Nuclear Cardiology and Positron Emission Tomography in the Assessment of Patients with Cardiovascular Disease

Introduction to Nuclear Cardiology

Nuclear cardiology involves the imaging of cardiac radiopharmaceutical distribution to characterize physiologic and pathophysiologic processes in the heart. The ability to image myocardial perfusion, function, and metabolism noninvasively with nuclear techniques has led to the development of a field that has been validated extensively and provides powerful diagnostic and prognostic information in the management of patients with known or suspected coronary artery disease (CAD). Moreover, nuclear cardiology procedures have been used widely in the evaluation of patients before cardiac and noncardiac surgery. This chapter provides an overview of the concepts and techniques used in nuclear cardiology and summarizes its role in the assessment of patients with stable coronary disease and acute coronary syndromes and in the determination of myocardial viability in patients considered for revascularization. A complete discussion of the technical and procedural aspects of nuclear cardiology is beyond the scope of this chapter; therefore, the central focus will be on the use of nuclear cardiology in patients with known or suspected CAD, with an emphasis on patients undergoing cardiac surgery. For a more detailed discussion, the reader is referred to other more comprehensive reviews.

General Principles

Nuclear cardiology has been dominated by radionuclide myocardial perfusion imaging (MPI) as a means to evaluate patients with known or suspected coronary disease. MPI is performed for diagnostic evaluation of patients with symptoms suggestive of myocardial ischemia and for risk stratification of patients with known CAD. Radionuclide MPI plays a central role in the evaluation of the cardiac patient, and it is in widespread clinical use, with more than 7 million MPI procedures performed in the United States annually.

Myocardial perfusion is governed during resting conditions by the coronary resistance vessels. During periods of increased work, such as during exercise, flow is increased to balance the metabolic demands of the myocardium. This is achieved by vasodilation of resistance vessels, which reduces vascular resistance in the coronary arterial bed. In stenotic, atherosclerotic coronary arteries, resting flow is maintained by decreasing downstream vascular resistance. Although this compensation maintains flow under resting conditions, a critical stenosis (>50% to 70% narrowing of the lumen) impairs coronary flow reserve or the ability of the artery to increase flow appropriately during periods of increased demand.

Radioactive Tracers

Myocardial perfusion is imaged with the use of radiopharmaceuticals that accumulate rapidly in the myocardium in proportion to myocardial blood flow. The most commonly used radiotracers currently are the ^99m Tc- labeled compounds sestamibi and tetrofosmin and, to a lesser extent, thallium ( ²⁰¹ Tl). When injected intravenously, these tracers are extracted from the blood pool and accumulate in cells, including myocytes, which have an intact cell membrane and are metabolically active. ^99m Tc-sestamibi and tetrofosmin are lipophilic cationic complexes that are taken up by myocytes across mitochondrial membranes, but at equilibrium are retained within the mitochondria because of a large negative transmembrane potential. ²⁰¹ Tl is transported like potassium across the myocyte sarcolemmal membrane, via the Na-K adenosine triphosphatase transport system. Because the retention of radiotracer is proportional to myocardial flow, the amount of tracer uptake is a surrogate visualized representation of regional myocardial perfusion. The tracers used are radioactive isotopes that undergo radioactive decay over a short period of time.

Equipment and Procedures

As the accumulated radiotracer decays, photons are emitted that exit the body and can be detected using a specialized gamma camera. MPI uses single photon emission computed tomography (SPECT) techniques to acquire and ultimately display the perfusion distribution obtained from the radiotracer uptake. After the radiopharmaceutical is injected, the patient lies supine on the SPECT camera table and is positioned in the gantry of the camera. The photons emitted from the heart are then detected via large crystals or solid state detectors in the SPECT camera as it revolves around the patient.

As the camera detector moves around the patient, emitted photons interact with the camera's crystal and produce scintillations of light that represent the spatial distribution of radioactivity in the patient. The emitted “counts” localized to each region of the myocardium are then stored digitally. This three-dimensional representation of the myocardial perfusion is then processed and reconstructed using computer algorithms to display the acquired information in a series of slices, oriented in the short axis and the horizontal and vertical long axes of the left ventricle. The slices are then displayed on a computer screen for visual inspection of regional myocardial perfusion and computer quantification of tracer uptake. The stress images, acquired after injection of radiotracer during exercise or pharmacologic stress (described later in detail) are displayed adjacent to images acquired at rest, permitting direct comparison of perfusion in the two imaging states. The maximum uptake of radiotracer in the heart is used to represent normal perfusion, and the rest of the counts are considered as relative uptake to this maximum. As shown in Figure 54-1 , a regional perfusion defect on the stress images that is not present on the resting study is considered to be reversible and consistent with stress-induced ischemia in that vascular territory. A defect that persists on stress and rest is deemed fixed and representative of scar from prior myocardial infarction. Quantitative programs are commonly used to assess the extent and severity of each defect, which is then incorporated into the final interpretation of regional myocardial perfusion. The perfusion images are also obtained in concert with electrocardiographic (ECG) gating, which stores the counts with respect to the timing of the cardiac cycle. By gating the acquisition to the R-R interval of the ECG, images from each frame can be summed and displayed as a cine movie of the left ventricle contracting from diastole to systole. Performing gated SPECT facilitates measurement of left ventricular ejection fraction (LVEF) and left ventricle (LV) volumes by automated computer algorithms, as well as visual inspection of the movie for regional wall motion and thickening ( Fig. 54-2 ).

FIGURE 54-1, Visual display of single photon emission computed tomography (SPECT) myocardial perfusion images. The stress study (rows labeled A ) is shown immediately above the rest study (rows labeled B ) for comparison. There are three representations of the same imaging procedure, each oriented differently: short-axis slices from apex to mid-ventricle and mid-ventricle to base (top), vertical long-axis slices from septum to lateral wall (middle), and horizontal long-axis slices from inferior to anterior wall (bottom). A, Normal study in grayscale, with uniform uptake of radiotracer on stress and rest. B, Color-enhanced study in which the stress images demonstrate a perfusion defect in the anterolateral wall, as evidenced by less radiotracer accumulation relative to other regions of the left ventricle. As the corresponding rest images show normal perfusion throughout the myocardium, the perfusion defect is considered “reversible,” consistent with ischemia. C, These SPECT images demonstrate large perfusion defects in the anteroseptal, inferoseptal, and apical regions, which are present on both the stress and rest images. Because these defects do not show any change from stress to rest, they are termed fixed defects, consistent with scar (i.e., prior myocardial infarction).

$FIGURE 54-2, Gated single photon emission computed tomography (SPECT) still-frame images of diastole and systole. During SPECT image acquisition, the acquired images can be stored in relationship to the cardiac cycle using the R-R interval of the electrocardiogram. The resulting images that are “gated” to the cardiac cycle can then be viewed as a cine-loop from diastole to systole. Moreover, these data can be used to calculate left ventricular (LV) volumes during diastole and systole, as well as the corresponding left ventricular ejection fraction (diastole-systole).$

A typical SPECT MPI protocol involves the performance of exercise, typically on a treadmill or bicycle, or with a pharmacologic stressor, such as adenosine, dipyridamole, regadenoson, or dobutamine in patients who are unable to perform physical exercise. The radiotracer is injected at peak stress and the stressor is then continued for an additional 1 to 2 minutes to maximize myocardial extraction of the circulating tracer. Imaging is performed 30 to 60 minutes later for sestamibi or tetrofosmin, because these agents have only minimal redistribution, or washout from the myocardium. The initial imaging can be either at rest or at stress, and both studies can be performed on the same day depending on the patient's weight. While ²⁰¹ Tl is used less commonly for stress MPI, it can be used for rest imaging in a “dual isotope” protocol. In this protocol ²⁰¹ Tl is injected for resting imaging, which is then followed immediately by stress perfusion imaging with ^99m Tc agent, thus obviating the need to wait 2 to 3 hours for the first dose to decay. As such, imaging time is reduced and patient throughput is increased; however, the radiation dose the patient receives is greater. Recent advances in camera technology and processing have facilitated faster image acquisition and the use of lower doses of radiopharmaceuticals.

Stable Coronary Artery Disease (Diagnosis and Risk Stratification)

Stress Testing in the Detection of Coronary Artery Disease

Nuclear cardiology is a central part of the evaluation of patients with suspected or proven coronary artery disease. The ability of SPECT myocardial perfusion imaging to detect CAD in patients with symptoms suggestive of ischemic heart disease has been validated extensively.

Exercise Stress Testing

Exercise stress testing without adjunct noninvasive imaging is frequently used as the initial screening test in patients without known coronary artery disease who have chest pain syndromes or symptoms suggestive of ischemia. The premise of exercise stress testing is that the increased myocardial oxygen demand during exercise will produce clinical signs of ischemia (e.g., angina, ECG changes) in the setting of a flow-limiting stenosis that impairs myocardial blood supply. The diagnostic performance of this test varies greatly depending on the pretest likelihood of the population being studied. In patients with an intermediate pretest probability of CAD on the basis of symptoms and risk factors, exercise treadmill testing is useful as an initial screening test. However, the overall sensitivity of treadmill exercise testing is approximately 70%. A meta-analysis of more than 24,000 patients undergoing exercise stress testing and coronary angiography observed a mean sensitivity on 68% and a mean specificity of 77%. Accuracy was greatest in patients with multivessel coronary disease and those with left main or three vessel coronary artery disease.

Exercise Stress Myocardial Perfusion Imaging

Exercise treadmill testing relies on changes in the 12-lead ECG as a surrogate of ischemia, rendering the accuracy of the test highly dependent on the baseline electrocardiogram. Abnormalities, such as previous myocardial infarction (Q waves or left bundle branch block) or ST-T wave changes owing to left ventricular hypertrophy or therapy with digoxin, hamper the ability to interpret ischemic changes accurately during exercise. In patients with an abnormal ECG, myocardial perfusion imaging adds significant diagnostic accuracy to the treadmill test for detecting coronary artery disease. Large studies have consistently shown that SPECT myocardial perfusion imaging with technetium-labeled agents, such as sestamibi, yields a greater than 90% sensitivity for the detection of coronary artery disease. False-negative scans tend to occur in the setting of single-vessel disease, particularly in the left circumflex artery distribution, with a mild degree of stenosis (<70%), or when the patient is unable to achieve the target heart rate or is taking antianginal therapy. These studies have also observed that the specificity of stress SPECT imaging is in the range of 68%. The less optimal specificity can be attributed to referral bias (performing angiography in only those patients with abnormal scans) and false-positive scans with defects resulting from artifacts produced by soft tissue attenuation (diaphragm, breast) or patient motion. Contemporary imaging techniques that use ECG-gating have facilitated the simultaneous assessment of myocardial perfusion and function. Examination of regional wall motion and thickening enhances the evaluation of a suspect area of hypoperfusion by providing the ability to distinguish true myocardial scarring from attenuation. Specificity can also be enhanced with the use of attenuation correction. These algorithms incorporate additional data obtained from an external radioactive source or computed tomography to create a soft tissue attenuation image of the chest and then to adjust the regional counts on the emission scan to correct for the loss of counts because of attenuation from overlying breast, diaphragm, and chest wall structures.

Stress-Only Imaging

For patients who have normal stress imaging, rest imaging can result in increased patient inconvenience, radiation exposure, laboratory inefficiency, and cost. As a result, stress-only imaging protocols have been examined. A study of 460 stress-rest technetium myocardial perfusion studies noted that in 20% of studies, the stress images were completely normal and that the addition of rest images added no additional information. In addition to reduced radiation exposure and patient cost, stress-only imaging has been verified from a prognostic standpoint as well, with follow-up studies of patients with normal stress-only studies demonstrating a less than 1% annualized cardiac event rate.

Pharmacologic Stress Myocardial Perfusion Imaging

Many patients are unable to perform physical exercise to a workload adequate for a diagnostic exercise stress test; therefore, myocardial perfusion imaging performed after pharmacologic stress is used frequently as an alternative. This imaging is typically performed after the intravenous infusion of a vasodilator, such as dipyridamole, adenosine, or regadenoson, or after administration of the inotrope dobutamine. Dipyridamole stimulates the release of endogenous adenosine in the distal coronary vasculature, which then binds adenosine receptors in the vasculature, producing the desired effect of coronary artery vasodilation and undesirable effects such as flushing, bronchospasm, headache, and transient heart block. This vasodilation of the resistance vessels increases myocardial blood flow, mimicking the effects of physical exercise. Dipyridamole is typically administered intravenously as a bolus injection over 4 minutes with peak effect occurring at 8 minutes, at which time the radiotracer is injected. A 4- to 6-minute continuous infusion of intravenous adenosine is now used more commonly. Both agents are equally effective in increasing myocardial blood flow threefold to fivefold over rest, which is similar to that produced by exercise; however, adenosine tends to achieve maximal flow in more patients than dipyridamole does, and side effects are more common with adenosine. Regadenoson is an adenosine A2a receptor agonist that selectively increases coronary blood flow without producing side effects, such as hypotension, AV block, chest pain and flushing, which are common with adenosine and dipyridamole. Regadenoson can be used as an alternative stressor in patients with lung disease, because its receptor selectivity helps to avoid bronchospasm that can occur with the other vasodilators.

An intravenous infusion of dobutamine is also effective for pharmacologic stress. It is typically used as an alternative to vasodilator stress in patients with bronchospasm and pulmonary disease. The dobutamine infusion produces increased myocardial oxygen demand by increasing heart rate, blood pressure, and myocardial contractility.

All the currently used pharmacologic stress agents have similar ability to produce flow heterogeneity and corresponding perfusion defects in the presence of a significant (>50% to 70%) stenosis of a coronary artery. A meta-analysis of dipyridamole SPECT imaging demonstrated a sensitivity of 89% and specificity of 65% for the detection of coronary artery disease. Dipyridamole and adenosine tests had essentially similar sensitivities and specificities. The sensitivity of dobutamine SPECT imaging to detect CAD is approximately 80%, which is slightly lower than the vasodilator agents.

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