Positron Emission Tomography / Magnetic Resonance Imaging in Aortic Stenosis
Positron Emission Tomography / Magnetic Resonance Imaging in Aortic Stenosis
Aortic stenosis is the most common valve disease requiring surgery in the Western world. It
 is defined by progressive calcification and fibrosis of the valve leaflets and restricted
 valve opening. This in turn exposes the heart muscle (left ventricle) to increasing pressure
 leading to heart muscle thickening (left ventricular hypertrophy, LVH) to normalise wall
 stress and maintain heart output (stroke volume). The only treatment available is relief of
 pressure overload by surgical or minimally invasive valve replacement (TAVI).

 Transthyretin (TTR) amyloidosis is a condition characterised by deposition of insoluble
 transthyretin protein (a small protein tetramer produced in the liver) in various tissues,
 predominantly in the heart. Although there are inherited forms caused by specific TTR gene
 mutations, most cases occur in older individuals with non-mutated TTR (wild-type). The
 finding of TTR plaques in elderly individuals is relatively common; in a post-mortem study
 22-25% of patients over the age of 80 had evidence of cardiac amyloid deposition. However,
 there is significant progressive amyloid accumulation in a small percentage of individuals
 leading to heart muscle thickening and heart failure. No medical treatments are currently
 licensed although several agents are at advanced stages of clinical trials.

 As both the above conditions are increasingly common in the elderly population and
 characterised by increased heart muscle thickening, there is the potential for them to
 coexist unrecognised in individual patients. The prevalence of cardiac amyloidosis in
 clinical populations with significant aortic stenosis is not known however small series have
 estimated somewhere in the region of 6-29%. Other data have suggested that patients with
 aortic stenosis and concurrent cardiac amyloidosis have an adverse prognosis even despite
 AVR. It is therefore important to identify aortic stenosis patients with coexistent
 amyloidosis both in terms of predicting prognosis and because it may influence decisions
 about whether to proceed to valve intervention.

 PET/MR is an emerging technique, which combines the excellent temporal and spatial resolution
 of MRI with the sensitive molecular imaging of PET. PET/MR has significant advantages over
 PET/CT (the currently more widely used approach) in that it offers superior tissue
 characterisation, improved correction for cardiac and respiratory motion and major reductions
 in radiation exposure. Whilst there are concerns about its ability to provide reliable
 attenuation correction of the PET data, these issues appear to have been largely overcome
 with recent techniques proposed by our group. MR is also more naturally suited to the imaging
 of certain tissues in the body compared to CT including the left ventricular myocardium.

 In aortic stenosis, MRI has become the gold-standard technique for examining the heart muscle
 (myocardium) with the unique ability to assess its tissue composition. In particular both
 late gadolinium enhancement (LGE) and T1 mapping based techniques are able to detect heart
 scarring (fibrosis) which act as biomarkers of left ventricular decompensation and are
 strongly associated with poor patient outcomes. CMR is also the gold-standard non-invasive
 technique for detecting cardiac amyloid, which is associated with both a characteristic
 pattern of LGE and high native T1 values. However it is not currently able to differentiate
 between the two different types of cardiac amyloid TTR and AL amyloidosis, which have
 different prognoses and treatments. Preliminary studies conducted by our group have suggested
 that 18F-NaF PET when added to CMR can make this distinction on the basis that this tracer
 binds to TTR deposits but not AL deposits, may be able to differentiate between the two.
 Importantly we have also used the same PET tracer as a marker of calcification activity in
 the aortic valve, demonstrating its ability to predict disease progression and cardiac
 events.

 In this study, we will investigate whether PET/MR could be used as "one-stop" imaging in
 aortic stenosis in whom valve intervention is being considered to assess in detail functional
 and structural properties of both the valve and myocardium and identify cases of significant
 cardiac TTR amyloid deposition.
Inclusion Criteria (AS group)

 -  Severe aortic stenosis

 -  Referred for aortic valve intervention (surgical AVR / TAVI)

 -  High clinical suspicion of amyloid (e.g. low-flow low-gradient AS, inappropriate LVH)

 -  Age >70 years

 -  Willing and able to comply with study protocol

 Exclusion Criteria (AS group)

 -  Inability to give informed consent

 -  Contraindication to MRI scanning (e.g. permanent pacemaker)

 -  Significant renal impairment (eGFR <30 ml/min/1.73 m2)

 -  Coexistent moderate or severe aortic regurgitation or mitral stenosis

 -  Acute valvular heart disease (e.g. acute mitral regurgitation or endocarditis)

 -  Acute pulmonary oedema or cardiogenic shock

 Inclusion Criteria (Healthy volunteers)

 -  No symptoms suggesting current cardiovascular disease

 -  Age >70

 -  Willing and able to comply with study protocol

 Exclusion Criteria (Healthy volunteers)

 -  Inability to give informed consent

 -  Contraindication to MRI scanning (e.g. permanent pacemaker)

 -  Significant renal impairment (eGFR <30 ml/min/1.73 m2)

 -  Known significant valvular heart disease (more than mild regurgitant valve lesion or
 any stenotic lesion)