The Role of Valvular Fibrosis in Patients with Aortic Stenosis

In patients with narrowing of the aortic valve (aortic stenosis), the valve becomes thickened with scarring (fibrosis) and hardening (calcification) of the valve leaflets. Progression of the disease is also due to scarring (fibrosis) of the heart muscle. This condition is very common, affecting more than 10% of patients aged over 75 years. No medical therapy has been shown to slow progression of the disease or improve survival. The progressive decline in valve function means that many patients require aortic valve replacement, now the most common form of valve surgery in high income countries. We estimate this costs up to £1 billion per year for the NHS alone. In order to be able to develop effective treatments to slow down or stop progression of aortic stenosis, understanding the balance between fibrosis and calcification at varying stages of the disease will be crucial.

In order to better understand this process, we will use currently available scanning techniques including echocardiography (ultrasound) and CT scans, as well as state-of-the-art scanning technology called Positron Emission Tomography (PET) using radiotracers (a colourless liquid injected into a vein in order to take the pictures). These radiotracers have
been used in recent research studies investigating heart muscle and heart valve diseases. These tests will help us measure the severity of aortic stenosis and the amount of activity of fibrosis and calcification at different time points during the study.

In this study we will collect up to 2000 CT scans, echocardiograms and linked anonymised clinical data from around the world, and analyse the images using new image analysis software which we believe will improve on the current analysis of CT scans done routinely in the NHS. We will also recruit 85 patients and 10 healthy volunteers and invite them for an echocardiogram, CT scan with contrast and state-of-the-art PET scan with a new radiotracer looking at scarring activity within the aortic valve, to see when the scarring activity is at its highest and how it relates to the severity of the disease. We will ask these participants to return 12 months later for repeat assessments, to see if the radiotracer can predict disease progression.

Overall we hope this research can support widespread clinical adoption of an improved diagnostic tool to aid clinical decision making, and through looking at scarring activity identify a target biomarker which would be helpful for potential clinical trials.

Aortic stenosis is a common condition which carries significant mortality and morbidity, for which there are no disease-modifying therapies. Whilst valvular calcium can be quantified by CT calcium scoring and aid in the assessment of disease severity, this ignores the contribution of valvular fibrosis and may underestimate disease severity, particularly in women. We have recently developed a more complete CT-based anatomic assessment of the valve to provide an overall assessment of disease burden that includes both the fibrotic and calcific volume of aortic valve leaflet thickening. A large-scale multi-centre validation study is now essential to support potential widespread clinical adoption.

Moreover, active valvular fibrosis may represent an earlier and more modifiable stage of the aortic valve disease than established fibrosis or calcification. Using a novel in vivo PET/CT-based imaging technique, this fellowship aims to understand the relationship between fibrosis activity (fibroblast activation), non-calcific leaflet thickening (fibrotic volume) and aortic stenosis severity (peak jet velocity and valve area) in a prospective longitudinal cohort study.

Together, these non-invasive imaging techniques have the potential to improve our understanding of the pathogenesis of aortic stenosis, to enhance assessments of disease activity and severity, and to guide the development of novel therapies.