Myocardial Uptake and Redistribution of 99mTc-N-NOET in Dogs With Either Sustained Coronary Low Flow or Transient Coronary Occlusion
Comparison With 201Tl and Myocardial Blood Flow
Background 99mTc-N-NOET (NOET) is a new myocardial perfusion imaging agent that redistributes over time. We sought to better define the redistribution kinetics of NOET using open-chest canine models of sustained low coronary flow (protocol 1) and transient coronary occlusion followed by reflow (protocol 2).
Methods and Results In protocol 1 (n=10), NOET and 201Tl were injected during low flow in the left anterior descending coronary artery (LAD) that was sustained for 2 hours. Protocol 2 dogs (n=6) were injected with NOET during 20 minutes of LAD occlusion followed by 2 hours of reflow. In both protocols, serial NOET planar images were acquired, and myocardial flow and 2-hour tracer activities were determined by gamma-well counting. Defect resolution was observed on images in both protocols. Initial defect count ratios, reflecting flow disparity at injection (0.66±0.03 and 0.57±0.04, respectively), increased over 2 hours (0.73±0.02 and 0.75±0.04, respectively; P<.001 versus initial). Quantitative imaging showed that NOET redistribution resulted from greater clearance from normal areas versus low-flow or transiently occluded areas. In protocol 1, 2-hour NOET and 201Tl stenotic-to-normal tissue activity ratios were similar (0.76±0.06 versus 0.73±0.04, P=NS) and higher than injection flow ratios (0.52±0.06 and 0.56±0.07, respectively, P<.001), consistent with tracer redistribution. In protocol 2, NOET redistributed to an even greater extent (injection flow ratio, 0.27±0.04; 2-hour tissue activity ratio, 0.84±0.03, P<.001).
Conclusions NOET is the first 99mTc-labeled myocardial imaging agent with kinetics similar to 201Tl in experimental models, permitting redistribution imaging. NOET appears to be a promising agent for assessing patients with coronary artery disease.
To date, the quest for an optimal myocardial perfusion imaging agent that combines the radiophysical properties of 99mTc with the redistribution kinetics of 201Tl has largely been unsuccessful. 99mTc-sestamibi, the most widely used 99mTc-labeled imaging agent, permits high-quality imaging, but because it exhibits minimal redistribution over time, assessment of coronary artery disease requires two separate injections.1 2 3 4 5 6 7 8 9
99mTc-N-NOET is a new neutral, lipophilic 99mTc-labeled myocardial perfusion imaging agent.10 11 99mTc-N-NOET has a high first-pass extraction fraction, its myocardial uptake correlates with coronary blood flow, and it exhibits significant redistribution when injected during dipyridamole stress in canine models of coronary stenosis.12 Preliminary data suggest that 99mTc-N-NOET myocardial perfusion scans provide diagnostic information comparable to 201Tl in patients undergoing exercise testing for assessment of coronary artery disease.13 Furthermore, delayed normalization of initial 99mTc-N-NOET defects has been shown to be correlated with 201Tl redistribution imaging and was interpreted as 99mTc-N-NOET redistribution.13
Although these earlier animal and clinical studies strongly suggest that 99mTc-N-NOET redistribution does indeed occur under some conditions, to date there has been no carefully controlled experimental study that has examined 99mTc-N-NOET redistribution kinetics. Accordingly, the aims of this study were (1) to better define 99mTc-N-NOET redistribution kinetics by simultaneously comparing the myocardial uptake and redistribution of 99mTc-N-NOET with those of 201Tl in a canine model of sustained coronary artery low flow and (2) to assess the redistribution kinetics of 99Tc-N-NOET in a canine model of transient coronary artery occlusion followed by early reflow. The sustained-low-flow model was selected because it is the model most frequently used to assess the ability of a tracer to redistribute (eg, 201Tl) during prolonged hypoperfusion and consequent asynergy when flow is unchanged from the time of tracer administration to the end of the “redistribution” period. Although the second model, in which 99mTc-N-NOET was injected during transient coronary occlusion followed by early reflow, does not have a direct clinical correlate, it is relevant because it optimizes the potential for redistribution of a tracer to occur and thus can give insights into mechanisms. This was the model used 20 years ago to define 201Tl redistribution kinetics.14
Sixteen fasted male adult mongrel dogs were anesthetized with sodium pentobarbital (30 mg/kg) and prepared as previously described.7 A left thoracotomy was performed at the level of the fifth intercostal space, and the heart was suspended in a pericardial cradle. A flare-type catheter was introduced into the left atrial appendage for continuous left atrial pressure monitoring and for injection of radiolabeled microspheres. An ≈1.5-cm section of the LAD was dissected and loosely encircled with a snare occluder that was used to maintain the LAD stenosis (protocol 1) or to set the transient LAD occlusion (protocol 2). An ultrasonic flow probe (T206, Transonic Systems) was placed around the LAD distal to the occluder. In protocol 1, a similar ultrasonic flow probe was placed around the LCx. To measure regional left ventricular systolic wall thickening, a sonomicrometer crystal (Crystal Biotech) was sutured to the epicardial surface of the heart in the central region supplied by the LAD. In protocol 1, a crystal was also placed in the LCx region. Throughout each experiment, heart rate, systemic arterial pressure, left atrial pressure, left ventricular pressure, dP/dt, LAD flow, and LAD regional systolic wall thickening were continuously recorded on a 12-channel thermal array strip-chart recorder (K2G, Astromed Inc) and simultaneously digitized and stored in real time onto a 133-MHz Pentium IBM-compatible personal computer equipped with an optical drive.
All experiments were performed with the approval of the University of Virginia Animal Research Committee and were in compliance with the position of the American Heart Association on the use of research animals.
Protocol 1: Comparison of 201Tl and 99mTc-N-NOET During 2 Hours of Sustained Coronary Artery Low Flow
Experiments were performed in a canine model (n=10) of sustained low flow, and the protocol is summarized in the top panel of Fig 1⇓. Radiolabeled microspheres were injected during baseline for the determination of myocardial blood flow. The LAD was then partially occluded to decrease ultrasonic flow by ≈50%. Fifteen minutes later, 18.5 MBq (0.5 mCi) of 201Tl and a set of microspheres were injected simultaneously. A 201Tl image was acquired 5 minutes later over a period of 4 minutes. Immediately after the end of the acquisition, 296 MBq (8 mCi) of 99mTc-N-NOET was injected simultaneously with microspheres. Serial planar 99mTc-N-NOET images were acquired 15, 30, 60, 90, and 120 minutes after injection. Before the dogs were killed with an overdose of potassium chloride and sodium pentobarbital, the LAD was totally occluded and 20 mL of monastral blue dye was rapidly injected into the left atrial catheter to delineate the anatomic risk area.
Protocol 2: Myocardial Kinetics of 99mTc-N-NOET Injected During 15 Minutes of Total LAD Occlusion Followed by 120 Minutes of Reflow
Six dogs were prepared as in protocol 1 (bottom panel, Fig 1⇑). After the injection of baseline microspheres, the LAD was completely occluded. Two minutes later, 296 MBq (8 mCi) of 99mTc-N-NOET and a second set of microspheres were simultaneously injected. An initial 99mTc-N-NOET image was acquired 15 minutes later, and the LAD was then slowly reperfused over 10 minutes to restore baseline blood flow with limited hyperemia. After completion of reflow, a third set of microspheres was injected, followed by serial 99mTc-N-NOET imaging at 15, 30, 60, 90, and 120 minutes after reflow. Serial 1-mL arterial blood samples were also collected for measurement of 99mTc-N-NOET blood activity.
Preparation and Quality Control of 99mTc-N-NOET
99mTc-N-NOET kits were obtained from CIS-Bio International (Gif sur Yvette, France). Sodium 99mTc-N-pertechnetate (740 MBq [20 mCi]) was introduced into a vial containing tin chloride dihydrate (0.02 mg), 1,2-diaminopropane-N,N,N′,N′-tetraacetic acid (5.00 mg), succinyl dihydrazine (10.00 mg), and sodium phosphate buffer (pH 7.8). After 15 minutes at room temperature, 1 mL of a solution containing N-ethoxy-N-ethyl dithiocarbamate of sodium monohydrate (10.00 mg/mL) and 1 mL of a solution of dimethyl-β-cyclodextrine (10.00 mg/mL) were added to the first vial. Ten minutes later, 99mTc-N-NOET was ready to be injected. Quality control was performed with thin-layer chromatography with Silicagel plates (Gelman Sciences) and dichloromethane. Radiochemical purity was >90% in each experiment.
Microsphere-Derived Regional Myocardial Blood Flow, Quantification of Tracer Uptake, and 99mTc-N-NOET Blood Kinetics
The technique used in our laboratory to quantify myocardial blood flow by radiolabeled microspheres in 72 myocardial segments from normal and stenotic regions has been described previously.15 16 The myocardial segments were counted for 99mTc activities in a gamma-well scintillation counter (MINAXI 5550, Packard Instruments) within 24 hours. In protocol 1, the myocardial segments were counted for 201Tl activity after 48 hours, when the 99mTc had decayed. Finally, a third count was performed for myocardial flow determination 3 weeks later, when 201Tl activity was negligible. The gamma counter window settings were 113Sn, 340 to 440 keV; 103Ru, 450 to 550 keV; 95Nb, 640 to 840 keV; and 46Sc, 842 to 1300 keV. To compare regional 201Tl and 99mTc-N-NOET tissue activities with microsphere flow, the data from the 72 myocardial segments were expressed as stenotic-to-normal activity and flow ratios. Hypoperfused segments were defined as those in which flow at the time of tracer injection was <75% of baseline, whereas normal segments had flow >75% baseline.
In Vivo Image Acquisition and Defect Magnitude Quantification
Planar 201Tl and 99mTc-N-NOET images were acquired in the left lateral projection with a standard gamma camera (Technicare 420, Ohio Nuclear) equipped with an all-purpose, low-to-medium-energy collimator as previously described.16 Background was subtracted from all images by use of a previously validated algorithm17 18 without thresholding or filtering. To quantify the 201Tl and 99mTc-N-NOET images, ROIs were drawn on the defect area of the anteroseptal wall supplied by the LAD and on the normally perfused posterior wall supplied by the LCx. The LAD-to-LCx imaging defect count ratio was computed by dividing the average counts in the ischemic ROI by the average counts in the nonischemic ROI. Time-activity curves were plotted by use of the activities obtained from the ROIs on serial images, and myocardial fractional clearance of 99mTc-N-NOET in the LAD and LCx ROIs was calculated as [(initial mean activity per pixel−final mean activity per pixel)/initial mean activity per pixel]×100.
Postmortem Determination of Risk Area and Infarct Size
The endocardial and epicardial surfaces of each heart slice and the borders of the monastral blue dye–determined risk area were traced on acetate sheets. The heart slices were then incubated for 10 minutes at 37°C in a 2% solution of TTC to delineate infarct area, and the infarct area was traced onto the previous acetate sheets. Risk and infarct areas were determined with a digital planimeter program as previously described.19
Mean and SEM computations were performed with SYSTAT software (SPSS, Inc). Comparisons within each group were made with either a paired Student’s t test or repeated-measures ANOVA with post hoc comparisons of changes determined, a priori, to be of interest.
Protocol 1: Comparison of 201Tl and 99mTc-N-NOET During Sustained LAD Low Flow
Hemodynamics. Table 1⇓ summarizes the hemodynamic parameters that remained stable throughout the experiment. LAD flow decreased significantly after the setting of the stenosis and remained constant throughout the rest of the experiment. LAD regional wall thickening fell markedly after the stenosis was set and remained akinetic or slightly dyskinetic for the remainder of the experiment. There was no significant difference in LAD systolic thickening at the time points when 201Tl and 99mTc-N-NOET were injected.
Risk area and infarct size. The LAD risk area by monastral blue dye was 27.9±1.7% of the total left ventricle (range, 20.6% to 36.6%). By TTC staining, only two dogs had small subendocardial myocardial infarction involving 1.6% and 0.8% of the left ventricle, respectively.
Microsphere blood flow and 201Tl and99mTc-N-NOET activities. The mean stenotic-to-normal blood flow ratio was 0.98±0.02 during baseline. It decreased significantly after the stenosis was set and was 0.56±0.07 at the time of 201Tl injection (P<.001 versus baseline), 0.52±0.06 at the time of 99mTc-N-NOET injection (P<.001 versus baseline), and 0.49±0.07 at the end of the experiment (P<.001 versus baseline). The stenotic-to-normal blood flow ratio at the time of 201Tl injection was not different from that at the time of 99mTc-N-NOET injection.
Both 201Tl and 99mTc-N-NOET stenotic-to-normal tissue activity ratios after 2 hours of low flow were significantly higher than the flow ratio at the time of injection (201Tl, 0.73±0.04; 99mTc-N-NOET, 0.76±0.06; P<.001 versus injection flow ratio), indicative of rest redistribution (Fig 2⇓). As shown in the figure, there was no significant difference between 201Tl and 99mTc-N-NOET tissue activity ratios. However, in segments with very low flow (flow reduction >80% from baseline), the 201Tl tissue activity ratio was significantly higher than that of 99mTc-N-NOET (Fig 3⇓). In contrast, in segments with moderate flow reduction (20% to 50% of baseline), 201Tl tissue activity ratio was lower than that of 99mTc-N-NOET.
Image defect ratios. The initial 201Tl imaging defect count ratio (0.67±0.03) was not significantly different from the 99mTc-N-NOET defect count ratio on images acquired 15 minutes after injection (0.66±0.03, P=NS). Thus, in this low-flow model, initial 99mTc-N-NOET myocardial uptake, like 201Tl, reflected the flow disparity at the time of injection. There was a significant increase in the 99mTc-N-NOET imaging defect count ratio over time (0.73±0.02 at 120 minutes after injection, P<.001 versus 15-minute images) (Fig 4⇓, top). As can be seen in Fig 5⇓, there was significantly faster 99mTc-N-NOET clearance from the normal-flow LCx zone compared with the hypoperfused LAD zone. The myocardial fractional clearance of 99mTc-N-NOET was 43.4±3.0% in the normal LCx zone and 37.9±3.1% in the hypoperfused LAD zone (P<.01). In addition, the myocardial 99mTc-N-NOET clearance half-time was 143±18 minutes in the normal-flow LCx zone and 201±29 minutes in the hypoperfused LAD zone (P=.01), indicating delayed clearance from the low-flow zone.
Protocol 2: Myocardial Kinetics of 99mTc-N-NOET Injected During 15 Minutes of Total LAD Occlusion Followed by 2 Hours of Reflow
Hemodynamics. Table 2⇓ summarizes the hemodynamic data for protocol 2. LAD flow decreased significantly after occlusion at the time 99mTc-N-NOET injection returned to baseline after reflow and remained constant throughout the experiment. LAD regional wall thickening decreased dramatically after the setting of the stenosis, with no significant variation over time, even after reperfusion.
Risk area and infarct size. The LAD risk area by monastral blue dye was 27.9±2.7% of the total left ventricle (range, 22.7% to 38.1%). None of the 6 dogs had myocardial infarction by TTC staining.
99mTc-N-NOET arterial blood activity. 99mTc-N-NOET blood activity decreased rapidly after injection and was 34.4±4.0%, 13.9±1.7%, 7.1±1.1%, 3.9±0.5%, and 2.7±0.4% of maximal activity at 1, 5, 15, 30, and 120 minutes after injection, respectively.
Microsphere blood flow and 99mTc-N-NOET tissue activity. The mean LAD-to-LCx blood flow ratio was 0.99±0.03 at baseline, and it decreased to 0.27±0.04 at the time of 99mTc-N-NOET injection during LAD occlusion (P<.001 versus baseline). After reperfusion, the LAD-to-LCx blood flow ratio increased to 1.19±0.03 (P<.001 versus occlusion) (Fig 6⇓). This ratio was higher than at baseline (P<.01), consistent with a mild transient hyperemic response in the previously occluded region, although LAD flow measured by ultrasonic flow probe at this time had returned to baseline. This hyperemic response resolved over time, and the LAD-to-LCx blood flow ratio at the end of the experiment was slightly lower than at baseline (0.84±0.03, P=.054). The 99mTc-N-NOET LAD-to-LCx tissue activity ratio after 2 hours of reperfusion (0.84±0.03) was significantly higher than the flow ratio at the time of injection (P<.001) and was identical to the blood flow ratio at the end of the experiment, indicative of complete redistribution of 99mTc-N-NOET after 2 hours of reflow (Fig 6⇓).
Image defect ratios. The initial 99mTc-N-NOET imaging defect count ratio (0.57±0.04) partially reflected the flow disparity at the time of injection but was significantly higher than the LAD-to-LCx flow ratio at the time of injection (0.27±0.04, P<.001), leading to an underestimation of flow disparity. There was a significant increase in the 99mTc-N-NOET imaging defect ratio over time (P<.001): 0.68±0.04, 0.70±0.04, 0.71±0.04, 0.74±0.04, and 0.75±0.04, respectively, at 15, 30, 60, 90, and 120 minutes after reperfusion (Fig 4⇑, bottom). As shown in Fig 7⇓, there was significantly greater clearance of 99mTc-N-NOET from the normal-flow LCx area (64±5%) than from the transiently occluded LAD area (52±7%, P<.05). The clearance half-time values for the reflow period were 121±17 and 145±21 minutes for the normal and transiently occluded–reperfused zones, respectively (P<.05).
99mTc-N-NOET is the most promising member of the new class of bis-(dithiocarbamato)-nitrido, agents being investigated for myocardial perfusion imaging. 99mTc-N-NOET has been shown to have a relatively high heart uptake in rats (4.28±0.18% of injected dose), and high-quality myocardial scans have been obtained in preliminary animal studies.10 The precise mechanism underlying myocardial sequestration and retention of 99mTc-N-NOET in myocardium remains unclear. Ucelli et al11 showed that in rat myocardium, most of the 99mTc-N-NOET activity was associated with the hydrophobic components of the cell. No evidence of association of 99mTc-N-NOET with the cytosol or mitochondria was observed, and the authors concluded that cell membranes are the most likely site of localization of 99mTc-N-NOET in heart tissue. This concept was confirmed by the study of Johnson et al,20 showing an extremely high retention of 99mTc-N-NOET in isolated, perfused rat hearts but a markedly increased 99mTc-N-NOET clearance after cell membrane disruption by Triton X-100.
In a canine model of 50% flow reduction, Ghezzi et al12 found a high first-pass 99mTc-N-NOET extraction fraction of 75.5±4% under basal conditions and a linear correlation between myocardial 99mTc-N-NOET tissue activity and microsphere blood flow 15 minutes after injection (r=.94) . In another group of dogs, these same investigators found that when 99mTc-N-NOET was injected during low flow followed by 90 minutes of reperfusion, relative tracer activity appeared to increase in the previously ischemic region, consistent with tracer redistribution.12 Although 99mTc-N-NOET redistribution can be inferred from these studies, serial imaging was not performed, and thus the precise mechanism of redistribution was unknown. A clinical study comparing stress-redistribution-reinjection 201Tl SPECT with stress–delayed rest 99mTc-N-NOET SPECT in 25 patients determined that the tracers were comparable for detecting the presence and extent of coronary artery disease.13 Furthermore, some patients showed normalization of myocardial 99mTc-N-NOET activity 4 hours after injection, consistent with 99mTc-N-NOET redistribution. Nevertheless, before this study, 99mTc-N-NOET had not yet been simultaneously compared with 201Tl in controlled experimental models, and the redistribution kinetics of 99mTc-N-NOET had not been thoroughly assessed.
Data from the present study show 99mTc-N-NOET redistribution in canine models of sustained low flow and transient coronary artery occlusion followed by reflow. Furthermore, 99Tc-N-NOET and 201Tl uptake and kinetics are comparable during sustained low flow. The sustained-low-flow model was chosen because it is the model most frequently used to assess the ability of a tracer to redistribute (eg, 201Tl) during prolonged hypoperfusion and consequent asynergy when flow is unchanged from the time of tracer administration to the end of the redistribution period. The ability of 99mTc-NOET imaging to reflect myocardial blood flow disparity and to redistribute over time in the absence of significant myocardial infarction has direct clinical application in the setting of assessing myocardial ischemia with exercise or pharmacological stress. The model of transient occlusion followed by reflow, although less clinically relevant, was performed to better understand the mechanism by which 99mTc-N-NOET redistributes because it optimizes the conditions for redistribution to occur, ie, transient flow disparity with elevated blood levels of the tracer, and it was the model originally used to define 201Tl redistribution kinetics.14
Sustained Coronary Artery Low Flow
When injected during sustained coronary artery low flow, initial 201Tl and 99mTc-N-NOET defects on initial images were similar and reflected the transmural myocardial blood flow disparity at the time of injection. Serial 99mTc-N-NOET images showed significant defect resolution over time, which cannot be attributed to resolution of the partial-volume effect in the hypoperfused region, because LAD zone regional systolic wall thickening remained akinetic or dyskinetic throughout the experiment. This redistribution over time at rest resulted from a slower clearance of 99mTc-N-NOET in the hypoperfused than in the normally perfused regions, rather than accumulation of tracer in the low-flow zone. Postmortem in vitro analysis of myocardial activity confirmed 201Tl and 99mTc-N-NOET redistribution. By gamma-well counting, the 99mTc-N-NOET stenotic-to-normal tissue activity ratio after 2 hours of low flow was comparable to that of 201Tl. For both tracers, this ratio was significantly greater than the stenotic-to-normal blood flow ratio at the time they were injected. Thus, 201Tl and 99mTc-N-NOET kinetics are comparable in this model of sustained low flow. These data are consistent with those of Pohost et al,21 who demonstrated that 201Tl defects observed soon after tracer injection in dogs with a severe coronary stenosis showed delayed defect resolution over 2 hours. These investigators found that 201Tl redistribution was the consequence of both washout of 201Tl from the nonischemic regions and accumulation of 201Tl in the ischemic myocardium. We observed that 99mTc-N-NOET defect resolution in this model results predominantly from differential washout, because 99mTc-N-NOET cleared more rapidly from the normal than the hypoperfused areas and no accumulation of 99mTc-N-NOET in the low-flow zone was observed. Our model did not permit the concurrent study of 201Tl kinetics over time, and we were therefore unable to confirm relative accumulation of 201Tl in the hypoperfused zone, as has been previously demonstrated.21 These 99mTc-N-NOET data are in contrast to observations made regarding the degree of delayed rest redistribution of other 99mTc-labeled perfusion agents. Under conditions of sustained low flow, minimal to no redistribution has been reported for 99mTc-sestamibi and 99mTc-tetrofosmin.16 22
Transient Total LAD Occlusion Followed by 2 Hours of Reflow
The initial 99mTc-N-NOET defect ratio on images acquired 15 minutes after tracer injection during LAD occlusion underestimated the myocardial blood flow disparity at the time of tracer injection. This underestimation of flow discrepancy may have resulted from different but not mutually exclusive mechanisms. 99mTc-N-NOET uptake in a low-flow area may be higher than the microsphere-determined regional blood flow because of increased extraction fraction of the tracer at low flow rates, as has been demonstrated with 99mTc-sestamibi or 201Tl.23 24 25 Another mechanism is that very early redistribution of 99mTc-N-NOET occurred during the first 15 minutes after injection. Such a rapid tracer clearance from normal myocardium has been shown to occur with 99mTc-teboroxime, another neutral, highly lipophilic tracer.26 27
In this model, the 99mTc-N-NOET imaging defect also resolved over time, because of greater clearance of the tracer in the normal region than in the transiently occluded–reperfused region. Interestingly, a significant amount of redistribution occurred during the first 15 to 30 minutes after reflow, suggesting a rapid redistribution of 99mTc-N-NOET in this model. This early redistribution, although slower than that described for 99mTc-teboroxime,26 27 could be a potential problem for the clinical use of 99mTc-N-NOET, because some defects might partially resolve before image acquisition. However, in a preliminary study, the sensitivity of 99mTc-N-NOET scans acquired 30 minutes after injection for the detection of coronary artery disease in patients was not different from that of 201Tl.13 By gamma-well counting, the 99mTc-N-NOET LAD-to-LCx myocardial tissue activity ratio after 2 hours of reflow was significantly higher than the LAD-to-LCx blood flow ratio at the time of injection, confirming significant redistribution in this model.
The mechanism of 201Tl redistribution in the same transient occlusion and reflow model was investigated in two previous experimental animal studies. Pohost et al14 demonstrated that when 201Tl was injected during transient coronary artery occlusion, initial myocardial 201Tl uptake was markedly decreased. After restoration of flow, myocardial 201Tl concentration increased over time. Similarly, Beller et al28 established that 201Tl activity measured after 10 minutes of occlusion was reduced by 80% compared with normal activity. After reflow, near normalization of 201Tl activity between ischemic and nonischemic regions occurred within 4 hours, related to both delayed accumulation of tracer in the previously occluded area and rapid washout from the normal area, as already demonstrated in low-flow models.
In summary, (1) during sustained coronary low flow and transient coronary artery occlusion in open-chest dogs, initial 99mTc-N-NOET defects on quantitative planar scintigraphy reflect the myocardial blood flow disparity at the time of tracer injection. (2) In both models, 99mTc-N-NOET undergoes significant redistribution over time. With sustained low flow, 99mTc-N-NOET undergoes redistribution despite the presence of a 50% flow heterogeneity; however, redistribution in this model was not complete over 2 hours. Interestingly, in this model, 99mTc-N-NOET and 201Tl redistribution are identical, although the two tracers have very different chemical properties. (3) In the transient occlusion model, despite a nearly 75% flow heterogeneity at the time of injection, 99mTc-N-NOET undergoes complete redistribution, as evidenced by similar blood flow and 99mTc-N-NOET tissue activity ratios 2 hours after tracer injection. (4) The mechanism of 99mTc-N-NOET redistribution on serial myocardial scans results from faster clearance in the normal than in the ischemic area.
99mTc-N-NOET redistribution kinetics in the present study were assessed only by serial imaging, which is subject to technical difficulties such as scatter, attenuation, partial-volume and motion artifacts, and tissue cross talk. Alternative methods to study tracer redistribution, however, also have significant limitations: Gamma-well counting assessment of tracer kinetics requires killing different groups of animals at different times after injection, and comparison between groups may be altered by subtle changes in experimental conditions such as the degree of ischemia or the hemodynamic parameters. Serial myocardial biopsies can lead to myocardial injury, necessitate the analysis of very small myocardial pieces, and are subject to sampling error. Analysis of regional tracer activity by miniature cadmium telluride probes may be influenced by the changes in myocardial thickness or by activity in the underlying blood pool. A second limitation of this study is the relatively small sample size used in protocol 1 (n=10). This could result in a limited statistical power to detect moderate differences between 201Tl and 99mTc-N-NOET tissue activity ratios. However, such small differences would not likely have important clinical implications with regard to their use for the detection of myocardial ischemia. The transient occlusion model was chosen to optimize the redistribution of 99mTc-N-NOET and to assess the mechanisms of 99mTc-N-NOET redistribution on serial images. The clinical implication of this model is limited, however, and the results obtained after a 20-minute occlusion might not apply to a clinical setting of coronary occlusion such as acute myocardial infarction.
99mTc-N-NOET is the first 99Tc-labeled myocardial perfusion imaging agent with kinetics similar to that of 201Tl in experimental canine models, permitting redistribution imaging. Because of better radiophysical properties of 99mTc, 99mTc-N-NOET is a very promising agent for the detection and assessment of coronary artery disease.
Selected Abbreviations and Acronyms
|LAD||=||left anterior descending coronary artery|
|LCx||=||left circumflex coronary artery|
|ROI||=||region of interest|
|SPECT||=||single-photon emission computed tomography|
|99mTc-N-NOET||=||bis-(N-ethoxy,N-ethyl dithiocarbamato)nitrido 99mTc|
|TTC||=||triphenyl tetrazolium chloride|
This work was partially supported by a research grant from CIS-Bio International. Dr Vanzetto was supported by a grant from Parke Davis, France, and Merck Clevenot, France.
Reprint requests to David K. Glover, ME, Cardiovascular Division, Department of Medicine, Box 158, University of Virginia Health Sciences Center, Charlottesville, VA 22908.
- Received October 17, 1996.
- Revision received April 28, 1997.
- Accepted May 1, 1997.
- Copyright © 1997 by American Heart Association
Udelson JE, Coleman PS, Metherall J, Pandian NG, Gomez AR, Griffith JL, Shea NL, Oates E, Konstam MA. Predicting recovery of severe regional ventricular dysfunction: comparison of resting scintigraphy with 201Tl and 99mTc-sestamibi. Circulation. 1994;89:2552-2561.
Kauffman GJ, Boyne TS, Watson DD, Smith WH, Beller GA. Comparison of rest thallium-201 imaging and rest technetium-99m-sestamibi imaging for assessment of myocardial viability in patients with coronary artery disease and severe left ventricular dysfunction. J Am Coll Cardiol. 1996;27:1592-1597.
Cuocolo A, Pace L, Ricciardelli B, Chiariello M, Trimarco B, Salvatore M. Identification of viable myocardium in patients with chronic coronary artery disease: comparison of thallium-201 scintigraphy with reinjection and technetium-99m methoxy isobutyl isonitrile. J Nucl Med. 1992;33:505-511.
Dilsizian V, Arrighi JA, Diodati JG, Quyyumi AA, Alavi K, Bacharach SL, Marin-Neto JA, Katsiyiannis PT, Bonow RO. Myocardial viability in patients with chronic coronary artery disease: comparison of 99mTc-sestamibi with thallium reinjection and [18F]fluorodeoxyglucose. Circulation. 1994;89:578-587.
Sinusas AJ, Bergin JD, Edwards NC, Watson DD, Ruiz M, Makuch RW, Smith WH, Beller GA. Redistribution of 99mTc-sestamibi and 201Tl in the presence of a severe coronary artery stenosis. Circulation. 1994;89:2332-2341.
Li Q-S, Solot G, Frank TL, Wagner HN Jr, Becker LC. Myocardial redistribution of technetium-99m-methoxy isobutyl isonitrile (SESTAMIBI). J Nucl Med. 1990;31:1069-1076.
Leon AR, Eisner RL, Martin SE, Schmarkey LS, Aaron AM, Boyers AS, Burnham KM, Oh DJ, Patterson RE. Comparison of single-photon emission computed tomographic (SPECT) myocardial perfusion imaging with thallium-201 and technetium-99m-sestamibi in dogs. J Am Coll Cardiol. 1992;20:1612-1625.
Pasqualini R, Duatti A, Bellande E, Comazzi V, Brucato V, Hoffshir D, Fagret D, Comet M. Bis(dithiocarbamato) nitrido technetium 99m radiopharmaceuticals: a class of neutral myocardial imaging agents. J Nucl Med. 1994;35:334-341.
Ucelli L, Giganti M, Duatti A, Bolzati C, Pasqualini R, Cittanti C, Colamussi P, Piffanelli A. Subcellular distribution of technetium 99m N-NOEt in rat myocardium. J Nucl Med. 1995;36:2075-2079.
Ghezzi C, Fagret D, Arvieux C, Mathieu JP, Bontron R, Pasqualini R, de Leiris J, Comet M. Myocardial kinetics of Tc-N-NOET: a neutral lipophilic complex tracer of regional myocardial blood flow. J Nucl Med. 1995;36:1069-1077.
Fagret D, Marie PY, Brunotte F, Giganti M, Le Guludec D, Bertrand A, Wolf JE, Piffanelli A, Chossat F, Bekhechi D, Pasqualini R, Machecourt J, Comet M. Myocardial perfusion imaging with 99mTc-N-NOET: comparison with thallium-201 and coronary angiography. J Nucl Med. 1995;36:936-943.
Pohost GM, Zir LM, Moore RH, McKusick KA, Guiney TE, Beller GA. Differentiation of transient ischemic from infarcted myocardium by serial imaging after a single dose of thallium-201. Circulation. 1977;55:294-302.
Domenech RJ, Hoffman JIE, Noble MIM, Saunders KB, Henson JR, Subijanto S. Total and regional coronary blood flow measured by radioactive microspheres in conscious and anesthetized dogs. Circ Res. 1969;25:587-596.
Sansoy V, Glover DK, Watson DD, Ruiz M, Smith WH, Simanis JP, Beller GA. 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.
Sinusas AJ, Beller GA, Smith WH, Vinson EL, Brookeman V, Watson DD. Quantitative planar imaging with technetium-99m methoxyisobutyl isonitrile: comparison of uptake patterns with thallium-201. J Nucl Med. 1989;30:1456-1463.
Pohost GM, Okada RD, O’Keefe DD, Gewirtz H, Beller GA, Strauss HV, Chaffin JS, Leppo J, Daggett WM. Thallium 201 redistribution in dogs with severe coronary artery stenosis of fixed caliber. Circ Res. 1981;48:439-446.
Koplan BA, Beller GA, Ruiz M, Yang JY, Watson DD, Glover DK. Comparison between thallium-201 and technetium-99m-tetrofosmin uptake with sustained low flow and profound systolic dysfunction. J Nucl Med. 1996;37:1398-1402.
Glover DK, Ruiz M, Edwards NC, Cunningham M, Simanis JP, Smith WH, Watson DD, Beller GA. Comparison between thallium-201 and Tc-99m-sestamibi uptake during adenosine-induced vasodilatation as a function of coronary stenosis severity. Circulation. 1995;91:813-820.
Canby RC, Silber S, Pohost GM. Relation of the myocardial imaging agents 99mTc-sestamibi and 201 Tl to myocardial blood flow in a canine model of myocardial ischemic insult. Circulation. 1990;81:289-296.
Stewart RE, Schwaiger M, Hutchkins GD, Chiao PC, Gallagher KP, Nguyen N, Petry NA, Rogers WL. Myocardial clearance kinetics of technetium 99m SQ 30217: a marker of regional myocardial blood flow. J Nucl Med. 1990;31:1183-1190.
Johnson G, Glover DK, Hebert CB, Okada RD. Early myocardial clearance kinetics of technetium-99m teboroxime differentiates normal and flow-restricted canine myocardium at rest. J Nucl Med. 1993;34:630-636.
Beller GA, Watson DD, Ackell P, Pohost GM. Time course of thallium-201 redistribution after transient myocardial ischemia. Circulation. 1980;61:791-797.