Myocardial fibroblast activation in aortic stenosis: progression and response to invervention

Abstract Introduction Activated fibroblasts are key effector cells driving adverse remodelling and myocardial fibrosis across many cardiomyopathic disorders. The novel positron emitting radiotracer Gallium-68 Fibroblast Activation Protein Inhibitor ([68Ga]FAPI) binds to activated fibroblasts, allowing non-invasive imaging of these cells for the first time. We aimed to assess the role of activated fibroblasts in the left ventricular remodelling response in patients with aortic stenosis over time and following aortic valve replacement. Methods In a prospective observational cohort, patients with aortic stenosis and control subjects underwent [68Ga]FAPI positron emission tomography and magnetic resonance imaging (MRI) at baseline and ≥1 year later or after aortic valve replacement. Myocardial [68Ga]FAPI uptake was quantified using a target-to-background ratio (TBRmax) and myocardial fibrosis was quantified by late gadolinium enhancement (LGE) on MRI. Results Eighty-six patients (11 with aortic sclerosis, and 25 each with mild, moderate or severe aortic stenosis; age 72±11 years, 32% female) and 8 control subjects (age 71±8 years, 30% female) participated. [68Ga]FAPI uptake was increased in the left ventricular myocardium of patients with aortic stenosis and sclerosis compared with control subjects (TBRmax 1.5 [0.9 – 1.8] versus 0.9 [0.9 – 1.3], p=0.04). [68Ga]FAPI uptake increased with disease severity and was particularly prominent in patients with severe aortic stenosis (Figure 1). Fifty-five patients (63%) had visually increased myocardial [68Ga]FAPI uptake, that was associated with LGE in half of these subjects (n=29; 33%). Baseline myocardial [68Ga]FAPI uptake correlated with increased indexed left ventricular mass (r=0.514, p