American Society of Nuclear Cardiology information statement: Standardized reporting matrix for radionuclide myocardial perfusion imaging.
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Humans↗
Biomedical subjects
David K Glover
Publications and source records attributed to David K Glover.
Organ biodistribution and myocardial uptake, washout, and redistribution kinetics of Tc-99m N-DBODC5 when injected during vasodilator stress in canine models of coronary stenoses.
BACKGROUND: Technetium 99m N-DBODC5 is a new myocardial perfusion tracer shown to exhibit high heart uptake and rapid liver clearance in normal rats. The objectives of this canine study were (1) to compare the organ biodistribution and myocardial uptake, washout, and redistribution kinetics of Tc-99m N-DBODC5 with Tc-99m sestamibi over a period of 3 hours in a more clinically relevant large animal species and (2) to compare the myocardial uptake of Tc-99m N-DBODC5 with thallium 201 when co-injected during vasodilator stress in dogs with coronary stenoses. METHODS AND RESULTS: At peak adenosine-induced hyperemia, 10 dogs with critical left anterior descending artery stenoses received either Tc-99m N-DBODC5 (n = 6) or Tc-99m sestamibi (n = 4) and microspheres, followed by serial imaging and blood sampling over a period of 3 hours. Another 14 dogs with either critical (n = 7) or mild (n = 7) left anterior descending artery stenoses underwent simultaneous injection of Tc-99m N-DBODC5, Tl-201, and microspheres during peak vasodilator stress. Like sestamibi, Tc-99m N-DBODC5 showed good myocardial uptake with slow washout and minimal redistribution over a period of 3 hours (P = not significant); however, Tc-99m N-DBODC5 cleared more rapidly from the liver (heart-lung ratio at 30 minutes, 0.92+/-0.11 versus 0.51 +/- 0.05; P < .05). When injected during hyperemic flow, the myocardial extraction plateau for Tc-99m N-DBODC5 was lower than that for Tl-201 and was intermediate between Tc-99m sestamibi and Tc-99m tetrofosmin. CONCLUSIONS: Excellent organ biodistribution and myocardial uptake and clearance kinetic properties, combined with rapid liver clearance and a favorable flow-extraction relationship, make Tc-99m N-DBODC5 a very promising new myocardial perfusion imaging agent.
Adenosine↗
Reduction of infarct size and postischemic inflammation from ATL-146e, a highly selective adenosine A2A receptor agonist, in reperfused canine myocardium.
Adenosine and adenosine A(2A) receptor agonists have been shown to limit myocardial infarct size when given at vasodilatory doses during reperfusion. This beneficial effect is thought to be due, in part, to stimulation of adenosine A(2A) receptors on inflammatory cells. The specific aims of this study were to determine whether the anti-inflammatory and cardioprotective properties of a novel adenosine A(2A) receptor agonist, ATL-146e (ATL), alone or in combination with the phosphodiesterase IV inhibitor rolipram would occur using very low, nonvasodilating doses. In a canine model of reperfused myocardial infarction, low-dose ATL given alone reduced infarct size by 45% (P < 0.05 vs. control). When ATL was combined with a very low dose of rolipram (0.001 microg.kg(-1).min(-1)), a marked reduction in P-selectin expression and neutrophil infiltration (51% lower; P < 0.001 vs. control) was seen and the infarct size reduction (58% lower; P < 0.01 vs. control) was greater than observed with ATL (45% lower; P < 0.05) or rolipram (33% lower; P < 0.05) alone. In conclusion, a low, nonvasodilating dose of ATL, a highly selective adenosine A(2A) receptor agonist, reduced infarct size after reperfusion. Furthermore, combining ATL and the phosphodiesterase IV inhibitor rolipram reduced infarct size even more than either agent alone. Such combination therapy may be beneficial clinically by potentiating cardioprotection after coronary reperfusion at doses far below those producing vasodilatation or side effects.
3',5'-Cyclic-AMP Phosphodiesterases↗
Molecular imaging identifies regions with microthromboemboli during primary angioplasty in acute coronary thrombosis.
UNLABELLED: Microthromboemboli (MTE) may contribute to the no-reflow phenomenon in acute myocardial infarction (AMI) either spontaneously or after primary percutaneous transluminal coronary angioplasty (PTCA). We hypothesized that myocardial MTE in acute coronary syndromes can be identified on imaging by in vivo (99m)Tc labeling of the coronary thrombus with a compound that binds to the glycoprotein IIb/IIIa present on activated platelets (DMP-444). METHODS: Fifteen dogs underwent left anterior descending coronary artery (LAD) injury in to produce thrombus, whereas 5 control dogs had LAD ligation. Before recanalization, the risk area (RA) and myocardial blood flow (MBF) were measured, and in vivo thrombus labeling was performed using (99m)Tc-labeled DMP-444. Nine of the 15 LAD injury dogs had occlusive thrombus on angiography and underwent PTCA. MBF measurements were repeated 30 and 60 min after recanalization, and (99m)Tc autoradiography (hot spot imaging) was performed ex vivo to determine the extent and magnitude of MTE. RESULTS: The ratio of hot spot size to RA size was higher in the 9 LAD injury dogs with thrombus compared with the 6 dogs with no thrombus (90% +/- 22% vs. 42% +/- 16%; P = 0.005). In control dogs, this ratio was significantly lower (29% +/- 11%; P = 0.05). (99m)Tc activity within the RA was higher in 8 of the 15 coronary injury dogs with AMI compared with those without AMI (1.8 +/- 0.48 vs. 1.24 +/- 0.22; P = 0.02). CONCLUSION: MTE can be detected and quantified after primary PTCA. The infarct size is proportional to the magnitude and extent of MTE, indicating that MTE may contribute to the AMI. Thus, in vivo thrombus labeling during reperfusion may provide important information in patients with AMI that may lead to better adjuvant therapy during PTCA.
Acute Disease↗
99mTc-N-DBODC5, a new myocardial perfusion imaging agent with rapid liver clearance: comparison with 99mTc-sestamibi and 99mTc-tetrofosmin in rats.
UNLABELLED: (99m)Tc-[bis (dimethoxypropylphosphinoethyl)-ethoxyethylamine (PNP5)]-[bis (N-ethoxyethyl)-dithiocarbamato (DBODC)] nitride (N-PNP5-DBODC or N-DBODC5) is a new monocationic myocardial perfusion tracer. We sought to compare the myocardial uptake and clearance kinetics and organ biodistribution of (99m)Tc-N-DBODC5 with (99m)Tc-sestamibi and (99m)Tc-tetrofosmin. METHODS: Seventy-five anesthetized Sprague-Dawley rats were injected intravenously with 22.2-29.6 MBq (99m)Tc-N-DBODC5 (n = 25), (99m)Tc-sestamibi (n = 25), or (99m)Tc-tetrofosmin (n = 25). Rats were euthanized at either 2, 10, 20, 30, or 60 min after injection and gamma-well counting was performed on excised organ (heart, lung, and liver) and blood samples. In 3 additional rats, serial in vivo whole-body gamma-camera imaging with each tracer was performed. RESULTS: (99m)Tc-N-DBODC5 cleared rapidly from the blood pool. At 2 min after injection, (99m)Tc-N-DBODC5 blood activity was significantly lower than either (99m)Tc-sestamibi or (99m)Tc-tetrofosmin (P < 0.01) and remained lower over 60 min. Myocardial (99m)Tc-N-DBODC5 uptake was rapid (2.9% +/- 0.1% injected dose/g at 2 min), and there was no significant clearance over 60 min, similar to (99m)Tc-sestamibi and (99m)Tc-tetrofosmin. All 3 tracers exhibited rapid lung clearance. Importantly, (99m)Tc-N-DBODC5 cleared more rapidly from the liver than either (99m)Tc-sestamibi or (99m)Tc-tetrofosmin. As early as 30 min after injection, (99m)Tc-N-DBODC5 heart-to-liver ratio was 5.7 +/- 1.0 versus 1.6 +/- 0.1 and 2.9 +/- 0.3 for (99m)Tc-sestamibi and (99m)Tc-tetrofosmin (P < 0.05). By 60 min, (99m)Tc-N-DBODC5 heart-to-liver ratio further increased to 18.4 +/- 2.0 compared with 2.6 +/- 0.2 and 5.8 +/- 0.7 for (99m)Tc-sestamibi and (99m)Tc-tetrofosmin (P < 0.001). The rapid blood pool, lung, and liver clearance of (99m)Tc-N-DBODC5 resulted in excellent-quality myocardial images within 30 min after injection. CONCLUSION: (99m)Tc-N-DBODC5 is a promising new myocardial perfusion tracer with superior biodistribution properties. The rapid (99m)Tc-N-DBODC5 liver clearance may shorten the duration of imaging protocols by allowing earlier image acquisition and may markedly reduce the problem of photon scatter from the liver into the inferoapical wall on myocardial images.
Animals↗
Effects of increased lipid concentration and hyperemic blood flow on the intrinsic myocardial washout kinetics of (99m)TcN-NOET.
UNLABELLED: Bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium (V) ((99m)Tc) ((99m)TcN-NOET) is a myocardial perfusion imaging agent demonstrating significant redistribution and currently in phase III clinical trials. Previous studies have suggested that (99m)TcN-NOET is bound intravascularly. Therefore, we sought to determine whether modifications in the vascular compartment would provide further insights into the mechanisms of (99m)TcN-NOET myocardial washout and redistribution. METHODS: (99m)TcN-NOET cardiac washout was studied ex vivo in 15 isolated perfused rat hearts after bolus injection (1.5 MBq) in the absence (n = 6) or presence of bovine serum albumin ([BSA] 0.03%) with (n = 5) or without (n = 4) bound lipids. The intrinsic myocardial washout of the tracer was also studied in vivo in 6 dogs after intracoronary bolus injection of the tracer (0.75 MBq) before and after hyperlipidemia induced by intravenous administration of 300 mL of 20% intralipids (n = 3) or hyperemia induced by intravenous infusion of the adenosine A(2A) receptor agonist ATL-146e (0.3 micro g/kg/min; n = 6). RESULTS: On isolated hearts, there was no significant myocardial washout of (99m)TcN-NOET with Krebs-Henseleit buffer. Addition of BSA without bound lipids resulted in a significant cardiac washout of the tracer (P < 0.001 by repeated measures ANOVA). The presence of lipids bound to BSA further accelerated the washout rate of (99m)TcN-NOET (half-life [t(1/2)], 431.5 +/- 23.2 min vs. 242.9 +/- 63.2 min; P < 0.05). In vivo in dogs, intralipid administration significantly increased the intrinsic washout rate of (99m)TcN-NOET (t(1/2), 108.0 +/- 23.9 min vs. 51.8 +/- 11.8 min; P < 0.05). In addition, vasodilatation with ATL-146e resulted in a 4.9-fold increase in coronary flow (P < 0.05 vs. baseline) and a significantly faster intrinsic (99m)TcN-NOET myocardial washout (t(1/2), 81.1 +/- 12.1 min vs. 40.7 +/- 7.3 min; P < 0.05). CONCLUSION: The myocardial washout kinetics of (99m)TcN-NOET are affected by a variety of intravascular factors, supporting the hypothesis that the tracer is most likely localized on the vascular endothelium. The potential impact of variations in circulating lipid levels among patients on clinical imaging with (99m)TcN-NOET requires further investigation.
Animals↗
Influence of propranolol, enalaprilat, verapamil, and caffeine on adenosine A(2A)-receptor-mediated coronary vasodilation.
OBJECTIVES: The study was done to determine the effects of propranolol, enalaprilat, verapamil, and caffeine on the vasodilatory properties of the adenosine A(2A)-receptor agonist ATL-146e (ATL). BACKGROUND: ATL is a new adenosine A(2A)-receptor agonist proposed as a vasodilator for myocardial stress perfusion imaging. Beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and calcium blockers are commonly used for the treatment of coronary artery disease (CAD), and their effect on ATL-mediated vasodilation is unknown. Dietary intake of caffeine is also common. METHODS: In 19 anesthetized, open-chest dogs, hemodynamic responses to bolus injections of ATL (1.0 microg/kg) and adenosine (60 microg/kg) were recorded before and after administration of propranolol (1.0 mg/kg, ATL only), enalaprilat (0.3 mg/kg, ATL only), caffeine (5.0 mg/kg, ATL only), and verapamil (0.2 mg/kg bolus, ATL and adenosine). RESULTS: Neither propranolol nor enalaprilat attenuated the ATL-mediated vasodilation (225 +/- 86% and 237 +/- 67% increase, respectively, p = NS vs. control). Caffeine had an inhibitory effect (97 +/- 28% increase, p < 0.05 vs. control). Verapamil blunted both ATL- and adenosine-induced vasodilation (63 +/- 20% and 35 +/- 7%, respectively, p < 0.05 vs. baseline), and also inhibited the vasodilation induced by the adenosine triphosphate-sensitive potassium (K(ATP)) channel activator pinacidil. CONCLUSIONS: Beta-blockers and ACE inhibitors do not reduce the maximal coronary flow response to adenosine A(2A)-agonists, whereas verapamil attenuated this vasodilation through inhibition of K(ATP) channels. The inhibitory effect of verapamil and K(ATP) channel inhibitors like glybenclamide on pharmacologic stress using adenosine or adenosine A(2A)-receptor agonists should be evaluated in the clinical setting to determine their potential for reducing the sensitivity of CAD detection with perfusion imaging.
Adrenergic beta-Antagonists↗
Assessment of myocardial inflammation produced by experimental coronary occlusion and reperfusion with 99mTc-RP517, a new leukotriene B4 receptor antagonist that preferentially labels neutrophils in vivo.
BACKGROUND: 99mTc-RP517 is a new leukotriene B4 (LTB4) receptor antagonist developed for imaging acute inflammation or infection. A unique property of 99mTc-RP517 is its ability to label white blood cells in vivo after intravenous injection. The goals of this study were to determine relative 99mTc-RP517 binding to human leukocyte subtypes and the 99mTc-RP517 uptake pattern in canine myocardium where inflammation was induced by either coronary occlusion and reperfusion or tumor necrosis factor alpha (TNFalpha) injection. METHODS AND RESULTS: Fluorescence-activated cell sorter analysis was performed on whole human blood (n=2) and isolated neutrophils (n= 4) with a fluorescent analog of 99mTc-RP517, [F]-RP517. In whole blood, [F]-RP517 (500 nmol/L) preferentially labeled neutrophils. On isolated neutrophils, [F]-RP517 (10 nmol/L) binding was inhibited by 44% when LTB4 (400 nmol/L) was added. 99mTc-RP517 was injected intravenously in anesthetized, open-chest dogs before coronary occlusion (90 minutes) and reperfusion (120 minutes) (n=9) or before intramyocardial TNFalpha injection (n=3). Ex vivo images of heart slices were acquired. The left ventricle was divided into 72 segments for flow and 99mTc-RP517 uptake analysis. There was an inverse exponential relationship between 99mTc-RP517 uptake and occlusion flow (r=0.73). In the same 15 segments, 99mTc-RP517 uptake was highly correlated with the neutrophil enzyme myeloperoxidase (r=0.91). Ex vivo images revealed tracer uptake in the reperfused area (ischemic to normal count ratio=2.7+/-0.2). CONCLUSIONS: RP517 binds to the neutrophil LTB4 receptor after intravenous injection. After reperfusion, 99mTc-RP517 uptake correlated with myeloperoxidase and was observed on ex vivo images, indicating that this tracer may have potential as an inflammation-imaging agent.
Animals↗
Arbutamine stress perfusion imaging in dogs with critical coronary artery stenoses: (99m)Tc-sestamibi versus (201)Tl.
UNLABELLED: Having previously shown that dobutamine reduces (99m)Tc-methoxyisobutylisonitrile (sestamibi [MIBI]) uptake in normal myocardium by elevating intracellular calcium, we hypothesized that arbutamine, which has less inotropic effect than dobutamine, might cause less reduction in MIBI uptake, thereby improving defect contrast. In this study using a canine model, we compared the effects of arbutamine stress on myocardial blood flow, myocardial MIBI uptake, and systolic thickening in the presence of a coronary artery stenosis. METHODS: Arbutamine was infused (0.5-250 ng/kg/min) in 8 open-chest dogs with critical coronary stenoses that abolished flow reserve. At the time of peak arbutamine effect, MIBI (296 MBq), (201)Tl (27.75 MBq), and microspheres were coinjected. The dogs were killed 5 min later, and myocardial tracer activities and flow were quantified by well counting. Ex vivo imaging of heart slices was also performed. RESULTS: Arbutamine increased mean heart rate, peak positive left ventricular pressure and its first time-derivative, and normal-zone myocardial thickening. Stenotic zone flow and thickening did not increase during arbutamine infusion. MIBI uptake versus flow was significantly lower than (201)Tl uptake at the same flow values. By imaging, defect magnitude (stenotic/normal) was greater for (201)Tl than MIBI (0.57 vs. 0.77; P < 0.001) [corrected]. CONCLUSION: In the presence of coronary stenoses that abolished regional flow reserve, myocardial uptake of MIBI, compared with (201)Tl, significantly underestimated the arbutamine-induced flow heterogeneity. The attenuation of MIBI uptake and diminished defect contrast during arbutamine stress were comparable with those previously reported for dobutamine stress.
Animals↗
Accuracy of detection of myocardial viability and residual infarct vessel stenoses with rest Tl-201 and adenosine Tc-99m sestamibi imaging after coronary reperfusion in dogs with experimental acute myocardial infarction.
BACKGROUND: We sought to determine whether a dual-isotope imaging strategy (rest thallium 201/stress technetium 99m sestamibi) might be useful for assessing myocardial viability and residual ischemia in the infarct zone very early after reperfusion. METHODS AND RESULTS: Fifteen open-chest dogs had left anterior descending coronary artery occlusion for 60 minutes, followed by full reperfusion (group 1, n = 8) or reperfusion through a residual critical stenosis (group 2, n = 7). Tl-201 was injected at rest 45 minutes after reperfusion, and initial and 2-hour redistribution images were acquired. Tc-99m sestamibi was then injected during vasodilator stress, followed by imaging. Infarct size was similar in both groups (risk area, 21% +/- 4% vs 22% +/- 3%). Rest Tl-201 defect count ratios (left anterior descending coronary artery/left circumflex artery) were comparable (0.71 +/- 0.03 vs 0.74 +/- 0.02) and reflected infarct size. With vasodilation, Tc-99m sestamibi defect count ratio in group 1 (0.71 +/- 0.02) was comparable to rest Tl-201 and was significantly greater than in group 2 (0.62 +/- 0.02) with residual stenoses (P <.01). Although vasodilator Tc-99m sestamibi imaging unmasked the presence of residual stenoses, Tc-99m sestamibi uptake underestimated their functional severity (flow ratio, 0.38 +/- 0.03). CONCLUSIONS: Dual-isotope imaging very early after reperfusion may have limited utility for detecting residual stenoses in the infarct zone. Underestimation of the flow disparity by Tc-99m sestamibi may make the detection of stenoses more difficult, and impaired flow reserve after ischemic insult may complicate the detection of fully reperfused segments.
Animals↗
Pharmacologic stress testing: new methods and new agents.
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Adenosine↗