Myocardial Uptake of 99mTc-Tetrofosmin, Sestamibi, and 201Tl in a Model of Acute Coronary Reperfusion
Background To investigate whether tetrofosmin uptake is affected by myocardial viability as has been noted for 201Tl and sestamibi, we analyzed the initial and delayed distribution patterns of tetrofosmin in a rat coronary artery occlusion-reperfusion model.
Methods and Results Animals were intubated and ventilated, and their arterial pressures were monitored. A left thoracotomy was performed. After 1-hour occlusion and 1-hour reperfusion of a major branch of the circumflex artery, 201Tl and either tetrofosmin or sestamibi were injected intravenously. Radiolabeled microspheres were used to document the area at risk and reperfusion. Five minutes or 1 hour after administration of the diffusible tracers, the animals were killed. Tracer distribution was determined by use of segmental tissue analysis, and tissue viability was determined by use of histochemical staining. Both the initial and delayed retention of tetrofosmin were sensitive to myocardial viability, as shown by significantly lower uptake (30±14%) and retention (24±12%) of tetrofosmin in the nonviable segments compared with the viable segments. In addition, the initial myocardial distribution of tetrofosmin was similar to that noted for 201Tl, but after 1 hour of tracer circulation, the tetrofosmin tissue distribution appeared unchanged compared with the initial regional blood flow distribution. This is in direct contrast to our present observations of significant 201Tl redistribution and some changes in sestamibi distribution as well.
Conclusions The clinical implication of these observations suggests that initial and delayed imaging after tetrofosmin administration would reflect both the initial regional blood flow pattern and myocardial viability.
Stress 201Tl myocardial perfusion imaging is widely used for the scintigraphic evaluation of coronary artery disease,1 2 3 and both 99mTc-sestamibi and 99mTc-tetrofosmin have shown diagnostic ability similar to that of 201Tl.4 5 In addition, 201Tl and sestamibi are used in the evaluation of early myocardial infarction in the emergency department as well as recent myocardial infarction at predischarge. In these types of studies, conventional prethrombolytic and postthrombolytic myocardial scintigraphy have demonstrated utility in the detection of viable myocardium and additional myocardium at risk.6 7 8 9 Although both 201Tl and sestamibi have been used in these types of clinical situations, the precise impact of viability and the overall stability of the cellular tracer deposition in relation to the initial distribution patterns have not been fully evaluated.
In addition, although clinical observations have shown that tetrofosmin can be imaged for up to several hours after injection at stress or rest in patients with stable chronic coronary artery disease,10 11 its uptake and retention after acute reperfusion is unknown. Because tetrofosmin is a lipophilic cation-like sestamibi,12 its cardiac kinetics may be similar to that of sestamibi. Therefore, we hypothesized that as noted for 201Tl and sestamibi, the cardiac transport of tetrofosmin would be affected by tissue viability and that initial tetrofosmin myocardial uptake would be relatively stable over time compared with 201Tl.
To evaluate these hypotheses, we compared initial and delayed distribution patterns of tetrofosmin in a rat model designed to simulate the clinical problem of assessing flow and viability after successful thrombolysis or reperfusion in an acute ischemic event. The distribution pattern of tetrofosmin was then compared with simultaneously injected 201Tl. Furthermore, to include a similar comparison with sestamibi, we performed a duplicate trial of initial and delayed distribution patterns of sestamibi and 201Tl in the same experimental model.
Tetrofosmin was supplied by Amersham/Medi-Physics Healthcare (Arlington Heights, Ill) as freeze-dried vials. Each vial was reconstituted with 4 to 8 mL of 99mTc as sodium pertechnetate containing ≤30 mCi of 99mTc per milliliter. The vial was shaken to ensure adequate mixing and then allowed to stand at room temperature for 15 minutes. Radiochemical purity was tested by thin-layer chromatography.
Sestamibi was supplied by DuPont Pharma Radiopharmaceuticals (Billerica, Mass) as a lyophilized kit formulation. Kits were reconstituted and tested for radiochemical purity by use of previously described methods.12
Sprague-Dawley male rats (n=24; weight, 300 to 600 g; Taconic Farms, Germantown, NY) were sedated with intramuscular ketamine (0.14 mg/g) and xylazine (0.035 mg/g) and then anesthetized with 0.5% to 2.0% isoflurane administered through an anesthesia apparatus (Ohio 7000, Ohio Medical). Ventilatory parameters and supplemental oxygen were adjusted to maintain physiological arterial blood gases. The carotid artery was catheterized and arterial pressure was recorded continuously (Lineacorder WR3101, Graphtec Corp). In addition, the first derivative of arterial blood pressure (dP/dt) was obtained by electric differentiation of the pressure signal to measure heart rate. One femoral artery was isolated and cannulated for withdrawal of arterial blood samples (microsphere references and blood gases). One femoral vein was isolated and cannulated for administration of fluids, tetrofosmin, or sestamibi and 201Tl. The heart was exposed in a pericardial cradle through a left thoracotomy. A catheter was placed in the left atrium for the injection of radiolabeled microspheres.
The experimental design is shown schematically in Fig 1⇓. Severe segmental hypoperfusion was induced by occlusion of a major branch of the left circumflex artery for 1 hour. After 55 minutes of occlusion, a first set of microspheres (95Nb, 5×105, 12 to 15 μm) was injected through a left atrial catheter.13 Simultaneously, a 2-minute reference blood sample was drawn at a rate of 0.97 mL/min from a femoral arterial catheter with the use of an infusion pump (Harvard Apparatus). After 1 hour of reperfusion, either 99mTc-labeled tetrofosmin or sestamibi (15 mCi) and 201Tl (250 μCi) were administered.13 14 Immediately after administration of the tracers, a second set of microspheres (103Ru, 5×105, 12 to 15 μm) was injected, and the reference blood sample was withdrawn for 2 minutes to document the extent of reperfusion flow. The tracers were allowed to circulate for 5 minutes (group 1TF, n=5; group 1SM, n=7) to evaluate initial distribution or for 1 hour (group 2TF, n=5; group 2SM, n=7) to assess delayed distribution, after which the rats were killed by an intravenous injection of potassium chlorine.
Hearts were excised and then frozen to allow for uniform sectioning. Transmural left ventricular segments were collected and weighed (37 to 43 segments per heart). Average left ventricle and sample weights were 1.15±0.19 and 0.03±0.01 g, respectively. Because histochemical stains have been shown to affect the postmortem distribution of 201Tl and sestamibi,15 16 each thawed segment was incubated separately in a bath of NBT (1 mL, 0.05% PBS, pH 8.0) at 37°C. On the basis of histochemical results, segments were classified as viable (100% blue stain) or nonviable (mosaic [mix of pale and blue stain] or infarct [100% pale]).
The tissue segments were removed from the histochemical buffer and, along with the NBT solution and arterial blood samples, were then counted in a sodium iodide (Tl) gamma well scintillation counter (Auto-Gamma 5530, Packard Instrument Co). This permitted us to account for any postmortem tracer activity loss. All samples were corrected for interradionuclide crossover and tracer decay during the counting period. Tracer activity concentration was expressed as dpm/g.
Absolute Myocardial Blood Flow
Absolute myocardial blood flow (mL·min−1·g−1) was determined as previously described.17 Briefly, the myocardial microsphere density in each segment (dpm/g) was determined and the microsphere content in the 2-minute reference blood collection (dpm·mL−1·min−1) was then used to calculate absolute flow (dpm/g divided by dpm·mL−1·min−1).
Tracer Activity Concentration (RC)
The relative blood flow in each segment (dpm/g) was also normalized to the average left ventricular activity concentration (dpm/g) as defined by the following equation:|<|\Sigma|>|_|<|LV|>|A/|<|\Sigma|>|_|<|LV|>|mwhere ΣLVA and ΣLVm represent the total counts and total mass of the left ventricle, respectively. The microsphere content for each segmental tissue sample could then be expressed as an RC18 19 compared with the average left ventricular activity concentration.
We also used a similar normalization procedure for each diffusible tracer (201Tl, 99mTc-tetrofosmin, and sestamibi) so the RC of each tracer could be compared across a similar range of values. In these analyses, a value of 1.0 represents unity and is the average activity concentration of any specific isotope in the myocardium. Therefore, RC values >1.0 define higher flow or diffusible tracer content whereas values <1.0 have low flow or tracer content.
Because the myocardial distribution of 201Tl can be accurately determined independently of the presence of coinjected tracers (99mTc-tetrofosmin and sestamibi), we combined the 201Tl data for presentation from both groups. Thus, overall 201Tl results represent a summation of observations from the 5-minute experiments in groups 1TF and 1SM as well as results from the 1-hour experiments involving groups 2TF and 2SM.
Tissue Retention After Histochemical Staining
To evaluate the effect of NBT staining on the distribution of each diffusible tracer, we measured tissue retention (TR) in the viable and nonviable region as follows:
All data are presented as mean±1SD. Univariate analysis of groups was performed by use of a paired Student's t test, unpaired two-sample t test, or Wilcoxon signed rank test. An ANOVA and Bonferroni t test were used when multiple comparisons were made as a function of time. All curves were analyzed with the use of a computer-assisted, nonlinear, least-squares estimation of their constants. All these statistical calculations were performed with the use of a commercially available computer program (Sigma Stat, Jandel Corp).
Hemodynamic variability in heart rate and peak systolic pressure during baseline, occlusion, and reperfusion periods is shown in Table 1⇓. All groups showed stability in heart rate during the experimental protocol. The heart rate during both occlusion and reperfusion periods in group 2TF was lower than that of group 1TF. In addition, the heart rate in group 2SM was lower than that of group 1SM. Blood pressure fell slightly during occlusion in both groups, although the difference did not reach statistical significance in group 2TF.
Measurement of Myocardial Blood Flow
To simplify the comparison of the tracer uptake in the viable and nonviable myocardium, all individual segments were placed into one of four categories based on normalized reperfusion measurements, as shown in Table 2⇓. We used a lowest-flow region represented as <0.75 of average left ventricular reperfusion flow, and a lower-flow reduction was defined by a flow level of 0.75 to 0.99 of average left ventricular reperfusion flow. A higher-flow group was classified as a normalized level of 1 to 1.25, and a highest-flow level was >1.25. This arbitrary division into four continuous subgroups of lowest to highest reperfusion flow permitted us to evaluate the effect of viability on tracer content independently of variations in regional blood flow. This subdivision of the data into four subgroups permits a more precise statistical comparison of tracer concentration than could be achieved by the more typical linear regression comparison.
In each of the four subgroups, RC values are displayed for viable and nonviable segments as well as for occlusion and reperfusion flow. As expected, both the absolute (mL·min−1·g−1) and normalized occlusion blood flow in the nonviable segments were significantly lower than those noted for the viable segments at all flow levels of all groups. In addition, we documented successful reperfusion, because the absolute blood flow during reperfusion increased significantly compared with the flow during occlusion in the nonviable segments in all four subgroups (P<.01). In the viable segments, the absolute blood flow during reperfusion significantly increased (P<.05) or was stable compared with the absolute blood flow during occlusion except at the lowest-flow levels of groups 1TF and 2SM. The absolute reperfusion blood flow was not significantly different between groups 1TF and 2TF except in the viable segments at the lowest-flow level and in the nonviable segments at the highest-flow levels (P<.01). The absolute reperfusion blood flow was not statistically different between groups 1SM and 2SM except in the viable segments at the higher- and highest-flow levels (P<.01).
Myocardial Distribution of Diffusible Tracers and Reperfusion Blood Flow Between Viable and Nonviable Segments
Given the small number of mosaic segments, mosaic and infarct segments were combined into a nonviable category that should be comparable to standard methods of planimetry because only a single plane from a stained short-axis slice was used to define viability for the entire slice.
As displayed in Table 2⇑, the reperfusion blood flow in most subgroups at the time of diffusible tracer administration was similar between the viable and nonviable segments. In contrast, the mean activity concentration of diffusible tracers was significantly lower in the nonviable segments than in the viable segments. At the highest-flow level (RC >1.25), the difference did not reach statistical significance in groups 2TF or 2SM, which is probably related to the observed reperfusion blood flow, which was significantly higher in the nonviable than in the viable segments. At the lowest-flow level, in groups 1TF and 1SM, the nonviable segmental flow was ≈20% less than that noted for the viable segments. In contrast, the diffusible tracer content in the nonviable segments was ≈50% and 40% less than that noted for the viable segments for groups 1TF and 1SM, respectively. These findings indicate that uptake of these diffusible tracers was affected by myocardial viability as well as by perfusion.
In group 1TF, a comparison of the normalized activity between tetrofosmin and 201Tl showed no significant differences between the viable and nonviable segments at all flow levels. However, in group 2TF, the 201Tl activity was significantly higher than that of tetrofosmin at the lowest-flow level in both the viable (P<.001) and nonviable segments (P<.01). In addition, the 201Tl activity was significantly lower than that of tetrofosmin in the viable segments at the highest-flow level (P<.01). These observations are probably due to the process of 201Tl redistribution and suggest that tetrofosmin does not undergo a similar process.
A similar pattern was observed when sestamibi and 201Tl were compared; once again, the process of 201Tl redistribution was a likely mechanism for the decrease in 201Tl activity in group 2 viable segments.
Myocardial Distribution of Diffusible Tracers Between Group 1 and Group 2
Fig 2A⇓ shows normalized activity concentration of tetrofosmin in group 1TF and group 2TF. In both groups 1TF and 2TF, the tracer content in the nonviable segments was significantly lower (by an average of 27%) than that noted for the viable segments at all flow levels, except at the highest-flow level in group 2TF. In this subgroup, the normalized flow at the time of injection was significantly higher in the nonviable segments than in the viable segments. In addition, no differences were noted for tetrofosmin concentration or reperfusion flow between groups 1TF and 2TF for all segments and flow levels. These findings suggest that the distribution of tetrofosmin is affected by viability and remains stable for 1 hour after injection.
Fig 2B⇑ shows the correlation of tetrofosmin as a function of reperfusion flow for groups 1TF and 2TF. The slope for the regression line of the nonviable segments was higher than that of the viable segments in both groups. Consequently, the intercept of the nonviable segments was lower than that of the viable segments. In both groups, the nonviable segments appeared to have less tetrofosmin content than the viable piece across a wide range of blood flows. In addition, the slope and intercept for the initial (5 minutes, group 1TF) and delayed (1 hour, group 2TF) experimental protocols showed essentially no change, which again suggests that tetrofosmin distribution is stable.
Similar findings were observed in the sestamibi experiments (groups 1SM and 2SM) and are displayed in Fig 3A and 3B⇓⇓. The tissue content of sestamibi in the nonviable segments was significantly lower (by an average of 22%) than that noted in the viable segments at all flow levels, except at the highest-flow level in group 2SM. In this subgroup, both the absolute and normalized reperfusion flows were significantly higher in the nonviable segments than in the viable segments. Although the normalized reperfusion flow was not significantly different between groups 1SM and 2SM in all subgroups of flow level, the normalized activity concentration of sestamibi was significantly lower in the viable segment at the highest-flow level in group 2SM than in group 1SM. This finding suggests that the distribution of sestamibi shows some redistribution during 1 hour of tracer recirculation. In Fig 3B⇓, the linear regression analysis demonstrates that the viable and nonviable segments are easily differentiated among both groups (1SM and 2SM). However, the slope for the regression lines was slightly lower in group 2SM than in group 1SM, and consequently, the intercept was also slightly higher in group 2SM. These findings are consistent with minimal redistribution of sestamibi during 1 hour of tracer recirculation.
As displayed in Fig 4A⇓, both the initial and delayed 201Tl uptakes were significantly lower (by an average of 23%) in the nonviable segments than in the viable segments. Although the normalized reperfusion flow was not significantly different between groups 1 and 2 for all subgroups, the delayed uptake of 201Tl was significantly lower than the initial uptake in the viable segments at the higher- and highest-flow levels. In addition, the delayed uptake was significantly higher than the initial uptake at the lowest-flow levels. These findings are also most likely a consequence of 201Tl redistribution, which is apparent in the observation that the slope for the regression lines from group 2 is much lower than that of group 1 hearts (Fig 4B⇓). Consequently, the intercept was also higher in group 2 than in group 1.
Effect of NBT Staining on the Distribution of Tetrofosmin, Sestamibi, and 201Tl
Table 3⇓ shows the tissue retention for all diffusible tracers in both the viable and nonviable segments. In both group 1 and 2 hearts, the tissue retention of 201Tl in the nonviable region was significantly higher than that noted for the viable region. In contrast, the tissue retention of both tetrofosmin and sestamibi in the nonviable region was significantly lower than that noted for the viable region. In addition, although the values for tetrofosmin and sestamibi tissue retention were similar, we noticed that the retention of 201Tl was ≈50% of the value of these 99mTc-labeled tracers.
This study shows that both the initial (5-minute) uptake and delayed (1-hour) retention of tetrofosmin, sestamibi, and 201Tl are affected by the status of myocardial viability. This was demonstrated by significantly lower uptake and retention values for all diffusible tracers when nonviable segments were compared with viable segments at all flow levels. In addition, although the initial distribution (at 5 minutes) of these tracers was similar, after 1 hour of in vivo recirculation, tetrofosmin appeared to show the least amount of tracer redistribution compared with 201Tl and sestamibi.
Interaction of Viability and Tracer Uptake
The finding that tetrofosmin uptake is affected by viability is consistent with a preliminary study in a canine model.20 Our observation that the myocardial uptake of sestamibi and 201Tl is affected by tissue viability is also consistent with previous reports in equivalent animal models.6 21 However, the myocellular mechanism associated with the uptake and extraction of tetrofosmin is undefined. There have been several prior investigations into the cellular mechanism governing the retention of sestamibi and thallium, whereas there have been relatively few such reports dealing with tetrofosmin. Specifically, Piwnica-Worms et al12 reported that sestamibi transport involves passive diffusion across the plasma and mitochondrial membranes, and it is sequestered largely within mitochondria by the large negative transmembrane potentials. When plasma or mitochondrial membrane potentials are depolarized secondary to irreversible myocardial injury, there is an inhibition in net uptake of sestamibi and thereby a reduction in myocyte retention. Given the similar lipophilic cation nature and composition of tetrofosmin,22 it may also be distributed across similar biological membranes in response to alterations in transmembrane potential. In fact, some recent publications23 24 have suggested this as a possible explanation for tetrofosmin transport, which is supported by our observation that both tetrofosmin and sestamibi uptake were lower in the nonviable segments than in the viable segments at all flow levels. In addition, a similar mechanism may account for the reduction in 99mTc-tracer retention noted in the nonviable segments after exposure to NBT staining.
Despite a reduction in both uptake and retention of all three tracers in the nonviable segments, overall myocardial activity distribution was proportional to regional blood flow. As with all diffusible flow tracers, when flow is at the highest level, the difference in tracer activity between the viable and nonviable segments may become statistically insignificant. In considering the interrelationship of flow and viability, these tracers should be administered after reactive hyperemia has abated to evaluate myocardial viability independently of potential differences in regional coronary perfusion.
Myocardial Tracer Stability
Although the initial myocardial distribution of tetrofosmin was similar to that noted for 201Tl after 1 hour of tracer recirculation, tetrofosmin appears to be stable in contrast to 201Tl redistribution, which occurs in both viable and nonviable segments. To a lesser extent, sestamibi also appears to show redistribution in both the viable and nonviable segments. This result is consistent with previous experimental25 and clinical26 studies that demonstrate a rest redistribution of sestamibi in jeopardized but viable myocardium. The mechanism of sestamibi redistribution is uncertain and may be due to differential myocardial clearance, because sestamibi blood levels fall to very low levels after injection.25 In contrast to the findings of Beller et al,27 which showed a substantial loss of myocardial sestamibi activity from the reperfused infarct, we did not find this. This discordance may be due to the difference in the timing of sestamibi administration. We injected diffusible tracers 1 hour after reperfusion, whereas in the previous report,27 sestamibi was administered 2 to 5 minutes after reperfusion or baseline. Accordingly, substantial loss of sestamibi from reperfused infarct may be observed only during the early reperfusion period.
Effect of NBT Staining on Tetrofosmin, 201Tl, and Sestamibi Distribution
Postmortem incubation by NBT was shown to liberate all three cationic tracers from myocardium. Our group has previously reported that the postmortem distribution of 201Tl and sestamibi is affected by triphenyltetrazolium chloride.15 We have shown that histochemical staining can affect the postmortem distribution of diffusible tracers, and our observations on tetrofosmin are consistent with those previously made for sestamibi.16 If we had not taken into account the possible effect of postmortem tracer washout with NBT, we might have overestimated the effect of suppressed sestamibi and tetrofosmin uptake in nonviable tissue. In contrast, NBT exposure results in enhanced 201Tl retention from nonviable cells that could have caused an underestimation of the effect of viability on myocardial 201Tl uptake if uncorrected.
Overall, our observations that histochemical staining has an effect on tracer retention in postmortem tissue suggests that there are differences in the intracellular binding properties of 201Tl, tetrofosmin, and sestamibi. This could entail differences in the NBT effect on the 99mTc-label stability as well as differences in the subcellular localization of tracer binding sites in the parenchymal cell. Clearly, additional specific investigations in this area are needed.
There are several important limitations to note:
There are known species differences that affect the myocardial retention of tetrofosmin when canine28 and rabbit29 studies are compared. However, a preliminary rat study30 demonstrated that tetrofosmin cardiac clearance was comparable to that found in human studies. Therefore, our decision to use rat hearts was made on the basis that rats are the species that most closely emulates clinical observations.
The present study did not assess serial tracer changes over time in the same group of rats. In addition, the absolute reperfusion blood flow was not exactly matched at all of the four flow levels when groups 1 and 2 were compared. Despite this limitation in methodology that precluded the use of paired t test comparisons and the statistical variations in blood flow, we were still able to show consistent and significant differences between viable and nonviable tissue tracer uptake and retention.
The time course of delayed tracer distribution may appear relatively short at 1 hour, but in rats, with a heart rate that is approximately threefold higher than humans, this is a sufficient period of time to evaluate for redistribution.
The reduction of heart rate in group 2 compared with group 1 may make comparison between groups difficult. However, the normalized reperfusion blood flow was not significantly different between groups 1 and 2. In addition, 201Tl redistribution was clearly suggested, although the reduction of heart rate might have caused less redistribution.
Although we confirmed our hypothesis that the cardiac transport of tetrofosmin would be affected by viability, we did not specifically address the mechanism of cellular uptake and retention. In addition, the difference in tissue retention noted for tetrofosmin compared with sestamibi also requires additional investigations to evaluate the cellular mechanism that accounts for these observations.
When tetrofosmin is administered in patients with acute myocardial infarction after revascularization therapy, its distribution may reflect both myocardial viability and reperfusion blood flow. Initial tetrofosmin distribution should be similar to that of simultaneously injected 201Tl, but delayed imaging after tetrofosmin administration would still reflect initial regional flow and viability. Although we noted a depression of diffusible tracer uptake in nonviable tissue, its impact on the highest-flow regions was less than that noted in the very-low-flow regions. Additional clinical trials including quantitative myocardial scan analysis will need to be performed to determine the impact of these basic observations in the evaluation of myocardial viability. Overall, when the initial and delayed distribution of tetrofosmin in reperfused myocardium are considered, our results suggest that tetrofosmin appears to be equivalent to sestamibi imaging and perhaps retains its initial distribution pattern for a longer period of time after administration.
Selected Abbreviations and Acronyms
|dpm||=||disintegrations per minute|
|1SM||=||5-minute sestamibi circulation|
|2SM||=||1-hour sestamibi circulation|
|tetrofosmin||=||99mTc-1,2-bis[bis(2-ethoxyethyl) phosphino] ethane|
|1TF||=||5-minute tetrofosmin circulation|
|2TF||=||1-hour tetrofosmin circulation|
The authors wish to thank Dr Seth Dahlberg for his useful discussion and Harriet Kay for editorial assistance. We are also grateful to Amersham International PLC for providing tetrofosmin and DuPont Pharma Radiopharmaceuticals for providing sestamibi and microspheres used in these experiments.
- Received December 28, 1995.
- Revision received June 24, 1996.
- Accepted July 5, 1996.
- Copyright © 1996 by American Heart Association
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