Fibroblast activation protein-specific inhibitor imaging in heart failure

Abstract Background Although myocardial fibrosis can be quantified by magnetic resonance (MR), assessment of fibrosis activity is important as this will inform disease activity and the presence of ongoing adverse cardiac remodelling. Fibroblast activation protein (FAP) is expressed on the surface of activated myofibroblasts and is a marker of ongoing fibrosis activity. Radiolabelled FAP-specific ligands, such as 68-Gallium (68Ga)-FAP inhibitor (FAPI), represent a promising new approach to quantify fibrosis activity in the myocardium. Purpose To investigate whether 68Ga-FAPI positron emission tomography (PET)/MR can detect myocardial fibrosis activity in patients with heart failure with reduced ejection fraction. Methods In a prospective cross-sectional study, patients with heart failure with reduced ejection fraction and healthy volunteers underwent 68Ga-FAPI PET/MR. 10 patients had repeat imaging at 6 months. Standardised uptake values (SUVmax) and tissue to background ratios (TBR) were calculated within the left ventricular (LV) wall. Results Participants were predominantly middle-aged men: patients with heart failure (n=45; median age 65 [60-74] years, 76% male) and healthy volunteers (59 [56-62] years,70% male). LV ejection fraction was reduced in patients with heart failure (40±8%) but was normal in healthy volunteers (60±6%; P<0.001). Within the heart failure cohort, 22 patients had ischaemic cardiomyopathy and 23 patients had non-ischaemic cardiomyopathy. Compared with healthy volunteers, patients with heart failure had higher myocardial uptake of 68Ga-FAPI (SUVmax 3.2±1.5 versus 1.5±0.3, p<0.001; TBR 1.9±0.8 versus 1.1±0.2, p<0.001; Figure 1). Myocardial 68Ga-FAPI uptake was higher in patients with either ischaemic or non-ischaemic cardiomyopathy compared to healthy volunteers (SUVmax 4.0±1.7 and 2.3±0.5 versus 1.5±0.3 respectively; p<0.001 for both) and was higher in patients with ischaemic compared to non-ischaemic cardiomyopathy (p<0.001). Differential patterns of 68Ga-FAPI uptake were also observed with increased LV uptake seen particularly in the basal septum of patients with non-ischaemic cardiomyopathy and in the infarct zone of patients with ischaemic cardiomyopathy (Figure 2). Based on the Youden’s index of the receiver-operator curves, the optimal threshold for identifying myocardial fibrosis in patients with heart failure was SUVmax of 1.9 with a specificity of 90%, sensitivity of 89% and area under the curve of 0.94. At 6 months, 68Ga-FAPI uptake was unchanged in the 10 patients with chronic heart failure that underwent repeat scanning (p=0.91). Conclusion Increased myocardial fibrosis activity can be detected with 68Ga-FAPI PET/MR in patients with heart failure. Differential patterns of 68Ga-FAPI uptake are seen in patients with non-ischaemic cardiomyopathy or ischaemic cardiomyopathy. This may help characterise and prognosticate patients with heart failure and inform the future development of novel heart failure therapies.Figure 1Figure 2