Molecular imaging of calcification and inflammation in aortic valve disease and atherosclerosis

Abstract

Introduction. Calcific aortic valve disease (CAVD) and atherosclerosis are important public health problems. Our ability to allocate patients to treatment strategies optimally and monitor progression is limited. Hybrid positron emission and computed tomography (PET/CT) is able to demonstrate both anatomy (CT) and molecular processes (PET) in vivo. The 18F-sodium fluoride (18F-fluoride) isotope has shown promise in early cardiovascular studies. The purpose of this thesis was to elucidate the mechanisms of cardiovascular 18Ffluoride uptake and define how 18F-fluoride PET/CT might play a role in the assessment of CAVD and atherosclerosis. Methods. Three cohorts were recruited constituting patients with: CAVD, coronary atherosclerosis and carotid atherosclerosis. Using in vitro, ex vivo and in vivo techniques, a model of the mechanism of 18F-fluoride uptake and its pharmacology was elaborated. In observational clinical studies, 18F-fluoride and 18F-FDG uptake in aortic valvular, coronary and carotid arterial tissue was assessed. Techniques for uptake quantification were evaluated for accuracy and reliability. Tissue uptake was related to established clinical and image-based variables as well as prospectively gathered clinical outcome data. Results. In the CAVD cohort, 121 volunteers were recruited. 18F-fluoride PET/CT correlated with tissue markers of active calcification and predicted the genesis of new areas of calcification within the aortic valve. 18F-fluoride uptake was associated with disease progression and clinical events. In the coronary cohort, 80 volunteers were recruited. In patients with acute myocardial infarction the highest coronary 18F-fluoride uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40–2·25] versus highest non-culprit 1·24 [1·06–1·38], p<0·0001). In patients with stable angina, plaques with focal 18F-fluoride uptake were associated with more high-risk features on intravascular ultrasound than those without uptake. In the carotid cohort, 38 volunteers were recruited (26 +12, separate studies). 18F-fluoride plaque uptake was associated with neurovascular symptoms (log10 mean standardized uptake value 0.29±0.10 versus 0.23±0.11, P=0.001) as well as image and tissue derived features of high-risk plaque. 18F-fluoride selectively highlighted areas of pathologically high risk nascent microcalcification and was proven to have pharmacological properties highly favourable for PET imaging. Conclusions. 18F-fluoride PET/CT is a valuable tool for exploring pathobiology in CAVD and atherosclerosis may represent an attractive method for assessing response to novel therapies.