Publications by authors named "James H F Rudd"

113 Publications

Pattern of arterial inflammation and inflammatory markers in people living with HIV compared with uninfected people.

J Nucl Cardiol 2021 Feb 10. Epub 2021 Feb 10.

Division of Cardiology, Department of Experimental Diagnostic and Specialty Medicine, IRCCS Policlinico di St.Orsola, Alma Mater Studiorum-University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.

Study Design: To compare arterial inflammation (AI) between people living with HIV (PLWH) and uninfected people as assessed by F-Fluorodeoxyglucose (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 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). The independent relationships between HIV status and both TBR 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 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 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 in AA. PLWH also had an increased independent risk of IFN-γ, IL-10, and VCAM-1 levels.
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http://dx.doi.org/10.1007/s12350-020-02522-5DOI Listing
February 2021

Assessing robustness of carotid artery CT angiography radiomics in the identification of culprit lesions in cerebrovascular events.

Sci Rep 2021 Feb 10;11(1):3499. Epub 2021 Feb 10.

Department of Medicine, University of Cambridge, Cambridge, UK.

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.
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http://dx.doi.org/10.1038/s41598-021-82760-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876096PMC
February 2021

Novel Positron Emission Tomography Tracers for Imaging Vascular Inflammation.

Curr Cardiol Rep 2020 Aug 9;22(10):119. Epub 2020 Aug 9.

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.

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 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.
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http://dx.doi.org/10.1007/s11886-020-01372-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415747PMC
August 2020

Greater aortic inflammation and calcification in abdominal aortic aneurysmal disease than atherosclerosis: a prospective matched cohort study.

Open Heart 2020 11;7(1):e001141. Epub 2020 Mar 11.

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.

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 TBR2.23±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 TBR2.16±0.51 vs 1.70±0.22, p=0.001; AAA mean TBR2.23±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 TBR2.14±0.43 vs 2.43±0.45, p=0.018), with thrombus itself showing low tracer uptake (mean TBR 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.
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http://dx.doi.org/10.1136/openhrt-2019-001141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066636PMC
June 2020

Dual-Tracer Positron-Emission Tomography for Identification of Culprit Carotid Plaques and Pathophysiology In Vivo.

Circ Cardiovasc Imaging 2020 03 13;13(3):e009539. Epub 2020 Mar 13.

Department of Clinical Neurosciences (N.R.E., E.A.W.), University of Cambridge, Cambridge, United Kingdom.

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) F-fluorodeoxyglucose (FDG) and 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) and macrocalcification quantified using Agatston scoring.

Results: In 26 individuals, median most diseased segment TBR (interquartile range) was higher in culprit than in nonculprit atheroma for both FDG (2.08 [0.52] versus 1.89 [0.40]; <0.001) and NaF (2.68 [0.63] versus 2.39 [1.02]; <0.001). However, whole vessel TBR was higher in culprit arteries for FDG (1.92 [0.41] versus 1.71 [0.31]; <0.001) but not NaF (1.85 [0.28] versus 1.79 [0.60]; =0.10). NaF uptake was concentrated at carotid bifurcations, while FDG was distributed evenly throughout arteries. Correlations between FDG and NaF TBR differed between bifurcations with low macrocalcification (=0.38; <0.001) versus high macrocalcification (=0.59; <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.
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http://dx.doi.org/10.1161/CIRCIMAGING.119.009539DOI Listing
March 2020

Atherosclerosis imaging using PET: Insights and applications.

Br J Pharmacol 2019 Sep 13. Epub 2019 Sep 13.

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK.

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. F-fluorodeoxyglucose ( F-FDG) is the most commonly used radiotracer in vascular studies and is employed as a surrogate marker of plaque inflammation. Increasingly, 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.
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http://dx.doi.org/10.1111/bph.14868DOI Listing
September 2019

Alcohol use disorders and the heart.

Addiction 2019 09 15;114(9):1670-1678. Epub 2019 Jul 15.

Division of Cardiovascular Medicine, University of Cambridge, Honorary Consultant Cardiologist, Addenbrooke's Hospital, Cambridge, UK.

Alcohol use is an important preventable and modifiable cause of non-communicable disease, and has complex effects on the cardiovascular system that vary with dose. Observational and prospective studies have consistently shown a lower risk of cardiovascular and all-cause mortality in people with low levels of alcohol consumption when compared to abstainers (the 'J'-shaped curve). Maximum potential benefit occurs at 0.5 to one standard drinks (7-14 g pure ethanol) per day for women (18% lower all-cause mortality, 95% confidence interval (CI) = 13-22%) and one to two standard drinks (14-28 g ethanol) per day for men (17% lower all-cause mortality, 95% CI = 15-19%). However, this evidence is contested, and overall the detrimental effects of alcohol far outweigh the beneficial effects, with the risk of premature mortality increasing steadily after an average consumption of 10 g ethanol/day. Blood pressure (BP) is increased by regular alcohol consumption in a dose-dependent manner, with a relative risk for hypertension (systolic BP > 140 mm Hg or diastolic > 90 mm Hg) of 1.7 for 50 g ethanol/day and 2.5 at 100 g/day. Important reductions in BP readings can be expected after as little as 1 month of abstinence from alcohol. Heavy alcohol consumption in a binge pattern is associated with the development of acute cardiac arrhythmia, even in people with normal heart function. Atrial fibrillation is the most common arrhythmia associated with chronic high-volume alcohol intake, and above 14 g alcohol/day the relative risk increases 10% for every extra standard drink (14 g ethanol). Ethanol and its metabolites have toxic effects on cardiac myocytes, and alcoholic cardiomyopathy (ACM) accounts for a third of all cases of non-ischaemic dilated cardiomyopathy. Screening people drinking alcohol above low-volume levels and delivering a brief intervention may prevent the development of cardiovascular complications. Although people with established cardiovascular disease show improved outcomes with a reduction to low-volume alcohol consumption, there is no safe amount of alcohol to drink and patients with ACM should aim for abstinence in order to optimize medical treatment.
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http://dx.doi.org/10.1111/add.14703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771559PMC
September 2019

Vascular Positron Emission Tomography and Restenosis in Symptomatic Peripheral Arterial Disease: A Prospective Clinical Study.

JACC Cardiovasc Imaging 2020 04 12;13(4):1008-1017. Epub 2019 Jun 12.

Division of Vascular Surgery, Department of Surgery, Addenbrooke's Hospital, University of Cambridge, United Kingdom.

Objectives: This study determined whether in vivo positron emission tomography (PET) of arterial inflammation (F-fluorodeoxyglucose [F-FDG]) or microcalcification (F-sodium fluoride [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 F-FDG and 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 (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 (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 F-FDG (cut-off TBR value of 1.98) and F-NaF (cut-off TBR 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.
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http://dx.doi.org/10.1016/j.jcmg.2019.03.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136751PMC
April 2020

A zero coronary artery calcium score in patients with stable chest pain is associated with a good prognosis, despite risk of non-calcified plaques.

Open Heart 2019;6(1):e000945. Epub 2019 Apr 11.

Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

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.
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http://dx.doi.org/10.1136/openhrt-2018-000945DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519430PMC
February 2021

Cardiovascular disease risk prediction using automated machine learning: A prospective study of 423,604 UK Biobank participants.

PLoS One 2019 15;14(5):e0213653. Epub 2019 May 15.

University of California Los Angeles, Los Angeles, California, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0213653PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519796PMC
January 2020

Detection and Prediction of Bioprosthetic Aortic Valve Degeneration.

J Am Coll Cardiol 2019 03;73(10):1107-1119

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Background: Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences.

Objectives: The authors sought to assess whether 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, F-fluoride PET, and serial echocardiography during 2 years of follow-up.

Results: All ex vivo, degenerate bioprosthetic valves displayed 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 F-fluoride PET uptake (target-to-background ratio 1.55 [interquartile range (IQR): 1.44 to 1.88]). Patients with increased 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/year; p < 0.001). Indeed 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 F-fluoride uptake at baseline (target-to-background ratio 1.89 [IQR: 1.46 to 2.59]). On multivariable analysis, F-fluoride uptake was the only independent predictor of future bioprosthetic dysfunction.

Conclusions: 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).
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http://dx.doi.org/10.1016/j.jacc.2018.12.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424589PMC
March 2019

F-Fluoride Positron Emission Tomographic Imaging of Penile Arteries and Erectile Dysfunction.

J Am Coll Cardiol 2019 04 4;73(12):1386-1394. Epub 2019 Mar 4.

Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, New York; Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2018.10.076DOI Listing
April 2019

Imaging as a surrogate marker of drug efficacy in cardiovascular disease.

Heart 2019 04 31;105(7):567-578. Epub 2018 Oct 31.

Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

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http://dx.doi.org/10.1136/heartjnl-2017-311213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580750PMC
April 2019

Low-dose interleukin-2 in patients with stable ischaemic heart disease and acute coronary syndromes (LILACS): protocol and study rationale for a randomised, double-blind, placebo-controlled, phase I/II clinical trial.

BMJ Open 2018 09 17;8(9):e022452. Epub 2018 Sep 17.

Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge Medicine, Cambridge, UK.

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 (CD4CD25FOXP3; 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 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 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.
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http://dx.doi.org/10.1136/bmjopen-2018-022452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144322PMC
September 2018

Vascular inflammation and aortic stiffness: potential mechanisms of increased vascular risk in chronic obstructive pulmonary disease.

Respir Res 2018 05 24;19(1):100. Epub 2018 May 24.

Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, UK.

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 antitrypsin deficiency (αATD) as a comparator lung disease group.

Methods: Participants underwent 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 αATD-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 αATD patients smoked significantly less (19 ± 11, p < 0.001 for both). By design, spirometry measures were lower in COPD and αATD-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 αATD 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.
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http://dx.doi.org/10.1186/s12931-018-0792-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968523PMC
May 2018

F-FDG Uptake on PET/CT in Symptomatic versus Asymptomatic Carotid Disease: a Meta-Analysis.

Eur J Vasc Endovasc Surg 2018 08 2;56(2):172-179. Epub 2018 May 2.

Division of Vascular and Endovascular Surgery, Addenbrooke's Hospital, Cambridge University Hospital Trust, Cambridge, UK.

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 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 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 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 = 65%).

Conclusions: PET/CT using 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.
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http://dx.doi.org/10.1016/j.ejvs.2018.03.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105570PMC
August 2018

Response to "Re. Abdominal Aortic Aneurysm Calcification: Are Biochemical Markers a Missing Piece of the Puzzle?"

Eur J Vasc Endovasc Surg 2018 06 2;55(6):900-901. Epub 2018 Apr 2.

Division of Vascular and Endovascular Surgery, Addenbrooke's Hospital, Cambridge University Hospital Trust, Cambridge, UK.

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http://dx.doi.org/10.1016/j.ejvs.2018.03.010DOI Listing
June 2018

PET imaging of the neurovascular interface in cerebrovascular disease.

Nat Rev Neurol 2018 May 3;14(5):313. Epub 2018 Apr 3.

This corrects the article DOI: 10.1038/nrneurol.2017.129.
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http://dx.doi.org/10.1038/nrneurol.2018.42DOI Listing
May 2018

The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial.

PLoS One 2018 22;13(3):e0194197. Epub 2018 Mar 22.

Department of Experimental Medicine and Immunotherapeutics, University of Cambridge, Cambridge, United Kingdom.

Background: Cardiovascular disease is a major cause of morbidity and mortality in COPD patients. Systemic inflammation associated with COPD, is often hypothesised as a causal factor. p38 mitogen-activated protein kinases play a key role in the inflammatory pathogenesis of COPD and atherosclerosis.

Objectives: This study sought to evaluate the effects of losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, on vascular inflammation and endothelial function in chronic obstructive pulmonary disease (COPD) patients with systemic inflammation (defined by plasma fibrinogen >2·8g/l).

Methods: This was a randomised, double-blind, placebo-controlled, Phase II trial that recruited COPD patients with plasma fibrinogen >2.8g/l. Participants were randomly assigned by an online program to losmapimod 7·5mg or placebo tablets twice daily for 16 weeks. Pre- and post-dose 18F-Fluorodeoxyglucose positron emission tomography co-registered with computed tomography (FDG PET/CT) imaging of the aorta and carotid arteries was performed to quantify arterial inflammation, defined by the tissue-to-blood ratio (TBR) from scan images. Endothelial function was assessed by brachial artery flow-mediated dilatation (FMD).

Results: We screened 160 patients, of whom, 36 and 37 were randomised to losmapimod or placebo. The treatment effect of losmapimod compared to placebo was not significant, at -0·05 for TBR (95% CI: -0·17, 0·07), p = 0·42, and +0·40% for FMD (95% CI: -1·66, 2·47), p = 0·70. The frequency of adverse events reported was similar in both treatment groups.

Conclusions: In this plasma fibrinogen-enriched study, losmapimod had no effect on arterial inflammation and endothelial function at 16 weeks of treatment, although it was well tolerated with no significant safety concerns. These findings do not support the concept that losmapimod is an effective treatment for the adverse cardiovascular manifestations of COPD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0194197PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863984PMC
July 2018

Editor's Choice - Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity.

Eur J Vasc Endovasc Surg 2018 01 7;55(1):101-108. Epub 2017 Dec 7.

Division of Vascular and Endovascular Surgery, Addenbrooke's Hospital, Cambridge University Hospital Trust, Cambridge, UK.

Introduction: Cardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known.

Patients And Methods: Calcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity.

Results: A total of 319 patients (123 TAA and 196 AAA; median age 77 [71-84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591-9.476; p < 0.001) and 1.321 (1.076-2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574-6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765-4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973-4.342; p = 0.002).

Conclusions: Aortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.
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http://dx.doi.org/10.1016/j.ejvs.2017.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772171PMC
January 2018

PET imaging of the neurovascular interface in cerebrovascular disease.

Nat Rev Neurol 2017 Nov 6;13(11):676-688. Epub 2017 Oct 6.

Department of Clinical Neurosciences, University of Cambridge, Box 83, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK.

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.
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http://dx.doi.org/10.1038/nrneurol.2017.129DOI Listing
November 2017

Coronary CT angiography features of ruptured and high-risk atherosclerotic plaques: Correlation with intra-vascular ultrasound.

J Cardiovasc Comput Tomogr 2017 Nov 5;11(6):455-461. Epub 2017 Sep 5.

Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Background: Features of ruptured and high-risk plaque have been described on coronary computed tomography angiography (coronary CTA), but not systematically assessed against intravascular ultrasound (IVUS). We examined the ability of coronary CTA to identify IVUS defined ruptured plaque and Virtual Histology Intravascular Ultrasound (VH-IVUS) defined thin-cap fibroatheroma (TCFA).

Methods: Sixty-three patients (32 with acute coronary syndrome and 31 with stable angina) underwent coronary CTA, IVUS and VH-IVUS. Plaque rupture on CTA was defined as intra-plaque contrast and its frequency compared with IVUS-defined plaque rupture. We then examined the relationship of conventional coronary CTA high-risk features (low attenuation plaque, positive remodeling, spotty calcification and the Napkin-Ring sign) in VH-IVUS-defined TCFA. We compared these with a novel index based on quantifying the ratio of necrotic core to fibrous plaque using x-ray attenuation cut-offs derived from the relationship of plaque to luminal contrast attenuation.

Results: Of the 71 plaques interrogated with IVUS, 39 were ruptured. Coronary CTA correctly detected 13-ruptured plaques with 3 false positives giving high specificity (91%) but low sensitivity (33%). None of the conventional coronary CTA high-risk features were significantly more frequent in the higher-risk (VH-IVUS defined thin-cap) compared with thick-cap fibroatheroma. However, the new index (necrotic core/fibrous plaque ratio) was higher in thin-cap (mean 0.90) vs. thick-cap fibroatheroma (mean 0.59), p < 0.05.

Conclusions: Compared with intravascular ultrasound, coronary CTA identifies ruptured plaque with good specificity but poor sensitivity. We have identified a novel high-risk feature on coronary CTA (necrotic core/fibrous plaque ratio that is associated with VH-IVUS defined-TCFA.
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http://dx.doi.org/10.1016/j.jcct.2017.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725309PMC
November 2017

Lower limb arterial calcification (LLAC) scores in patients with symptomatic peripheral arterial disease are associated with increased cardiac mortality and morbidity.

PLoS One 2017 8;12(9):e0182952. Epub 2017 Sep 8.

Division of Vascular and Endovascular Surgery, Addenbrooke's Hospital, Cambridge University Hospital Trust, Cambridge, United Kingdom.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0182952PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5590737PMC
October 2017

Detection of Atherosclerotic Inflammation by Ga-DOTATATE PET Compared to [F]FDG PET Imaging.

J Am Coll Cardiol 2017 Apr;69(14):1774-1791

Division of Cardiovascular Medicine, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Background: Inflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([F]FDG PET), [F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover.

Objectives: This study tested the efficacy of gallium-68-labeled DOTATATE (Ga-DOTATATE), a somatostatin receptor subtype-2 (SST)-binding PET tracer, for imaging atherosclerotic inflammation.

Methods: We confirmed Ga-DOTATATE binding in macrophages and excised carotid plaques. Ga-DOTATATE PET imaging was compared to [F]FDG PET imaging in 42 patients with atherosclerosis.

Results: Target SSTR2 gene expression occurred exclusively in "proinflammatory" M1 macrophages, specific Ga-DOTATATE ligand binding to SST receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBR) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). Ga-DOTATATE mTBR predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [ROC AUC]: 0.86; 95% CI: 0.80 to 0.92; p < 0.0001), and correlated with Framingham risk score (r = 0.53; 95% CI: 0.32 to 0.69; p <0.0001) and [F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [F]FDG mTBR differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [F]FDG spillover rendered coronary [F]FDG scans uninterpretable in 27 patients (64%). Coronary Ga-DOTATATE PET scans were readable in all patients.

Conclusions: We validated Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188).
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http://dx.doi.org/10.1016/j.jacc.2017.01.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381358PMC
April 2017

F-Fluoride and F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Circ Cardiovasc Imaging 2017 Mar;10(3)

From the BHF Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (A.T.V., W.S.A.J., A.M., G.S., R.O.F., N.L.M., E.J.R.v.B., M.R.D., D.E.N.); Division of Experimental Medicine and Immunotherapeutics, University of Cambridge, United Kingdom (A.I., J.R., A.P.D.); and Clinical Research Imaging Centre (T.C., G.R., A.F., C.L., E.J.R.v.B., M.R.D., D.E.N.) and Centre for Clinical Brain Sciences (R.A.-S.S., M.D., W.W.), University of Edinburgh, United Kingdom.

Background: Combined positron emission tomography (PET) and computed tomography (CT) can assess both anatomy and biology of carotid atherosclerosis. We sought to assess whether F-fluoride or F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque.

Methods And Results: We performed F-fluoride and F-fluorodeoxyglucose PET/CT in 26 patients after recent transient ischemic attack or minor ischemic stroke: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 controls without culprit carotid atheroma. We compared standardized uptake values in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk (ASSIGN score [Assessing Cardiovascular Risk Using SIGN Guidelines to Assign Preventive Treatment]). We also performed micro PET/CT and histological analysis of excised plaque. On histological and micro PET/CT analysis, F-fluoride selectively highlighted microcalcification. Carotid F-fluoride uptake was increased in clinically adjudicated culprit plaques compared with asymptomatic contralateral plaques (logstandardized uptake value 0.29±0.10 versus 0.23±0.11, =0.001) and compared with control patients (logstandardized uptake value 0.29±0.10 versus 0.12±0.11, =0.001). F-Fluoride uptake correlated with high-risk plaque features (remodeling index [=0.53, =0.003], plaque burden [=0.51, =0.004]), and predicted cardiovascular risk [=0.65, =0.002]). Carotid F-fluorodeoxyglucose uptake appeared to be increased in 7 of 16 culprit plaques, but no overall differences in uptake were observed in culprit versus contralateral plaques or control patients. However, F-fluorodeoxyglucose did correlate with predicted cardiovascular risk (=0.53, =0.019), but not with plaque phenotype.

Conclusions: F-Fluoride PET/CT highlights culprit and phenotypically high-risk carotid plaque. This has the potential to improve risk stratification and selection of patients who may benefit from intervention.
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http://dx.doi.org/10.1161/CIRCIMAGING.116.004976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5367506PMC
March 2017

Molecular imaging of atherosclerosis with integrated PET imaging.

J Nucl Cardiol 2017 06 11;24(3):938-943. Epub 2017 Jan 11.

Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Atherosclerotic diseases account for nearly half of all deaths and are leading causes of adult disability. Our understanding of how atherosclerosis leads to cardiovascular disease events has evolved: from a concept of progressive luminal narrowing, to that of sudden rupture and thrombosis of biologically active atheroma. In concert with this conceptual shift, contemporary imaging techniques now allow imaging of biological processes that associate with plaque instability: active calcification and plaque inflammation. This review focuses on opportunities provided by positron emission tomography/computed tomography, to identify these high-risk biological features of atherosclerosis.
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http://dx.doi.org/10.1007/s12350-016-0766-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491686PMC
June 2017

Coronary Plaque Morphology and the Anti-Inflammatory Impact of Atorvastatin: A Multicenter 18F-Fluorodeoxyglucose Positron Emission Tomographic/Computed Tomographic Study.

Circ Cardiovasc Imaging 2016 Dec;9(12)

From the Division of Cardiology, New York Presbyterian Hospital and Weill Cornell Medical College (P.S.); Cardiac MR PET CT Program, Division of Cardiac Imaging (H.E., S.S., P.M.-H., G.M.-S., Amr Abdelbaky, U.H., A.T.) and Division of Cardiology (A.T.), Massachusetts General Hospital and Harvard Medical School, Boston; MTA-SE Cardiovascular Imaging Research Group, Semmelweis University, Budapest, Hungary (P.M.-H.); Fundacion Cardio-Infantil, Bogota, Colombia (H.M.M.); Merck and Company, Inc, Kenilworth, NJ (Achilles Alon, S.S.S.); Division of Cardiovascular Medicine, University of Cambridge, United Kingdom (J.H.F.R.); and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY (Z.A.F.).

Background: Nonobstructive coronary plaques manifesting high-risk morphology (HRM) associate with an increased risk of adverse clinical cardiovascular events. We sought to test the hypothesis that statins have a greater anti-inflammatory effect within coronary plaques containing HRM.

Methods And Results: In this prospective multicenter study, 55 subjects with or at high risk for atherosclerosis underwent F-fluorodeoxyglucose positron emission tomographic/computed tomographic imaging at baseline and after 12 weeks of treatment with atorvastatin. Coronary arterial inflammation (F-fluorodeoxyglucose uptake, expressed as target-to-background ratio) was assessed in the left main coronary artery (LMCA). While blinded to the PET findings, contrast-enhanced computed tomographic angiography was performed to characterize the presence of HRM (defined as noncalcified or partially calcified plaques) in the LMCA. Arterial inflammation (target-to-background ratio) was higher in LMCA segments with HRM than those without HRM (mean±SEM: 1.95±0.43 versus 1.67±0.32 for LMCA with versus without HRM, respectively; P=0.04). Moreover, atorvastatin treatment for 12 weeks reduced target-to-background ratio more in LMCA segments with HRM than those without HRM (12 week-baseline Δtarget-to-background ratio [95% confidence interval]: -0.18 [-0.35 to -0.004] versus 0.09 [-0.06 to 0.26]; P=0.02). Furthermore, this relationship between coronary plaque morphology and change in LMCA inflammatory activity remained significant after adjusting for baseline low-density lipoprotein and statin dose (β=-0.27; P=0.038).

Conclusions: In this first study to evaluate the impact of statins on coronary inflammation, we observed that the anti-inflammatory impact of statins is substantially greater within coronary plaques that contain HRM features. These findings suggest an additional mechanism by which statins disproportionately benefit individuals with more advanced atherosclerotic disease.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00703261.
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http://dx.doi.org/10.1161/CIRCIMAGING.115.004195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175997PMC
December 2016