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Effects of Increased Lipid Concentration and Hyperemic Blood Flow on the Intrinsic Myocardial Washout Kinetics of ^99mTcN-NOET

Cardiovascular Division, University of Virginia Health System, Charlottesville, Virginia

Bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium (V) (^99mTc) (^99mTcN-NOET) is a myocardial perfusion imaging agent demonstrating significant redistribution and currently in phase III clinical trials. Previous studies have suggested that ^99mTcN-NOET is bound intravascularly. Therefore, we sought to determine whether modifications in the vascular compartment would provide further insights into the mechanisms of ^99mTcN-NOET myocardial washout and redistribution. Methods:^99mTcN-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 µg/kg/min; n = 6). Results: On isolated hearts, there was no significant myocardial washout of ^99mTcN-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 ^99mTcN-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 ^99mTcN-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 ^99mTcN-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 ^99mTcN-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 ^99mTcN-NOET requires further investigation.

Key Words: bis(N-ethoxy,N-ethyldithiocarbamato)nitrido technetium (V) (^99mTc) • myocardial kinetics • lipids • redistribution • mechanisms