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

Abstract

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.

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

“…Despite a reduction in FDG-positive tumor burden, the uptake of glucose by individual tumor masses remained consistent, suggesting that tumor growth is arrested at the start of insulin supplementation (i.e., 4-7 days after cell injection), but metabolic activity was maintained in the existing tumor. This observation may also reflect the late analysis time point (50-60 minutes after 18F-FDG administration), as time activity curves indicate earlier saturation of 18F-FDG uptake (i.e., within 30 minutes) (16). Notably, in both tumor cell types (B16F10 and C26), glucose uptake was insulin independent and addition of insulin did not stimulate glucose uptake or cell proliferation.…”

“…Regions of interest (ROI) were defined using set parameters for the myocardium and left atrial blood pool as image-derived input function (16). Tissue 18 F-FDG uptake at 50-60 minutes after injection was analyzed semiquantitatively, as percentage injected dose per gram (%ID/g), and calculated as follows: activity concentration (Bq/ml)/injected Dose (Bq) × 100%.…”

Longitudinal evaluation of myocardial glucose metabolism and contractile function in obese type 2 diabetic db/db mice using small-animal dynamic 18F-FDG PET and echocardiography

“…In our study, 17.5 % of PET images were uninterpretable, mostly because of non-, scarce or heterogeneous myocardial 18 F-FDG uptake. Although several methods measuring the input function, such as a hybrid modeling approach [ 44 ] and an inferior vena cava time-activity curve [ 45 , 46 ], have been proposed, further validations should be undertaken. The LC used to account for differences in transport and phosphorylation rates between 18 F-FDG and glucose is an important parameter in the determination of MRGlu in the dynamic PET [ 47 , 48 ].…”

Cardiac Metabolic Deregulation Induced by the Tyrosine Kinase Receptor Inhibitor Sunitinib is rescued by Endothelin Receptor Antagonism

“…FDG accumulation was quantified as mean Standard Uptake Value (SUV, ratio of the radioactivity concentration in myocardium on the whole body concentration of the injected radioactivity) between 45 and 60min post-injection in 3D volumes-of-interest (VOI) delineated semi-automatically by iso-contours at 45% threshold of maximal value in the myocardium on PET/CT fusion slices using the PMOD software package (PMOD Technologies Ltd, Zürich, Switzerland). Metabolic flux was quantified using compartmental modeling tool of PMOD software using the same VOI as above and a VOI semi-automatically delineated on the vena cava for the arterial input function as previously described 65 . Metabolic rate of glucose were calculated by the multiplication of the metabolic flux by [plasma glucose (mmol/l)/lumped constant (fixed at 0.69)].…”