Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis

$\textbf{BACKGROUND}$: 18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging. $\textbf{METHODS AND RESULTS}$: Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11). $\textbf{CONCLUSIONS}$: Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies. $\textbf{CLINICAL TRIAL REGISTRATION}$ - URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.The study was funded by the British Heart Foundation (FS/14/78/31020). Drs Pawade, Cartlidge, Jenkins, Dweck, and Newby are supported by the British Heart Foundation (SS/CH/09/002/26360, FS/13/77/30488, SS/CH/09/002/2636, FS/14/78/31020, and CH/09/002). Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr Dweck is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015. Dr Adamson is supported by New Zealand Overseas Training and Research Fellowship (1607) and Edinburgh and Lothians Health Foundation (50–534). The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by NHS Research Scotland (NRS) through NHS Lothian. Dr Rudd is partly supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust

18^{18}F-Fluoride and 18^{18}F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

BACKGROUND: Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether $^{18}$F-fluoride or $^{18}$F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. METHODS AND RESULTS: We performed $^{18}$F-fluoride and $^{18}$F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, $^{18}$F-fluoride selectively highlighted microcalcification. Carotid $^{18}$F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (log$_{10}$ standardized uptake value$_{mean}$ 0.29±0.10 versus 0.23±0.11, P=0.001) and compared with control patients (log$_{10}$ standardized uptake value$_{mean}$ 0.29±0.10 versus 0.12±0.11, P=0.001). $^{18}$F-Fluoride uptake correlated with high-risk plaque features (remodeling index [r=0.53, P=0.003], plaque burden [r=0.51, P=0.004]), and predicted cardiovascular risk [r=0.65, P=0.002]). Carotid $^{18}$F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, $^{18}$F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (r=0.53, P=0.019), but not with plaque phenotype. CONCLUSIONS: $^{18}$F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.Dr Vesey and the study were funded by program grants from the British Heart Foundation (PG12/8/29371) and Chest Heart and Stroke Scotland (R13/A147). Dr Jenkins, Vesey, Dweck, and Newby are supported by the British Heart Foundation (FS/14/78/31020, CH/09/002) and the Wellcome Trust (WT103782AIA). Dr Dweck is the recipient of the Sir Jules Thorn Biomedical Research Award 2015. The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by National Health Service (NHS) Research Scotland (NRS) through NHS Lothian. Dr Beek is supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Dr Rudd is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust

Left Ventricular Fibrois in Patients with Aortic Stenosis

Aortic valve stenosis is the commonest form of valvular heart disease in the Western world, currently affecting about 7% of the population over the age of 60, while 3% of people over the age of 75 have severe stenosis. With an aging population, its prevalence is expected to increase dramatically in the next few decades with major financial implications for global healthcare systems. Aortic stenosis is characterized by progressive valve narrowing that leads to a high-pressure load on the left ventricle (LV), triggering hypertrophy of cardiac myocytes, and increase in LV wall thickness and mass. At present there is no effective medical therapy capable of altering disease progression so that the only treatment is aortic valve replacement (AVR), usually with either surgical or percutaneous techniques. Current international guidelines recommended AVR in patients with severe stenosis and evidence of LV decompensation (either on the basis of symptoms or a reduced ejection fraction). Following AVR patients demonstrate a variable degree of regression of the ventricular hypertrophy with favorable prognosis demonstrated in the cohort of patients with the highest level of regression. Myocardial fibrosis is often seen in patients before intervention, and its presence is associated with worse perioperative and long-term outcome. In this chapter we review the literature pertaining to the importance of myocardial fibrosis in patients with aortic stenosis and evaluate the mechanisms, detection, and clinical significance