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

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<0.001), indexed extracellular volume (r=0.453, p<0.0001), troponin I (r=0.492, p<0.0001) and NTproBNP (r=0.355, p<0.001). On multivariable analysis, [68Ga]FAPI TBRmax independently predicted the presence of LGE. At a median of 15 months, [68Ga]FAPI uptake increased in patients with aortic stenosis (n=42), but declined following aortic valve replacement (n=15, 6 [3 – 8] months following intervention). (Figure 2). Baseline [68Ga]FAPI uptake was associated with an increase in LGE burden at follow up (r=0.591, p<0.001). Conclusions For the first time, we have demonstrated myocardial fibroblast activation in patients with aortic stenosis both with and without established fibrosis. Myocardial fibroblast activation increases with aortic stenosis severity, the left ventricular hypertrophic response and other markers of adverse remodelling, predicting subsequent increases in myocardial fibrosis. Myocardial fibroblast activation increases with time until aortic valve replacement after which reductions in fibroblast activation are observed. [68Ga]FAPI positron emission tomography therefore holds promise in evaluating medical therapies targeting the myocardium in aortic stenosis, and identifying patients at risk of myocardial decompensation.