Potential of [64Cu]Cu-RGD PET/CT for detection of cardiotoxicity in a rat model of doxorubicin induced heart failure

Type of funding sources: Foundation. Main funding source(s): This work was supported by the European Union’s Horizon 2020 research and innovation program (ERC Advanced Grant) and the Novo Nordisk Foundation.

Doxorubicin is a common and highly effective chemotherapeutic. However, its use is limited by cardiotoxic side effects, which occur in 5-23 % of patients treated, and the lack of methods to detect these conditions at early time points.

In the present study, we evaluated if [64Cu]Cu-RGD positron emission tomography/computed tomography (PET/CT) could detect cardiotoxicity in a rat model of doxorubicin induced heart failure.

Male Lewis rats were divided into two groups and treated with either a cumulative dose of 15 mg/kg doxorubicin (n = 15) or left untreated (n = 10). Cardiac anatomy and function were assessed using magnetic resonance imaging at baseline and in week eight. [64Cu]Cu-RGD PET/CT scans were performed in week four. All animal experiments were approved by the Danish Animal Experiments Inspectorate (authorization number 2016-15-0201-00920) and study performed in accordance with the ARRIVA guidelines.

Doxorubicin treatment led to a decline in left ventricular ejection fraction (66.5 ± 0.85 % to 46.67 ± 0.84 %, p < 0.001), as well as an increase in septal and thymic uptake of [64Cu]Cu-RGD (0.46 ± 0.02 vs. 0.29 ± 0.04, <0.001 and 0.87 ± 0.03 vs. 0.40 ± 0.07, p < 0.001, respectively). In addition, doxorubicin altered the cardiac gene expression, led to infiltration of macrophages (0.90 ± 0.12 % vs. 0.30 ± 0.04 %, p <0.001), reduced endothelial content (0.19 ± 0.02 % vs. 0.47 ± 0.07 %, p < 0.001), and increased interstitial fibrosis (13.6 ± 0.86 % vs. 10.5 ± 0.66 %, p = 0.014). Furthermore, concentrations of inflammatory plasma proteins were increased in the doxorubicin group.

Doxorubicin treatment resulted in the development of cardiotoxicity and heart failure, which could be detected using [64Cu]Cu-RGD PET/CT at early time points. [64Cu]Cu-RGD uptake in the myocardial septum and thymus predicted low left ventricular ejection fraction in week eight, thus it may serve as an early marker of cardiotoxicity.

Experimental setup and timeline