18F-NaF Uptake on Vascular PET Imaging in Symptomatic versus Asymptomatic Atherosclerotic Disease: a Meta-Analysis

Abstract Introduction 18F-sodium fluoride (NaF) positron-emission tomography (PET) is increasingly being used to measure microcalcification in atherosclerotic disease in vivo. Correlations have been drawn between sodium fluoride uptake and the presence of high-risk plaque features, as well as its association with clinical atherosclerotic sequelae. The aim of this review was to perform a meta-analysis of NaF uptake on PET imaging and its relation to symptomatic and asymptomatic disease. Methods A systematic review was performed according to PRISMA guidelines, via searching the MEDLINE database up to August 2023. The search strategy included the terms "NaF", "PET" and "plaque", and all studies were included where there was data listed regarding the degree of microcalcification, as measured by 18F-NaF uptake in symptomatic and asymptomatic atherosclerotic plaques. Analysis involved calculating standardized mean differences between uptake values and comparison using a random-effects model. Results A total of 15 articles, involving 423 participants, were included in the meta-analysis. Comparing 18F-NaF uptake in symptomatic vs asymptomatic atherosclerotic plaques, a standardized mean difference of 0.42 (95% CI 0.29-0.56; p<0.001, I2 = 54.1%) was noted for those studies comparing symptomatic and asymptomatic plaques in the same participant, with no significant change in effect based on arterial territory studied (QM = 5.02, p = 0.08). In those studies where data was included from participants with and without symptomatic disease, the standardized mean difference between symptomatic and asymptomatic plaques was 0.44 (95% CI 0.03-0.85, p=0.037, I2 = 40.4%). All studies including asymptomatic participants were investigating carotid disease. Conclusions PET imaging using 18F-NaF can detect differences in microcalcification between symptomatic and asymptomatic atherosclerotic plaques within and between individuals, and is a marker of symptomatic disease. The standardization of 18F-NaF PET imaging protocols, and its future use as a risk stratification tool or outcome measure, requires further study. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement SB is supported by a Research Training Fellowship from The Dunhill Medical Trust [JBGS22\20]. The ICARUSS study was supported as part of a Research Training Fellowship awarded to NRE by The Dunhill Medical Trust [RTF44/0114], and by the NIHR Cambridge Biomedical Research Centre (NIHR203312). MC is supported by a BHF Career Development Fellowship and the NIHR. JMT is supported by a Wellcome Trust Clinical Research Career Development Fellowship (211100/Z/18/Z) and the Cambridge BHF Centre for Research Excellence (18/1/34212). JHFR is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE, the EPSRC and the Wellcome Trust. NRE is supported by a Stroke Association Senior Clinical Lectureship [SA-SCL-MED-22\100006]. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Not applicable Study registered to PROSPERO: www.crd.york.ac.uk/CRDWeb/ShowRecord.asp?ID=42023451363 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All anonymised data will be provided on reasonable request to the corresponding author.