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Introduction: 18 F-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 18 F-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 18 F-NaF uptake in symptomatic versus asymptomatic atherosclerotic plaques, a mean difference of 0.43 (95% CI 0.29 to 0.57; p < 0.0001, I 2 = 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 (χ 2 = 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, I 2 = 85%)., Conclusions: PET imaging using 18 F-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 18 F-NaF PET imaging protocols, and its future use as a risk stratification tool or outcome measure, requires further study. (PROSPERO Registration ID: CRD42023451363)., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Immune-mediated inflammatory diseases (IMIDs) are a spectrum of disorders of overlapping immunopathogenesis, with a prevalence of up to 10% in Western populations and increasing incidence in developing countries. Although targeted treatments have revolutionized the management of rheumatic IMIDs, cardiovascular involvement confers an increased risk of mortality and remains clinically under-recognized. Cardiovascular pathology is diverse across rheumatic IMIDs, ranging from premature atherosclerotic cardiovascular disease (ASCVD) to inflammatory cardiomyopathy, which comprises myocardial microvascular dysfunction, vasculitis, myocarditis and pericarditis, and heart failure. Epidemiological and clinical data imply that rheumatic IMIDs and associated cardiovascular disease share common inflammatory mechanisms. This concept is strengthened by emergent trials that indicate improved cardiovascular outcomes with immune modulators in the general population with ASCVD. However, not all disease-modifying therapies that reduce inflammation in IMIDs such as rheumatoid arthritis demonstrate equally beneficial cardiovascular effects, and the evidence base for treatment of inflammatory cardiomyopathy in patients with rheumatic IMIDs is lacking. Specific diagnostic protocols for the early detection and monitoring of cardiovascular involvement in patients with IMIDs are emerging but are in need of ongoing development. This Review summarizes current concepts on the potentially targetable inflammatory mechanisms of cardiovascular pathology in rheumatic IMIDs and discusses how these concepts can be considered for the diagnosis and management of cardiovascular involvement across rheumatic IMIDs, with an emphasis on the potential of cardiovascular imaging for risk stratification, early detection and prognostication., (© 2024. Springer Nature Limited.)

Purpose: To assess radiomics and deep learning (DL) methods in identifying symptomatic Carotid Artery Disease (CAD) from carotid CT angiography (CTA) images. We further compare the performance of these novel methods to the conventional calcium score., Methods: Carotid CT angiography (CTA) images from symptomatic patients (ischaemic stroke/transient ischaemic attack within the last 3 months) and asymptomatic patients were analysed. Carotid arteries were classified into culprit, non-culprit and asymptomatic. The calcium score was assessed using the Agatston method. 93 radiomic features were extracted from regions-of-interest drawn on 14 consecutive CTA slices. For DL, convolutional neural networks (CNNs) with and without transfer learning were trained directly on CTA slices. Predictive performance was assessed over 5-fold cross validated AUC scores. SHAP and GRAD-CAM algorithms were used for explainability., Results: 132 carotid arteries were analysed (41 culprit, 41 non-culprit, and 50 asymptomatic). For asymptomatic vs symptomatic arteries, radiomics attained a mean AUC of 0.96(± 0.02), followed by DL 0.86(± 0.06) and then calcium 0.79(± 0.08). For culprit vs non-culprit arteries, radiomics achieved a mean AUC of 0.75(± 0.09), followed by DL 0.67(± 0.10) and then calcium 0.60(± 0.02). For multi-class classification, the mean AUCs were 0.95(± 0.07), 0.79(± 0.05), and 0.71(± 0.07) for radiomics, DL and calcium, respectively. Explainability revealed consistent patterns in the most important radiomic features., Conclusions: Our study highlights the potential of novel image analysis techniques in extracting quantitative information beyond calcification in the identification of CAD. Though further work is required, the transition of these novel techniques into clinical practice may eventually facilitate better stroke risk stratification., Competing Interests: The authors declare no competing interests., (© 2024 Published by Elsevier Ltd.)

Aims: While acute cardiovascular complications of COVID-19 are well-described, less is known about longer-term cardiac sequelae. For many individuals with cardiac signs or symptoms arising after COVID-19 infection, the aetiology remains unclear. We examined immune profiles associated with magnetic resonance imaging (MRI) abnormalities in patients with unexplained cardiac injury after COVID-19., Methods and Results: Twenty-one participants (mean age 47 [SD 13] years, 71% female) with long COVID (n=17), raised troponin (n=2), or unexplained new-onset heart failure (n=2), who did not have pre-existing heart conditions or recent steroid/immunosuppression treatment were enrolled a mean 346 (SD 191) days after COVID-19 infection in a prospective observational study. Cardiac MRI and blood sampling for deep immunophenotyping using mass cytometry by time of flight and measurement of proteomic inflammatory markers was performed. Nine of 21 (43%) participants had MRI abnormalities (MRI(+)), including non-ischaemic patterns of late gadolinium enhancement and/or visually overt myocardial oedema in 8 people. One patient had mildly impaired biventricular function without fibrosis or oedema, and 2 had severe left ventricular impairment. MRI(+) individuals had higher blood CCL3, CCL7, FGF-23 and CD4 Th2 cells, and lower CD8 T effector memory (TEM) cells, than MRI(-). Cluster analysis revealed lower expression of inhibitory receptors PD1 and TIM3 in CD8 TEM cells from MRI(+) patients than MRI(-) patients, and functional studies of CD8 T αβ cells showed higher proportions of cytotoxic granzyme B+ secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a LASSO regression model (composite AUC 0.96, 95%CI 0.88-1.0). CCL7 was correlated with diffuse myocardial fibrosis/oedema detected by quantitative T1 mapping (r=0.47, p=0.04)., Conclusion: COVID-19 related cardiac injury in symptomatic patients with non-ischaemic myocarditis-like MRI abnormalities is associated with immune dysregulation, including decreased peripheral CD8 TEM cells and increased CCL7, persisting long after the initial infection., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Microcalcification and macrocalcification are critical processes in atherosclerotic plaque progression, though how these processes relate to the risk of stroke recurrence in symptomatic carotid atherosclerosis is poorly understood., Methods: We performed a post hoc analysis of data from the ICARUSS (Imaging Carotid Atherosclerosis in the Recovery and Understanding of Stroke Severity) study, where individuals with acute ischemic stroke originating from ipsilateral carotid stenosis of ⩾ 50% underwent 18 F-sodium fluoride positron emission tomography (NaF-PET) to measure microcalcification. Tracer uptake was quantified using maximum tissue-to-background ratio (TBR max ). Macrocalcification was measured on computed tomography (CT) using Agatston scoring. Patients were followed up for 6 months for recurrent ipsilateral neurovascular events., Results: Five (27.8%) of 18 individuals had a recurrent ischemic stroke or transient ischemic attack. Ipsilateral carotid plaque NaF uptake at baseline was higher in those with recurrent events compared to those without, and this association remained after adjustment for other vascular risk factors (adjusted odds ratio (aOR) = 1.24, 1.03-1.50). Macrocalcification score in the symptomatic artery was also significantly independently associated with ipsilateral recurrence, but the effect size was relatively smaller (aOR = 1.12, 1.06-1.17 for each 100 unit increase)., Conclusions: Our findings indicate that microcalcification in symptomatic carotid plaques is independently associated with ipsilateral ischemic stroke recurrence. Furthermore, differences in the extent of active microcalcification in macrocalcified plaques may help explain variation in the relationship between calcified carotid plaques and stroke recurrence reported in the literature. Our pilot study indicates that evaluation of carotid artery microcalcification using NaF-PET may be a useful method for risk-stratification of carotid atherosclerosis, though our findings require confirmation in larger cohorts., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: To assess pericoronary adipose tissue (PCAT) density on coronary computed tomography angiography (CCTA) as a marker of inflammatory disease activity in coronary allograft vasculopathy (CAV)., Methods and Results: PCAT density, lesion volumes, and total vessel volume-to-myocardial mass ratio (V/M) were retrospectively measured in 126 CCTAs from 94 heart transplant patients [mean age 49 (SD 14.5) years, 40% female] who underwent imaging between 2010 and 2021; age- and sex-matched controls; and patients with atherosclerosis. PCAT density was higher in transplant patients with CAV [n = 40; -73.0 HU (SD 9.3)] than without CAV [n = 86; -77.9 HU (SD 8.2)], and controls [n = 12; -86.2 HU (SD 5.4)], P < 0.01 for both. Unlike patients with atherosclerotic coronary artery disease (n = 32), CAV lesions were predominantly non-calcified and comprised of mostly fibrous or fibrofatty tissue. V/M was lower in patients with CAV than without [32.4 mm3/g (SD 9.7) vs. 41.4 mm3/g (SD 12.3), P < 0.0001]. PCAT density and V/M improved the ability to predict CAV from area under the receiver operating characteristic curve (AUC) 0.75-0.85 when added to donor age and donor hypertension status (P < 0.0001). PCAT density above -66 HU was associated with a greater incidence of all-cause mortality {odds ratio [OR] 18.0 [95% confidence interval (CI) 3.25-99.6], P < 0.01} and the composite endpoint of death, CAV progression, acute rejection, and coronary revascularization [OR 7.47 (95% CI 1.8-31.6), P = 0.01] over 5.3 (SD 2.1) years., Conclusion: Heart transplant patients with CAV have higher PCAT density and lower V/M than those without. Increased PCAT density is associated with adverse clinical outcomes. These CCTA metrics could be useful for the diagnosis and monitoring of CAV severity., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Immune-mediated inflammatory diseases (IMIDs) are recognised risk factors for accelerated atherosclerotic cardiovascular disease (CVD), particularly in younger individuals and women who lack traditional CVD risk factors. Reflective of the critical role that inflammation plays in the formation, progression and rupture of atherosclerotic plaques, research into immune mechanisms of CVD has led to the identification of a range of therapeutic targets that are the subject of ongoing clinical trials. Several key inflammatory pathways implicated in the pathogenesis of atherosclerosis are targeted in people with IMIDs. However, cardiovascular risk continues to be systematically underestimated by conventional risk assessment tools in the IMID population, resulting in considerable excess CVD burden and mortality. Hence, there is a pressing need to improve methods for CVD risk-stratification among patients with IMIDs, to better guide the use of statins and other prognostic interventions. CT coronary angiography (CTCA) is the current first-line investigation for diagnosing and assessing the severity of coronary atherosclerosis in many individuals with suspected angina. Whether CTCA is also useful in the general population for reclassifying asymptomatic individuals and improving long-term prognosis remains unknown. However, in the context of IMIDs, it is conceivable that the information provided by CTCA, including state-of-the-art assessments of coronary plaque, could be an important clinical adjunct in this high-risk patient population. This narrative review discusses the current literature about the use of coronary CT for CVD risk-stratification in three of the most common IMIDs including rheumatoid arthritis, psoriasis and systemic lupus erythematosus., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The adaptive immune response plays an important role in atherosclerosis. In response to a high-fat/high-cholesterol (HF/HC) diet, marginal zone B (MZB) cells activate an atheroprotective programme by regulating the differentiation and accumulation of 'poorly differentiated' T follicular helper (Tfh) cells. On the other hand, Tfh cells activate the germinal centre response, which promotes atherosclerosis through the production of class-switched high-affinity antibodies. We therefore investigated the direct role of Tfh cells and the role of IL18 in Tfh differentiation in atherosclerosis., Methods and Results: We generated atherosclerotic mouse models with selective genetic deletion of Tfh cells, MZB cells, or IL18 signalling in Tfh cells. Surprisingly, mice lacking Tfh cells had increased atherosclerosis. Lack of Tfh not only reduced class-switched IgG antibodies against oxidation-specific epitopes (OSEs) but also reduced atheroprotective natural IgM-type anti-phosphorylcholine (PC) antibodies, despite no alteration of natural B1 cells. Moreover, the absence of Tfh cells was associated with an accumulation of MZB cells with substantially reduced ability to secrete antibodies. In the same manner, MZB cell deficiency in Ldlr-/- mice was associated with a significant decrease in atheroprotective IgM antibodies, including natural anti-PC IgM antibodies. In humans, we found a positive correlation between circulating MZB-like cells and anti-OSE IgM antibodies. Finally, we identified an important role for IL18 signalling in HF/HC diet-induced Tfh., Conclusion: Our findings reveal a previously unsuspected role of MZB cells in regulating atheroprotective 'natural' IgM antibody production in a Tfh-dependent manner, which could have important pathophysiological and therapeutic implications., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

The aim of this study was to develop and validate an automated pipeline that could assist the diagnosis of active aortitis using radiomic imaging biomarkers derived from [18F]-Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography (FDG PET-CT) images. The aorta was automatically segmented by convolutional neural network (CNN) on FDG PET-CT of aortitis and control patients. The FDG PET-CT dataset was split into training (43 aortitis:21 control), test (12 aortitis:5 control) and validation (24 aortitis:14 control) cohorts. Radiomic features (RF), including SUV metrics, were extracted from the segmented data and harmonized. Three radiomic fingerprints were constructed: A-RFs with high diagnostic utility removing highly correlated RFs; B used principal component analysis (PCA); C-Random Forest intrinsic feature selection. The diagnostic utility was evaluated with accuracy and area under the receiver operating characteristic curve (AUC). Several RFs and Fingerprints had high AUC values (AUC > 0.8), confirmed by balanced accuracy, across training, test and external validation datasets. Good diagnostic performance achieved across several multi-centre datasets suggests that a radiomic pipeline can be generalizable. These findings could be used to build an automated clinical decision tool to facilitate objective and standardized assessment regardless of observer experience.

Background: Assessing inflammatory disease activity in large vessel vasculitis (LVV) can be challenging by conventional measures., Objectives: We aimed to investigate somatostatin receptor 2 (SST 2 ) as a novel inflammation-specific molecular imaging target in LVV., Methods: In a prospective, observational cohort study, in vivo arterial SST 2 expression was assessed by positron emission tomography/magnetic resonance imaging (PET/MRI) using 68 Ga-DOTATATE and 18 F-FET-βAG-TOCA. Ex vivo mapping of the imaging target was performed using immunofluorescence microscopy; imaging mass cytometry; and bulk, single-cell, and single-nucleus RNA sequencing., Results: Sixty-one participants (LVV: n = 27; recent atherosclerotic myocardial infarction of ≤2 weeks: n = 25; control subjects with an oncologic indication for imaging: n = 9) were included. Index vessel SST 2 maximum tissue-to-blood ratio was 61.8% (P < 0.0001) higher in active/grumbling LVV than inactive LVV and 34.6% (P = 0.0002) higher than myocardial infarction, with good diagnostic accuracy (area under the curve: ≥0.86; P < 0.001 for both). Arterial SST 2 signal was not elevated in any of the control subjects. SST 2 PET/MRI was generally consistent with 18 F-fluorodeoxyglucose PET/computed tomography imaging in LVV patients with contemporaneous clinical scans but with very low background signal in the brain and heart, allowing for unimpeded assessment of nearby coronary, myocardial, and intracranial artery involvement. Clinically effective treatment for LVV was associated with a 0.49 ± 0.24 (standard error of the mean [SEM]) (P = 0.04; 22.3%) reduction in the SST 2 maximum tissue-to-blood ratio after 9.3 ± 3.2 months. SST 2 expression was localized to macrophages, pericytes, and perivascular adipocytes in vasculitis specimens, with specific receptor binding confirmed by autoradiography. SSTR2-expressing macrophages coexpressed proinflammatory markers., Conclusions: SST 2 PET/MRI holds major promise for diagnosis and therapeutic monitoring in LVV. (PET Imaging of Giant Cell and Takayasu Arteritis [PITA], NCT04071691; Residual Inflammation and Plaque Progression Long-Term Evaluation [RIPPLE], NCT04073810)., Competing Interests: Funding Support and Author Disclosures This work was funded by grants to Dr Tarkin from the Wellcome Trust (Clinical Research Career Development Fellowship 211100/Z/18/Z), the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC); and the British Heart Foundation (BHF) (Clinical Research Training Fellowship for Dr Ćorović [FS/CRTF/20/24035]). This work was additionally supported by the Cambridge BHF Centre of Research Excellence (18/1/34212) and the Cancer Research UK Cambridge Centre (A25177). For the purpose of open access, the lead author has applied a CC BY public copyright license to any Author Accepted Manuscript. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. Dr Nus; authors Imaz and Lambert; Dr Frontini (FS/18/53/33863); Dr Davenport (TG/18/4/33770); and Drs Huang, Mallat, Dweck, Newby, and Bennett are supported by the BHF. Author Zulcinski is supported by the European Union’s Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement no. 813545). Drs Jayne, Rassl, and Graves are supported by the NIHR Cambridge BRC. Dr Fayad is supported by the National Institutes of Health/National Heart, Lung, and Blood Institute (R01HL135878). Dr Reynolds is supported by the Wellcome Trust. Dr Morgan is supported by the Medical Research Council (MRC) (MR/N011775/1), the NIHR Leeds BRC, the NIHR Leeds Medtech, and In Vitro Diagnostics Co-operative as well as an NIHR Senior Investigator award. Dr Aboagye acknowledges support from Imperial Experimental Cancer Research Centre and MRC (MR/J007986/1, MR/N020782/1); and is an inventor on the patent that developed the (18)F-FET-βAG-TOCA radiotracer. Dr Peters is supported by a UK Research and Innovation Fellowship at Health Data Research UK (MR/S004068/2). Dr Rudd is partly supported by the NIHR Cambridge BRC, the BHF, the Higher Education Funding Council for England, the Engineering and Physical Sciences Research Council, and the Wellcome Trust. Drs Gopalan, Maughan, Pericleous, Barwick, Aboagye, Peters, and Mason acknowledge support from the NIHR Imperial BRC. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Multimodality cardiovascular imaging is an essential component of the clinical management of patients with large-vessel vasculitis (LVV), a chronic, relapsing and remitting inflammatory disease of the aorta and its major branches. Imaging is needed to confirm the initial diagnosis, to survey the extent and severity of arterial involvement, to screen for cardiovascular complications and for subsequent long-term disease monitoring. Indeed, diagnosing LVV can be challenging due to the non-specific nature of the presenting symptoms, which often evoke a broad differential. Identification of disease flares and persistent residual arteritis following conventional treatments for LVV present additional clinical challenges. However, by identifying and tracking arterial inflammation and injury, multimodality imaging can help direct the use of disease-modifying treatments that suppress inflammation and prevent or slow disease progression. Each of the non-invasive imaging modalities can provide unique and complementary information, contributing to different aspects of the overall clinical assessment. This article provides a focused review of the many roles of multimodality imaging in LVV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The use of positron emission tomography imaging with 18 F-fluorodeoxyglucose in the diagnostic workup of patients with suspected prosthetic valve endocarditis and cardiac device infection (implantable electronic device and left ventricular assist device) is gaining momentum in clinical practice. However, in the absence of prospective randomized trials, guideline recommendations about 18 F-fluorodeoxyglucose positron emission tomography in this setting are currently largely based on expert opinion. Measurement of aortic valve microcalcification occurring as a healing response to valvular inflammation using 18 F-sodium fluoride positron emission tomography represents another promising clinical approach, which is associated with both the risk of native valve stenosis progression and bioprosthetic valve degeneration in research trials. In this review, we consider the role of molecular imaging in cardiac valvular diseases, including aortic stenosis and valvular endocarditis, as well as cardiac device infections.

Study Design: To compare arterial inflammation (AI) between people living with HIV (PLWH) and uninfected people as assessed by 18 F-Fluorodeoxyglucose ( 18 F-FDG)-positron emission tomography (PET)., Methods: We prospectively enrolled 20 PLWH and 20 uninfected people with no known cardiovascular disease and at least 3 traditional cardiovascular risk factors. All patients underwent 18 F-FDG-PET/computed tomography (CT) of the thorax and neck. Biomarkers linked to inflammation and atherosclerosis were also determined. The primary outcome was AI in ascending aorta (AA) measured as mean maximum target-to-background ratio (TBR max ). The independent relationships between HIV status and both TBR max and biomarkers were evaluated by multivariable linear regression adjusted for body mass index, creatinine, statin therapy, and atherosclerotic cardiovascular 10-year estimated risk (ASCVD)., Results: Unadjusted mean TBR max in AA was slightly higher but not statistically different (P = .18) in PLWH (2.07; IQR 1.97, 2.32]) than uninfected people (2.01; IQR 1.85, 2.16]). On multivariable analysis, PLWH had an independent risk of increased mean log-TBR max in AA (coef = 0.12; 95%CI 0.01,0.22; P = .032). HIV infection was independently associated with higher values of interleukin-10 (coef = 0.83; 95%CI 0.34, 1.32; P = .001), interferon-γ (coef. = 0.90; 95%CI 0.32, 1.47; P = .003), and vascular cell adhesion molecule-1 (VCAM-1) (coef. = 0.75; 95%CI: 0.42, 1.08, P < .001)., Conclusions: In patients with high cardiovascular risk, HIV status was an independent predictor of increased TBR max in AA. PLWH also had an increased independent risk of IFN-γ, IL-10, and VCAM-1 levels., (© 2021. The Author(s).)

In recent years, cardiovascular immuno-imaging by positron emission tomography (PET) has undergone tremendous progress in preclinical settings. Clinically, two approved PET tracers hold great potential for inflammation imaging in cardiovascular patients, namely FDG and DOTATATE. While the former is a widely applied metabolic tracer, DOTATATE is a relatively new PET tracer targeting the somatostatin receptor 2 (SST2). In the current study, we performed a detailed, head-to-head comparison of DOTATATE-based radiotracers and [ 18 F]F-FDG in mouse and rabbit models of cardiovascular inflammation. For mouse experiments, we labeled DOTATATE with the long-lived isotope [ 64 Cu]Cu to enable studying the tracer's mode of action by complementing in vivo PET/CT experiments with thorough ex vivo immunological analyses. For translational PET/MRI rabbit studies, we employed the more widely clinically used [ 68 Ga]Ga-labeled DOTATATE, which was approved by the FDA in 2016. DOTATATE's pharmacokinetics and timed biodistribution were determined in control and atherosclerotic mice and rabbits by ex vivo gamma counting of blood and organs. Additionally, we performed in vivo PET/CT experiments in mice with atherosclerosis, mice subjected to myocardial infarction and control animals, using both [ 64 Cu]Cu-DOTATATE and [ 18 F]F-FDG. To evaluate differences in the tracers' cellular specificity, we performed ensuing ex vivo flow cytometry and gamma counting. In mice subjected to myocardial infarction, in vivo [ 64 Cu]Cu-DOTATATE PET showed higher differential uptake between infarcted (SUV max 1.3, IQR, 1.2-1.4, N = 4) and remote myocardium (SUV max 0.7, IQR, 0.5-0.8, N = 4, p = 0.0286), and with respect to controls (SUV max 0.6, IQR, 0.5-0.7, N = 4, p = 0.0286), than [ 18 F]F-FDG PET. In atherosclerotic mice, [ 64 Cu]Cu-DOTATATE PET aortic signal, but not [ 18 F]F-FDG PET, was higher compared to controls (SUV max 1.1, IQR, 0.9-1.3 and 0.5, IQR, 0.5-0.6, respectively, N = 4, p = 0.0286). In both models, [ 64 Cu]Cu-DOTATATE demonstrated preferential accumulation in macrophages with respect to other myeloid cells, while [ 18 F]F-FDG was taken up by macrophages and other leukocytes. In a translational PET/MRI study in atherosclerotic rabbits, we then compared [ 68 Ga]Ga-DOTATATE and [ 18 F]F-FDG for the assessment of aortic inflammation, combined with ex vivo radiometric assays and near-infrared imaging of macrophage burden. Rabbit experiments showed significantly higher aortic accumulation of both [ 68 Ga]Ga-DOTATATE and [ 18 F]F-FDG in atherosclerotic (SUV max 0.415, IQR, 0.338-0.499, N = 32 and 0.446, IQR, 0.387-0.536, N = 27, respectively) compared to control animals (SUV max 0.253, IQR, 0.197-0.285, p = 0.0002, N = 10 and 0.349, IQR, 0.299-0.423, p = 0.0159, N = 11, respectively). In conclusion, we present a detailed, head-to-head comparison of the novel SST2-specific tracer DOTATATE and the validated metabolic tracer [ 18 F]F-FDG for the evaluation of inflammation in small animal models of cardiovascular disease. Our results support further investigations on the use of DOTATATE to assess cardiovascular inflammation as a complementary readout to the widely used [ 18 F]F-FDG., (© 2022. The Author(s).)

Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR)., Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18 F-sodium fluoride ( 18 F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18 F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol., Results: In patients with TAVI, native aortic valves demonstrated 18 F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI ( r =0.36, P =0.023). 18 F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2-1.7] versus 1.3 [1.2-1.5], respectively; P =0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P =0.78), computed tomography (15% versus 14%, respectively; P =0.87), and positron emission tomography (15% versus 29%, respectively; P =0.09). Baseline 18 F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI ( r =0.7, P <0.001) and SAVR ( r =0.7, P <0.001). On multivariable analysis, 18 F-NaF uptake was the only predictor of peak velocity progression ( P <0.001)., Conclusions: In patients with TAVI, native aortic valves demonstrate evidence of ongoing active disease. Across imaging modalities, TAVI degeneration is of similar magnitude to bioprosthetic SAVR, suggesting comparable midterm durability. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02304276.

Background: Atherosclerosis is a systemic inflammatory disease, with common inflammatory processes implicated in both atheroma vulnerability and blood-brain barrier disruption. This prospective multimodal imaging study aimed to measure directly the association between systemic atheroma inflammation ("atheroinflammation") and downstream chronic cerebral small vessel disease severity. Methods: Twenty-six individuals with ischemic stroke with ipsilateral carotid artery stenosis of >50% underwent 18 fluoride-fluorodeoxyglucose-positron emission tomography within 2 weeks of stroke. Small vessel disease severity and white matter hyperintensity volume were assessed using 3-tesla magnetic resonance imaging also within 2 weeks of stroke. Results: Fluorodeoxyglucose uptake was independently associated with more severe small vessel disease (odds ratio 6.18, 95% confidence interval 2.1-18.2, P < 0.01 for the non-culprit carotid artery) and larger white matter hyperintensity volumes (coefficient = 14.33 mL, P < 0.01 for the non-culprit carotid artery). Conclusion: These proof-of-concept results have important implications for our understanding of the neurovascular interface and potential therapeutic exploitation in the management of systemic atherosclerosis, particularly non-stenotic disease previously considered asymptomatic, in order to reduce the burden of chronic cerebrovascular disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Evans, Tarkin, Walsh, Chowdhury, Patterson, Graves, Rudd and Warburton.)

Aims: To examine pericoronary adipose tissue (PCAT) and periaortic adipose tissue (PAAT) density on coronary computed tomography angiography for assessing arterial inflammation in Takayasu arteritis (TAK) and atherosclerosis., Methods and Results: PCAT and PAAT density was measured in coronary ( n = 1016) and aortic ( n = 108) segments from 108 subjects [TAK + coronary artery disease (CAD), n = 36; TAK, n = 18; atherosclerotic CAD, n = 32; matched controls, n = 22]. Median PCAT and PAAT densities varied between groups (mPCAT: P < 0.0001; PAAT: P = 0.0002). PCAT density was 7.01 ± standard error of the mean (SEM) 1.78 Hounsfield Unit (HU) higher in coronary segments from TAK + CAD patients than stable CAD patients ( P = 0.0002), and 8.20 ± SEM 2.04 HU higher in TAK patients without CAD than controls ( P = 0.0001). mPCAT density was correlated with Indian Takayasu Clinical Activity Score ( r = 0.43, P = 0.001) and C-reactive protein ( r = 0.41, P < 0.0001) and was higher in active vs. inactive TAK ( P = 0.002). mPCAT density above -74 HU had 100% sensitivity and 95% specificity for differentiating active TAK from controls [area under the curve = 0.99 (95% confidence interval 0.97-1)]. The association of PCAT density and coronary arterial inflammation measured by 68 Ga-DOTATATE positron emission tomography (PET) equated to an increase of 2.44 ± SEM 0.77 HU in PCAT density for each unit increase in 68 Ga-DOTATATE maximum tissue-to-blood ratio ( P = 0.002). These findings remained in multivariable sensitivity analyses adjusted for potential confounders., Conclusions: PCAT and PAAT density are higher in TAK than atherosclerotic CAD or controls and are associated with clinical, biochemical, and PET markers of inflammation. Owing to excellent diagnostic accuracy, PCAT density could be useful as a clinical adjunct for assessing disease activity in TAK., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose of Review: To examine the use of positron emission tomography (PET) for imaging post-infarct myocardial inflammation and repair., Recent Findings: Dysregulated immune responses after myocardial infarction are associated with adverse cardiac remodelling and an increased likelihood of ischaemic heart failure. PET imaging utilising novel tracers can be applied to visualise different components of the post-infarction inflammatory and repair processes. This approach could offer unique pathophysiological insights that could prove useful for the identification and risk-stratification of individuals who would ultimately benefit most from emerging immune-modulating therapies. PET imaging could also bridge the clinical translational gap as a surrogate measure of drug efficacy in early-stage clinical trials in patients with myocardial infarction. The use of hybrid PET/MR imaging, in particular, offers the additional advantage of simultaneous in vivo molecular imaging and detailed assessment of myocardial function, viability and tissue characterisation. Further research is needed to realise the true clinical translational value of PET imaging after myocardial infarction.

PET imaging is able to harness biological processes to characterise high-risk features of atherosclerotic plaque prone to rupture. Current radiotracers are able to track inflammation, microcalcification, hypoxia, and neoangiogenesis within vulnerable plaque. 18 F-fluorodeoxyglucose ( 18 F-FDG) is the most commonly used radiotracer in vascular studies and is employed as a surrogate marker of plaque inflammation. Increasingly, 18 F-FDG and other PET tracers are also being used to provide imaging endpoints in cardiovascular interventional trials. The evolution of novel PET radiotracers, imaging protocols, and hybrid scanners are likely to enable more efficient and accurate characterisation of high-risk plaque. This review explores the role of PET imaging in atherosclerosis with a focus on PET tracers utilised in clinical research and the applications of PET imaging to cardiovascular drug development., (© 2019 The British Pharmacological Society.)

Radiomics, quantitative feature extraction from radiological images, can improve disease diagnosis and prognostication. However, radiomic features are susceptible to image acquisition and segmentation variability. Ideally, only features robust to these variations would be incorporated into predictive models, for good generalisability. We extracted 93 radiomic features from carotid artery computed tomography angiograms of 41 patients with cerebrovascular events. We tested feature robustness to region-of-interest perturbations, image pre-processing settings and quantisation methods using both single- and multi-slice approaches. We assessed the ability of the most robust features to identify culprit and non-culprit arteries using several machine learning algorithms and report the average area under the curve (AUC) from five-fold cross validation. Multi-slice features were superior to single for producing robust radiomic features (67 vs. 61). The optimal image quantisation method used bin widths of 25 or 30. Incorporating our top 10 non-redundant robust radiomics features into ElasticNet achieved an AUC of 0.73 and accuracy of 69% (compared to carotid calcification alone [AUC: 0.44, accuracy: 46%]). Our results provide key information for introducing carotid CT radiomics into clinical practice. If validated prospectively, our robust carotid radiomic set could improve stroke prediction and target therapies to those at highest risk.

Competing Interests: Funding Support and Author Disclosures This study received infrastructure support from the Imperial College National Institute for Health Research Biomedical Research Centre, London, United Kingdom. Dr. Tarkin is supported by Wellcome Trust. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Positron emission tomography (PET) imaging is useful in cardiovascular disease across several areas, from assessment of myocardial perfusion and viability, to highlighting atherosclerotic plaque activity and measuring the extent of cardiac innervation in heart failure. Other important roles of PET have emerged in prosthetic valve endocarditis, implanted device infection, infiltrative cardiomyopathies, aortic stenosis and cardio-oncology. Advances in scanner technology, including hybrid PET/MRI and total body PET imaging, as well as the development of novel PET tracers and cardiac-specific postprocessing techniques using artificial intelligence will undoubtedly continue to progress the field., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Atherosclerosis is a systemic inflammatory disease typified by the development of lipid-rich atheroma (plaques), the rupture of which are a major cause of myocardial infarction and stroke. Anatomical evaluation of the plaque considering only the degree of luminal stenosis overlooks features associated with vulnerable plaques, such as high-risk morphological features or pathophysiology, and hence risks missing vulnerable or ruptured non-stenotic plaques. Consequently, there has been interest in identifying these markers of vulnerability using either MRI for morphology, or positron emission tomography (PET) for physiological processes involved in atherogenesis. The advent of hybrid PET/MRI scanners offers the potential to combine the strengths of PET and MRI to allow comprehensive assessment of the atherosclerotic plaque. This review will discuss the principles and technical aspects of hybrid PET/MRI assessment of atherosclerosis, and consider how combining the complementary modalities of PET and MRI has already furthered our understanding of atherogenesis, advanced drug development, and how it may hold potential for clinical application.

Purpose of Review: To provide a focused update on recent advances in positron emission tomography (PET) imaging in vascular inflammatory diseases and consider future directions in the field., Recent Findings: While PET imaging with 18 F-fluorodeoxyglucose (FDG) can provide a useful marker of disease activity in several vascular inflammatory diseases, including atherosclerosis and large-vessel vasculitis, this tracer lacks inflammatory cell specificity and is not a practical solution for imaging the coronary vasculature because of avid background myocardial signal. To overcome these limitations, research is ongoing to identify novel PET tracers that can more accurately track individual components of vascular immune responses. Use of these novel PET tracers could lead to a better understanding of underlying disease mechanisms and help inform the identification and stratification of patients for newly emerging immune-modulatory therapies. Future research is needed to realise the true clinical translational value of PET imaging in vascular inflammatory diseases.

Objectives: This study determined whether in vivo positron emission tomography (PET) of arterial inflammation ( 18 F-fluorodeoxyglucose [ 18 F-FDG]) or microcalcification ( 18 F-sodium fluoride [ 18 F-NaF]) could predict restenosis following PTA., Background: Restenosis following lower limb percutaneous transluminal angioplasty (PTA) is common, unpredictable, and challenging to treat. Currently, it is impossible to predict which patient will suffer from restenosis following angioplasty., Methods: In this prospective observational cohort study, 50 patients with symptomatic peripheral arterial disease underwent 18 F-FDG and 18 F-NaF PET/computed tomography (CT) imaging of the superficial femoral artery before and 6 weeks after angioplasty. The primary outcome was arterial restenosis at 12 months., Results: Forty subjects completed the study protocol with 14 patients (35%) reaching the primary outcome of restenosis. The baseline activities of femoral arterial inflammation ( 18 F-FDG tissue-to-background ratio [TBR] 2.43 [interquartile range (IQR): 2.29 to 2.61] vs. 1.63 [IQR: 1.52 to 1.78]; p < 0.001) and microcalcification ( 18 F-NaF TBR 2.61 [IQR: 2.50 to 2.77] vs. 1.69 [IQR: 1.54 to 1.77]; p < 0.001) were higher in patients who developed restenosis. The predictive value of both 18 F-FDG (cut-off TBR max value of 1.98) and 18 F-NaF (cut-off TBR max value of 2.11) uptake demonstrated excellent discrimination in predicting 1-year restenosis (Kaplan Meier estimator, log-rank p < 0.001)., Conclusions: Baseline and persistent femoral arterial inflammation and micro-calcification are associated with restenosis following lower limb PTA. For the first time, we describe a method of identifying complex metabolically active plaques and patients at risk of restenosis that has the potential to select patients for intervention and to serve as a biomarker to test novel interventions to prevent restenosis., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Using combined positron emission tomography and CT (PET-CT), we measured aortic inflammation and calcification in patients with abdominal aortic aneurysms (AAA), and compared them with matched controls with atherosclerosis., Methods: We prospectively recruited 63 patients (mean age 76.1±6.8 years) with asymptomatic aneurysm disease (mean size 4.33±0.73 cm) and 19 age-and-sex-matched patients with confirmed atherosclerosis but no aneurysm. Inflammation and calcification were assessed using combined 18F-FDG PET-CT and quantified using tissue-to-background ratios (TBRs) and Agatston scores., Results: In patients with AAA, 18F-FDG uptake was higher within the aneurysm than in other regions of the aorta (mean TBR max 2.23±0.46 vs 2.12±0.46, p=0.02). Compared with atherosclerotic control subjects, both aneurysmal and non-aneurysmal aortae showed higher 18F-FDG accumulation (total aorta mean TBR max 2.16±0.51 vs 1.70±0.22, p=0.001; AAA mean TBR max 2.23±0.45 vs 1.68±0.21, p<0.0001). Aneurysms containing intraluminal thrombus demonstrated lower 18F-FDG uptake within their walls than those without (mean TBR max 2.14±0.43 vs 2.43±0.45, p=0.018), with thrombus itself showing low tracer uptake (mean TBR max thrombus 1.30±0.48 vs aneurysm wall 2.23±0.46, p<0.0001). Calcification in the aneurysmal segment was higher than both non-aneurysmal segments in patients with aneurysm (Agatston 4918 (2901-8008) vs 1017 (139-2226), p<0.0001) and equivalent regions in control patients (442 (304-920) vs 166 (80-374) Agatston units per cm, p=0.0042)., Conclusions: The entire aorta is more inflamed in patients with aneurysm than in those with atherosclerosis, perhaps suggesting a generalised inflammatory aortopathy in patients with aneurysm. Calcification was prominent within the aneurysmal sac, with the remainder of the aorta being relatively spared. The presence of intraluminal thrombus, itself metabolically relatively inert, was associated with lower levels of inflammation in the adjacent aneurysmal wall., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background: Inflammation and microcalcification are interrelated processes contributing to atherosclerotic plaque vulnerability. Positron-emission tomography can quantify these processes in vivo. This study investigates (1) 18 F-fluorodeoxyglucose (FDG) and 18 F-sodium fluoride (NaF) uptake in culprit versus nonculprit carotid atheroma, (2) spatial distributions of uptake, and (3) how macrocalcification affects this relationship., Methods: Individuals with acute ischemic stroke with ipsilateral carotid stenosis of ≥50% underwent FDG-positron-emission tomography and NaF-positron-emission tomography. Tracer uptake was quantified using maximum tissue-to-background ratios (TBR max ) and macrocalcification quantified using Agatston scoring., Results: In 26 individuals, median most diseased segment TBR max (interquartile range) was higher in culprit than in nonculprit atheroma for both FDG (2.08 [0.52] versus 1.89 [0.40]; P <0.001) and NaF (2.68 [0.63] versus 2.39 [1.02]; P <0.001). However, whole vessel TBR max was higher in culprit arteries for FDG (1.92 [0.41] versus 1.71 [0.31]; P <0.001) but not NaF (1.85 [0.28] versus 1.79 [0.60]; P =0.10). NaF uptake was concentrated at carotid bifurcations, while FDG was distributed evenly throughout arteries. Correlations between FDG and NaF TBR max differed between bifurcations with low macrocalcification ( r s =0.38; P <0.001) versus high macrocalcification ( r s =0.59; P <0.001)., Conclusions: This is the first study to demonstrate increased uptake of both FDG and NaF in culprit carotid plaques, with discrete distributions of pathophysiology influencing vulnerability in vivo. These findings have implications for our understanding of the natural history of the disease and for the clinical assessment and management of carotid atherosclerosis.

Objectives: To estimate the prevalence of non-calcified coronary artery disease (CAD) in patients with suspected stable angina and a zero coronary artery calcification (CAC) score, and to assess the prognostic significance of a zero CAC in these symptomatic patients., Methods: In this prospective cohort study, consecutive patients with stable chest pain underwent CAC scoring ± CT coronary angiography (CTCA) as part of routine clinical care at a single tertiary centre over 7 years. Major adverse cardiac event (MACE) was defined as cardiac death, non-fatal myocardial infarction and/or non-elective revascularisation., Results: A total of 915 of 1753 (52.2%) patients (mean age 56.8 ± 12.0 years; 46.2% male) had a zero CAC score. Of the 751 (82.1%) patients with a zero CAC in whom CTCA was performed, 674 (89.7%) had normal coronary arteries, 63 (8.4%) had non-calcified CAD with < 50% stenosis and 14 (1.9%) had ≥ 50% stenosis in at least one coronary artery. The negative predictive value of a zero CAC for excluding a ≥ 50% CTCA stenosis was 98.1%. Over a median follow-up period of 2.2 years (range 1.0-7.0 years), the absolute annualised rates of MACE were as follows: zero CAC 1.9 per 1000 person-years and non-zero CAC 7.4 per 1000 person-years (HR 3.8, p = 0.009). However, after adjusting for age, gender and cardiovascular risk factors using a multivariable Cox proportional hazards model, there was no statistically significant difference in the risk of MACE between the two patient cohorts (p = 0.19). After adjusting for age, gender and cardiovascular risk factors, the HR for all-cause mortality among the zero CAC cohort vers non-zero CAC was 2.1 (p = 0.27)., Conclusion: A zero CAC score in patients undergoing CT scanning for suspected stable angina has a high negative predictive value for the exclusion of obstructive CAD and is associated with a good medium-term prognosis., Competing Interests: Competing interests: None declared.

Competing Interests: Competing interests: None declared.

Introduction: The role of positron emission tomography (PET)/computed tomography (CT) in the determination of inflammation in arterial disease is not well defined. This can provide information about arterial wall inflammation in atherosclerotic disease, and may give insight into plaque stability. The aim of this review was to perform a meta-analysis of PET/CT with 18 F-FDG (fluorodeoxyglucose) uptake in symptomatic and asymptomatic carotid artery disease., Methods: This was a systematic review, following PRISMA guidelines, which interrogated the MEDLINE database from January 2001 to May 2017. The search combined the terms, "inflammation", "FDG", and "stroke". The search criteria included all types of studies, with a primary outcome of the degree of arterial vascular inflammation determined by 18 F-FDG uptake. Analysis involved an inverse weighted variance estimate of pooled data, using a random effects model., Results: A total of 14 articles (539 patients) were included in the meta-analysis. Comparing carotid artery 18 F-FDG uptake in symptomatic versus asymptomatic disease yielded a standard mean difference of 0.94 (95% CI 0.58-1.130; p < .0001; I 2  = 65%)., Conclusions: PET/CT using 18 F-FDG can demonstrate carotid plaque inflammation, and is a marker of symptomatic disease. Further studies are required to understand the clinical implication of PET/CT as a risk prediction tool., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Nicorandil and long-acting nitrates are vasodilatory drugs used commonly in the management of chronic stable angina pectoris. Both nicorandil and long-acting nitrates exert anti-angina properties via activation of nitric oxide (NO) signalling pathways, triggering vascular smooth muscle cell relaxation. Nicorandil has additional actions as an arterial K + ATP channel agonist, resulting in more "balanced" arterial and venous vasodilatation than nitrates. Ultimately, these drugs prevent angina symptoms through reductions in preload and diastolic wall tension and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. While there is some evidence to suggest a modest reduction in cardiovascular events among patients with stable angina treated with nicorandil compared to placebo, this prognostic benefit has yet to be proven conclusively. In contrast, there is emerging evidence to suggest that chronic use of long-acting nitrates might cause endothelial dysfunction and increased cardiovascular risk in some patients., Competing Interests: Disclosure: JM Tarkin is supported by the NIHR and the Wellcome Trust. The authors have no others conflict of interests to declare.

Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Although structural imaging techniques such as MRI are the mainstay of clinical care and research in cerebrovascular disease, they have limited ability to detect these pathophysiological processes in vivo. By contrast, PET can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. PET has also helped to elucidate the relationships between chronic hypoxia, neuroinflammation, and amyloid-β deposition in cerebral small vessel disease. This Review describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.

Aims: The association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD)., Methods: LLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality., Results: 220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31-64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884-0.974]) than for the Bollinger score (0.824: 95% CI [0.758-0.890]) for the primary outcome. A LLAC score ≥ 4400 had the best diagnostic accuracy to determine the outcome measure., Conclusion: This is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT-derived measure of calcification-the LLAC score.