Robert D. Okada

Clearance of technetium 99m N-NOET in normal, ischemic-reperfused, and membrane-disrupted myocardium

BackgroundTechnetium 99m-labeled bis (N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(v) (99mTcN-NOET) is a new neutral cardiac perfusion imaging agent that has been shown to have very high uptake and retention in vitro. The purpose of this study was to determine the clearance kinetics of 99m TcN-NOET in control, ischemic-reperfused, and membrane-disrupted myocardium.Methods and ResultsAfter a 100 μCi (3.7×106 Bq) bolus of 99mTcN-NOET was injected, myocardial clearance was monitored for 1 hour by the use of a sodium iodide detector in 30 isolated, Krebs-Henseleit (KH) perfused rat hearts. Seven hearts were used as controls (group 1). In seven ischemic-reperfused hearts, tracer administration and uptake was followed by 30 minutes of no flow and 1 hour of reflow (group 2). In six additional ischemic-reperfused hearts, tracer administration was followed by deprivation of flow for 1 hour followed by 1 hour of reflow (group 3). Six hearts were perfused with a 0.5% Triton X-100 KH perfusate for 1 hour (group 4). Four hearts were perfused with KH for 10 minutes, followed by cyanide for 10 minutes (group 5). This cycle was repeated three times. Activities remaining in each heart at the end of each experiment were quantitated, and activity at peak uptake was calculated. The 99mTcN-NOET myocardial clearance was near linear in the control (0.6±0.4) and both ischemic-reperfused groups with virtually no fractional clearance (1.2%±0.6% and 2.1%±0.6%, respectively; p=NS). In the Triton X-100 membrane-disrupted hearts, clearance was substantial (94.2%±4.0%; p<0.0001 compared with the control and ischemic-reperfused groups). Cyanide treatment produced rapid clearance, which was arrested by a return to the standard KH perfusate. Peak uptake as a percentage of injected dose was 74.9%±1.4% for all groups combined.ConclusionThus 99mTcN-NOET has extremely high myocardial retention after 1 hour in normal myocardium and is not significantly affected by ongoing myocardial ischemia or reperfusion injury in this model. Clearance is increased markedly in extreme conditions of membrane disruption. These data are consistent with the concept that 99mTc-NOET is localized predominantly in or on cell membranes. 99mTcN-NOET is a promising, new myocardial perfusion imaging agent that exhibits a stable myocardial distribution in the setting of acute developing injury.

Myocardial technetium 99m sestamibi kinetics after reperfusion in a canine model

Clinical sestamibi imaging protocols after reperfusion therapy are based on the premise that redistribution does not occur. However, animal studies that use punch biopsies or imaging have variably reported either some or no redistribution. This study was designed to (1) utilize implantable radiation detectors to determine whether sestamibi is redistributed after reperfusion, (2) accurately determine the time course, extent, and kinetics of the redistribution, and (3) determine whether sestamibi kinetics can be used to document reperfusion and salvage after a single dose of sestamibi. Twenty-five dogs were injected with 5.0 mCi of technetium 99m sestamibi and microspheres during circumflex occlusion, and reperfusion occurred within 5 minutes in group 1 (15-minute occlusion) and group 2 (1-hour occlusion). Group 3 was not reperfused. Sestamibi activities in the normal and occluded zones were monitored with radiation detectors for 2 hours, and serial gamma camera imaging and arterial blood sampling was begun. No dogs in group 1 and all dogs in groups 2 and 3 had infarcts as shown by triphenyltetrazolium chloride stain. The final occluded/normal zone technetium 99m activity ratio was significantly higher than the flow ratio at the time of sestamibi injection only in the group 1 dogs (0.51 +/- 0.05 vs 0.38 +/- 0.06, p = < 0.0001). In addition, the mean 2-hour fractional sestamibi clearance from the occluded/reperfused zone (0.03 +/- 0.02) was significantly slower in the group 1 dogs compared with normal zone clearance (0.09 +/- 0.01, p = 0.03). Gamma camera images demonstrated large posterior wall perfusion defects initially, which persisted 2 hours later with no visual evidence of redistribution in any of the reperfused dogs in groups 1 and 2. Thus in an experimental animal model under ideal conditions, sestambi is redistributed into reperfused viable myocardium; however, the amount of this redistribution is small and could not be perceived by visual image analysis. Sestamibi is not redistributed into reperfused nonviable myocardium or into nonreperfused myocardium. Therefore sestamibi kinetics after a single dose of tracer in an experimental animal model can be used to document reperfusion of viable myocardium but cannot differentiate reperfusion of the infarcted territory from nonreperfused infarcted myocardium.

HL-91-Technetium-99m: A new marker of viability in ischemic myocardium

BackgroundTechnetium 99m-HL91 is a new hypoxia imaging agent that demonstrates increased uptake in ischemic, viable myocardium. This study was performed to determine whether HL91 is taken up by nonviable myocardium.MethodsTwenty-three Krebs-Henseleit buffer-perfused, isolated rat hearts were studied. Tc-99m-HL91 300 μCi was infused over 10 minutes, followed by a 60-minute clearance. Myocardial activity was monitored by use of an NaI crystal. Four groups were studied: control (flow=12 mL/min, n=7), low flow (flow=1 mL/min, n=6), no flow/reflow (60 minutes no flow/60 minutes reflow before Tc-99m-HL91 infusion, flow=12 mL/min, n=5), and cyanidetreated (before Tc-99m-HL91 infusion, flow=12 mL/min, n=5). Injury was assessed by creatine kinase, transmission electron microscopy, and triphenyltetrazolium chloride.ResultsControl (no injury) and cyanide-treated (severe injury) hearts demonstrated low uptake (6.3±0.5 mean±SEM and 5.7±1.2 μCi, respectively) and low 60-minute retention (13.8%±2.2% and 13.7%±3.9%, respectively). Low-flow hearts (minimal injury) demonstrated markedly increased uptake (43.5±2.8 μCi, P<.01) and increased 60-minute retention (33.2% ±2.9%, P<.01) compared with control. No-flow/reflow hearts (moderate injury) demonstrated intermediate uptake (8.7±0.5 μCi, P<.05 to control), although retention was not significantly different (18.9%±3.5%, P=ns). Severely and rapidly injured myocardium demonstrated Tc-99m-HL91 peak uptake and retention indistinguishable from normal. Moderately injured myocardium demonstrated uptake intermediate between severely injured and low-flow-induced ischemic, viable myocardium.ConclusionThus Tc-99m-HL91 is not taken up or retained in nonviable and irreversibly injured myocardium.

Technetium 99m—HL-91: A potential new marker of myocardial viability assessed by nuclear imaging early after reperfusion☆

Objective99mTc-HL-91 (Prognox) is a potential new hypoxia-avid myocardial imaging agent. The purpose of this study was to determine whether this tracer would demonstrate increased activity in nonviable myocardium in vivo.Methods and ResultsA 3-hour left circumflex artery (LCx) occlusion was followed by 1 hour of reperfusion, injection of 99mTc-HL-91 (185 MBq), and 2 hours of gamma camera imaging in 6 open-chest canine experiments. Microspheres were injected during baseline, at occlusion, at the time of tracer injection, and at the end of the experiment. After the animals were killed, heart slices were imaged. Blood flow and tracer activity were determined by well counting. Mean infarct size was 19.2%±2.2% (SEM). All six dogs demonstrated no increased 99mTc-HL-91 myocardial activity other than small foci on in vivo and ex vivo gamma camera images. The mean large region of interest (ROI)-determined LCx/LAD (left anterior descending) ratio was 1.10±0.03 in vivo, and 1.0±0.02 ex vivo. Mean clearance curves from LCx and LAD ROI were not significantly different, and 2-hour retention was 15.2%±2.1% for the LCx and 18.6%±2.7% for the LAD (p=NS). ROI clearance curves demonstrated biexponential clearance over the first hour and linear clearance over the second hour. Myocardial blood flow (microspheres) versus well-counted tracer uptake curves were linear with near-zero slopes for viable tissue, non-viable tissue, and mosaic tissue. Blood clearance was triexponential with a 2-hour retention of 7.8%±1.1%.ConclusionsIn contrast to viable ischemic tissue, normal and nonviable myocardium demonstrate similar 99mTc-HL-91 uptake and retention kinetics. This agent warrants further clinical studies in situations where there is a need to differentiate ischemic viable from nonviable myocardium.

Planar imaging of 99mTc-labeled (bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(V)) can detect resting ischemia

Background99mTc-labeled (bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(V)) (99mTcN-NOET) is a new lipophilic, neutral-charge cardiac perfusion imaging agent that demonstrates apparent redistribution in animal models and humans. The purpose of this study was to determine whether the kinetics of 99mTcN-NOET are suitable for the detection of resting ischemia.Methods and ResultsMicrospheres were injected at baseline and simultaneously with 99mTcN-NOET after a 90% reduction in resting flow in the left circumflex coronary artery in six open-chest canine experiments. The relationship of flow and activity early after injection was determined in one experiment by termination at 10 minutes. The flow ratio (left circumflex/left anterior descending coronary artery) after stenosis fell significantly (0.87±0.04 vs 0.46±0.04; p<0.05). The end-tissue 99mTc ratio (0.78±0.05) was significantly higher than the flow ratio at injection (0.46±0.04; p<0.05), indicating substantial redistribution. In vivo imaging was conducted during 2 hours in five experiments, followed by ex vivo imaging. Myocardial clearance from 10 minutes onward was biphasic in left anterior descending and monophasic in left circumflex coronary arteries. Myocardial clearance from 10 to 60 minutes was delayed in left circumflex (35.5%±8.1%) versus left anterior descending coronary arteries (49.2%±8.6%; p<0.05). No significant difference was observed from 60- to 120-minute clearance. Five of five experiments demonstrated initial defects and complete fill-in at 90 to 120 minutes by qualitative assessment. Quantitation of ex vivo images confirmed significant redistribution.ConclusionsResting ischemia caused by moderate to severe stenosis can be detected on scans with 99mTcN-NOET. Redistribution was near complete in this model by 90 to 120 minutes. 99mTcN-NOET is a promising new agent for the detection of coronary artery disease in viable myocardium and warrants further investigation.

Effects of low flow and hypoxia on myocardial retention of technetium-99m BMS181321

The purpose of the present study was to determine whether graded levels of low-flow ischemia would lead to graded differences in uptake and clearance of BMS 181321. Using a perfused rat heart model, 7.4 MBq (200 μCi) of BMS181321 was infused over 20 min, followed by a 60-min clearance phase. Activity was monitored using an NaI detector. Four groups were studied using Krebs-Henseleit buffer perfusion using low flow or hypoxia: group 1=12 ml/min, group 2=3 ml/min, and group 3=1 ml/min during uptake and clearance phases, and group 4=12 ml/min with hypoxia during clearance. Control and low-flow groups were also perfused using red blood cells and albumin. There was a stepwise increase in peak myocardial uptake (% injected dose) as flow progressively decreased (group 1=2.4%±0.2% SEM, group 2=13.1%±0.7%, group 3=28.6%±2.4%,P <0.05). Group 3/group 1 mean peak activity ratio was 12:1. Mean 1-h fractional retention significantly increased in a stepwise manner as flow decreased (group 1=0.32±0.02, group 2=0.43±0.03, group 3=0.59±0.05,P <0.05). Group 3/group 1 mean 1-h clearance activity ratio was 30:1. Groups 5 and 6 perfused with red blood cells and albumin demonstrated similar increases in peak uptake and 1-h retention in the low-flow hearts. This study demonstrates a stepwise increase in uptake and a stepwise increase in retention rate of BMS 181321 with progressive reduction in. flow.

Technetium 99m-Q12 kinetics in perfused rat myocardium: effects of hypoxia and low flow.

Technetium 99m-Q12 is a new cationic myocardial perfusion imaging agent that produces excellent images in human beings. The purpose of this study was to examine the separate effects of hypoxia and low flow on myocardial clearance kinetics. After a 1 mCi bolus injection, myocardial 99mTc-Q12 clearance was monitored for 1 hour by using an Nal detector in 24 isolated perfused rat hearts. In 6 control hearts, flow was 12 ml/min, and oxygenation was normal. In 6 hypoxic hearts, flow was normal, but oxygenation was reduced (<5% 02). In 6 low-flow hearts, flow was 3 ml/min, and oxygenation was normal. In 6 very low flow hearts, flow was 1 ml/min, and oxygenation was normal. 99mTc-Q12 myocardial clearance was biphasic in all four groups, consisting of a rapid early phase and a second slow phase that began after 10 minutes. Myocardial retention between 1 and 10 minutes was 56.8% +/- 1.8% for control, 49.2% +/- 2.2% (p < 0.05 compared with control) for hypoxic, 56.8% +/- 2.6% (p = NS compared with control) for low flow (3 ml/min), and 63.7% +/- 2.1 % (p < 0.05 compared with control) for very low flow hearts (1 ml/min). Myocardial retention between 10 and 60 minutes was 90.5% +/- 0.2% for control, 90.2% +/- 1.6% for hypoxic, 90.0% +/- 0.8% for low-flow hearts (3 ml/min), and 87.6% +/- 0.3% (p < 0.05 compared with other groups) for very low flow hearts (1 ml/min). In conclusion, 99mTc-012 demonstrates biphasic clearance from normal, hypoxic, low-flow, and very low flow ischemic myocardium. Early-phase myocardial retention is decreased by hypoxia and increased by very low flow.

Monocationic radiotracer kinetics and myocardial infarct size : a perfused rat heart study

ObjectiveTo compare the myocardial kinetics of three 99mtechnetium-labeled monocationic tracers [methoxy-isobutylisonitrile (MIBI), tetrofosmin, and Q12] in a model of ischemia-reperfusion (IR) to determine their abilities to assess myocardial viability.MethodsIsolated perfused rat hearts (n = 30) were studied in control and IR groups for each tracer. IR hearts were treated with 120 min global no-flow followed by 5 min reflow, then 60 min tracer uptake/clearance. Tracer kinetics were monitored using a scintillation detector.ResultsThis model produced significant myocardial injury, without significant differences in the percentage of injured myocardium by triphenyltetrazolium chloride (TTC) staining and creatine kinase (CK) assay. Transmission electron microscopy analysis also confirmed necrosis with abundant mitochondrial damage in the IR hearts. All three IR groups exhibited significantly less mean (±standard error of the mean) tracer retention than matched controls (MIBI 73.4 ± 4.9% vs. 96.9 ± 1.76%, tetrofosmin 38.7 ± 4.6% vs. 82.2 ± 3.5%, and Q12 23.0 ± 2.5% vs. 43.8 ± 1.8%, respectively; P < 0.05). Tetrofosmin IR hearts exhibited 54 ± 9% of control myocardial retention, which was significantly less than either MIBI (86 ± 5%, P < 0.05) or Q12 (63 ± 6%, P < 0.05); thus, tetrofosmin provided the best differentiation between nonviable and normal myocardium. Furthermore, tetrofosmin end activity (%id/g) in controls was significantly higher than Q12 (4.09 ± 0.04 vs. 1.71 ± 0.06, respectively, P < 0.05), and tetrofosmin end activity (%id/g) in IR hearts was significantly higher than Q12 (2.19 ± 0.37 vs. 1.06 ± 0.12, respectively, P < 0.05). The correlation between end activity and viable myocardium determined by TTC staining was r = 0.66 (P < 0.05) for MIBI, r = 0.94 (P < 0.05) for tetrofosmin, and r = 0.91 (P < 0.05) for Q12. The correlation between myocardial end activity and myocardial CK leak was r = −0.62 (P < 0.05) for MIBI, r = −0.87 (P < 0.05) for tetrofosmin, and r = −0.89 (P < 0.05) for Q12.ConclusionsNonviable myocardium can be distinguished from normal myocardium by the retention kinetics of all three monocationic tracers studied. Tetrofosmin and Q12 end activities demonstrate the best correlation with infarct size. However, tetrofosmin kinetics may combine the greatest differentiation between nonviable and normal myocardium, while still retaining adequate activity for imaging.