Publications by authors named "Alison M Fletcher"

11 Publications

  • Page 1 of 1

In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis.

Heart 2019 12 17;105(24):1868-1875. Epub 2019 Aug 17.

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK.

Objectives: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αβ) integrin pathway. We investigated the applicability of the αβ-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis.

Methods: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBR). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring.

Results: 18F-Fluciclatide uptake co-localised with regions of increased αβ integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBR 1.29 vs 1.21, p=0.02).

Conclusions: In vivo expression of αβ integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αβ integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.
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http://dx.doi.org/10.1136/heartjnl-2019-315103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6929706PMC
December 2019

Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides.

Cell Metab 2018 Jun 24;27(6):1348-1355.e4. Epub 2018 May 24.

BHF/University Centre for Cardiovascular Science, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland, UK. Electronic address:

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.
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http://dx.doi.org/10.1016/j.cmet.2018.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988566PMC
June 2018

Glucocorticoids Acutely Increase Brown Adipose Tissue Activity in Humans, Revealing Species-Specific Differences in UCP-1 Regulation.

Cell Metab 2016 07;24(1):130-41

British Heart Foundation/University Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, Scotland, UK. Electronic address:

The discovery of brown adipose tissue (BAT) in adult humans presents a new therapeutic target for metabolic disease; however, little is known about the regulation of human BAT. Chronic glucocorticoid excess causes obesity in humans, and glucocorticoids suppress BAT activation in rodents. We tested whether glucocorticoids regulate BAT activity in humans. In vivo, the glucocorticoid prednisolone acutely increased (18)fluorodeoxyglucose uptake by BAT (measured using PET/CT) in lean healthy men during mild cold exposure (16°C-17°C). In addition, prednisolone increased supraclavicular skin temperature (measured using infrared thermography) and energy expenditure during cold, but not warm, exposure in lean subjects. In vitro, glucocorticoids increased isoprenaline-stimulated respiration and UCP-1 in human primary brown adipocytes, but substantially decreased isoprenaline-stimulated respiration and UCP-1 in primary murine brown and beige adipocytes. The highly species-specific regulation of BAT function by glucocorticoids may have important implications for the translation of novel treatments to activate BAT to improve metabolic health.
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http://dx.doi.org/10.1016/j.cmet.2016.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949380PMC
July 2016

Systemic Atherosclerotic Inflammation Following Acute Myocardial Infarction: Myocardial Infarction Begets Myocardial Infarction.

J Am Heart Assoc 2015 Aug 27;4(9):e001956. Epub 2015 Aug 27.

Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (N.V.J., I.T., A.V.S., K.C., A.T.V., S.R.A., A.S., T.Y.H., A.J.M., S.P.L., W.A.J., N.G.U., N.L.M., K.A.F., M.R.D., D.E.N.) Clinical Research Imaging Centre, University of Edinburgh, United Kingdom (N.V.J., I.T., A.V.S., K.C., A.T.V., S.R.A., W.A.J., N.G.U., N.L.M., A.M.F., E.R.B., K.A.F., M.R.D., D.E.N.) Edinburgh Heart Centre, Royal Infirmary of Edinburgh, United Kingdom (N.V.J., I.T., A.V.S., K.C., A.T.V., S.R.A., W.A.J., N.G.U., N.L.M., K.A.F., M.R.D., D.E.N.).

Background: Preclinical data suggest that an acute inflammatory response following myocardial infarction (MI) accelerates systemic atherosclerosis. Using combined positron emission and computed tomography, we investigated whether this phenomenon occurs in humans.

Methods And Results: Overall, 40 patients with MI and 40 with stable angina underwent thoracic 18F-fluorodeoxyglucose combined positron emission and computed tomography scan. Radiotracer uptake was measured in aortic atheroma and nonvascular tissue (paraspinal muscle). In 1003 patients enrolled in the Global Registry of Acute Coronary Events, we assessed whether infarct size predicted early (≤30 days) and late (>30 days) recurrent coronary events. Compared with patients with stable angina, patients with MI had higher aortic 18F-fluorodeoxyglucose uptake (tissue-to-background ratio 2.15±0.30 versus 1.84±0.18, P<0.0001) and plasma C-reactive protein concentrations (6.50 [2.00 to 12.75] versus 2.00 [0.50 to 4.00] mg/dL, P=0.0005) despite having similar aortic (P=0.12) and less coronary (P=0.006) atherosclerotic burden and similar paraspinal muscular 18F-fluorodeoxyglucose uptake (P=0.52). Patients with ST-segment elevation MI had larger infarcts (peak plasma troponin 32 300 [10 200 to >50 000] versus 3800 [1000 to 9200] ng/L, P<0.0001) and greater aortic 18F-fluorodeoxyglucose uptake (2.24±0.32 versus 2.02±0.21, P=0.03) than those with non-ST-segment elevation MI. Peak plasma troponin concentrations correlated with aortic 18F-fluorodeoxyglucose uptake (r=0.43, P=0.01) and, on multivariate analysis, independently predicted early (tertile 3 versus tertile 1: relative risk 4.40 [95% CI 1.90 to 10.19], P=0.001), but not late, recurrent MI.

Conclusions: The presence and extent of MI is associated with increased aortic atherosclerotic inflammation and early recurrent MI. This finding supports the hypothesis that acute MI exacerbates systemic atherosclerotic inflammation and remote plaque destabilization: MI begets MI.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01749254.
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http://dx.doi.org/10.1161/JAHA.115.001956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599491PMC
August 2015

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.

Lancet 2014 Feb 11;383(9918):705-13. Epub 2013 Nov 11.

Centre for Cardiovascular Science, Clinical Research Imaging Centre, and Division of Pathology, University of Edinburgh, Edinburgh, UK.

Background: The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG).

Methods: In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction.

Findings: In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001).

Interpretation: (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease.

Funding: Chief Scientist Office Scotland and British Heart Foundation.
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http://dx.doi.org/10.1016/S0140-6736(13)61754-7DOI Listing
February 2014

A randomized controlled trial of peripheral blood mononuclear cell depletion in experimental human lung inflammation.

Am J Respir Crit Care Med 2013 Aug;188(4):449-55

University of Edinburgh/Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, United Kingdom.

Rationale: Depletion of monocytes reduces LPS-induced lung inflammation in mice, suggesting monocytes as potential therapeutic targets in acute lung injury.

Objectives: To investigate whether depletion of circulating blood monocytes has beneficial effects on markers of systemic and pulmonary inflammation in a human model of acute lung inflammation.

Methods: A total of 30 healthy volunteers were enrolled in a randomized controlled trial. Volunteers inhaled LPS at baseline, and were randomized to receive active mononuclear cell depletion by leukapheresis, or sham leukapheresis, in a double-blind fashion (15 volunteers per group). Serial blood counts were measured, bronchoalveolar lavage (BAL) was performed at 9 hours, and [(18)F]fluorodeoxyglucose positron emission tomography at 24 hours. The primary endpoint was the increment in circulating neutrophils at 8 hours.

Measurements And Main Results: As expected, inhalation of LPS induced neutrophilia and an up-regulation of inflammatory mediators in the blood and lungs of all volunteers. There was no significant difference between the depletion and sham groups in the mean increment in blood neutrophil count at 8 hours (6.16 × 10(9)/L and 6.15 × 10(9)/L, respectively; P = 1.00). Furthermore, there were no significant differences in BAL neutrophils or protein, positron emission tomography-derived measures of global lung inflammation, or cytokine levels in plasma or BAL supernatant between the study groups. No serious adverse events occurred, and no symptoms were significantly different between the groups.

Conclusions: These findings do not support a role for circulating human monocytes in the early recruitment of neutrophils during LPS-mediated acute lung inflammation in humans.
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http://dx.doi.org/10.1164/rccm.201212-2334OCDOI Listing
August 2013

Coronary arterial 18F-sodium fluoride uptake: a novel marker of plaque biology.

J Am Coll Cardiol 2012 Apr;59(17):1539-48

Centre for Cardiovascular Sciences, University of Edinburgh, United Kingdom.

Objectives: With combined positron emission tomography and computed tomography (CT), we investigated coronary arterial uptake of 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) as markers of active plaque calcification and inflammation, respectively.

Background: The noninvasive assessment of coronary artery plaque biology would be a major advance particularly in the identification of vulnerable plaques, which are associated with specific pathological characteristics, including micro-calcification and inflammation.

Methods: We prospectively recruited 119 volunteers (72 ± 8 years of age, 68% men) with and without aortic valve disease and measured their coronary calcium score and 18F-NaF and 18F-FDG uptake. Patients with a calcium score of 0 were used as control subjects and compared with those with calcific atherosclerosis (calcium score >0).

Results: Inter-observer repeatability of coronary 18F-NaF uptake measurements (maximum tissue/background ratio) was excellent (intra-class coefficient 0.99). Activity was higher in patients with coronary atherosclerosis (n = 106) versus control subjects (1.64 ± 0.49 vs. 1.23 ± 0.24; p = 0.003) and correlated with the calcium score (r = 0.652, p < 0.001), although 40% of those with scores >1,000 displayed normal uptake. Patients with increased coronary 18F-NaF activity (n = 40) had higher rates of prior cardiovascular events (p = 0.016) and angina (p = 0.023) and higher Framingham risk scores (p = 0.011). Quantification of coronary 18F-FDG uptake was hampered by myocardial activity and was not increased in patients with atherosclerosis versus control subjects (p = 0.498).

Conclusions: 18F-NaF is a promising new approach for the assessment of coronary artery plaque biology. Prospective studies with clinical outcomes are now needed to assess whether coronary 18F-NaF uptake represents a novel marker of plaque vulnerability, recent plaque rupture, and future cardiovascular risk. (An Observational PET/CT Study Examining the Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis; NCT01358513).
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http://dx.doi.org/10.1016/j.jacc.2011.12.037DOI Listing
April 2012

Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.

Circulation 2012 Jan 16;125(1):76-86. Epub 2011 Nov 16.

Centre for Cardiovascular Science, University of Edinburgh, Little France Crescent, Edinburgh, United Kingdom.

Background: The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown.

Methods And Results: Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001).

Conclusions: Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF.

Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.111.051052DOI Listing
January 2012

I-123 MIBG cardiac uptake measurements: limitations of collimator choice and scatter correction in the clinical context.

Nucl Med Commun 2010 Jul;31(7):629-36

Department of Nuclear Cardiology, Royal Infirmary, Glasgow, UK.

Objective: Low uptake of metaiodobenzylguanidine (MIBG) in patients with heart failure generally indicates poor prognosis. Our objective was to determine the best method for calculating I-123 MIBG uptake. MIBG uptake as a percentage of the injected dose is presented as an alternative method for serial assessment.

Methods: Patients with chronic heart failure were imaged with I-123 MIBG with both a medium-energy (ME) collimator and a low-energy high-sensitivity (LEHS) collimator. Scatter correction was used to correct the LEHS images. Heart-to-mediastinal (H/M) ratio and the percentage of myocardial uptake of MIBG were obtained.

Results: Mean H/M ratios for the ME images, LEHS images and scatter-corrected LEHS images were 2.45+/-0.61, 2.22+/-0.47 and 2.51+/-0.62, respectively. Mean H/M ratio was significantly different among all the three sets (P<0.001) of images. The average difference in H/M ratios between the ME images and LEHS images was lower when scatter correction was applied (4.95% vs. 9.79%). The error in calculating the myocardial uptake as a percentage of the injected dose was significantly lower than the error in calculating H/M ratio (0.2 vs.10.2% LEHS; 0.3 vs.16.0% ME; 0.2 vs.11.8% LEHS scatter corrected).

Conclusion: For quantitative assessment of H/M ratio in I-123 MIBG imaging a LEHS collimator can be used in place of a ME collimator to achieve better counting statistics, but scatter correction must be used. The calculation of the myocardial uptake as a percentage of the injected dose has potential as an alternative method of measurement, particularly for serial assessment.
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http://dx.doi.org/10.1097/MNM.0b013e3283375639DOI Listing
July 2010

MR imaging assessment of myelination in the very preterm brain.

AJNR Am J Neuroradiol 2002 May;23(5):872-81

Robert Steiner Magnetic Resonance Unit, Imaging Sciences Department, Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, England.

Background And Purpose: MR imaging was performed in very preterm infants by using an MR imager in the neonatal intensive care unit. The aims of this study were to assess the development of myelination in the preterm brain based on MR imaging findings and to compare the ability of T1-weighted conventional spin-echo, inversion recovery fast spin-echo, and T2-weighted fast spin-echo MR imaging to show myelination in these infants.

Methods: MR imaging was performed for 26 preterm infants with a median gestational age of 28 weeks who had normal neurodevelopmental outcomes at 2 years corrected age.

Results: Myelin was evident in the gracile and cuneate nuclei and fasciculi, vestibular nuclei, cerebellar vermis, inferior and superior cerebellar peduncles, dentate nucleus, medial longitudinal fasciculus, medial geniculate bodies, subthalamic nuclei, inferior olivary nuclei, ventrolateral nuclei of the thalamus, decussation of the superior cerebellar peduncles, medial lemnisci, lateral lemnisci, and inferior colliculi at < or = 28 weeks gestational age. From this gestational age, myelination was not visualized at any new site until 36 weeks gestational age, when myelin was visualized in the corona radiata, posterior limb of the internal capsule, corticospinal tracts of the precentral and postcentral gyri, and lateral geniculate bodies. T2-weighted fast spin-echo MR imaging showed myelin in gray matter nuclei at an earlier gestational age than did T1-weighted conventional spin-echo or inversion recovery fast spin-echo MR imaging. T1-weighted conventional spin-echo MR imaging showed myelin earlier in some white matter tracts in the preterm brain.

Conclusion: Myelination was evident in numerous gray and white matter structures in the very preterm brain. A knowledge of myelination milestones will allow delays to be detected at an early stage.
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May 2002