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.
- Kerber RE, Abboud FM, Echocardiographic detection of regional myocardial infarction, Circulation, 1973;47:997–1005.
- Wann LS, Faris JV, Childress RH, et al., Exercise cross-sectional echocardiography in ischemic heart disease, Circulation, 1979;60:1300–1308.
- Armstrong WF, O’Donnell J, Dillon JC, et al., Complementary value of two-dimensional exercise echocardiography to routine treadmill exercise testing, Ann Intern Med, 1986;105:829–35.
- Robertson WS, Feigenbaum H, Armstrong WF, et al., Exercise echocardiography: a clinically practical addition in the evaluation of coronary artery disease, J Am Coll Cardiol, 1983;2:1085–91.
- Pellikka PA, Nagueh SF, Elhendy AA, et al., American Society of Echocardiography recommendations for performance, interpretation, and application of stress echocardiography, J Am Soc Echocardiogr, 2007;20:1021–41.
- Kraunz RF, Kennedy JW, Ultrasonic determination of left ventricular wall motion in normal man. Studies at rest and after exercise, Am Heart J, 1970;79:36–43.
- Mason SJ, Weiss JL, Weisfeldt ML, et al., Exercise echocardiography: detection of wall motion abnormalities during ischemia, Circulation, 1979;59:50–59.
- Gould KL, Westcott RJ, Albro PC, et al., Non-invasive assessment of coronary stenoses by myocardial imaging during pharmacologic coronary vasodilatation, Am J Cardiol, 1978;41:279–87.
- Picano E, Bedetti G, Varga A, et al., The comparable diagnostic accuracies of dobutamine and dipyridamole stress echocardiographies, Coron Artery Dis, 2000;11:151–9.
- Chuah SC, Pellikka PA, Roger VL, et al., Role of dobutamine stress echocardiography in predicting outcome in 860 patients with known or suspected coronary artery disease, Circulation, 1998;97:1474–80.
- Marwick TH, Case C, Sawada S, et al., Prediction of mortality using dobutamine echocardiography, J Am Coll Cardiol, 2001;37:754–60.
- Marwick TH, Case C, Vasey C, et al., Prediction of mortality by exercise echocardiography: a strategy for combination with the duke treadmill score, Circulation, 2001;103:2566–71.
- McCully RB, Roger VL, Mahoney DW, et al., Outcome after normal exercise echocardiography and predictors of subsequent cardiac events, J Am Coll Cardiol,1998;31:144–9.
- Sawada SG, Ryan T, Conley MJ, et al., Prognostic value of a normal exercise echocardiogram, Am Heart J, 1990;120:49–55.
- Sozzi FB, Elhendy A, Roelandt JR, et al., Long-term prognosis after normal dobutamine stress echocardiography, Am J Cardiol, 2003;92:1267–70.
- Chaowalit N, McCully RB, Callahan MJ, et al., Outcomes after normal dobutamine stress echocardiography and predictors of adverse events: long-term follow-up of 3,014 patients, Eur Heart J, 2006;27:3039–44.
- Arruda-Olson AM, Juracan EM, Mahoney DW, et al., Prognostic value of exercise echocardiography in 5,798 patients: is there a gender difference?, J Am Coll Cardiol, 2002;39:625–31.
- Chaowalit N, Arruda AL, McCully RB, et al., Dobutamine stress echocardiography in patients with diabetes mellitus: enhanced prognostic prediction using a simple risk score, J Am Coll Cardiol, 2006;47:1029–36.
- Sicari R, Pasanisi E, Venneri L, et al., Stress echo results predict mortality: a large-scale multicenter prospective international study, J Am Coll Cardiol, 2003;41:589–95.
- Tsutsui JM, Elhendy A, Anderson JR, et al., Prognostic value of dobutamine stress myocardial contrast perfusion echocardiography, Circulation, 2005;112:1444–50.
- Hanekom L, Jenkins C, Jeffries L, et al., Incremental value of strain rate analysis as an adjunct to wall-motion scoring for assessment of myocardial viability by dobutamine echocardiography, Circulation, 2005;112:3892–3900.
- Hoffmann R, Altiok E, Nowak B, et al., Strain rate measurement by doppler echocardiography allows improved assessment of myocardial viability inpatients with depressed left ventricular function, J Am Coll Cardiol, 2002;39:443–9.
- Corsi C, Lang RM, Veronesi F, et al., Volumetric quantification of global and regional left ventricular function from realtime 3D echocardiographic images, Circulation, 2005;112:1161–70.
- Takeuchi M, Otani S, Weinert L, et al., Comparison of contrastenhanced real-time live 3D dobutamine stress echocardiography with contrast 2D echocardiography for detecting stress-induced wall-motion abnormalities, J Am Soc Echocardiogr, 2006;19:294–9.
- Yang HS, Pellikka PA, McCully RB, et al., Role of biplane and biplane echocardiographically guided 3D echocardiography during dobutamine stress echocardiography, J Am Soc Echocardiogr, 2006;19:1136–43.
- Armstrong WF, O’Donnell J, Ryan T, et al., Effect of prior myocardial infarction and extent and location of coronary disease on accuracy of exercise echocardiography, J Am Coll Cardiol, 1987;10:531–8.
- Crouse LJ, Harbrecht JJ, Vacek JL, et al., Exercise echocardiography as a screening test for coronary artery disease and correlation with coronary arteriography, Am J Cardiol, 1991;67:1213–18.
- Marwick TH, Nemec JJ, Pashkow FJ, et al., Accuracy and limitations of exercise echocardiography in a routine clinical setting, J Am Coll Cardiol, 1992;19:74–81.
- Hecht HS, DeBord L, Shaw R, et al., Digital supine bicycle stress echocardiography: a new technique for evaluating coronary artery disease, J Am Coll Cardiol, 1993;21:950–56.
- Beleslin BD, Ostojic M, Stepanovic J, et al., Stress echocardiography in the detection of myocardial ischemia. Head-to-head comparison of exercise, dobutamine, and dipyridamole tests, Circulation, 1994;90:1168–76.
- Luotolahti M, Saraste M, Hartiala J, Exercise echocardiography in the diagnosis of coronary artery disease, Ann Med, 1996;28:73–7.
- Roger VL, Pellikka PA, Bell MR, et al., Sex and test verification bias. Impact on the diagnostic value of exercise echocardiography, Circulation, 1997;95:405–10.
- Cohen JL, Greene TO, Ottenweller J, et al., Dobutamine digital echocardiography for detecting coronary artery disease, Am J Cardiol, 1991;67:1311–18.
- Sawada SG, Segar DS, Ryan T, et al., Echocardiographic detection of coronary artery disease during dobutamine infusion, Circulation, 1991;83:1605–14.
- Marcovitz PA, Armstrong WF, Accuracy of dobutamine stress echocardiography in detecting coronary artery disease, Am J Cardiol, 1992;69:1269–73.
- McNeill AJ, Fioretti PM, el-Said SM, et al., Enhanced sensitivity for detection of coronary artery disease by addition of atropine to dobutamine stress echocardiography, Am J Cardiol, 1992;70:41–6.
- Takeuchi M, Araki M, Nakashima Y, et al., Comparison of dobutamine stress echocardiography and stress thallium-201 single-photon emission computed tomography for detecting coronary artery disease, J Am Soc Echocardiogr, 1993;6: 593–602.
- Previtali M, Lanzarini L, Fetiveau R, et al., Comparison of dobutamine stress echocardiography, dipyridamole stress echocardiography and exercise stress testing for diagnosis of coronary artery disease, Am J Cardiol, 1993;72:865–70.
- Elhendy A, yan Domburg RT, Roelandt JR, et al., Accuracy of dobutamine stress echocardiography for the diagnosis of coronary artery stenosis in patients with myocardial infarction: the impact of extent and severity of left ventricular dysfunction, Heart, 1996;76:123–8.
- Ling LH, Pellikka PA, Mahoney DW, et al., Atropine augmentation in dobutamine stress echocardiography: role and incremental value in a clinical practice setting, J Am Coll Cardiol, 1996;28:551–7.
- Wu CC, Ho YL, Kao SL, et al., Dobutamine stress echocardiography for detecting coronary artery disease, Cardiology, 1996;87:244–9.
- Bigi R, Galati A, Curti G, et al., Prognostic value of residual ischaemia assessed by exercise electrocardiography and dobutamine stress echocardiography in low-risk patients following acute myocardial infarction, Eur Heart J, 1997;18:1873–81.
- Hennessy TG, Codd MB, Kane G, et al., Evaluation of patients with diabetes mellitus for coronary artery disease using dobutamine stress echocardiography, Coron Artery Dis, 1997;8:171–4.
- Smart SC, Knickelbine T, Stoiber TR, et al., Safety and accuracy of dobutamine-atropine stress echocardiography for the detection of residual stenosis of the infarct-related artery and multivessel disease during the first week after acute myocardial infarction, Circulation, 1997;95:1394–1401.
- Elhendy A, Geleijnse ML, van Domburg RT, et al., Gender differences in the accuracy of dobutamine stress echocardiography for the diagnosis of coronary artery disease, Am J Cardiol, 1997;80:1414–18.
- Hennessy TG, Codd MB, Hennessy MS, et al., Comparison of dobutamine stress echocardiography and treadmill exercise electrocardiography for detection of coronary artery disease, Coron Artery Dis, 1997;8:689–95.
- Salustri A, Fioretti PM, McNeill AJ, et al., Pharmacological stress echocardiography in the diagnosis of coronary artery disease and myocardial ischaemia: a comparison between dobutamine and dipyridamole, Eur Heart J, 1992;13:1356–62.
- Dagianti A, Penco M, Agati L, et al., Stress echocardiography: comparison of exercise, dipyridamole and dobutamine in detecting and predicting the extent of coronary artery disease, J Am Coll Cardiol, 1995;26:18–25.
- Pingitore A, Picano E, Colosso MQ, et al., The atropine factor in pharmacologic stress echocardiography. Echo Persantine (EPIC) and Echo Dobutamine International Co-operative (EDIC) Study Groups, J Am Coll Cardiol, 1996;27:1164–70.
- Minardi G, Di Segni M, Manzara CC, et al., Diagnostic and prognostic value of dipyridamole and dobutamine stress echocardiography in patients with Q-wave acute myocardial infarction, Am J Cardiol, 1997;80:847–51.
- Santoro GM, Sciagra R, Buonamici P, et al., Head-to-head comparison of exercise stress testing, pharmacologic stress echocardiography, and perfusion tomography as first-line examination for chest pain in patients without history of coronary artery disease, J Nucl Cardiol, 1998;5:19–27.
- Loimaala A, Groundstroem K, Pasanen M, et al., Comparison of bicycle, heavy isometric, dipyridamole-atropine and dobutamine stress echocardiography for diagnosis of myocardial ischemia, Am J Cardiol, 1999;84:1396–1400.