Recent advances in myocardial perfusion scintigraphy

Clinical Radiology (1996) 51, 677 683

Review Recent Advances in Myocardial Perfusion Scintigraphy M. G. GUNNING and S. R. UNDERWOOD

Royal Brornpton Hospital, London, UK

Since the 1970s the role of scintigraphic imaging in clinical cardiology has become clearly defined. Thallium-201 myocardial perfusion scintigraphy provides an alternative to exercise electrocardiography for the identification of myocardial ischaemia [1], and advantages over the exercise ECG have been reported in a number of studies [2]. Stress techniques, gamma camera technology, image reconstruction, tracer agents and operator expertise have all matured on the substrate of this experience to improve the accuracy, safety and efficiency of myocardial perfusion imaging. This article reviews some of the developments that have contributed to recent advances in the field.

Pharmacological Stress Dynamic exercise is well established in assessing patients with coronary artery disease both combined with electrocardiography and with myocardial perfusion scintigraphy. Pharmacological alternatives to dynamic exercise however have extended the role of perfusion imaging particularly for patients unable to exercise maximally [3,4]., Pharmacological techniques are safe, convenient, and accurate and they have been used in conjunction with a number of perfusion tracers [5,6,7]. Dipyridamole has been used since 1978 [8,9]. It inhibits adenosine deaminase and prevents cellular uptake of adenosine, thereby increasing interstitial levels of adenosine and causing vasodilatation with moderate selectivity for the coronary arterioles [10]. Relative perfusion defects arise from differential flow increases in normal and diseased arteries although myocardial ischaemia may also be induced by a number of mechanisms. A disadvantage however is its relatively long half-life with the hyperaemic response persisting for up to half an hour [11]. Side effects include flushing, headache, throat discomfort, chest pain and bronchospasm in susceptible subjects [12]. More recently, adenosine has been used directly and its pharmacological half-life of less than 10 s provides enormous advantages. Like dipyridamole it causes near-maximal coronary vasodilatation by binding to the A2 receptor leading to increased intracellular cyclic AMP [13]. While the safety of adenosine is well validated, it has similar side effects to dipyridamole [14]. It is contraindicated in asthma [15], sinoatrial disease [16], and high degree atrioventricular block [17]. Pennell and colleagues [18] demonstrated that combining adenosine with submaximal exercise reduced non-cardiac side effects by 43% and major arrhythmias by 90%, without any loss of diagnostic accuracy and the value of the technique has Correspondence to: Professor S. R. Underwood, National Heart and Lung Institute, Imperial College, Dovehouse St, London SW3 6LY, UK. © 1996 The Royal College of Radiologists.

been demonstrated in other studies [19]. In patients with left bundle branch block, exercise may provoke reversible perfusion abnormalities in the absence of coronary artery disease [20]. This may be related to delayed relaxation of the septum and less time for diastolic coronary_ perfusion or it may be the result of reduced mechanical stress in the septum in systole [21]. The artefact is minimized by using adenosine alone and hence avoiding the exercise-induced tachycardia, and a normal perfusion scintigram in a patient with LBBB make the presence of obstructive coronary artery disease very unlikely. The exercise ECG is of course unhelpful in these circumstances. When adenosine or dipyridamole are contraindicated, /3-sympathetic agonists can be very effective. Dobutamine has mixed/31,/32 and c~2 effects and it has been used most extensively [22-24]. It has both inotropic and chronotropic actions and it also increases coronary flow approximately two-fold [25,26]. These actions are very similar to dynamic exercise and it is the increase in myocardial perfusion that produces defects in perfusion images, very similar to the vasodilators. It should probably not be used in patients on /3-blocker medication, although the effect of /3-blockers on the increase in coronary flow caused by dobutamine is unclear. Dobutamine has a pharmacological half-life of approximately 2min and it is normally infused in increments from 5 to 40#g/kg/min. Adverse effects are usually minor and include transient bradycardia, hypotension, non-sustained ventricular and supraventricular arrhythmias, and symptoms such as tingling, flushing, nausea, palpitation and chest pain [27]. Dobutamine is safe [27] but the usual protocol is longer than for adenosine and it is most valuable as an alternative to adenosine in patients with reversible airways obstruction [28]. Arbutamine is a new synthetic catecholamine with non-selective /3 and weak c~1 activity. It has greater chronotropic action than dobutamine but less inotropic action, and it has a longer pharmacological half-life (approximately 8 min). Because of this it is best administered using a computer-controlled syringe pump, and in combination with both echocardiography and with perfusion scintigraphy the system is effective [29-32].

Myocardial Perfusion Tracers Thallium-201 has been used as a perfusion tracer for over two decades [1]. It has excellent physiological properties as a combined perfusion and viability tracer but it does not have ideal physical properties as an imaging agent. Its low energy X-ray emission (80 keV) leads to low resolution images with marked attenuation in soft tissues such as the breast, and its relatively long physical half-life (72 h) restricts the dose that can be used

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Fig. 1. - Gated [99mTc]-tetrofosmin SPECT. Diastolic and systolic frames from ECG-gated myocardial perfusion tomograms. (a) 50-year-old female with atypical chest pain and normal coronary arteries. There is homogeneous uptake of tracer, and symmetrical myocardial motion and thickening.

(b) 45-year-old male with previous myocardial infarction, three vessel coronary disease and impaired left ventricular function. The lateral and basal anterior walls have normal tracer uptake, motion and thickening, but there is absent uptake in the remainder of the anterior wall, the apex and the septum. The inferior wall has severely reduced uptake but there is some thickening in systole compatible with a small amount of remaining viable myocardium (best seen in the short axis). (VLA, vertical long axis; HLA, horizontal long axis; SA, short axis). © 1996 The Royal College of Radiologists, Clinical Radiology, 51, 677 683.

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if radiation exposure to the patient is to be minimized [33]. Technetium-99m analogues of thaliium-201 such as teboroxime, 2-methoxybutyl-isonitrile (MIBI), and tetrofosmin therefore have a number of advantages. They have the higher energy gamma emission of 140 keV for which gamma cameras have been specifically designed, and they have a shorter half-life of 6 h [34]. [99mTc]-Teboroxime clears very rapidly from the myocardium [35] and whilst this complicates routine clinical use, it does allow the possibility of serial studies. Cameras with multiple heads and short imaging protocols can provide good results [36] but the agent is not widely used and it is not available in all countries. Both 99mTc-tetrofosmin and 99mTc-MIBI, on the other hand, show little in the way of redistribution [37,38] and this may either be an advantage or a disadvantage depending upon the setting. Stress and rest studies are best performed on separate days and this is a greater inconvenience for the patient compared with the single day protocol for thallium-201. To overcome this problem, single day protocols with injection of 250 MBq (stress or rest) followed by 750MBq (rest or stress) can be used, but they are less reliable because of the activity remaining from the previous injection. Simultaneous assessment of ventricular function and myocardial perfusion is possible using the technetium99m tracers and this is achieved either by imaging the first passage of the tracer through the central circulation as it is injected [39], or by gating the perfusion images from the ECG to visualize myocardial motion and thickening [40]. First-pass ventriculography can be performed at rest or during stress and it has been validated using both single and dual planes [41]. Gated emission tomogra'phy not only provides additional functional information [42] but it may also increase the specificity of the perfusion technique by allowing areas of reduced tracer activity but with normal wall motion (perhaps caused by attenuation) to be correctly classified as normal (Fig. 1). A practical disadvantage of these combined techniques is that they are relatively time consuming and ventricular function is often known already from other imaging techniques. It is likely that they will be used in selected circumstances, perhaps particularly when information on myocardial thickening is required at the same time as myocardial viability in the assessment of hibernating myocardium (see below). The functional information from these techniques compares well with echocardiography or magnetic resonance imaging [43,44], but there are uncertainties when tracer uptake is too low to visualize the myocardium. Since such areas do not contain clinically significant amounts of viable myocardium, the theoretical disadvantage may not be important in practice. A series of monophosphine agents is also being developed [45]. [ 99mTc]-Q12 and [ 99mTc]-Q3 have good myocardial uptake but less liver uptake than MIBI and tetrofosmin. They appear to be effective in practice [46,47] but they are not yet available commercially and further experience is required.

Myocardial Viability The importance of left .ventricular function as an indicator or prognosis in patients with ischaemic heart disease is well known. During the 1970s several studies challenged the notion that chronic regional dysfunction © 1996 The RoyM College of Radiologists, Clinical Radiology, 51, 677 683.

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was synonymous with irreversible myocardial damage, and improvements in regional and global ventricular function were demonstrated after bypass grafting [48,49]. Terms such as 'viable', 'stunned' and 'hibernating' myocardium are now prominent in the literature and imaging techniques have a particular role in identifying these different states. The term viable should ideally refer to myocardium which is alive without further implications for its metabolic or functional state. Sometimes however the term is used erroneously to be synonymous with hibernating myocardium. Hibernation is in fact a subset of the various types of viable myocardium and it refers to myocardium which is alive but has reduced function at rest, with the potential to recover after revascularisation [50]. Positron emission tomography is most widely validated for the detection of hibernation. Most commonly metabolic imaging of [18F]-fluorodeoxyglucose, a glucose analogue [51 53] is combined with perfusion imaging using 13NH3, H2150 or 38K. In the normal fasting state fatty acids are the preferred metabolic substrates of the myocardium but this switches to glucose in ischaemia [54]. A glucose load, especially if combined with insulin, forces even normally perfused myocardium to metabolize glucose and most clinical studies have been performed under these conditions. Preserved uptake of FDG in a region combined with decreased uptake of the perfusion tracer indicates viable myocardium that is under-perfused and hence likely to be hibernating if it is also not contracting normally. Positive predictive accuracy of this technique for the identification of myocardium that will improve in function with revascularisation ranges from 72 to 95% [51-53]. Other positron emitting agents that provide metabolic information include [11C]-acetate, which is a marker of oxidative metabolism unaffected by variables such as substrate environment, and this has a similar predictive accuracy [511. The disadvantage of PET is that it is not widely available, but single photon tracers may be equally effective. Uptake of thallium requires an active myocyte membrane since transport across the membrane is partly passive, down an electrochemical gradient generated by the membrane, and partly active, using the ATPase dependent Na+-K + exchange pump. Because a viable cell requires an intact membrane, thallium is a viability tracer, and equilibration between the intra- and extracellular pools of thallium ensures that it will ultimately be taken up by any cell which is viable, irrespective of initial delivery. A rest injection of thallium with immediate and delayed imaging provides a viability image (delayed) and the same image modulated by perfusion at rest (immediate). Areas of viable myocardium that are underperfused at rest can therefore be identified as regions with redistribution of thallium between the two images (Fig. 2) [55]. Such myocardium is likely to be hibernating but it is also thought that hibernating myocardium may have variable perfusion at rest, alternating between normal and reduced (the theory of recurrent stunning). The best indicator of hibernating myocardium may therefore be a discrepancy between the amount of viable myocardium and its function, and the problem reduces to a combined assessment of viability and function. In assessing viability several thallium protocols have been used to overcome the problem of slow redistribution of the stress injection [56], including imaging at

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Fig. 2 Hibernating myocardium. Stress, redistribution, and separate day early and late resting Thallium-201 tomograms of a male patient (53 years) with occlusion of all three native coronary arteries (the LAD after a diagonal branch). There is an extensive reversible perfusion defect of the anteroseptal wall (best seen in the short axis) and the apex (best seen in the long axis), with almost complete redistribution in this area in the redistribution images. In the infero-lateral wall there is also a reversible perfusion defect which improves partially in the redistribution images and also shows redistribution between the early and late resting images, implying reduced perfusion at rest. LV function was impaired at rest and improved considerably after revascularisation. The patient's exertional dyspnoea also improved. (Abbreviations as in Fig. 1).

8-72 h after injection [57 59], injection at rest soon after the stress-redistribution images [60], and adjuncts such as ribose [61] or nitrates [62]. Any of these may be appropriate but they must be combined with an assessment of regional myocardial function using echocardiography or magnetic resonance imaging (MRI). The role of echocardiography or MRI combined with low-dose dobutamine is uncertain. Dobutamine may certainly provoke contraction of viable but hibernating myocardium but a similar pattern might be expected in areas with partial thickness infarction. Another drawback of dobutamine is that it can provoke ischaemia even at low doses, and so failure to augment function may not indicate absence of viable myocardium. Tracers that do not redistribute may be limited in assessing myocardial viability and several studies have shown that [99mTc]-MIB! may underestimate the amount of viable myocardium because delivery to myocardium with reduced perfusion is reduced [63,64]. Although injection under nitrate cover may overcome this limitation there are not yet sufficient data to recommend this protocol routinely. Of other potential techniques, dynamic imaging of [123I]-iodopentadecanoic acid compares well with FDG and thallium [65], and F D G can be imaged using a conventional

gamma camera rather than a dedicated positron camera [661.

Prognosis Developments in nuclear cardiology have contributed significantly to the value of myocardial perfusion imaging for the detection and assessment of coronary artery disease. Of equal importance is its role in the assessment of prognosis and the prediction of future cardiac events. The technique has both positive and negative predictive value in that abnormal stress scintigraphy implies a high likelihood of events and normal scintigraphy a low likelihood. In a review published in 1991, Brown [67] summarized a number of previous studies and the overall rate of cardiac events in patients with normal myocardial perfusion was 0.9% per year in a meta-analysis of 3594 patients. Machecourt and colleagues [68] found an even lower rate with an annual mortality of 0.1% in 715 patients. Similar results have been reported using MIBI as the perfusion agent [69,70]. This good negative predictive value of myocardial perfusion imaging means that, when used as part of a diagnostic strategy, the technique can avoid invasive investigation since normal or near normal perfusion mean that conservative O 1996 The Royal College of Radiologists, Clinical Radiology, 51,677-683.

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management is feasible irrespective of the presence of coronary irregularity. Several features of the abnormal scan are important in the prediction of events. Ladenheim and colleagues [11] showed that both the extent and the severity of thallium201 perfusion defects in planar images were independent predictors of future hard events in 1689 patients without a history of previous myocardial infarction, and this is supported in the findings of more recent studies [68,72]. In addition, increased uptake of thallium-201 in the lungs shortly after injection predicts an adverse outcome [73], and the phenomenon is a reflection of impaired left ventricular function and elevated pulmonary capillary pressure during stress. Dilation of the left ventricle in the stress images is also an adverse sign especially when the ventricle is smaller at res t [74]. The prognostic power of myocardial perfusion imaging provides additional and independent information compared with other parameters such as exercise time and number of diseased coronary vessels. Thus, incremental value is provided by the technique even when exercise testing and coronary arteriography have already been performed [75]. A number of techniques including myocardial perfusion imaging have been used after myocardial infarction to assess the presence of myocardium at further risk. Perfusion imaging is certainly very valuable in patients who do not have thrombolysis [76], but whether the value is the same in patients who do undergo thrombolysis is less clear, partly because of the influence that perfusion imaging routinely has upon the management of these patients. The value of perfusion imaging for assessing outcome has both clinical and economic implications. The need for invasive cororiary arteriography can be reduced and patients can be more appropriately selected for revascularisation. Strategies of investigation and management using myocardial perfusion imaging at an early stage are likely both to improve quality of care and to reduce cost [77,78]. The cardiologist and physician can no longer afford to ignore myocardial perfusion imaging. Facilities and expertise in the technique may be at a premium, but awareness of recent developments in the field is an essential step towards providing appropriate care.

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