RADIOPHARMACEUTICALS

Although several tracers have been used for evaluating myocardial perfusion with PET, the most widely used in clinical practice are rubidium 82 and ammonia N 13. In addition, ¹⁸FDG is the radiotracer of choice for the evaluation of myocardial viability.¹

Rubidium 82

Rubidium 82 is the most widely used radiotracer for clinical PET myocardial perfusion imaging (MPI). It is a potassium analogue that is a generator-product and does not require a cyclotron on site. It has a physical half-life of 76 seconds. This physical characteristic allows the generator to be eluted with greater than 90% yield every 10 minutes. In addition, the rapid reconstitution of the generator allows for fast sequential perfusion imaging and laboratory throughput, maximizing clinical efficiency. The generator is replaced every 28 days (reflecting the physical half-life of its parent radionuclide, strontium 82).

After infusion, rubidium 82 rapidly crosses the capillary membrane and is actively transported to the cell via the sodium/potassium ATP transporter, which depends on coronary blood flow.² Compared with fluorine 18 or nitrogen 13, the positron range and the spatial uncertainty in the location of the decaying nucleus of rubidium 82 (2.6 mm FWHM [full width at half maximum]) is greater than for fluorine 18 (0.2 mm FWHM) or nitrogen 13 (0.7 mm FWHM), mitigating the improved spatial resolution of PET.

Ammonia N 13

Being a cyclotron product, ammonia N 13 use in routine clinical practice is limited to institutions that have a cyclotron on site. It has a physical half-life of 9.96 minutes and has a shorter positron range compared with rubidium 82, resulting in higher signal-to-noise ratio. After injection, ammonia N 13 rapidly disappears from the circulation, permitting the acquisition of images of excellent quality. Although the sequestration of ammonia N 13 in the lungs is usually minimal, it may be increased in patients with depressed left ventricular systolic function or chronic pulmonary disease and, occasionally, in smokers; this may adversely affect the quality of the images. In these cases, it may be necessary to increase the time between injection and image acquisition to optimize the contrast between myocardial and background activity. When inside the myocyte, ammonia N 13 is incorporated into the glutamine pool and becomes metabolically trapped. Only a small fraction diffuses back into the intravascular space.³

Myocardial retention of ammonia N 13 is heterogeneous, with retention in the lateral left ventricular wall being about 10% lower than that of other segments, even in normal subjects. This heterogeneous retention could result in an apparent perfusion defect in the inferolateral wall, limiting its evaluation. Ammonia N 13 allows the acquisition of ungated and gated images of excellent quality. These studies take full advantage of the superior resolution of PET relative to single photon emission computed tomography (SPECT) because the half-life of ammonia N 13 is sufficiently long, and its average positron range is very short. Gated ammonia N 13 imaging can provide accurate assessments of regional and global cardiac function.⁴ This imaging agent is not well suited for peak stress gated imaging, however, because of the 3- to 4-minute time interval between radiotracer injection and start of imaging, and the relatively long (20 minutes) acquisition time.

¹⁸FDG

¹⁸FDG is an imaging agent that is used to assess myocardial metabolic activity. Fluorine 18 has a physical half-life of 109 minutes, allowing regional distribution to clinical sites from local cyclotrons. Although normal myocardium preferentially uses free fatty acids, ischemic myocardium switches to preferential glucose metabolism. Because ¹⁸FDG is a glucose analogue, it provides a unique opportunity to image ischemic but viable myocardium. ¹⁸FDG traces the initial transport of glucose across the myocyte membrane and its subsequent hexokinase-mediated phosphorylation to FDG-6-phosphate. Because the latter is a poor substrate for further metabolism and is impermeable to the cell membrane, it becomes virtually trapped in the myocardium, allowing the imaging of viable cells.

ASSESSMENT OF MYOCARDIAL PERFUSION

Figure 24-1 illustrates common protocols used for imaging myocardial perfusion with PET/CT, where the low-dose CT scan is used for attenuation correction.¹ This scan is also called a CT-based attenuation correction scan (CTAC).

FIGURE 24-1 A-D, Protocols for clinical cardiac PET/CT imaging. CAC, coronary artery calcium; CTA, CT angiography; CTAC, CT-based attenuation scan.

(From Di Carli MF, Dorbala S, Meserve J, et al. Clinical myocardial perfusion PET/CT. J Nucl Med 2007; 48:783-793.)

Computed Tomography Scans

After obtaining the topogram, a low-dose CT scan covering the heart region is obtained. The parameters of this low-dose, non–ECG gated CT scan include a slow gantry rotation combined with a high pitch (e.g., 0.5 : 1 to 0.6 : 1), a high tube potential (e.g., 140 kVp), and a low tube current (10 to 20 mA). The scan is obtained during tidal expiration breath-hold or shallow breathing. The rest and stress emission images should each be corrected with its own dedicated transmission scan because of known changes in cardiac and pulmonary volumes during pharmacologic stress. Whether one attenuation scan (e.g., one CTAC) is sufficient to correct the stress and rest transmission scans is yet to be determined.

Emission Scans

For rubidium 82, approximately the same dose (40 to 60 mCi) is injected for the rest and stress myocardial perfusion studies because of the short physical half-life of rubidium 82 (76 seconds). For ammonia N 13, the general trend is to use a lower dose for the rest images (10 mCi) and a higher dose for the stress images (30 mCi), analogous to 1-day SPECT imaging protocols. The low-dose/high-dose protocol is faster than same-dose protocols for rest and stress because it does not require waiting for decay of ammonia N 13 to background levels before a second dose can be administered. Large patients may require large doses for the rest and stress studies. Some laboratories perform stress imaging first because a normal scan may avoid the need for rest imaging. This approach limits the ability to assess rest myocardial blood flow and coronary vasodilator reserve, however, limiting the ability to identify patients with extensive CAD and “balanced” ischemia, as discussed subsequently.

Different protocols can be used to acquire emission scans (see Fig. 24-1), as follows:

1 ECG gated imaging. This is the most common clinical approach. Imaging begins 90 to 120 seconds after rubidium 82 injection, or 3 to 5 minutes after ammonia N 13 injection, to allow for clearance of radioactivity from the lungs and blood pool; the scan duration is approximately 5 minutes for rubidium 82 or 20 minutes for ammonia 13 N (see Fig. 24-1B).

2 Multiframe or dynamic imaging. Imaging begins with the bolus (short infusion) of rubidium 82 or ammonia 13 N and continues for 7 to 8 minutes or 20 minutes (see Fig. 24-1C). The advantage of this approach is that it allows quantification of myocardial blood flow (in mL/min/g) by fitting regional tissue and blood time-activity curves to a suitable kinetic model. Its main disadvantage is that one needs to perform a separate radionuclide injection to obtain ECG gated images from which to assess cardiac function, especially when using rubidium 82. Using ammonia 13 N, one can acquire a short multiframe or dynamic scan (4 minutes) that can be followed with a separate, approximately 15-minute ECG gated scan to assess myocardial perfusion and left ventricular ejection fraction (LVEF), without the need of an additional radionuclide injection owing to its longer physical half-life (approximately 10 minutes) (see Fig. 24-1D). To measure the left ventricular blood time-activity curves noninvasively, one must acquire many dynamic PET image frames while the tracer bolus passes through the right ventricle, the lungs, and the left ventricle. During this interval, it is common for a large amount of activity (approximately 20 to 30 mCi) to be located entirely within the PET scanner’s axial field of view. Because of possible count-rate limitations under such conditions, particularly in three-dimensional scan mode, great care must be taken to ensure the accuracy of the PET system’s corrections for random and scatter coincidences and dead time.

3 List mode imaging. This is the ideal approach because a single injection and data acquisition allows multiple image reconstructions (i.e., summed, ECG gated, and multiframe or dynamic) for a comprehensive physiologic examination of the heart. With this approach, image acquisition begins with the bolus injection of the radionuclide and continues for 7 to 8 minutes for rubidium 82 or 20 minutes for ammonia N 13 (see Fig. 24-1A). List mode imaging requires significant computer power to perform the multiple reconstructions, especially for the three-dimensional image acquisition mode.

Stress testing is most commonly performed using adenosine, dipyridamole, or dobutamine. Protocols using exercise stress testing with PET/CT have been described.⁵ The use of exercise PET in clinical practice is very limited, however, especially with shorter half-life agents such as rubidium 82 (half-life 76 seconds).

Quality Assurance for Cardiac PET/CT

Hybrid imaging using PET/CT is prone to significant artifacts if not performed correctly. Quality control measures, including routine inspection of the transmission and emission data and the transmission-emission alignment, should always be enforced to obtain high-quality studies. These quality control measures include the following:

1 Count density. The level of statistical noise in the emission and transmission images should be checked to see if enough counts have been acquired; this is crucial with rubidium 82 imaging because of the short half-life of the isotope. Although the image quality of CT transmission images may be suboptimal in heavy patients, this does not seem to compromise the quality of the attenuation correction because the attenuation map is integrated along the PET lines of response to obtain attenuation-correction factors. The most common sources of count-poor emission studies include large patient size, inadequate radionuclide dose or delivery (e.g., problems with intravenous access), and inadequate scan duration.

2 Heart-to-blood pool count ratio. Acquisition of emission images before complete clearance of radiotracer from the blood pool may potentially degrade image quality. The optimal prescan delay for acquisition of ammonia 13 N images is about 3 minutes and for rubidium 82 images is approximately 90 seconds in healthy subjects. The most common factors that prolong circulation time of the radionuclide include severe left ventricular systolic dysfunction (LVEF <30%, either chronic or acute secondary to severe ischemia during stress), right ventricular systolic dysfunction, and primary lung disease. In these clinical settings, increased prescan delay is usually required to improve image quality.¹^,⁶ The use of the list mode imaging protocols is very helpful because assumptions regarding prescan delay are not required.

3 Transmission-emission misalignment. Misregistration of transmission and emission images can result from respiratory or patient motion, and can lead to inaccurate clinical results (Fig. 24-2). Because transmission and emission imaging are sequential, patient or respiratory (e.g., deep inspiration) motion during the emission images is most likely to lead to transmission-emission misalignment and potential attenuation-correction artifacts (see Fig. 24-2). The extent and direction of this misalignment determine whether artifacts are apparent in the attenuation-corrected images. Most commercial PET/CT systems now include software tools to correct for transmission-emission misalignments.

FIGURE 24-2 Transmission-emission misalignment. A, The misaligned CT transmission and rubidium 82 images (right), and the resulting anterolateral perfusion defect on stress-rest rubidium 82 PET (left). The perfusion defect results from applying incorrect attenuation coefficients during tomographic reconstruction to the area of the left ventricular myocardium overlaying on the lung field on the CT transmission scan (arrows). B, The correction of the emission-transmission misalignment (right), and the resulting normal perfusion study.

(From Di Carli MF, Dorbala S, Meserve J, et al. Clinical myocardial perfusion PET/CT. J Nucl Med 2007; 48:783-793.)

Diagnostic Accuracy

Table 24-1 summarizes the published studies documenting the diagnostic accuracy of myocardial perfusion PET imaging for detecting obstructive CAD.⁷ The average weighted sensitivity for detecting at least one coronary artery with greater than 50% stenosis is 90% (range 83% to 100%), and the average specificity is 89% (range 73% to 100%). The corresponding average positive and negative predictive values are 94% (range 80% to 100%) and 73% (range 36% to 100%), and the overall diagnostic accuracy is 90% (range 84% to 98%). Most of the available data have been obtained with dedicated PET cameras, rather than with PET/CT systems. In a more recent study using PET/CT (where the CT was used only for attenuation correction), Sampson and colleagues⁸ reported a sensitivity of 93%, a specificity of 83%, and a normalcy rate of 100%. In this study of patients without known prior CAD, the positive and negative predictive values of PET/CT were 80% and 94%, with an overall accuracy of 87%. All patients with a low likelihood for CAD showed normal scans, for a normalcy rate of 100%. The sensitivity for detecting CAD in patients with single vessel and multivessel (two or more vessels) disease was 92% and 95%. These results were applicable to men and women and to obese and nonobese individuals.

TABLE 24-1 Summary of Published Literature Regarding Diagnostic Accuracy of PET

Comparative Studies of Positron Emission Tomography versus Single Photon Emission Computed Tomography

Two studies have performed a direct comparison of the diagnostic accuracy of rubidium 82 myocardial perfusion PET and thallium 201 imaging in the same patient populations. Go and colleagues ⁹ compared PET and SPECT in 202 patients and showed higher sensitivity with PET than with SPECT (93% vs. 76%), without significant changes in specificity (78% vs. 80%). Stewart and coworkers¹⁰ compared PET and SPECT in 81 patients and observed a higher specificity with PET than with SPECT (83% vs. 53%), without significant differences in sensitivity (86% vs. 84%). The differences between these two studies are likely to be attributable to patient selection resulting in differences in prescan likelihood of CAD.

More recently, Bateman and associates ¹¹ compared rubidium 82 PET and Tc 99m sestamibi SPECT in two matched patient cohorts undergoing clinically indicated pharmacologic stress perfusion imaging using contemporary technology for SPECT and PET. Overall diagnostic accuracy was higher for PET than for SPECT (87% vs. 71% with a 50% angiographic threshold, and 89% vs. 79% with a 70% angiographic threshold). Differences in diagnostic accuracy reflected primarily the increased specificity (with a marginal advantage in sensitivity) of PET versus SPECT, and applied to men and women and to obese and nonobese individuals.

Evaluation of Multivessel Coronary Artery Disease

The diagnosis of multivessel or left main CAD with diffuse balanced ischemia using MPI remains a challenge. PET (similar to SPECT) often uncovers only the coronary territory supplied by the most severe stenosis. The use of ancillary high-risk markers often helps in ascertaining the presence of multivessel CAD. ECG gating provides a unique opportunity to assess left ventricular function at rest and during peak stress (as opposed to poststress with gated SPECT). More recent data suggest that in normal subjects, LVEF increases during peak vasodilator stress.¹² In the presence of CAD, changes in LVEF (from baseline to peak stress) are inversely related to the magnitude of perfusion abnormalities during stress (reflecting myocardium at risk) (Fig. 24-3) and the extent of angiographic CAD (Fig. 24-4). In patients with three-vessel or left main CAD, LVEF during peak stress decreases even in the absence of apparent perfusion abnormalities (Fig. 24-5). In contrast, patients without significant CAD or with one-vessel disease show a normal increase in LVEF. Consequently, the negative predictive value of an increase in LVEF (from rest to peak stress) of 5% or greater to exclude the presence of three-vessel or left main CAD or both is 97%.¹²

FIGURE 24-3 Bar graph showing the relationship between the magnitude of stress-induced perfusion abnormalities and the delta change in left ventricular ejection fraction (LVEF) (from baseline to peak stress).

(From Dorbala S, Vangala D, Sampson U, et al. Value of vasodilator left ventricular ejection fraction reserve in evaluating the magnitude of myocardium at risk and the extent of angiographic coronary artery disease: a 82Rb PET/CT study. J Nucl Med 2007; 48:349-358.)