Fibroblast activation in atrial fibrillation analysis of the SALTIRE aortic stenosis programme

Introduction Atrial fibrosis is heavily implicated in the pathogenesis of atrial fibrillation (AF) and embolic stroke. However, atrial fibrosis is challenging to accurately detect and quantify using established imaging modalities. The novel positron emitting radiotracer gallium-68 Fibroblast Activation Protein Inhibitor ([68Ga]FAPI) binds specifically to activated fibroblasts, the key cell driving fibrosis in cardiac tissues, and may identify active atrial fibrosis. We aimed to describe the pattern and intensity of atrial fibroblast activation in patients with and without AF. Methods In analysis from a prospective observational cohort study, patients with aortic stenosis, patients with prior aortic valve replacement and control subjects underwent transthoracic echocardiography, cardiac magnetic resonance and hybrid [68Ga]FAPI positron emission tomography and cardiac computed tomography angiography. [68Ga]FAPI maximum standardised uptake values were recorded in the posterior wall of the left atrium, the pulmonary veins, the interatrial septum and the right atrium, and divided by the mean standardised uptake value in the superior vena cava to quantify a target-to-background ratio (TBRmax). The association between atrial [68Ga]FAPI uptake and a history of AF as well as atrial volumes and function was assessed. Results 103 patients (10 with aortic sclerosis, 25 with mild, moderate or severe aortic stenosis, 18 with prior aortic valve replacement; 73±7 years, 25% female) participated, of whom 22 had a history of paroxysmal, persistent or peri-operative AF, and 9 matched control subjects (72±8 years, 33% female) with normal aortic valves and without AF. 20/22 (91%) patients with AF had visually positive [68Ga]FAPI uptake in the atria and/or pulmonary veins, compared with 46/81 (57%) of patients with aortic stenosis but no AF and 2/9 (22%) of the control participants. The maximal [68Ga]FAPI uptake within the defined regions of interest was increased in patients with AF compared with patients with aortic stenosis but no AF, with [68Ga]FAPI uptake in both of these groups increased compared with controls (TBRmax 1.6 [1.5 – 1.9] versus 1.5 [1.3 – 1.7] versus 1.1 [1.1 – 1.3], respectively, p<0.0001). The number of [68Ga]FAPI positive regions was associated with increased maximum left atrial volume (r=0.372, p<0.001) and reduced left atrial strain rate (r=-0.337, p<0.01). Conclusions We have demonstrated that atrial fibroblast activation is observed almost universally in patients with AF, but is infrequently seen in healthy patients without AF or valve disease. Increased fibroblast activation was also seen in patients with aortic stenosis without AF at a lower level than those with AF, and the overall burden of increased fibroblast activation was associated with indices of adverse left atrial remodelling. [68Ga]FAPI may therefore have an important role to play in measuring the effects of novel medical therapies or ablation on atrial fibrosis.