Molecular imaging of valvular fibroblast activation and established fibrosis in aortic stenosis: analysis from the SALTIRE programme

Abstract Introduction Progressive leaflet thickening in aortic stenosis is driven by fibrosis and calcification. Recent studies have quantified valvular fibrosis using contrast enhanced computed tomography (CT) techniques, with the combined fibro-calcific score correlating better with disease severity than CT-calcium scoring alone. However, understanding fibrosis activity within the aortic valve may allow detection of disease prior to extracellular matrix remodelling and progressive valve thickening. Gallium68 Fibroblast Activation Protein Inhibitor (68Ga-FAPI) binds to activated fibroblasts, the key effector cell of fibrosis formation, and provides a readout of fibroblast activation and fibrosis activity. We aimed to identify the relationship between 68Ga-FAPI intensity, CT calcium score, and quantified fibrocalcific volume. Methods In a prospective cohort, patients across the spectrum of aortic stenosis severity and a control population with normal aortic valves underwent combined 68Ga-FAPI Positron Emission Tomography (PET), non-contrast CT and contrast-enhanced CT. Valvular 68Ga-FAPI uptake was quantitatively assessed in a standardised fashion, with the maximal standardised uptake value (SUVmax) recorded within the defined region of interest, and divided by right atrial bloodpool uptake to provide a tissue-to-background ratio (TBRmax). CT-Calcium Scores were quantified in Agatston Units. The fibrocalcific volume was quantified by the sum of non-calcific and calcific tissue volume using bespoke software (Autoplaque, Cedars-Sinai). Results 29 patients with aortic valve disease (mean age 71 ± 8 years; 76% male; peak velocity 3.4 ± 0.7 m/s) and 4 control participants (mean age 66 ± 7 years; 50% male) were included. 5 patients had aortic sclerosis or mild stenosis, 15 had moderate stenosis and 8 had severe aortic stenosis. Increased 68Ga-FAPI activity was observed in the aortic valves of all patients with aortic stenosis (mean SUVmax 2.1 ± 0.3; TBRmax 1.5 ± 0.1), of higher intensity than that of controls (mean TBRmax 1.3 ± 0.0, p<0.05; Figure 2). There was a moderate relationship between 68Ga-FAPI uptake and the CT-Calcium Score (r = 0.371, p<0.05), but a stronger correlation between the combined fibrocalcific volume and 68Ga-FAPI TBRmax (r = 0.562, p = 0.002). Conclusion In patients with aortic stenosis, valvular fibrosis activity can be measured using 68Ga-FAPI PET. Increased 68Ga-FAPI uptake correlates better with complete anatomical quantification combining calcific and non-calcific leaflet thickening than with CT-Calcium Score alone. 68Ga-FAPI PET is a promising technique to assess fibroblast activation and fibrosis activity in aortic stenosis.Figure 1 Figure 2