On the detection of vulnerable plaques in human coronary atherosclerosis
Creators: name: Moss, Alastair James
Publisher: name: The University of Edinburgh
Year: 2020
Subjects: coronary artery disease
scanning
CT scan
18F-sodium fluoride

description: BACKGROUND Coronary atherosclerosis is a chronic inflammatory disease which progresses to luminal stenosis and plaque rupture events. Recent developments in non-invasive cardiovascular imaging have enabled the identification of coronary plaques with an increased propensity to rupture. Coronary computed tomography angiography allows visualisation of thearterial wall to discern regions of high-risk plaque in patients with non-obstructive and obstructive coronary artery disease. The anatomical assessment afforded by coronary computed tomography angiography can be combined with hybrid positron emission tomography computed tomography to provide a measure of disease activity. Using novel radiotracers targeted at specific cellular pathways in atherosclerosis, it is now possible to observe plaque activitywith 18F-sodium fluoride in vivo. The principal aims of this thesis were to evaluate the prognostic impact of adverse plaque features using standard coronary computed tomography angiography,to perform reproducibility and histological validation studies ofa novel non-invasive imaging technique for detecting high-risk plaquewith coronary 18F-fluoride imagingand assess whether coronary 18F-fluoride could be used to select high-risk individuals as part a phase 3 clinical trial of an investigational medicinal product. ADVERSE CORONARY ARTERY PLAQUE CHARACTERISTICS IN PATIENTS WITH CORONARY ARTERY DISEASEIn a prognostic substudy of the SCOT-HEART trial, adverse plaque features were associated with a three-fold increase in coronary heart disease death or non-fatal myocardial infarction (hazard ratio 3.01 (95% confidence intervals 1.61 to 5.63); p=0.001). Patients with both obstructive disease and adverse plaque had the highest event rate with a greater than 10-fold increase in events (hazard ratio 11.50 (95% confidence interval 3.39 to 39.04); p&lt;0.001). However, these associations weredependent coronary artery calcium score, a surrogate measureof coronary plaque burden.MOLECULAR CORONARY PLAQUE IMAGING USING 18F-FLUORIDE To explore whether a novel non-invasive imaging technique could accurately detect regions of coronary microcalcification in patients with coronary artery disease, a scan-rescan reproducibility study of 30 patients was undertaken.Using a standardised metric (coronary to atrial blood pool ratio, TBRMAX), 18F-fluoride activity couldbe precisely and reproducibly measured within the coronary vasculature. The analytical performance of coronary 18F-fluoride activity was sufficient to determine whether this radiotracer couldbe used as a non-invasive imaging marker of plaque vulnerability in clinical trials.EX VIVO 18F-FLUORIDE UPTAKE IN HUMAN CORONARY ATHEROSCLEROSISEx vivovalidation of coronary artery specimens using 18F-fluoride demonstrated highly selectivity for hydroxyapatite deposition in atherosclerotic coronary plaque.Specifically, coronary 18F-fluoride binding has a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride binding are associated with osteopontin, an inflammatory-stimulated glycophosphoproteinthat increases tissue mineralisation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation. TICAGRELOR TO REDUCE MYOCARDIAL INJURY IN PATIENTS WITH HIGH-RISK CORONARY ARTERY PLAQUEIn a double-blind randomised placebo-controlled trial, 191 patients with multivessel coronary artery disease underwent 18F-fluoride positron emission tomography and computed tomography coronary angiography. In patients with high-risk plaque defined by 18F-fluoride uptake in at least one coronary plaque (n=120/191), there was no evidence thatdual antiplatelet therapy with ticagrelor affected 30-day plasma troponin concentrations (ratio of geometric means1.11 [95% confidence interval 0.90-1.36], p=0.32). CONCLUSIONThese observations suggest that high-risk plaque detection identifies individuals at increased risk of cardiovascular events. Coronary 18F-fluoride can be utilised in the setting of randomised controlled trials as a precise biomarker of plaque activity. Further projects to assess whether coronary 18F-fluoride can predict plaque rupture events are ongoing.