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Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride (AoRTAS)

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ClinicalTrials.gov Identifier: NCT04083118
Recruitment Status : Recruiting
First Posted : September 10, 2019
Last Update Posted : September 10, 2019
Sponsor:
Information provided by (Responsible Party):
University of Edinburgh

Tracking Information
First Submitted Date September 2, 2019
First Posted Date September 10, 2019
Last Update Posted Date September 10, 2019
Actual Study Start Date April 1, 2019
Estimated Primary Completion Date August 3, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: September 5, 2019)
Aortic growth rate [ Time Frame: At 1-2 years after baseline visit ]
Correlate baseline 18F sodium fluoride PET uptake with aortic growth rate, a marker of aortic wall remodelling, over 1-2 years
Original Primary Outcome Measures Same as current
Change History No Changes Posted
Current Secondary Outcome Measures
 (submitted: September 5, 2019)
  • Aortic stiffness [ Time Frame: 1-2 years (at second study visit) ]
    Aortic stiffness, which is a biomechanical marker of how elastic the aortic wall is, has been associated with increased aortic event rates in patients with connective tissue disorders. We will measure aortic stiffness using a variety of metrics including distensibility, elastic modulus, stiffness index (all MRI derived) and pulse wave velocity (deprived using application tomography). The change in aortic stiffness and baseline aortic stiffness will be correlated with baseline PET
  • Wall shear stress [ Time Frame: 1 year (at baseline visit) ]
    Wall shear stress is extrapolated from 4D MRI and is proposed to be linked with histological changes in the aortic wall as well as increased dilatation. We will compare areas of high wall shear stress to those of high PET uptake.
Original Secondary Outcome Measures Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride
Official Title Non-invasive Detection of Bicuspid Aortic Valve-Related Thoracic Aortopathy
Brief Summary Patients with bicuspid aortic valve-related aortopathy are at increased risk of aortic dilatation, dissection and rupture. Currently, risk stratification is largely based on aortic diameter measurements, with those deemed high risk referred for aortic replacement surgery. This approach is imperfect, and potentially exposes many patients to unnecessary high-risk aortic surgery, or fails to identify those at risk of dissection or rupture with smaller diameters. In patients with abdominal aortic aneurysms, the investigators recently demonstrated that uptake of 18F-sodium fluoride predicts disease progression and clinical events independent of aneurysm diameter and standard clinical risk factors. Based on the investigators preliminary data, a study was proposed to look at 18F-sodium fluoride uptake in patients with bicuspid aortic valve-related aortopathy. The proposed study will shed light on the underlying pathological processes involved in aortic complications of this disease as well as potentially providing an important risk marker to predict disease progression and guide the need for major aortic surgery.
Detailed Description

Bicuspid aortic valve, along with other congenital conditions affecting the aortic wall, has been associated with elastic fibre loss, decrease in size of elastic lamellae, increased collagen deposition and smooth muscle loss compared to healthy controls on both light microscopy and electron microscopy. Further, analysis of site specific regions of the ascending aorta using biopsy specimens demonstrated significant differences in the apoptosis rate and survival of smooth muscle cells favouring the lesser curvature over the greater curvature of the aorta (the area of greater wall shear stress).

Studies to date suggest vessel wall microcalcification (lesions<50μm) is a dynamic marker of this vessel wall pathology: the end-product of a pathological process involving vessel wall inflammation, apoptosis and necrosis of medial smooth muscle cells and subsequent elastic fibre degradation. Granular medial calcinosis, the deposition of microcalcification in the medial layer of resected aortic tissue, has been recognised as a significant feature of bicuspid aortic valve-related aortopathy when compared to aortic samples taken from patients with tricuspid valves.

Recent histological analysis of human and murine Marfan aortas demonstrated elastin breaks co- localising with areas of microcalcification in aortic media. Further, the areas of elastin break were significantly correlated to decreased distensibility and increased aortic diameter. Finally, the group demonstrated an elastin receptor complex-ERK1/2-ALP-mediated mechanism for increased microcalcification deposition. Although focused on Marfan syndrome, these results are relevant to bicuspid aortic valve-related aortopathy as they suggest microcalcification is associated with elastic fibre breakdown, a proposed mechanism of bicuspid aortic valve aneurysm formation at areas of high wall shear stress. The ability to demonstrate and quantify aortic microcalcification, both ex vivo and non-invasively in vivo in patients with bicuspid aortic valve-related aortopathy would be important step in improving our knowledge of the pathological process underpinning this condition.

Positron emission tomography (PET) utilises a radiotracer which provides functional information on tissues at the cellular or molecular level. Because of its limited spatial resolution, PET images are combined with computed tomography (CT) or magnetic resonance imaging (MRI) so that the functional PET images can be co-registered with the detailed anatomical and structural images afforded by CT or MRI. While CT or MRI alone has been utilised in a wide range of cardiovascular diseases and can identify larger areas of macrocalcification (>200 μm), PET/CT using 18F-sodium fluoride has been used to identify vessel wall microcalcification (calcific lesions <50 μm) that is not detectable on CT or MRI. 18F-Sodium fluoride has been extensively validated as a radiotracer of microcalcification utilising electron microscopy, immunohistochemical analysis, pharmacodynamic concentration-response curves, and ex vivo and in vivo micro-PET/CT on vessel wall sections. 18F-Sodium fluoride uptake is mediated through exchange of fluoride ions with hydroxyl groups of hydroxyapatite, the major constituent of vessel wall calcification. Positron emission tomography using 18F-sodium fluoride has demonstrated significant promise as identifying active vessel wall pathology in a number of cardiovascular diseases including carotid, coronary, aortic valve, and abdominal aortic aneurysm disease. The use of 18F-sodium fluoride PET imaging in thoracic aortic aneurysms is novel.

There is a correlation between areas of high wall stress and intimal tear location location. Further, aneurysmal aortic tissue has been demonstrated to have reduced delamination strength in both longitudinal and circumferential dimensions: evidence for an involvement of haemodynamic effects on precipitating dissection. Time resolved 3D blood flow captured on MRI, also known as 4D-flow MRI, is an evolving research tool which non-invasively captures patient-specific regionalised blood flow and velocity, allowing calculation of aortic wall sheer stress, and has been used to study bicuspid aortic valve-related aortopathy. A study pairing pre-operative 4D-flow MRI and post-operative biopsies of aortic tissue have demonstrated a decrease in elastin at sites of high aortic wall stress, suggesting a relationship between haemodynamics and the structural composition of the aneurysmal aortic wall. The ability to demonstrate a pathological process associated with aneurysmal weakness could be an important step to better identifying high risk lesions.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
Blood samples taken at each visit with ethical approval and consent to store for DNA
Sampling Method Non-Probability Sample
Study Population Patients with bicuspid aortic valve and a variety of ascending aortic sizes
Condition
  • Bicuspid Aortic Valve
  • Thoracic Aortic Aneurysm
  • Aortic Dissection
Intervention
  • Diagnostic Test: clinical evaluation, blood markers, pulse wave analysis, 18F sodium fluoride PET/CT and PET/MRI
    Patients will receive a structured clinic history, examination, blood sampling, pulse wave analysis, pulse wave velocity, 18F-sodium fluoride PET/CT, 18F-sodium fluoride PET/MRI with detailed cardiac magnetic resonance imaging and magnetic resonance imaging of the aorta
  • Diagnostic Test: Repeat 18F sodium fluoride PET/MRI
    as per first study visit but without the PET/CT
Study Groups/Cohorts
  • Bicuspid aortic valve
    80 patients with bicuspid aortic valve with or without an aortic aneurysm
    Interventions:
    • Diagnostic Test: clinical evaluation, blood markers, pulse wave analysis, 18F sodium fluoride PET/CT and PET/MRI
    • Diagnostic Test: Repeat 18F sodium fluoride PET/MRI
  • controls
    20 healthy volunteer controls age and sex matched to 20 of the bicuspid aortic valve patients
    Intervention: Diagnostic Test: clinical evaluation, blood markers, pulse wave analysis, 18F sodium fluoride PET/CT and PET/MRI
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: September 5, 2019)
100
Original Estimated Enrollment Same as current
Estimated Study Completion Date August 3, 2021
Estimated Primary Completion Date August 3, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Bicuspid aortic Valve or Age-sex matched healthy volunteer

Exclusion Criteria:

  • Pregnancy
  • eGFR < 30
  • previous aortic replacement surgery
  • previous aortic valve surgery
  • contrast allergy
  • other reason unable to undergo MRI
Sex/Gender
Sexes Eligible for Study: All
Ages 20 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers Yes
Contacts
Contact: Chris Coner 0131 242 3326 ext 23326 Chris.Coner@ed.ac.uk
Contact: David E Newby, MD, PhD, DSc 0131 242 6515 ext 26515 D.E.Newby@ed.ac.uk
Listed Location Countries United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number NCT04083118
Other Study ID Numbers 2018/0261
FS/19/15/34155 ( Other Grant/Funding Number: British Heart Foundation )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party University of Edinburgh
Study Sponsor University of Edinburgh
Collaborators Not Provided
Investigators
Principal Investigator: Alexander J Fletcher, MD University of Edinburgh
PRS Account University of Edinburgh
Verification Date September 2019