Myocardial perfusion imaging agents: SPECT and PET

MAJOR ACHIEVEMENTS IN NUCLEAR CARDIOLOGY: II Myocardial perfusion imaging agents: SPECT and PET George A. Beller, MD,a and Steven R. Bergmann, MD, PhDb INTRODUCTION Myocardial perfusion imaging for the evaluation of regional myocardial blood flow and viability under rest or stress conditions has emerged as the major nuclear cardiology technique in clinical practice. The evolution of this technique over the years has occurred in parallel with advances in instrumentation, particularly with the transformation from planar gamma camera approaches to image acquisition to tomographic imaging with single photon emission computed tomography (SPECT) technology, which now can include gated acquisition for simultaneous assessment of function and attenuation correction for enhancing specificity with reduction in attenuation artifacts. Simultaneously, positron emission tomographic (PET) imaging has become more prevalent as an alternative approach to evaluating myocardial blood flow by use of positron-emitting radionuclides that are short-lived. Although current tracers used for perfusion imaging have provided valuable clinical information, further advances are needed to enhance the detection rate of coronary artery lesions as well as the capability of monitoring subtle changes in defect size with medical therapy aimed at alleviating stress-induced ischemia and/or improving coronary endothelial function.

reduce residual activity from the first procedure (eg, resting imaging). Images were obtained on a rectilinear scanner by use of planar anterior and oblique projections. When used clinically, K-43 myocardial imaging was shown to detect, localize, and size myocardial infarctions and detect exercise-induced hypoperfusion.1 The next radionuclide monovalent cation evaluated was rubidium 81 (Rb-81), which had myocardial uptake and clearance characteristics similar to those of K-43. Perfusion imaging with Rb-81 was accomplished with a scintillation camera equipped with a special collimator that prevented the penetration of the high-energy emission of both Rb-81 and rubidium 82m, the latter being a contaminant. This imaging agent was also successful for noninvasive detection of inducible myocardial ischemia in patients with coronary artery disease (CAD).2 The limitation of Rb-81 was difficulty with image interpretation with pinhole collimation, particularly if the heart was not well centered within the camera’s field of view. Both K-43 and Rb-81 virtually disappeared from further clinical evaluation with the emergence of another potassium analog, thallium 201 (Tl-201). The introduction of Tl201 in nuclear cardiology was the most significant important advance in making noninvasive radionuclide perfusion imaging feasible for detection of CAD and risk stratification by use of the standard gamma scintillation camera.

SPECT PERFUSION IMAGING AGENTS Historical Perspective Potassium 43 (K-43) was one of the first radionuclides to be used for imaging in patients but was limited by its rather high-energy photons (373-keV peak) that made imaging with gamma cameras somewhat problematic. The tracer also had a 22.4-hour physical half-life, so studies had to be separated by a minimum of 4 days to From the Cardiovascular Division, Department of Medicine, University of Virginia Health System, Charlottesville, VA,a and Division of Cardiology, Beth-Israel Medical Center, New York, NY.b Reprint requests: Steven R. Bergmann, MD, PhD, Division of Cardiology, Beth-Israel Medical Center, First Avenue at 16th Street, New York, NY 10003. J Nucl Cardiol 2004;11:71-86. Copyright © 2004 by the American Society of Nuclear Cardiology. 1071-3581/2004/$30.00 ⫹ 0 doi:10.1016/j.nuclcard.2003.12.002

Tl-201 Thallium is a metallic element in group III-A of the periodic table of elements. Its half-life is 73 hours. The 69- to 80-keV x-rays emitted permitted imaging with high-resolution, low-energy collimators that were not practical for imaging myocardial distribution of K-43 or Rb-81. The initial myocardial uptake of Tl-201 after intravenous administration was shown to be dependent upon both myocardial blood flow and the myocardial extraction fraction for Tl-201.3,4 The extraction fraction under normal basal flow conditions is in the range of 85%. This is unaltered by transient myocardial ischemia, even if significant myocardial stunning occurs.5 Similarly, intracellular extraction of Tl-201 is not altered with sustained low-flow ischemia, which produces hemodynamic and functional correlates of myocardial hibernation.6 Myocardial Tl-201 uptake is unaffected by hyp71

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Figure 1. Serial determination of myocardial Tl-201 activity, expressed as a percent of initial normal thallium activity, in 5 groups of dogs occluded for 20 minutes and reperfused for 5, 20, 90, 240, and 360 minutes. Tl-201 was injected during the occlusion phase, and the initial value of Tl-201 activity in the ischemic region was obtained before reflow and represents the mean for 27 dogs. Near equalization of Tl-201 concentration in normal and previously ischemic myocardial regions appears by 4 hours. This is a graphic example of the phenomenon of Tl-201 redistribution and forms the basis of clinical imaging after the injection of a single dose of Tl-201 during ischemia and acquisition of redistribution images 3 to 4 hours later. (Reproduced with permission from Beller GA, Watson DD, Ackell P, Pohost GM. Time course of thallium-201 redistribution after transient myocardial ischemia. Circulation 1980;61:791-7.)

oxia when coronary flow is held constant.7 More than 60% of Tl-201 uptake occurs via active transport by use of the Na⫹, K⫹–adenosine triphosphatase sarcolemmal membrane transport system.8 In vivo, Tl-201 myocardial uptake reaches its peak within several minutes after intravenous injection, corresponding with rapid clearance of the tracer from the blood pool. It is only when irreversible sarcolemmal membrane injury occurs that Tl-201 cannot be sequestered intracellularly by myocytes. This forms the basis of the application of rest Tl-201 imaging for the clinical determination of myocardial viability in CAD patients with severe left ventricular dysfunction. Like all diffusible tracers, there is increased intracellular extraction of Tl-201 in areas of marked flow diminution with sustained cellular viability. This is because, at low flow rates, tracers such as Tl-201 spend more time in contact with the capillary membrane, resulting in higher extraction. The uptake of Tl-201, like other perfusion imaging agents that are diffusible tracers, is not linear with respect to myocardial blood flow as flow increases into the hyperemic range. As flow increases, more of the diffusible tracer passes through the capillary without being extracted and will reach a plateau at certain levels of high flow. At high flow rates, the uptake of tracers such as Tl-201 underestimates the true flow as measured with microspheres. The roll-off begins at higher flow with Tl-201 than other tracers such as technetium 99m

(Tc-99m) sestamibi and Tc-99m tetrofosmin, where the plateau occurs at a lower flow level because of lower first-pass extraction of these Tc-99m–labeled tracers.9 The clinical implications of this nonlinearity of tracer uptake with flow will be discussed later in this review. It can be a significant limitation for detection of mild coronary stenoses with vasodilator stress imaging. Redistribution kinetics. A major characteristic of Tl-201, not shared by Tc-99m sestamibi and Tc-99m tetrofosmin, is its redistribution properties. Tl-201 does not remain fixed in myocardial cells after the initial phase of extraction. It is continually exchanged with new Tl-201 from the systemic circulation. This phenomenon of redistribution after transient myocardial ischemia, or during a sustained low-flow state, formed the basis of serial imaging 5 to 10 minutes after Tl-201 administration, with delayed imaging performed 3 to 4 hours later. An early experimental study showed that when Tl-201 was injected during a period of temporary left anterior descending coronary occlusion, the initial intracellular Tl-201 concentration in the ischemic zone was markedly decreased.10 Subsequently, with restoration of normal perfusion and resolution of ischemia, the myocardial cellular Tl-201 concentration increased over time. Scintigraphically, this would correlate with the disappearance of a transient defect. Figure 1 shows the serial determination of myocardial Tl-201 activity, expressed as a percentage of initial normal Tl-201 activity, in 5 groups

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of dogs occluded for 20 minutes and subsequently reperfused. Near equalization of Tl-201 concentration in normal and previously ischemic myocardial regions appears by 4 hours.11 The Tl-201 redistribution shown after transient ischemia is related to both delayed accumulation of Tl-201 into previously ischemic myocardial segments and more rapid washout of the tracer from normal segments.12 The kinetic characteristics of delayed Tl-201 washout under conditions of ischemia were exploited clinically in improving the detection rate of multivessel CAD. Certain patients with extensive CAD demonstrated only abnormal myocardial Tl-201 clearance in segments perfused by significantly stenotic vessels, which often was found simultaneously with perfusion abnormalities in other myocardial segments in the same patient.13 Quantitation of planar Tl-201 imaging including the identification of regions with abnormal regional Tl-201 washout increased the prediction of multivessel disease in one study from 39% to 78%.13 The explanation for this marked difference was that with only visual inspection of serial images, certain segments demonstrating abnormal Tl-201 washout or increasing tracer uptake over time were not readily identified. In the majority of patients with multivessel disease, a dominant defect is present usually in the distribution of the coronary artery with the greatest degree of stenosis and/or in an area of prior infarction. This dominant defect is easily observed both visually and with quantitative image analysis. In these patients, however, other vascular segments supplied by stenotic vessels often show only increasing uptake of Tl-201 on delayed images as a result of reduced tracer washout, compared with a net clearance of Tl-201 from totally normally perfused regions. Some patients with uniform Tl-201 uptake on postexercise scintigrams showed upsloping myocardial Tl-201 time-activity curves reflective of increasing Tl-201 uptake during the redistribution phase. In the instance of 3-vessel disease with “balanced ischemia,” the ability to determine myocardial clearance kinetics by quantitative imaging was a strength of Tl-201 scintigraphy, which permitted the identification of more abnormal areas than identified by appreciation of defects alone. This feature is not exploited with Tc-99m sestamibi or Tc-99m tetrofosmin planar or SPECT imaging, where myocardial clearance of these radionuclides is slow and no significant redistribution occurs. When Tl-201 is administered intravenously under conditions of a myocardial scar, a persistent or fixed defect is observed in the coronary supply zone of the irreversibly damaged area. In such a situation, no delayed redistribution or defect resolution can be detected. With a mixture of scar and ischemia, partial Tl-201 redistribution is observed. After several years of experi-

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ence with Tl-201 imaging, it became apparent that some mild fixed defects showed improved Tl-201 uptake after revascularization.14 The differentiation between ischemia and scar was enhanced with Tl-201 “reinjection” imaging, in which a second dose of Tl-201 is given at rest after acquisition of the poststress redistribution images.15 Approximately 30% to 40% of fixed defects will show visually enhanced Tl-201 uptake after reinjection. Tl-201 redistributes in the resting state after intravenous injection and forms the basis of one of the most sensitive techniques by which to noninvasively evaluate myocardial viability in patients with ischemic cardiomyopathy.16 Many patients with extensive multivessel disease with viable myocardium have initial resting defects that fill in over a 4-hour period at rest, which has been referred to as rest redistribution. The greater the delayed Tl-201 uptake on these redistribution images, the greater the chance for improved regional function after revascularization. One of the significant limitations of myocardial perfusion imaging with Tl-201 was poor-quality images in obese patients and problems distinguishing attenuation artifacts from defects that were due to underlying CAD. Even with quantitation of either planar or SPECT images, specificity was problematic, particularly in women. Tc-99m produces less scatter and attenuation than Tl201, and approximately 10- to 20-fold larger doses of the Tc-99m radiopharmaceuticals can be administered than are feasible with Tl-201 because of the difference in physical properties. Image quality was considered superior for Tc-99m perfusion agents compared with Tl-201 when they were objectively compared. For these and other reasons, stress Tl-201 imaging is being performed with far lower frequency than stress perfusion imaging with the Tc-99m–labeled tracers now that SPECT has overtaken the planar technique for image acquisition and display. Image quality and specificity have improved considerably with the switch to Tc-99m radiopharmaceuticals. In many laboratories in which a dual-isotope imaging protocol is used, rest Tl-201 imaging is undertaken in conjunction with stress Tc-99m imaging. Tc-99m–Labeled Myocardial Perfusion Agents Tc-99m–labeled myocardial perfusion agents provide better image quality than Tl-201 because the 140keV photon energy peak of Tc-99m is optimal for gamma camera imaging.17 The relatively short half-life (6 hours) of Tc-99m provides favorable patient dosimetry and makes it possible to administer a dose of the radiopharmaceutical 10 to 15 times greater than Tl-201. The higher count rates for Tc-99m easily permit gated

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Figure 2. Myocardial Tc-99m sestamibi (TcMIBI) and Tl-201 activities versus regional flow from a dog with a critical left anterior coronary stenosis that received intravenous adenosine. The data points represent transmural tracer activities expressed as a percentage of activity at normal flow (1 mL · min⫺1 · g⫺1). The curves are mathematical fits to the following form: Y ⫽ B0 ⫻ X ⫻ (1 ⫺ e⫺B1 ⫻ x). (Copyright 1995, American Heart Association, Inc. Reproduced with permission from Glover DK, Ruiz M, Edwards NC, et al. Comparison between 201Tl and 99mTc sestamibi uptake during adenosine-induced vasodilation as a function of coronary stenosis severity. Circulation 1995;91:813-20.)

acquisition for the assessment of regional wall motion or regional thickening. Tc-99m sestamibi. Tc-99m sestamibi was the first Tc-99m–labeled perfusion imaging agent to be applied in the clinical setting. It belongs to a class of cationic technetium compounds, the hexakis alkylisonitrile technetium(I) complexes. Tc-99m sestamibi showed the most favorable myocardial/background ratio for myocardial imaging than any of the other isonitriles that were being tested. Its kinetics have been well investigated in a number of experimental models.18,19 When Tc-99m sestamibi is administered under basal conditions, it is taken up in the myocardium in proportion to regional myocardial blood flow. When it is administered at flow rates of 2 to 2.5 mL · min⫺1 · g⫺1 or greater, there is a plateau in extraction, which has been discussed previously.20,21 Because the first-pass myocardial extraction of Tc-99m sestamibi is in the 55% to 65% range, it plateaus at a lower level of increased flow above baseline compared with Tl-201.22 Figure 2 shows myocardial Tc-99m sestamibi and Tl-201 activities versus regional blood flow in a dog with a critical left anterior descending stenosis after adenosine infusion. Note that the plateau in Tc-99m sestamibi uptake occurs earlier than with Tl-201, which is a result of the difference in the extraction fraction of the two tracers. Tc-99m sestamibi is transported passively across both plasma and mitochondrial membranes and is sequestered within mitochondria by large negative transmembrane potentials. When mitochondrial membranes

are depolarized, as occurs with irreversible myocyte injury, the uptake of Tc-99m sestamibi is impaired.23 Metabolic interventions that injure sarcolemmal or mitochondrial membranes result in loss of cellular retention of Tc-99m sestamibi.24 As with Tl-201, the uptake of Tc-99m sestamibi in intact dogs is dependent on myocardial viability, and defect size correlates well with infarct size.25 Thus Tc-99m sestamibi is a valid imaging agent for viability assessment in the clinical setting. As with Tl-201, postischemic myocardial stunning and low-flow ischemia producing systolic dysfunction do not affect Tc-99m sestamibi uptake.6 The major difference between Tc-99m sestamibi and Tl-201 kinetics relates to myocardial clearance after initial myocardial distribution after intravenous injection. After initial uptake, clearance of Tc-99m sestamibi is slow.26 As expected from this very slow washout, the amount of Tc-99m sestamibi redistribution is small and far lower than that observed with Tl-201.27,28 Despite the lack of any significant redistribution when injected at rest, there is substantial uptake of the tracer in areas of low-flow ischemia.28 In patients with CAD and left ventricular dysfunction, Tc-99m sestamibi uptake is comparable to delayed Tl-201 uptake.29 Figures 3 and 4 depict these observations. Clinically, the lack of any significant delayed redistribution makes imaging of patients with acute coronary syndromes very feasible when the tracer can be injected during pain but images acquired substantially later. When such images are acquired, the perfusion defect

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Figure 3. Bar graph showing Tl-201 and Tc-99m sestamibi image defect ratios (ischemic/normal) in 16 dogs with a sustained reduction in resting flow causing short-term hibernation. The final delayed defect magnitude after 2 hours of redistribution was slightly but significantly greater than the Tc-99m sestamibi defect magnitude. That is, approximately 5% more Tl-201 than Tc-99m sestamibi uptake was observed in these dogs with chronic low flow and severe systolic dysfunction. (Copyright 1995, American Heart Association, Inc. Reproduced with permission from Sansoy V, Glover DK, Watson DD, et al. Comparison of thallium-201 resting redistribution with technetium-99m-sestamibi uptake and functional response to dobutamine for assessment of myocardial viability. Circulation 1995;92:994-1004.)

pattern observed is reflective of perfusion at the time of injection. Tc-99m sestamibi imaging by use of SPECT has also been useful for quantitating infarct size and has been used to evaluate the efficacy of therapy in acute myocardial infarction.30 Tc-99m tetrofosmin. Tc-99m tetrofosmin is a lipophilic cationic complex that is rapidly cleared from the blood with intravenous injection and, like Tc-99m sestamibi, exhibits a relatively slow myocardial clearance with no redistribution.31,32 Tetrofosmin is a compound of the diphosphine group, and its chemical name is 1,2bis[bis(2-ethoxyethyl)phosphinol]ethane. The radionuclide is taken up by myocardial tissue in proportion to blood flow and myocardial cellular viability.33,34 Tc-99m tetrofosmin accumulates in mitochondria similar to Tc99m sestamibi, and only viable tissue sequesters the tracer. Its myocardial uptake is reduced by metabolic inhibitors that cause severe cell injury or death.35,36 The mean myocardial first-pass extraction fraction for Tc-99m tetrofosmin was 54%, which is lower than previously published extraction fraction values for Tl201 and Tc-99m sestamibi.37 When administered intravenously during vasodilator stress in the setting of a mild coronary stenosis, the myocardial Tc-99m tetrofosmin uptake is almost flat at 1.5 times normal flow, whereas Tl-201 uptake continues to show an increase in uptake relative to the degree of hyperemia.37 Because of the lower extraction fraction compared with Tl-201, the uptake of the tracer underestimates flow disparity be-

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tween stenotic and normal perfusion beds in the instance of mild coronary stenosis in the clinical setting. When Tc-99m tetrofosmin is administered in the resting state, its uptake reflects the extent of viability in patients with ischemic cardiomyopathy.38 Tc-99m teboroxime. Tc-99m teboroxime is a neutral lipophilic agent that is in the class of compounds designated as boronic acid adducts of technetium oximes. Its uptake is not dependent on any enzymatic or active transport mechanism. Its myocardial extraction exceeds 90%, with subsequent rapid myocardial washout.39,40 At 1 minute after injection, the relationship between Tc-99m teboroxime myocardial retention to blood flow is quite linear over a wide range of flows. However, after only 5 minutes, tracer retention underestimates flow changes at moderate and high flow rates.40 This is because of its rapid myocardial clearance rate. Cellular retention of Tc-99m teboroxime is less than that of Tl-201 and Tc-99m sestamibi because of the high volume of backdiffusion of the tracer. In an animal model of an experimental coronary stenosis, the rapid clearance of Tc-99m teboroxime resulted in a loss of defect contrast from 2 to 4 minutes after tracer injection on serial gamma camera images.41 By 2 minutes after injection, Tl-201 defect magnitude reflected the flow decrement better than Tc-99m teboroxime defect magnitude in the same animals during adenosine stress in the presence of a left anterior descending coronary artery stenosis.41 Tc-99m teboroxime washout is slower from ischemic zones than from normal zones, which exhibits the scintigraphic correlate of “redistribution” observed on serial Tl-201 scintigrams. The clearance is very fast from normally perfused zones (7 minutes) as compared with 3.4 hours for clearance of Tl-201 from normal zones.42 Figure 5 shows Tc-99m teboroxime myocardial timeactivity curves from normal and occluded regions in a canine model after adenosine infusion. In this example the clearance half-time was significantly slower in the zone perfused by the stenotic coronary artery.43 To date, Tc-99m teboroxime imaging in the clinical setting has seen limited application, but perhaps with more rapid SPECT acquisition yielding higher-quality SPECT images of Tc-99m teboroxime uptake, good-quality clinical images could be obtained. Tc-99m N-NOET. Tc-99m N-NOET [bis(Nethoxy,N-ethyldithiocarbamato)nitrido technetium(V)] is a neutral and lipophilic myocardial perfusion agent.44 The uptake of Tc-99m N-NOET is proportional to regional myocardial blood flow over a wide flow range in canine models of coronary artery stenoses (Figure 6).45,46 Its initial uptake is more linear with flow in the hyperemic range compared with Tc-99m sestamibi and Tc99m tetrofosmin. Like Tl-201, Tc-99m N-NOET has

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Figure 4. Bar graph showing quantitative analysis of rest Tl-201 activity (REST-TL), delayed Tl-201 redistribution activity (RD-TL), and Tc-99m sestamibi (MIBI) uptake after 1 hour postinjection in 31 patients with CAD and regional and global left ventricular dysfunction. (Reproduced with permission from Udelson JE, Coleman PS, Metherall J, et al. Predicting recovery of severe regional ventricular dysfunction. Comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi. Circulation 1994;89:2552-61.)

Figure 5. Differential washout of Tc-99m teboroxime in an animal model of an experimental coronary stenosis and adenosine stress. Note that the clearance is more rapid from the nonoccluded region when compared with tracer clearance in the occluded zone. These curves show that defect normalization would have occurred by 8 minutes, but a substantial resolution in the differential initial uptake of the tracer between occluded and nonoccluded zones occurs very rapidly. Ln, Log transformation. (Reproduced with permission from Stewart RE, Heyl B, O’Rourke RA, Blumhardt R, Miller DD. Demonstration of differential post-stenotic myocardial technetium-99mteboroxime clearance kinetics after experimental ischemia and hyperemic stress. J Nucl Med 1991;32:2000-11.)

been shown to undergo redistribution in experimental models of transient ischemia or with sustained low-flow ischemia (Figure 7).45,47 The myocardial uptake of Tc99m N-NOET was shown to reflect reperfusion myocardial blood flow, and not viability, in an experimental model of reperfused acute myocardial infarction.48 This is different from what is seen with Tl-201, where myocardial uptake in a reperfused infarction represents viability and not flow. Another difference between Tl201 and Tc-99m N-NOET is that redistribution is rapid with the latter, with a significant resolution of defect magnitude by 20 minutes after injection.49 Redistribution is complete by 120 minutes. In this animal model of transient ischemia, lung activity significantly fell in the first 10 minutes from a heart/lung activity ratio of 1.07 at 2 minutes to 1.44 at 10 minutes.49 The tracer appears to bind to endothelial cells and is not sequestered intracellularly. It is thought that there is a bi-directional transfer of Tc-99m N-NOET between the myocardium and blood elements,50 which is in accordance with the supposition that this agent binds on the vascular endothelial surface. The myocardial clearance rate of Tc-99m N-NOET is affected by lipid levels in the blood pool.51 Because Tc-99m N-NOET is bound to albumin in the blood stream, the half-life of the intrinsic

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Figure 6. Normalized myocardial Tc-99m N-NOET activity versus flow at the time of injection during adenosine stress, plotted together with corresponding curves for Tl-201 and Tc-99m sestamibi derived from previous experiments in similar canine models. With adenosine stress, myocardial uptake of Tc-99m N-NOET, like that of thallium, is closely proportional to blood flow over a wide range of hyperemic flows. Note that the plateau in uptake is seen at flow rates of greater than 3 mL · min⫺1 · g⫺1. The curve of Tc-99m sestamibi uptake shows a plateau earlier during adenosine hyperemia, with flow rates of 2 to 2.5 mL · min⫺1 · g⫺1. (Copyright 1999, American Heart Association, Inc. Reproduced with permission from Calnon DA, Ruiz M, Vanzetto G, et al. Myocardial uptake of 99mTc-N-NOET and 201Tl during dobutamine infusion: comparison with adenosine stress. Circulation 1999;100:1653-9.)

Figure 7. Myocardial Tc-99m N-NOET activity versus time in the normal left circumflex (LCX) region of interest (ROI) and stenotic left anterior descending (LAD) ROI zones. Note that in the normal LCX zone, myocardial activity was maximal by 2 minutes after injection, whereas Tc-99m N-NOET activity in the stenotic LAD zone peaked at 6 minutes after injection. Over the next 2 hours, there was significantly greater clearance from the normal LCX zone compared with that in the stenotic LAD zone, and by 120 minutes, Tc-99m N-NOET redistribution was nearly complete. Asterisk, P ⬍ .01 versus LCX activity. (Copyright 2000, American Society of Nuclear Cardiology. Reproduced with permission from Petruzella FD, Ruiz M, Katsiyiannis P, et al. Optimal timing for initial and redistribution technetium-99m-N-NOET image acquisition. J Nucl Cardiol 2000;7:12331.)

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myocardial washout is significantly faster with increased lipid concentrations.51 The intrinsic myocardial washout of Tc-99m N-NOET is also flow-dependent. With prolonged hyperemia after injection, as when dipyridamole is used instead of adenosine for vasodilator stress, the redistribution kinetics may be more rapid because of accelerated washout of Tc-99m N-NOET from normal high-flow regions. Thus Tc-99m N-NOET washout can be affected by a host of intravascular factors because it is most likely bound to vascular endothelium, whereas Tl-201, which is localized within the cytosol, is less influenced by such perturbations and is in equilibrium with the extracellular tracer concentration. Tc-99m teboroxime, which is another neutral lipophilic molecule, also has flow-dependent myocardial washout. Tc-99m N-NOET has been used clinically with satisfactory detection of CAD and stress-induced ischemia. A phase III trial was recently completed, but the data have not been published at the time of this writing. One problem with this agent may be the progressive loss of defect contrast soon after injection because of rapid redistribution. This is similar to what has limited the clinical application of Tc-99m teboroxime stress imaging, although Tc-99m N-NOET redistribution (differential washout) is not as rapid as that seen with Tc-99m teboroxime (Figure 5 vs Figure 7). PET PERFUSION IMAGING AGENTS Background Assessment of myocardial perfusion is critical for evaluating the significance of diseases that affect the coronary artery and for evaluation of their severity. Although SPECT constitutes the primary modality for assessing myocardial perfusion with radioactive tracers, PET provides several significant advantages over SPECT imaging. These include accurate attenuation correction, because of the physical characteristics of the positronemitting radionuclides, and the ability to quantify myocardial perfusion in absolute terms (ie, milliliters per gram per minute). This quantitative aspect of PET sets it apart from perfusion imaging that is achieved with SPECT, and although the primary use of this quantitative capability has been in the research setting, there are a number of circumstances in which quantitative assessment of myocardial perfusion can be particularly helpful. Whereas clinically, the absolute severity of coronary artery stenoses is determined from coronary arteriography, it is well known that this “lumenography” does not accurately predict maximal flow in response to physiologic or pharmacologic stimuli. Although SPECT techniques with either Tl-201– or Tc-99m– based tracers play a significant role in the diagnostic and prognostic eval-

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uation of patients with suspected or existent CAD, accurate attenuation correction with SPECT has proved challenging. Quantification of perfusion in absolute terms has been unattainable with SPECT because of the depth-dependent attenuation of single photon-emitting tracers and their complex biokinetics. PET has emerged as the most accurate noninvasive approach for the quantification of regional myocardial blood flow.52 Even without absolute quantification, because of the accurate attenuation correction provided by PET, as well as the high energy of positron-emitting radionuclides (511 keV), PET is highly sensitive and specific for the delineation of CAD.53 However, the limited availability of centers with cardiac PET expertise has limited the use of PET as a primary perfusion imaging modality. With the use of generator-produced rubidium 82 (see below), the feasibility of freestanding cardiac PET as an alternative to SPECT has emerged, and a number of high-volume cardiac practices are using myocardial perfusion imaging with PET as an alternative to SPECT. It should be remembered, however, that the exercise component of a stress test in patients who are able to exercise has important independent prognostic and diagnostic value. Because stress testing with PET must be performed with a pharmacologic agent, appropriate triage to PET as compared with SPECT imaging as the primary diagnostic modality is based on other factors such as body habitus, the anticipated use of a pharmacologic stress agent, a prior equivocal SPECT study, or a patient who does not wish to undergo coronary angiography. Quantitative Assessment of Myocardial Perfusion With PET Quantitative measurement of myocardial perfusion in absolute terms may be important for the evaluation of patients in whom perfusion is homogeneous (that is, without regional disparity, such as those with chest pain and angiographically normal coronary arteries, those with cardiac transplants, those with cardiomyopathy, or those with balanced CAD in whom regional disparities may not be obvious). In addition, quantitative analysis is particularly useful in evaluating vascular function in patients in whom overt macroscopic coronary stenoses are not present, such as those with hypercholesterolemia or diabetes.54,55 Even the routine use of nicotine has been shown to impair endothelial function as defined by PET.56 PET can be extraordinarily helpful for evaluating vascular physiology in a precise and reproducible fashion and plays an important role in the delineation of therapies designed to improve myocardial perfusion. Accurate measurement of myocardial perfusion requires an understanding of, and attention to, tracer

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Figure 8. Schematic diagram of data acquisition for obtaining blood and tissue time-activity curves for estimation of physiologic parameters such as flow. The arterial input function [Ca(t)] and the tissue time-activity curve [CT(t)] are determined from dynamically obtained images. Flow is then calculated by use of an appropriate mathematical model. BP, Blood pool; ROI, region of interest. (Reproduced with permission from Bergmann SR. Quantification of myocardial perfusion with positron emission tomography. In: Bergmann SR, Sobel BE, editors. Positron emission tomography of the heart. Mount Kisco (NY): Futura; 1982. p. 97-127.)

kinetics on which the mathematical models are based and used to describe the biologic behavior of administered tracers in blood and myocardial tissue over time.52 All quantitative approaches use compartmental techniques in which dynamic acquisitions of tracers are obtained (Figure 8). Regions of interest placed within the blood pool—typically the left atrial or basal left ventricular chambers—provide the input function of administered tracers, and multiple regions placed in the myocardium provide the tissue time-activity response. On the basis of an understanding of the transfer of tracer from blood to myocardium, quantitative assessment can be made with physiologically appropriate mathematical models. Because of the limited spatial resolution of the current generation of PET tomographs and the fact that most perfusion estimates are performed without cardiac gating, and because of volume averaging imposed by cardiac and respiratory motion, time-activity curves must be corrected for partial volume and spillover. Corrections can be performed independently with measurement of dimensions by use of other modalities, within the mathematical model, or with factor analysis.52 PET instruments must faithfully record the temporal changes in counts in blood and tissue and have appropriate software for input into mathematical models. The accuracy of quantification of perfusion by PET

in low-flow regions is challenging because of the reduced activity of tracers based on flow, as well as the further limitation that can be imposed by wall thinning and therefore decreased count recovery. Accurate partial volume corrections are essential. These, in some respect, have become less significant with scanners that have increased resolution, but given that most cardiac studies are performed without cardiac gating and without respect to respiratory motion, the accurate recovery of radioactivity counts remains an important objective. PET Perfusion Tracers There are three tracers that are currently used widely for the assessment of myocardial perfusion with cardiac PET: Rb-82 chloride, nitrogen 13 (N-13) ammonia, and oxygen 15 (O-15) water (Table 1). O-15 water and N-13 ammonia, because of their short physical half-lives, need to be produced by an onsite cyclotron, whereas Rb-82 chloride is generator-produced, thus obviating the need for a cyclotron. All of the tracers used for measurement of myocardial perfusion with PET have permitted identification of CAD in patients with stenoses of greater than approximately 40%. With regard to the perfusion tracers available with PET, they can be divided into those that are freely

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Table 1. Positron-emitting radiotracers currently used for measurement of myocardial perfusion

Isotope Generator-produced Rb-82 (parent:strontium-82) Cyclotron-produced O-15 N-13

Physical half-life

Compound

Class

1.3 min (26 days)

Chloride

Extracted

2.1 min 10 min

Water Ammonia

Diffusible Extracted

diffusible (O-15 water) and those that are extracted (Rb-82 chloride and N-13 ammonia). The uptake and clearance of diffusible tracers from the myocardium are solely based on myocardial perfusion and unaffected by metabolism. Thus they are theoretically the preferable tracers. Because they reside both in blood as well as in myocardium, the images obtained are not of as high quality as those obtained with extractable tracers and need to be corrected for vascular activity. Extracted tracers are distributed to the myocardium by blood flow; thus their uptake is a reflection of flow. However, their uptake and retention are dependent on metabolic processes. Because they are retained in myocardium, and blood clearance is generally rapid, they provide diagnostic images of higher quality compared with diffusible tracers and also have sufficient residence time, so they can be used for gated functional studies, providing additional diagnostic and prognostic information. Rb-82 chloride. Rubidium is an extracted tracer that is partially extracted by the myocardium during a single capillary transit. Similar to the case for N-13 ammonia (and for other extracted perfusion tracers), there is an inverse and nonlinear relationship between extraction fraction and flow (Figure 9).57 Rb-82 chloride is an attractive tracer because it is produced from a strontium generator. The half-life of the parent is 26 days, and the half-life of Rb-82 is 76 seconds. Because the absolute uptake of Rb-82 plateaus at flows exceeding 2 to 3 mL · g⫺1 · min⫺1, uptake at hyperemic flows is somewhat insensitive to changes in flow, although this “role off ” is likely clinically insignificant. It does, however, have some implications for quantitative flow estimates in the hyperemic range. In addition, experimental studies have demonstrated that myocardial ischemia and reperfusion reduce the uptake of rubidium, not because of diminished flow but rather because of reduction in the extraction fraction as a result of diminished cellular transport.58 This occurs even after short periods of transient ischemia.59 To quantify myocardial perfusion, a 2-compartment model, originally described by Mullani and Gould60 and Goldstein et al,57 is used. When faithful time-activity curves are obtained, this has been shown to be accurate

over wide range of flows. One issue with rubidium is, because of the short physical half-life and thus limited absolute count data, time-activity curves are somewhat “noisy.” Newer noise-reduction techniques, such as the wavelet approach, have been used to de-noise rubidium curves.61 Rubidium has been used extensively for the clinical assessment of myocardial perfusion in patients with CAD62-66 and is approved for this purpose by the Food and Drug Administration. Typically, 30 to 60 mCi is administered from the generator-elution system as an infusion over a 30 to 60-second period. After a 1 to 3-minute interval to allow for clearance of tracer from arterial blood, a static image is obtained over a 3 to 7-minute period. As the generator ages, the infusion time becomes longer and image quality is somewhat degraded by residual blood activity. Good correlation has been made comparing the uptake of rubidium with the severity of CAD and in demonstrating improved perfusion after angioplasty. An intriguing concept, which has not been fully realized with Rb-82, was suggested by Goldstein,67 who demonstrated that the backward flux of extracted Rb-82 may delineate viable from irreversibly injured myocardium. Further studies will be required to determine whether rubidium can be used to assess not only perfusion but also myocardial viability. N-13 ammonia. N-13 ammonia has been used extensively for assessment of myocardial perfusion with PET.68-70 The mechanism of transport across the myocardial membrane has not been delineated, although it is likely carrier-mediated. N-13 ammonia exhibits high single-pass extraction and has a long tissue retention. Although uptake of tracer into the lungs (especially in smokers and in those with congestive failure) and liver can interfere with images, N-13 ammonia provides good to excellent images of the heart (Figure 10). Similar to the case for Rb-82, extraction of N-13 ammonia is inversely and nonlinearly related to flow and uptake plateaus at flows greater than 2 mL · g⫺1 · min⫺1.71 In addition, the uptake and retention are related to metabolism because the trapping of N-13 ammonia depends on the conversion of ammonia to glutamine by

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Figure 9. Relationship of net myocardial uptake of Rb-82 to myocardial blood flow as measured experimentally (A). Because of the inverse and nonlinear relationship between extraction fraction and flow (B), net myocardial uptake plateaus at flows greater than approximately 2 mL · g⫺1 · min⫺1. Correcting net uptake for this extraction relationship permits quantitative estimates of flow to be obtained (C). (Reproduced with permission from Goldstein RA, Mullani NA, Marani SK, et al. Myocardial perfusion with rubidium-82. II. Effects of metabolic and pharmacologic interventions. J Nucl Med 1983;24: 907-15.)

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the glutamine synthetase pathway.52 Because of regional heterogeneity in the uptake and/or retention of N-13 ammonia, there is decreased uptake in the inferolateral myocardium, even in the hearts of normal subjects.72 This fact highlights one of the inherent difficulties with use of all extractable tracers, which is that their uptake and retention are related to the metabolism by the heart. Another factor that may be important in quantification is the fact that more than 50% of administered N-13 ammonia is degraded to metabolic intermediates, predominantly urea and glutamine, within 5 minutes of intravenous administration.73 Nonetheless, the effect of this breakdown, which varies in individual subjects, is modest, as most flow models only use the first 2 minutes of dynamic data for quantification. For absolute quantification, 2- and 3-compartmental models have been proposed and used for quantitative assessment (Figure 11).71,74 An important issue in the use of N-13 ammonia is that flows obtained with this tracer are approximately 70% to 80% of flows obtained with either Rb-82 or O-15 water. A recent study has suggested that the model configuration used is largely responsible for this underestimation.75 Quantitative assessment of myocardial perfusion can be used to assess coronary flow reserve and endothelial function in the clinical setting. It has been shown that asymptomatic subjects with a family history of heart disease and CAD risk factors had diminished flow reserve (the ratio of flow at maximum hyperemia to flow at rest).54,74,76 Thus abnormal endothelial and vascular function can be delineated before the development of macrovascular or symptomatic disease. Cholesterol-lowering therapy ameliorates this abnormal response.76 Nicotine was shown to similarly impair maximum coronary hyperemia.56 N-13 has been used extensively for imaging of the heart in patients. Approximately 10 to 15 mCi of tracer is injected, and 5- to 10-minute static images are taken, starting approximately 5 to 10 minutes after administration. Experimental and clinical studies have demonstrated good correlation between the uptake of N-13 ammonia and myocardial perfusion.52,77 The long halflife of N-13 activity in the myocardium permits cardiac gating. O-15 water. O-15 water is the only diffusible tracer currently used for measuring myocardial perfusion with PET. Its kinetics is solely related to perfusion. However, because O-15 water also circulates in the blood, tracer in the vascular compartment needs to be corrected for to visualize myocardial activity (Figure 12).52,78 To quantify myocardial perfusion, dynamic scans are obtained for up to 5 minutes after bolus intravenous administration of typically 15 to 25 mCi. Correlations

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Figure 10. A, Short- and long-axis images of myocardial perfusion obtained at stress (adenosine) and at rest with N-13 ammonia. Maximum count density is displayed in red. There is a large anteroapical and lateral flow deficit with stress that is near normal at rest. SA, Short axis; VLA, vertical long axis; HLA, horizontal long axis. B, Polar map of the stress images (left) and rest images (right) demonstrating the large contiguous area of inducible flow disparity. Ant, Anterior; Sep, septal; Lat, lateral; Inf, inferior.

between flow estimated with a 1-compartment mathematical approach are reproducible and highly accurate.52 An alternative to the use of intravenous O-15 water is the use of O-15–labeled carbon dioxide given by inhalation, which is converted to labeled water by carbonic anhydrase located in both the blood and lungs.79 However, this approach is somewhat less convenient, increases the radiation burden to the patient

(especially in the airways), and is associated with some increased lung dose burden. Tomographic visualization of the heart after use of O-15 water requires correction for activity within the vascular compartment (Figure 12). This can be accomplished by use of a separate administration of O-15 carbon monoxide to label erythrocytes but also can be accomplished by use of an image obtained early (ie, 20 to

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Figure 11. Quantitative flow analysis from the subject whose scans are shown in Figure 10 demonstrates homogeneous flow (in milliliters per gram per minute) at rest, with diminished flow in the anteroapex and lateral myocardium with stress (normal ⫽ ⬎2.5 times rest flow). In addition, it should be noted that absolute hyperemic flow even in areas that are presumably normal with stress (ie, the septal and inferior myocardium) show some limitation to hyperemic flow in response to adenosine, suggesting that even areas presumed to have normal perfusion have impaired to hyperemic flow. MPR, Myocardial perfusion reserve.

40 seconds) after the administration of O-15 water (representing a vascular image) before significant radioactivity reaches the coronary arteries. Factor analysis has also been used to visualize the myocardium with O-15 water. Absolute flows in human beings, as well as salutary effects of thrombolysis and angioplasty, have been delineated with O-15 water.52,77,80 In addition, analysis of flow patterns in patients with chest pain but angiographically normal coronary arteries has also been defined.81 Some investigators believe that O-15 water can also been used to define myocardial viability,82 although the physiologic basis for this approach is controversial.83 Future Issues With PET Tracers The choice of tracers for the assessment of myocardial perfusion with PET is typically defined by the presence or absence of a cyclotron and local expertise. Centers that do not have access to a cyclotron use Rb-82. The short physical half-life of this tracer requires close attention to the technical aspects of study acquisition. In sites that have a cyclotron, N-13 ammonia is used most frequently for clinical studies because it provides images of excellent diagnostic quality. O-15 water has the theoretical advantage of being independent of metabolic processes and may provide the most accurate assessment of myocardial perfusion, but for diagnostic purposes, the requirement to correct for vascular radioactivity is significant. An important question is whether quantification of absolute blood flow in milliliters per gram per minute improves outcomes for clinical studies. Although there are clearly populations of patients who might benefit from quantitative analysis, absolute quantification of perfusion remains predominantly a research tool. How-

ever, future therapies, such as enhancement of perfusion with progenitor cells or angiogenic factors or assessment of the effect of various therapeutic agents on endothelial function, will require accurate absolute measurement of myocardial perfusion, and PET is currently the most accurate approach for these assessments. CONCLUSIONS The advent of myocardial perfusion imaging 30 years ago was a major landmark, which heralded the emergence of the field of nuclear cardiology into clinical practice. Over the years, the different tracers cited in this review have been used with SPECT or PET imaging technologies for the noninvasive evaluation of regional myocardial blood flow, which has enhanced our ability to diagnose CAD, assess prognosis, detect viable myocardium, and evaluate the efficacy of therapies aimed at improving myocardial blood flow. In the future, new SPECT perfusion agents should be developed and validated in the experimental laboratory for feasibility in the clinical setting. Hopefully, such new radiolabeled perfusion agents will have a high first-pass extraction, will be more linear with flow increases in the hyperemic range, and will be labeled with Tc-99m. The clearance rates from the myocardium after initial uptake should be slow enough, as with Tl-201, to acquire high-quality poststress gated SPECT images. Ideally, such perfusion agents should also be extracted intracellularly with quantitative uptake reflecting the degree of viability (eg, as with Tl-201). Absolute quantitation of myocardial blood flow in milliliters per minute per gram by use of SPECT technology would be highly desirable, particularly to increase the detection rate of multivessel disease in which flow reserve is uniformly diminished. This is often categorized as balanced ischemia. Absolute quantitation

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is a major strength of PET perfusion tracers, as is the ability to accurately correct for attenuation, thereby providing high sensitivity and specificity for CAD detection. The roll-off or plateau in myocardial uptake with hyperemia is also seen with the PET perfusion tracers such as N-13 ammonia and Rb-82. Despite the advent of molecular imaging and the introduction of new imaging agents by which to noninvasively evaluate biologic processes such as apoptosis and angiogenesis in vivo, myocardial perfusion imaging will remain the mainstay of nuclear cardiology in the near future. Continued research and development for this imaging technique are warranted for the reasons cited in this review. Acknowledgment We acknowledge Ms Erika Laurion and Mr Jerry Curtis for assistance in the preparation of this review, as well as the contribution of our fellows and colleagues over the years. The authors have indicated they have no financial conflicts of interest.

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Figure 12. Tomographic image of myocardial perfusion obtained after administration of O-15 water (top); image obtained after administration of O-15 carbon monoxide (middle), representing the vascular blood pool; and image obtained after correcting total myocardial activity for the vascular pool (bottom), showing excellent delineation of the myocardium. (Reproduced with permission from Bergmann SR, Fox KA, Rand AL, et al. Quantification of regional myocardial blood flow in vivo with H215O. Circulation 1984;70:724-33.)

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