Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride
Condition: Bicuspid Aortic Valve; Thoracic Aortic Aneurysm; Aortic Dissection
MeSH terms: Aortic Dissection; Aneurysm; Aortic Aneurysm; Bicuspid Aortic Valve Disease; Aortic Aneurysm, Thoracic; Heart Valve Diseases
Study type: Observational

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.
    

Intervention name(s): clinical evaluation, blood markers, pulse wave analysis, 18F sodium fluoride PET/CT and PET/MRI; Repeat 18F sodium fluoride PET/MRI
Intervention type(s): Diagnostic Test; Diagnostic Test
Intervention description(s): 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; as per first study visit but without the PET/CT
Intervention MeSH terms: Listerine; Fluorides; Sodium Fluoride
Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with bicuspid aortic valve and a variety of ascending aortic sizes
      
Biospecimen description: 
      Blood samples taken at each visit with ethical approval and consent to store for DNA
    
Keywords: positron emission tomography; sodium fluoride; bicuspid aortic valve; thoracic aortic aneurysm; aortopathy