Positron Emission Tomography / Magnetic Resonance Imaging in Aortic Stenosis (PASS)

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.

Study Overview

• Status: Unknown
• Conditions: Aortic Stenosis; Transthyretin Amyloidosis

• Study Type: Observational
• Enrollment (Anticipated): 30

Contacts and Locations

• Study Contact: Name: Russell J Everett, MBBS; Phone Number: 01312426361; Email: russell.everett@ed.ac.uk

Study Locations

• United Kingdom
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH164SB
      • Recruiting
      • University of Edinburgh / NHS Lothian
      • Contact: Russell J Everett, MBBS; Phone Number: 01312426361; Email: russell.everett@ed.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

AS group: patients at NHS Lothian referred for aortic valve intervention

Healthy volunteer group: healthy volunteers from South-East Scotland who meet the inclusion criteria

Description

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)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Aortic stenosis group; Patients with severe aortic stenosis >70 years of age referred for aortic valve intervention
Healthy volunteer group; Patients with no history of symptoms to suggest current cardiovascular disease >70 years of age

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
PET signal intensity quantified by calculation of standard uptake values	Pre surgery scan

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Investigators: Principal Investigator: Russell J Everett, MBBS, University of Edinburgh / NHS Lothian

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2017
• Primary Completion (Anticipated): November 1, 2018
• Study Completion (Anticipated): November 1, 2018

Study Registration Dates

• First Submitted: November 20, 2017
• First Submitted That Met QC Criteria: November 22, 2017
• First Posted (Actual): November 24, 2017

Study Record Updates

• Last Update Posted (Actual): November 24, 2017
• Last Update Submitted That Met QC Criteria: November 22, 2017
• Last Verified: November 1, 2017

More Information

Terms related to this study

• Keywords: Magnetic resonance imaging; Positron emission tomography
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction; Proteostasis Deficiencies; Aortic Valve Stenosis; Amyloidosis; Constriction, Pathologic
• Other Study ID Numbers: 17/SS/0066

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No