Abstract
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Objectives Anthracycline-based chemotherapy of cancer induces serious secondary effects, such as progressive congestive heart failure. Early detection of signs of cardiotoxicity is crucial to avoid irreversible damages. Cardiac PET imaging was used in a mouse model of doxorubicin-induced cardiotoxicity to identify early biomarkers of heart failure.
Methods Administration of 40 mg/kg cumulative dose of doxorubicin over 7 weeks was used to induce cardiotoxicity in Balb/c mice (n=9). Control (n=9) and treated mice were followed by PET during 17 weeks to monitor cardiac parameters. 18F-FDG was used to measure the left ventricular ejection fraction (LVEF) and determine the myocardial radiotracer uptake rate (Ki). 11C-acetoacetate, a ketone body tracer partly following the acetate pathways, was used to measure the uptake (K1) and clearance (k2) rates as indexes of perfusion and oxidative metabolism.
Results Normal values of LVEF, Ki, K1 and k2 were 79.4 ± 4.9%, 0.10 ± 0.02 min-1, 3.4 ± 0.4 min-1 and 1.3 ± 0.2 min-1, respectively, and remained fairly constant throughout the study in the control group. After 9 weeks, K1 and k2 gradually dropped to reach 2.3 ± 0.3 min-1 and 0.8 ± 0.1 min-1 in the treated group. These changes were shortly followed by a gradual drop of LVEF to 49.3 ± 2.5% at the end of the follow-up period, reflecting a significant increase of ventricular volumes. This was paralleled by a steep Ki increase becoming significant relative to normal values around the 11th week. These findings suggesting heart failure were confirmed by histopathology at the end of follow-up.
Conclusions By monitoring several cardiac parameters noninvasively, PET imaging enables early functional and metabolic biomarkers of cardiotoxicity to be detected during doxorubicin chemotherapy.