99mTc-glucarate kinetics differentiate normal, stunned, hibernating, and nonviable myocardium in a perfused rat heart model.

PURPOSE: (99m)Tc-glucarate is an infarct-avid imaging agent. However, patients may have mixtures of normal, irreversibly injured, stunned, and hibernating myocardium. The purposes were to determine (99m)Tc-glucarate uptake and clearance kinetics in these four conditions, and its ability to determine the extent of injury. METHODS: Twenty-two perfused rat hearts were studied: controls (n = 5), stunned (n = 5; 20-min no-flow followed by 5-min reflow), hibernating (n = 6; 120-min low flow at 4 ml/min), and ischemic-reperfused (n = 6; 120-min no-flow followed by reflow). (99m)Tc-glucarate was then infused. Tracer activity was monitored using a NaI scintillation detector and a multichannel analyzer. Creatine kinase, electron microscopy, and triphenyltetrazolium chloride determined viability. RESULTS: (99m)Tc-glucarate 10-min myocardial uptake was significantly greater in ischemic-reperfused (2.50 +/- 0.09) (cpm, SEM) than in control (1.74 +/- 0.07), stunned (1.68 +/- 0.11), and hibernating (1.59 +/- 0.11) (p < 0.05). Tracer retention curves for ischemic-reperfused were elevated at all time points as compared with the other groups. (99m)Tc-glucarate 60-min myocardial uptake was significantly greater in ischemic-reperfused (7.60 +/- 0.63) than in control (1.98 +/- 0.15), stunned (1.79 +/- 0.08), and hibernating (2.33 +/- 0.15) (p < 0.05). The 60-min well-counted tracer activity ratio of ischemic-reperfused to control was 9:1 and corroborated the NaI detector results. Creatine kinase, triphenyltetrazolium chloride, and electron microscopy all demonstrated significantly greater injury in ischemic-reperfused compared to the other groups. An excellent correlation was observed between viability markers and tracer activity (r = 0.99 triphenyltetrazolium chloride; r = 0.90 creatine kinase). CONCLUSION: (99m)Tc-glucarate activity continually and progressively increased in irreversibly injured myocardium. (99m)Tc-glucarate uptake was strongly correlated with myocardial necrosis as determined by three independent assessments of viability. There were minimal and similar (99m)Tc-glucarate uptakes in control, stunned, and hibernating myocardium.

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

OBJECTIVE: To compare the myocardial kinetics of three (99m)technetium-labeled monocationic tracers [methoxy-isobutylisonitrile (MIBI), tetrofosmin, and Q12] in a model of ischemia-reperfusion (IR) to determine their abilities to assess myocardial viability. METHODS: Isolated 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. RESULTS: This 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. CONCLUSIONS: Nonviable 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.

99mTc-sestamibi kinetics predict myocardial viability in a perfused rat heart model.

INTRODUCTION: (99m)Tc-sestamibi has been proposed as a viability imaging agent. The purposes of this study were: (1) to determine the relationship between myocardial viability and (99m)Tc-sestamibi kinetics using perfused rat heart models across a full spectrum of viability, (2) to do so under conditions where myocardial flow was controlled and held constant, and (3) to do so using multiple quantitative methods to assess myocardial viability. METHODS: Twenty-three isolated rat hearts were perfused retrogradely with a modified Krebs-Henseleit (KH) solution. Four groups were studied: controls (C, n = 6), stunned (S, n = 6), ischemic-reperfused (IR, n = 6), and calcium injured (CAL, n = 5). Following a 20-min baseline and subsequent treatment phase, (99m)Tc-sestamibi was infused over 60 min (uptake) followed by 60 min clearance. Treatment phases consisted of 20 min no flow for S, 60 min no flow followed by 60 min reflow for IR, and 10 min infusion of KH solution without calcium followed by 20 min infusion of KH solution with 2 times normal calcium for CAL hearts. Creatine kinase (CK) assay, triphenyltetrazolium chloride (TTC) staining, and transmission electron microscopic (TEM) analysis were used to determine tissue viability. RESULTS: Myocardial peak (99m)Tc-sestamibi uptake (%id) was significantly decreased in IR (4.11 +/- 0.22 SEM; p < 0.05) and CAL (1.07 +/- 0.13; p < 0.05), but not in S (4.88 +/- 0.17) as compared with C (5.99 +/- 0.50). One hour fractional retention was 79.3 +/- 1.9% for C, 80.3 +/- 1.3% for S (p = n.s.), 79.1 +/- 1.8% for IR (p = n.s.), and 14.9 +/- 4.3% for CAL (p < 0.05 compared to all other groups). (99m)Tc-sestamibi absolute retention (%id) 1 h after the end of tracer administration was significantly decreased in IR (3.26 +/- 0.23) and CAL (0.15 +/- 0.02) as compared with both S (3.92 +/- 0.16) and C (4.52 +/- 0.32) (p < 0.05). CK increased significantly from baseline in the IR and CAL hearts. TTC determined percent viability was 100 +/- 0% for C, 98.3 +/- 1.1% for S, 82.8 +/- 2.6% for IR, and 0.0 +/- 0% for CAL. TEM analysis supported these findings. End tracer activity was significantly correlated with TTC determined percentage viable myocardium (r = 0.93, p < 0.05) and CK leak (r = -0.90, p < 0.05). CONCLUSION: (99m)Tc-sestamibi myocardial activity is significantly reduced in areas of nonviability after 1 h of tracer uptake and 1 h of tracer clearance. There is a linear correlation between myocardial viability, as determined by three independent methods, and tracer activity.

The effect of insulin deficiency on tau and neurofilament in the insulin knockout mouse.

Complications of diabetes mellitus within the nervous system are peripheral and central neuropathy. In peripheral neuropathy, defects in neurofilament and microtubules have been demonstrated. In this study, we examined the effects of insulin deficiency within the brain in insulin knockout mice (I-/-). The I-/- exhibited hyperphosphorylation of tau, at threonine 231, and neurofilament. In addition, we showed hyperphosphorylation of c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3 beta) at serine 9. Extracellular signal-regulated kinase 1 (ERK 1) showed decrease in phosphorylation, whereas ERK 2 showed no changes. Ultrastructural examination demonstrated swollen mitochondria, endoplasmic reticulum, and Golgi apparatus, and dispersion of the nuclear chromatin. Microtubules showed decrease in the number of intermicrotubule bridges and neurofilament presented as bunches. Thus, lack of insulin brain stimulation induces JNK hyperphosphorylation followed by hyperphosphorylation of tau and neurofilament, and ultrastructural cellular damage, that over time may induce decrease in cognition and learning disabilities.