Early detection of anthracycline-induced cardiotoxicity using [68 Ga]Ga-FAPI-04 imaging

Purpose: Anthracycline-induced cardiotoxicity (AIC), whose major manifestation is diffuse myocardial fibrosis, is an important clinical problem in Cancer therapy. Therefore, early identification and treatment are clinically important. This study aims to explore the feasibility of using ⁶⁸ Ga-labelled fibroblast activation protein (FAP) inhibitor ([⁶⁸ Ga]Ga-FAPI) positron emission tomography/computed tomography (PET/CT) for the early identification of the fibrotic process and guidance of antifibrosis therapy in AIC.

Methods: An AIC rat model was induced by the intravascular administration of doxorubicin (DOX) once per week for 1, 2, 3 and 6 weeks (2.5 mg/kg/injection, groups 1-4), whereas intravascular saline was administered to control rats. Experimental and control groups (n = 4) underwent [⁶⁸ Ga]Ga-FAPI PET/CT following disease induction. Groups 5 and 6 received DOX injections for 3 and 6 weeks, treated with angiotensin-converting Enzyme (ACE) inhibitor starting at 3 weeks, treated with enalapril (20 mg/kg, gastric gavage) daily and underwent echocardiography and [⁶⁸ Ga]Ga-FAPI PET/CT at 3 weeks after treatment. Rat hearts were subjected to haematoxylin and eosin staining, FAP immunohistochemistry, Sirius red staining and Masson's trichrome staining to investigate the pathological changes and deposition of collagen fibres. Rat blood was sampled weekly for the enzyme-linked immunosorbent assay of various markers of myocardial injury, such as plasma cardiac troponin I, B-type natriuretic peptide and angiotensin II.

Results: [⁶⁸ Ga]Ga-FAPI-04 uptake by the heart was significantly higher in the cardiotoxicity group than in the control group at weeks 3 (SUVmax: 1.21 ± 0.23 vs 0.67 ± 0.01, P < 0.05) and 6 (SUVmax: 1.48 ± 0.28 vs 0.67 ± 0.08, P < 0.001), whereas left ventricle ejection fraction (LVEF) did not significantly differ between normal and AIC rats at week 3. FAP⁺ expression began to increase starting at week 3, before irreversible fibrotic changes were detected, until week 6. After 3 weeks of enalapril treatment, [⁶⁸ Ga]Ga-FAPI-04 accumulation decreased in groups 5 and 6 (SUVmax decreased from 1.21 ± 0.23 to 0.77 ± 0.08 and 1.48 ± 0.28 to 1.09 ± 1.06, P < 0.05). Cardiac function was preserved (LVEF was 75.7% ± 7.38% in group 3 vs 74.5% ± 2.45% in group 5, P > 0.05) and improved (LVEF increased from 51.6% ± 9.03% in group 4 to 65.2% ± 4.27% in group 6, P < 0.05), and myocardial fibrosis attenuated (from 6.5% ± 1.2% in group 4 to 4.31% ± 0.37% in group 6, P < 0.01).

Conclusion: [⁶⁸ Ga]Ga-FAPI PET/CT can be used for the early detection of active myocardial fibrosis in AIC and the evaluation of the efficacy of therapeutic interventions. Early treatment guided by [⁶⁸ Ga]Ga-FAPI PET/CT may reduce anthracycline-induced myocardial injury and improve heart function.

ACE inhibition; Anthracycline-induced cardiotoxicity; Fibroblast activation protein; PET/CT; [68 Ga]Ga-FAPI.