Clinically relevant strategies for lowering cardiomyocyte glucose uptake for 18F-FDG imaging of myocardial inflammation in mice.
OBJECTIVE
Myocardial inflammation is an emerging target for novel therapies and thus for molecular imaging. Positron emission tomography (PET) with (18)F-fluorodeoxyglucose (FDG) has been employed, but requires an approach for suppression of cardiomyocyte uptake. We tested clinically viable strategies for their suitability in mouse models in order to optimize preclinical imaging protocols.


METHODS
C57BL/6 mice (n = 56) underwent FDG PET under various conditions. In healthy animals, the effect of low-dose (5 units/kg) or high-dose (500 units/kg, 15 min prior) intravenous heparin, extended fasting (18 h) and the impact of conscious injection with limited, late application of isoflurane anaesthesia after 40 min of conscious uptake were examined in comparison to ketamine/xylazine anaesthesia. Conscious injection/uptake strategies were further evaluated at 3 days after permanent coronary artery occlusion.


RESULTS
Under continuous isoflurane anaesthesia, neither heparin administration nor extended fasting significantly impacted myocardial (18)F-FDG accumulation. Injection with 40 min uptake in awake mice resulted in a marked reduction of global myocardial (18)F-FDG uptake compared to standard isoflurane anaesthesia (5.7 ± 1.1 %ID/g vs 30.2 ± 7.9 %ID/g, p < 0.01). Addition of heparin and fasting further reduced uptake compared to conscious injection alone (3.8 ± 1.5 %ID/g, p < 0.01) similar to ketamine/xylazine (2.4 ± 2.2 %ID/g, p < 0.001). In the inflammatory phase, 3 days after myocardial infarction, conscious injection/uptake with and without heparin/fasting identified a marked increase in myocardial (18)F-FDG accumulation that was similar to that observed under ketamine/xylazine.


CONCLUSIONS
Continuous isoflurane anaesthesia obscures any suppressive effect of heparin or fasting on cardiomyocyte glucose utilization. Conscious injection of FDG in rodents significantly reduces cardiomyocyte uptake and enables further suppression by heparin and fasting, similar to clinical observations. In contrast to ketamine/xylazine, this represents a more physiological, translatable strategy for suppression of cardiomyocyte (18)F-FDG uptake when targeting myocardial inflammation.
Department of Nuclear Medicine, Hanover Medical School, Carl Neuberg-Str. 1, 30625, Hanover, Germany.
James T
JT
Thackeray
Jens P
JP
Bankstahl
Yong
Y
Wang
Kai C
KC
Wollert
Frank M
FM
Bengel
D018681:Anesthetics, General / Q000494:pharmacology; D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D005215:Fasting; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D005947:Glucose / Q000378:metabolism*; D006493:Heparin / Q000494:pharmacology; D007249:Inflammation / Q000000981:diagnostic imaging; D007530:Isoflurane / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D014991:Xylazine / Q000494:pharmacology
D018681:Anesthetics, General; D000925:Anticoagulants; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D014991:Xylazine; D007649:Ketamine; D006493:Heparin; D007530:Isoflurane; D005947:Glucose