Increased myocardial [⁶⁴Cu]Cu-DOTATATE uptake is associated with subsequent cancer therapy- related cardiac dysfunction in rats

Background Doxorubicin-induced cancer therapy-related cardiac dysfunction (CTRCD) remains a major clinical challenge, often progressing to heart failure. Early detection is limited by the lack of sensitive imaging biomarkers. This exploratory study evaluated whether positron emission tomography/magnetic resonance imaging (PET/MR) with [⁶⁴Cu]Cu-DOTATATE, targeting somatostatin receptor–expressing macrophages, enables identification of early changes during CTRCD development. Methods Male Lewis rats (220 ± 20 g) received intravenous doxorubicin (10.5 or 12.5 mg/kg), with untreated controls. Cardiac function and tracer uptake were assessed by simultaneous PET/MR at baseline, week 4, and week 7. Blood and tissue samples were collected for hematologic and transcriptomic analyses. Results Doxorubicin treatment induced CTRCD with a > 10% points decline in left ventricular ejection fraction (LVEF). Cardiac [⁶⁴Cu]Cu-DOTATATE uptake increased dose-dependently and week 4 uptake correlated with LVEF at week 7. Hematologic analysis revealed anemia and immune cell alterations. Transcriptomics showed signatures of mitochondrial dysfunction, extracellular remodeling, and cardiomyopathy. Conclusion Increased myocardial [⁶⁴Cu]Cu-DOTATATE uptake was associated with later decline in LVEF, suggesting that [⁶⁴Cu]Cu-DOTATATE PET/MR may capture early changes during CTRCD development. Larger studies are needed to determine if this approach can guide cardioprotective interventions and improve clinical outcomes.