Publications by authors named "Alex T Vesey"

22 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

Ferumoxytol magnetic resonance angiography: a dose-finding study in patients with chronic kidney disease.

Eur Radiol 2019 Jul 27;29(7):3543-3552. Epub 2019 Mar 27.

Department of Radiology, Queen Elizabeth University Hospital, Glasgow, UK.

Objectives: Ferumoxytol is an alternative to gadolinium-based compounds as a vascular contrast agent for magnetic resonance angiography (MRA), particularly for patients with chronic kidney disease (CKD). However, dose-related efficacy data are lacking. We aimed to determine the optimal (minimum effective) dose of ferumoxytol for MRA in patients with CKD.

Methods: Ferumoxytol-enhanced MRA (FeMRA) was performed at 3.0 T in patients with CKD after dose increments up to a total of 4 mg/kg. Image quality was assessed by contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) in the abdominal aorta and inferior vena cava. Quadratic regression analyses were performed to estimate the effects of dose increments on CNR and SNR.

Results: Twenty-three patients underwent FeMRA (mean age 60 [SD 13] years, 87% men, 48% had diabetic nephropathy) with cumulative doses of 0, 1, 2, 3 and 4 mg/kg of ferumoxytol. On regression analyses, a parabolic relationship was observed between ferumoxytol dose and signal with progressive signal loss using doses exceeding 4 mg/kg. A dose of 3 mg/kg achieved ≥ 75% of predicted peak CNR and SNR and images were deemed of excellent diagnostic quality.

Conclusions: In patients with CKD undergoing FeMRA, a dose of 3 mg/kg provides excellent arterial and venous enhancement. The benefits of increasing the dose to a theoretically optimal value of 4 mg/kg appear to be negligible and likely of minimal, if any, diagnostic value.

Key Points: • Ferumoxytol is used off-label as an MRI contrast agent but dose-related data are lacking. • In patients with CKD requiring MR angiography, a dose of 3 mg/kg provides excellent vascular enhancement.
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http://dx.doi.org/10.1007/s00330-019-06137-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6554242PMC
July 2019

Disease Activity in Mitral Annular Calcification.

Circ Cardiovasc Imaging 2019 02;12(2):e008513

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, United Kingdom (J.P.M.A., A.R.C., W.S.A.J., A.T.V., M.K.D., T.A.P., D.E.N., M.R.D.).

Background: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression.

Methods: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent F-sodium fluoride (calcification activity) and F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years.

Results: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity (F-fluoride uptake) was closely associated with the local calcium score and F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression.

Conclusions: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.008513DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366554PMC
February 2019

F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA Study.

J Am Coll Cardiol 2018 02;71(5):513-523

British Heart Foundation Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom; Edinburgh Imaging Facility, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom; National Health Service Lothian, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom.

Background: Fluorine-18-sodium fluoride (F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque.

Objectives: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes.

Methods: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture.

Results: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043).

Conclusions: Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758).
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http://dx.doi.org/10.1016/j.jacc.2017.11.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800891PMC
February 2018

Ferumoxytol-enhanced magnetic resonance angiography for the assessment of potential kidney transplant recipients.

Eur Radiol 2018 Jan 4;28(1):115-123. Epub 2017 Jul 4.

Department of Radiology, Queen Elizabeth University Hospital, Glasgow, UK.

Objectives: Traditional contrast-enhanced methods for scanning blood vessels using magnetic resonance imaging (MRI) or CT carry potential risks for patients with advanced kidney disease. Ferumoxytol is a superparamagnetic iron oxide nanoparticle preparation that has potential as an MRI contrast agent in assessing the vasculature.

Methods: Twenty patients with advanced kidney disease requiring aorto-iliac vascular imaging as part of pre-operative kidney transplant candidacy assessment underwent ferumoxytol-enhanced magnetic resonance angiography (FeMRA) between December 2015 and August 2016. All scans were performed for clinical indications where standard imaging techniques were deemed potentially harmful or inconclusive. Image quality was evaluated for both arterial and venous compartments.

Results: First-pass and steady-state FeMRA using incremental doses of up to 4 mg/kg body weight of ferumoxytol as intravenous contrast agent for vascular enhancement was performed. Good arterial and venous enhancements were achieved, and FeMRA was not limited by calcification in assessing the arterial lumen. The scans were diagnostic and all patients completed their studies without adverse events.

Conclusions: Our preliminary experience supports the feasibility and utility of FeMRA for vascular imaging in patients with advanced kidney disease due for transplant listing, which has the advantages of obtaining both arteriography and venography using a single test without nephrotoxicity.

Key Points: • Evaluation of vascular disease is important in planning kidney transplantation. • Standard vascular imaging methods are often problematic in kidney disease patients. • FeMRA has the advantage of arteriography and venography in a single test. • FeMRA is safe and non-nephrotoxic. • FeMRA is not limited by arterial calcification.
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http://dx.doi.org/10.1007/s00330-017-4934-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5717122PMC
January 2018

Inhaled Nanoparticles Accumulate at Sites of Vascular Disease.

ACS Nano 2017 05 26;11(5):4542-4552. Epub 2017 Apr 26.

National Institute for Public Health and the Environment (RIVM) , 3721 MA Bilthoven, The Netherlands.

The development of engineered nanomaterials is growing exponentially, despite concerns over their potential similarities to environmental nanoparticles that are associated with significant cardiorespiratory morbidity and mortality. The mechanisms through which inhalation of nanoparticles could trigger acute cardiovascular events are emerging, but a fundamental unanswered question remains: Do inhaled nanoparticles translocate from the lung in man and directly contribute to the pathogenesis of cardiovascular disease? In complementary clinical and experimental studies, we used gold nanoparticles to evaluate particle translocation, permitting detection by high-resolution inductively coupled mass spectrometry and Raman microscopy. Healthy volunteers were exposed to nanoparticles by acute inhalation, followed by repeated sampling of blood and urine. Gold was detected in the blood and urine within 15 min to 24 h after exposure, and was still present 3 months after exposure. Levels were greater following inhalation of 5 nm (primary diameter) particles compared to 30 nm particles. Studies in mice demonstrated the accumulation in the blood and liver following pulmonary exposure to a broader size range of gold nanoparticles (2-200 nm primary diameter), with translocation markedly greater for particles <10 nm diameter. Gold nanoparticles preferentially accumulated in inflammation-rich vascular lesions of fat-fed apolipoproteinE-deficient mice. Furthermore, following inhalation, gold particles could be detected in surgical specimens of carotid artery disease from patients at risk of stroke. Translocation of inhaled nanoparticles into the systemic circulation and accumulation at sites of vascular inflammation provides a direct mechanism that can explain the link between environmental nanoparticles and cardiovascular disease and has major implications for risk management in the use of engineered nanomaterials.
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http://dx.doi.org/10.1021/acsnano.6b08551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5444047PMC
May 2017

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

J Cell Physiol 2017 Nov 24;232(11):2985-2995. Epub 2017 May 24.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush, Edinburgh, United Kingdom.

Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.
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http://dx.doi.org/10.1002/jcp.25935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575563PMC
November 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

Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis.

JACC Cardiovasc Imaging 2017 11 21;10(11):1320-1333. Epub 2016 Dec 21.

BHF/Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, United Kingdom. Electronic address:

Objectives: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality.

Background: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis.

Methods: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up.

Results: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m vs. 16.1 ± 3.2 ml/m in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009).

Conclusions: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936).
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http://dx.doi.org/10.1016/j.jcmg.2016.10.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683736PMC
November 2017

Cardiac αβ integrin expression following acute myocardial infarction in humans.

Heart 2017 04 7;103(8):607-615. Epub 2016 Dec 7.

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

Objective: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αβ integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αβ integrin expression determines myocardial recovery following MI.

Methods: F-Fluciclatide (a novel αβ-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR.

Results: F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBR) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBR 1.34±0.22 vs 0.70±0.03; p<0.001). There was no F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBR 0.71±0.06 vs 0.70±0.03, p=0.83). F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBR 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), F-fluciclatide uptake was increased in segments displaying functional recovery (TBR 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery.

Conclusion: F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery.

Trial Registration Number: NCT01813045; Post-results.
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http://dx.doi.org/10.1136/heartjnl-2016-310115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5566089PMC
April 2017

Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification.

Sci Rep 2016 Apr 20;6:24807. Epub 2016 Apr 20.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, EH25 9RG, UK.

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention.
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http://dx.doi.org/10.1038/srep24807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4837411PMC
April 2016

Smooth Muscle Enriched Long Noncoding RNA (SMILR) Regulates Cell Proliferation.

Circulation 2016 May 6;133(21):2050-65. Epub 2016 Apr 6.

From BHF Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom (M.D.B., R.D., L.D., R.M., R.G., P.W., N.S., M.W.N., R.A.M., A.H.B.); British Heart Foundation/University of Edinburgh Centre for Cardiovascular Science, Edinburgh, United Kingdom (M.D.B., K.P., A.T.V., N.J., M.R.D., D.E.N., R.A.M., A.H.B.); Glasgow Polyomics, College of Medical, Veterinary and Life Sciences, The University of Glasgow, United Kingdom (G.H.); and Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, NY (J.M.M.).

Background: Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology.

Methods And Results: Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein.

Conclusions: These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.115.021019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872641PMC
May 2016

MR Imaging of Coronary Arteries and Plaques.

JACC Cardiovasc Imaging 2016 Mar;9(3):306-16

Institute for Experimental and Translational Cardiovascular Imaging, DZHK Centre for Cardiovascular Imaging, University Hospital Frankfurt, Frankfurt am Main, Germany. Electronic address:

Cardiac magnetic resonance offers the promise of radiation-free imaging of the coronary arteries, providing information with respect to luminal stenosis, plaque burden, high-risk plaque characteristics, and disease activity. In combination, this would provide a comprehensive, individualized assessment of coronary atherosclerosis that could be used to improve patient risk stratification and to guide treatment. However, the technical challenges involved with delivering upon this promise are considerable, requiring sophisticated approaches to both data acquisition and post-processing. In this review, we describe the current status of this technology, its capabilities, its limitations, and what will be required in the future to translate this technology into routine clinical practice.
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http://dx.doi.org/10.1016/j.jcmg.2015.12.003DOI Listing
March 2016

Utility of Combining PET and MR Imaging of Carotid Plaque.

Neuroimaging Clin N Am 2016 Feb;26(1):55-68

Imaging Science Laboratories, Department of Radiology, Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA; Imaging Science Laboratories, Department of Medicine, Translational and Molecular Imaging Institute, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA. Electronic address:

By harnessing the versatility and soft tissue imaging capabilities of MR imaging alongside the unmatched sensitivity and biomolecular flexibility of PET, the potential to provide detailed multiparametric plaque characterization in the carotid arteries is clear. The ability to acquire simultaneous, and dynamic multimodal data is perhaps PET/MR's greatest strength that will be of major interest to researchers investigating carotid and coronary atherosclerosis alike. This review summarizes the current status of dedicated hybrid PET/MR imaging; to crystallize the rationale for and advantages of this technique with respect to carotid atherosclerosis; and to discuss current limitations, challenges, and future directions.
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http://dx.doi.org/10.1016/j.nic.2015.09.005DOI Listing
February 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

Identifying active vascular microcalcification by (18)F-sodium fluoride positron emission tomography.

Nat Commun 2015 Jul 7;6:7495. Epub 2015 Jul 7.

Division of Experimental Medicine &Immunotherapeutics (EMIT), Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK.

Vascular calcification is a complex biological process that is a hallmark of atherosclerosis. While macrocalcification confers plaque stability, microcalcification is a key feature of high-risk atheroma and is associated with increased morbidity and mortality. Positron emission tomography and X-ray computed tomography (PET/CT) imaging of atherosclerosis using (18)F-sodium fluoride ((18)F-NaF) has the potential to identify pathologically high-risk nascent microcalcification. However, the precise molecular mechanism of (18)F-NaF vascular uptake is still unknown. Here we use electron microscopy, autoradiography, histology and preclinical and clinical PET/CT to analyse (18)F-NaF binding. We show that (18)F-NaF adsorbs to calcified deposits within plaque with high affinity and is selective and specific. (18)F-NaF PET/CT imaging can distinguish between areas of macro- and microcalcification. This is the only currently available clinical imaging platform that can non-invasively detect microcalcification in active unstable atherosclerosis. The use of (18)F-NaF may foster new approaches to developing treatments for vascular calcification.
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http://dx.doi.org/10.1038/ncomms8495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506997PMC
July 2015

Salt in the wound: (18)F-fluoride positron emission tomography for identification of vulnerable coronary plaques.

Cardiovasc Diagn Ther 2015 Apr;5(2):150-5

Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, EH16 4TJ, Scotland.

Ischaemic vascular events occur in relation to an underlying vulnerable plaque. The pathological hallmarks of high-risk plaques are well described and include inflammation and microcalcification. To date, non-invasive imaging modalities have lacked the spatial resolution to detect these processes with the necessary precision to facilitate clinical utility. Positron emission tomography (PET) using targeted radiopharmaceuticals affords a highly sensitive tool for identifying features of interest and has been in use for several decades in oncological practice. Recent developments have created hybrid scanning platforms which add the detailed spatial resolution of computed tomography (CT) and, for the first time, made imaging of individual coronary plaques feasible. In this study we compared the utility of PET-CT using (18)F-fluoride and (18)F-fluorodeoxglucose ((18)F-FDG) to detect high-risk or ruptured atherosclerotic plaques in vivo. (18)F-fluoride localized to culprit and vulnerable plaques as determined by a combination of invasive imaging and histological tissue examination. In contradistinction, (18)F-FDG analysis was compromised by non-specific myocardial uptake that obscured the coronary arteries. We discuss the findings of this study, the limitations of the current approach of vulnerable plaque assessment and some on-going developments in cardiovascular imaging with (18)F-fluoride.
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http://dx.doi.org/10.3978/j.issn.2223-3652.2015.03.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420673PMC
April 2015

18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis.

Circ Cardiovasc Imaging 2014 Mar 7;7(2):371-8. Epub 2014 Feb 7.

Centre for Cardiovascular Science.

Background: 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression.

Methods And Results: Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/

Background: =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66).

Conclusions: 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.
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http://dx.doi.org/10.1161/CIRCIMAGING.113.001508DOI Listing
March 2014

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