Coronary 18F-NaF Research Articles

Latent Coronary Plaque Morphology From Computed Tomography Angiography, Molecular Disease Activity on Positron Emission Tomography, and Clinical Outcomes.

Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography and radiomics-based precision coronary plaque phenotyping derived from coronary computed tomography angiography may enhance risk stratification in patients with coronary artery disease. We sought to investigate whether the prognostic information provided by these 2 approaches is complementary in the prediction of myocardial infarction. Patients with known coronary artery disease underwent coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography on a hybrid positron emission tomography/computed tomography scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity. We performed quantitative plaque analysis of coronary computed tomography angiography datasets and extracted 1103 radiomic features for each plaque. Using weighted correlation network analysis, we derived latent morphological features of coronary lesions which were aggregated to patient-level radiomics nomograms to predict myocardial infarction. Among 260 patients with established coronary artery disease (age, 65±9 years; 83% men), 179 (69%) participants showed increased coronary 18F-NaF activity (coronary microcalcification activity>0). Over 53 (40-59) months of follow-up, 18 patients had a myocardial infarction. Using weighted correlation network analysis, we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns in an unsupervised fashion. Following adjustments for calcified, noncalcified, and low-density noncalcified plaque volumes and 18F-NaF coronary microcalcification activity, 4 radiomic features remained independent predictors of myocardial infarction (hazard ratio, 1.46 [95% CI, 1.03-2.08]; P=0.03; hazard ratio, 1.62 [95% CI, 1.04-2.54]; P=0.02; hazard ratio, 1.49 [95% CI, 1.07-2.06]; P=0.01; and hazard ratio, 1.50 (95% CI, 1.05-2.13); P=0.02). In patients with established coronary artery disease, latent coronary plaque morphological features, quantitative plaque volumes, and disease activity on 18F-sodium fluoride positron emission tomography are additive predictors of myocardial infarction.

Automated nonlinear registration of coronary PET to CT angiography using pseudo-CT generated from PET with generative adversarial networks

BackgroundCoronary 18F-sodium-fluoride (18F-NaF) positron emission tomography (PET) showed promise in imaging coronary artery disease activity. Currently image processing remains subjective due to the need for manual registration of PET and computed tomography (CT) angiography data. We aimed to develop a novel fully automated method to register coronary 18F-NaF PET to CT angiography using pseudo-CT generated by generative adversarial networks (GAN). MethodsA total of 169 patients, 139 in the training and 30 in the testing sets were considered for generation of pseudo-CT from non-attenuation corrected (NAC) PET using GAN. Non-rigid registration was used to register pseudo-CT to CT angiography and the resulting transformation was used to align PET with CT angiography. We compared translations, maximal standard uptake value (SUVmax) and target to background ratio (TBRmax) at the location of plaques, obtained after observer and automated alignment. ResultsAutomatic end-to-end registration was performed for 30 patients with 88 coronary vessels and took 27.5 seconds per patient. Difference in displacement motion vectors between GAN-based and observer-based registration in the x-, y-, and z-directions was 0.8 ± 3.0, 0.7 ± 3.0, and 1.7 ± 3.9 mm, respectively. TBRmax had a coefficient of repeatability (CR) of 0.31, mean bias of 0.03 and narrow limits of agreement (LOA) (95% LOA: − 0.29 to 0.33). SUVmax had CR of 0.26, mean bias of 0 and narrow LOA (95% LOA: − 0.26 to 0.26). ConclusionPseudo-CT generated by GAN are perfectly registered to PET can be used to facilitate quick and fully automated registration of PET and CT angiography.

18F-sodium fluoride positron emission tomography and coronary plaque radiomics derived from computed tomography angiography for prediction of myocardial infarction

Abstract Background Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography (18F-NaF PET) and radiomics-based precision coronary plaque phenotyping derived from contrast-enhanced computed tomography (CT) have both been shown to enhance risk stratification in patients with coronary artery disease (CAD). To date, no study has investigated whether these two promising methods (which can be obtained during a single imaging session on a hybrid PET/CT scanner) are interchangeable or can provide superior predictive performance when used in combination. Purpose We sought to investigate whether the prognostic information provided by latent morphological radiomic coronary plaque features and assessments of disease activity by 18F-NaF PET are complementary in prediction of myocardial infarction. Methods Patients with known CAD underwent coronary 18F-NaF PET and CT angiography on a hybrid PET/CT scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity (CMA). We performed quantitative plaque analysis of coronary CT angiography datasets. Additionally, coronary plaque segmentations on CT angiography were used to extract 1103 radiomic features. Using weighted correlation network analysis we derived latent morphological features of coronary plaques which were aggregated to patient-level radiomic normograms to predict myocardial infarction using univariate and multivariate Cox proportional hazard models. Results The study cohort comprised of 260 patients with established CAD (age: 65±9 years; 84% men); 179 (69%) participants showed increased coronary 18F-NaF activity (CMA >0). Over 53 [40–59] months of follow-up 18 patients had a myocardial infarction. Using weighted correlation network analysis, from the 1103 radiomic features we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns. On univariate cox modelling 7 of these emerged as predictors of myocardial infarction (Figure). Following adjustments for calcified, noncalcified and low-density noncalcified plaque volumes and 18F-NaF CMA 4 radiomic features (related to texture and geometry) remained independent predictors of myocardial infarction (Figure). Conclusion(s) In patients with established CAD latent morphological features of coronary plaques are predictors of myocardial infarction above and beyond plaque volumes and 18F-NaF uptake. Comprehensive plaque analysis with radiomics may enhance risk stratification of CAD patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIH, Wellcome Trust

In Vivo Coronary 18F-Sodium Fluoride Activity: Correlations With Coronary Plaque Histological Vulnerability and Physiological Environment

Background18F-sodium fluoride (18F-NaF) positron emission tomography (PET)/computed tomography (CT) is a promising new approach for assessing microcalcification in vascular plaque. ObjectivesThis prospective study aimed to evaluate the associations between in vivo coronary 18F-NaF PET/CT activity and ex vivo histological characteristics, to determine whether coronary 18F-NaF activity is a novel biomarker of plaque pathological vulnerability, and to explore the underlying physiological environment of 18F-NaF adsorption to vascular microcalcification. MethodsPatients with coronary artery disease (CAD) underwent coronary computed tomography angiography (CTA) and 18F-NaF PET/CT. Histological vulnerability and immunohistochemical characteristics were evaluated in coronary endarterectomy (CE) specimens from patients who underwent coronary artery bypass grafting with adjunctive CE. Correlations between in-vivo coronary 18F-NaF activity with coronary CTA adverse plaque features and with ex vivo CE specimen morphological features, CD68 expression, inflammatory cytokines expression (tumor necrosis factor-α, interleukin-1β), osteogenic differentiation cytokines expression (osteopontin, runt-related transcription factor 2, osteocalcin) were evaluated. High- and low- to medium-risk plaques were defined by standard pathological classification. ResultsA total of 55 specimens were obtained from 42 CAD patients. Coronary 18F-NaF activity of high-risk specimens was significantly higher than low- to medium-risk specimens (median [25th-75th percentile]: 1.88 [1.41-2.54] vs 1.12 [0.91-1.54]; P < 0.001). Coronary 18F-NaF activity showed high discriminatory accuracy in identifying high-risk plaque (AUC: 0.80). Coronary CTA adverse plaque features (positive remodeling, low-attenuation plaque, remodeling index), histologically vulnerable features (large necrotic core, thin-fibro cap, microcalcification), CD68 expression, tumor necrosis factor-α expression, and interleukin-1β expression correlated with coronary 18F-NaF activity (all P < 0.05). No significant association between coronary 18F-NaF activity and osteogenic differentiation cytokines was found (all P > 0.05). ConclusionsCoronary 18F-NaF activity was associated with histological vulnerability, CD68 expression, inflammatory cytokines expression, but not with osteogenic differentiation cytokines expression. 18F-NaF PET/CT imaging may provide a powerful tool for detecting high-risk coronary plaque and could improve the risk stratification of CAD patients.

Respiration-averaged CT versus standard CT attenuation map for correction of 18F-sodium fluoride uptake in coronary atherosclerotic lesions on hybrid PET/CT

BackgroundTo evaluate the impact of respiratory-averaged computed tomography attenuation correction (RACTAC) compared to standard single-phase computed tomography attenuation correction (CTAC) map, on the quantitative measures of coronary atherosclerotic lesions of 18F-sodium fluoride (18F-NaF) uptake in hybrid positron emission tomography and computed tomography (PET/CT). MethodsThis study comprised 23 patients who underwent 18F-NaF coronary PET in a hybrid PET/CT system. All patients had a standard single-phase CTAC obtained during free-breathing and a 4D cine-CT scan. From the cine-CT acquisition, RACTAC maps were obtained by averaging all images acquired over 5 seconds. PET reconstructions using either CTAC or RACTAC were compared. The quantitative impact of employing RACTAC was assessed using maximum target-to-background (TBRMAX) and coronary microcalcification activity (CMA). Statistical differences were analyzed using reproducibility coefficients and Bland-Altman plots. ResultsIn 23 patients, we evaluated 34 coronary lesions using CTAC and RACTAC reconstructions. There was good agreement between CTAC and RACTAC for TBRMAX (median [Interquartile range]): CTAC = 1.65 [1.23 to 2.38], RACTAC = 1.63 [1.23 to 2.33], p = 0.55), with coefficient of reproducibility of 0.18, and CMA: CTAC = 0.10 [0 to 1.0], RACTAC = 0.15 [0 to 1.03], p = 0.55 with coefficient of reproducibility of 0.17 ConclusionRespiratory-averaged and standard single-phase attenuation correction maps provide similar and reproducible methods of quantifying coronary 18F-NaF uptake on PET/CT.

18F-Sodium fluoride uptake is associated with severity of atherosclerotic stenosis in stable ischemic heart disease

BackgroundIncreased uptake of 18F-Sodium fluoride (18F-NaF) PET has potential to identify atherosclerotic plaques that are vulnerable to rupture. Whether 18F-NaF PET can evaluate the significance of atherosclerotic plaque in patients with stable coronary artery disease is less clear. We evaluated 18F-NaF PET uptake in coronary arteries in patients without acute coronary artery syndrome to determine the association of 18F-NaF signal uptake with severity of coronary stenosis. Methods and ResultsWe retrospectively identified 114 patients who received both regadenoson stress 82Rb myocardial perfusion PET and 18F-NaF PET study with an average interval of 5 months. Out of this cohort, forty-one patients underwent invasive coronary angiography. In a patient-based analysis, patients with ischemic regadenoson stress 82Rb PET had significantly higher coronary 18F-NaF uptake than patients with normal myocardial perfusion (P < .01). Among the 41 patients who underwent coronary angiography, per-vessel 18F-NaF uptake in both obstructive and nonobstructive coronary arteries was significantly higher than in normal coronary arteries (P < .05) regardless of the severity of coronary calcification. There was poor correlation between calcification and 18F-NaF uptake in coronary arteries (r = 0.41) ConclusionCoronary arterial 18F-NaF uptake is associated with coronary stenosis severity in patients with stable coronary artery disease. 18F-NaF PET studies may be useful for characterizing coronary atherosclerotic plaques.

18F-Sodium fluoride positron emission tomography, aortic disease activity and ischaemic stroke risk

Abstract Background Arterial 18F-sodium fluoride (18F-NaF) activity on positron emission tomography (PET) is a marker of active microcalcification and atherosclerosis. Coronary 18F-NaF activity (CMA) predicts coronary artery disease progression and subsequent myocardial infarction. Objective To investigate whether aortic 18F-NaF activity (AMA) predicts thoracic aortic atherosclerotic disease progression and subsequent ischaemic stroke or myocardial infarction in patients with established cardiovascular disease. Methods In a post-hoc observational cohort study, we evaluated AMA and CMA in patients with stable coronary artery disease (n=239) or aortic stenosis (n=158) who had underwent thoracic 18F-NaF PET and computed tomography (CT). We assessed the associations between AMA or CMA and progression of calcified atherosclerotic plaque in both thoracic aortic and coronary territories on follow up CT, as well as subsequent ischaemic stroke or myocardial infarction. Results In 141 and 231 patients with repeat aortic and coronary CT imaging respectively at 12.7±2.7 months, AMA correlated with log progression of thoracic aortic calcium scores (r=0.21, p=0.011), volume (r=0.29, p&amp;lt;0.01) and mass (r=0.29, P&amp;lt;0.01) as well as log coronary calcium score progression (r=0.21, p=0.03). CMA correlated with log coronary (r=0.42, p&amp;lt;0.01), but not log aortic (p&amp;gt;0.80) calcium score progression. In 397 patients, 16 had an ischaemic stroke and 25 had a myocardial infarction after 4.7±1.6 years. After adjusting for clinical risk factors, CMA and calcium scoring, AMA was associated with stroke (hazard ratio, 1.71 [95% confidence interval 1.00–2.90], p=0.048]). AMA was superior to clinical risk and calcium scores in identifying patients with stroke (c-statistic 0.76 versus 0.58 versus 0.63 respectively, p&amp;lt;0.05). Survival analysis demonstrated that AMA was associated with ischaemic stroke (p&amp;lt;0.001) but not myocardial infarction (p=0.45), whereas CMA was associated with myocardial infarction (p&amp;lt;0.001) but not stroke (p=0.39). Conclusions In patients with established cardiovascular disease, AMA is associated with progression of aortic atherosclerosis and future ischaemic stroke. Arterial 18F-NaF identifies localised areas of atherosclerotic disease activity that relate to regional atherothrombotic events. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart Foundation AMA, disease progression and outcomesVariables associated with stroke

Machine Learning with 18F-Sodium Fluoride PET and Quantitative Plaque Analysis on CT Angiography for the Future Risk of Myocardial Infarction.

Coronary 18F-sodium fluoride (18F-NaF) PET and CT angiography-based quantitative plaque analysis have shown promise in refining risk stratification in patients with coronary artery disease. We combined both of these novel imaging approaches to develop an optimal machine-learning model for the future risk of myocardial infarction in patients with stable coronary disease. Methods: Patients with known coronary artery disease underwent coronary 18F-NaF PET and CT angiography on a hybrid PET/CT scanner. Machine-learning by extreme gradient boosting was trained using clinical data, CT quantitative plaque analysis, measures and 18F-NaF PET, and it was tested using repeated 10-fold hold-out testing. Results: Among 293 study participants (65 ± 9 y; 84% male), 22 subjects experienced a myocardial infarction over the 53 (40-59) months of follow-up. On univariable receiver-operator-curve analysis, only 18F-NaF coronary uptake emerged as a predictor of myocardial infarction (c-statistic 0.76, 95% CI 0.68-0.83). When incorporated into machine-learning models, clinical characteristics showed limited predictive performance (c-statistic 0.64, 95% CI 0.53-0.76) and were outperformed by a quantitative plaque analysis-based machine-learning model (c-statistic 0.72, 95% CI 0.60-0.84). After inclusion of all available data (clinical, quantitative plaque and 18F-NaF PET), we achieved a substantial improvement (P = 0.008 versus 18F-NaF PET alone) in the model performance (c-statistic 0.85, 95% CI 0.79-0.91). Conclusion: Both 18F-NaF uptake and quantitative plaque analysis measures are additive and strong predictors of outcome in patients with established coronary artery disease. Optimal risk stratification can be achieved by combining clinical data with these approaches in a machine-learning model.

Advances in Quantitative Analysis of 18F-Sodium Fluoride Coronary Imaging.

18F-sodium fluoride (18F-NaF) positron emission tomography (PET) has emerged as a promising noninvasive imaging tool for the assessment of active calcification processes in coronary artery disease. 18F-NaF uptake colocalizes to high-risk and ruptured atherosclerotic plaques. Most recently, 18F-NaF coronary uptake was shown to be a robust and independent predictor of myocardial infarction in patients with advanced coronary artery disease. In this review, we provide an overview of the advances in coronary 18F-NaF imaging. In particular, we discuss the recently developed and validated motion correction techniques which address heart contractions, tidal breathing, and patient repositioning during the prolonged PET acquisitions. Additionally, we discuss a novel quantification approach—the coronary microcalcification activity (which has been inspired by the widely employed method in oncology total active tumor volume measurement). This new method provides a single number encompassing 18F-NaF activity within the entire coronary vasculature rather than just information regarding a single area of most intense tracer uptake.

Coronary 18F-sodium fluoride PET detects high-risk plaque features on optical coherence tomography and CT-angiography in patients with acute coronary syndrome

Background and aims18F-Sodium Fluoride Positron Emission Tomography (18F–NaF PET) non-invasively detects micro-calcification activity, the earliest stage of atherosclerotic arterial calcification. We studied the association between coronary 18F–NaF uptake and high-risk plaque features on intra-coronary optical coherence tomography (OCT) and CT-angiography (CTCA) and the potential application to patient-level risk stratification. MethodsSixty-two prospectively recruited patients with acute coronary syndrome (ACS) underwent multi-vessel OCT, 18F–NaF PET and CTCA. The maximum tissue to background ratio (TBRmax = standardised uptake value (SUV)max/SUVbloodpool) was measured in each coronary segment on 18F–NaF PET scans. High-risk plaque features on OCT and CTCA were compared in matched coronary segments. The number of patients testing positive (>2SD above the normal range) for micro-calcification activity was determined. ResultsIn 62 patients (age, mean ± standard deviation (SD) = 61 ± 9 years, 85% male) the coronary segments with elevated 18F–NaF uptake had higher lipid arc (LA) (median [25th-75th centile]: 74° [35°–117°] versus 48° [15°–83°], p=0.021), higher prevalence of macrophages [n(%): 37 (62%) versus 89 (39%), p=0.008] and lower plaque free wall (PFW) (50° [7°–110°] versus 94° [34°–180°], p=0.027) on OCT, and a higher total plaque burden (p=0.011) and higher dense calcified plaque burden (p= 0.001) on CTCA, when compared with 18F–NaF negative segments. Patients grouped by increasing number of coronary lesions positive for microcalcification activity (0,1, ≥2) showed decreasing plaque free wall, increasing calcification and increasing macrophages on OCT (respectively p=0.008, p < 0.001 and p=0.028). Conclusions18F–NaF uptake is associated with high-risk plaque features on OCT and CTCA in a per-segment and per-patient analysis in subjects hospitalized for ACS.

18F-sodium fluoride coronary uptake in patients with coronary artery bypass grafts

Abstract 18F-Sodium fluoride (18F-NaF) positron emission tomography (PET) provides an assessment of active calcification (microcalcification) across a wide range of cardiovascular conditions including coronary artery disease, carotid and penile atherosclerosis, aortic and mitral valve disease, and abdominal aortic aneurysms. To date the significance of 18F-NaF uptake in patients with coronary artery bypass grafts (CABG) is unknown. We aimed to characterize 18F-NaF activity in CABG patients. We performed 18F-NaF PET (30-min long single bed position acquisition 1h after a 250mB injection of 18F-NaF) and coronary CT angiography in patients with multivessel coronary artery disease and followed them for fatal or non-fatal myocardial infarction over 42 [31,49] months. On motion-corrected datasets we quantified the whole-vessel coronary 18F-NaF PET uptake (the coronary microcalcification activity (CMA)) by measuring the activity of voxels above the background (right atrium activity) + 2 * standard deviations threshold. All study subjects underwent a comprehensive baseline clinical assessment including evaluation of their cardiovascular risk factor profile with the SMART [Secondary Manifestations of Arterial Disease] risk score calculated, and the coronary calcium burden assessed with calcium scoring (CCS). Among 293 study participants (65±9 years; 84% male), 48 (16%) had a history of CABG. Although the majority 124/128 (97%) of coronary bypass grafts showed no uptake, 4 saphenous vein grafts presented with a CMA&amp;gt;0 (range: 2.5–11.5, Figure). While a similar proportion of patients with and without prior CABG showed increased coronary 18F-NaF uptake (CMA&amp;gt;0) (58.3% versus 71.4%, p=0.11) overall prior-CABG subjects had higher CMA (2.0 [0.3, 6.6] versus 0.6 [0, 2.7], p=0.001) and CCS (1135 [631, 2120] versus 225 [59, 542], p&amp;lt;0.001), respectively. In line with the differences in the calcification activity and the coronary calcium burden, the SMART risk scores were higher in CABG patients (23 [17, 28] versus 17 [12, 24], p=0.01), and these patients were also older (68±8 versus 64±8, p=0.01). Despite the aforementioned differences the incidence of myocardial infarction 5/48 (9%) versus 15/245 (6%) and MACE 6/48 (12%) versus 34/245 (14%) during follow-up between subjects with and without prior CABG was similar (p=0.44 and p=0.80, respectively). CABG patients have a higher coronary microcalcification activity on 18F-NaF PET than multivessel coronary artery disease patients without prior CABG. Despite evidence of higher 18F-NaF uptake there is no difference in outcome between these two groups. Figure 1. 18F-NaF uptake in CABG patients. (A) 63-year old male with prominent uptake in stented saphenous vein bypass grafts and native coronary arteries who experienced a non-fatal non ST elevation myocardial infarction during follow-up. (B) 70-year old male with evident uptake in native coronary arteries and only little 18F-NaF activity within coronary bypasses. Funding Acknowledgement Type of funding source: Other. Main funding source(s): National Heart, Lung, and Blood Institute/National Institute of Health (NHLBI/NIH), British Heart Foundation

Coronary artery 18F-NaF PET analysis with the use of an elastic motion correction software

Introduction18F-Sodium Fluoride Positron Emission Tomography (18F-NaF PET) is a novel molecular imaging modality with promise for use as a risk stratification tool in cardiovascular disease. There are limitations in the analysis of small and rapidly moving coronary arteries using traditional PET technology. We aimed to validate the use of a motion correction algorithm (eMoco) on coronary 18F-NaF PET outcome parameters. MethodsPatients admitted with an acute coronary syndrome underwent 18F-NaF PET and computed tomography coronary angiography. 18F-NaF PET data were analyzed using a diastolic reconstruction, an ungated reconstruction and the eMoco reconstruction. ResultsTwenty patients underwent 18F-NaF PET imaging and 17 patients had at least one positive lesion that could be used to compare PET reconstruction datasets. eMoco improved noise (the coefficient of variation of the blood pool radiotracer activity) compared to the diastolic dataset (0.09 [0.07 to 0.12] vs 0.14[0.11 to 0.17], p < .001) and marginally improved coronary lesion maximum tissue-to-background ratios compared to the ungated dataset (1.33 [1.05 to 1.48]vs 1.29 [1.04 to 1.40], p = .011). ConclusionIn this pilot dataset, the eMoco reconstruction algorithm for motion correction appears to have potential in improving coronary analysis of 18F-NaF PET by reducing noise and increasing maximum counts. Further testing in a larger patient dataset is warranted.

Coronary 18F-Sodium Fluoride Uptake Predicts Outcomes in Patients With Coronary Artery Disease

BackgroundReliable methods for predicting myocardial infarction in patients with established coronary artery disease are lacking. Coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) provides an assessment of atherosclerosis activity. ObjectivesThis study assessed whether 18F-NaF PET predicts myocardial infarction and provides additional prognostic information to current methods of risk stratification. MethodsPatients with known coronary artery disease underwent 18F-NaF PET computed tomography and were followed up for fatal or nonfatal myocardial infarction over 42 months (interquartile range: 31 to 49 months). Total coronary 18F-NaF uptake was determined by the coronary microcalcification activity (CMA). ResultsIn a post hoc analysis of data collected for prospective observational studies, the authors studied 293 study participants (age: 65 ± 9 years; 84% men), of whom 203 (69%) showed increased coronary 18F-NaF activity (CMA >0). Fatal or nonfatal myocardial infarction occurred only in patients with increased coronary 18F-NaF activity (20 of 203 with a CMA >0 vs. 0 of 90 with a CMA of 0; p < 0.001). On receiver operator curve analysis, fatal or nonfatal myocardial infarction prediction was highest for 18F-NaF CMA, outperforming coronary calcium scoring, modified Duke coronary artery disease index and Reduction of Atherothrombosis for Continued Health (REACH) and Secondary Manifestations of Arterial Disease (SMART) risk scores (area under the curve: 0.76 vs. 0.54, 0.62, 0.52, and 0.54, respectively; p < 0.001 for all). Patients with CMA >1.56 had a >7-fold increase in fatal or nonfatal myocardial infarction (hazard ratio: 7.1; 95% confidence interval: 2.2 to 25.1; p = 0.003) independent of age, sex, risk factors, segment involvement and coronary calcium scores, presence of coronary stents, coronary stenosis, REACH and SMART scores, the Duke coronary artery disease index, and recent myocardial infarction. ConclusionsIn patients with established coronary artery disease, 18F-NaF PET provides powerful independent prediction of fatal or nonfatal myocardial infarction.

Relationship between coronary arterial 18F-sodium fluoride uptake and epicardial adipose tissue analyzed using computed tomography.

18F-Sodium fluoride (18F-NaF) positron emission tomography (PET) has the potential to detect high-risk coronary plaques. Epicardial adipose tissue (EAT) reportedly correlates with coronary atherosclerosis progression. We evaluated the relationship between coronary arterial 18F-NaF uptake and EAT findings using computed tomography (CT). We studied 40 patients with ≥ 1 coronary plaque detected on cardiac CT who underwent 18F-NaF PET/CT. EAT volume was measured using CT and indexed to body surface area in each patient. Each plaque was evaluated for CT-based luminal stenosis and high-risk features. The mean EAT density surrounding each plaque was calculated as perilesional EAT density (PLED) using non-contrast CT images. Focal 18F-NaF uptake in each plaque was quantified using the maximum tissue-to-background ratio (TBRmax). EAT volume index was similar between patients with TBRmax ≥ 1.28 (previously reported optimal cutoff to predict coronary events) and those with lower TBRmax, but patients with TBRmax ≥ 1.28 showed higher maximum PLED per patient (- 86 ± 12 Hounsfield units (HU) versus - 98 ± 11 HU, P =0.0044). In the lesion-based analysis (n = 92), PLED was positively correlated with TBRmax, and the optimal PLED cutoff to identify TBRmax ≥ 1.28 was - 97 HU. On multivariate analysis adjusted for lesion location, obstructive stenosis, and high-risk plaque on CT, PLED ≥ - 97 HU remained a significant predictor of TBRmax ≥ 1.28. Increased PLED was associated with significant coronary arterial 18F-NaF uptake. Step-by-step analyses of EAT density on CT and coronary arterial 18F-NaF uptake on PET may offer novel strategies for risk prediction in coronary artery disease.

Whole-vessel coronary 18F-sodium fluoride PET for assessment of the global coronary microcalcification burden.

18F-sodium fluoride (18F-NaF) has shown promise in assessing disease activity in coronary arteries, but currently used measures of activity - such as maximum target to background ratio (TBRmax) - are defined by single pixel count values. We aimed to develop a novel coronary-specific measure of 18F-NaF PET reflecting activity throughout the entire coronary vasculature (coronary microcalcification activity [CMA]). Patients with recent myocardial infarction and multi-vessel coronary artery disease underwent 18F-NaF PET and coronary CT angiography. We assessed the association between coronary 18F-NaF uptake (both TBRmax and CMA) and coronary artery calcium scores (CACS) as well as low attenuation plaque (LAP, attenuation < 30 Hounsfield units) volume. In 50 patients (64% males, 63 ± 7years), CMA and TBRmax were higher in vessels with LAP compared to those without LAP (1.09 [0.02, 2.34] versus 0.0 [0.0, 0.0], p < 0.001 and 1.23 [1.16, 1.37] versus 1.04 [0.93, 1.11], p < 0.001). Compared to a TBRmax threshold of 1.25, CMA > 0 had a higher diagnostic accuracy for detection of LAP: sensitivity of 93.1 (83.3-98.1)% versus 58.6 (44.9-71.4)% and a specificity of 95.7 (88.0-99.1)% versus 80.0 (68.7-88.6)% (both p < 0.001). 18F-NaF uptake assessed by CMA correlated more closely with LAP (r = 0.86, p < 0.001) than the CT calcium score (r = 0.39, p < 0.001), with these associations outperforming those observed for TBRmax values (LAP r = 0.63, p < 0.001; CT calcium score r = 0.30, p < 0.001). Automated assessment of disease activity across the entire coronary vasculature is feasible using 18F-NaF CMA, providing a single measurement that has closer agreement with CT markers of plaque vulnerability than more traditional measures of plaque activity.

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

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.

5966Whole-vessel coronary 18F-sodium fluoride coronary microcalfication activity is associated with Low density plaque

Abstract Background 18F-sodium fluoride (18F-NaF) showed promise in imaging vulnerable coronary plaques. To date reporting of the highest per patient target to background ratio (TBR), total number of lesions with visual uptake and whole-heart tracer activity have been proposed. Unfortunately, each of these approaches has limitations which become especially prominent in patients with multiple foci of uptake, where reproducible global per-vessel measures are required. In oncology, the total metabolic active tumor volume has been found to be a significant prognostic factor for disease progression, recurrence and death. We evaluated if such methodology could be applied to coronary PET imaging. Purpose To quantify whole-vessel coronary 18F-NaF PET activity by utilizing automatically derived coronary vessel regions of interest (ROI) from CT angiography and assess the relationship between coronary microcalcification activity (CMA) and per vessel quantitative plaque characteristics on coronary CT angiography (CTA). Methods Twenty patients (68±6 years old, 70% males) with multivessel coronary artery disease underwent a 30 min single bed position PET 1h after a 250mB injection of 18F-NaF and CTA on a hybrid PET/CT scanner. We assessed coronary 18F-NaF uptake using novel whole-vessel tubular and tortuous 3D ROIs which were automatically extracted from CTA datasets. Within such ROIs we measured mean standard uptake value (SUV), maximum TBR (TBRmax) and the activity of voxels (CMA) above 1.25 the background SUV (left atrium activity). We used a previously established 1.25 TBRmax threshold to distinguish vessels positive and negative for 18F-NaF uptake. Coronary CTA datasets were analyzed by semi-automated software to quantify volumes and percentage lesion content of non-calcified plaque (NCP), low-density non-calcified plaque (LD-NCP, attenuation &lt;30 Hounsfield units) and calcified plaque (CP). Results 13 (65%) patients and 24 (40%) out of 60 main epicardial vessels presented with 18F-NaF uptake exceeding the 1.25 TBRmax threshold. While coronaries positive for uptake had higher CMA 0.92 [0.17, 2.03] vs 0.0, p&lt;0.001 and TBRmax 1.42 [1.35, 1.74] vs 1.09 [1.0, 1.19], there was no difference in whole-vessel SUVmean 0.90 [0.77, 1.17] vs 0.87 [0.78, 0.96], p=0.33 compared to 18F-NaF negative arteries. Of the quantitative plaque characteristics vessels positive for uptake had higher NCP 278.4 [145.6, 576.9] vs 184.6 [63.8, 367.0]mm3, p=0.030; and LD-NCP 8.4 [0.3, 11.0] vs 2.7 [12.1, 43.5]mm3, p=0.01. CMA showed a stronger correlation with LD-NCP (r=0.70, p&lt;0.001) than TBRmax (r=0.52, p&lt;0.001). On regression analysis LD-NCP acted as an independent predictor of CMA after adjustments for CP and vessel SUVmean (p&lt;0.001). Figure 1 Conclusions Whole-vessel 18F-NaF coronary microcalcification activity assessment with CT angiography automatically derived 3-dimensional ROIs is feasible and the measured coronary microcalcification burden correlates well with low density plaque. Acknowledgement/Funding This research was supported by grants R01HL135557 and R01HL133616 from the NHLBI/NIH and a grant from the Dr. Miriam &amp; Sheldon G. Adelson MRF

Triple-gated motion and blood pool clearance corrections improve reproducibility of coronary 18F-NaF PET.

To improve the test-retest reproducibility of coronary plaque 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) uptake measurements. We recruited 20 patients with coronary artery disease who underwent repeated hybrid PET/CT angiography (CTA) imaging within 3weeks. All patients had 30-min PET acquisition and CTA during a single imaging session. Five PET image-sets with progressive motion correction were reconstructed: (i) a static dataset (no-MC), (ii) end-diastolic PET (standard), (iii) cardiac motion corrected (MC), (iv) combined cardiac and gross patient motion corrected (2 × MC) and, (v) cardiorespiratory and gross patient motion corrected (3 × MC). In addition to motion correction, all datasets were corrected for variations in the background activities which are introduced by variations in the injection-to-scan delays (background blood pool clearance correction, BC). Test-retest reproducibility of PET target-to-background ratio (TBR) was assessed by Bland-Altman analysis and coefficient of reproducibility. A total of 47 unique coronary lesions were identified on CTA. Motion correction in combination with BC improved the PET TBR test-retest reproducibility for all lesions (coefficient of reproducibility: standard = 0.437, no-MC = 0.345 (27% improvement), standard+BC = 0.365 (20% improvement), no-MC + BC = 0.341 (27% improvement), MC + BC = 0.288 (52% improvement), 2 × MC + BC = 0.278 (57% improvement) and 3 × C + BC = 0.254 (72% improvement), all p < 0.001). Importantly, in a sub-analysis of 18F-NaF-avid lesions with gross patient motion >10mm following corrections, reproducibility was improved by 133% (coefficient of reproducibility: standard = 0.745, 3 × MC = 0.320). Joint corrections for cardiac, respiratory, and gross patient motion in combination with background blood pool corrections markedly improve test-retest reproducibility of coronary 18F-NaF PET.

Predictors of 18F-sodium fluoride uptake in patients with stable coronary artery disease and adverse plaque features on computed tomography angiography.

In patients with stable coronary artery disease (CAD) and high-risk plaques (HRPs) on coronary computed tomography angiography (CTA), we sought to define qualitative and quantitative CTA predictors of abnormal coronary 18F-sodium fluoride uptake (18F-NaF) by positron emission tomography (PET). Patients undergoing coronary CTA were screened for HRP. Those who presented with ≥3 CTA adverse plaque features (APFs) including positive remodelling; low attenuation plaque (LAP, <30 HU), spotty calcification; obstructive coronary stenosis ≥50%; plaque volume >100 mm3 were recruited for 18F-NaF PET. In lesions with stenosis ≥25%, quantitative plaque analysis and maximum 18F-NaF target to background ratios (TBRs) were measured. Of 55 patients, 35 (64%) manifested coronary 18F-NaF uptake. Of 68 high-risk lesions 49 (70%) had increased PET tracer activity. Of the APFs, LAP had the highest sensitivity (39.4%) and specificity (98.3%) for predicting 18F-NaF uptake. TBR values were higher in lesions with LAP compared to those without [1.6 (1.3-1.8) vs. 1.1 (1.0-1.3), P = 0.01]. On adjusted multivariable regression analysis, LAP (both qualitative and quantitative) was independently associated with plaque TBR [LAP qualitative: β = 0.47, 95% confidence interval (CI) 0.30-0.65; P < 0.001] and (LAP volume: β = 0.20 per 10 mm3, 95% CI 0.13-0.27; P < 0.001). In stable CAD patients with HRP, LAP is predictive of 18F-NaF coronary uptake, but 18F-NaF is often seen in the absence of LAP. If 18F-NaF uptake is shown to be associated with adverse outcomes and becomes clinically used, the presence of LAP may define patients who would not benefit from the added testing.

Peri-Coronary Adipose Tissue Density Is Associated With 18F-Sodium Fluoride Coronary Uptake in Stable Patients With High-Risk Plaques

ObjectivesThis study aimed to assess the association between increased lesion peri-coronary adipose tissue (PCAT) density and coronary 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) in stable patients with high-risk coronary plaques (HRPs) shown on coronary computed tomography angiography (CTA). BackgroundCoronary 18F-NaF uptake reflects the rate of calcification of coronary atherosclerotic plaque. Increased PCAT density is associated with vascular inflammation. Currently, the relationship between increased PCAT density and 18F-NaF uptake in stable patients with HRPs on coronary CTA has not been characterized. MethodsPatients who underwent coronary CTA were screened for HRP, which was defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP) (<30 Hounsfield units [HU]) and spotty calcification; and obstructive coronary stenosis ≥50% (plaque volume >100 mm3). Patients with HRPs were recruited to undergo 18F-NaF PET/CT. In lesions with stenosis ≥25%, quantitative plaque analysis, mean PCAT density, maximal coronary motion−corrected 18F-NaF standard uptake values (SUVmax), and target-to-background ratios (TBR) were measured. ResultsForty-one patients (age 65 ± 6 years; 68% men) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronary 18F-NaF activity. Lesions with 18F-NaF uptake had higher surrounding PCAT density than those without 18F-NaF uptake (−73 HU; interquartile range −79 to −68 HU vs. −86 HU; interquartile range −94 to −80 HU; p < 0.001). 18F-NaF TBR and SUVmax were correlated with PCAT density (r = 0.63 and r = 0.68, respectively; all p < 0.001). On adjusted multiple regression analysis, increased lesion PCAT density and LAP volume were associated with 18F-NaF TBR (β = 0.25; 95% confidence interval: 0.17 to 0.34; p < 0.001 for PCAT, and β = 0.07; 95% confidence interval: 0.03 to 0.11; p = 0.002 for LAP). ConclusionsIn patients with HRP features on coronary CTA, increased density of PCAT was associated with focal 18F-NaF PET uptake. Simultaneous assessment of these imaging biomarkers by 18F-NaF PET and CTA might refine cardiovascular risk prediction in stable patients with HRP features.