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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 study 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 Ovid MEDLINE, Ovid Embase, Cochrane Library, PubMed, Scopus, and Web of Science Core Collection databases up to May 2024. The search strategy included the terms ‘NaF’, ‘PET’, and ‘plaque’, and all studies with data regarding the degree of microcalcification, as measured by ¹⁸F-NaF uptake in symptomatic and asymptomatic atherosclerotic plaques, were included. Analysis involved calculating mean differences between uptake values and comparison using a random-effects model.

Results:

A total of 16 articles, involving 423 participants, were included in the meta-analysis (10 carotid artery studies, five coronary artery studies, and one in peripheral vascular disease). Comparing ¹⁸F-NaF uptake in symptomatic versus asymptomatic atherosclerotic plaques, a mean difference of 0.43 (95% CI 0.29 to 0.57; p < 0.0001, I² = 65%) was noted in studies comparing symptomatic and asymptomatic plaques in the same participant, with a significant difference in effect based on arterial territory studied (χ² = 12.68, p = 0.0018). In studies of participants with and without symptomatic disease, there was no significant difference between symptomatic and asymptomatic plaques (mean difference 0.27, 95% CI −0.26 to 0.80, p = 0.28, I² = 85%).

Conclusions:

PET imaging using ¹⁸F-NaF can detect differences in microcalcification between symptomatic and asymptomatic atherosclerotic plaques within, but not between, individuals, and thus, 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. (PROSPERO Registration ID: CRD42023451363)

Keywords

atherosclerosis microcalcification positron emission tomography (PET)vascular imaging/diagnostics risk stratification

Introduction

Atherosclerosis is a systemic chronic arterial disease,¹ involving the accumulation of lipids and inflammatory cells² to form foci of disease, termed ‘plaques’, at the vessel wall. It is the cause of over one-third of all deaths,³ through resulting diseases such as myocardial infarction, ischemic stroke, and critical limb-threatening ischemia. In some patients, minor or less severe clinical symptoms may be a marker of higher risk for progressing to more severe clinical disease, such as stable angina preceding myocardial infarction,^4,5 or transient ischemic attack, conferring a higher risk of ischemic stroke in the short term.^6,7

Plaques may have heterogenous appearances,⁸ with certain plaque features indicating a higher risk of rupture and subsequent clinical sequelae.^8,9 These high-risk features include the presence of a lipid-rich necrotic core,¹⁰ intraplaque hemorrhage,¹¹ a thin or ruptured fibrous cap,¹² and the presence of microcalcification.¹³ The mechanisms determining the transition from a low-risk (‘stable’) to a high-risk (‘unstable’) plaque and vice versa are incompletely understood,^14,15 but microcalcification has been recognized as a potential cause for acute plaque rupture through mechanical destabilization of the fibrous cap of the plaque,¹⁶ as well as causing an increased inflammatory response within the plaque,¹⁷ leading to enzymatic destabilization of the plaque.¹⁸ Microcalcifications are calcium deposits of < 50 μm in diameter, which is below the spatial resolution of commonly used clinical vascular imaging techniques,¹⁹ such as computed tomography (CT) or magnetic resonance imaging (MRI).

Positron emission tomography (PET) is a nuclear imaging technique used in vascular imaging due to its high sensitivity to detect low concentrations of radiolabeled ligands (termed ‘tracers’), which can be directed to detect the presence of a specific target or process.²⁰ Sodium fluoride (NaF), labeled with fluorine-18, has been validated as a tracer for the identification of microcalcification in vascular imaging.²¹

NaF adsorbs to the surface of hydroxyapatite within the body,²² with hydroxyapatite being the most common calcium-containing crystal structure in atherosclerotic plaques in vivo.^23,24 Fluorine exchanges with hydroxyl groups on the surface of these crystals, with substantially less tracer uptake deeper within the crystal structure of the molecule.²² Calcium deposits with an increased surface area therefore have increased fluoride ion uptake over the uptake durations used in clinical PET scanning.^22,25 Using NaF, this process of hydroxyl-ion substitution can be used to detect microcalcifications via PET imaging. Owing to their high surface area to volume ratio, microcalcifications will demonstrate higher uptake on PET compared to areas with no microcalcification, or those with larger deposits of calcium (‘macrocalcification’).^26–28 NaF-PET can be preferred for vascular imaging compared to other PET imaging techniques for visualizing high-risk plaques due to issues such as ‘spill-over artifact’ when using fluorodeoxyglucose (FDG)-PET in cardiac imaging.

There is an increasing body of literature demonstrating the use of NaF-PET for vascular imaging in atherosclerosis,²⁹ and specifically, in symptomatic disease. This meta-analysis focuses on the role of NaF-PET imaging to differentiate between symptomatic versus asymptomatic atherosclerotic disease.

Methods

Protocol, search strategy, and selection criteria

Details for the protocol were prospectively registered on PROSPERO (ID: CRD42023451363).³⁰ The selection process and reporting items were based on the preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram and checklist.³¹ The primary outcome was to determine differences in NaF tracer uptake between symptomatic and asymptomatic atherosclerotic plaques. A search strategy was formulated using Embase and MEDLINE via Ovid, the Cochrane Library, PubMed, Scopus, and Web of Science Core Collection Databases (Supplementary Figures S1a–e). Additionally, a manual search was performed to identify relevant records through reference searches. Duplicate records were removed, and the retrieved records were checked for inclusion and exclusion criteria.

Studies were eligible for inclusion if they investigated the association between NaF uptake and symptomatic and asymptomatic atherosclerotic plaques, where symptomatic plaques were those that were associated with a recent clinical vascular event, including, but not limited to, stroke, transient ischemic attack, or myocardial infarction, diagnosed by recognized clinical or imaging criteria, whereas asymptomatic plaques were those not associated with a recent clinical vascular event. Studies were excluded if animal or preclinical data were used, nonatherosclerotic or nonsymptomatic atherosclerotic disease was investigated, or if the study did not provide details regarding the type or location of symptomatic disease. In addition, studies not using NaF-PET were excluded, along with editorial or review articles and case reports. Abstracts were eligible for inclusion in the systematic review and meta-analysis to ensure the completeness of the data obtained, and to ensure the most recent research was included in this emerging field.

Data selection, extraction, and risk of bias assessment

Data were extracted by one study investigator (SB) and checked by another researcher (NRE), from the included records, using a standardized electronic data collection form. Discrepancies were resolved by re-extraction or by third-party adjudication (EAW) as required. Retrieved characteristics from the studies included, but were not limited to, the number of participants, participant population, targeted vascular territory, time from symptomatic event to imaging, dose of NaF injected, uptake time, imaging protocols, primary endpoint measures for PET/CT, and main findings, which were tabulated as per published guidance.³² The Risk of Bias in Observational Studies of Exposures (ROBINS-E) tool³³ was used to assess the risk of bias of the studies included in the analysis.

Statistical analysis

The mean and associated SD, or the median and the associated IQR of the measurement of NaF signal were extracted from the included studies. Extracted median and IQR data were converted into mean and SD data to calculate a unified outcome.³⁴ In studies where multiple measures of NaF signal were reported, the value corresponding to the tissue-to-background ratio (TBR) related to the maximum standardized uptake value (SUV) (TBR_max) was taken. The absolute difference between the populations when NaF signal is measured using SUV versus TBR is minor, given the low blood pool activity of NaF following an appropriate uptake time.¹⁹

Studies were classified by their included participants – those with only symptomatic participants, or those also including an asymptomatic control population. Given that considerable between-study heterogeneity was anticipated, random-effects models were used for meta-analysis. We used Knapp–Hartung adjustments³⁵ to calculate the confidence interval around the pooled effect. The restricted maximum likelihood estimator³⁶ was used to calculate the between-study variance. I² statistics were also calculated to determine the variability in effect estimate due to between-study heterogeneity. Meta-analyses were performed where there were two or more studies using the same type of included population. Pooled outcomes from the included studies were reported as mean differences.

Funnel plot asymmetry was assessed visually and using Egger’s test,³⁷ where 10 or more studies were included in the meta-analysis to identify any small study effects. Two-tailed tests were used, and a p-value of 0.05 was taken as the limit of statistical significance. Statistical analyses were performed using the meta³⁸ package, using R Statistical Software (v4.3.1; R Foundation for Statistical Computing, 2023), with mean and SD values estimated from extracted median and IQR data by the Method for Unknown Non-Normal Distributions.³⁹

Subgroup analyses were performed between the different arterial territories assessed in the included studies to generate mean difference measurements for symptomatic atherosclerotic plaques compared with asymptomatic plaques, and to determine any statistical differences in NaF uptake between different arterial territories.

Results

Included studies

A total of 2811 titles were initially identified from the search (Figure 1).⁴⁰ Manual de-duplication of results was performed, and the remaining 1611 records underwent manual screening of the titles and abstracts.⁴¹ Of those, 1475 were excluded as not meeting the inclusion criteria (618 not related to atherosclerotic disease, 303 not related to NaF-PET imaging, 291 being of the incorrect article type, and 263 reporting only animal or preclinical data). A total of 136 articles were therefore sought for retrieval. One article was not available for analysis due to the abstract being withdrawn, and therefore 135 articles were assessed for eligibility through full-text review. Of these, 119 were excluded (81 due to not reporting outcomes related to symptomatic atherosclerotic disease, 23 due to no documented comparison between symptomatic and asymptomatic disease, and 15 due to reporting data or outcome measures insufficient for meta-analysis). The remaining 16 articles were included in the meta-analysis and form the study population analyzed. A summary of study details is shown in Supplementary Tables S1 and S2, dichotomized based on the comparator of symptomatic disease used in each study.

Figure 1.

PRISMA diagram of systematic review search synthesis.

Comparative intra-individual ¹⁸F-NaF tracer uptake between symptomatic and asymptomatic atherosclerotic disease

Twelve studies, including 312 participants, reported data in participants comparing NaF uptake in the symptomatic atherosclerotic plaque to asymptomatic plaques within the same participant’s vascular territory being observed, including data for 312 symptomatic and 377 asymptomatic plaques (Supplementary Table S1).

Pooled comparisons of these studies demonstrated a significantly higher uptake in symptomatic lesions compared to asymptomatic plaques (mean difference 0.43, 95% CI 0.29 to 0.57, p < 0.0001; Figure 2). A funnel plot (Supplemental Figure S2) assessing standard error about the mean difference in the included studies did not appear asymmetric visually, and the result of Egger’s test was not statistically significant (p = 0.33). Subgroup analysis to compare results from different arterial territories showed a significant difference in this relationship based on the site of the symptomatic plaque (χ² = 12.68, p = 0.0018). Significant heterogeneity was noted between the studies (τ² = 0.023, I² = 65%, p = 0.00097).

Figure 2.

Forest plot of included studies^{25,41,52,69–77} summarizing data comparing symptomatic and asymptomatic atherosclerotic disease within individuals.

A sensitivity analysis was performed, including those studies found to be at low risk of bias other than due to residual confounding or where there were some concerns about risk of bias only in one domain, due to percutaneous coronary intervention being indicated clinically in participants with myocardial infarction (Supplementary Figure S3). This analysis, which included three carotid artery studies, one coronary artery study, and one study investigating the superficial femoral arteries, showed similar findings to the parent analysis (mean difference 0.39, 95% CI 0.11 to 0.68, p = 0.019; Supplementary Figure S4). This sensitivity analysis excluded data obtained from nonpeer-reviewed articles^42–44 as these were deemed to be at high risk of bias.

Comparative 18F-NaF tracer uptake in symptomatic and asymptomatic atherosclerotic plaques where a healthy control population was included

Eight studies, including 212 participants, reported data in participants comparing NaF uptake in the symptomatic atherosclerotic plaque compared to asymptomatic plaques, pooling data from asymptomatic disease within the same symptomatic individual and plaques from asymptomatic control participants, including data for 189 symptomatic and 189 asymptomatic plaques (Supplementary Table S2). Six studies assessed atherosclerotic disease within the carotid arteries, with the remaining two studies assessing disease within the coronary arteries. The risk of bias assessment for these studies is shown in Supplementary Figure S5.

Analysis of the pooled data from these studies demonstrated no significant overall difference in NaF uptake in symptomatic atherosclerotic lesions compared to asymptomatic lesions, present in either the same individuals or in healthy controls (mean difference 0.27, 95% CI −0.26 to 0.80, p = 0.28; Figure 3). Subgroup analysis was performed to investigate differences between studies assessing NaF uptake in asymptomatic control participants only, or in asymptomatic control participants and asymptomatic plaques within a symptomatic participant. Studies investigating asymptomatic plaques within and between participants were solely performed in the carotid arteries, and in this group of five studies, symptomatic arteries showed a higher NaF uptake (mean difference 0.60, 95% CI 0.08 to 1.12, p = 0.03), whereas those studies including asymptomatic participants only as comparators, without assessing asymptomatic plaques within the symptomatic individual (two coronary artery studies and one carotid artery study), showed no significant difference in NaF uptake (mean difference −0.12, 95% CI −1.11 to 0.86, p = 0.74). There was significant heterogeneity between studies included in this analysis (τ² = 0.40, I² = 85%, p < 0.0001).

Figure 3.

Forest plot of included studies^{25,70,72,75,78–81} summarizing data comparing symptomatic and asymptomatic atherosclerotic disease between individuals.

Discussion

These results demonstrate the utility of NaF-PET, combined with CT or MRI, to differentiate between symptomatic and asymptomatic atherosclerotic disease within individuals in a number of different vascular territories. A mean difference of 0.43 units in the meta-analysis of studies included in Figure 2 shows the sensitivity and reproducibility⁴⁵ of PET as an imaging modality for the investigation of atherosclerosis, and the detection of differing levels of microcalcification between plaques in at-risk individuals using commonly used imaging protocols and analysis methods. In the context of potential clinical ramifications, in a small study, a one-unit increase in TBR_max in the carotid arteries has been associated with an up to 31% increased risk of recurrent ipsilateral stroke.⁴⁶ Studies have also demonstrated a correlation between NaF uptake and high-risk morphological features on MRI, such as the presence of a lipid-rich necrotic core, or intraplaque hemorrhage.⁴⁷ In addition, there is emerging evidence of a prognostic link between NaF signal on PET and the risk of recurrent disease,⁴⁸ where coronary NaF imaging had the ability to predict myocardial infarction and cardiovascular death in symptomatic patients. NaF-PET imaging also has been shown to predict future symptomatic coronary disease in high-risk individuals.⁴⁹

As noted in Supplementary Tables S1 and S2 and Figures 2 and 3, there is significant clinical and methodological heterogeneity between studies. We utilized random-effects models in this analysis given these noted differences had the potential to affect the outcome data, and specifically the magnitude of difference between the two groups. These differences are in part due to the clinical diversity of the populations included in the study, including different research sites, with associated differences in the prevalence and diagnosis of the relevant atherosclerotic disease, and participants undergoing clinical interventions prior to imaging, such as percutaneous coronary intervention in some participants with myocardial infarction, with the effects on NaF uptake not well described in the literature. There is also significant heterogeneity in the results due to the methodological variation of the included studies, including a range of different doses of NaF radiotracer used, along with a nonstandardized uptake time, blood pool measurement for TBR calculations, and outcome measurement, including how and where maximum uptake was calculated. Irkle et al.²⁵ demonstrated an optimum uptake time of around 60 minutes, based on in vitro and in vivo data, and a 60-minute uptake time was the modal NaF uptake time in the included studies. This heterogeneity may introduce confounding factors, but the study participants seem to represent the range of patients seen in clinical practice. In addition, the results appear in keeping with the larger body of literature describing NaF-PET in atherosclerosis due to its associations with high-risk plaque histology^50,51 and imaging appearance,^52,53 and its links with new^49,54 or symptomatic disease.^46,48

There was also significant heterogeneity in the included studies between the time of symptom onset and imaging being performed (Supplementary Tables S1 and S2).^82,83 Insufficient data are available concerning the temporal changes in microcalcification and NaF uptake following an acute atherosclerotic event, and further investigation of the optimum time for imaging microcalcification in relation to symptomatic disease, and further data on the change in microcalcification with time following symptomatic disease, could further standardize imaging protocols and improve the robustness of outcomes measured using NaF-PET.

NaF-PET lacks a consensus on best practice, in contrast to vascular FDG-PET imaging, following the 2016 position paper from the European Association of Nuclear Medicine.⁵⁵ Having a standardized methodology for performing and analyzing vascular NaF imaging would allow increased comparability and reproducibility between studies. Aspects for standardization would include the administered radiotracer dose, duration between dose administration and imaging, and between clinical event and imaging, along with imaging protocols and analysis, such as how imaging should be performed in order to best remove motion artifact, as well as how to measure and describe uptake levels, which could include plaque-based or anatomical uptake, SUV versus TBR (or alternatives⁵⁶), and whether the TBR_max should be reported, or some other measure, such as the ‘most diseased segment’, being the mean of the TBR_max over the region of interest (ROI) with the highest reading and the TBR_max of the two adjacent ROIs.^55,57 In addition, in comparisons involving intra-participant imaging data, description and analysis in a paired manner may be an interesting avenue for future research in this area, as this could provide information as to the differences in uptake between symptomatic and asymptomatic plaques, removing some confounding due to underlying genetic and physiological differences between individuals.

Of note, in the subgroup analysis, there appeared to be a reduced mean difference between symptomatic and asymptomatic disease within the same individual in the carotid artery studies. Though this may be a result of the clinical and methodological heterogeneity discussed above, an underlying pathophysiological difference in how carotid artery plaques behave in vivo compared to other sites of atherosclerosis is also biologically plausible. Some studies have suggested relationships between vessel wall shear stress and NaF uptake,⁵⁸ the effects of vessel geometry on shear stress,^59,60 and differences in shear stress in different arterial territories,⁶¹ which theoretically could lead to increased microcalcification in carotid atherosclerotic plaques, leading to the smaller difference between symptomatic and nonculprit carotid plaques within the same individual, as seen in the above analysis. Future research investigating NaF uptake in different arterial territories simultaneously would help answer this question of differential uptake, and the associated clinical implications; for example, relative risks of future disease within each territory, and whether different clinical management may be recommended based on the site of highest uptake.

In the analysis of culprit vessels compared to nonculprit vessels, including those in asymptomatic control participants, no overall mean difference between culprit and nonculprit plaques was demonstrated. This follows from the above discussion, as NaF-PET imaging in atherosclerosis has been used to identify symptomatic disease, as well as high-risk disease in asymptomatic individuals, suggesting NaF-PET may not be able to distinguish between presymptomatic (but high-risk) and symptomatic plaques. Therefore, rather than providing a threshold value, over which any plaque in any person may be deemed ‘high-risk’, this analysis demonstrates that comparison of plaques within individuals rather than between individuals is more useful to identify high-risk or symptomatic plaque. This would also concur with the current understanding of the underlying physiology around microcalcification, where there is a higher risk of plaque rupture with increasing microcalcification due to induced changes and responses to wall shear stress,^62,63 rather than a threshold level of microcalcification below which the plaque is stable, and above which confers risk of disease.

In atherosclerosis, PET has been demonstrated to have a high sensitivity for the target pathophysiology and can be combined with other imaging modalities to provide additional utility, such as in combination with CT and CT angiography to assess for stenotic disease⁶⁴ and calcium scores in the coronary vasculature,⁶⁵ or with MRI to identify high-risk appearances as discussed above.⁶⁶ In vascular imaging, NaF may be superior to FDG as it may have a superior ability to discriminate between symptomatic and asymptomatic disease in high-risk individuals.⁶⁷ In addition, NaF does not require fasting prior to the uptake period, and can be used with a shorter uptake time compared to FDG-PET.^25,55 NaF is also less susceptible to spill-over artifact, such as from the myocardium, which can limit FDG-based PET imaging of the arteries.⁶⁷ However, the cost, radiation exposure, and uptake and scanning time mean the role of PET imaging in routine clinical assessment of atherosclerotic disease is currently limited. There remain technical issues with PET imaging in atherosclerosis, mainly related to partial volume effects due to low spatial resolution and the small plaque volumes encountered. In addition, specific gating techniques are generally required to correct for cardiac motion over the image acquisition time, and there has been interest in different methodological approaches to correct for these issues.^68,69

Microcalcification is known to confer an increased risk of plaque rupture through enzymatic¹⁸ and mechanical¹⁷ destabilization of the plaque surface. Therefore, targeting this process may reduce the risk of early recurrence following symptomatic atherosclerotic disease. NaF-PET can be utilized to assess responses to clinical interventions, given its accuracy and sensitivity in determining differences in the presence of microcalcification in vivo.⁷⁰ Additionally, the process by which microcalcification evolves into macrocalcification, which is thought to be protective for the atherosclerotic plaque, is poorly defined and understood.⁷¹ Temporal evaluation of the microcalcification-macrocalcification process through NaF-PET/CT could shed more light on the factors which confer a greater or lesser degree of risk with calcification in atherosclerosis. In addition, NaF imaging could potentially have a role in risk stratification in patients where there is uncertainty about the risk of recurrent stroke or the need for surgical intervention, which is particularly relevant for those with moderate 50–69% stenoses and those where frailty or comorbidity may lead to a preference to avoid surgical intervention. In addition, there is interest in the use of NaF-PET imaging to identify study participants at higher risk of future clinical disease,⁷² or to provide surrogate endpoints in interventional trials.⁷³

Conclusion

Our findings support vascular NaF-PET imaging as a reliable method for the assessment of atherosclerotic disease that is able to help differentiate between culprit and nonculprit plaques within an individual but is unable to reliably differentiate between symptomatic and asymptomatic plaques in a population that includes unmatched asymptomatic individuals. The majority of data involve analysis of the carotid or coronary circulation, but NaF-PET imaging is also a viable imaging technique in other arterial territories. There is a potential future role of NaF-PET in clinical atherosclerosis imaging and providing surrogate markers of impact in interventional trials, but harmonization of imaging protocols including outcome measures, injected doses, and uptake times is required to ensure comparability between studies.

Supplemental Material

sj-pdf-1-vmj-10.1177_1358863X241287692 – Supplemental material for 18F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis

Supplemental material, sj-pdf-1-vmj-10.1177_1358863X241287692 for 18F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis by Shiv Bhakta, Mohammed M Chowdhury, Jason M Tarkin, James HF Rudd, Elizabeth A Warburton and Nicholas R Evans in Vascular Medicine

Footnotes

Data availability statement

The data underlying this article will be shared on reasonable request to the corresponding author.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

Shiv Bhakta 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 Nicholas Evans by The Dunhill Medical Trust [RTF44/0114], and by the NIHR Cambridge Biomedical Research Centre (NIHR203312). Mohammed Chowdhury is supported by a BHF Career Development Fellowship and the NIHR. Jason Tarkin 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). James Rudd is part-supported by the NIHR Cambridge Biomedical Research Centre, the British Heart Foundation, HEFCE, the EPSRC, and the Wellcome Trust. Nicholas Evans is supported by a Stroke Association Senior Clinical Lectureship [SA-SCL-MED-22\100006].

ORCID iD

Shiv Bhakta

Supplemental material

Supplemental material for this article is available online.

References

Libby

Buring

Badimon

, et al. Atherosclerosis. Nat Rev Dis Primers 2019; 5: 56.

Jebari-Benslaiman

Galicia-García

Larrea-Sebal

, et al. Pathophysiology of atherosclerosis. Int J Mol Sci 2022; 23: 3346.

Timmis

Vardas

Townsend

, et al. European Society of Cardiology: Cardiovascular disease statistics 2021. Eur Heart J 2022; 43: 716–799.

Eisen

Bhatt

Steg

, et al. Angina and future cardiovascular events in stable patients with coronary artery disease: Insights from the Reduction of Atherothrombosis for Continued Health (REACH) Registry. J Am Heart Assoc 2016; 5: e004080.

Kannel

Feinleib

Natural history of angina pectoris in the Framingham Study. Prognosis and survival. Am J Cardiol 1972; 29: 154–163.

Rothwell

Warlow

CP.

Timing of TIAs preceding stroke: Time window for prevention is very short. Neurology 2005; 64: 817–820.

Johansson

Cuadrado-Godia

Hayden

, et al. Recurrent stroke in symptomatic carotid stenosis awaiting revascularization: A pooled analysis. Neurology 2016; 86: 498–504.

Insull

The pathology of atherosclerosis: Plaque development and plaque responses to medical treatment. Am J Med 2009; 122: S3–S14.

Finn

Nakano

Narula

, et al. Concept of vulnerable/unstable plaque. Arterioscler Thromb Vasc Biol 2010; 30: 1282–1292.

10.

Fleg

Stone

Fayad

, et al. Detection of high-risk atherosclerotic plaque: Report of the NHLBI Working Group on current status and future directions. JACC Cardiovasc Imaging 2012; 5: 941–955.

11.

Deng

Yang

, et al. Carotid plaque magnetic resonance imaging and recurrent stroke risk: A systematic review and meta-analysis. Medicine (Baltimore) 2020; 99: e19377.

12.

Redgrave

Gallagher

Lovett

, et al. Critical cap thickness and rupture in symptomatic carotid plaques: The Oxford Plaque Study. Stroke 2008; 39: 1722–1729.

13.

Vancheri

Longo

Vancheri

, et al. Coronary artery microcalcification: Imaging and clinical implications. Diagnostics (Basel) 2019; 9: 125.

14.

Fox

KAA

Metra

Morais

, et al. The myth of ‘stable’ coronary artery disease. Nat Rev Cardiol 2020; 17: 9–21.

15.

Akers

Nicholls

Di Bartolo

BA.

Plaque calcification. Arterioscler Thromb Vasc Biol 2019; 39: 1902–1910.

16.

Shi

Gao

, et al. Calcification in atherosclerotic plaque vulnerability: Friend or foe? Front Physiol 2020; 11: 56.

17.

Kawtharany

Bessueille

Issa

, et al. Inflammation and microcalcification: A never-ending vicious cycle in atherosclerosis? J Vasc Res 2022; 59: 137–150.

18.

Hansson

Libby

Tabas

Inflammation and plaque vulnerability. J Intern Med 2015; 278: 483–493.

19.

Tzolos

Dweck

MR.

¹⁸F-sodium fluoride (¹⁸F-NaF) for imaging microcalcification activity in the cardiovascular system. Arterioscler Thromb Vasc Biol 2020; 40: 1620–1626.

20.

Sriranjan

Tarkin

Evans

, et al. Atherosclerosis imaging using PET: Insights and applications. Br J Pharmacol 2021; 178: 2186–2203.

21.

Høilund-Carlsen

Sturek

Alavi

, et al. Atherosclerosis imaging with ¹⁸F-sodium fluoride PET: State-of-the-art review. Eur J Nucl Med Mol Imaging 2020; 47: 1538–1551.

22.

Blau

Ganatra

Bender

MA.

18 F-fluoride for bone imaging. Semin Nucl Med 1972; 2: 31–37.

23.

Schmid

McSharry

Pameijer

, et al. Chemical and physicochemical studies on the mineral deposits of the human atherosclerotic aorta. Atherosclerosis 1980; 37: 199–210.

24.

Bischetti

Scimeca

Bonanno

, et al. Carotid plaque instability is not related to quantity but to elemental composition of calcification. Nutr Metab Cardiovasc Dis 2017; 27: 768–774.

25.

Irkle

Vesey

Lewis

, et al. Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography. Nat Commun 2015; 6: 7495.

26.

Derlin

Richter

Bannas

, et al. Feasibility of 18F-sodium fluoride PET/CT for imaging of atherosclerotic plaque. J Nucl Med 2010; 51: 862–865.

27.

Morbelli

Fiz

Piccardo

, et al. Divergent determinants of 18F–NaF uptake and visible calcium deposition in large arteries: Relationship with Framingham risk score. Int J Cardiovasc Imaging 2014; 30: 439–447.

28.

Fiz

Morbelli

Piccardo

, et al. 18F-NaF uptake by atherosclerotic plaque on PET/CT imaging: Inverse correlation between calcification density and mineral metabolic activity. J Nucl Med 2015; 56: 1019–1023.

29.

Mayer

Borja

Hancin

, et al. Imaging atherosclerosis by PET, with emphasis on the role of FDG and NaF as potential biomarkers for this disorder. Front Physiol 2020; 11: 511391.

30.

Bhakta

Chowdhury

Tarkin

, et al. 18F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023451363 (2023, accessed September 1, 2023).

31.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.

32.

Higgins

JPT

Thomas

Chandler

(eds) Cochrane Handbook for Systematic Reviews of Interventions, Version 6.4, www.training.cochrane.org/handbook (2023).

33.

ROBINS-E Development Group ( Higgins

JPT

Morgan

Rooney

, et al.) Risk Of Bias In Non-randomized Studies - of Exposure (ROBINS-E). Launch version, 20 June 2023, https://www.riskofbias.info/welcome/robins-e-tool (2024, accessed June 10, 2024 ).

34.

McGrath

Katzenschlager

Zimmer

, et al. Standard error estimation in meta-analysis of studies reporting medians. Stat Methods Med Res 2023; 32: 373–388.

35.

Knapp

Hartung

Improved tests for a random effects meta-regression with a single covariate. Stat Med 2003; 22: 2693–2710.

36.

Viechtbauer

Bias and efficiency of meta-analytic variance estimators in the random-effects model. J Educ Behav Stat 2005; 30: 261–293.

37.

Egger

Davey Smith

Schneider

, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

38.

Balduzzi

Rücker

Schwarzer

How to perform a meta-analysis with R: A practical tutorial. Evid Based Ment Health 2019; 22: 153–160.

39.

Cai

Zhou

Pan

Estimating the sample mean and standard deviation from order statistics and sample size in meta-analysis. Stat Methods Med Res 2021; 30: 2701–2719.

40.

Haddaway

Page

Pritchard

, et al. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and open synthesis. Campbell Syst Rev 2022; 18: e1230.

41.

Ouzzani

Hammady

Fedorowicz

, et al. Rayyan—A web and mobile app for systematic reviews. Syst Rev 2016; 5: 210.

42.

Dweck

Joshi

Jenkins

, et al. Assessment of calcification and inflammation with positron emission tomography in aortic stenosis and atherosclerosis. Lancet 2013; 381: S11.

43.

Andrews

Moss

Doris

, et al. 18 18F-flouride pet MR in valvular and coronary heart disease; A pilot investigational study. Heart 2018; 104: A12.

44.

Sood

Jois

Singhal

, et al. Role of ¹⁸F-NaF PET/CT based imaging of atherosclerotic plaques in patients with myocardial infarction and chronic stable angina. J Nucl Med 2018; 59: 1509.

45.

Evans

Tarkin

Chowdhury

, et al. PET imaging of atherosclerotic disease: Advancing plaque assessment from anatomy to pathophysiology. Curr Atheroscler Rep 2016; 18: 30.

46.

Bhakta

Tarkin

Chowdhury

, et al. Carotid atherosclerotic plaque microcalcification is independently associated with recurrent neurovascular events: A pilot study. Int J Stroke 2024: 17474930241264734.

47.

Kaczynski

Sellers

Seidman

, et al. ¹⁸F-NaF PET/MRI for detection of carotid atheroma in acute neurovascular syndrome. Radiology 2022; 305: 137–148.

48.

Moss

Daghem

Tzolos

, et al. Coronary atherosclerotic plaque activity and future coronary events. JAMA Cardiol 2023; 8: 755–764.

49.

Kwiecinski

Tzolos

Adamson

, et al. Coronary ¹⁸F-sodium fluoride uptake predicts outcomes in patients with coronary artery disease. J Am Coll Cardiol 2020; 75: 3061–3074.

50.

Wen

Gao

Yun

, et al. In vivo coronary ¹⁸F-sodium fluoride activity: Correlations with coronary plaque histological vulnerability and physiological environment. JACC Cardiovasc Imaging 2023; 16: 508–520.

51.

Youn

Al’Aref

Narula

, et al. ¹⁸F-sodium fluoride positron emission tomography/computed tomography in ex vivo human coronary arteries with histological correlation. Arterioscler Thromb Vasc Biol 2020; 40: 404–411.

52.

Majeed

Bellinge

Butcher

, et al. Coronary ¹⁸F-sodium fluoride PET detects high-risk plaque features on optical coherence tomography and CT-angiography in patients with acute coronary syndrome. Atherosclerosis 2021; 319: 142–148.

53.

Lee

Bang

Koo

, et al. Clinical relevance of ¹⁸F-sodium fluoride positron-emission tomography in noninvasive identification of high-risk plaque in patients with coronary artery disease. Circ Cardiovasc Imaging 2017; 10: e006704.

54.

Kitagawa

Yamamoto

Nakamoto

, et al. Predictive value of ¹⁸F-sodium fluoride positron emission tomography in detecting high-risk coronary artery disease in combination with computed tomography. J Am Heart Assoc 2018; 7: e010224.

55.

Bucerius

Hyafil

Verberne

, et al. Position paper of the Cardiovascular Committee of the European Association of Nuclear Medicine (EANM) on PET imaging of atherosclerosis. Eur J Nucl Med Mol Imaging 2016; 43: 780–792.

56.

Tzolos

Kwiecinski

Lassen

, et al. Observer repeatability and interscan reproducibility of 18F-sodium fluoride coronary microcalcification activity. J Nucl Cardiol 2022; 29: 126–135.

57.

Evans

Tarkin

Chowdhury

, et al. Dual-tracer positron-emission tomography for identification of culprit carotid plaques and pathophysiology in vivo. Circ Cardiovasc Imaging 2020; 13: e009539.

58.

Minderhoud

SCS

Fletcher

MacNaught

, et al. Vascular biomechanics and molecular disease activity in the thoracic aorta: A novel imaging method. Eur Heart J Cardiovasc Imaging 2022; 23: 1698–1707.

59.

Zhang

Xie

, et al. Flow patterns and wall shear stress distribution in human internal carotid arteries: The geometric effect on the risk for stenoses. J Biomech 2012; 45: 83–89.

60.

Zhang

Ding

Evaluation of spatial distribution and characterization of wall shear stress in carotid sinus based on two-dimensional color Doppler imaging. Biomed Eng Online 2018; 17: 141.

61.

Zhang

Chan

Kang

, et al. Comparison of the haemodynamic parameters of venous and arterial coronary artery bypass conduits. Ann Acad Med Singap 2016; 45: 369–372.

62.

Maldonado

Kelly-Arnold

Vengrenyuk

, et al. A mechanistic analysis of the role of microcalcifications in atherosclerotic plaque stability: Potential implications for plaque rupture. Am J Physiol Heart Circ Physiol 2012; 303: H619–628.

63.

Cheng

Loree

Kamm

, et al. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions. A structural analysis with histopathological correlation. Circulation 1993; 87: 1179–1187.

64.

Saba

Loewe

Weikert

, et al. State-of-the-art CT and MR imaging and assessment of atherosclerotic carotid artery disease: Standardization of scanning protocols and measurements – A consensus document by the European Society of Cardiovascular Radiology (ESCR). Eur Radiol 2023; 33: 1063–1087.

65.

Kaul

Douglas

PS.

Atherosclerosis imaging: Prognostically useful or merely more of what we know?

Circ Cardiovasc Imaging 2009; 2: 150–160.

66.

Evans

Tarkin

, et al. Integrated cardiovascular assessment of atherosclerosis using PET/MRI. Br J Radiol 2020; 93: 20190921.

67.

McKenney-Drake

Moghbel

Paydary

, et al. ¹⁸F-NaF and ¹⁸F-FDG as molecular probes in the evaluation of atherosclerosis. Eur J Nucl Med Mol Imaging 2018; 45: 2190–2200.

68.

Doris

Otaki

Krishnan

, et al. Optimization of reconstruction and quantification of motion-corrected coronary PET-CT. J Nucl Cardiol 2020; 27: 494–504.

69.

Lassen

Kwiecinski

Cadet

, et al. Data-driven gross patient motion detection and compensation: Implications for coronary ¹⁸F-NaF PET imaging. J Nucl Med 2019; 60: 830–836.

70.

Bing

SALTIRE II: Bisphosphonates and RANKL inhibition in aortic stenosis, https://clinicaltrials.gov/study/NCT02132026 (2014, accessed Feb 3, 2024).

71.

Montanaro

Scimeca

Anemona

, et al. The paradox effect of calcification in carotid atherosclerosis: Microcalcification is correlated with plaque instability. Int J Mol Sci 2021; 22: 395.

72.

Moss

Dweck

Doris

, et al. Ticagrelor to reduce myocardial injury in patients with high-risk coronary artery plaque. JACC Cardiovasc Imaging 2020; 13: 1549–1560.

73.

Bhakta

RJ Warburton

Evans

NR.

Using minocycline to help to identify carotid artery disease that may cause future strokes. https://www.isrctn.com/pdf/68072469 (ISRCTN registry, 2024, accessed Mar 1, 2024).

74.

Joshi

Vesey

Williams

, et al. 18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: A prospective clinical trial. Lancet 2014; 383: 705–713.

75.

Quirce

Martinez-Rodriguez

Banzo

, et al. New insight of functional molecular imaging into the atheroma biology: 18F-NaF and 18F-FDG in symptomatic and asymptomatic carotid plaques after recent CVA. Preliminary results. Clin Physiol Funct Imaging 2016; 36: 499–503.

76.

Vesey

Jenkins

Irkle

, et al. ¹⁸F-fluoride and ¹⁸F-fluorodeoxyglucose positron emission tomography after transient ischemic attack or minor ischemic stroke: Case-control study. Circ Cardiovasc Imaging 2017; 10: e004976.

77.

Marchesseau

Seneviratna

Sjoholm

, et al. Hybrid PET/CT and PET/MRI imaging of vulnerable coronary plaque and myocardial scar tissue in acute myocardial infarction. J Nucl Cardiol 2018; 25: 2001–2011.

78.

Zhang

Jia

, et al. Noninvasive assessment of carotid plaques calcification by ¹⁸F-sodium fluoride accumulation: Correlation with pathology. J Stroke Cerebrovasc Dis 2018; 27: 1796–1801.

79.

Chowdhury

Tarkin

Albaghdadi

, et al. Vascular positron emission tomography and restenosis in symptomatic peripheral arterial disease: A prospective clinical study. JACC Cardiovasc Imaging 2020; 13: 1008–1017.

80.

Cocker

Spence

Hammond

, et al. [¹⁸F]-NaF PET/CT identifies active calcification in carotid plaque. JACC Cardiovasc Imaging 2017; 10: 486–488.

81.

Hop

de Boer

Reijrink

, et al. ¹⁸F-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques. J Nucl Cardiol 2019; 26: 1064–1075.

82.

Kim

Lee

Park

, et al. Analysis of ¹⁸F-fluorodeoxyglucose and ¹⁸F-fluoride positron emission tomography in Korean stroke patients with carotid atherosclerosis. J Lipid Atheroscler 2019; 8: 232–241.

83.

Mechtouff

Sigovan

Douek

, et al. Simultaneous assessment of microcalcifications and morphological criteria of vulnerability in carotid artery plaque using hybrid ¹⁸F-NaF PET/MRI. J Nucl Cardiol 2022; 29: 1064–1074.

Supplementary Material

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18 F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis

Abstract

Introduction:

Methods:

Results:

Conclusions:

Keywords

Introduction

Methods

Protocol, search strategy, and selection criteria

Data selection, extraction, and risk of bias assessment

Statistical analysis

Results

Included studies

Comparative intra-individual 18F-NaF tracer uptake between symptomatic and asymptomatic atherosclerotic disease

Comparative 18F-NaF tracer uptake in symptomatic and asymptomatic atherosclerotic plaques where a healthy control population was included

Discussion

Conclusion

Supplemental Material

sj-pdf-1-vmj-10.1177_1358863X241287692 – Supplemental material for 18F-NaF uptake on vascular PET imaging in symptomatic versus asymptomatic atherosclerotic disease: A meta-analysis

Footnotes

Data availability statement

Declaration of conflicting interests

Funding

ORCID iD

Supplemental material

References

Supplementary Material

Comparative intra-individual ¹⁸F-NaF tracer uptake between symptomatic and asymptomatic atherosclerotic disease