Abstract
3330
Introduction: Heart failure with preserved ejection fraction (HFpEF) is a huge and growing unmet need in cardiology in nowadays. Left ventricular hypertrophy (LVH) and diastolic dysfunction are considered as the hallmarks of HFpEF, caused by the large amount of accumulation of collagens. In this pathogenesis, the fibroblasts that express high level of fibroblast activation proteins (FAP), are activated. Thus, the FAP targeted imaging could be a great indicator for the qualitative and quantitative analysis of HFpEF. As reported, [18F]AlF-NOTA-FAPI-04 with nanomolar level of affinity to FAP and rapid plasma clearance, has been used as PET-CT imaging agent for various cancers and some heart disease. In this study, [18F] AlF-NOTA-FAPI-04 was further explored in the PET-CT imaging of the activated fibroblasts in the rat model with HFpEF.
Methods: The HFpEF rat model was established by the combination of high-fat diet (HFD) (60% kilocalories from fat (lard)) and L-NAME (Nω-nitro-L-arginine methyl ester, 0.5 g/L in drinking water) (two-hit model; L-NAME+HFD) for 8 weeks. Cardiac ultrasound and blood pressure levels were used to assess the progression of heart failure with preserved ejection fraction. The HFpEF and control rats were randomly selected for [18F]AlF-NOTA-FAPI-04 PET-CT imaging every week. Three rats from the HFpEF group were also preformed with the dynamic [18F]AlF-NOTA-FAPI-04 PET-CT scanning for 90 min. After imaging, the rats were euthanized and their hearts were taken out for pathological analysis. Paraffin sections were obtained for Mason staining, H&E staining and FAP immunofluorescence staining.
Results: The echocardiography and blood pressure tests suggested that the hypertensive ejection fraction retention heart failure model was successfully established after the administration of HFD+L-NAME for 8 weeks. [18F]AlF-NOTA-FAPI-04 PET-CT results showed obvious diseased rat heart images in the HFpEF group compared with the control group, in which [18F]AlF-NOTA-FAPI-04 significantly accumulated in the fibrotic left ventricle. In addition, there was only minimal uptake in the neighbouring organs (PET image derived ratio of heart to liver, 10.3 ± 3.2). Masson and H&E staining of paraffin sections revealed a large number of vascular and interstitial fibrosis and inflammatory cells accumulating in the hearts of HFpEF group. Immunofluorescence staining confirmed the presence of FAP-positive myofibroblasts in the fibrotic left ventricle.
Conclusions: [18F]AlF-NOTA-FAPI-04 showed a great potential to be a radiotracer for in vivo non-invasive imaging of HFpEF, which could benefit the clinical management of HFpEF patients.