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

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ClinicalTrials.gov Identifier: NCT03352089
Recruitment Status : Recruiting
First Posted : November 24, 2017
Last Update Posted : November 24, 2017
Sponsor:
Information provided by (Responsible Party):
University of Edinburgh

Brief Summary:

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.


Condition or disease
Aortic Stenosis Transthyretin Amyloidosis

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Study Type : Observational
Estimated Enrollment : 30 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Positron Emission Tomography / Magnetic Resonance Imaging in Aortic Stenosis
Actual Study Start Date : November 1, 2017
Estimated Primary Completion Date : November 1, 2018
Estimated Study Completion Date : November 1, 2018


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



Primary Outcome Measures :
  1. PET signal intensity quantified by calculation of standard uptake values [ Time Frame: Pre surgery scan ]

Biospecimen Retention:   None Retained
lood samples


Information from the National Library of Medicine

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Ages Eligible for Study:   70 Years and older   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03352089


Contacts
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Contact: Russell J Everett, MBBS 01312426361 russell.everett@ed.ac.uk

Locations
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United Kingdom
University of Edinburgh / NHS Lothian Recruiting
Edinburgh, Midlothian, United Kingdom, EH164SB
Contact: Russell J Everett, MBBS    01312426361    russell.everett@ed.ac.uk   
Sponsors and Collaborators
University of Edinburgh
Investigators
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Principal Investigator: Russell J Everett, MBBS University of Edinburgh / NHS Lothian

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Responsible Party: University of Edinburgh
ClinicalTrials.gov Identifier: NCT03352089     History of Changes
Other Study ID Numbers: 17/SS/0066
First Posted: November 24, 2017    Key Record Dates
Last Update Posted: November 24, 2017
Last Verified: November 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Edinburgh:
Magnetic resonance imaging
Positron emission tomography
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Amyloidosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Proteostasis Deficiencies
Metabolic Diseases
Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction