocardiography
It is well-known that myocardial ischaemia or infarction is closely related to adverse outcomes. As the pathophysiological basis of stress echocardiography relies on the presence of inducible ischaemia provoked by the stress-induced supply–demand mismatch, this technique is evidently of prognostic importance. Apart from the diagnostic accuracy, the prognostic value of stress echocardiography has been demonstrated in a variety of patient populations, including patients with chronic CAD, after myocardial infarction, before non-cardiac surgery, after cardiac transplantation, in the elderly, in women and in patients with LV dysfunction, LV hypertrophy, bundle branch block, atrial fibrillation and diabetes mellitus. The prognostic implication of stress echocardiography in each of these selected populations is strongly supported by an evidence base. Favourable prognosis after normal stress echocardiography has been extensively reported in several studies.10–15 Patients with normal stress echocardiography (defined as normal wall motion at rest and with stress) represent a low-risk population and require no further cardiac interventions.10,11,13,15 It is important to emphasise that an inability to exercise is itself an ominous prognostic sign, and patients referred for pharmacological stress echocardiography may have a higher event rate than those referred for exercise echocardiography. Chaowalit et al. demonstrated that the outcome after normal dobutamine stress echocardiography is not as good as that reported after normal exercise echocardiography.16 The study showed that in patients with suspected CAD who were unable to exercise, the rate of mortality and cardiac events was relatively high despite normal dobutamine stress echocardiography. The risk of adverse outcomes increases in patients with abnormal stress echocardiography, indicating a high-risk population.11,17–19 In the presence of inducible ischaemia, stress echocardiographic parameters such as ischaemic threshold and the extent and severity of ischaemia determine the risk of developing adverse outcomes. The incremental predictive power of a positive pharmacological stress echocardiography over clinical and resting echocardiographic data was also demonstrated.11,17,19
Advantages of Stress Echocardiography
Important advantages of stress echocardiography over other stress imaging modalities include its wide availability, portability, relatively low cost and versatility. Echocardiography provides information regarding left and right ventricular function and dimensions, atrial sizes, wall thicknesses, diastolic function, valve function, pericardial effusion, assessment of the aortic root and estimation of intracardiac pressures. Thus, in addition to the diagnosis of ischaemic heart disease, other forms of heart disease can be recognised. The absence of radiation exposure makes stress echocardiography a desirable form of testing if serial studies are needed.
How Far Can We Go?
Despite the variety of useful information obtained by stress echocardiography that is applicable for clinical practice, there are still limitations such as a relatively subjective interpretation and the dependence on image quality. Recognition of ischaemia may be challenging in the setting of extensive resting wall motion abnormalities. Technical developments in echocardiography such as contrast echocardiography, myocardial Doppler imaging and 3D echocardiography may play an important complementary role. These new, promising techniques may provide additional sensitivity and quantitation. Contrast echocardiography improves myocardial border detection and is useful for the assessment of myocardial perfusion. Opacification of LV cavity by injection of commercially available contrast agents improves visualisation of the endocardium, leading to a more complete assessment of wall motion. This offers the potential to increase the sensitivity and specificity of the stress test. Recent studies have confirmed the feasibility, accuracy and prognostic value of contrast stress echocardiography. Tsutsui et al. demonstrated the incremental value of perfusion information obtained by realtime contrast echocardiography during dobutamine stress to wall motion assessment, as well as the prognostic value of perfusion detects in predicting cardiac events.20 However, the clinical implications of contrast stress echocardiography are limited due to the lack of a standardised technique.
Strain and strain rate imaging are novel parameters derived from tissue Doppler imaging and offer a more quantitative approach to regional LV function. Recent studies have documented the value of strain rate analysis during dobutamine infusion for the assessment of myocardial viability.21,22 Strain rate analysis provides an incremental value to wall motion assessment and increases sensitivity for the detection of viable segments. The limitations of strain and strain rate imaging in stress echocardiography are the lack of standardised methodology and consensus on the most appropriate parameters. Data regarding the use of 3D echocardiography in stress echocardiography are limited. Theoretically, stress echocardiography with realtime 3D echocardiography has some additional advantages such as a higher sensitivity in detecting small areas of wall motion abnormalities and a shortened time for image acquisition. Recent studies have reported the ability of realtime 3D echocardiography to assess wall motion abnormalities at rest23 and during dobutamine stress with and without contrast agents.24,25 Further technical advances in realtime 3D stress echocardiography are expected to result in its ultimate widespread use in routine clinical practice.
Stress echocardiography has become a mainstay in the diagnosis of CAD, and its prognostic value is evident in a broad range of patient subsets. Newer techniques in echocardiography such as myocardial contrast echocardiography for the assessment of myocardial perfusion, detailed evaluation of myocardial mechanics using strain rate imaging and 3D imaging show great promise in the field of stress echocardiography. As we seek ways to more efficiently, safely, accurately and cost-effectively evaluate our patients, the future of stress echocardiography is bright.