Noninvasive Monitoring of Reparative Fibrosis after Myocardial Infarction in Rats Using 68Ga-FAPI-04 PET/CT

Abstract

Noninvasively monitoring activated fibroblasts is of great value for understanding the dynamic process of myocardial fibrosis after myocardial infarction (MI). This study aimed to evaluate the feasibility of ⁶⁸Ga-labeled fibroblast activation protein inhibitor 04 (⁶⁸Ga-FAPI-04) for monitoring reparative fibrosis and reactive fibrosis after MI. MI models were prepared by ligation of the left anterior descending (LAD) coronary artery and validated by electrocardiogram and ¹⁸F-FDG PET/CT 1 day after MI and hematoxylin and eosin (HE) staining. ⁶⁸Ga-FAPI-04 PET/CT scans (1, 3, 6, 9, 12, 15, 18, 21, 28, and 35 days after MI) were carried out in MI rats and sham-operated rats without ligation of LAD. Blocking experiments were carried out on MI rats on day 7 after MI with ⁶⁸Ga-FAPI-04 and excessive FAPI-04. Autoradiography, HE staining, Masson's trichrome staining, and immunofluorescence staining were carried out for ex vivo validation. The infarcted area with decreased or defective myocardial metabolic activity in ¹⁸F-FDG PET/CT correspondingly showed high ⁶⁸Ga-FAPI-04 uptake in the MI rats. The myocardial tracer uptake was significantly different between MI and sham-operated rats from day 1 to 28 after MI and reached peak value 6 days after MI (0.806 ± 0.257%ID/cc vs 0.199 ± 0.012%ID/cc, P < 0.05). Tracer uptake at the infarcted myocardium and normal tissues in MI rats decreased significantly after blocking. Obvious tracer uptake was confirmed by autoradiography, and immunofluorescence staining showed FAP+ cells in the infarcted myocardium and border zone. Masson's trichrome staining of the heart sections of MI rats at different times suggested the presence of myocardial fibrosis. ⁶⁸Ga-FAPI-04 uptake was not observed in the distal uninjured myocardium throughout the observation period. In conclusion, ⁶⁸Ga-FAPI-04 PET could noninvasively monitor the activated fibroblasts in the early stage post acute MI and may be helpful for evaluating the degree of reparative fibrosis, while reactive fibrosis monitoring still needs further study.

Keywords: 68Ga-FAPI-04; fibroblast activation protein; myocardial fibrosis; myocardial infarction; positron emission tomography/computed tomography (PET/CT).