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Imaging of VEGF Receptor in a Rat Myocardial Infarction Model Using PET

¹ Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Division of Nuclear Medicine, Stanford University, Stanford, California; ² Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; ³ Department of Bioengineering, Stanford University, Stanford, California; ⁴ Department of Cardiology, Stanford University, Stanford, California; and ⁵ Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston, Texas

View larger version (58K): [in this window] [in a new window]   FIGURE 1.  Cardiac functional assessment using 18F-FDG PET and high-resolution ultrasound (at frequency of 30 MHz). (Top) 18F-FDG PET of sham-operated animal (A) and animal after MI (B). Sham operation did not induce any 18F-FDG defect, whereas MI was associated with medium-sized defect in anterolateral wall (white arrow). (Bottom) M-mode ultrasound at midventricle level in sham-operated animal (C) and animal after MI (D). After MI, there was akinesis of anterolateral wall and significant decrease in fractional shortening compared with that of sham-operated animals.

View larger version (57K): [in this window] [in a new window]   FIGURE 2.  Myocardial origin of 64Cu-DOTA-VEGF121 PET signal after MI. (Top) Representative coregistered images of microCT (left), PET (right), and fused PET/CT image (center) in MI animal clearly demonstrates that the 64Cu-DOTA-VEGF121 signal detected with PET corresponds to anterolateral myocardium (PET and fused images, red arrow) and clearly separated from intercostal muscle layer (microCT image, white arrow). There is also increased uptake in area of surgical wound (PET image, arrowhead). (Bottom) Representative images of 64Cu-DOTA-VEGF121 (left), 18F-FDG (right), and 64Cu-DOTA-VEGF121/18F-FDG fused image (middle). 18F-FDG scan shows that coronary artery ligation resulted in lack of 18F-FDG uptake (yellow arrow) and that uptake of 64Cu-DOTA-VEGF121 occurs in areas supplied by ligated coronary artery (turquoise arrow). Fusion of both scans results in complementation of 18F-FDG and 64Cu-DOTA-VEGF121 signals. There is also increased uptake in area of surgical wound (arrowhead).

View larger version (45K): [in this window] [in a new window]   FIGURE 3.  (Top) Representative images at baseline (left), animals after MI (middle left), and sham-operated animals (middle right) show difference in myocardial uptake in MI animals compared with baseline and sham animals. Red arrow shows the 64Cu-DOTA-VEGF121 signal from myocardium (seen only in MI animals), and arrowheads show 64Cu-DOTA-VEGF121 signal from the surgical wound (muscle layer), which is present in both sham-operated and MI animals. Right panel shows typical image acquired using VEGFmutant, with minimal uptake, supporting the specificity of 64Cu-DOTA-VEGF121 probe for VEGFRs. (Middle) Representative images correspond to 1 animal of MI group illustrating uptake of 64Cu-DOTA-VEGF121 over time (in days after induction of MI), clearly showing time-dependent effect on uptake of 64Cu-DOTA-VEGF121. Red arrow points to myocardial upake, whereas white arrowhead points to chest wall muscular layer uptake. (Bottom) Quantification of 64Cu-DOTA-VEGF121 after MI over time, expressed in %ID/g of tissue. 64Cu-DOTA-VEGF121 uptake was highest on day 3 postoperatively (compared with baseline, day –4) and continues to be elevated until day 17 postoperatively. 64Cu-DOTA-VEGF121 uptake was also significantly different compared with sham-operated animals and VEGFmutant. *P < 0.05 compared with baseline; ¥P < 0.05 compared with sham and 64Cu-DOTA-VEGF121; ¶P < 0.05 compared with VEGFmutant and 64Cu-DOTA-VEGF121.

View larger version (36K): [in this window] [in a new window]   FIGURE 4.  Ex vivo studies. (A) Autoradiography of 30-µm myocardial slices of both sham-operated (left) and MI (right) animals after injection of 64Cu-DOTA-VEGF121 shows increased signal in anterolateral wall of LV of MI animals, whereas no activity is detected in sham group. Red arrows point to area affected by ligated artery (anterolateral wall), clearly showing the myocardial origin of signal observed. (B) Immunofluorescence staining for VEGFR-1 (left) and VEGFR-2 (right) in sham-operated and MI animals (on days 3 and 17 after MI). MI is associated with marked increase in VEGFR-1 and VEGFR-2 immunostaining, which was higher than that of sham animals. VEGFR expression is higher on day 3 and diminishes over time, similar to what it is observed with PET. MIN = minimum; MAX = maximum.