Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride
Assessment of Risk in Thoracic Aortopathy Using 18F-Sodium Fluoride
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.
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.
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