Thallium scanning

Summary
Thallium scanning in coronary artery disease (CAD) using radioactive thallium-201(201Tl) is a widely available technique which is sensitive, accurate and noninvasive. It detects CAD accurately in patients with (1) atypical chest pain and a positive exercise ECG or (2) typical chest pain and a negative exercise ECG. In known CAD, it determines the severity, extent and haemodynamic significance of a stenosis. In patients with recurrent chest pain following coronary artery graft surgery (CAGS) or angioplasty, scanning can detect the presence and severity of any ischaemia, when graft occlusion or restenosis has occurred. 201Tl has important prognostic value in predicting cardiac complications (death and acute myocardial infarction) in patients undergoing major surgery - usually vascular. In patients with acute myocardial infarction, it may contribute to risk stratification.

Introduction
Coronary artery disease (CAD), although decreasing, is still the leading cause of death in Australia. Hence, accurate noninvasive methods of diagnosis and assessment are essential. ²⁰¹Tl scanning fulfils these requirements. It is highly sensitive in detecting CAD, predicting outcome, assessing the severity of ischaemia, and it can also provide risk stratification before surgery and after acute myocardial infarction.¹

Rationale of use
²⁰¹Tl is a monovalent cation which acts as a potassium analogue, concentrating in viable cells - not dead ones. It is distributed to all parts of the body, largely in proportion to regional blood flow.

The concentration of ²⁰¹Tl in the myocardium is proportional to coronary blood flow over a wide range of flows. This is important in exercise or pharmacological stress testing where flows can be as high as 4-5 times normal. Once inside the myocardial cell, the ²⁰¹Tl ion does not stay there. There is constant and continuous thallium exchange between the myocardial cell and the extra cellular space. This unique property is taken advantage of clinically during ²⁰¹Tl stress testing and is the basis for the `redistribution' or late 4 hour image.

Imaging
Thallium scanning requires a gamma or scintillation camera which detects gamma ray emissions and converts them into an image of the tracer's distribution.

Planar images are recorded in the anterior, 45 and 70 left anterior oblique views. These are quick and simple, but have overlying activity in them and vessel territory identification is less accurate.

Tomography, known as Single Photon Emission Computed Tomography or SPECT, gives 3-dimensional information and is now the method of choice. The camera rotates around the left chest and the image is reconstructed by the computer to give 3 planes through the left ventricle horizontal, long and short axis slices. SPECT has the advantage of removing overlying activity and making vessel territory identification much easier.

SPECT can also assess the severity of a coronary stenosis, or stenoses, by the degree to which ²⁰¹Tl uptake is decreased (mild, moderate, severe) in a perfusion defect. The severity and extent of disease can be semi quantified using comparative data from the SPECT ²⁰¹Tl scans of a cohort of normal subjects. The result is displayed as a polar map or bull's eye plot of the heart, showing the uptake of ²⁰¹Tl, in varying colours, outside 2.5 standard deviations from normal. The three vessel territories (left anterior descending, left circumflex and right coronary arteries) are ascribed areas on the bull's-eye and their contributions to perfusion can be calculated as a percentage.

Clinical application -- physiology

Exercise stress testing
Exercise is the most frequently used form of stress in the testing of cardiac function. During exercise, myocardial blood flow normally increases by up to 3-4 fold to supply the increase in oxygen demand. ²⁰¹Tl scanning measures this flow reserve. If coronary flow is limited by a stenosis, there will be less ²⁰¹Tl extracted from the blood by the myocardium in the territory of that artery compared with the normal, surrounding myocardium. This will cause a perfusion defect.

Over 2-4 hours, this perfusion defect will redistribute, or `fill in', as ²⁰¹Tl washes out of the normally perfused cells and some more ²⁰¹Tl is extracted by the hypoperfused myocardial cells. Hence, in ischaemia, the ²⁰¹Tl perfusion defect disappears with time and is called a reversible defect. By contrast, areas of scar tissue or infarction do not change with time and appear as fixed defects.

Pharmacological stress testing
In the patient who cannot exercise for various reasons, e.g. those with amputations or peripheral vascular disease, pharmacological `stress' may be used. This form of testing is also used in patients with left bundle branch block which frequently causes false positive septal defects after exercise testing. Intravenous dipyridamole is used as it is a potent coronary vasodilator increasing myocardial blood flow by 4-5 times normal - even higher than exercise. A higher flow, and therefore higher ²⁰¹Tl extraction by normal myocardium compared to that supplied by a stenosed artery, reveals an apparent perfusion defect.

Procedure

Patient preparation
The patient should allow the best part of a day for a ²⁰¹Tl stress test. The patient fasts overnight and may only have the occasional glass of water until the test is complete. This is because eating increases the blood flow to the gut, thus diverting thallium away from other organs, including the heart.

Exercise stress
The patient performs symptom limited exercise on a treadmill or bicycle ergometer under ECG monitoring. A heart rate of 85% of the predicted maximum is needed for a ²⁰¹Tl scan. Lower rates lead to suboptimal uptake of ²⁰¹Tl, a poorer quality image and a possible false negative study. In most circumstances, beta blockers should be suspended at least 48 hours before the test.

Thallium is injected at peak exercise (or when typical chest pain develops and/or significant ST depression occurs). Exercise is continued for one minute after injection to ensure maximum myocardial extraction of ²⁰¹Tl. The patient is scanned within 10 minutes.

Dipyridamole stress
The ECG is monitored for the 12 minutes of the procedure. The patient receives dipyridamole intravenously over 4 minutes. At 6 minutes, the patient performs isometric hand grip or low level exercise for two minutes. ²⁰¹Tl is given at 7 minutes after the infusion commences.

The patient may experience facial flushing, headache, abdominal symptoms or chest pain. The effects of dipyridamole are reversed promptly by intravenous aminophylline. A relative contraindication to dipyridamole is asthma. The patient should avoid caffeine and theophylline based medications for 48 hours before the test.

Clinical utility -- interpretation

No ischaemia
In a patient without significant CAD, there will be uniform distribution of ²⁰¹Tl in all myocardial segments in the immediate post stress and 4 hour redistribution image. If the ²⁰¹Tl scan is normal, there is usually a very low probability of angiographically significant CAD.²

Ischaemia present
In a patient with significant CAD (a stenosis of at least 70%), myocardial ²⁰¹Tl uptake will be reduced, causing a perfusion defect in the distribution of the stenosed vessel in the immediate post stress image. After 4 hours, the perfusion defect will `fill in' or redistribute giving a uniform <sup>201</sup>Tl distribution throughout the myocardium on reimaging (Figs 1 and 2). Some perfusion defects only partially redistribute, or do not `fill in' at all by 4 hours. These patients are now re-injected with a smaller dose of ²⁰¹Tl and reimaged after 30 minutes or alternatively reimaged at 24 hours without reinjection. Following reinjection and/or delayed imaging, patients with severe ischaemia usually demonstrate full or partial redistribution. Fixed defects which do not redistribute are interpreted as scar tissue from myocardial infarction or nonviable myocardium which would not benefit from revascularisation.

The bull's-eye plot is very helpful for interpretation. It provides quantitative data on severity and extent of ischaemia, especially in multi vessel disease.

Viability
The question of whether myocardium is viable can also be addressed using rest and redistribution imaging. Following thallium injection, coronary blood flow at rest is assessed immediately and again at 4 hours. In a patient with a critical stenosis, there will be very low flow at rest producing a perfusion defect of varying severity. If there is viable myocardium present, the defect will redistribute over time, to a greater or lesser extent, as it does in stress induced ischaemia. The degree of redistribution probably depends on the amount of collateral blood flow to the severely ischaemic zone.

Diagnostic utility

(Table 1)
²⁰¹Tl scanning is more sensitive than an exercise ECG.³ However, the type of imaging affects the sensitivity and specificity (see box). The fall in specificity is due to artefacts, causing false positives, which cannot be distinguished from true ischaemia or infarction. Artefacts can simulate ischaemia or infarction in patients with or without CAD. A thorough knowledge of the causes of artefacts, especially in SPECT imaging, by the interpreting nuclear medicine physician is critical. A large number can be prevented or detected by meticulous attention to scan technique and quality control procedures.

Diagnosis
The diagnostic utility of a ²⁰¹Tl stress test is invaluable in certain frequently encountered clinical situations. Two major diagnostic problems for the clinician are (1) positive exercise ECGs, often in females with atypical chest pain, and (2) negative exercise ECGs, often in males with typical chest pain. A significant number of these patients do not have CAD. A ²⁰¹Tl stress test can distinguish false positive from true positive exercise ECGs, and false negative from true negative exercise ECGs, and may allow the patient to avoid cardiac catheterisation.

Revascularisation
Coronary angiography locates the site and number of stenoses, whether they are suitable for bypass grafting or angioplasty, and the presence or absence of collateral flow. A ²⁰¹Tl stress test provides complementary functional information about the haemodynamic significance of stenoses and therefore the presence and extent of jeopardised, viable myocardium. In multi vessel disease, it will distinguish which lesions are causing most ischaemia and require particular attention at revascularisation.

One aim of revascularisation is to restore blood flow to viable but jeopardised myocardium. Wall motion abnormalities can be due to prior myocardial infarction (nonviable) or chronic severe ischaemia (viable), known as `hibernating' myocardium. ²⁰¹Tl scanning can distinguish scar from viable myocardium in most (85-90%) cases, predicting which patients are likely to have regional contraction restored by revascularisation.

²⁰¹Tl stress testing has a major role in the investigation of the recurrence of chest pain after revascularisation. There may even be an argument to perform a ²⁰¹Tl stress test routinely, following revascularisation, as a baseline to assess future changes in a patient who experiences recurrence of angina.

Prognostic value
²⁰¹Tl stress testing has prognostic value in a variety of patients with suspected or known CAD (Table 1). Patients with one or more reversible perfusion defects on a ²⁰¹Tl stress test have a 6-12 fold increased risk of future cardiac events - cardiac death or acute myocardial infarction (MI) - compared with normal.⁴ The best predictor of future cardiac events is the number of reversible ²⁰¹Tl defects.¹ Conversely, a normal ²⁰¹Tl scan, even in the presence of angiographically proven CAD, has a very high predictive value for a low (approaching the normal population) rate of future cardiac events.

Increased lung uptake of ²⁰¹Tl and transient ventricular dilatation are markers of severe CAD.¹ Both are signs of exercise induced ischaemic left ventricular dysfunction which has serious prognostic implications. In one series⁵, uptake of ²⁰¹Tl by the lungs was the best predictor of cardiac events among all clinical and angiographic variables tested.

Following MI, ²⁰¹Tl stress testing has an important role in risk stratification. It is superior to sub-maximal exercise ECG testing alone because it has increased sensitivity for detecting multi vessel disease, localises vascular territories, distinguishes ischaemia from infarct and identifies exercise induced left ventricular dysfunction.¹ Dipyridamole ²⁰¹Tl stress is better than sub-maximal exercise ²⁰¹Tl stress and is the only significant predictor of late cardiac death and recurrent MI. The incidence of cardiac events, post-MI, in patients with dipyridamole induced ischaemia is 64% compared with 8% if there is no ischaemia.¹

²⁰¹Tl stress testing has also been used in preoperative risk stratification. Peripheral vascular disease is associated with CAD, which is often asymptomatic. Clinical assessment can be unreliable as ischaemia may be silent. As the patients may be unable to exercise, dipyridamole stress is usually employed. The incidence of perioperative cardiac events in patients with proven ischaemia on ²⁰¹Tl stress testing ranges from 33-50%. This is in comparison to no events in patients who had a fixed defect (infarct) or a normal ²⁰¹Tl scan. In one series, 17% of all surgical cases with severe and extensive ischaemia had an 80% probability of perioperative cardiac events.¹