Clinically relevant strategies for lowering cardiomyocyte glucose uptake for 18F-FDG imaging of myocardial inflammation in mice

Thackeray, James T.; Bankstahl, Jens P.; Wang, Yong; Wollert, Kai C.; Bengel, Frank M.

doi:10.1007/s00259-014-2956-7

Cited by 50 publications

(52 citation statements)

References 18 publications

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“…However, the robust uptake by healthy cardiomyocytes presents a considerable challenge for image acquisition and analysis, and necessitates strategies to suppress endogenous myocyte tracer uptake such as ketamine/xylazine anesthesia or extended fasting in rodents 8, 25, or high fat diet preparations and heparin administration in humans 5, 26. Such preparations have variable success and often lack clear translation between preclinical evaluation and clinical application.…”

Section: Discussionmentioning

confidence: 99%

“…However, FDG uptake by viable cardiomyocytes may be a confounding factor which obscures the inflammatory signal and necessitates the use of protocols to suppress endogenous myocyte FDG transport 8, 9. This limitation of FDG-based inflammation imaging stimulates the search for alternative radiotracers for the evaluation of myocardial inflammation.…”

Section: Introductionmentioning

confidence: 99%

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Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

Thackeray¹,

Bankstahl²,

Wang³

et al. 2016

Theranostics

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Acute tissue inflammation after myocardial infarction influences healing and remodeling and has been identified as a target for novel therapies. Molecular imaging holds promise for guidance of such therapies. The amino acid 11C-methionine is a clinically approved agent which is thought to accumulate in macrophages, but not in healthy myocytes. We assessed the suitability of positron emission tomography (PET) with 11C-methionine for imaging post-MI inflammation, from cell to mouse to man. Uptake assays demonstrated 7-fold higher 11C-methionine uptake by polarized pro-inflammatory M1 macrophages over anti-inflammatory M2 subtypes (p<0.001). C57Bl/6 mice (n=27) underwent coronary artery ligation or no surgery. Serial 11C-methionine PET was performed 3, 5 and 7d later. MI mice exhibited a perfusion defect in 32-50% of the left ventricle (LV). PET detected increased 11C-methionine accumulation in the infarct territory at 3d (5.9±0.9%ID/g vs 4.7±0.9 in remote myocardium, and 2.6±0.5 in healthy mice; p<0.05 and <0.01 respectively), which declined by d7 post-MI (4.3±0.6 in infarct, 3.4±0.8 in remote; p=0.03 vs 3d, p=0.08 vs healthy). Increased 11C-methionine uptake was associated with macrophage infiltration of damaged myocardium. Treatment with anti-integrin antibodies (anti-CD11a, -CD11b, -CD49d; 100µg) lowered macrophage content by 56% and 11C-methionine uptake by 46% at 3d post-MI. A patient study at 3d after ST-elevation MI and early reperfusion confirmed elevated 11C-methionine uptake in the hypoperfused myocardial region. Targeting of elevated amino acid metabolism in pro-inflammatory M1 macrophages enables PET imaging-derived demarcation of tissue inflammation after MI. 11C-methionine-based molecular imaging may assist in the translation of novel image-guided, inflammation-targeted regenerative therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

Thackeray¹,

Bankstahl²,

Wang³

et al. 2016

Theranostics

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“…Third, most of the mice evaluated in the present study were under continuous isoflurane anesthesia, which has a pronounced stimulatory effect on myocardial glucose uptake (22,23). Patlak kinetics are certainly augmented by this anesthesia effect, though uptake differences occurring with metabolic preparation or in cardiovascular disease models remain discernible, if somewhat blunted as with fasting (23).…”

Section: Discussionmentioning

confidence: 99%

Impact of Image-Derived Input Function and Fit Time Intervals on Patlak Quantification of Myocardial Glucose Uptake in Mice

2015

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Limited blood volume in mice precludes repeated sampling, rendering a reliable image-derived input function (IDIF) desirable for quantification of glucose uptake. We aimed to compare different IDIF volumes and to evaluate the effects of changing fit time interval on Patlak uptake kinetics in hearts of healthy mice. Methods: C57BL/6 mice (n 5 27) were studied under a range of metabolic conditions: no intervention (ctl), overnight fasting, insulin and glucose (6 mU/g, 1 mg/g) under isoflurane, and under ketamine-xylazine anesthesia to suppress glucose uptake. Dynamic PET imaging with 18 F-FDG (7.7 ± 0.9 MBq) was conducted. Images were analyzed using left ventricle cavity, left atrial cavity, or inferior vena cava as the IDIF. Patlak analysis was conducted using variable fit time intervals: automated fit, fit from 10 to 60 min (late), fit from 2 to 30 min (early), or fit from 2 to 10 min (very early). Results: Both the ventricle and the atrial cavities displayed spill-in from the myocardium in late frames as compared with the vena cava (percentage injected dose per gram, ctl: 21.4 ± 6.1 vs. 10.0 ± 3.9 vs. 2.5 ± 0.3, P , 0.001). Higher and more rapid passage of peak activity was observed in the vena cava, but the area under the curve over 2 min was similar. The Patlak slope was significantly higher for the vena cava than atrial IDIF (mL/g/min, ctl: 0.11 ± 0.02 vs. 0.07 ± 0.01; fasting: 0.09 ± 0.03 vs. 0.06 ± 0.02; insulin: 0.52 ± 0.09 vs. 0.23 ± 0.12; ketamine-xylazine: 0.001 ± 0.001 vs. 0.002 ± 0.002; P , 0.01). The rate of glucose uptake was similarly elevated depending on the IDIF (P , 0.01). The various IDIF Patlak values were significantly correlated (r 5 0.867, P , 0.001). Automated fit performed reliably in untreated, fasted, and ketamine-xylazine-treated mice, with no statistical difference compared with late, early, or very early fits. The Patlak composite rate constant (K i ) was markedly underestimated with automated and late fit after acute insulin treatment, reflecting the rapid early 18 F-FDG uptake. Conclusion: The choice of IDIF has a profound effect on Patlak kinetics and calculated 18 F-FDG uptake. Adjustment of the time interval for fit may be necessary for accurate calculations, particularly with acute insulin treatment. Even without partial-volume correction, the inferior vena cava provides a reliable and reproducible IDIF for Patlak analysis of myocardial glucose uptake in mice.

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“…Dynamic PET scans in nonfasted mice were conducted at baseline (7-14 days before implant) and early (7 days after implant) and advanced cancer time points (11-21 days after implant) under continuous isoflurane anesthesia (1.5% at 0.6 l/min O 2 ) as previously described (30). Briefly, mice were positioned prone on the scanner bed and centered in the PET camera (Inveon DPET, Siemens) field of view.…”

Section: Methodsmentioning

confidence: 99%

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

Thackeray¹,

Pietzsch²,

Stapel³

et al. 2017

JCI Insight

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Clinically relevant strategies for lowering cardiomyocyte glucose uptake for 18F-FDG imaging of myocardial inflammation in mice

Cited by 50 publications

References 18 publications

Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

Targeting Amino Acid Metabolism for Molecular Imaging of Inflammation Early After Myocardial Infarction

Impact of Image-Derived Input Function and Fit Time Intervals on Patlak Quantification of Myocardial Glucose Uptake in Mice

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

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