The era of noninvasive radionuclide cardiac imaging in humans began in the early 1970s with the first reports of noninvasive evaluation of myocardial blood flow at rest. Since that time, major advances have been achieved in the technical ability to image cardiac physiology and pathophysiology, including that of myocardial blood flow, myocardial metabolism, and ventricular function. Just as important has been a major growth in the understanding of how to apply the image information to care of patients and the effect of that information on clinical decision making. Ultimately, the role of information derived from any imaging procedure is to enhance the clinician’s decision-making process for amelioration of symptoms or improvement of clinical outcomes or both.
Technical Aspects of Image Acquisition, Display, and Interpretation
The most commonly performed imaging procedure in nuclear cardiology is single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). After injection of the chosen radiotracer, the isotope is extracted from the blood by viable myocytes and retained within the myocyte for some time. Photons are emitted from the myocardium in proportion to the magnitude of tracer uptake, in turn related to perfusion. The standard camera used in nuclear cardiology studies, a gamma camera, captures the gamma ray photons and converts the information into digital data representing the magnitude of uptake and the location of the emission. The photoemissions collide along their flight path with a detector crystal. There, the gamma photons are absorbed and converted into visible light events (a scintillation event). Emitted gamma rays are selected for capture and quantitation by a collimator attached to the face of the camera detector system. Most often, parallel-hole collimators are used so that only photon emissions coursing perpendicular to the camera head and parallel to the collimation holes are accepted (Fig. 16-1). This arrangement allows appropriate localization of the source of the emitted gamma rays. Photomultiplier tubes, the final major component in the gamma camera, sense the light scintillation events and convert the events into an electrical signal to be further processed (see Fig. 16-1). The final result of SPECT imaging is the creation of multiple tomograms, or slices, of the organ of interest, composing a digital display representing radiotracer distribution throughout the organ.1 With SPECT MPI, the display represents the distribution of perfusion throughout the myocardium.
New Technology: High-Speed SPECT Imaging
High-speed SPECT technology introduces a new design of SPECT in terms of both photon acquisition and reconstruction algorithms. Standard SPECT imaging with collimators using a parallel-hole design is inherently inefficient, as only a relatively small proportion of the camera and collimator surface area is used to capture photons emitted from the heart. Advances in camera and collimator technology have substantially increased the efficiency of count capture, by design features that allow much of the available detector area to image the cardiac field of view, increasing count sensitivity many-fold. One approach uses a series of small, pixilated solid-state detector columns with cadmium zinc telluride or cessium iodide : thallium crystals, which provide considerably more information for each detected gamma ray. In addition, the design of the solid-state detector with wide-angle tungsten collimators combined with a novel image reconstruction algorithm provides true three-dimensional, patient-specific images localized to the heart.3 Compared with the conventional SPECT cameras, the high-speed SPECT systems can provide up to eightfold increase in count rates, thereby reducing imaging times significantly from 14 to 15 minutes with a conventional Anger camera to 5 to 6 minutes with the newer solid-state cameras while achieving a twofold increase in spatial resolution from 9 to 11 mm for Anger cameras to 4.3 to 4.9 mm for cadmium zinc telluride cameras.
In addition to advances in camera technology, software driving image reconstruction has also evolved. One technique, known as resolution recovery, improves spatial resolution while at the same time reducing noise in the images. Thus studies acquired over a much shorter period of time when reconstructed using these techniques can yield images with the same signal-to-noise ratio as those acquired and reconstructed with standard techniques and timing.4 Reduced imaging times should translate to improved patient comfort and satisfaction as well as less motion and fewer motion artifacts. An additional advantage of high-speed SPECT imaging is the potential for administration of lower doses of radiopharmaceuticals without sacrificing image resolution and quality, thereby reducing radiation dose to patients. The reduced imaging time in concert with reduced radiopharmaceutical doses may be cost-effective, with implications for future appropriateness of SPECT imaging.5
SPECT Perfusion Tracers and Protocols
Thallium-201 (201Tl) was introduced in the 1970s and propelled the clinical application of MPI as an adjunct to exercise treadmill testing. 201Tl is a monovalent cation with biologic properties similar to those of potassium. Because potassium is the major intracellular cation in muscle and is virtually absent in scar tissue, 201Tl is a well-suited radionuclide for differentiation of normal and ischemic myocardium from scarred myocardium.6 201Tl emits 80 keV of photon energy and has a physical half-life of 73 hours. The initial myocardial uptake early after intravenous injection of thallium is proportional to regional blood flow. First-pass extraction fraction (the proportion of tracer extracted from the blood as it passes through the myocardium) is high, in the range of 85%. It is transported across the myocyte cell membrane by the Na+,K+–adenosine triphosphatase (ATPase) transport system and by facilitative diffusion. Peak myocardial concentration of thallium is achieved within 5 minutes of injection, with rapid clearance from the intravascular compartment. Although the initial uptake and distribution of thallium are primarily a function of blood flow, the subsequent redistribution of thallium, which begins within 10 to 15 minutes after injection, is unrelated to flow but is related to the rate of its clearance from myocardium, linked to the concentration gradient between myocyte levels and blood levels of thallium (Fig. 16-3A). Thallium clearance is more rapid from normal myocardium with high thallium activity than from myocardium with reduced thallium activity (ischemic myocardium), a process termed differential washout (Fig. 16-3B).
Thallium studies can be divided into protocols in which 201Tl is administered during stress and those in which it is given with the subject at rest.6 After stress, the reversal of a thallium defect from the initial peak stress to delayed 3- to 4-hour or 24-hour redistribution images is a marker of reversibly ischemic, viable myocardium. When thallium is injected in the resting state, the extent of thallium defect reversibility from the initial rest images to delayed redistribution images (at 3 to 4 hours) reflects viable myocardium with hypoperfusion at rest. When scarred myocardium is present, the initial rest or stress thallium defect persists over time; such deficits are termed irreversible or fixed defects. However, in some patients with coronary artery disease (CAD), the initial uptake of thallium during stress may be severely decreased, and tracer accumulation from the recirculating thallium in the blood during the redistribution phase may be slow or even absent because of rapid decline of thallium levels in the blood. The result is that some severely ischemic but viable regions may show no redistribution on either early (3- to 4-hour) or late (24-hour) imaging, even if viable myocardium is present. Viable myocardium in this situation can be revealed by raising blood levels of thallium by reinjection of a small dose (1 to 2 mCi) of thallium at rest. Thus, in some patients, thallium reinjection is necessary to identify viable myocardium when there are irreversible defects on stress-redistribution images.
Technetium 99m–Labeled Tracers
Technetium 99m (99mTc)–labeled myocardial perfusion tracers were introduced in the clinical arena in the 1990s.6 99mTc emits 140 keV of photon energy and has a physical half-life of 6 hours. Despite the excellent myocardial extraction and flow kinetic properties of 201Tl, its energy spectrum of 80 keV is suboptimal for conventional gamma cameras (ideal photopeak in the 140-keV range). In addition, the long physical half-life of 201Tl (73 hours) limits the amount of 201Tl that may be administered to stay within acceptable radiation exposure parameters. Thus 99mTc-labeled tracers improve on these two limitations of 201Tl. Although three 99mTc-labeled tracers—sestamibi, teboroxime, and tetrofosmin—have received U.S. Food and Drug Administration (FDA) approval for detection of CAD, only sestamibi and tetrofosmin are available for clinical use at present.
Sestamibi and tetrofosmin are lipid-soluble cationic compounds with first-pass extraction fraction in the range of 60%. Myocardial uptake and clearance kinetics of both tracers are similar. They cross sarcolemmal and mitochondrial membranes of myocytes by passive distribution, driven by the transmembrane electrochemical gradient, and they are retained within the mitochondria.6 Redistribution of these tracers is minimal compared with that for thallium. Consequently, myocardial perfusion studies with 99mTc-labeled tracers require two separate injections, one at peak stress and the second at rest.
Three basic protocols7 with 99mTc-labeled tracers have been used: (1) a single-day study, in which myocardial blood flow is interrogated at rest and at peak stress, or in the reverse order, as long as the first injected dose is low (8 to 12 mCi) and the second injected dose is high (24 to 36 mCi); (2) a 2-day study (commonly performed in patients with large body habitus), in which higher doses of the tracer are injected (24 to 36 mCi) both at rest and at peak stress to optimize myocardial count rate; and (3) a dual-isotope technique, in which injection of 201Tl at rest is followed by injection of a 99mTc tracer at peak stress. The last approach takes advantage of the favorable properties of each of the two tracers, including the high-quality gated SPECT images obtained with 99mTc and the potential to acquire redistribution images with 201Tl (either at 4 hours before the stress study or at 24 hours after the 99mTc activity has decayed). A comparison of the properties of the available isotopes for perfusion imaging is presented in Table 16-1.
Properties of SPECT Tracers
|TRACER||PHYSICAL HALF-LIFE||UPTAKE||MYOCARDIAL CLEARANCE||DIFFERENTIAL WASHOUT||MAXIMUM EXTRACTION|
|201Tl||73 hours||Active||∼50% at 6 hours||Yes||∼0.70|
|99mTc-teboroxime||6 hours||Passive||∼50% at 10 minutes||Yes||0.72|
From Gerson MC, McGoron A, Roszell N, et al: Myocardial perfusion imaging: Radiopharmaceuticals and tracer kinetics. In Gerson MC (ed): Cardiac Nuclear Medicine. New York, McGraw-Hill, 1997, pp 3-27.
Incorporating Bayesian Principles into Image Interpretation
Although it is possible to interpret MPI data in isolation and report only on what the images demonstrate, a more accepted interpretive methodologic principle is that the final interpretation should take into account the entirety of the data at hand. Hence the image data build on the already known clinical and stress test data, and the clinician should take all of this information into account when interpreting MPI data. An understanding of Bayesian probability principles is useful in this regard. Bayes theorem posits that the post-test probability of disease (or risk of an event after a test) is influenced not only by the sensitivity and specificity of the test but also importantly by the pretest probability of disease (see Chapter 13). This principle is illustrated in Figure 16-9. For a given positive test result, the post-test probability of disease may be distinctly lower in a patient with a very low pretest probability of disease compared with a different patient with a much higher pretest probability (Fig. 16-9A). In practice, MPI results are not simply positive or negative; rather, positive (i.e., abnormal) results can range from borderline-abnormal (uncertainty whether the abnormality may be an artifact or a mild perfusion defect) to strongly abnormal (i.e., extensive and severe defects, highly likely to be real and unlikely to represent artifact). Thus the “test positive” curve in Figure 16-9A can be thought of as a family of positivity curves, with distinct implications for post-test likelihood of disease (Fig. 16-9B).
The implication of incorporating these concepts for image interpretation can be illustrated by considering a mildly positive MPI study demonstrating a small mild reversible inferobasal defect. Although it is possible that this defect represents a small area of inferior inducible ischemia, it is also possible that the image may reflect diaphragm attenuation of the inferobasal wall predominantly affecting the stress image. The influence of the pretest probability data (i.e., pre-MPI) is illustrated in Figure 16-9C. For a young patient with nonanginal chest pain, the pretest probability of CAD is low. If the patient undergoes an exercise treadmill test (ETT) (see Chapter 13) as the stress portion of the MPI test and exercises to a good workload with no symptoms and no changes on the electrocardiogram (ECG), the post-ETT probability is even lower. The post-ETT probability then becomes the pre-MPI probability, as seen in Figure 16-9D. A positive test result, especially a mildly positive result, is still associated with a relative low post-test probability of CAD. A result reported as positive is more likely to represent a false-positive than a true-positive finding. By contrast, for an older patient being evaluated for anginal chest pain in whom ETT reproduces those symptoms and who exhibits positive ECG changes, the pre-MPI probability is very high, so the same MPI results are far more likely to represent a true-positive finding than a false-positive finding, as illustrated in Figure 16-9C and D. These examples illustrate how the clinical data may be incorporated into the MPI interpretation and also how Bayesian probability principles may be incorporated sequentially so that the image reader conveys information to the referring clinician that reflects the post-test probability of disease (and risk), rather than simply reporting what the image data show in isolation.
Important Signs in SPECT Imaging Analysis Beyond Myocardial Perfusion
Other abnormal findings provide additional information beyond that indicated by the perfusion pattern alone, including lung uptake of tracer (particularly 201Tl) and transient ischemic dilation of the left ventricle.
In some patients, substantial tracer uptake is apparent throughout the lung fields after stress that is not present at rest (Fig. 16-10A). Patients with lung uptake often have severe multivessel disease and exhibit elevation of pulmonary capillary wedge pressure and decreases in ejection fraction (EF) during exercise, all implying extensive myocardial ischemia.6 It is likely that ischemia-induced elevation in left atrial and pulmonary pressures slows pulmonary transit of the tracer, allowing more time for extraction or transudation into the interstitial spaces of the lung, accounting for this imaging sign.
Lung uptake of 201Tl has been more extensively validated than lung uptake of the 99mTc tracers sestamibi and tetrofosmin. Splanchnic or background activity is minimal after thallium stress injection, allowing image acquisition earlier after stress. In addition, the redistribution properties of thallium mandate that imaging begin relatively early after stress, so lung uptake may be more apparent.
With the 99mTc perfusion tracers, liver uptake is more prominent than that in the heart immediately after injection; accordingly, image acquisition should begin 15 to 30 minutes after exercise stress injection and 30 to 60 minutes after pharmacologic stress.6 Thus lung uptake, even if it had been present early after stress, may be missed with 99mTc tracers because of the more delayed onset of imaging than with thallium.
Transient Ischemic Dilation of the Left Ventricle
Transient ischemic dilation refers to an imaging pattern in which the left ventricle or left ventricular (LV) cavity appears larger on the stress images than on those obtained with the subject at rest11 (Fig. 16-10B). For patients in whom the entire left ventricle appears larger during stress, the pathophysiology probably is related to extensive ischemia and prolonged postischemic systolic dysfunction, resulting in a dilated, dysfunctional left ventricle during the stress acquisition relative to the rest acquisition. In other patients, the epicardial silhouette appears similar at stress and at rest, but with apparent dilation of the LV cavity. This pattern probably represents diffuse subendocardial ischemia (relatively less tracer uptake in the subendocardium, creating the appearance of an enlarged LV cavity) and also is associated with severe and extensive CAD. Contemporary processing systems can automatically quantify transient ischemic dilation.
Both lung uptake and transient ischemic dilation provide clues to more extensive CAD than may have been suspected from the perfusion pattern alone. Both signs have been associated with angiographically extensive and severe CAD and with unfavorable long-term outcomes; accordingly, such changes are considered high-risk findings.
Attenuation Correction Methods
The 511-keV photons emitted by positron-emitting radiotracers in PET imaging are attenuated less per centimeter of soft tissue than are the lower-energy 80- to 140-keV photons typically emitted by SPECT radiotracers. In SPECT imaging, a single photon needs to travel from the heart to the camera; in PET imaging, two coincident photons (i.e., emitted simultaneously) need to travel across the entire body to reach their respective detectors (see later under Positron Emission Tomography). Although the total attenuation may actually be greater for PET than for SPECT, an important distinction in the case of PET is that the attenuation is the same along a projection line (the path the pair of photons traverse) independent of how deep in the body the annihilation took place. Thus, in PET, only the total attenuation through the whole body along a specific direction must be known. On the other hand, in SPECT, it is necessary to know the exact depth along a projection line where the radioactive decay took place in order to correct for attenuation. Therefore attenuation correction for SPECT is theoretically more challenging. In recent years, several approaches to correct for attenuation in both PET and SPECT imaging have emerged, with the goal of “correcting” attenuation artifacts to minimize false-positive defects and to improve specificity.
PET Attenuation Correction.
To measure the attenuation correction factor, a rod that rotates about the patient is filled with a relatively long-lived positron emitter, germanium-68, or a single photon emitter, cesium-137. The rod is first made to rotate at a fixed speed in the gantry, and total coincident counts are measured without the patient (the blank scan) and repeated with the patient (the transmission scan). The ratio of coincident counts of blank scan and those of transmission scan yields the array of attenuation correction factors needed to correct each projection line. Once each projection line has been corrected for attenuation (and scatter), the emission data may be reconstructed into an attenuation-corrected emission image for clinical interpretation. So long as the patient does not move during the scanning procedure, cardiac PET images will be free from attenuation artifacts.