Search

Aims: While acute cardiovascular complications of coronavirus disease 2019 (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 [standard deviation (SD) 13] years, 71% female} with long COVID-19 (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 were performed. Nine of the 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 two had severe left ventricular (LV) 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+(GZB+)-secreting cells upon stimulation. CD8 TEM cells and CCL7 were the strongest predictors of MRI abnormalities in a least absolute shrinkage and selection operator regression model (composite area under the curve 0.96, 95% confidence interval 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., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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: 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.)

For healthcare datasets, it is often impossible to combine data samples from multiple sites due to ethical, privacy, or logistical concerns. Federated learning allows for the utilization of powerful machine learning algorithms without requiring the pooling of data. Healthcare data have many simultaneous challenges, such as highly siloed data, class imbalance, missing data, distribution shifts, and non-standardized variables, that require new methodologies to address. Federated learning adds significant methodological complexity to conventional centralized machine learning, requiring distributed optimization, communication between nodes, aggregation of models, and redistribution of models. In this systematic review, we consider all papers on Scopus published between January 2015 and February 2023 that describe new federated learning methodologies for addressing challenges with healthcare data. We reviewed 89 papers meeting these criteria. Significant systemic issues were identified throughout the literature, compromising many methodologies reviewed. We give detailed recommendations to help improve methodology development for federated learning in healthcare., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Background: Classifying samples in incomplete datasets is a common aim for machine learning practitioners, but is non-trivial. Missing data is found in most real-world datasets and these missing values are typically imputed using established methods, followed by classification of the now complete samples. The focus of the machine learning researcher is to optimise the classifier's performance., Methods: We utilise three simulated and three real-world clinical datasets with different feature types and missingness patterns. Initially, we evaluate how the downstream classifier performance depends on the choice of classifier and imputation methods. We employ ANOVA to quantitatively evaluate how the choice of missingness rate, imputation method, and classifier method influences the performance. Additionally, we compare commonly used methods for assessing imputation quality and introduce a class of discrepancy scores based on the sliced Wasserstein distance. We also assess the stability of the imputations and the interpretability of model built on the imputed data., Results: The performance of the classifier is most affected by the percentage of missingness in the test data, with a considerable performance decline observed as the test missingness rate increases. We also show that the commonly used measures for assessing imputation quality tend to lead to imputed data which poorly matches the underlying data distribution, whereas our new class of discrepancy scores performs much better on this measure. Furthermore, we show that the interpretability of classifier models trained using poorly imputed data is compromised., Conclusions: It is imperative to consider the quality of the imputation when performing downstream classification as the effects on the classifier can be considerable., (© 2023. Springer Nature Limited.)

Background: Pneumonitis is one of the most common adverse events induced by the use of immune checkpoint inhibitors (ICI), accounting for a 20% of all ICI-associated deaths. Despite numerous efforts to identify risk factors and develop predictive models, there is no clinically deployed risk prediction model for patient risk stratification or for guiding subsequent monitoring. We believe this is due to systemic suboptimal approaches in study designs and methodologies in the literature. The nature and prevalence of different methodological approaches has not been thoroughly examined in prior systematic reviews., Methods: The PubMed, medRxiv and bioRxiv databases were used to identify studies that aimed at risk factor discovery and/or risk prediction model development for ICI-induced pneumonitis (ICI pneumonitis). Studies were then analysed to identify common methodological pitfalls and their contribution to the risk of bias, assessed using the QUIPS and PROBAST tools., Results: There were 51 manuscripts eligible for the review, with Japan-based studies over-represented, being nearly half (24/51) of all papers considered. Only 2/51 studies had a low risk of bias overall. Common bias-inducing practices included unclear diagnostic method or potential misdiagnosis, lack of multiple testing correction, the use of univariate analysis for selecting features for multivariable analysis, discretization of continuous variables, and inappropriate handling of missing values. Results from the risk model development studies were also likely to have been overoptimistic due to lack of holdout sets., Conclusions: Studies with low risk of bias in their methodology are lacking in the existing literature. High-quality risk factor identification and risk model development studies are urgently required by the community to give the best chance of them progressing into a clinically deployable risk prediction model. Recommendations and alternative approaches for reducing the risk of bias were also discussed to guide future studies., Competing Interests: Authors BT, KB and EH were employed by the company AstraZeneca. The remaining 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. This study received funding from AstraZeneca. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2023 Chen, Welsh, Pillay, Tannenwald, Bliznashki, Hutchison, Aston, Schönlieb, Rudd, Jones and Roberts.)

Atherosclerosis is a chronic systemic inflammatory condition of the vasculature and a leading cause of stroke. Luminal stenosis severity is an important factor in determining vascular risk. Conventional imaging modalities, such as angiography or duplex ultrasonography, are used to quantify stenosis severity and inform clinical care but provide limited information on plaque biology. Inflammatory processes are central to atherosclerotic plaque progression and destabilization. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is a validated technique for quantifying plaque inflammation. In this review, we discuss the evolution of FDG-PET as an imaging modality to quantify plaque vulnerability, challenges in standardization of image acquisition and analysis, its potential application to routine clinical care after stroke, and the possible role it will play in future drug discovery.

The National COVID-19 Chest Imaging Database (NCCID) is a centralized UK database of thoracic imaging and corresponding clinical data. It is made available by the National Health Service Artificial Intelligence (NHS AI) Lab to support the development of machine learning tools focused on Coronavirus Disease 2019 (COVID-19). A bespoke cleaning pipeline for NCCID, developed by the NHSx, was introduced in 2021. We present an extension to the original cleaning pipeline for the clinical data of the database. It has been adjusted to correct additional systematic inconsistencies in the raw data such as patient sex, oxygen levels and date values. The most important changes will be discussed in this paper, whilst the code and further explanations are made publicly available on GitLab. The suggested cleaning will allow global users to work with more consistent data for the development of machine learning tools without being an expert. In addition, it highlights some of the challenges when working with clinical multi-center data and includes recommendations for similar future initiatives., (© 2023. The Author(s).)

Background: In 2016, the National Institute for Health and Care Excellence Clinical Guideline Number 95 ("Chest pain of recent onset") (CG95) recommended coronary computed tomography angiography (CCTA) as the first-line test for possible angina., Objectives: The purpose of this study was to determine the impact of temporal trends in imaging use on outcomes for coronary artery disease (CAD) following the CG95 recommendations., Methods: Investigations from 2012 to 2018 were extracted from a national database and linked to hospital admission and mortality registries. Growth rates were adjusted for population size, with image modality use, cardiovascular hospital admissions, and mortality compared using Kendall's rank correlation. The impact of CG95 was assessed using an interrupted time-series analysis., Results: A total of 1,909,314 investigations for CAD were performed, with an annualized per capita growth of 4.8%. Costs were £0.35 million/100,000 population/year with an increase of 2.8%/year mirroring inflation (2.5%/year). CG95 was associated with a rise in CCTA (exp[β]: 1.10; 95% CI: 1.03-1.18), no change in myocardial perfusion imaging, and a potential modest fall (exp[β]: 0.997; 95% CI: 0.993-1.00]) in invasive coronary angiography. There was an apparent trend between computed tomography angiography growth and invasive catheter angiography reduction across regions (Kendall Tau: -0.19; P = 0.08). CCTA growth was associated with a reduction in cardiovascular mortality (Kendall Tau: -0.21; P = 0.045), and ischemic heart disease deaths (Kendall Tau: -0.22; P = 0.042), with an apparent trend with reduced all-cause mortality (Kendall Tau: -0.19; P = 0.07)., Conclusions: Imaging investigations for CAD are increasing. Greater regional increases in CCTA were associated with fewer hospitalizations for myocardial infarction and a more rapid decline in CAD mortality., Competing Interests: Funding Support and Author Disclosures Drs Weir-McCall and Rudd are supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Dr Rudd is supported by the British Heart Foundation, HEFCE, the EPSRC, and the Wellcome Trust. Dr Newby is supported by the British Heart Foundation (CH/09/002, RG/16/10/32375, RE/18/5/34216) and is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA). Dr Williams (FS/ICRF/20/26002) is supported by the British Heart Foundation. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) license to any Author Accepted Manuscript version arising from this submission. Drs Weir-McCall, Williams, Roditi, and Newby were investigators in the SCOT-HEART trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Introduction: Obsolete bleep/long-range pager equipment remains firmly embedded in the National Health Service (NHS)., Objective: To introduce a secure, chart-integrated messaging system (Epic Secure Chat) in a large NHS tertiary referral centre to replace non-emergency bleeps/long-range pagers., Methods: The system was socialised in the months before go-live. Operational readiness was overseen by an implementation group with stakeholder engagement. Cutover was accompanied by a week of Secure Chat and bleeps running in parallel., Results: Engagement due to socialisation was high with usage stabilising approximately 3 months after go-live. Contact centre internal call activity fell significantly after go-live. No significant patient safety concerns were reported., Discussion: Uptake was excellent with substantial utilisation well before cutover indirectly supporting high levels of engagement. The majority of those who previously carried bleeps were content to use personal devices for messaging because of user convenience after reassurance about privacy., Conclusion: An integrated secure messaging system can replace non-emergency bleeps with beneficial impact on service., Competing Interests: Competing interests: None at the time of implementation however AC will be leaving the role of Director of Digital at Cambridge University Hospitals in February 2023 to take up a post with Epic Systems Corporation. (This is not a conflict of interest as per the COI form but we include it for complete transparency.), (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

Introduction: Inflammation plays a critical role in the pathogenesis of atherosclerosis, the leading cause of ischaemic heart disease (IHD). Studies in preclinical models have demonstrated that an increase in regulatory T cells (Tregs), which have a potent immune modulatory action, led to a regression of atherosclerosis. The Low-dose InterLeukin 2 (IL-2) in patients with stable ischaemic heart disease and Acute Coronary Syndromes (LILACS) study, established the safety of low-dose IL-2 and its biological efficacy in IHD. The IVORY trial is designed to assess the effects of low-dose IL-2 on vascular inflammation in patients with acute coronary syndromes (ACS)., Methods and Analysis: In this study, we hypothesise that low-dose IL-2 will reduce vascular inflammation in patients presenting with ACS. This is a double-blind, randomised, placebo-controlled, phase II clinical trial. Patients will be recruited across two centres, a district general hospital and a tertiary cardiac centre in Cambridge, UK. Sixty patients with ACS (unstable angina, non-ST elevation myocardial infarction or ST elevation myocardial infarction) with high-sensitivity C reactive protein (hsCRP) levels >2 mg/L will be randomised to receive either 1.5×10 6  IU of low-dose IL-2 or placebo (1:1). Dosing will commence within 14 days of admission. Dosing will comprise of an induction and a maintenance phase. 2-Deoxy-2-[fluorine-18] fluoro-D-glucose ( 18 F-FDG) positron emission tomography/CT (PET/CT) scans will be performed before and after dosing. The primary endpoint is the change in mean maximum target to background ratios (TBR max ) in the index vessel between baseline and follow-up scans. Changes in circulating T-cell subsets will be measured as secondary endpoints of the study. The safety and tolerability of extended dosing with low-dose IL-2 in patients with ACS will be evaluated throughout the study., Ethics and Dissemination: The Health Research Authority and Health and Care Research Wales, UK (19/YH/0171), approved the study. Written informed consent is required to participate in the trial. The results will be reported through peer-reviewed journals and conference presentations., Trial Registration Number: NCT04241601., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To provide estimates for how different treatment pathways for the management of severe aortic stenosis (AS) may affect National Health Service (NHS) England waiting list duration and associated mortality., Design: We constructed a mathematical model of the excess waiting list and found the closed-form analytic solution to that model. From published data, we calculated estimates for how the strategies listed under Interventions may affect the time to clear the backlog of patients waiting for treatment and the associated waiting list mortality., Setting: The NHS in England., Participants: Estimated patients with AS in England., Interventions: (1) Increasing the capacity for the treatment of severe AS, (2) converting proportions of cases from surgery to transcatheter aortic valve implantation and (3) a combination of these two., Results: In a capacitated system, clearing the backlog by returning to pre-COVID-19 capacity is not possible. A conversion rate of 50% would clear the backlog within 666 (533-848) days with 1419 (597-2189) deaths while waiting during this time. A 20% capacity increase would require 535 (434-666) days, with an associated mortality of 1172 (466-1859). A combination of converting 40% cases and increasing capacity by 20% would clear the backlog within a year (343 (281-410) days) with 784 (292-1324) deaths while awaiting treatment., Conclusion: A strategy change to the management of severe AS is required to reduce the NHS backlog and waiting list deaths during the post-COVID-19 'recovery' period. However, plausible adaptations will still incur a substantial wait to treatment and many hundreds dying while waiting., Competing Interests: Competing interests: BG acknowledges grants not related to this project from the David Telling Charitable Trust, and the Biotechnology and Biological Sciences Research Council, he additionally declared Associate Editorship of Anesthesia Journal, and being the chair DMSC for the COPIA Trial. All other authors confirm that they have no competing interests to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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.)

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.

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.

Background: Identifying people at risk of cardiovascular diseases (CVD) is a cornerstone of preventative cardiology. Risk prediction models currently recommended by clinical guidelines are typically based on a limited number of predictors with sub-optimal performance across all patient groups. Data-driven techniques based on machine learning (ML) might improve the performance of risk predictions by agnostically discovering novel risk predictors and learning the complex interactions between them. We tested (1) whether ML techniques based on a state-of-the-art automated ML framework (AutoPrognosis) could improve CVD risk prediction compared to traditional approaches, and (2) whether considering non-traditional variables could increase the accuracy of CVD risk predictions., Methods and Findings: Using data on 423,604 participants without CVD at baseline in UK Biobank, we developed a ML-based model for predicting CVD risk based on 473 available variables. Our ML-based model was derived using AutoPrognosis, an algorithmic tool that automatically selects and tunes ensembles of ML modeling pipelines (comprising data imputation, feature processing, classification and calibration algorithms). We compared our model with a well-established risk prediction algorithm based on conventional CVD risk factors (Framingham score), a Cox proportional hazards (PH) model based on familiar risk factors (i.e, age, gender, smoking status, systolic blood pressure, history of diabetes, reception of treatments for hypertension and body mass index), and a Cox PH model based on all of the 473 available variables. Predictive performances were assessed using area under the receiver operating characteristic curve (AUC-ROC). Overall, our AutoPrognosis model improved risk prediction (AUC-ROC: 0.774, 95% CI: 0.768-0.780) compared to Framingham score (AUC-ROC: 0.724, 95% CI: 0.720-0.728, p < 0.001), Cox PH model with conventional risk factors (AUC-ROC: 0.734, 95% CI: 0.729-0.739, p < 0.001), and Cox PH model with all UK Biobank variables (AUC-ROC: 0.758, 95% CI: 0.753-0.763, p < 0.001). Out of 4,801 CVD cases recorded within 5 years of baseline, AutoPrognosis was able to correctly predict 368 more cases compared to the Framingham score. Our AutoPrognosis model included predictors that are not usually considered in existing risk prediction models, such as the individuals' usual walking pace and their self-reported overall health rating. Furthermore, our model improved risk prediction in potentially relevant sub-populations, such as in individuals with history of diabetes. We also highlight the relative benefits accrued from including more information into a predictive model (information gain) as compared to the benefits of using more complex models (modeling gain)., Conclusions: Our AutoPrognosis model improves the accuracy of CVD risk prediction in the UK Biobank population. This approach performs well in traditionally poorly served patient subgroups. Additionally, AutoPrognosis uncovered novel predictors for CVD disease that may now be tested in prospective studies. We found that the "information gain" achieved by considering more risk factors in the predictive model was significantly higher than the "modeling gain" achieved by adopting complex predictive models., Competing Interests: The authors have declared that no competing interests exist.

Background: Fluorine-18 sodium fluoride (NaF), a bone-seeking radiopharmaceutical used to detect osseous metastases, localizes in regions of microcalcification in atherosclerosis., Objectives: To determine if atherosclerosis of penile arteries plays a role in erectile dysfunction (ED), this study analyzed NaF images in prostate cancer patients., Methods: NaF positron emission tomography-computed tomography bone scans were evaluated in 437 prostate cancer patients (age 66.6 ± 8.7 years). Their urologic histories were reviewed for prevalent ED (diagnosed before the scan date) or incident ED (no ED at first scan, but developed during 1-year follow-up); patients with no ED (neither before the scan nor during follow-up) were included as a control group. A semicircular region of interest was set on the dorsal one-half of the penis (to avoid residual excreted activity in the urethra) on 5 contiguous slices at the base of the penis on positron emission tomography-computed tomography coronal reconstructions, and the average standardized uptake value (SUVmax) was described as NaF uptake., Results: Of 437 patients, 336 (76.9%) had prevalent ED, 60 incident ED (13.7%), and 41 had no ED (9.4%). SUVmax in patients with prevalent (median 1.88; interquartile range [IQR]: 1.67 to 2.16) or incident (median 1.86; IQR: 1.72 to 2.08) ED was significantly higher than no ED (median 1.42; IQR: 1.25 to 1.54) patients (p < 0.001). After adjustment for other risk factors, the odds ratio of prevalent or incident ED was 25.2 (95% confidence interval: 9.5 to 67.0) for every 0.5-U increment in SUVmax with receptor operating characteristic area of 0.91 (95% confidence interval: 0.88 to 0.94)., Conclusions: NaF uptake in penile vessels suggests that atherosclerosis is associated with ED in prostate cancer patients. The importance of NaF uptake needs to be tested in noncancer subjects and cause-effect relationship needs to be established., (Copyright © 2019. Published by Elsevier Inc.)

Background: Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences., Objectives: The authors sought to assess whether 18 F-fluoride positron emission tomography (PET)-computed tomography (CT) can detect bioprosthetic aortic valve degeneration and predict valve dysfunction., Methods: Explanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography, 18 F-fluoride PET, and serial echocardiography during 2 years of follow-up., Results: All ex vivo, degenerate bioprosthetic valves displayed 18 F-fluoride PET uptake that colocalized with tissue degeneration on histology. In 71 patients without known bioprosthesis dysfunction, 14 had abnormal leaflet pathology on CT, and 24 demonstrated 18 F-fluoride PET uptake (target-to-background ratio 1.55 [interquartile range (IQR): 1.44 to 1.88]). Patients with increased 18 F-fluoride uptake exhibited more rapid deterioration in valve function compared with those without (annualized change in peak transvalvular velocity 0.30 [IQR: 0.13 to 0.61] vs. 0.01 [IQR: -0.05 to 0.16] ms -1 /year; p < 0.001). Indeed 18 F-fluoride uptake correlated with deterioration in all the conventional echocardiographic measures of valve function assessed (e.g., change in peak velocity, r = 0.72; p < 0.001). Each of the 10 patients who developed new overt bioprosthesis dysfunction during follow-up had evidence of 18 F-fluoride uptake at baseline (target-to-background ratio 1.89 [IQR: 1.46 to 2.59]). On multivariable analysis, 18 F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction., Conclusions: 18 F-fluoride PET-CT identifies subclinical bioprosthetic valve degeneration, providing powerful prediction of subsequent valvular dysfunction and highlighting patients at risk of valve failure. This technique holds major promise in the diagnosis of valvular degeneration and the surveillance of patients with bioprosthetic valves. (18F-Fluoride Assessment of Aortic Bioprosthesis Durability and Outcome [18F-FAABULOUS]; NCT02304276)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Inflammation and dysregulated immune responses play a crucial role in atherosclerosis, underlying ischaemic heart disease (IHD) and acute coronary syndromes (ACSs). Immune responses are also major determinants of the postischaemic injury in myocardial infarction. Regulatory T cells (CD4 + CD25 + FOXP3 + ; Treg) induce immune tolerance and preserve immune homeostasis. Recent in vivo studies suggested that low-dose interleukin-2 (IL-2) can increase Treg cell numbers. Aldesleukin is a human recombinant form of IL-2 that has been used therapeutically in several autoimmune diseases. However, its safety and efficacy is unknown in the setting of coronary artery disease., Method and Analysis: Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes is a single-centre, first-in-class, dose-escalation, two-part clinical trial. Patients with stable IHD (part A) and ACS (part B) will be randomised to receive either IL-2 (aldesleukin; dose range 0.3-3×10 6 IU) or placebo once daily, given subcutaneously, for five consecutive days. Part A will have five dose levels with five patients in each group. Group 1 will receive a dose of 0.3×10 6 IU, while the dose for the remaining four groups will be determined on completion of the preceding group. Part B will have four dose levels with eight patients in each group. The dose of the first group will be based on part A. Doses for each of the subsequent three groups will similarly be determined after completion of the previous group. The primary endpoint is safety and tolerability of aldesleukin and to determine the dose that increases mean circulating Treg levels by at least 75%., Ethics and Dissemination: The study received a favourable opinion by the Greater Manchester Central Research Ethics Committee, UK (17/NW/0012). The results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report., Trial Registration Number: NCT03113773; Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

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.)

Background: Chronic obstructive pulmonary disease (COPD) is a complex inflammatory condition in which an important extra-pulmonary manifestation is cardiovascular disease. We hypothesized that COPD patients would have increased aortic inflammation and stiffness, as candidate mechanisms mediating increased cardiovascular risk, compared to two negative control groups: healthy never-smokers and smokers without COPD. We also studied patients with COPD due to alpha - 1 antitrypsin deficiency (α 1 ATD) as a comparator lung disease group., Methods: Participants underwent 18 F-Fluorodeoxyglucose (FDG) positron emission tomography imaging to quantify aortic inflammation as the tissue-to-blood-ratio (TBR) of FDG uptake. Aortic stiffness was measured by carotid-femoral aortic pulse wave velocity (aPWV)., Results: Eighty-five usual COPD (COPD due to smoking), 12 α 1 ATD-COPD patients and 12 each smokers and never-smokers were studied. There was no difference in pack years smoked between COPD patients and smokers (45 ± 25 vs 37 ± 19, p = 0.36), but α 1 ATD patients smoked significantly less (19 ± 11, p < 0.001 for both). By design, spirometry measures were lower in COPD and α 1 ATD-COPD patients compared to smokers and never-smokers. Aortic inflammation and stiffness were increased in COPD (TBR: 1.90 ± 0.38, aPWV: 9.9 ± 2.6 m/s) and α 1 ATD patients (TBR: 1.94 ± 0.43, aPWV: 9.5 ± 1.8 m/s) compared with smokers (TBR: 1.74 ± 0.30, aPWV: 7.8 ± 1.8 m/s, p < 0.05 all) and never-smokers (TBR: 1.71 ± 0.34, aPWV: 7.9 ± 1.7 m/s, p ≤ 0.05 all)., Conclusions: In this cross-sectional prospective study, novel findings were that both usual COPD and α1ATD-COPD patients have increased aortic inflammation and stiffness compared to smoking and never-smoking controls, regardless of smoking history. These findings suggest that the presence of COPD lung disease per se may be associated with adverse aortic wall changes, and aortic inflammation and stiffening are potential mechanisms mediating increased vascular risk observed in COPD patients.