Thallium-201 was the major radiopharmaceutical in nuclear cardiology for almost two decades. Although hundreds of studies have demonstrated the clinical value of Tl-201 myocardial perfusion scintigraphy, the physical characteristics of this radionuclide are suboptimal for scintillation camera imaging. Therefore, in the late 1970s and early 1980s, many investigators attempted to develop an MPI agent labeled with Tc-99m to circumvent the physical limitations of Tl-201. The potential advantages of a Tc-99m-labeled agent over Tl-201 are significant and include the following:
The 140-keV photon energy of Tc-99m, which is optimal for standard gamma camera imaging, results in an improved resolution due to less Compton scatter and less tissue attenuation in the patient (in comparison to the low photon energy of 68–80 keV for Tl-201).
The much shorter physical half-life of Tc-99m (6 hours vs. 73 hours for Tl-201) and the better radiation dosimetry permit the administration of a 10 times higher dose of a Tc-99m-labeled compound than Tl-201. This yields better image quality, and images can be performed in a shorter time period.
The resulting overall better counting statistics of Tc-99m allows for the perfusion images to be optimally obtained in a gated mode. Simultaneous assessment of perfusion and function (global and regional wall motion) can thus be obtained.
It is possible to perform first-pass function studies (if the initial lung transit is rapid enough) with a Tc-99m-labeled radiopharmaceutical agent.
Because Tc-99m is constantly available from a molybdenum generator in a nuclear medicine laboratory, special deliveries from a distribution center or a commercial radiopharmacy are not required. A Tc-99m-labeled MPI agent can thus be available almost 24 hours a day.
For the above reasons, Tc-99m-labeled agents have enormous potential to assess myocardial perfusion and could be very useful clinically.9–11
The first member of the Tc-99m-isonitrile family to be evaluated in humans was the hexakis (t-butyl-isonitrile)-technetium (I), also known as Tc-99m-TBI.12,13 Although the myocardial uptake of Tc-99m-TBI was proportional to myocardial blood flow and was satisfactory for imaging purposes, its routine clinical use was limited by an increased lung uptake and prominent and persistent liver uptake. The initial lung uptake and subsequent washout of Tc-99m-TBI from the lungs also created significant imaging problems. A subsequently developed Tc-99m-isonitrile compound emerged from intensive search,14–16 initially known by the coded name of RP-30A (nonlyophilized form) or RP-30 (lyophilized form), and then as either Tc-99m-hexakis 2-methoxyisobutyl isonitrile, Tc-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile, Tc-99m-hexamibi, or Tc-99m-MIBI, and currently by its generic name Tc-99m-sestamibi or Cardiolite™. Tc-99m-sestamibi has favorable biological characteristics for clinical applications with transient liver uptake and rapid hepatobiliary excretion, along with minimal lung uptake. Tc-99m-sestamibi was approved by the U.S. Food and Drug Administration for clinical application in December 1990.
Intravenous injections of Tc-99m-sestamibi have been associated with very few adverse reactions. According to the product monograph, during clinical trials (Phase III study) approximately 5% to 10% of patients experienced transient parosmia and/or taste perversion (metallic or bitter taste) occurring a few seconds after the injection. Usually, this side effect disappears within 15 to 30 seconds. This adverse effect seems to be related to the presence of the copper salt in the kit formulation, and its incidence may be related to the concentration of Tc-99m-sestamibi used.
Tc-99m-sestamibi is a cationic complex that is taken up by myocytes in proportion to regional myocardial blood flow. The cationic charge of the compound provides hydrophilic properties, and the six isonitrile groups allow hydrophobic interaction with cell membranes.
Tc-99m-sestamibi, which is retained within cells because of the negative charge generated on the mitochondria, has a high affinity for cytoplasm and shows very little extracellular exchange. Thus, metabolic derangements affecting myocytes' viability would also result in decreased Tc-99m-sestamibi uptake, independently of myocardial blood flow. Using aerobic metabolic blockade, Beanlands et al.17 showed that an irreversible cellular injury resulted in a marked increase in Tc-99m-sestamibi clearance rate. They concluded that the accumulation and clearance kinetics of Tc-99m-sestamibi were dependent on sarcolemmal integrity and on aerobic metabolism and were significantly affected by cell viability.
Okada et al.18 investigated the myocardial kinetics of Tc-99m-sestamibi in dogs undergoing a partial occlusion of the left circumflex coronary artery. They showed that Tc-99m-sestamibi was rapidly taken up by nonischemic and ischemic myocardium at rest in proportion to regional myocardial blood flow. There was a good correlation between the initial myocardial flow at normal resting flow rates and the Tc-99m-sestamibi myocardial distribution. Another study from the same group of investigators19 using the same animal model evaluated the myocardial kinetics of Tc-99m-sestamibi after pharmacologic vasodilation with dipyridamole and showed that the initial myocardial uptake was closely related in a linear fashion to the regional myocardial blood flow at rates up to approximately 2.0 mL/min/g. However, at higher flow rates, there is a plateau in the myocardial distribution versus flow curve, resulting in an underestimation of coronary blood flow. Similar findings have been reported other investigators, which parallel the kinetics of thallium-201.20,21 There is overestimation of myocardial blood flow at low flows which is probably related to an increased extraction seen with diffusible indicators. Thus myocardial uptake of Tc-99m-sestamibi is proportional to regional myocardial blood flow over the physiological flow range with decreased extraction at hyperemic flows and increased extraction at low flows.
In contrast to Tl-201, Tc-99m-sestamibi shows a very slow myocardial clearance after its initial myocardial uptake. A fractional Tc-99m-sestamibi clearance of 10% to 15% over a period of 4 hours has been measured by Okada et al.18 in a canine model of partial coronary occlusion. The clearance was similar in the hypoperfused and normal zones. Animal studies have shown that after Tc-99m-sestamibi injection during brief periods (6–15 minutes) of coronary occlusion in dogs, the occluded zone shows a continued myocardial uptake during the reperfusion phase. Thus, following transient ischemia and reperfusion, there is some degree of myocardial redistribution of Tc-99m-sestamibi, although it is slower and less complete than Tl-201.22
Sinusas et al.23 studied the myocardial uptake of Tc-99m-sestamibi and Tl-201 showed that as long as myocardial cells were still viable, the myocardial uptake of the tracer was not affected by an ischemia. These data suggest that the agent can also assess myocardial viability. Tc-99m-sestamibi uptake is maintained in viable myocardium but reduced in necrotic tissue. Using a dog model with coronary occlusion and reperfusion, Verani et al.24 demonstrated that the size of the perfusion defect during occlusion as detected by scintigraphic images correlated with the amount of myocardium supplied by the occluded vessel, the area at risk. A smaller perfusion defect was detected on Tc-99m-sestamibi imaging during reperfusion. This defect correlated with the amount of infarcted myocardium and the area showing improved perfusion pattern after reflow represented the salvaged myocardium.
Biodistribution and Dosimetry
The blood clearance, biodistribution, dosimetry, and safety of Tc-99m-sestamibi were initially reported by Wackers et al.15 Both rest and stress blood clearance curves approximate a dual exponential curve with an initial fast and later slow component. The maximal activity at rest was noted at 1 minute after injection (36 ± 18% of injected dose), and the maximal activity after injection during exercise was measured at 0.5 minute. At 1 hour after the intravenous injection of Tc-99m-sestamibi, the blood pool activity progressively decreased to 1.10 ± 0.01% and 0.7 ± 0.1% of the injected dose at rest and after stress, respectively. At 60 minutes after the injection at rest, the uptake in the heart was 1.0 ± 0.4% of injected dose. The 24-hour urinary excretion was 29.5% of injected dose, whereas the 48-hour fecal excretion was 36.9% of injected dose. The study of the upper-body organ distribution showed that the highest initial Tc-99m-sestamibi concentration (counts/pixel) is found in the gallbladder and liver followed by heart, spleen, and lungs. The myocardial activity remained relatively stable over time (27 ± 4% of initial activity has cleared from the heart at 3 hours), whereas activity in the spleen and lung decreased gradually. The maximal accumulation in the gallbladder occurred approximately at 60 minutes after the injection. Similar biodistribution and radiation dosimetry was noted after exercise.
Radiation dose estimates for Tc-99m-sestamibi have been evaluated from whole-body images.15 The estimated radiation absorbed dose at rest and at stress, assuming a 2.0-hour void, are summarized in Table 3-2. The uptake in the heart is 1.06 ± 0.4% of injected dose at 60 minutes after injection at rest and 1.4 ± 0.3% at 60 minutes for the stress study. The upper large intestine wall receives the highest dose of radioactivity, both at rest and at stress. To decrease dosimetry to the urinary bladder, increasing voiding frequency should be encouraged. If patients are administered a total dose of 30 mCi of Tc-99m-sestamibi, no individual organ dose will exceed 5 rads (50 mGy). Although there is accumulation of Tc-99m-sestamibi in the mammary glands, there is a minimal transfer into milk: approximately 0.01% to 0.03% of the injected Tc-99m-sestamibi activity can be excreted in human breast milk of a breastfeeding patient.25
Tc-99m-tetrofosmin, a diphosphine complex of Tc-99m, was the third Tc-99m-labeled MPI FDA-approved agent, following Tc-99m-teboroxime (no longer clinically available) and Tc-99m-sestamibi. Tc-99m-tetrofosmin shows similar myocardial uptake, retention, and blood clearance kinetics to Tc-99m-sestamibi. However, its clearance from both the liver and the lung is faster than that of Tc-99m-sestamibi. These characteristics can have an impact on the injection and imaging protocols. Tetrofosmin is a ligand that forms a lipophilic, cationic complex with Tc-99m. Tc-99m-tetrofosmin is the generic name for 1,2,-bis [bis(2-ethoxyethyl) phosphino] ethane, also called p53 or MyoviewTM. Tetrofosmin has a molecular weight of 382, and an empirical formula of C18H40O4P2. The functionalized diphosphine complex of Tc-99m has a molecular weight of 895 and a formula of [TcO2 (tetrofosmin)2].1 There are no known contraindications to intravenous administration.
Sinusas et al.26 tested the hypothesis that Tc-99m-tetrofosmin was a reliable coronary blood flow tracer over a physiologic range of flows seen in ischemia or infarction conditions. Dogs were injected with 30 mCi Tc-99m-tetrofosmin during peak pharmacological stress performed with either adenosine or dipyridamole. Myocardial Tc-99m-tetrofosmin activity at 15 minutes after the injection correlated linearly with radiolabeled microsphere flow during peak stress in each dog. Myocardial Tc-99m-tetrofosmin activity appeared to underestimate flow at flows exceeding 1.5 to 2.0 mL/min/g. The plot of Tc-99m-tetrofosmin activity versus blood flow achieved a plateau at approximately 2.0 mL/min/g (see Fig. 3-1). On the other hand, as with Tc-99m-sestamibi and Tl-201, Tc-99m-tetrofosmin activity overestimated coronary blood flow in low flow ranges, at less than 0.2 mL/min/g. Tc-99m-tetrofosmin activity cleared rapidly from the blood with 2.8% and 0.8% of peak activity remaining in the blood at 5 and 15 minutes, respectively. The myocardial clearance between 3 and 15 minutes was similar in both ischemic and nonischemic regions. The myocardial activity cleared 18 ± 11% in the ischemic region. Lung activity remained lower than myocardial activity and the liver activity remained elevated over the initial 15-minute period following injection.
Mechanisms of Tc-99m-tetrofosmin myocardial uptake have been studied using different experimental models. Dahlberg and Leppo27 evaluated the effect of coronary blood flow on the uptake of Tc-99m-tetrofosmin in the isolated rabbit heart model. The Emax of 0.37 for Tc-99m-tetrofosmin suggests a PS cap similar to that of Tc-99m-sestamibi. In comparison, Emax for Tl-201 is 0.73 and for Tc-99m-sestamibi is 0.39. However, Tc-99m-tetrofosmin has the lowest Enet among all perfusion agents. Although this lower value of Enet for Tc-99m-tetrofosmin in rabbits suggests myocardial clearance of this compound, human studies28 have shown a stable myocardial retention of Tc-99m-tetrofosmin, at least up to 4 hours. This difference between animal and human data is not really surprising, considering that similar interspecies variability has been previously observed for the kinetics of other Tc-99m-labeled phosphine compounds.29 Platts et al.30 found that the uptake of Tc-99m-tetrofosmin into rat myocytes was rapid, temperature-dependent and independent of extracellular Tc-99m-tetrofosmin concentration. The lack of effect of ion channel inhibitors on Tc-99m-tetrofosmin uptake is similar to that on uptake of other cations such as Tc-99m-sestamibi. Thus, Tc-99m-tetrofosmin differs from Tl-201 in that it does not appear to act as potassium analog.
Based on experimental studies, mitochondrial membrane potential appears to play a major role in the myocardial uptake and retention of Tc-99m-tetrofosmin, as seen with Tc-99m-sestamibi. Younes et al.31 demonstrated that Tc-tetrofosmin uptake into myocytes is likely the potential-driven transport of the lipophilic cation and myocardial uptake in vivo was related to the metabolic status of the myocytes.
Biodistribution and Dosimetry
Human biodistribution, dosimetry, and safety of Tc-99m-tetrofosmin administration at rest and during exercise were by Higley et al.32 By 10 minutes after the injection, there was less than 5% of the injected dose in the whole blood volume and less than 3.5% of the injected dose in the total plasma volume. The blood clearance was initially faster following exercise. At 2 hours after injection, the urinary clearance was 13.1 ± 2.1% in the resting study and 8.9 ± 1.7% in the exercise study (p < 0.001). At 48 hours postinjection, the rate of urinary clearance was almost identical for both physiological conditions: 39.0 ± 3.7% at rest and 40.0 ± 3.7% at exercise. Analysis of whole-body images showed that good quality images of the heart can be obtained as early as 5 minutes after the injection of Tc-99m-tetrofosmin, and this uptake persisted for several hours. Myocardial background clearance resulting from activity in the blood, liver, and lung was rapid. After exercise, there was less Tc-99m-tetrofosmin activity in certain organs, mainly liver, urinary bladder, and salivary glands, in comparison to the rest study. As with Tc-99m-sestamibi, this relatively reduced liver uptake at stress can be explained by an enhanced retention in peripheral muscles as a result of the increased blood flow induced by physical exercise and by splanchnic vasoconstriction during exercise.
After a stress injection, the myocardial uptake of Tc-99m-tetrofosmin, although relatively stable over time, slightly decreases from 1.3% of the injected dose at 5 minutes to 1.0% at 2 hours after the injection. From 5 to 60 minutes after injection, the heart-to-lung ratio increases from 4.0 ± 1.1 to 5.9 ± 1.3 and the heart-to-liver ratio increases from 0.8 ± 0.3 to 3.1 ± 3.0. After a rest injection, similar kinetics were noted, and the heart-to-lung ratio increases from 3.1 ± 1.8 to 7.3 ± 4.4, and the heart-to-liver ratio increases from 0.4 ± 0.1 to 1.2 ± 0.8 from 5 to 60 minutes after injection.
Sridhara et al.33 compared Tc-99m-tetrofosmin and Tl-201 myocardial imaging in patients with documented coronary artery disease and showed that there was no significant Tc-99m-tetrofosmin myocardial redistribution with a slow myocardial washout of approximately 4% to 5% per hour after exercise and 0.4% to 0.6% per hour after a rest injection. The estimated absorbed radiation doses at rest and at stress are given in Table 3-2. The results show that both at rest and at stress, the gallbladder wall is the target organ, followed by the other excretory organs, such as upper large intestine, lower large intestine, bladder wall, and small intestine. Overall, the radiation dose to most organs is significantly reduced during exercise in comparison to rest study.
Cardiac amyloidosis, a significantly underdiagnosed cause of heart failure, is usually detected late when the heart is already significantly affected. Differentiating immunoglobulin light-chain (AL) from transthyretin-related (ATTR) cardiac amyloidosis is important given the implications for prognosis, therapy, and genetic counseling.34
During the last two decades, noninvasive detection of cardiac amyloidosis using nuclear medicine techniques has gained in popularity.35–38 99mTc-labeled phosphate derivatives, initially developed as bone-seeking radiotracers for bone scintigraphy, were noted to localize to amyloid deposits. Different agents were used to detect myocyte necrosis and calcifications in amyloid deposits (with localized increased tissue calcium deposits) such as 99mTc-diphosphonate, 99mTc-pyrophosphate, 99mTc-MDP (methylene-diphosphonate) and 99mTc-DPD (diphosphino-propanodicarboxylic acid). The latter radiotracer is extensively used in European countries but is not yet approved by the FDA. Therefore, 99mTc-pyrophosphate (PYP), approved since more than 30 years for bone scintigraphy, blood pool imaging and detection of myocardial infarction, is currently used in clinical practice. The precise mechanism by which 99mTc-PYP (and the other bone-seeking radiotracers) accumulates in the myocardium of patients with cardiac amyloidosis remains unclear but is probably related to high calcium levels in amyloidosis. Different studies have shown that 99mTc-PYP cardiac imaging can distinguish ATTR from AL amyloidosis possibly because 99mTc-PYP may bind TTR amyloid fibrils more intensely than AL fibrils as a result of higher calcium containing substances in ATTR hearts. Using quantitative 99mTc-PYP cardiac imaging, Bokhari et al39 were able to differentiate light-chain cardiac amyloidosis from the TTR-related familial and senile cardiac amyloidosis. Using a heart-to-contralateral uptake ratio of more than 1.5, they showed a sensitivity of 97% and a specificity of 100% for identifying ATTR cardiac amyloidosis.
Two hours after intravenous injection of 99mTc-PYP, 40% to 50% of the injected dose is taken up by the skeleton. Within a period of 1 hour, 10% remains in the vascular system. The average urinary excretion is about 40% of the administered dose after 24 hours. The usual injected dose for cardiac scintigraphy is 15 mCi (555 MBq). The target organs are the bladder (1.46 rads/15 mCi with a 2-hour void and 3.45 rads/mCi with a 4-hour void) and the kidneys (2.1 rads/15 mCi).