Clinical Single Photon Emission Computed Tomography Cardiac Protocols

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CHAPTER 21 Clinical Single Photon Emission Computed Tomography Cardiac Protocols

Nuclear medicine has become a remarkable diagnostic tool to identify and to stratify patients with suspected coronary artery disease (CAD) with pivotal prognostic implications. Myocardial perfusion imaging (MPI) provides an accurate measurement of coronary narrowing leading to inducible perfusion abnormalities with prognostic implications (Fig. 21-1). The relationship between the degree of coronary stenosis and the maximal hyperemic response was first reported more than 30 years ago.¹ Myocardial regions with relatively decreased post-stress radiotracer uptake and resting normalization indicate a misbalance between oxygen supply and myocardial demands, characteristic of ischemia. Nonreversible myocardial perfusion defects normally relate to necrosis or infarction. Current imaging protocols allow the accurate assessment of relative regional perfusion and myocardial function at rest and stress based on regional blood flow heterogeneity. Gated single photon emission computed tomography (SPECT) represents nearly 95% of all procedures performed today in cardiac nuclear medicine. This chapter reviews the different imaging SPECT acquisition protocols that are currently in use as well as the principal indications.

FIGURE 21-1 Evaluation of CAD: a prognostic approach.

TECHNICAL REQUIREMENTS

²⁰¹Tl Imaging Protocols

During the last two decades, thallium 201 (²⁰¹Tl) has been used as a myocardial perfusion tracer. After an intravenous injection, the initial myocyte uptake is mainly determined by regional myocardial perfusion, whereas the integrity of the cell membrane is predominantly important for delayed imaging of tracer retention (potassium ion total distribution). Regional thallium activity on delayed images acquired early (3 to 4 hours) or late (8 to 72 hours) after stress has been used to demonstrate the presence and extent of viable myocardium based on the phenomenon termed thallium redistribution.² Intracellular thallium uptake through the sarcolemmal membrane is maintained during long periods if regional myocardial blood flow is sufficiently preserved to be able to deliver the isotope to the myocytes. Redistribution is thought to represent areas of ischemic but viable myocardium, whereas fixed, non-redistributing defects are thought to represent nonviable, fibrotic scar.

When ²⁰¹Tl alone is used, a variety of different acquisition protocols of stress imaging have been employed, including redistribution and reinjection imaging. Although different ²⁰¹Tl imaging protocols have been employed, stress-redistribution-reinjection and rest-redistribution SPECT imaging protocols are the most currently used to assess myocardial viability.³ Reinjection of 1 mCi of ²⁰¹Tl after 3 to 4 hours of redistribution imaging detects viable tissue in 35% to 49% of segments with fixed irreversible ²⁰¹Tl defects with conventional stress-redistribution protocols.⁴ An inverse relationship has been reported between regional thallium activity in irreversible defects and the amount of myocardial fibrosis.⁵ Perrone-Filardi and colleagues⁶ demonstrated the nearly linear relation between thallium activity and the likelihood of recovery of regional function after revascularization. Overall sensitivity of several stress-redistribution-reinjection studies averaged 85% with a lower specificity (averaging 47%), suggesting that this protocol tends to overestimate the potential for contractile function recovery.²

Rest-redistribution ²⁰¹Tl imaging is a valid alternative to discriminate viable from nonviable myocardium when the clinical question is to identify viability and not inducible ischemia.⁷^,⁸ Studies have reported that 24-hour imaging after rest injection detects additional areas of viable myocardium compared with 4-hour imaging alone, possibly related to higher resting blood flow levels.⁹

Tc 99m Labeled Imaging Protocols

A technetium Tc 99m labeled compound, either sestamibi or tetrofosmin, is a synthetic lipophilic cationic perfusion agent that distributes passively across sarcolemmal and mitochondrial membranes remaining fixed to the mitochondria. A negative mitochondrial gradient charge is essential for its accumulation and retention within the myocyte. Unlike ²⁰¹Tl, it does not redistribute over time. This lack of significant redistribution means that separate rest and stress injections are standard with ^99mTc-labeled compounds. Different acquisition protocols can be used with these agents, including 2-day stress/rest, same-day rest/stress, same-day stress/rest, and dual-isotope protocols.

Two-Day Protocol

From a technical point of view, to optimize imaging quality, the 2-day stress/rest is one of the most preferred acquisition protocols. The main advantage is the use of two high doses of Tc 99m labeled compounds, which enables high-quality images to be obtained because of the elevated high count rate. The stress study should be performed first because the rest study can be omitted if the stress study is normal. Obviously, the major disadvantage is the delay in reporting of the final analysis.

One-Day Protocol

This is probably the most commonly employed protocol with low-dose rest/high-dose stress; its major drawback is the risk of reducing the stress image’s contrast; up to 15% of the radiotracer uptake observed at the time of stress imaging comes from the preexisting resting myocardial distribution. The order sequence for this protocol should be related to the main indication. If the study is performed for the diagnosis of myocardial ischemia, the stress portion should be done first because that will avoid the reduction of contrast that a previously resting injection would have on a stress-induced defect. If detection of viable myocardium or assessment of the reversibility of a perfusion defect is the indication, performance of the resting study first may be preferable.

As with all Tc 99m labeled compounds, imaging should begin between 60 and 90 minutes after injection to allow hepatobiliary clearance and to minimize subdiaphragmatic activity if vasodilators were administered. To enhance the washout of gastrointestinal activity from liver and gallbladder, fluids or a fatty meal can be suggested.

Regarding viability assessment, earlier studies using primarily planar scintigraphy and visual interpretation suggested that Tc 99m sestamibi underestimates myocardial viability in chronic CAD and left ventricular dysfunction. Dilsizian and colleagues ¹⁰ described the utility of quantitative Tc 99m sestamibi imaging when the severity of decrease in Tc 99m sestamibi uptake within irreversible defects was considered or when an additional redistribution image was acquired after the rest injection for detection of dysfunctional but viable myocardium. A significant inverse linear relationship has been described between Tc 99m sestamibi uptake and myocardial fibrosis in biopsy specimens.¹¹ Several approaches have been introduced to increase the diagnostic performance of Tc 99m sestamibi for the identification of viable myocardium, such as functional evaluation of the left ventricle by first-pass radionuclide ventriculography, gated SPECT acquisition perfusion images,¹² and intravenous administration of nitrates to reduce resting hypoperfusion and to increase the correspondence of the resting images with myocardial viability.¹³

Fatty acid analogues marked with iodine isotopes (¹²³I, ¹³¹I) have been employed to study myocardial metabolism on the basis of the principle that in a viable but ischemic myocardium, fatty acids are mainly esterified and incorporated into the triglyceride and phospholipid blood pool and are slowly metabolized, with subsequent clearance rate reduction.¹⁴ Early data suggested that this method may provide data comparable to ²⁰¹Tl protocols in patients with left ventricular dysfunction or after an acute myocardial infarction. These tracers may prove to be of more value in the near future, considering the key role that oxidative metabolism plays in preservation of myocardial function.

Dual-Isotope Protocols

Dual-isotope imaging protocols using Tc 99m labeled compounds and ²⁰¹Tl are based on the ability of the Anger camera to collect data from the two different energy windows representing each radiotracer. Simultaneous and separate dual-isotope imaging protocols have been described.¹⁵^,¹⁶ Two of the major advantages of these protocols are the possibility of shortening the duration of a complete stress or rest redistribution protocol and the superior capability of ²⁰¹Tl to assess myocardial viability. Separate acquisition times can reduce the necessity of downscatter correction that can diminish ²⁰¹Tl contrast images, leading to an overestimation of defect reversibility; this can be achieved by acquiring ²⁰¹Tl data sets before the administration of Tc 99m because of the very limited (2.2%) contribution of ²⁰¹Tl into the Tc 99m energy window.

Gated SPECT

Most of the current imaging protocols perform a simultaneous ECG gating during at least the stress data set acquisition.¹⁷ Gated SPECT can be performed with ²⁰¹Tl or Tc 99m compounds. One of the major advantages is the possibility of measuring contractile function and the left ventricular ejection fraction.

STRESS PROTOCOLS

The primary aim of stress MPI is to detect CAD and to risk stratify those patients with known CAD. To achieve this goal, SPECT MPI is based on the assessment of the relative regional blood flow perfusion to myocardial regions supplied by stenotic vessels and its comparison with myocardial territories supplied by normal vessels. The principal difference between stress methods relates to the mechanisms used to disclose regional myocardial blood flow abnormalities as an indication of coronary stenosis. It is critical to select the most appropriate test by the indication on a patient by patient basis. When the goal is to evaluate exercise tolerance, the duration of the exercise, symptoms developed, and hemodynamic changes are the primary factors to consider. On the other hand, if the aim is to detect CAD or to risk stratify the patient, the factors that determine myocardial oxygen demand are the most important to take into account.

Exercise Testing

This is the most common form of stress during MPI. Exercise testing is performed on the treadmill according to the Bruce protocols and allows the assessment of different hemodynamic variables, such as exercise capacity, blood pressure, and heart rate responses. It is imperative that the intravenous injection of the radiotracer be performed at maximal stress and that exercise continue for at least an additional 60 seconds to ensure optimal myocardial concentration. The traditional goal of the test as an acceptable level of cardiac workload has been the achievement of at least 85% of the maximum predicted heart rate (220 − age). Prognostic information from the exercise test should be integrated with MPI because the patients with mild to moderate perfusion defects who achieved a heart rate higher than 80% had a very low risk for major cardiac events and cardiac death.¹⁸ At the same time, patients with a reported normal MPI study but abnormal heart rate reserve were at the same risk for suffering a major cardiac event as those with normal heart rate reserve achieved and abnormal MPI studies (Tables 21-1 and 21-2). A maximal stress test may satisfy diagnostic purposes if it goes beyond the hemodynamic threshold of triggering the ischemic symptoms. However, it may not reveal the full amount of jeopardized myocardium and may be inadequate for the evaluation of cardiac risk in a patient scheduled to have major noncardiac surgery. A submaximal exercise test (not achieving 85% of the targeted heart rate) may still be a valid alternative for evaluation of ischemic risks after cardiac events. To achieve the most adequate level of cardiac stress and to avoid suboptimal stress testing, patients should discontinue antianginal medications (β blockers and calcium blockers for 36 to 48 hours and long-acting nitrates for 12 hours).¹⁹ Furthermore, all patients should be studied in the fasting state, having been in a nothing-by-mouth status for at least 4 hours before the study, regardless of the stress method to be employed. All caffeine, including beverages and chocolate, especially before pharmacologic stress testing, should be avoided for at least 24 to 48 hours to avoid block of the endothelial receptors and their dilatory effect.

TABLE 21-1 Exercise Protocols

Bicycle or treadmill

Maximal exercise and at least 85% of age-predicted maximum heart rate

Monitor ECG continuously (9 or 12 leads)

Blood pressure recorded every 2 to 3 minutes

Tracer injection at peak exercise; keep exercising for at least 1 additional minute

Assess electrical changes or symptoms

TABLE 21-2 Exercise Stress Contraindications

Acute aortic dissection

Symptomatic aortic stenosis

Uncontrolled cardiac arrhythmias

Severe pulmonary hypertension

Acute myocardial infarction within the last 5 days

Uncontrolled, severe hypertension (blood pressure > 200/110 mm Hg)

Decompensated congestive heart failure

Uncontrolled unstable angina

Pharmacologic Stress Protocols

These tests are generally performed in those patients who cannot achieve an adequate level of exercise. The two types of drugs used for pharmacologic stress are vasodilators and inotropics such as dobutamine. Coronary local autoregulatory mechanisms maintain adequate regional blood flow at rest, even when a significant coronary stenosis is present. For this reason, patients may be asymptomatic at rest, having normal myocardial perfusion studies. The hyperemic pharmacologic stress response is based on the ability of the coronary vessel to preserve its vasodilatory response. When this autoregulation fails, the vessel is unable to augment the supply required for an increased demand, producing therefore a related image defect. This is a manifestation of a decreased coronary flow reserve when it is considered as the ratio between the peak myocardial blood flow achieved at stress and its counterpart at rest. Thus, a hemodynamically significant coronary narrowing could be defined by a blunted coronary flow reserve in the presence of hyperemic stress; the greater the stress and the related increase in flow in normal vessels, the greater the possibility of identifying those regions with different degrees of coronary stenosis. Normal vessels increase their blood flow four to five times after adequate stress. Current SPECT instruments allow the detection of regional perfusion distribution when there is a 30% change in radiotracer concentration.

Vasodilators

Dipyridamole and adenosine are the most commonly used coronary vasodilators (Figs. 21-2 and 21-3). Briefly, dipyridamole is a pyrimidopyrimidine that has been widely used since 1987. Its blocks the cellular reuptake of adenosine, increasing its extracellular concentration, which produces vasodilation. Dipyridamole denies the extracellular access to the activity of red cell membrane–bound adenosine deaminase. The coronary dilating effect is related to the A₂ receptor binding and activation mediated by G proteins, which ultimately result in vascular smooth muscle relaxation and vasodilation. The stimulation of the A₁ receptor in the sinus and atrioventricular nodes reduces the sinus rate and the atrioventricular conduction that may cause heart block during stress testing.

FIGURE 21-2 Structure of dipyridamole.

FIGURE 21-3 Structure of adenosine.

Individuals with normal coronary arteries increase their blood flow up to four times of the resting levels. In patients with CAD, there is heterogeneity of perfusion without ischemia that may be observed in cases of severe CAD, often in association with a coronary steal.²⁰ It has been reported that diagnostic accuracy for the detection of CAD with pharmacologic stress MPI is similar to that with exercise MPI, despite the fact that coronary flow may be increased to a greater degree than during exercise. Symptomatic myocardial ischemia is less commonly produced with vasodilators, possibly owing to the lower oxygen demands as opposed to exercise.²¹ Unlike with exercise, patients are instructed to withhold the use of methylxanthines, such as theophylline and caffeine, for at least 24 hours before the study to minimize interference with vasodilators due to the competition for the adenosine receptors. As with exercise, it appears preferable to withhold antianginal medications and calcium blockers for at least 24 hours before imaging; some studies have suggested that they may diminish the extent of myocardial perfusion defects.²² On the other hand, patients with known CAD should be imaged without withholding of medications, similar to exercise testing, to evaluate the effect of medical therapy.

A mild increase in the incidence of ischemia has been described by the addition of low-level exercise to the pharmacologic stress, which may add more diagnostic sensitivity to the test. The low-level exercise reduces the splanchnic blood flow and therefore the liver uptake of the radiopharmaceuticals.²³

Dipyridamole is infused intravenously at rest, in the supine position, at a rate of 0.142 mg/kg/min for 4 minutes for a total dose of 0.57 mg/kg. The maximal vasodilator effect is achieved 3 minutes after completion of the infusion, the time of injection of the radiopharmaceutical. It persists at this level for 30 to 60 minutes. Injection of the radiotracer can be done earlier than 7 to 8 minutes if severe hemodynamic effects develop or clear symptoms are noted or there are acute ischemic ECG changes that can jeopardize the safety of the test. A wide range of side effects occur in up to 30% to 40% of all patients. They are mostly mild and nonspecific and should be accepted as an indicator of the drug effect. They include symptoms such as chest discomfort, dizziness, shortness of breath, and headache.²⁴ Side effects are commonly reversed with a single intravenous dose of aminophylline (75 to 125 mg), although the dose may have to be repeated on some occasions, or rarely nitroglycerin is used. Aminophylline occupies endothelial adenosine binding sites and ends dipyridamole-induced vasodilation. Aminophylline is administered 3 to 4 minutes after administration of the radionuclide to allow adequate time for radiotracer extraction, and then the dipyridamole test is ended. It should be given slowly, however, to avoid some of its own side effects, including nausea, tachycardia, and hypotension. Unlike with adenosine, whose hemodynamic effects occur during the drug infusion, a fall in blood pressure and an increase in heart rate occur when the dipyridamole infusion is completed. There is generally no significant change in the double product and myocardial oxygen demand.

Adenosine is a heterocyclic compound with a purine base and ribose, synthesized intracellularly through the breakdown of adenosine triphosphate (ATP) through the S-adenosylhomocysteine pathways. During myocardial ischemia, there is ATP breakdown; the generated adenosine binds the endothelial A₂ receptors, dilates the coronary arteries, and restores flow. Adenosine has a partial A₁ receptor effect and can decrease the heart rate and attenuate the effects of β-adrenergic agonists, causing bronchospasm. However, even patients with a history of bronchospasm may be studied safely if symptoms are controlled with sympathomimetic inhalers or steroids.

Adenosine is infused intravenously at a standard dose of 140 µg/kg/min during 4 to 6 minutes, with administration of the radiopharmaceutical at 2 minutes with a 4-minute infusion or at 3 minutes with the 6-minute infusion protocol. Because of the very limited (several seconds) half-life of adenosine, the number of side effects are generally time limited. The only major side effect is an increased risk of heart block; thus, adenosine is considered to be contraindicated in patients with second-degree atrioventricular block and sick sinus syndrome. Common episodes of atrioventricular block are normally overridden by the vagolytic effect of the drug, and they do not produce severe symptoms or cerebral hypoperfusion. ST segment depression has been reported in approximately 15% of those patients with adenosine-induced chest pain, which occurs in a third of the patients tested with this drug. Because of the potency of adenosine, it must be administered through a pump infusion. Like dipyridamole, it may be irritative for the skin and should be infused through a large proximal vein.

Inotropic Agents

Dobutamine, an adrenergic agonist, is generally used in patients with severe chronic obstructive pulmonary disease or asthma (Fig. 21-4). Dobutamine stimulates α₁ receptors and β₁ receptors, increasing myocardial contractility, and β₂ receptors, which may cause hypotension due to peripheral vasodilation. As a consequence, there is an increase in heart rate, systolic blood pressure, cardiac output, and stroke volume. The cardiac effect varies, depending on the infused dose. At doses up to 10 µg/kg/min, dobutamine preferentially stimulates α₁ and β₁ receptors to increase contractility, making it a good tool for assessment of myocardial viability. Increased chronotropic effects occur at higher doses, with a subsequent increase in contractility and thickening that may be useful for identification of hibernating myocardium. When it is performed with echocardiography, the infusion is stopped when wall motion abnormalities develop. Dobutamine infusion should be maintained while the radiotracer is distributed. In recent years, different protocols have been recommended.²⁵

FIGURE 21-4 Structure of dobutamine.

Dobutamine is infused in a stepwise increased titration at 3-minute intervals, from low (5 to 10 µg/kg/min) to high (40 µg/kg/min) doses, with increments that are based on the patient’s symptoms to produce ischemia. The endpoint of the dobutamine test is a true ischemic response. The main side effect is nonsustained tachycardia; however, because of its ischemic mechanism, it has increased risks for development of serious events in patients with known severe proximal CAD or dynamic coronary syndromes. Because of its peripheral vasodilatory effect, dobutamine has been described to produce hypotension at higher doses in 20% of the patients.²⁶ β Blockers are the antidote to dobutamine side effects. Esmolol drip should also be available in serious situations because of the short half-life of dobutamine (2.4 minutes). Dobutamine has been reported to have a diagnostic sensitivity of 91% and specificity of 86% in patients with suspected CAD.²⁷ Dobutamine stress SPECT is more sensitive than dobutamine echocardiography, and it is generally used as an alternative to dipyridamole or adenosine in the presence of their contraindications. Dobutamine is the only pharmacologic stress for use with echocardiography.

BASIC IMAGE INTERPRETATION

Location, size, and intensity of the perfusion defect are determined by the conventional correlation of image findings with anatomic relationships, generally the 17-segment model of the left ventricle standardized by the American Society of Nuclear Cardiology. Determination of the degree of reversibility is made by visual or semiquantitative comparison between the post-stress images and the resting data sets.

Transient, stress-induced cavitary dilation has been demonstrated in planar and SPECT studies, being related to either true enlargement or induced subendocardial ischemia. It has been related to a higher likelihood of major cardiac events and death.

As a general rule, use of a computer monitor and a linear color scale is recommended to interpret the results, even though the gray scale has been largely used as well. It is critical to follow a systematic approach to the images and to properly align stress and rest images, displayed on the three standard image sets—short axis, vertical long axis, and horizontal long axis (Figs. 21-5 to 21-16). Review of the projection (raw) data is crucial to provide evidence for motion of the patient that would create artifacts and reduce diagnostic accuracy. Projection data also provide information on the cardiac size and other potential areas of thoracic radiotracer uptake, such as lung uptake. Lung uptake in the presence of reversible perfusion defects is another sign of more severe disease. Although it is sometimes difficult to fully appreciate lung uptake in SPECT images, additional projection images should help accurately identify this finding.²⁸ Extracardiac radiopharmaceutical activity may reflect a variety of neoplastic lesions, either primary or metastatic, that may involve the lung, breast, thyroid, parathyroid glands, mediastinum, or liver. In addition, intense subdiaphragmatic activity from the gastrointestinal tract or from the liver may confound the interpretation of the inferior wall by creating virtual perfusion defects, or it may obscure the presence of a true perfusion abnormality. When substantial activity is noted in the gastrointestinal tract, the image acquisition should be repeated. Soft tissue attenuation, such as breast activity, may reduce the specificity for the detection of CAD. Rotating SPECT images will clarify this point and help in the correct image interpretation.