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

Abstract 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 [ 64 Cu]Cu-DOTATATE, targeting somatostatin receptor-expressing macrophages, enables identification of early changes during CTRCD development. Male Lewis rats (220 ± 20 g) received intravenous doxorubicin (10.5, n = 10 or 12.5 mg/kg, n = 5), with untreated controls ( n = 4). Cardiac function and tracer uptake were assessed by simultaneous PET/MR at baseline, week four, and week seven. Blood and tissue samples were collected for hematologic and transcriptomic analyses. Doxorubicin treatment induced CTRCD with a > 10% points decline in left ventricular ejection fraction (LVEF), however, only one rat survived in the 12.5 mg/kg dose group. Cardiac [ 64 Cu]Cu-DOTATATE uptake increased dose-dependently and week four uptake correlated with LVEF at week seven. Hematologic analysis revealed anemia and immune cell alterations. Transcriptomics showed enrichment of pathways related to engulfment of apoptotic cells, extracellular remodeling and vascular perturbations. Increased myocardial [ 64 Cu]Cu-DOTATATE uptake was associated with later decline in LVEF, suggesting that [ 64 Cu]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.