Molecular imaging of arterial fibroblast activation protein: association with calcified plaque burden and cardiovascular risk factors

Abstract

Purpose: We aimed to assess prevalence, distribution, and intensity of in-vivo arterial wall fibroblast activation protein (FAP) uptake, and its association with calcified plaque burden, cardiovascular risk factors (CVRFs), and FAP-avid tumor burden.

Methods: We analyzed 69 oncologic patients who underwent [⁶⁸ Ga]Ga-FAPI-04 PET/CT. Arterial wall FAP inhibitor (FAPI) uptake in major vessel segments was evaluated. We then investigated the associations of arterial wall uptake with calcified plaque burden (including number of plaques, plaque thickness, and calcification circumference), CVRFs, FAP-positive total tumor burden, and image noise (coefficient of variation, from normal liver parenchyma).

Results: High focal arterial FAPI uptake (FAPI +) was recorded in 64/69 (92.8%) scans in 800 sites, of which 377 (47.1%) exhibited concordant vessel wall calcification. The number of FAPI + sites per patient and (FAPI +)-derived target-to-background ratio (TBR) correlated significantly with the number of calcified plaques (FAPI + number: r = 0.45, P < 0.01; TBR: r = - 0.26, P = 0.04), calcified plaque thickness (FAPI + number: r = 0.33, P < 0.01; TBR: r = - 0.29, P = 0.02), and calcification circumference (FAPI + number: r = 0.34, P < 0.01; TBR: r = - 0.26, P = 0.04). In univariate analysis, only body mass index was significantly associated with the number of FAPI + sites (OR 1.06; 95% CI, 1.02 - 1.12, P < 0.01). The numbers of FAPI + sites and FAPI + TBR, however, were not associated with other investigated CVRFs in univariate and multivariate regression analyses. Image noise, however, showed significant correlations with FAPI + TBR (r = 0.30) and the number of FAPI + sites (r = 0.28; P = 0.02, respectively). In addition, there was no significant interaction between FAP-positive tumor burden and arterial wall FAPI uptake (P ≥ 0.13).

Conclusion: [⁶⁸ Ga]Ga-FAPI-04 PET identifies arterial wall lesions and is linked to marked calcification and overall calcified plaque burden, but is not consistently associated with cardiovascular risk. Apparent wall uptake may be partially explained by image noise.

Keywords: Atherosclerosis; Atherosclerotic plaque; Cardiovascular risk factors; Fibroblast activation protein; Tumor burden; [68 Ga]Ga-FAPI.

Fig. 1

Fused axial [⁶⁸ Ga]Ga fibroblast activation protein inhibitor (FAPI) PET/CT images of the aorta of a 72-year-old man: coronal PET/CT image (A) and corresponding axial PET/CT slices (B and C). In B, radiotracer uptake in the vessel wall coincides with and exceeds vessel wall calcification, while other calcifications show no increased tracer uptake. In C, FAPI uptake is colocalized with vessel wall calcifications

Fig. 2

Associations of numbers of fibroblast activation protein inhibitor uptake (FAPI +) sites (upper row) and tracer accumulation defined as target-to-background ratio (TBR; lower row) with parameters of calcified plaque (CP +) burden: number of CP + sites (A and D), calcification score (B and E), and calcification thickness (C and F). For B, C, E, and F, cumulative values were used

Fig. 3

Scatter plots showing the number of high fibroblast activation protein inhibitor uptake sites (FAPI +) (A), the mean target-to-background ratio (TBR) in FAPI + sites (B), and the number of calcified plaque sites (CP +) (C), grouped by the number of cardiovascular risk factors (CVRF). Horizontal black line indicates median. The numbers in respective CVRF subgroups vary depending whether uptake on PET (for both number of FAPI + sites and FAPI + TBR) or CP + sites were assessable

Fig. 4

Associations of tracer accumulation defined as target-to-background ratio (TBR) and parameters contributing to image noise, including injected activity (A) and body mass index (BMI) (B). Higher injected activities were linked to less uptake. Overweight patients had higher TBR, which can also be explained by image noise [27]

Fig. 5

PET-based FAPI uptake in the arterial tree is linked to plaque burden, but is not consistently associated with cardiovascular risk, which may be explained by image noise. PET, positron emission tomography. FAPI, fibroblast activation protein inhibitor