Dynamic SPECT imaging of 123I-mIBG for early detection of doxorubicin-induced cardiotoxicity in dogs

101 Objectives: Doxorubicin is an effective chemotherapy agent, but induces cardiotoxicity in up to 26% of patients, which is dose-dependent, generally irreversible, and often manifests as heart failure. Assessment of left ventricular ejection fraction (LVEF) is the clinical standard for assessing cardiotoxicity, but is not sensitive for early detection due to large technical and physiological variability. To develop a more effective tool for early detection of cardiotoxicity, we have investigated absolute quantification of cardiac pre-sympathetic nerve function using 4D dynamic SPECT imaging of 123I-mIBG in canines chronically receiving doxorubicin. Methods: Six healthy dogs were treated with doxorubicin HCl at the dose of 1 mg/kg weekly for 12-14 weeks. Dynamic SPECT 123I-mIBG scans (GE Discovery 570c SPECT/CT) were performed over a 3-h period in anesthetized animals at baseline and at cumulative doxorubicin doses of 3-5, 7-9, 12-14 mg/kg. Arterial blood samples were taken and analyzed by HPLC for plasma metabolite correction. Ex vivo tissue metabolite analysis was performed at the study end-point for the left atrium (LA) and LV in two animals. List-mode SPECT data were reframed into dynamic frames and reconstructed using the MLEM algorithm with corrections for attenuation, scatter, resolution recovery, and decay. Myocardium and blood pool regions of interest were drawn to obtain the input function and myocardial time activity curve (TAC). Plasma parent fraction data were averaged among studies for each dog and used in the metabolite correction of the input function. Both 2T model and likelihood estimation in graphical analysis (LEGA) technique were used for kinetic modeling to calculate the volume of distribution (VT). VT parametric images were obtained using voxel-by-voxel LEGA modeling. In addition, transthoracic echocardiography (TTE, Philips iE33 Ultrasound) was performed in awake animals at the same imaging time points as 123I-mIBG to determine LVEF. LVEF, myocardial uptake in both static and parametric VT images, and myocardium/blood ratio in static images were compared across different cumulative doxorubicin doses. Results: Plasma parent fraction data were similar for the same dog at different cumulative doxorubicin doses, indicating doxorubicin has little impact on peripheral 123I-mIBG metabolism. Chronic doxorubicin administration also had little effect on myocardial 123I-mIBG metabolism, as the tissue parent fraction in LV and LA were 96.0±0.5% and 96.1±1.0%, respectively at the study end-point. Both 2T and LEGA models fitted the myocardial TAC well and generated similar VT results. Good-quality VT images were obtained using voxel-by-voxel LEGA fitting. In 5/6 dogs, the reductions of myocardial uptake in static images were moderate and not significant (8%, p=0.2 at cumulative doxorubicin doses of 3-5 mg/kg; 20%, p=0.1 at 7-9 mg/kg), while myocardial VT showed larger and significant reductions as early as 3-5 mg/kg (39%, p=0.02). The myocardium/blood ratio in static image at around 3-h post-injection showed similar reductions (34%, p=0.02 at 3-5 mg/kg) as VT, indicating that this ratio may be used as a simplified index for VT since 123I-mIBG clearance and metabolism did not change with doxorubicin dosing. However, this assumption should be carefully investigated in future human studies. On the other hand, LVEF was not sensitive to detect cardiotoxicity, as it did not decrease in most dogs until reaching cumulative doxorubicin doses of 12-14 mg/kg. Conclusion: SPECT dynamic imaging of 123I-mIBG can be used as an effective tool in the early detection of doxorubicin-induced cardiotoxicity, since 123I-mIBG quantification using VT decreased as early as cumulative doxorubicin doses of 3-5 mg/kg and preceded systolic dysfunction as derived by echocardiography. Additional large-animal studies are ongoing to further confirm this conclusion.