Molecular Imaging of Fibroblast Activity After Myocardial Infarction Using a ⁶⁸Ga-Labeled Fibroblast Activation Protein Inhibitor, FAPI-04

Abstract

Heart failure remains a major source of late morbidity and mortality after myocardial infarction (MI). The temporospatial presence of activated fibroblasts in the injured myocardium predicts the quality of cardiac remodeling after MI. Therefore, monitoring of activated fibroblasts is of great interest for studying cardiac remodeling after MI. Fibroblast activation protein (FAP) expression is upregulated in activated fibroblasts. This study investigated the feasibility of imaging activated fibroblasts with a new 68 Ga-labeled FAP inhibitor (68 Ga-FAPI-04) for PET imaging of fibroblast activation in a preclinical model of MI. Methods: MI and sham-operated rats were scanned with 68 Ga-FAPI-04 PET/CT (1, 3, 6, 14, 23, and 30 d after MI) and with 18 F-FDG (3 d after MI). Dynamic 68 Ga-FAPI-04 PET and blocking studies were performed on MI rats 7 d after coronary ligation. After in vivo scans, the animals were euthanized and their hearts harvested for ex vivo analyses. Cryosections were prepared for autoradiography, hematoxylin and eosin (H&E), and immunofluorescence staining. Results: 68 Ga-FAPI-04 uptake in the injured myocardium peaked on day 6 after coronary ligation. The tracer accumulated intensely in the MI territory, as identified by decreased 18 F-FDG uptake and confirmed by PET/MR and H&E staining. Autoradiography and H&E staining of cross-sections revealed that 68 Ga-FAPI-04 accumulated mainly at the border zone of the infarcted myocardium. In contrast, there was only minimal uptake in the infarct of the blocked rats, comparable to the uptake in the remote noninfarcted myocardium (PET image-derived ratio of infarct uptake to remote uptake: 6 ± 2). Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the injured myocardium. Morphometric analysis of the whole-heart sections demonstrated 3-and 8-fold higher FAP-positive fibroblast density in the border zone than in the infarct center and remote area, respectively. Conclusion: 68 Ga-FAPI-04 represents a promising radiotracer for in vivo imaging of post-MI fibroblast activation. Noninvasive imaging of activated fibroblasts may have significant diagnostic and prognostic value, which could aid clinical management of patients after MI.

FAPI-74 PET/CT Using Either18F-AlF or Cold-Kit68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients

“…In this study histopathology of biopsy or surgical specimens served as the gold standard for the final patients's classification (30). In addition to its oncological application, "FAPI-PET" was also found promising to evaluate immune-related and heart diseases (31,32). As a practical (i.e.…”

Cardiac fibroblast activation detected by Ga-68 FAPI PET imaging as a potential novel biomarker of cardiac injury/remodeling

“…This cannot be finally proven at the moment as there are not conclusive histopathological studies validating cardiac FAPI uptake with fibroblast activation as it is the case for FAPI uptake in malignancy. 9,10 Fibroblast activation may also play a role in generalized fibrotic remodeling, as previously shown in heart failure, where the deposition of extracellular matrix proteins increasing myocardial stiffness 1 is primarily driven by cardiac fibroblasts. 22 As fibrosis is involved in the disruption of myocardial excitation- Figure 2.…”

“…6 However, in adult humans, intensive expression is only found in the setting of wound healing, in fibrotic remodeling processes like in liver fibrosis and cirrhosis 7 and in the stroma of the majority of malignant cancer types. [8][9][10] The highest FAPI uptake was reported in sarcoma, esophageal, breast and lung cancer, and cholangiocarcinoma pointing at the dominant expression of FAP in solid tumors. 9 A study analyzing brain samples could even demonstrate increased FAP expression in high-grade gliomas.…”

FAP: The Next Billion Dollar Nuclear Theranostics Target?

“…This may, for instance, render the differentiation between chronic pancreatitis and pancreatic ductal adenocarcinoma difficult (19). Conversely, FAP-targeted PET imaging may be useful for many non-oncologic imaging applications such as myocardial infarction (20)(21)(22), chronic inflammatory diseases (23), and lung, liver or kidney fibrosis (24).…”