Vulnerable plaque imaging using ¹⁸F-sodium fluoride positron emission tomography

Abstract

Positron emission tomography (PET) with ¹⁸F-sodium fluoride (¹⁸F-NaF) has emerged as a promising non-invasive imaging modality to identify high-risk and ruptured atherosclerotic plaques. By visualizing microcalcification, ¹⁸F-NaF PET holds clinical promise in refining how we evaluate coronary artery disease, shifting our focus from assessing disease burden to atherosclerosis activity. In this review, we provide an overview of studies that have utilized ¹⁸F-NaF PET for imaging atherosclerosis. We discuss the associations between traditional coronary artery disease measures (risk factors) and ¹⁸F-NaF plaque activity. We also present the data on the histological validation as well as show how ¹⁸F-NaF uptake is associated with plaque morphology on intravascular and CT imaging. Finally, we discuss the technical challenges associated with ¹⁸F-NaF coronary PET highlighting recent advances in this area.

Introduction

Despite improvements in therapies for atherosclerotic disease, myocardial infarction (MI) remains the leading cause of death worldwide.¹ The underlying etiology of MI is most commonly rupture of a high-risk plaque.^{2 3} While standard non-invasive tests can detect coronary artery disease (CAD) and assess ischemia or high-risk plaque features, they fail to identify the biologic activity of CAD, potentially limiting the discrimination of stable from high-risk disease which may result in imprecision in assigning patients for intensive therapies. A reliable warning of an acute coronary syndrome after initial testing could facilitate highly targeted application of more intensive treatments in a well-defined highest risk group.

Recently, ¹⁸F-sodium fluoride positron emission tomography (¹⁸F-NaF PET) has shown promise in imaging the activity of calcification processes in vivo.⁴ In a landmark study, Joshi et al showed that intense ¹⁸F-NaF uptake localizes to recent plaque rupture in patients with acute MI and in those with symptomatic carotid disease.⁵ Moreover, in patients with stable CAD, ¹⁸F-NaF uptake identified coronary plaques with high-risk features on intravascular ultrasound.

¹⁸F-sodium fluoride in nuclear medicine

¹⁸F-NaF has been used for decades in nuclear medicine to image bone malignancies.⁶ In the skeleton, fluoride binding is facilitated through a chemical reaction with hydroxyapatite, a crystalline structure that is a key component of both bone and vascular calcification.^7,8 In an initial retrospective feasibility study, Derlin et al showed that arterial wall ¹⁸F-NaF distribution is consistent with established atherosclerotic topography, with increased uptake in the thoracic aorta and at the carotid bifurcation.⁹ In a second study, Derlin et al demonstrated a correlation of ¹⁸F-NaF uptake in calcified carotid plaque with conventional cardiovascular risk factors in a large cohort of asymptomatic individuals who were investigated for non-cardiovascular indications.¹⁰ The authors concluded that ¹⁸F-NaF PET can potentially have a role as a tool for visualizing calcification activity the carotids and other major arteries.

Dedicated ¹⁸F-NaF cardiovascular PET

The feasibility of ¹⁸F-NaF for imaging calcification activity was based on retrospective analyses of ¹⁸F-NaF PET studies acquired for oncological purposes.^8–10 In 2012, a dedicated cardiac ¹⁸F-NaF approach for assessing coronary activity was introduced. In a cohort of 106 patients with aortic stenosis and concomitant coronary atherosclerosis, Dweck et al performed ¹⁸F-NaF PET of the thorax with ECG-gated breath-hold non-contrast CT performed for calcium scoring as anatomical reference.¹¹ The authors described ¹⁸F-NaF uptake in the coronary arteries with PET/CT. They demonstrated that this technique is both feasible and reproducible and that it can provide key insights into coronary artery plaque biology. The effective radiation dose associated with 18F-NaF PET ranges from 3.5 to 4 miniSieverts.

Association of ¹⁸F-NaF uptake with traditional risk factors

Considered together, the early literature provided clear evidence that ¹⁸F-NaF PET uptake is associated with the presence and extent of atherosclerosis and cardiovascular risk factors.^8,11,12 The latter included associations with age, male sex, hypertension, hypercholesterolemia and cumulative smoking exposure. Of interest, the prevalence of radiotracer uptake was strongly associated with the number of atherogenic risk factors.¹⁰ Dweck et al made the distinction between patients with increased tracer uptake (active calcification) and those with inactive calcification by using a threshold equating to the highest ¹⁸F-NaF uptake value reported in a control group without coronary artery calcification on CT.¹¹ In their study, those with active calcification (38%) were more likely to have clinically significant CAD, a higher incidence of previous major adverse cardiovascular events, lower serum high-density lipoprotein cholesterol concentrations, and higher Framingham risk prediction scores. Since the authors performed longer single bed position acquisitions than in oncological studies (10 vs 3 min) and used non-contrast CT for anatomical reference, they observed localization of the ¹⁸F-NaF signal to specific coronary territories. Further, the authors reported that although ¹⁸F-NaF activity was most commonly observed overlying existing calcium and a strong correlation was observed with coronary calcium scores, 41% of patients with scores > 1000 had no significant ¹⁸F-NaF uptake and that areas of increased tracer uptake were also found in regions remote from established calcium. They speculated that increased tracer activity potentially relates to developing microcalcification that is below the resolution of CT. Microcalcification in coronary plaques is believed to be associated with increased mechanical stress and risk of future cardiovascular events.^13–19 Accordingly, Dweck et al suggested that ¹⁸F-NaF might to be able to distinguish patients with dormant calcific disease, established many months or years previously, and subjects with metabolically active disease where the calcification processes are ongoing.¹¹ Importantly, this distinction showed clinical potential as those with increased coronary ¹⁸F-NaF uptake demonstrated higher rates of anginal symptoms, prior MACE events, and cardiovascular risk factor scores.

¹⁸F-NaF uptake in patients with stable and unstable CAD

In an elegant study, using coronary ¹⁸F-NaF assessments performed alongside coronary CT angiography, Joshi et al studied coronary ¹⁸F-NaF activity in 40 patients with recent acute MI and 40 patients with stable angina undergoing elective invasive coronary angiography.⁵ Increased ¹⁸F-NaF uptake was found in 37/40 (93%) of patients with recent infarction, with uptake localizing to the culprit plaque that had ruptured and caused the infarct, independent of stenting (Figure 1). Further, increased ¹⁸F-NaF uptake was observed in 45% of the stable patients and was associated with multiple adverse plaque features (e.g. positive remodeling, macrophage burden, necrotic core, microcalcification) on intravascular ultrasound and on coronary CT angiography. Thus, it appears that ¹⁸F-NaF can identify high-risk and culprit coronary atherosclerotic plaques, providing hope that that this novel method could aid in the prediction of heart attacks.

Figure 1.

Focal ¹⁸F-NaF in patients with myocardial infarction and stable angina. Patient with acute ST-segment elevation myocardial infarction with (A) proximal occlusion (red arrow) of the left anterior descending artery on invasive coronary angiography and (B) intense focal ¹⁸F-NaF [ tissue-to-background ratios, culprit 2.27 vs reference segment 1.09 (108% increase)] uptake (yellow-red) at the site of the culprit plaque (red arrow) on the combined PET and CT. Patient with anterior non-ST-segment elevation MI with (C) culprit (red arrow; left anterior descending artery) and bystander non-culprit (white arrow; circumflex artery) lesions on invasive coronary angiography that were both stented during the index admission. Only the culprit lesion had increased 18F-NaF uptake [tissue-to-background ratios, culprit 2.03 vs reference segment 1.08 (88% increase)] on PET-CT (D) after percutaneous coronary intervention. In a patient with stable angina with previous coronary artery bypass grafting, invasive coronary angiography (E) showed non-obstructive disease in the right coronary artery. Corresponding PET-CT scan (F) showed a region of increased 18F-NaF activity (positive lesion, red line) in the mid-right coronary artery (tissue-to-background ratio, 3.13) and a region without increased uptake in the proximal vessel (negative lesion, yellow line). This figure was originally published in the Lancet under the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). (Data from Joshi NV, Vesey AT, Williams MC, 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.^{5 18}F-NaF, ¹⁸F-sodium fluoride; PET, positron emission tomography.

In a subsequent study, Lee et al sought to evaluate the association between ¹⁸F-NaF uptake and adverse plaque features on intravascular ultrasound and optical coherence tomography.²⁰ Again, increased ¹⁸F-NaF uptake was associated with greater positive remodeling, more microcalcification, larger necrotic cores, higher maximum lipid arc and prominent microvessels compared with ¹⁸F-NaF–negative plaques. Importantly, such differences were not observed in relation to the lumen area or coronary calcium.

Histological validation of ¹⁸F-NaF coronary uptake

In the context of cardiovascular imaging, histological validation of ¹⁸F-NaF PET has been provided by investigation of the carotid plaques excised after endarterectomy using electron microscopy, autoradiography, and μPET/CT. These have consistently demonstrated that ¹⁸F-NaF binds preferentially to microcalcification beyond the resolution of μCT and co-localizes to regions of active mineralization within vascular tissue.²¹ The preferential binding to microcalcification is likely to be due to the high surface area of hydroxyapatite in regions where this nanocrystal builds up.^22,23 These findings have been recently corroborated in study by Creager et al.²⁴ By employing near-infrared fluorescence molecular imaging, histology and ex vivo human atherosclerotic plaque specimens, the authors provided evidence that regions identified as PET-positive and CT-negative with ¹⁸F-fluoride PET/CT imaging are the result of the presence of developing microcalcifications within atherosclerotic plaques.

¹⁸F-NaF activity in high-risk plaques on CT angiography

Pathological studies have identified the adverse histological plaque features that are associated with culprit coronary lesions. These vulnerable or adverse plaque features include a large lipid core, spotty calcification, positive remodeling, and inflammatory cell infiltration.^25–30

To date, several studies have addressed the relationship between coronary ¹⁸F-NaF uptake and the presence of adverse coronary plaque features (APF) in a wide range of clinical settings. Kitagawa et al studied the relationship of coronary CT angiography findings and ¹⁸F-NaF PET in a cohort of 41 patients with stable CAD of whom 26 presented with positive remodeling and low attenuation plaque.³¹ The authors demonstrated that these plaque features are more prevalent in patients with coronary ¹⁸F-NaF target to background ratios (TBR) >1.28, but provided only an analysis of combined adverse features (both low attenuation plaque and positive remodeling) but not on distinct associations of each APF with ¹⁸F-NaF uptake.³² In a recent study, we have shown that almost two-thirds of stable CAD patients with high-risk plaques on coronary CT angiography (defined as a simultaneous presence of a large plaque volume, over 50% lesion stenosis and at least one adverse plaque feature) have abnormal ¹⁸F-NaF uptake.^33,34 We demonstrated that low attenuation plaque is closely associated with increased tracer activity with over 90% of such lesions having increased ¹⁸F-NaF uptake (Figure 2). Of lesions with positive remodeling and spotty calcifications, however, only 55 and 57% presented with increased ¹⁸F-NaF. While low attenuation plaque was strongly associated with ¹⁸F-NaF, a substantial proportion of the plaques with increased ¹⁸F-NaF uptake did not have low attenuation plaque. Jointly, these studies suggest that there is substantial discordance in morphological plaques characteristics (the presence of adverse plaque characteristics) and the activity of the disease (measured with ¹⁸F-NaF PET) indicating that the two imaging modalities provide complementary information. To this end, we have recently demonstrated a relationship between coronary ¹⁸F-NaF uptake and increased attenuation in pericoronary adipose tissue, which has been proposed as a method for examining coronary plaque inflammation.³⁴ This observation provides further evidence that both imaging techniques contribute unique assessments of high-risk atherosclerotic plaques.

Figure 2.

Examples of ¹⁸F-NaF uptake in coronary lesions with adverse plaque features. Patient 1: 67-year-old male with a LAD plaque with low attenuation plaque (green arrow) (A) and focal ¹⁸F-NaF uptake (orange arrow) with increased TBR of 1.93 (B, C). Patient 2: 58-year-old male with a RCA lesion with spotty calcifications (green arrow) (D), and focal ¹⁸F-NaF uptake (orange arrow) with increased TBR of 1.59 (E, F). Reprinted by permission from Oxford University Press: European Heart Journal – Cardiovascular Imaging, Predictors of 18F-sodium fluoride uptake in patients with stable coronary artery disease and adverse plaque features on computed tomography angiography, Jacek Kwiecinski, Damini Dey, Sebastien Cadet et al, 2019. LAD, left anterior descending; RCA, right coronary artery; TBR, target to background ratio.

Technical challenges for ¹⁸F-NaF coronary PET

Despite the promising results of initial studies, widespread dissemination of ¹⁸F-NaF PET is hampered by the inherent complexities of this imaging modality.^35,36 The measured uptake is adversely affected by blurring of the tracer signal in target lesions by cardiorespiratory motion which occurs as a result of physiological tidal breathing and heart contractions. Additionally, due to the small target lesions size, the measured uptake is prone to partial volume effects. Moreover, to ensure adequate count statistics, ¹⁸F-NaF coronary PET requires long emission scanning. The duration of the acquisition has evolved from 90 s per bed position in the initial retrospective analysis by Derlin et al to 10 min in the first cardiac specific study by Dweck et al to 30 min in currently ongoing prospective trials.^9,11 Such long emission scanning times increase the risk of interscan patient motion as subjects may find it difficult to remain still over the entire length of the acquisition.³⁷ Finally, for evaluating uptake ¹⁸F-NaF PET anatomical reference for attributing foci of increased tracer activity to coronary arteries is required. In view of the small target lesion sizes and the combined effects of cardiorespiratory motion, ¹⁸F-NaF PET would undoubtedly benefit from refinement of image acquisition, reconstruction and analysis methods.

Motion

The quality of coronary PET and the accuracy of uptake measurements are degraded by cardiorespiratory and patient motion during the 30 min scans. It has been shown that physiological tidal breathing alone causes the heart to move more than 1 cm.³⁸ The amplitude of coronary artery motion during the cardiac cycle is about 8–26 mm, depending on the artery and location, with the highest motion in the RCA.³⁹ Further, typical gross patient motion (other than cardiorespiratory motion) results in repositioning of the heart, typically by 5–15 mm, during a 30 min scan.³⁷

To mitigate the effect of motion associated with heart contraction, ECG gating has been employed. In many studies to date, only the end-diastolic phase has been utilized because coronary motion is much lower during this phase of the cardiac cycle. Unfortunately, this approach uses only 25% of PET counts, consequently increasing image noise.⁴⁰ Recent studies have reduced the risks of potential false-negative findings by correcting for cardiac motion. Rubeaux et al have developed a correction method to tackle coronary motion in ¹⁸F-NaF PET imaging data by applying level-set based non-linear PET registration of individual PET time-bins to the end-diastolic position.⁴¹ The proposed registration was constrained to the coronary regions extracted from the co-registered coronary CT angiography to avoid registration to spurious noise signal outside of the arteries in question. As compared to the diastolic imaging, they have demonstrated increased uptake values, while drastically reducing noise (Figure 3). According to this study, best results can be obtained with 10-bin motion corrected data as it provides the best time-resolved motion correction. The same group has recently evaluated frequency and relative effect of gross patient motion (repositioning during coronary PET emission scanning) and developed a method for compensation of such events.⁴² According to the study, patient repositioning events occur approximately 3–4 times during the 30 min long acquisition. The proposed compensation approach can increase the uptake measurements by up to 30% potentially limiting the number on false negative findings on ¹⁸F-NaF PET. Importantly, this simple, but effective automated data-driven patient motion compensation technique, which utilizes exclusively list-mode data, does not require any additional hardware during image acquisition, and can be applied retrospectively to data obtained with standard coronary PET protocols.

Figure 3.

Motion-correction of physiological motion of the right coronary artery. Systolic excursion of the tricuspid annular plane leads to displacement of the PET signal during the cardiac cycle (zoomed area of interest in blue squares). The difference in the shift of PET from reference is shown on the end-systolic (top-right) and late-diastolic (mid-right) images. Green arrows represent the vectors of mid-RCA motion. By co-registration of all PET data to the reference end-diastolic gate, the final motion-corrected image is corrected for the 14 mm mid RCA motion (bottom-right). Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Journal of Nuclear Cardiology, Optimization of reconstruction and quantification of motion-corrected coronary PET-CT, Mhairi K. Doris, Yuka Otaki, Sandeep K. Krishnan et al, 2018. RCA, rightcoronary artery; PET, positron emission tomography.

Small target lesion size

Due to the small volume of coronary plaques (usually below 200 mm³ and only rarely exceeding 300 mm³), coronary ¹⁸F-NaF PET is prone to partial volume effects. State-of-the-art PET scanners ameliorate this issue to some degree with resolution recovery. However, since size of the plaques of interest is at best comparable to the minimum spatial resolution of PET, further corrections for partial volume effects are needed. In a recent study, Cal-Gonzalez et al employed a local projection method which was previously validated in the context of single photon emission CT and preclinical PET imaging.⁴³ By applying this elaborate compensation technique, the authors were able to enhance the carotid plaque uptake values by up to 227%.⁴⁴ Such impressive results were achieved by means of a single post-processing step which results in a partial-volume-corrected image and can in principle be easily disseminated, as the proposed method does not require projection data nor any upgrade of the existing reconstruction algorithms.

Uncertainty regarding reconstruction parameters

Another potential aspect of ¹⁸F-NaF PET imaging which requires attention is image reconstruction.⁴⁵ The number of iterations, the use of filtering, applying point spread functions as well as taking full advantage of the time of flight and resolution recovery techniques, all have a profound impact on the uptake values.⁴⁶ In a recent study, Doris et al showed how particular settings affect the signal to noise ratio and influence image quality.⁴⁰ The authors demonstrated that while more iterations and no post-filtering result in higher uptake values, such images are excessively noisy and difficult to interpret (Figure 4). It appears that standardization of reconstruction parameters would be an important step in disseminating ¹⁸F-NaF PET as it would enable making direct comparisons between centers and vendors.

Figure 4.

The impact of different PET reconstructions on visual image quality in diastolic and motion-corrected images in a patient with a positive culprit lesion in the left main coronary artery. The PET reconstruction using 4 iterations and 5 mm post-filtering was considered to provide superior image quality (TBR = 1.92 for motion-corrected image). Reprinted by permission from Springer Nature Customer Service Centre GmbH: Springer Nature, Journal of Nuclear Cardiology, Optimization of reconstruction and quantification of motion-corrected coronary PET-CT, Mhairi K. Doris, Yuka Otaki, Sandeep K. Krishnan et al, 2018. PET, positron emission tomography; TBR, target to background ratio.

Standardization of the uptake measurement utilized would be beneficial. While TBR remain the most widely used measure, it was pointed out that despite the broad application of TBR in the literature, particularly in the field of atherosclerosis PET imaging, its biologic significance and physiologic or mathematic explanation have not been provided.⁴⁷ Huet et al argued that blood activity adds to plaque activity because of the spatial blurring of PET images (which occurs as a result of the imperfect spatial resolution).⁴⁵ It was suggested that to correct for blood uptake, subtraction of venous standardized uptake value (SUV) from arterial SUV would be a more rational solution than dividing the two measured values. The rationale supporting this approach is the fact that the clearance of PET tracers from the venous blood pool can be quite variable from subject to subject, as it depends on multiple factors. As a result, dividing the vascular wall SUV with the venous blood pool SUV may introduce more variability and confusion to the TBR measurement.⁴⁷

Only modest difference in uptake between culprit and non-culprit plaques

The relatively modest TBR increases in culprit versus non-culprit plaques (~34% higher) reported by Joshi et al may hamper the clinical implementation of coronary ¹⁸F-NaF PET.⁵ It is however important to realize that the coronary ¹⁸F-NaF TBR relies on the background bloodpool activity (as it is calculated by dividing the maximum SUV of the tracer in the plaque by the mean SUVs of the background blood pool measured in the atria). These associations mandate performing image acquisition with relatively long injection to acquisition intervals as with time the tracer activity in the bloodpool decreases.

In cardiovascular PET, most studies to date have assessed ¹⁸F-NaF uptake in atherosclerotic plaques 1 h after tracer administration.^9–11,19 Although semi-quantitative analysis is feasible with 1 h images, it can be difficult to discriminate plaques with ¹⁸F-NaF uptake from noise. In fact, compared to uptake in the bony skeleton, ¹⁸F-NaF uptake due to active microcalcification formation in coronary plaque is very small. In one of the early studies, it was speculated that the optimal time for atherosclerotic plaque imaging with ¹⁸F-NaF might be longer than the 1 h post-injection time point used for bone imaging.¹⁰ Subsequently, longer delays for cardiovascular ¹⁸F-NaF PET imaging were evaluated by two studies to date. Blomberg et al concluded that delayed ¹⁸F-NaF PET imaging does not improve quantification of vascular calcification.⁴⁸ However, the authors measured only overall heart ¹⁸F-NaF activity (including blood pool) by placing regions of interest around the entire cardiac silhouette on ungated PET/CT images (excluding ¹⁸F-NaF activity originating from bones and cardiac valves) and averaged the SUV values derived from all slice. More recently, utilizing a dedicated coronary PET protocol, we showed that that prolonging the time from tracer injection to PET acquisition can facilitate image analysis and provide lower background activity and higher TBR values than the currently used 1 h post-injection protocol.⁴⁹ We demonstrated that by delaying image acquisition to 3 h, new lesions, categorized as false-negative on the 1 h PET, are readily identified (Figure 5). We reported a TBR increase of 80% in 3 h compared to 1 h imaging, providing evidence that delayed PET might be an important step in refining coronary PET imaging with ¹⁸F-NaF.

Figure 5.

Examples of coronary plaques with significant uptake on 3 h PET and low tracer activity of 1 h post injection imaging. Short axis images of proximal left anterior descending, proximal circumflex (A) and distal right coronary artery (B) plaques (arrows) which had a TBR <1.0 on 1 h PET (left column) and showed uptake exceeding the 1.25 TBR threshold at 3 h. This research was originally published in JNM. Kwiecinski J, Berman DS, Lee SE, Dey D, Cadet S, Lassen ML, Germano G, Jansen MA, Dweck MR, Newby DE, Chang HJ, Yun M, Slomka PJ. Three-Hour Delayed Imaging Improves Assessment of Coronary 18F-Sodium Fluoride PET. J Nucl Med. 2019 Apr;60²⁵ :530–535. doi: 10.2967/jnumed.118.217885. PET, positron emission tomography; SUV, standardized uptake value; TBR, target to background ratio.

High quality anatomical reference

As outlined above for coronary ¹⁸F-NaF PET image analysis, anatomical reference is essential: there is a need for exact registration of the ¹⁸F-NaF signal and the associated coronary artery. While initial studies utilized low dose CT images acquired for attenuation correction or coronary calcium scoring purposes to localize increased ¹⁸F-NaF activity to atherosclerotic plaques, this approach has several limitations. For instance, when assessing ¹⁸F-NaF activity in the left main or mid-left anterior descending artery uptake originating from the ascending aorta and main pulmonary artery can be erroneously assigned to the coronaries. Likewise, extra coronary foci of uptake (in patients who suffered from pericardial, aortic, or mitral disease which resulted in calcification outside of coronary arteries) can be problematic (Figure 6). Further, clear delineation of the coronary arteries is not possible in a large proportion of the coronary artery tree.

Figure 6.

Case example of coronary and non-coronary ¹⁸F-NaF uptake. A 67-year-old-male with uptake in the distal RCA (yellow arrow) and non-coronary uptake in the inferomedial papillary muscle (red arrow) (A). The uptake in the papillary muscle is more pronounced than in the coronary plaque (B). In the transverse plane the extra coronary foci of uptake can be easily seen (red arrows) (C) and have higher activity than the RCA plaques (yellow arrows) (D). Taking advantage of the CT angiography, which was used for anatomical reference, careful inspection of the dataset revealed an area of low attenuation within the inferior LV wall and the postero medial papillary muscle (red arrow) as compared to the LV anteroseptum (blue arrow) (E&F). Such low attenuation can be seen in infarcted myocardium—which might, in the process of healing, develop foci of microcalcification (which attract ¹⁸F-NaF). Without the reference of a CT angiography the foci of pronounced ¹⁸F-NaF uptake could potentially be erroneously attributed to plaques in the PDA or the PLV artery. Due to the findings on the PET study the patient underwent cardiac magnetic resonance imaging which revealed scarring of the inferior wall and postero medial papillary muscle (area of delayed enhancement [white] as opposed to the remote myocardium [black]) (G). While uptake situated within the myocardium is a rare finding, the same patient showed non-coronary ¹⁸F-NaF activity in the aorta—which without anatomical reference could be easily attributed to one of the left coronary proximal plaques (H). Yellow arrows indicate coronary plaque uptake (in the distal RCA and proximal LAD). The red arrow highlights the infarcted postero medial papillary muscle. The purple arrow indicates increased PET tracer activity in the ascending aorta and the blue arrow highlights uptake immediately adjacent to the left coronary cusp of the aortic valve. Reprinted by permission from Wolters Kluwer Health: Circulation: Cardiovascular Imaging, Feasibility of coronary ¹⁸F-sodium fluoride positron-emission tomography assessment with the utilization of previously acquired computed tomography angiography, Jacek Kwiecinski, Philip D Adamson, Martin Lassen et al, 2018, Volume 11, Issue 12, e0008325, https://www.ahajournals.org/journal/circimaging. LAD, left anterior descending; PDA, posterior descending artery; PET, positron emission tomography; PLV, posterior left ventricular; RCA, right coronary artery; RV, right ventricle; TBR, target to background ratio.

These caveats of image analysis have been addressed by employing coronary CT angiography as the anatomical reference. This approach enables localizing increased tracer to activity to individual coronary plaques. Studies to date have utilized CT angiography acquired using hybrid PET/CT scanner during the same imaging session.^5,31,50,51 This approach, however, does not lend itself to patient selection for imaging based on prior CT angiography findings. Most importantly, if the ¹⁸F-NaF imaging becomes part of a clinical assessment strategy, it is likely that patients would be selected for ¹⁸F-NaF PET based on the findings of a CT angiography performed for clinical purposes. Moreover, the single-session hybrid PET/CT protocol does not allow for the use of optimal CT equipment for CT angiography, which may only be available on standalone CT scanners. Finally, the use of hybrid PET/CT angiography requires multifaceted staff expertise in both PET and coronary CT angiography during a single session.

We have recently shown that these limitations can be eliminated by employing a prior coronary CT angiography approach with a subsequent standalone PET-only coronary scan can be used for the evaluation of coronary ¹⁸F-NaF PET uptake.⁵² Such a protocol enables equivalent categorization of plaques with increased ¹⁸F-NaF activity and accurate quantification of PET uptake. As the clinical application of ¹⁸F-NaF evolves, a coronary CT angiography performed clinically will be the most common basis for selection of patients who might benefit from assessment of disease activity with coronary PET imaging.⁵³ In this scenario, the requirement for a second CT angiography obtained at the time of coronary PET imaging would not be practical or economically feasible and would incur unnecessary additional radiation exposure. The coronary CT angiography first approach facilitates the selection of high-risk patients for PET-only ¹⁸F-NaF PET imaging, based on results from prior CT angiography scan. It enables taking full advantage of dedicated state-of-the-art CT scanners which provide superior image quality compared to hybrid PET/CT machines. Finally, given the simplicity of the prior CT angiography and subsequent PET-only acquisition protocol, this approach could facilitate dissemination of ¹⁸F-NaF coronary uptake imaging beyond experienced academic institutions.

Awaiting outcome

Over the last decade, extensive information has been gathered regarding the biologic mechanisms of increased coronary ¹⁸F-NaF uptake. Promising findings have been reported regarding the relationship of ¹⁸F-NaF uptake to adverse coronary plaque features and to culprit coronary plaques in patients with acute MI. Further, a great deal of progress has been made in optimizing coronary ¹⁸F-NaF acquisitions and measurements. This work has led to great interest in the potential of this approach to provide an important dimension beyond anatomy in guiding the management of patients with CAD. However, to date there is only sparse information regarding the prognostic implications of coronary ¹⁸F-NaF uptake.

Recently, one cohort of 32 patients with known or suspected CAD who were followed for 2 years for major adverse cardiac events demonstrated that higher coronary ¹⁸F-NaF uptake predicts adverse events.³¹ The study also confirmed previously reported findings regarding the added value of ¹⁸F-NaF PET over CT angiography alone and the associations between the presence of adverse plaque features and tracer activity. Of interest, in this small study, the 1.25 TBR threshold initially proposed by Joshi et al and subsequently utilized in multiple studies has been to some degree validated.^34,40,42 When applied in a Kaplan–Meier analysis, patients with TBR ≥ 1.28 had a higher risk of earlier coronary events than those with lower values. Finally, in the study by Kitagawa et al on a multivariate Cox proportional analysis adjusted for age, sex, presence of coronary risk factors, and statin use, this TBR threshold remained a significant predictor of adverse coronary events.³¹

A large multicenter study assessing the relationship between coronary ¹⁸F-NaF uptake and cardiac outcomes is currently underway: Prediction of Recurrent Events with ¹⁸F-Fluoride to Identify Ruptured and High-Risk Coronary Artery Plaques in Patients with Myocardial Infarction (PRE18FFIR) Study (NCT02278211). PRE18FFIR is an observational study that is following 700 high risk patients with CAD to determine whether baseline ¹⁸F-NaF PET can identify subjects who go on to sustain MI.⁵⁴ This study will provide important information regarding the potential of ¹⁸F-NaF to become an integral part of the routine clinical practice. Ultimately, if increased ¹⁸F-NaF activity emerges as a predictor of adverse events it could then serve as a risk stratification tool for targeting more aggressive therapies (such as PCSK9 inhibitors and interleukin 1-β inhibitors) to patients at greatest risk of adverse cardiovascular events.

Conclusions

The way calcification in atherosclerosis is perceived has recently evolved. Once regarded as a passive and degenerative phenomenon, it is now believed to be a highly dynamic and regulated process which plays a key role in plaque biology and vulnerability. ¹⁸F-NaF PET has emerged as potential tool for measuring disease activity in coronary atheroma and identifying high-risk vulnerable plaques. Further studies are now required to assess whether this imaging technique can prospectively identify patients at increased risk of MI and add prognostic data over and beyond currently used approaches. If future studies confirm ¹⁸F-NaF PET clinical potential, this imaging approach might revolutionize risk evaluation in CAD patients.