Coronary artery disease diagnosis of ischaemia: general considerations

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1 European Heart Journal (1997) 18 (Supplement D), D57D62 Coronary artery disease diagnosis of ischaemia: general considerations K. Schroder and H.P. Schultheiss Klinikum Benjamin Franklin, Dept. of Cardiology, Free University Berlin, Germany Stress echocardiography is a well established tool for the diagnosis of coronary artery disease. It combines the provocation of myocardial ischaemia (either dynamic or nondynamic) with images of the left ventricle obtained by twodimensional echocardiography. Different modalities can be used to unmask coronary artery disease: increase of myocardial oxygen demand (exercise, pacing, or dobutamine) or reduction in oxygen supply (dipyridamole). Each form of stress has its distinct characteristics such as haemodynamic changes, accuracy, feasibility, and adverse effects, which specifically influence the decision 'which test for which patient'. Before engaging in the task of performing stress echocardiography, the cardiologist must have undergone special training under the supervision of an experienced stress echocardiographer, followed by an individual learning curve of 'try out' studies without any diagnostic impact. Introduction Myocardial ischaemia is the result of a transient imbalance of myocardial oxygen supply and demand, leading to symptoms and signs which can be used as a diagnostic marker. The temporal sequence of events during the course of ischaemia is well described by Nesto et a/. [l] as a typical cascade in which the various markers are ranked and well defined. The supplydemand imbalance is the forerunner of ischaemia, followed by metabolic changes, alterations in the ventricular diastolic and later on systolic function, and only at a later stage by ECG changes and chest pain (Fig. 1). Most of the time chest pain will be the main reason for the patient to seek medical advice. Unfortunately however, the chest pain is often the result of extracardiac causes, which cannot be differentiated from angina pectoris without further examination. Furthermore, about 25% of patients will have an acute myocardial infarction without having chest pain prior to the event. Correspondence: Dr Klaus Schroder, RehaKlinik Ahrenshoop, Dorfstr. 55, Ahrenshoop, Germany. While performing a stress echocardiographic examination one must always keep the history and risk profile of the individual patient in mind. These factors influence the pretest likelihood of a patient having coronary artery disease, and therefore also the diagnostic merit of a stress test. While stress echocardiography is not the first test to be employed in patients with suspected coronary artery disease, it represents a diagnostic tool which, if used correctly, is likely to become the most important noninvasive technique in modern cardiology. (Eur Heart J 1997; 18 (Suppl D): D57D62) Key Words: Stress echocardiography, modalities, requirements, diagnostic approach. In patients suspected to have coronary artery disease a stress test should be performed to identify the potential vulnerability of the myocardium to ischaemia and thus help to clarify the reasons for the 'chest pain'. Since the traditional markers of ischaemia (pain and ECG changes) are often inaccurate, it is essential to correlate the symptoms which lead the patient to seek medical aid with other more sophisticated and powerful markers. Stresso o 8 S 1 G) C3 Rest Figure 1 ^^ Supplydemand imbalance Systolic dysfunction ^ ^ Diastolic dysfunction Ischaemic cascade. ^^ ECG changes ^^ Angina X/97/0D $18.00/ The European Society of Cardiology

2 D58 K. Schroder and H.P. Schultheiss Hyperkinesin Normal thickening Hypokinesii Akinesii. / Dyskinesia Figure 2 Reduced flow Normal flow Increased flow Transmural blood flow vs degree of dyssynergy. The ischaemic cascade identifies left ventricular dyssynergy as an early, sensitive, and specific marker of ischaemia, and thus a reasonably good noninvasive estimate of the presence, extent, and severity of ischaemia should be possible by imaging left ventricular function during stress. Various techniques have been proposed for this task: nuclear scintigraphy, echocardiography, magnetic resonance imaging, and fast computed tomography'21. Continuous realtime imaging as well as spatial orientation make twodimensional echocardiography, first attempted in 1979 by Wann et al.[3\ an ideal tool for noninvasive identification of myocardial ischaemia. In the last few years it has become a widely used clinical tool, mainly due to developments in digital image processing. By 1975 Kerber et al.m could show that reduction in myocardial blood flow results in regional dyssynergies, recognizable on twodimensional echocardiography. Blood flow must, however, be reduced to 50% in at least 5% of the myocardium for detectable wall motion abnormalities to occur'5'. The normal reaction of the myocardium to stress is a >5 mm inward movement of the endocardium (towards the centre of the ventricle) as well as systolic myocardial thickening. The response to ischaemia is reproducible and independent of the stress for the underlying disease (ranging from vasospasm to fixed stenosis). The same changes can be found in transient ischaemia (spontaneous or provoked) and acute infarction. Therefore, from an echocardiographic viewpoint ischaemia can be seen as reversible myocardial infarction. The echocardiographic marker of ischaemia is regional dyssynergy, usually classified in three diseases: (1) hypokinesia=<5 mm inward movement, reduced myocardial thickening; (2) akinesia=absence of movement and thickening; (3) dyskinesia=paradoxical movement and myocardial thinning. As can be seen, this classification is arbitrarily focused on three points among a variety of ongoing, Eur Heart J. Vol. 18, Suppl D 1997 ischaemiainduced changes in left ventricular mechanical function. Hypokinesia, with its greater observer variability (intra as well as interobserver) is, however, less reliable than dyskinesia which, because of its marked changes, is more reliably associated with severe ischaemia. From a pathophysiological viewpoint, the severity of dyssynergy is correlated with transmural blood flow (Fig. 2). Stress echocardiographic modalities All diagnostic tests of myocardial ischaemia, usually combined with 12lead ECG or nuclear imaging techniques, can also be used with twodimensional echocardiography. Modalities leading to an increase in O2 demand (exercise, pacing, or dobutamine) or a reduction in O2 supply (vasodilators such as dipyridamole) can be used to unmask coronary artery disease. Each form of stress had distinct advantages and disadvantages. The most widely used modality to provoke ischaemia is dynamic exercise using either a treadmill or bicycle ergometer (upright or supine). With treadmill exercise, images can only be obtained before and immediately after exercise, resulting in the loss of the peak exercise images. Since there is a critical time window of s following the stress to acquire the images to ensure optimal accuracy, important information may be lost on the way from the treadmill to the examination table. Ryan et al. showed an increase in sensitivity of 8% (83% to 91%) if peak exercise images were recorded as compared to post exercise'61. Supine bicycle ergometer exercise on the other hand, allows the continuous registration of echocardiographic images throughout the test, providing information on cardiac performance that is not available from treadmill testing. Unfortunately many patients may find it difficult to exercise in this position. Furthermore patients undergoing treadmill testing will have higher heart rates and a greater workload than those who perform bicycle exercise'71. /

3 Diagnosis of ischaemia D59 The evaluation of patients who are unable to exercise (approximately 30%) can be accomplished with nondynamic stressors such as pharmacological agents or atrial pacing. Various forms of pharmacological stress have been used clinically, with dobutamine (mostly combined with atropine) and dipyridamole being the most important. Echocardiography is continuously performed during graded infusion of these agents, allowing the sonographer adequate time to record images at peak simulation. The mechanism by which these agents provoke ischaemia varies considerably. Dobutamine exerts a positive inotropic and chronotropic (especially if combined with atropine) effect on the heart, leading to increased oxygen demand. Dipyridamole produces arterial vasodilatation, resulting in a mismatch of blood flow due to greater flow to areas supplied by normal arteries as compared to stenosed arteries, which are unable to dilate ('steal effect'). Pacing has only been used in a limited number of studies. Most of the centres working with this modality have reduced its use to the very rare cases in which the patients cannot be stressed by pharmacological agents and cannot exercise sufficiently. This was mainly because pacing could not be tolerated by the patients. In a study of 121 postinfarction patients, the test had to be stopped prematurely in 15% because of intolerance of the stimulation. Of the patients who underwent the test, another 10% refused a second examination' 81. In all techniques, images are obtained at rest, during, and at maximal stress, as well as at recovery. In addition, most centres employ a 12lead ECG with slightly modified lead positions so as to obtain optimal image quality. Blood pressure and heart rate registration are mandatory. In deciding which test to choose for the individual patient, it is important to know the advantages and disadvantages inherent in the different modalities. To answer this question we performed a direct comparison of the four most widespread stress modalities in 121 patients 161. Haemodynamic changes Using the double product of systolic blood pressure and heart rate as a marker of myocardial oxygen consumption, we demonstrated clear differences between the modalities, which were due to the different modes by which the ischaemic response is provoked. While exercise and dobutamineatropine lead to the most marked increase of the double product (65% and 43%, respectively), dipyridamole as a vasodilator produced only a moderate increase of 20%. The 50% increase produced by atrial pacing was due solely to a rise in heart rate of 47%. These findings correlate well with the literature' 91 (Fig. 3). Adverse effects In the 121 post myocardial infarction patients studied, there were no deaths, cases of myocardial infarction, or Hi n EX DASE DET TAP Figure 3 Stressinduced haemodynamic changes in the double product. EX = exercise; DASE=dobutamineatropine stress echocardiography; DET=dipyridamole echo test; TAP=transoesophageal atrial pacing. 20 Table 1 Percent of graded side effects n= 121 EX DASE DET TAP None or mild Moderate 4 13* 3 65t 50 Severe 0 6* 2 26f EX = dynamic exercise; DASE=dobutamineatropine stress echocardiography; DET=dipyridamole echo test; TAP=transoesophageal atrial pacing. *P<005 compared with EX (severe) and DET (moderate). t/'<001 compared with EX, DASE, and DET. lifethreatening arrhythmia due to the stress tests. With the exception of transoesophageal atrial pacing, the tests were all well tolerated with mostly no or only moderate side effects. Moderate side effects included slight dyspnoea, headache, heart pounding, nervousness, nausea, and flushing. Severe side effects, judged to necessitate termination of the test despite absence of ischaemia, were observed in 23 patients. Other than the 18 patients who did not tolerate pacing, two had severe hypotension during dipyridamole infusion. During dobutamineatropine, two patients developed nonsustained ventricular tachycardia and one suptraventricular tachycardia leading to atrial fibrillation. None of the adverse effects were life threatening (Table 1). Comparison of exercise ECG, nuclear scintigraphy and stress echocardiography concerning testinduced mortality and adverse events, show comparable results, with no significant difference. Mortality rates of 001% are reported for all of the tests, adverse events occur in 004, 007 and 009% (ECG, echocardiography, and scintigraphy, respectively). Diagnostic accuracy Some studies have directly compared the diagnostic accuracy of the different tests. Table 2 shows a summary

4 D60 K. Schroder and H. P. Schultheiss Table 2 Diagnostic accuracy regarding the identification of significant coronary artery disease n532 Overall SVD Sensitivity MVD Specificity Accuracy Table 4 n = 150 Extent Location Variability of stress echocardiography Interobserver Intraobserver EX DASE DET EX = dynamic exercise; DASE = dobutamineatropine stress echocardiography; DET=dipyridamole echo test; SVD = singlevessel disease; MVD = multivessel disease. Table 3 Diagnostic accuracy regarding the identification of significant coronary artery disease following an acute myocardial infarction n121 Sub. EX DASE DET Overall SVD Sensitivity MVD Specificity Sub. EX = submaximal dynamic exercise; DASE=dobutamineatropine stress echocardiography; DET=dipyridamole echo test; SVD = singlevessel disease; MVD = multivessel disease. of five studies performed in the last 4 years in a total of 532 patients' 10 " 141. While exercise and dobutamine show a comparable accuracy (85% and 83%, respectively), dipyridamole only has a diagnostic accuracy of 68%. This difference is due to the poor sensitivity of dipyridamole concerning the identification of singlevessel disease (38% vs 70% and 61% respectively). In our own study of 121 patients the difference between dipyridamole and dobutamine was also very clear (64% vs 71%). Since we examined patients following an acute myocardial infarction, exercise stress was performed submaximally leading, as expected, to a very poor accuracy (Table 3). Taking all of the facts stated above into account, we feel that the decision 'which test for which patient' must be tailored to the individual clinical setting based on the following facts: (1) Individual patient characteristics (i.e. contraindications for the different test, inability to exercise etc.). (2) The experience of the cardiologist with the different modalities. (3) The 'Fisherman's approach', a term introduced by Ostojic during the XVI th Congress of the European Society of Cardiology in Berlin, meaning that the kind of test used depends on the kind of coronary artery disease one wants to identify. If the cardiologist is satisfied with just detecting severe multivessel disease, than a dipyridamole test is sufficient. If the goal of the stress echocardiography, however, is the identification of a very subtle, distal lesion in a single vessel, then a test with high accuracy is needed (i.e. dobutamine or exercise). In some cases a combination of stressors (i.e. dobutaminedipyridamole, or dipyridamoleexercise etc.) will be necessary for this task. Requirements Before starting stress echocardiography it is essential that the cardiologist has completed training in twodimensional echocardiography and is experienced in detecting and correctly interpreting wall motion abnormalities. Specific training in stress echocardiography should only be started after these preliminary requirements have been fulfilled. Similarly, as with other techniques, the cardiologist will go through a learning curve with a certain amount of 'try out' studies without any diagnostic impact. In 1991 Picano et «/. [15) showed very nicely that it requires approximately 100 studies under the supervision of an experience stress echocardiographer, to reach a sufficient plateau of diagnostic accuracy. Many countries have adopted this number as the basic requirement for reimbursement of stress echocardiographic studies. Reproducibility in stress echocardiography in cardiologists who undergo specific training is very good. The data for our laboratory, regarding not only the extent but also the localization of the provoked dyssynergies, are shown in Table 4 (numbers represent the correlation coefficient). The different stress modalities, however, require individual training not only concerning the interpretation of the study but also as regards the specific indications, contraindications and possible adverse events. Nondynamic stresses allow minimization of factors which make examination during dynamic stress rather difficult: hyperventilation, tachycardia, excessive chest wall and cardiac movement. Therefore dipyridamole can be regarded as the 'elementary school' of stress echocardiography, since it is the easiest to interpret and its adverse events are mostly not life threatening. Dobutamine can be looked upon as the 'high school', while dynamic stress echocardiography is the stress echocardiographic 'university'. Diagnostic approach Even today, with all the 'high tech' possibilities of modern medicine, the most important factor in the

5 Diagnosis of ischaemia D61 Suspected CAD not possible Exercise ECG non diagnostic I Echocardiography^ positive negative, but suspicious poor quality Nondynamic stressecho Figure 4 Dynamic stressecho Stepwise diagnostic approach. diagnosis of coronary artery disease is still the history of the patient including the individual risk profile. For instance, a positive exercise ECG will correctly identify the disease in >90% if the patient has typical angina. 'Ischaemia' ST changes in an asymptomatic patient, however, only correlate in approximately 30% with significant disease. This pretest likelihood of having coronary artery disease should therefore always be taken into consideration before performing further examinations. If the history of the patient indicates the possibility of coronary artery disease, then a stress ECG should be employed to identify a potential myocardial vulnerability to stress. If, after this test the diagnosis is clear, it is up to the cardiologist and the patient to decide whether or not to continue with invasive testing and possible interventions. The exercise ECG, however, has a low accuracy (especially in subgroups such as middleaged women, or patients, with hypertrophy). If, therefore, the pretest likelihood is high and the ECG test nondiagnostic, further more sophisticated tests, combining stress with imaging modalities should be considered. Furthermore, all patients with uninterpretable ECGs should be further investigated with imaging modalities. The advantages of echocardiography make it the method of choice in these circumstances. If the image quality is sufficient, then stress echocardiography using either dynamic or nondynamic stressors should follow. Patients who cannot exercise, or who are likely to only exercise submaximally should be referred to pharmacological stress testing. Again, if the results indicate the presence of coronary artery disease, then further invasive testing may be necessary. In our institution nuclear scintigraphy is only employed in those patients (1015%) in whom the resting images are so poor as to prevent the cardiologist from interpreting the wall motion (Fig. 4). Conclusion While stress echocardiography is not the first technique to be employed in a patient with suspected coronary Nuclear artery disease, it represents a diagnostic tool which, if used correctly, is likely to become the most important noninvasive technique in modern cardiology. The unparalleled advantages of feasibility, safety, reliability, portability and cost, makes echocardiography the noninvasive technique of choice, in spite of its dependence upon the experience of the cardiologist interpreting the images, as well as upon the patient's acoustic window. Stress echocardiography is a tool ready for widespread clinical use, not only in highly sophisticated laboratories but also in the everyday routine of a cardiological practice. The author wishes to thank the team of stress echocardiographic laboratory of the KJinikum Benjamin Franklin for the excellent team work. References [1] Nesto R, Kowalchuk GJ. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987; 57: 23C 30C. [2] Roeland J, Sutherland GR, Hugenholtz PG. The 1980s renaissance in the cardiac imaging: the role of ultrasound. Eur Heart J 1989; 10:6803. [3] Wann LS, Faris JV, Childress RH, Dillon JC, Weyman AE, Feigenbaum H. Exercise crosssectional echocardiography in ischemic heart disease. Circulation 1979; 60: [4] Kerber RE, Marcus ML, Erhardt J, Wilson R, Abboud FM. Correlation between echocardiographically demonstrated segmental dyskinesis and regional myocardial perfusion. Circulation 1975; 52: [5] Armstrong WF. Echocardiography in coronary artery disease. Progr Cardiovasc Dis 1988; 30: [6] Ryan T, Segar DS, Swada SG el al Detection of coronary artery disease with upright bicycle exercise echocardiography. J Am Soc Echocardiogr 1993; 6: [7] Aldrich HR, Reichek N. Stress echocardiography. Curr Opin Cardiol 1993; 8: [8] Schroder K, Voller H, Dingerkus H et al. Comparison of the diagnostic potential of four echocardiographic stress tests shortly after acute myocardial infarction: submaximal exercise, transesophageal atrial pacing, dipyridamole, and dobutamineatropine. Am J Cardiol 1996; 77: [9] Picano E. Pathogenetic mechanisms of stress. In: Picano E. Stress echocardiography. Berlin: Springer Verlag, 528.

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