Imaging microcalcium in thoracic aortic disease
Fletcher, Alexander James
BACKGROUND: Disease of the thoracic aorta occurs in two major forms; atheroma and aneurysm formation. Both disease processes progress silently before catastrophic complications occur, such as stroke or aortic dissection. Current management strategies focus on preventative interventions which can include high-risk surgery. However, identifying those who are most appropriate for such interventions is challenging. Deposition of calcium crystals (microcalcification) in the aortic wall occurs as a response to inflammation, cell stress and death, and its presence is thought to confer a vulnerable disease state in both thoracic aortic atheroma and aneurysm formation. 18F-Sodium fluoride positron emission tomography (PET) identifies microcalcification not identifiable on conventionally computed tomography (CT). The aim of this thesis was to assess the application of 18F-sodium fluoride PET in identifying of patients with high-risk thoracic aortic disease. METHODS AND RESULTS: Reproducibility: The intra- and inter-rater repeatability as well as scan-rescan reproducibility of thoracic aortic 18F-sodium fluoride activity was measured for standard slice-by-slice methods, as well as a novel centreline-based method, in 20 patients undergoing two 18F-sodium fluoride PET-CT scans, no more than three weeks apart. We found that the novel centreline-based method was over 5 times quicker than standard methods (3.4±0.5 versus 15.1±1.7 min, P>0.0001), and had excellent intra- (intraclass correlation coefficient 0.98), and inter-rater repeatability (intraclass correlation coefficient 0.97). Scan-rescan reproducibility was very good (intraclass correlation coefficient 0.86) with a minimal mean error of 0.00, narrow 95% limits of agreement of - 0.13 to 0.13, and a coefficient of reproducibility of 0.11. Microcalcification, aortic atheroma and stroke: Arterial 18F-sodium fluoride PET identifies an early and active stage of atheromatous disease that is associated with plaque vulnerability and the culprit lesions underlying atherothrombotic events. In a post-hoc observational cohort study, thoracic aortic 18F-sodium fluoride activity was quantified in 461 patients with stable cardiovascular disease undergoing PET-CT. Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischaemic stroke. After 12.7±2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n=140, r=0.31, p=0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke after 6.1±2.3 years of follow up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischaemic stroke (HR 10.3 [3.1 to 34.8], p=0.0017). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was associated with ischaemic stroke (HR 1.47 [1.00 to 2.16], p=0.05). Microcalcification in aortopathy: histology study Thoracic aortopathies are associated with microcalcification which has the potential to be visualised non-invasively using 18F-sodium fluoride positron emission tomography. Thoracic aortic samples were collected from 75 patients with thoracic aortopathy and 19 control samples. Histopathological score, immunohistochemistry and nanoindentation were compared to the extent of microcalcification on histology (von Kossa staining) and autoradiography (18F-sodium fluoride activity). Compared to control samples (0.79 [0.36 to 1.90]), microcalcification content was higher in samples with mild (n=28; 6.17 [2.71 to 10.39], p≤0.00010) or moderate (n=30; 3.74 [0.87, to 11.80], p<0.042), but not severe (n=24; 0.40 [0.15 to 0.87], p=0.42) aortopathy. Microcalcification content was associated with tissue elastic modulus (n=28; r=0.43, p=0.026) and osteopontin staining across all severities of aortopathy (2 p=0.001). Severe aortopathy had substantially less microcalcification compared with mild (p<0.0001) or moderate aortopathy (p=0.00030), and this was closely linked with elastin fragmentation and loss (n=82; r=-0.36, p=0.001). Histological microcalcification demonstrated very good correlation with microcalcification quantified using 18F-sodium fluoride autoradiography (n=66; r=0.76, p<0.001). Microcalcification in aortopathy: imaging study Translating the results of the histological study, the relationship between thoracic aortic aneurysm 18F-sodium fluoride activity, diameter, and stiffness was assessed using 18F-sodium fluoride PET-CT, MRI and applanation tonometry in 75 patients with bicuspid aortic valve and 18 controls without aortic disease. Patients with bicuspid aortic valve had higher ascending aortic 18F- sodium fluoride activity than age and sex-matched control subjects (1.10±0.06 versus 1.06±0.08, p=0.046), but similar aortic arch 18F- sodium fluoride activity (1.09±0.11 versus 1.06±0.08, p=0.21). Maximal indexed aortic diameter correlated with ascending aortic 18F-sodium fluoride activity (Spearman r=0.24, p=0.018). Ascending aortic 18F-sodium fluoride activity was associated with aneurysm stiffness index after adjustment for age, sex, diabetes status and maximal indexed aortic diameter (ß=14.017, p=0.008). There was a moderate inverse correlation between ascending aortic 18F-sodium fluoride activity and the annualised progression of aortic strain (n=29, Spearman rho = -0.47, p=0.013), but no relationship with progression of aortic diameter (n=29, Spearman rho = 0.14, p=0.47). CONCLUSION 18F-Sodium fluoride PET can be reproducibly measured in the thoracic aorta and identifies those with aortic wall disease. In patients with established cardiovascular disease, 18F-sodium fluoride PET is associated with atheroma progression as well as the future risk of stroke and could be used to guide preventative therapy. In thoracic aortic aneurysm, 18F-sodium fluoride PET can track the disease activity of the aortic wall and may represent a crucial modality for identifying those at highest risk of devastating complications.