Prof Robin Choudhury FRCP

Research Area: Integrative Physiology (Systems Biology)
Technology Exchange: Cellular immunology, Flow cytometry, In vivo imaging, Magnetic resonance imaging & spectroscopy and Transcript profiling
Scientific Themes: Translational Medicine & Medical Technology and Cardiovascular Science
Carotid artery plaque rupture detected using 3T MRI (left).  The Oxford Acute Vascular Imaging Centre (right) applies novel imaging and diagnostics to characterisation of injury and repair with acute MI and stroke.  http://www.avic.ox.ac.uk/

Carotid artery plaque rupture detected using 3T MRI (left). The Oxford Acute Vascular Imaging ...

(A) Schematic of ligand-targeted MPIO1; (B) Dark areas on image-left side of brain corresponding to accumulation of VCAM-1 targeted MPIO in mouse brain2 and 3-D rendering of inflamed cerebral vessels (red); (C) MPIO targeted in VCAM-1 and P-selectin track with macrophage accumulation (Gal-3 stain) in mouse atherosclerosis and bind at target within 20 minutes;4 (D) single chain antibody against GPIIbIIIa to image activated platelets12 and (E) schematic, transmission EM (centre) and atomic force micrograph (right) of multimeric MPIO: a ‘multi-nano’ particle structure covalently joined with cathepsin-sensitive peptide bonds to micron size –range particles for molecular imaging.

(A) Schematic of ligand-targeted MPIO1; (B) Dark areas on image-left side of brain corresponding to ...

An overarching theme of the work in this group is that current paradigms for the diagnosis and characterization of vascular disease are crude and increasingly unworkable.  Understanding functionally important heterogeneity will enable better stratification of pathology and enable more targeted therapies.

 

(1) IMAGING TECHNIQUES TO CHARACTERIZE ATHEROSCLEROSIS AND VASCULAR INFLAMMATION.  The development and application of tools that will (a) provide insights into the pathophysiology of atherosclerosis and its complications; (b) obtain earlier and more refined diagnosis; and (c) quantify the response to therapeutic interventions.

Clinical Science: Using ‘multi-modal’ vascular MRI it has been possible to quantify vascular disease and measure response to specific treatments rapidly and in small numbers of patients (Lee JMS et al. J Am Coll Cardiol, 2009 PMID: 19874992). 
Current work focuses on the characterization of atherosclerotic plaque and in particular non-invasive quantification of plaque lipid-rich core using T2 mapping techniques (Biasiolli et al JCMR 2013 PMID: 23953780).

Basic science: The laboratory has developed a new class of ligand-conjugated micro-particles of iron oxide for molecular imaging with MRI. Using imaging probes that target specific molecules it has been possible to illuminate pathology in diverse models of disease that include: atherosclerosis and thrombosis, stroke, ischaemia, reperfusion injury and multiple sclerosis (McAteer MA et al ATVB 2012 PMID: 22499989; McAteer et al. Nat Med, 2007 PMID: 17891147). Current work (in collaboration with Prof Ben Davis and Dr Nicola Sibson) is focused on the clinical translation of this molecular imaging platform and on the development of multi-modal imaging particles.

 

(2) Understanding and manipulating MONOCYTE and MACROPHAGE HETEROGENEITY. The laboratory is interested in the role of monocytes in the development of atherosclerosis and how their function changes within the plaque, for instance in response to hyperlipidemia, diabetes and drug interventions (Digby et al Atherosclerosis 2010 PMID: 19781706; Digby et al ATVB 2012 PMID: 22267479; Chai et al PLoS One 2013 PMID: 23658787).  Current work (in collaboration with Mr Ashok Handa and colleagues in Vascular Surgery) examines aspects of macrophage function in explanted human atherosclerotic plaque using laser capture micro-dissection to obtain specific cell types.

 

(3) CHARACTERISATION of INJURY AND REPAIR IN ACUTE VASCULAR SYNDROMES.  The Oxford Acute Vascular Imaging Centre (below) provides unique opportunities to study the 'upstream' causes and 'downstream' consequences of acute myocardial infarction and stroke. This group develops and applies new MR techniques combined with invasive measures of cardiac physiology and the discovery of novel biomarkers of injury and repair (Dall’Armellina et al Circ Imaging 2011 PMID: 21447711; Lindsay et al JACC Imaging 2012 PMID: 22498328).  Current work combines characterization of myocardial injury defined by CMR with analyses of monocyte function using transcriptomic analyses (collaboration with Dr Nicholas Haining, Dana Farber Cancer Institute, Boston). 

 

Group Members

◦  Mr Naveed Akbar

◦  Dr Mohammad Alkhalil

◦  Dr Tom Cahill

◦  Dr Josh Chai

◦  Dr Erica Dall'Armellina

◦  Dr Janet Digby

◦  Dr Francesca Galassi

◦  Ms Laurienne Gardner

◦  Dr Neil Ruparelia

 

Sources of Funding

The British Heart Foundation

The Wellcome Trust

The Medical Research Council

Oxford Comprehensive Biomedical Research Centre, NIHR Funding Scheme

 

Public Engagement

This group is committed to public engagement. We want people to consider, question and debate the key issues in science and society and aim to engage audiences with biomedical science. Prof. Choudhury is pleased to consider outside speaking engagements, including  in schools. For examples of recent activity, please see below.

 

Oxford Biomedical Research Centre, Public Lecture Series

 

Ashmolean Museum University Engagement Programme, British Heart Foundation Centre of Research Excellence, Oxford NIHR Biomedical Research Centre. Representations of the Heart from Ancient Egypt to Contemporary Medicine. Public Lecture, Ashmolean Museum.

 

The “ALSO” Arts Festival

 

The Latitude Festival: Wellcome Trust Science and Secrets Hub

 

Atherosclerotic plaque imaging; Past, present, and future – BMJ Podcast 2012

Name Department Institution Country
Dr Daniel C Anthony (MPLS) Oxford University,
Prof Alastair M Buchan Investigative Medicine Division Oxford University, John Radcliffe Hospital United Kingdom
Prof Keith Channon FMedSci FRCP Cardiovascular Medicine Oxford University, John Radcliffe Hospital United Kingdom
Prof Shawn Chen NIH United States
Prof Ben Davis (MPLS) Chemistry Oxford University,
Prof Zahi Fayad Mount Sinai School of Medicine, New York United States
Prof Valentin Fuster Mount Sinai School of Medicine, New York United States
Dr Nicholas Haining Harvard / MIT United States
Dr Borja Ibanez Centro Nacional de Investigaciones Cardiovasculares Spain
Prof Peter Jezzard FMRIB, University of Oxford United Kingdom
Prof Stefan Neubauer FMedSci FRCP Cardiovascular Medicine Oxford University, John Radcliffe Hospital United Kingdom
Prof Jurgen E Schneider Cardiovascular Medicine Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Dr Niki Sibson (MPLS) Oxford University,
Fernández-Jiménez R, Sánchez-González J, Agüero J, García-Prieto J, López-Martín GJ, García-Ruiz JM, Molina-Iracheta A, Rosselló X, Fernández-Friera L, Pizarro G et al. 2015. Myocardial edema after ischemia/reperfusion is not stable and follows a bimodal pattern: imaging and histological tissue characterization. J Am Coll Cardiol, 65 (4), pp. 315-323. | Show Abstract | Read more

BACKGROUND: It is widely accepted that edema occurs early in the ischemic zone and persists in stable form for at least 1 week after myocardial ischemia/reperfusion. However, there are no longitudinal studies covering from very early (minutes) to late (1 week) reperfusion stages confirming this phenomenon. OBJECTIVES: This study sought to perform a comprehensive longitudinal imaging and histological characterization of the edematous reaction after experimental myocardial ischemia/reperfusion. METHODS: The study population consisted of 25 instrumented Large-White pigs (30 kg to 40 kg). Closed-chest 40-min ischemia/reperfusion was performed in 20 pigs, which were sacrificed at 120 min (n = 5), 24 h (n = 5), 4 days (n = 5), and 7 days (n = 5) after reperfusion and processed for histological quantification of myocardial water content. Cardiac magnetic resonance (CMR) scans with T2-weighted short-tau inversion recovery and T2-mapping sequences were performed at every follow-up stage until sacrifice. Five additional pigs sacrificed after baseline CMR served as controls. RESULTS: In all pigs, reperfusion was associated with a significant increase in T2 relaxation times in the ischemic region. On 24-h CMR, ischemic myocardium T2 times returned to normal values (similar to those seen pre-infarction). Thereafter, ischemic myocardium-T2 times in CMR performed on days 4 and 7 after reperfusion progressively and systematically increased. On day 7 CMR, T2 relaxation times were as high as those observed at reperfusion. Myocardial water content analysis in the ischemic region showed a parallel bimodal pattern: 2 high water content peaks at reperfusion and at day 7, and a significant decrease at 24 h. CONCLUSIONS: Contrary to the accepted view, myocardial edema during the first week after ischemia/reperfusion follows a bimodal pattern. The initial wave appears abruptly upon reperfusion and dissipates at 24 h. Conversely, the deferred wave of edema appears progressively days after ischemia/reperfusion and is maximal around day 7 after reperfusion.

Cuculi F, De Maria GL, Meier P, Dall'Armellina E, de Caterina AR, Channon KM, Prendergast BD, Choudhury RP, Forfar JC, Kharbanda RK, Banning AP. 2014. Impact of microvascular obstruction on the assessment of coronary flow reserve, index of microcirculatory resistance, and fractional flow reserve after ST-segment elevation myocardial infarction. J Am Coll Cardiol, 64 (18), pp. 1894-1904. | Show Abstract | Read more

BACKGROUND: Invasive assessment of coronary physiology (IACP) offers important prognostic insights in ST-segment elevation myocardial infarction (STEMI) but the dynamics of coronary recovery are poorly understood. OBJECTIVES: This study sought to examine the evolution of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), ratio of distal coronary pressure (Pd) to mean aortic pressure (Pa), and fractional flow reserve (FFR) in patients undergoing primary percutaneous coronary intervention (PPCI). METHODS: 82 patients with STEMI underwent IACP at PPCI. Repeat IACP was performed in 61 patients (74%) at day 1 and in 46 patients (56%) at 6 months. Contrast-enhanced cardiac magnetic resonance imaging (CMR) was performed in 45 patients (55%) at day 1 and in 41 patients (50%) at 6 months. Changes in IACP were compared between patients with and without microvascular obstruction (MVO) on CMR. RESULTS: MVO was present in 21 of 45 patients (47%). Patients with MVO had lower CFR at PPCI and day 1 (p < 0.05) and a trend toward higher IMR values (p = 0.07). At 6 months, CFR and IMR were not significantly different between the groups. Baseline flow and Pd/Pa remained stable over time but FFR reduced significantly between PPCI and 6 months (p = 0.008); this reduction was mainly observed in patients with MVO (p = 0.006) but not in those without MVO (p = 0.21). CONCLUSIONS: In PPCI-treated patients with STEMI, coronary microcirculation begins to recover within 24 h and recovery progresses further by 6 months. FFR significantly reduces from baseline to 6 months. The presence of MVO indicates a highly dysfunctional microcirculation.

Li L, Chai JT, Biasiolli L, Robson MD, Choudhury RP, Handa AI, Near J, Jezzard P. 2014. Black-blood multicontrast imaging of carotid arteries with DANTE-prepared 2D and 3D MR imaging. Radiology, 273 (2), pp. 560-569. | Show Abstract | Read more

PURPOSE: To prospectively compare the black-blood ( BB black blood ) imaging efficiency of a delay alternating with nutation for tailored excitation ( DANTE delay alternating with nutation for tailored excitation ) preparation module with conventional double inversion-recovery ( DIR double inversion recovery ) and motion-sensitive driven equilibrium ( MSDE motion-sensitive driven equilibrium ) preparation modules and to introduce a new three-dimensional ( 3D three-dimensional ) T1-weighted magnetic resonance (MR) imaging sequence. MATERIALS AND METHODS: Carotid artery wall imaging was performed in 10 healthy volunteers and 15 patients in accordance with an institutional review board-approved protocol. Two-dimensional ( 2D two-dimensional ) turbo spin-echo ( TSE turbo spin echo ) and 3D three-dimensional fast low-angle shot ( FLASH fast low-angle shot ) sequences served as readout modules. DANTE delay alternating with nutation for tailored excitation -prepared T1-, T2-, and proton density-weighted 2D two-dimensional TSE turbo spin echo images, as well as T1-weighted 3D three-dimensional DANTE delay alternating with nutation for tailored excitation -prepared FLASH fast low-angle shot (hereafter, 3D three-dimensional DASH DANTE-prepared FLASH ) images, were acquired in the region of the carotid artery bifurcation. For comparison, 2D two-dimensional DIR double inversion recovery -prepared, 2D two-dimensional MSDE motion-sensitive driven equilibrium -prepared multicontrast TSE turbo spin echo , and 3D three-dimensional MSDE motion-sensitive driven equilibrium -prepared FLASH fast low-angle shot (hereafter, 3D three-dimensional MERGE MSDE-prepared FLASH ) MR images were also acquired. The effective contrast-to-noise ratio ( CNReff effective contrast-to-noise ratio ) per unit time was calculated for all sequences. Paired t tests were performed to test within-group differences in vessel wall CNReff effective contrast-to-noise ratio . RESULTS: The CNReff effective contrast-to-noise ratio of DANTE delay alternating with nutation for tailored excitation -prepared T1-, T2-, and proton density-weighted sequences was 27.3, 14.7, and 25.7 mm(-1)min(-1/2), respectively; this represented an improvement of approximately 25%-100% (P < .05) when compared with the CNReff effective contrast-to-noise ratio attained with existing methods. The 3D three-dimensional DASH DANTE-prepared FLASH technique proved to be a fast (<2 seconds per section) and high-spatial-resolution (0.6 mm isotropic) BB black blood technique with higher (75%-100% improvement, P < .001) signal-to-noise ratio efficiency than the 3D three-dimensional MERGE MSDE-prepared FLASH technique. CONCLUSION: The DANTE delay alternating with nutation for tailored excitation -prepared multicontrast 2D two-dimensional BB black blood technique is a promising new tool for MR imaging of carotid artery walls. Additionally, the 3D three-dimensional DASH DANTE-prepared FLASH sequence enables 3D three-dimensional high-spatial-resolution fast T1-weighted imaging of carotid artery walls. ©RSNA, 2014 Online supplemental material is available for this article .

Ferreira V, Dall'Armellina E, Piechnik S, Karamitsos T, Francis J, Choudhury R, Channon K, Kharbanda R, Forfar C, Ormerod O et al. 2014. 121 High Diagnostic Yield in Patients Presenting with Acute Chest Pain, Positive Troponins but non-obstructive Coronaries by Cardiovascular Magnetic Resonance imaging with Conventional and Novel T1 Mapping Techniques. Heart, 100 Suppl 3 (Suppl 3), pp. A69-A70. | Show Abstract | Read more

Up to 10% of patients presenting with chest pain and elevated troponin levels demonstrate non-obstructive coronary arteries on angiography, posing a clinical challenge in diagnosis, prognosis and management. The final diagnosis has important implications for the patient, including prescription for treatment and fitness for permissible activities, occupation and medical insurance. Cardiovascular magnetic resonance (CMR) is superior to other cardiac imaging modalities in tissue characterisation. We hypothesised that CMR, when performed early using conventional and novel tissue characterisation techniques, can determine the cause of acute myocardial injury in these patients and provide a diagnosis.

Cited:

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Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Ntusi N, Holloway C, Choudhury RP, Kardos A, Robson MD et al. 2014. Native T1-mapping detects the location, extent and patterns of acute myocarditis without the need for gadolinium contrast agents Journal of Cardiovascular Magnetic Resonance, 16 (1), | Show Abstract | Read more

Background: Acute myocarditis can be diagnosed on cardiovascular magnetic resonance (CMR) using multiple techniques, including late gadolinium enhancement (LGE) imaging, which requires contrast administration. Native T1-mapping is significantly more sensitive than LGE and conventional T2-weighted (T2W) imaging in detecting myocarditis. The aims of this study were to demonstrate how to display the non-ischemic patterns of injury and to quantify myocardial involvement in acute myocarditis without the need for contrast agents, using topographic T1-maps and incremental T1 thresholds. Methods. We studied 60 patients with suspected acute myocarditis (median 3 days from presentation) and 50 controls using CMR (1.5 T), including: (1) dark-blood T2W imaging; >(2) native T1-mapping (ShMOLLI); (3) LGE. Analysis included: (1) global myocardial T2 signal intensity (SI) ratio compared to skeletal muscle; (2) myocardial T1 times; (3) areas of injury by T2W, T1-mapping and LGE. Results: Compared to controls, patients had more edema (global myocardial T2 SI ratio 1.71 ± 0.27 vs.1.56 ± 0.15), higher mean myocardial T1 (1011 ± 64 ms vs. 946 ± 23 ms) and more areas of injury as detected by T2W (median 5% vs. 0%), T1 (median 32% vs. 0.7%) and LGE (median 11% vs. 0%); all p < 0.001. A threshold of T1 > 990 ms (sensitivity 90%, specificity 88%) detected significantly larger areas of involvement than T2W and LGE imaging in patients, and additional areas of injury when T2W and LGE were negative. T1-mapping significantly improved the diagnostic confidence in an additional 30% of cases when at least one of the conventional methods (T2W, LGE) failed to identify any areas of abnormality. Using incremental thresholds, T1-mapping can display the non-ischemic patterns of injury typical of myocarditis. Conclusion: Native T1-mapping can display the typical non-ischemic patterns in acute myocarditis, similar to LGE imaging but without the need for contrast agents. In addition, T1-mapping offers significant incremental diagnostic value, detecting additional areas of myocardial involvement beyond T2W and LGE imaging and identified extra cases when these conventional methods failed to identify abnormalities. In the future, it may be possible to perform gadolinium-free CMR using cine and T1-mapping for tissue characterization and may be particularly useful for patients in whom gadolinium contrast is contraindicated. © 2014 Ferreira et al.; licensee BioMed Central Ltd.

Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Ntusi N, Holloway C, Choudhury RP, Kardos A, Robson MD et al. 2014. Native T1-mapping detects the location, extent and patterns of acute myocarditis without the need for gadolinium contrast agents. J Cardiovasc Magn Reson, 16 (1), pp. 36. | Show Abstract | Read more

BACKGROUND: Acute myocarditis can be diagnosed on cardiovascular magnetic resonance (CMR) using multiple techniques, including late gadolinium enhancement (LGE) imaging, which requires contrast administration. Native T1-mapping is significantly more sensitive than LGE and conventional T2-weighted (T2W) imaging in detecting myocarditis. The aims of this study were to demonstrate how to display the non-ischemic patterns of injury and to quantify myocardial involvement in acute myocarditis without the need for contrast agents, using topographic T1-maps and incremental T1 thresholds. METHODS: We studied 60 patients with suspected acute myocarditis (median 3 days from presentation) and 50 controls using CMR (1.5 T), including: (1) dark-blood T2W imaging; >(2) native T1-mapping (ShMOLLI); (3) LGE. Analysis included: (1) global myocardial T2 signal intensity (SI) ratio compared to skeletal muscle; (2) myocardial T1 times; (3) areas of injury by T2W, T1-mapping and LGE. RESULTS: Compared to controls, patients had more edema (global myocardial T2 SI ratio 1.71 ± 0.27 vs.1.56 ± 0.15), higher mean myocardial T1 (1011 ± 64 ms vs. 946 ± 23 ms) and more areas of injury as detected by T2W (median 5% vs. 0%), T1 (median 32% vs. 0.7%) and LGE (median 11% vs. 0%); all p < 0.001. A threshold of T1 > 990 ms (sensitivity 90%, specificity 88%) detected significantly larger areas of involvement than T2W and LGE imaging in patients, and additional areas of injury when T2W and LGE were negative. T1-mapping significantly improved the diagnostic confidence in an additional 30% of cases when at least one of the conventional methods (T2W, LGE) failed to identify any areas of abnormality. Using incremental thresholds, T1-mapping can display the non-ischemic patterns of injury typical of myocarditis. CONCLUSION: Native T1-mapping can display the typical non-ischemic patterns in acute myocarditis, similar to LGE imaging but without the need for contrast agents. In addition, T1-mapping offers significant incremental diagnostic value, detecting additional areas of myocardial involvement beyond T2W and LGE imaging and identified extra cases when these conventional methods failed to identify abnormalities. In the future, it may be possible to perform gadolinium-free CMR using cine and T1-mapping for tissue characterization and may be particularly useful for patients in whom gadolinium contrast is contraindicated.

Fan LM, Douglas G, Bendall JK, McNeill E, Crabtree MJ, Hale AB, Mai A, Li JM, McAteer MA, Schneider JE et al. 2014. Endothelial cell-specific reactive oxygen species production increases susceptibility to aortic dissection. Circulation, 129 (25), pp. 2661-2672. | Show Abstract | Read more

BACKGROUND: Increased production of reactive oxygen species (ROS) throughout the vascular wall is a feature of cardiovascular disease states, but therapeutic strategies remain limited by our incomplete understanding of the role and contribution of specific vascular cell ROS to disease pathogenesis. To investigate the specific role of endothelial cell (EC) ROS in the development of structural vascular disease, we generated a mouse model of endothelium-specific Nox2 overexpression and tested the susceptibility to aortic dissection after angiotensin II (Ang II) infusion. METHODS AND RESULTS: A specific increase in endothelial ROS production in Nox2 transgenic mice was sufficient to cause Ang II-mediated aortic dissection, which was never observed in wild-type mice. Nox2 transgenic aortas had increased endothelial ROS production, endothelial vascular cell adhesion molecule-1 expression, matrix metalloproteinase activity, and CD45(+) inflammatory cell infiltration. Conditioned media from Nox2 transgenic ECs induced greater Erk1/2 phosphorylation in vascular smooth muscle cells compared with wild-type controls through secreted cyclophilin A (CypA). Nox2 transgenic ECs (but not vascular smooth muscle cells) and aortas had greater secretion of CypA both at baseline and in response to Ang II stimulation. Knockdown of CypA in ECs abolished the increase in vascular smooth muscle cell Erk1/2 phosphorylation conferred by EC conditioned media, and preincubation with CypA augmented Ang II-induced vascular smooth muscle cell ROS production. CONCLUSIONS: These findings demonstrate a pivotal role for EC-derived ROS in the determination of the susceptibility of the aortic wall to Ang II-mediated aortic dissection. ROS-dependent CypA secretion by ECs is an important signaling mechanism through which EC ROS regulate susceptibility of structural components of the aortic wall to aortic dissection.

Bissell MM, Dall'Armellina E, Choudhury RP. 2014. Flow vortices in the aortic root: in vivo 4D-MRI confirms predictions of Leonardo da Vinci. Eur Heart J, 35 (20), pp. 1344. | Read more

Lindsay AC, Biasiolli L, Knight S, Cunnington C, Robson MD, Neubauer S, Kennedy J, Handa A, Choudhury RP. 2014. Non-invasive imaging of carotid arterial restenosis using 3T cardiovascular magnetic resonance. J Cardiovasc Magn Reson, 16 (1), pp. 5. | Show Abstract | Read more

BACKGROUND: Restenosis of the carotid artery is common following carotid endarterectomy, but analysis of lesion composition has mostly been based on histological study of explanted restenotic lesions. This study investigated the ability of 3T cardiovascular magnetic resonance (CMR) to determine the components of recurrent carotid artery disease and examined whether these differed from primary atherosclerotic plaque. METHODS: 50 patients underwent 3T CMR of both carotid arteries using a standard multicontrast protocol: time-of-flight (TOF), T1-weighted (T1W), T2-weighted (T2W), and PD-weighted (PDW) Turbo-Spin-Echo (TSE) sequences. 25 patients had previously undergone carotid endarterectomy (mean time since surgery 1580 days, range 45-6560 days), and 25 with primary asymptomatic atherosclerotic plaques served as controls. Two experienced reviewers analysed the multicontrast CMR images according to the presence or absence of major plaque features and assigned an overall classification type. RESULTS: In patients with recurrent carotid disease following endarterectomy, the mean degree of restenosis was 51% (range 30-90%). Three distinct types of restenosis were identified: 5 patients (20%) showed CMR characteristics of fibro-atheromatous tissue, 11 patients (44%) had plaque features consistent with possible myointimal (fibromuscular) hyperplasia, and 6 patients (24%) had recurrent plaque suggestive of further lipid accumulation. Three patients (12%) showed evidence of post-surgical dissection of the carotid intima. Compared to primary atherosclerotic plaques, restenotic plaques were more likely to contain fibro-atheromatous tissue (p = 0.05) and smooth muscle (p < 0.01), and less likely to contain lipid (p < 0.01). Composition did not differ significantly between patients with early and late restenosis. CONCLUSIONS: As defined by CMR, restenotic lesions of the carotid artery fall into three distinct types and differ in composition from primary atherosclerotic plaques. If validated by subsequent histological studies, these findings could suggest a role for CMR in detecting high-risk (i.e. lipid-rich) restenotic lesions.

Hadley G, Harrison P, Adlam D, Choudhury RP. 2014. Short bowel syndrome and clopidogrel non-responsiveness: a new indication for platelet aggregometry? BMJ Case Rep, 2014 (aug12 1), pp. bcr2013202241-bcr2013202241. | Read more

Ruparelia N, Lee R, Dall'Armellina E, Godec J, Medway D, Forfar C, Prendergast B, Kharbanda RK, Banning AP, Neubauer S et al. 2013. The Monocyte Genomic Response is Conserved Between Mice and Humans Following Acute Myocardial Infarction CIRCULATION, 128 (22),

Lee R, Adlam D, Fischer R, Di Gleria K, Valli A, Charles P, McGouran J, Ruparelia N, Dawkins S, Kharbanda RK et al. 2013. Integrated Plaque and Plasma Proteo-Lipidomics Reveal Novel Signatures of Coronary Atherosclerotic Plaque Disruption CIRCULATION, 128 (22),

Cuculi F, Dall'Armellina E, Manlhiot C, De Caterina AR, Colyer S, Ferreira V, Morovat A, Prendergast BD, Forfar JC, Alp NJ et al. 2014. Early change in invasive measures of microvascular function can predict myocardial recovery following PCI for ST-elevation myocardial infarction. Eur Heart J, 35 (29), pp. 1971-1980. | Show Abstract | Read more

AIMS: Predicting the likely success of primary PCI to salvage potential infarcted myocardium is desirable. We compared early invasive parameters of coronary microcirculation function with the levels of circulating endothelin (ET-1) and 6-month ejection fraction after STEMI. METHODS AND RESULTS: Forty-four STEMI patients underwent assessment of coronary flow reserve (CFR) and index of myocardial resistance (IMR) on completion of PPCI and one day later. Cardiac magnetic resonance (CMR) at 24 h and 6 months assessed ejection fraction, oedema, late gadolinium enhancement, and salvage. In patients with depressed EF, there was no difference in IMR or CFR measured immediately after PPCI compared with those with preserved EF. However, by Day 1, CFR was significantly lower in those with depressed EF [2.0(1.5-2.3) vs. 2.6(2.1-3.3), P = 0.008]. In multivariable models, higher CFR post-PPCI [EST: +8.9 (SE 3.7) per 1 CFR unit, P = 0.03] and greater increase in CFR between post-PPCI and Day 1 [EST: +8.5 (SE 3.4) per 1 CFR unit, P = 0.01] were associated with higher salvage index. Circulating endothelin levels were significantly elevated in the low EF group at both 6 and 24 h, and 24 h levels correlated with CFR. CONCLUSION: Changes of the coronary microcirculation in the first day after PPCI are associated with 6-month ejection fraction and myocardial salvage. Depressed CFR at 24 h is associated with CMR imaging indices of MVO and haemorrhage and elevated endothelin levels.

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Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Ntusi N, Holloway C, Choudhury RP, Kardos A, Robson MD et al. 2013. T<inf>1</inf> Mapping for the diagnosis of acute myocarditis using CMR: Comparison to T<inf>2</inf>-Weighted and late gadolinium enhanced imaging JACC: Cardiovascular Imaging, 6 (10), pp. 1048-1058. | Show Abstract | Read more

Objectives This study sought to test the diagnostic performance of native T1 mapping in acute myocarditis compared with cardiac magnetic resonance (CMR) techniques such as dark-blood T2-weighted (T2W)-CMR, bright-blood T2W-CMR, and late gadolinium enhancement (LGE) imaging. Background The diagnosis of acute myocarditis on CMR often requires multiple techniques, including T2W, early gadolinium enhancement, and LGE imaging. Novel techniques such as T1 mapping and bright-blood T2W-CMR are also sensitive to changes in free water content. We hypothesized that these techniques can serve as new and potentially superior diagnostic criteria for myocarditis. Methods We investigated 50 patients with suspected acute myocarditis (age 42 ± 16 years; 22% women) and 45 controls (age 42 ± 14 years; 22% women). CMR at 1.5-T (median 3 days from presentation) included: 1) dark-blood T2W-CMR (short-tau inversion recovery); 2) bright-blood T2W-CMR (acquisition for cardiac unified T2 edema); 3) native T1 mapping (shortened modified look-locker inversion recovery); and 4) LGE. Image analysis included: 1) global T2 signal intensity ratio of myocardium compared with skeletal muscle; 2) myocardial T1 relaxation times; and 3) areas of LGE. Results Compared with controls, patients had significantly higher global T2 signal intensity ratios by dark-blood T2W-CMR (1.73 ± 0.27 vs. 1.56 ± 0.15, p < 0.01), bright-blood T2W-CMR (2.02 ± 0.33 vs. 1.84 ± 0.17, p < 0.01), and mean myocardial T1 (1,010 ± 65 ms vs. 941 ± 18 ms, p < 0.01). Receiver-operating characteristic analysis showed clear differences in diagnostic performance. The areas under the curve for each method were: T1 mapping (0.95), LGE (0.96), dark-blood T2 (0.78), and bright-blood T2 (0.76). A T1 cutoff of 990 ms had a sensitivity, specificity, and diagnostic accuracy of 90%, 91%, and 91%, respectively. Conclusions Native T1 mapping as a novel criterion for the detection of acute myocarditis showed excellent and superior diagnostic performance compared with T2W-CMR. It also has a higher sensitivity compared with T2W and LGE techniques, which may be especially useful in detecting subtle focal disease and when gadolinium contrast imaging is not feasible. © 2013 by the American College of Cardiology Foundation.

Lee R, Antonopoulos AS, Alexopoulou Z, Margaritis M, Kharbanda RK, Choudhury RP, Antoniades C, Channon KM. 2013. Artifactual elevation of plasma sCD40L by residual platelets in patients with coronary artery disease International Journal of Cardiology, 168 (2), pp. 1648-1650. | Read more

Chai JT, Choudhury RP. 2013. Cardiometabolic interventions - focus on transcriptional regulators. Eur J Cardiovasc Med, 2 (3), pp. 212-218. | Show Abstract | Read more

Cardiovascular disease (CVD) remains the largest healthcare burden in the Western world; and the increasing prevalence of type II diabetes mellitus, at least partially driven by a trend in lifestyle changes associated with global economic development, is likely to fuel this CVD burden worldwide. Over the past two decades, there has been an increased awareness of the convergence of risk factors contributing to both cardiovascular disease and diabetes leading to the concept of the metabolic syndrome, and the realisation of the opportunity to intervene at this intersection to simultaneously target CVD and metabolic dysfunction. This brings together the fields of cardiovascular medicine, diabetology, and increasingly clinical immunology for a unified and concerted effort to reduce risk for both conditions simultaneously. The discovery of the targeted pathways of drugs already in clinical use such as fibrates and thiazolidinediones (TZD) has led to accelerated basic and clinical research into selective and dual PPAR-α and PPAR-γ agonists, which can theoretically target glucose, lipid and lipoprotein metabolism, as well as potentially exerting inhibitoryeffects in vascular inflammation, all of which might be predicted to reduce atherosclerosis. In this article, we will discuss the basic science as well as recent clinical development in the pursuit of optimal cardiometabolic intervention along with insight into strategies for future drug development.

Cuculi F, Herring N, De Caterina AR, Banning AP, Prendergast BD, Forfar JC, Choudhury RP, Channon KM, Kharbanda RK. 2013. Relationship of plasma neuropeptide y with angiographic, electrocardiographic and coronary physiology indices of reperfusion during ST elevation myocardial infarction Heart, 99 (16), pp. 1198-1203. | Show Abstract | Read more

Objectives: The co-transmitter neuropeptide Y (NPY) is released during high levels of sympathetic stimulation and is a potent vasoconstrictor. We defined the release profile of plasma NPY during acute ST elevation myocardial infarction, and tested the hypothesis that levels correlate with reperfusion measures after treatment with primary percutaneous coronary intervention (PPCI). Design: Prospective observational study. Setting: University hospital heart centre. Patients: 64 patients (62.6±11.7 years-old, 73% male) presenting throughout the 24-h cycle of clinical activity with ST elevation myocardial infarction. Interventions PPCI. Main outcome measures: NPY was measured (ELISA) in peripheral blood taken before and immediately after PPCI and at 6, 24 and 48 h post-PPCI. Reperfusion was assessed by angiographic criteria, ST segment resolution, invasive measurement of coronary flow reserve and the index of microcirculatory resistance. Results: Plasma NPY levels were highest before PPCI (17.4 (8.8-42.2) pg/ml, median (IQR)) and dropped significantly post-PPCI (12.4 (6.5-26.7) pg/ml, p<0.0001) and after 6 h (9.0 (2.6-21.5) pg/ml, p=0.008). Patients with admission NPY levels above the median were significantly more hypertensive and tachycardic and were more likely to have diabetes mellitus. Patients with angiographic no-reflow (less than thrombolysis in myocardial infarction 3 flow and myocardial blush grade >2, n=16) or no electrocardiographic ST resolution (<70%, n=30) following PPCI had significantly higher plasma NPY levels. Patients with a coronary flow reserve <1.5 or index of microcirculatory resistance >33 also had significantly higher plasma NPY levels pre-PPCI and post-PPCI. Conclusions: Plasma NPY levels correlate with indices of reperfusion and coronary microvascular resistance.

Margaritis M, Antonopoulos AS, Digby J, Lee R, Reilly S, Coutinho P, Shirodaria C, Sayeed R, Petrou M, De Silva R et al. 2013. Interactions between vascular wall and perivascular adipose tissue reveal novel roles for adiponectin in the regulation of endothelial nitric oxide synthase function in human vessels. Circulation, 127 (22), pp. 2209-2221. | Show Abstract | Read more

BACKGROUND: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. METHODS AND RESULTS: The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism. CONCLUSIONS: We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.

Dall'Armellina E, Ferreira VM, Kharbanda RK, Prendergast B, Piechnik SK, Robson MD, Jones M, Francis JM, Choudhury RP, Neubauer S. 2013. Diagnostic value of pre-contrast T1 mapping in acute and chronic myocardial infarction. JACC Cardiovasc Imaging, 6 (6), pp. 739-742. | Read more

Jefferson A, Ruparelia N, Choudhury R. 2013. EXOGENOUS MICROPARTICLES OF IRON OXIDE BIND TO ACTIVATED ENDOTHELIAL CELLS BUT, UNLIKE MONOCYTES, DO NOT TRIGGER AN ENDOTHELIAL RESPONSE HEART, 99 (suppl 2), pp. A116.3-A117. | Read more

Ruparelia N, Digby J, Jefferson A, Medway D, Neubauer S, Lygate C, Choudhury R. 2013. MYOCARDIAL INFARCTION CAUSES INFLAMMATION AND LEUKOCYTE RECRUITMENT AT REMOTE SITES IN THE MYOCARDIUM AND IN THE RENAL GLOMERULUS HEART, 99 (suppl 2), pp. A120.2-A121. | Read more

Ferreira V, Piechnik S, Dall'Armellina E, Karamitsos T, Francis J, Ntusi N, Holloway C, Choudhury R, Kardos A, Robson M et al. 2013. THE DETECTION OF ACUTE MYOCARDITIS USING CARDIOVASCULAR MRI: A CLINICAL STUDY COMPARING T1-MAPPING, T2-WEIGHTED AND LATE GADOLINIUM ENHANCEMENT IMAGING HEART, 99 (suppl 2), pp. A53-A54. | Read more

Biasiolli L, Chai J, Lindsay A, Handa A, Robson M, Choudhury R. 2013. IN-VIVO QUANTITATIVE T2 MAPPING OF CAROTID PLAQUES IN PATIENTS WITH RECENT CEREBROVASCULAR EVENTS: AHA PLAQUE TYPE CLASSIFICATION AND CORRELATION WITH PLAQUE HISTOLOGY HEART, 99 (suppl 2), pp. A127.1-A127. | Read more

Chai J, Digby J, Ruparelia N, Jefferson A, Handa A, Choudhury R. 2013. NICOTINIC ACID RECEPTOR GPR109A IS DOWN-REGULATED IN HUMAN MACROPHAGE-DERIVED FOAM CELLS HEART, 99 (suppl 2), pp. A97-A97. | Read more

Ferreira V, Dall'Armellina E, Piechnik S, Karamitsos T, Francis J, Choudhury R, Channon K, Banning A, Kharbanda R, Forfar C et al. 2013. THE USEFULNESS OF EARLY CARDIOVASCULAR MAGNETIC RESONANCE IN PATIENTS PRESENTING WITH ACUTE CHEST PAIN, POSITIVE TROPONIN AND NON-OBSTRUCTIVE CORONARY ARTERIES HEART, 99 (suppl 2), pp. A54.1-A54. | Read more

Cited:

21

Scopus

Ruparelia N, Digby JE, Jefferson A, Medway DJ, Neubauer S, Lygate CA, Choudhury RP. 2013. Myocardial infarction causes inflammation and leukocyte recruitment at remote sites in the myocardium and in the renal glomerulus Inflammation Research, 62 (5), pp. 515-525. | Show Abstract | Read more

Rationale and Objective Acute myocardial infarction (AMI) results in the recruitment of leukocytes to injured myocardium. Additionally, myocardium remote to the infarct zone also becomes inflamed and is associated with adverse left ventricular remodelling. Renal ischaemic syndromes have been associated with remote organ inflammation and impaired function. Here, we tested the hypothesis that AMI results in remote organ (renal) inflammation. Methods Mice were subjected to either AMI, sham procedure or no procedure and the inflammatory response in peripheral blood, injured and remote myocardium, and kidneys was studied at 24 h. Results AMI resulted in increased circulating neutrophils (P < 0.001) and monocytes (P < 0.001). mRNA for inflammatory mediators significantly increased in infarcted myocardium and in remote myocardium. VCAM-1 mRNA was increased in both infarcted and remote myocardium. VCAM-1 protein was also increased in the kidneys of AMI mice (P < 0.05) and immunofluorescence revealed localisation of VCAM-1 to glomeruli, associated with leukocyte infiltration and increased local inflammatory mRNA expression. Conclusions We conclude that in addition to local inflammation, AMI results in remote organ inflammation evidenced by (1) increased expression of mRNA for inflammatory cytokines, (2) marked upregulation of VCAM-1 in renal glomeruli, and (3) the recruitment and infiltration of leukocytes in the kidney. © The Author(s) 2013.

Chai JT, Digby JE, Choudhury RP. 2013. GPR109A and vascular inflammation. Curr Atheroscler Rep, 15 (5), pp. 325. | Show Abstract | Read more

GPR109A has generated expanding interest since its discovery as the receptor for niacin a decade ago, along with deorphanisation as the receptor for endogenous ligand 3-hydroxy-butyrate shortly after. This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein β-arrestins. In this article, we consider the role of GPR109A and its downstream effects in the context of atherosclerosis and vascular inflammation, along with insights into strategy for future drug development.

Mardiguian S, Serres S, Ladds E, Campbell SJ, Wilainam P, McFadyen C, McAteer M, Choudhury RP, Smith P, Saunders F et al. 2013. Anti-IL-17A treatment reduces clinical score and VCAM-1 expression detected by in vivo magnetic resonance imaging in chronic relapsing EAE ABH mice. Am J Pathol, 182 (6), pp. 2071-2081. | Show Abstract | Read more

IL-17 is argued to play an important role in the multiple sclerosis-like disease experimental autoimmune encephalitis (EAE). We investigated the therapeutic effects of anti-IL-17A in a chronic relapsing EAE ABH mouse model using conventional scoring, quantitative behavioral outcomes, and a novel vascular cell adhesion molecule 1 (VCAM-1)-targeted magnetic resonance imaging (MRI) contrast agent [anti-VCAM-microparticles of iron oxide (MPIO)] to identify conventionally undetectable neuropathology. Mice were administered prophylactic or treatment regimens of anti-IL-17A or IgG and two injections of anti-VCAM-MPIO before undergoing T2*-weighted three-dimensional and gadolinium-diethylenetriamine pentaacetic acid T1-weighted MRI. Rotarod, inverted screen, and open field motor function tests were performed, conventional clinical scores calculated, and central IL-17A mRNA expression quantified during acute disease, remission, and relapse. Prophylactic anti-IL-17A prevents acute disease and relapse and is associated with reduced clinical and functional severity. Treatment regimens delay relapse, improve functional scores, and are associated with reduced VCAM-MPIO lesions during remission. No significant alteration was detectable in levels of gadolinium-diethylenetriamine pentaacetic acid- or VCAM-MPIO-positive lesions during relapse. Prophylactic and treatment anti-IL-17A were therapeutically effective in chronic relapsing EAE, improving clinical and quantifiable functional outcomes. IL-17A expression seems significant during acute disease but less important chronically. Disease-related immunoneuropathology is more sensitively detected using VCAM-MPIO MRI, which may, therefore, be used to monitor therapy meaningfully.

Lee R, Antonopoulos AS, Alexopoulou Z, Margaritis M, Kharbanda RK, Choudhury RP, Antoniades C, Channon KM. 2013. Artifactual elevation of plasma sCD40L by residual platelets in patients with coronary artery disease. Int J Cardiol, 168 (2), pp. 1648-1650. | Read more

Ruparelia N, Digby JE, Jefferson A, Medway DJ, Neubauer S, Lygate CA, Choudhury RP. 2013. Myocardial infarction causes inflammation and leukocyte recruitment at remote sites in the myocardium and in the renal glomerulus. Inflamm Res, 62 (5), pp. 515-525. | Show Abstract | Read more

RATIONALE AND OBJECTIVE: Acute myocardial infarction (AMI) results in the recruitment of leukocytes to injured myocardium. Additionally, myocardium remote to the infarct zone also becomes inflamed and is associated with adverse left ventricular remodelling. Renal ischaemic syndromes have been associated with remote organ inflammation and impaired function. Here, we tested the hypothesis that AMI results in remote organ (renal) inflammation. METHODS: Mice were subjected to either AMI, sham procedure or no procedure and the inflammatory response in peripheral blood, injured and remote myocardium, and kidneys was studied at 24 h. RESULTS: AMI resulted in increased circulating neutrophils (P < 0.001) and monocytes (P < 0.001). mRNA for inflammatory mediators significantly increased in infarcted myocardium and in remote myocardium. VCAM-1 mRNA was increased in both infarcted and remote myocardium. VCAM-1 protein was also increased in the kidneys of AMI mice (P < 0.05) and immunofluorescence revealed localisation of VCAM-1 to glomeruli, associated with leukocyte infiltration and increased local inflammatory mRNA expression. CONCLUSIONS: We conclude that in addition to local inflammation, AMI results in remote organ inflammation evidenced by (1) increased expression of mRNA for inflammatory cytokines, (2) marked upregulation of VCAM-1 in renal glomeruli, and (3) the recruitment and infiltration of leukocytes in the kidney.

Cuculi F, Herring N, De Caterina AR, Banning AP, Prendergast BD, Forfar JC, Choudhury RP, Channon KM, Kharbanda RK. 2013. Relationship of plasma neuropeptide Y with angiographic, electrocardiographic and coronary physiology indices of reperfusion during ST elevation myocardial infarction. Heart, 99 (16), pp. 1198-1203. | Show Abstract | Read more

OBJECTIVES: The co-transmitter neuropeptide Y (NPY) is released during high levels of sympathetic stimulation and is a potent vasoconstrictor. We defined the release profile of plasma NPY during acute ST elevation myocardial infarction, and tested the hypothesis that levels correlate with reperfusion measures after treatment with primary percutaneous coronary intervention (PPCI). DESIGN: Prospective observational study. SETTING: University hospital heart centre. PATIENTS: 64 patients (62.6±11.7 years-old, 73% male) presenting throughout the 24-h cycle of clinical activity with ST elevation myocardial infarction. INTERVENTIONS: PPCI. MAIN OUTCOME MEASURES: NPY was measured (ELISA) in peripheral blood taken before and immediately after PPCI and at 6, 24 and 48 h post-PPCI. Reperfusion was assessed by angiographic criteria, ST segment resolution, invasive measurement of coronary flow reserve and the index of microcirculatory resistance. RESULTS: Plasma NPY levels were highest before PPCI (17.4 (8.8-42.2) pg/ml, median (IQR)) and dropped significantly post-PPCI (12.4 (6.5-26.7) pg/ml, p<0.0001) and after 6 h (9.0 (2.6-21.5) pg/ml, p=0.008). Patients with admission NPY levels above the median were significantly more hypertensive and tachycardic and were more likely to have diabetes mellitus. Patients with angiographic no-reflow (less than thrombolysis in myocardial infarction 3 flow and myocardial blush grade >2, n=16) or no electrocardiographic ST resolution (<70%, n=30) following PPCI had significantly higher plasma NPY levels. Patients with a coronary flow reserve <1.5 or index of microcirculatory resistance >33 also had significantly higher plasma NPY levels pre-PPCI and post-PPCI. CONCLUSIONS: Plasma NPY levels correlate with indices of reperfusion and coronary microvascular resistance.

Cited:

22

WOS

Chatrchyan S, Khachatryan V, Sirunyan AM, Tumasyan A, Adam W, Aguilo E, Bergauer T, Dragicevic M, Eroe J, Fabjan C et al. 2013. Search for a non-standard-model Higgs boson decaying to a pair of new light bosons in four-muon final states PHYSICS LETTERS B, 726 (4-5), pp. 564-586. | Show Abstract | Read more

Results are reported from a search for non-standard-model Higgs boson decays to pairs of new light bosons, each of which decays into the μ+μ- final state. The new bosons may be produced either promptly or via a decay chain. The data set corresponds to an integrated luminosity of 5.3 fb-1 of proton-proton collisions at s=7 TeV, recorded by the CMS experiment at the LHC in 2011. Such Higgs boson decays are predicted in several scenarios of new physics, including supersymmetric models with extended Higgs sectors or hidden valleys. Thus, the results of the search are relevant for establishing whether the new particle observed in Higgs boson searches at the LHC has the properties expected for a standard model Higgs boson. No excess of events is observed with respect to the yields expected from standard model processes. A model-independent upper limit of 0.86±0.06 fb on the product of the cross section times branching fraction times acceptance is obtained. The results, which are applicable to a broad spectrum of new physics scenarios, are compared with the predictions of two benchmark models as functions of a Higgs boson mass larger than 86 GeV/c2 and of a new light boson mass within the range 0.25-3.55 GeV/c2. © 2013 CERN.

Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Ntusi N, Holloway C, Choudhury RP, Kardos A, Robson MD et al. 2013. T(1) mapping for the diagnosis of acute myocarditis using CMR: comparison to T2-weighted and late gadolinium enhanced imaging. JACC Cardiovasc Imaging, 6 (10), pp. 1048-1058. | Show Abstract | Read more

OBJECTIVES: This study sought to test the diagnostic performance of native T1 mapping in acute myocarditis compared with cardiac magnetic resonance (CMR) techniques such as dark-blood T2-weighted (T2W)-CMR, bright-blood T2W-CMR, and late gadolinium enhancement (LGE) imaging. BACKGROUND: The diagnosis of acute myocarditis on CMR often requires multiple techniques, including T2W, early gadolinium enhancement, and LGE imaging. Novel techniques such as T1 mapping and bright-blood T2W-CMR are also sensitive to changes in free water content. We hypothesized that these techniques can serve as new and potentially superior diagnostic criteria for myocarditis. METHODS: We investigated 50 patients with suspected acute myocarditis (age 42 ± 16 years; 22% women) and 45 controls (age 42 ± 14 years; 22% women). CMR at 1.5-T (median 3 days from presentation) included: 1) dark-blood T2W-CMR (short-tau inversion recovery); 2) bright-blood T2W-CMR (acquisition for cardiac unified T2 edema); 3) native T1 mapping (shortened modified look-locker inversion recovery); and 4) LGE. Image analysis included: 1) global T2 signal intensity ratio of myocardium compared with skeletal muscle; 2) myocardial T1 relaxation times; and 3) areas of LGE. RESULTS: Compared with controls, patients had significantly higher global T2 signal intensity ratios by dark-blood T2W-CMR (1.73 ± 0.27 vs. 1.56 ± 0.15, p < 0.01), bright-blood T2W-CMR (2.02 ± 0.33 vs. 1.84 ± 0.17, p < 0.01), and mean myocardial T1 (1,010 ± 65 ms vs. 941 ± 18 ms, p < 0.01). Receiver-operating characteristic analysis showed clear differences in diagnostic performance. The areas under the curve for each method were: T1 mapping (0.95), LGE (0.96), dark-blood T2 (0.78), and bright-blood T2 (0.76). A T1 cutoff of 990 ms had a sensitivity, specificity, and diagnostic accuracy of 90%, 91%, and 91%, respectively. CONCLUSIONS: Native T1 mapping as a novel criterion for the detection of acute myocarditis showed excellent and superior diagnostic performance compared with T2W-CMR. It also has a higher sensitivity compared with T2W and LGE techniques, which may be especially useful in detecting subtle focal disease and when gadolinium contrast imaging is not feasible.

Biasiolli L, Lindsay AC, Chai JT, Choudhury RP, Robson MD. 2013. In-vivo quantitative T2 mapping of carotid arteries in atherosclerotic patients: segmentation and T2 measurement of plaque components. J Cardiovasc Magn Reson, 15 (1), pp. 69. | Show Abstract | Read more

BACKGROUND: Atherosclerotic plaques in carotid arteries can be characterized in-vivo by multicontrast cardiovascular magnetic resonance (CMR), which has been thoroughly validated with histology. However, the non-quantitative nature of multicontrast CMR and the need for extensive post-acquisition interpretation limit the widespread clinical application of in-vivo CMR plaque characterization. Quantitative T2 mapping is a promising alternative since it can provide absolute physical measurements of plaque components that can be standardized among different CMR systems and widely adopted in multi-centre studies. The purpose of this study was to investigate the use of in-vivo T2 mapping for atherosclerotic plaque characterization by performing American Heart Association (AHA) plaque type classification, segmenting carotid T2 maps and measuring in-vivo T2 values of plaque components. METHODS: The carotid arteries of 15 atherosclerotic patients (11 males, 71 ± 10 years) were imaged at 3 T using the conventional multicontrast protocol and Multiple-Spin-Echo (Multi-SE). T2 maps of carotid arteries were generated by mono-exponential fitting to the series of images acquired by Multi-SE using nonlinear least-squares regression. Two reviewers independently classified carotid plaque types following the CMR-modified AHA scheme, one using multicontrast CMR and the other using T2 maps and time-of-flight (TOF) angiography. A semi-automated method based on Bayes classifiers segmented the T2 maps of carotid arteries into 4 classes: calcification, lipid-rich necrotic core (LRNC), fibrous tissue and recent IPH. Mean ± SD of the T2 values of voxels classified as LRNC, fibrous tissue and recent IPH were calculated. RESULTS: In 37 images of carotid arteries from 15 patients, AHA plaque type classified by multicontrast CMR and by T2 maps (+ TOF) showed good agreement (76% of matching classifications and Cohen's κ = 0.68). The T2 maps of 14 normal arteries were used to measure T2 of tunica intima and media (T2 = 54 ± 13 ms). From 11865 voxels in the T2 maps of 15 arteries with advanced atherosclerosis, 2394 voxels were classified by the segmentation algorithm as LRNC (T2 = 37 ± 5 ms) and 7511 voxels as fibrous tissue (T2 = 56 ± 9 ms); 192 voxels were identified as calcification and one recent IPH (236 voxels, T2 = 107 ± 25 ms) was detected on T2 maps and confirmed by multicontrast CMR. CONCLUSIONS: This carotid CMR study shows the potential of in-vivo T2 mapping for atherosclerotic plaque characterization. Agreement between AHA plaque types classified by T2 maps (+TOF) and by conventional multicontrast CMR was good, and T2 measured in-vivo in LRNC, fibrous tissue and recent IPH demonstrated the ability to discriminate plaque components on T2 maps.

Jefferson A, Ruparelia N, Choudhury RP. 2013. Exogenous microparticles of iron oxide bind to activated endothelial cells but, unlike monocytes, do not trigger an endothelial response. Theranostics, 3 (6), pp. 428-436. | Show Abstract | Read more

Targeting particles to sites of inflammation is of considerable interest for applications relating to molecular imaging and drug delivery. We and others have described micron-sized particles of iron oxide (MPIO) that can be directed using specific ligands (e.g. antibodies, peptides and oligosaccharides) to bind to mediators of vascular inflammation in vivo. Since leukocyte binding to these molecules can induce changes in the target cell, an outstanding question has been whether the binding of imaging particles to these mediators induces biologically significant changes in the endothelial cells, potentially initiating or propagating inflammation. Here, we address these questions by looking for changes in endothelial cells following binding of contrast agent. Specifically, we have quantified calcium flux, rearrangement of the actin cytoskeleton, production of reactive oxygen species (ROS), apoptosis and potential secondary changes, such as changes in gene and protein expression follow binding events to primary endothelial cells in vitro. Although leukocytes induced changes to endothelial cell function, we did not see any significant changes to endothelial calcium flux, cytoskeletal organisation, production of ROS or induction of apoptosis in response to antibody-MPIO binding. Furthermore, there were no changes to gene expression monitored via real-time RT-PCR or presentation of protein on the cell surface measured using flow cytometry. Our experiments demonstrate that whilst antibody-targeted microparticles mimic the binding capability of leukocytes to inflamed endothelium, they do not trigger the same cellular responses and do not appear to initiate or compound inflammation. These properties are desirable for targeted therapeutic and diagnostic agents.

Chai JT, Digby JE, Ruparelia N, Jefferson A, Handa A, Choudhury RP. 2013. Nicotinic acid receptor GPR109A is down-regulated in human macrophage-derived foam cells. PLoS One, 8 (5), pp. e62934. | Show Abstract | Read more

Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from foam cells. In THP-1 cells NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNFα by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived foam cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in foam cells on either cholesterol efflux or key RCT genes transcription. Upon foam cell induction, NA lost its effect on PPARγ and cAMP pathways, since its receptor, GPR109A, was down-regulated by foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA's anti-inflammatory effect on human macrophages, it has no effect on foam cells in reverse cholesterol transport; due to GPR109A down-regulation.

Chai JT, Digby JE, Choudhury RP. 2013. GPR109A and Vascular Inflammation CURRENT ATHEROSCLEROSIS REPORTS, 15 (5), pp. 1-10. | Show Abstract | Read more

GPR109A has generated expanding interest since its discovery as the receptor for niacin a decade ago, along with deorphanisation as the receptor for endogenous ligand 3-hydroxy-butyrate shortly after. This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein β-arrestins. In this article, we consider the role of GPR109A and its downstream effects in the context of atherosclerosis and vascular inflammation, along with insights into strategy for future drug development. © 2013 The Author(s).

Choudhury RP, Ruparelia N. 2013. High-density lipoproteins and cardiovascular disease: The plots thicken Heart, 99 (4), pp. 222-224. | Read more

Lee R, Adlam D, Antoniades C, Digby JE, Kharbanda RK, Choudhury RP, Channon KM. 2013. Heparin administration leads to rapid decrease in plasma matrix metalloproteinase-9 International Journal of Cardiology, 163 (2), pp. 212-213. | Read more

McAteer MA, Choudhury RP. 2013. Targeted molecular imaging of vascular inflammation in cardiovascular disease using nano- and micro-sized agents Vascular Pharmacology, 58 (1-2), pp. 31-38. | Show Abstract | Read more

Molecular imaging is emerging as a key experimental tool for the identification of inflammatory cellular and molecular processes involved in the development of cardiovascular disease. This review summarises current molecular imaging approaches for the detection of vascular inflammation using a range of nano- and micro-sized contrast agents. We highlight strategies for detection of cell adhesion molecules, which are key regulators of endothelial activation and leukocyte recruitment in atherogenesis and ischaemia-reperfusion in jury. In particular, we address the properties of targeted microparticles of iron oxide (MPIO) for MRI detection of endothelial cell-specific activation of adhesion molecules in experimental models of atherosclerosis, acute vascular inflammation and ischaemia-reperfusion injury, which are otherwise undetectable by conventional imaging modalities. The ability of targeted MPIO to detect endothelial activation could enable early subclinical disease detection and development of novel therapeutic strategies. We discuss opportunities for further development and potential translation of targeted MPIO for clinical imaging of cardiovascular disease. © 2012 Elsevier Inc.

Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Ntusi N, Holloway C, Choudhury RP, Kardos A, Robson MD et al. 2012. Novel Techniques for the Diagnosis of Acute Myocarditis: A Clinical Cardiovascular Magnetic Resonance Study CIRCULATION, 126 (21),

McAteer MA, Choudhury RP. 2013. Targeted molecular imaging of vascular inflammation in cardiovascular disease using nano- and micro-sized agents. Vascul Pharmacol, 58 (1-2), pp. 31-38. | Show Abstract | Read more

Molecular imaging is emerging as a key experimental tool for the identification of inflammatory cellular and molecular processes involved in the development of cardiovascular disease. This review summarises current molecular imaging approaches for the detection of vascular inflammation using a range of nano- and micro-sized contrast agents. We highlight strategies for detection of cell adhesion molecules, which are key regulators of endothelial activation and leukocyte recruitment in atherogenesis and ischaemia-reperfusion in jury. In particular, we address the properties of targeted microparticles of iron oxide (MPIO) for MRI detection of endothelial cell-specific activation of adhesion molecules in experimental models of atherosclerosis, acute vascular inflammation and ischaemia-reperfusion injury, which are otherwise undetectable by conventional imaging modalities. The ability of targeted MPIO to detect endothelial activation could enable early subclinical disease detection and development of novel therapeutic strategies. We discuss opportunities for further development and potential translation of targeted MPIO for clinical imaging of cardiovascular disease.

Choudhury RP, Ruparelia N. 2013. High-density lipoproteins and cardiovascular disease: the plots thicken. Heart, 99 (4), pp. 222-224. | Read more

Lee R, Adlam D, Antoniades C, Digby JE, Kharbanda RK, Choudhury RP, Channon KM. 2013. Heparin administration leads to rapid decrease in plasma matrix metalloproteinase-9. Int J Cardiol, 163 (2), pp. 212-213. | Read more

Ferreira VM, Piechnik SK, Dall'Armellina E, Karamitsos TD, Francis JM, Choudhury RP, Friedrich MG, Robson MD, Neubauer S. 2012. Non-contrast T1-mapping detects acute myocardial edema with high diagnostic accuracy: a comparison to T2-weighted cardiovascular magnetic resonance. J Cardiovasc Magn Reson, 14 (1), pp. 42. | Show Abstract | Read more

BACKGROUND: T2w-CMR is used widely to assess myocardial edema. Quantitative T1-mapping is also sensitive to changes in free water content. We hypothesized that T1-mapping would have a higher diagnostic performance in detecting acute edema than dark-blood and bright-blood T2w-CMR. METHODS: We investigated 21 controls (55 ± 13 years) and 21 patients (61 ± 10 years) with Takotsubo cardiomyopathy or acute regional myocardial edema without infarction. CMR performed within 7 days included cine, T1-mapping using ShMOLLI, dark-blood T2-STIR, bright-blood ACUT2E and LGE imaging. We analyzed wall motion, myocardial T1 values and T2 signal intensity (SI) ratio relative to both skeletal muscle and remote myocardium. RESULTS: All patients had acute cardiac symptoms, increased Troponin I (0.15-36.80 ug/L) and acute wall motion abnormalities but no LGE. T1 was increased in patient segments with abnormal and normal wall motion compared to controls (1113 ± 94 ms, 1029 ± 59 ms and 944 ± 17 ms, respectively; p < 0.001). T2 SI ratio using STIR and ACUT2E was also increased in patient segments with abnormal and normal wall motion compared to controls (all p < 0.02). Receiver operator characteristics analysis showed that T1-mapping had a significantly larger area-under-the-curve (AUC = 0.94) compared to T2-weighted methods, whether the reference ROI was skeletal muscle or remote myocardium (AUC = 0.58-0.89; p < 0.03). A T1 value of greater than 990 ms most optimally differentiated segments affected by edema from normal segments at 1.5 T, with a sensitivity and specificity of 92 %. CONCLUSIONS: Non-contrast T1-mapping using ShMOLLI is a novel method for objectively detecting myocardial edema with a high diagnostic performance. T1-mapping may serve as a complementary technique to T2-weighted imaging for assessing myocardial edema in ischemic and non-ischemic heart disease, such as quantifying area-at-risk and diagnosing myocarditis.

Arnold JR, Karamitsos TD, Bhamra-Ariza P, Francis JM, Searle N, Robson MD, Howells RK, Choudhury RP, Rimoldi OE, Camici PG et al. 2012. Myocardial oxygenation in coronary artery disease: insights from blood oxygen level-dependent magnetic resonance imaging at 3 tesla. J Am Coll Cardiol, 59 (22), pp. 1954-1964. | Show Abstract | Read more

OBJECTIVES: The purpose of this study was to assess the diagnostic accuracy of blood oxygen-level dependent (BOLD) MRI in suspected coronary artery disease (CAD). BACKGROUND: By exploiting the paramagnetic properties of deoxyhemoglobin, BOLD magnetic resonance imaging can detect myocardial ischemia. We applied BOLD imaging and first-pass perfusion techniques to: 1) examine the pathophysiological relationship between coronary stenosis, perfusion, ventricular scar, and myocardial oxygenation; and 2) evaluate the diagnostic performance of BOLD imaging in the clinical setting. METHODS: BOLD and first-pass perfusion images were acquired at rest and stress (4 to 5 min intravenous adenosine, 140 μg/kg/min) and assessed quantitatively (using a BOLD signal intensity index [stress/resting signal intensity], and absolute quantification of perfusion by model-independent deconvolution). A BOLD signal intensity index threshold to identify ischemic myocardium was first determined in a derivation arm (25 CAD patients and 20 healthy volunteers). To determine diagnostic performance, this was then applied in a separate group comprising 60 patients with suspected CAD referred for diagnostic angiography. RESULTS: Prospective evaluation of BOLD imaging yielded an accuracy of 84%, a sensitivity of 92%, and a specificity of 72% for detecting myocardial ischemia and 86%, 92%, and 72%, respectively, for identifying significant coronary stenosis. Segment-based analysis revealed evidence of dissociation between oxygenation and perfusion (r = -0.26), with a weaker correlation of quantitative coronary angiography with myocardial oxygenation (r = -0.20) than with perfusion (r = -0.40; p = 0.005 for difference). Hypertension increased the odds of an abnormal BOLD response, but diabetes mellitus, hypercholesterolemia, and the presence of ventricular scar were not associated with significant deoxygenation. CONCLUSIONS: BOLD imaging provides valuable insights into the pathophysiology of CAD; myocardial hypoperfusion is not necessarily commensurate with deoxygenation. In the clinical setting, BOLD imaging achieves favorable accuracy for identifying the anatomic and functional significance of CAD.

Kylintireas I, Craig S, Nethononda R, Kohler M, Francis J, Choudhury R, Stradling J, Neubauer S. 2012. Atherosclerosis and arterial stiffness in obstructive sleep apnea--a cardiovascular magnetic resonance study. Atherosclerosis, 222 (2), pp. 483-489. | Show Abstract | Read more

OBJECTIVE: Obstructive sleep apnoea (OSA) has been linked to cardiovascular risk factors, such as hypertension, and clinical cardiovascular endpoints. Our aim was to assess whether OSA is independently associated with atherosclerosis and vascular dysfunction as assessed by cardiovascular magnetic resonance (CMR). METHODS: 58 patients with OSA and 39 matched control subjects without OSA underwent CMR of the aorta and carotid arteries. Carotid and aortic wall thickness and aortic distensibility were measured. Multi-weighted, high resolution CMR imaging was used for carotid atheroma characterization according to the American Heart Association (AHA) atheroma classification, modified for CMR. RESULTS: Carotid [1.47±0.03 mm vs. 1.26±0.05 mm, (P<0.01)] and aortic wall thickness [2.95±0.09 mm vs. 2.05±0.07 mm, (P<0.001)] were increased in patients with OSA compared to controls. Aortic distensibility was decreased in patients with OSA [3.62±0.3 vs. 4.75±0.2 mmHg(-1)×10(-3), (P<0.05)]. Prevalence of carotid plaque, average carotid atheroma class, and prevalence of high risk features of carotid atheroma were increased in patients with OSA (P<0.005 for all). On multivariate analysis, Oxygen desaturation index (ODI) emerged as an independent predictor of carotid and aortic wall thickness, but not of aortic stiffness. CONCLUSIONS: OSA is associated with increased carotid and aortic atheroma burden and with advanced, high risk carotid atherosclerotic plaques, but not with aortic stiffening.

McAteer MA, Mankia K, Ruparelia N, Jefferson A, Nugent HB, Stork LA, Channon KM, Schneider JE, Choudhury RP. 2012. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content. Arterioscler Thromb Vasc Biol, 32 (6), pp. 1427-1435. | Show Abstract | Read more

OBJECTIVE: Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. METHODS AND RESULTS: In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis-spared regions. CONCLUSIONS: This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity.

Lindsay AC, Biasiolli L, Lee JM, Kylintireas I, MacIntosh BJ, Watt H, Jezzard P, Robson MD, Neubauer S, Handa A et al. 2012. Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case-control, 3-T carotid artery MR imaging study. JACC Cardiovasc Imaging, 5 (4), pp. 388-396. | Show Abstract | Read more

OBJECTIVES: The goal of this study was to determine whether a 3-T magnetic resonance imaging (MRI) protocol combining carotid atherosclerotic plaque and brain imaging can identify features of high-risk acutely symptomatic plaque that correlate with brain injury. BACKGROUND: It has previously been demonstrated that, in asymptomatic patients, MRI can identify features of carotid plaque that are associated with stroke, such as the presence of a large lipid core. We hypothesized that the early phase (<7 days) after a cerebrovascular event, when risk of recurrence is highest, may be associated with particular plaque characteristics that associate with cerebral injury. METHODS: Eighty-one patients (41 presenting acutely with transient ischemic attack [TIA] or minor stroke and 40 asymptomatic controls) underwent multicontrast carotid artery MRI on 2 separate occasions, each accompanied by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging of the brain. RESULTS: Complex (American Heart Association [AHA] type VI) plaques were seen in 22 of 41 patients (54%) in the symptomatic group versus 8 of 40 (20%) in the asymptomatic group (p < 0.05). They were caused by intraplaque hemorrhage (34% vs. 18%; p = 0.08), surface rupture (24% vs. 5%; p = 0.03), or luminal thrombus (7% vs. 0%; p = 0.24). Noticeably, 17 of 30 (57%) cases of AHA type VI plaque were in vessels with <70% stenosis. At follow-up scanning (>6 weeks later), only 2 cases of symptomatic AHA type VI plaque showed evidence of full healing. The presence of fibrous cap rupture was associated with higher DWI brain injury at presentation and higher total cerebral FLAIR signal at follow-up (p < 0.05). CONCLUSIONS: Early carotid wall MRI in patients experiencing minor stroke or TIA showed a higher proportion of "complex" plaques compared with asymptomatic controls; a majority were in arteries of <70% stenosis. Fibrous cap rupture was associated with increases in DWI and FLAIR lesions in the brain. Combined carotid plaque and brain MRI may aid risk stratification and treatment selection in acute stroke and TIA.

Iacob AO, Choudhury RP. 2012. Targeting HDL-cholesterol to reduce residual cardiovascular risk. Curr Opin Lipidol, 23 (2), pp. 172-174. | Read more

Serres S, Soto MS, Hamilton A, McAteer MA, Carbonell WS, Robson MD, Ansorge O, Khrapitchev A, Bristow C, Balathasan L et al. 2012. Molecular MRI enables early and sensitive detection of brain metastases. Proc Natl Acad Sci U S A, 109 (17), pp. 6674-6679. | Show Abstract | Read more

Metastasis to the brain is a leading cause of cancer mortality. The current diagnostic method of gadolinium-enhanced MRI is sensitive only to larger tumors, when therapeutic options are limited. Earlier detection of brain metastases is critical for improved treatment. We have developed a targeted MRI contrast agent based on microparticles of iron oxide that enables imaging of endothelial vascular cell adhesion molecule-1 (VCAM-1). Our objectives here were to determine whether VCAM-1 is up-regulated on vessels associated with brain metastases, and if so, whether VCAM-1-targeted MRI enables early detection of these tumors. Early up-regulation of cerebrovascular VCAM-1 expression was evident on tumor-associated vessels in two separate murine models of brain metastasis. Metastases were detectable in vivo using VCAM-1-targeted MRI 5 d after induction (<1,000 cells). At clinical imaging resolutions, this finding is likely to translate to detection at tumor volumes two to three orders of magnitude smaller (0.3-3 × 10(5) cells) than those volumes detectable clinically (10(7)-10(8) cells). VCAM-1 expression detected by MRI increased significantly (P < 0.0001) with tumor progression, and tumors showed no gadolinium enhancement. Importantly, expression of VCAM-1 was shown in human brain tissue containing both established metastases and micrometastases. Translation of this approach to the clinic could increase therapeutic options and change clinical management in a substantial number of cancer patients.

Jefferson A, Wijesurendra RS, McAteer MA, Choudhury RP. 2012. Development and application of endothelium-targeted microparticles for molecular magnetic resonance imaging. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 4 (3), pp. 247-256. | Show Abstract | Read more

Molecular imaging of disease states can enhance diagnosis allowing for accurate and more effective treatment. By specifically targeting molecules differentially expressed in disease states, researchers and clinicians have a means of disease characterization at a cellular or tissue level. Targeted micron-sized particles of iron oxide (MPIO) have been used as molecule-specific contrast agents for use with magnetic resonance imaging (MRI), and early evidence suggests they may be suitable for use with other imaging modalities. Targeting of MPIO to markers of disease is commonly achieved through the covalent attachment of antibodies to the surface of the particles, providing an imaging agent that is both highly specific and which binds with high affinity. When comparing micron-sized particles with nanometre-sized particles, the former provide substantial signal dropout in MRI and confer the sensitivity to detect low levels of target. Furthermore, larger particles appear to bind to targets more potently than smaller particles. Animal models have also demonstrated favorable blood clearance characteristics of MPIO, which are important in achieving favorable signal over background and to attain clearance and disposal. Although the current generation of commercially available MPIO are not suitable for administration into humans, future work may focus on the development of biodegradable and nonimmunogenic MPIO that may allow the use of these imaging agents in a clinical setting.

Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R et al. 2012. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease. Circulation, 125 (11), pp. 1356-1366. | Show Abstract | Read more

BACKGROUND: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. METHODS AND RESULTS: Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. CONCLUSIONS: Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states.

Dall'Armellina E, Piechnik SK, Ferreira VM, Si QL, Robson MD, Francis JM, Cuculi F, Kharbanda RK, Banning AP, Choudhury RP et al. 2012. Cardiovascular magnetic resonance by non contrast T1-mapping allows assessment of severity of injury in acute myocardial infarction. J Cardiovasc Magn Reson, 14 (1), pp. 15. | Show Abstract | Read more

BACKGROUND: Current cardiovascular magnetic resonance (CMR) methods, such as late gadolinium enhancement (LGE) and oedema imaging (T2W) used to depict myocardial ischemia, have limitations. Novel quantitative T1-mapping techniques have the potential to further characterize the components of ischemic injury. In patients with myocardial infarction (MI) we sought to investigate whether state-of the art pre-contrast T1-mapping (1) detects acute myocardial injury, (2) allows for quantification of the severity of damage when compared to standard techniques such as LGE and T2W, and (3) has the ability to predict long term functional recovery. METHODS: 3T CMR including T2W, T1-mapping and LGE was performed in 41 patients [of these, 78% were ST elevation MI (STEMI)] with acute MI at 12-48 hour after chest pain onset and at 6 months (6M). Patients with STEMI underwent primary PCI prior to CMR. Assessment of acute regional wall motion abnormalities, acute segmental damaged fraction by T2W and LGE and mean segmental T1 values was performed on matching short axis slices. LGE and improvement in regional wall motion at 6M were also obtained. RESULTS: We found that the variability of T1 measurements was significantly lower compared to T2W and that, while the diagnostic performance of acute T1-mapping for detecting myocardial injury was at least as good as that of T2W-CMR in STEMI patients, it was superior to T2W imaging in NSTEMI. There was a significant relationship between the segmental damaged fraction assessed by either by LGE or T2W, and mean segmental T1 values (P < 0.01). The index of salvaged myocardium derived by acute T1-mapping and 6M LGE was not different to the one derived from T2W (P = 0.88). Furthermore, the likelihood of improvement of segmental function at 6M decreased progressively as acute T1 values increased (P < 0.0004). CONCLUSIONS: In acute MI, pre-contrast T1-mapping allows assessment of the extent of myocardial damage. T1-mapping might become an important complementary technique to LGE and T2W for identification of reversible myocardial injury and prediction of functional recovery in acute MI.

Biasiolli L, Lindsay AC, Choudhury RP, Robson MD. 2012. In-vivo T2 mapping of atherosclerotic plaques in carotid arteries. J Cardiovasc Magn Reson, 14 Suppl 1 (Suppl 1), pp. P134. | Read more

Digby JE, Martinez F, Jefferson A, Ruparelia N, Chai J, Wamil M, Greaves DR, Choudhury RP. 2012. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms. Arterioscler Thromb Vasc Biol, 32 (3), pp. 669-676. | Show Abstract | Read more

OBJECTIVE: Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. METHODS AND RESULTS: In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKβ by 42±2% (P<0.001) IKB-α by 54±14% (P<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). CONCLUSION: NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.

Cited:

25

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McAteer MA, Mankia K, Ruparelia N, Jefferson A, Nugent HB, Stork LA, Channon KM, Schneider JE, Choudhury RP. 2012. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content Arteriosclerosis, Thrombosis, and Vascular Biology, 32 (6), pp. 1427-1435. | Show Abstract | Read more

Objective-Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. Methods and Results-In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis- spared regions. Conclusion-This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity. © 2012 American Heart Association, Inc.

Lindsay AC, Biasiolli L, Lee JM, Kylilntireas I, MacIntosh BJ, Watt H, Jezzard P, Robson MD, Neubauer S, Handa A et al. 2011. Acute 3T Magnetic Resonance Imaging Reveals Features of Carotid Atherosclerotic Plaque Associated with Ipsilateral Cerebral Infarction in Minor Stroke and Transient Ischemic Attack CIRCULATION, 124 (21),

Cited:

52

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Digby JE, Martinez F, Jefferson A, Ruparelia N, Chai J, Wamil M, Greaves DR, Choudhury RP. 2012. Anti-inflammatory effects of nicotinic acid in human monocytes are mediated by GPR109A dependent mechanisms Arteriosclerosis, Thrombosis, and Vascular Biology, 32 (3), pp. 669-676. | Show Abstract | Read more

Objective-Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. Methods and Results-In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α(by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKβl by 42±2% (P<0.001) IKB-β by 54±14% (P<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). Conclusion-NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia. © 2012 American Heart Association, Inc.

Jefferson A, Wijesurendra RS, McAteer MA, Choudhury RP. 2012. Development and application of endothelium-targeted microparticles for molecular magnetic resonance imaging Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology, 4 (3), pp. 247-256. | Show Abstract | Read more

Molecular imaging of disease states can enhance diagnosis allowing for accurate and more effective treatment. By specifically targeting molecules differentially expressed in disease states, researchers and clinicians have a means of disease characterization at a cellular or tissue level. Targeted micron-sized particles of iron oxide (MPIO) have been used as molecule-specific contrast agents for use with magnetic resonance imaging (MRI), and early evidence suggests they may be suitable for use with other imaging modalities. Targeting of MPIO to markers of disease is commonly achieved through the covalent attachment of antibodies to the surface of the particles, providing an imaging agent that is both highly specific and which binds with high affinity. When comparing micron-sized particles with nanometre-sized particles, the former provide substantial signal dropout in MRI and confer the sensitivity to detect low levels of target. Furthermore, larger particles appear to bind to targets more potently than smaller particles. Animalmodels have also demonstrated favorable blood clearance characteristics of MPIO, which are important in achieving favorable signal over background and to attain clearance and disposal. Although the current generation of commercially available MPIO are not suitable for administration into humans, future work may focus on the development of biodegradable and nonimmunogenic MPIO that may allow the use of these imaging agents in a clinical setting. © 2012 Wiley Periodicals, Inc.

Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA et al. 2012. Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis. JACC Cardiovasc Imaging, 5 (9), pp. 911-922. | Show Abstract | Read more

OBJECTIVES: This study sought to determine the effects of a p38 mitogen-activated protein kinase inhibitor, losmapimod, on vascular inflammation, by (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography imaging. BACKGROUND: The p38 mitogen-activated protein kinase cascade plays an important role in the initiation and progression of inflammatory diseases, including atherosclerosis. METHODS: Patients with atherosclerosis on stable statin therapy (n = 99) were randomized to receive losmapimod 7.5 mg once daily (lower dose [LD]), twice daily (higher dose [HD]) or placebo for 84 days. Vascular inflammation was assessed by FDG positron emission tomography/computed tomography imaging of the carotid arteries and aorta; analyses focused on the index vessel (the artery with the highest average maximum tissue-to-background ratio [TBR] at baseline). Serum inflammatory biomarkers and FDG uptake in visceral and subcutaneous fat were also measured. RESULTS: The primary endpoint, change from baseline in average TBR across all segments in the index vessel, was not significantly different between HD and placebo (ΔTBR: -0.04 [95% confidence interval [CI]: -0.14 to +0.06], p = 0.452) or LD and placebo (ΔTBR: -0.02 [95% CI: -0.11 to +0.06], p = 0.579). However, there was a statistically significant reduction in average TBR in active segments (TBR ≥1.6) (HD vs. placebo: ΔTBR: -0.10 [95% CI: -0.19 to -0.02], p = 0.0125; LD vs. placebo: ΔTBR: -0.10 [95% CI: -0.18 to -0.02], p = 0.0194). The probability of a segment being active was also significantly reduced for HD when compared with placebo (OR: 0.57 [95% CI: 0.41 to 0.81], p = 0.002). Within the HD group, reductions were observed in placebo-corrected inflammatory biomarkers including high-sensitivity C-reactive protein (% reduction: -28% [95% CI: -46 to -5], p = 0.023) as well as FDG uptake in visceral fat (ΔSUV: -0.05 [95% CI: -0.09 to -0.01], p = 0.018), but not subcutaneous fat. CONCLUSIONS: Despite nonsignificant changes for the primary endpoint of average vessel TBR, HD losmapimod reduced vascular inflammation in the most inflamed regions, concurrent with a reduction in inflammatory biomarkers and FDG uptake in visceral fat. These results suggest a systemic anti-inflammatory effect. (A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging; NCT00633022).

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26

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Digby JE, Ruparelia N, Choudhury RP. 2012. Niacin in cardiovascular disease: Recent preclinical and clinical developments Arteriosclerosis, Thrombosis, and Vascular Biology, 32 (3), pp. 582-588. | Show Abstract | Read more

Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients. © 2012 American Heart Association, Inc.

Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R et al. 2012. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease Circulation, 125 (11), pp. 1356-1366.

Cited:

64

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Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R et al. 2012. Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease Circulation, 125 (11), pp. 1356-1366. | Show Abstract | Read more

BACKGROUND-: The endothelial nitric oxide synthase cofactor tetrahydrobiopterin (BH4) plays a pivotal role in maintaining endothelial function in experimental vascular disease models and in humans. Augmentation of endogenous BH4 levels by oral BH4 treatment has been proposed as a potential therapeutic strategy in vascular disease states. We sought to determine the mechanisms relating exogenous BH4 to human vascular function and to determine oral BH4 pharmacokinetics in both plasma and vascular tissue in patients with coronary artery disease. METHODS AND RESULTS-: Forty-nine patients with coronary artery disease were randomized to receive low-dose (400 mg/d) or high-dose (700 mg/d) BH4 or placebo for 2 to 6 weeks before coronary artery bypass surgery. Vascular function was quantified by magnetic resonance imaging before and after treatment, along with plasma BH4 levels. Vascular superoxide, endothelial function, and BH4 levels were determined in segments of saphenous vein and internal mammary artery. Oral BH4 treatment significantly augmented BH4 levels in plasma and in saphenous vein (but not internal mammary artery) but also increased levels of the oxidation product dihydrobiopterin (BH2), which lacks endothelial nitric oxide synthase cofactor activity. There was no effect of BH4 treatment on vascular function or superoxide production. Supplementation of human vessels and blood with BH4 ex vivo revealed rapid oxidation of BH4 to BH2 with predominant BH2 uptake by vascular tissue. CONCLUSIONS-: Oral BH4 treatment augments total biopterin levels in patients with established coronary artery disease but has no net effect on vascular redox state or endothelial function owing to systemic and vascular oxidation of BH4. Alternative strategies are required to target BH4-dependent endothelial function in established vascular disease states. © 2012 American Heart Association, Inc.

Digby JE, Ruparelia N, Choudhury RP. 2012. Niacin in cardiovascular disease: recent preclinical and clinical developments. Arterioscler Thromb Vasc Biol, 32 (3), pp. 582-588. | Show Abstract | Read more

Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients.

Digby JE, Martinez FO, Jefferson A, Ruparelia N, Wamil M, Greaves DR, Choudhury RP. 2011. Anti-inflammatory Effects of Nicotinic Acid: Mechanisms of Action in Human Monocytes CIRCULATION, 124 (21),

Kylintireas I, Shirodaria C, Lee JM, Cunningon C, Lindsay A, Francis J, Robson MD, Neubauer S, Channon KM, Choudhury RP. 2011. Multimodal cardiovascular magnetic resonance quantifies regional variation in vascular structure and function in patients with coronary artery disease: relationships with coronary disease severity. J Cardiovasc Magn Reson, 13 (1), pp. 61. | Show Abstract | Read more

BACKGROUND: Cardiovascular magnetic resonance (CMR) of the vessel wall is highly reproducible and can evaluate both changes in plaque burden and composition. It can also measure aortic compliance and endothelial function in a single integrated examination. Previous studies have focused on patients with pre-identified carotid atheroma. We define these vascular parameters in patients presenting with coronary artery disease and test their relations to its extent and severity. METHODS AND RESULTS: 100 patients with CAD [single-vessel (16%); two-vessel (39%); and three-vessel (42%) non-obstructed coronary arteries (3%)] were studied. CAD severity and extent was expressed as modified Gensini score (mean modified score 12.38 ± 5.3). A majority of carotid plaque was located in the carotid bulb (CB). Atherosclerosis in this most diseased segment correlated modestly with the severity and extent of CAD, as expressed by the modified Gensini score (R = 0.251, P < 0.05). Using the AHA plaque classification, atheroma class also associated with CAD severity (rho = 0.26, P < 0.05). The distal descending aorta contained the greatest plaque, which correlated with the degree of CAD (R = 0.222; P < 0.05), but with no correlation with the proximal descending aorta, which was relatively spared (R = 0.106; P = n. s.). Aortic distensibility varied along its length with the ascending aorta the least distensible segment. Brachial artery FMD was inversely correlated with modified Gensini score (R = -0.278; P < 0.05). In multivariate analysis, distal descending aorta atheroma burden, distensibility of the ascending aorta, carotid atheroma class and FMD were independent predictors of modified Gensini score. CONCLUSIONS: Multimodal vascular CMR shows regional abnormalities of vascular structure and function that correlate modestly with the degree and extent of CAD.

Serres S, Mardiguian S, Campbell SJ, McAteer MA, Akhtar A, Krapitchev A, Choudhury RP, Anthony DC, Sibson NR. 2011. VCAM-1-targeted magnetic resonance imaging reveals subclinical disease in a mouse model of multiple sclerosis. FASEB J, 25 (12), pp. 4415-4422. | Show Abstract | Read more

Diagnosis of multiple sclerosis (MS) currently requires lesion identification by gadolinium (Gd)-enhanced or T(2)-weighted magnetic resonance imaging (MRI). However, these methods only identify late-stage pathology associated with blood-brain barrier breakdown. There is a growing belief that more widespread, but currently undetectable, pathology is present in the MS brain. We have previously demonstrated that an anti-VCAM-1 antibody conjugated to microparticles of iron oxide (VCAM-MPIO) enables in vivo detection of VCAM-1 by MRI. Here, in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we have shown that presymptomatic lesions can be quantified using VCAM-MPIO when they are undetectable by Gd-enhancing MRI. Moreover, in symptomatic animals VCAM-MPIO binding was present in all regions showing Gd-DTPA enhancement and also in areas of no Gd-DTPA enhancement, which were confirmed histologically to be regions of leukocyte infiltration. VCAM-MPIO binding correlated significantly with increasing disability. Negligible MPIO-induced contrast was found in either EAE animals injected with an equivalent nontargeted contrast agent (IgG-MPIO) or in control animals injected with the VCAM-MPIO. These findings describe a highly sensitive molecular imaging tool that may enable detection of currently invisible pathology in MS, thus accelerating diagnosis, guiding treatment, and enabling quantitative disease assessment.

Jefferson A, Wijesurendra RS, McAteer MA, Digby JE, Douglas G, Bannister T, Perez-Balderas F, Bagi Z, Lindsay AC, Choudhury RP. 2011. Molecular imaging with optical coherence tomography using ligand-conjugated microparticles that detect activated endothelial cells: rational design through target quantification. Atherosclerosis, 219 (2), pp. 579-587. | Show Abstract | Read more

OBJECTIVES: Optical coherence tomography (OCT) is a high resolution imaging technique used to assess superficial atherosclerotic plaque morphology. Utility of OCT may be enhanced by contrast agents targeting molecular mediators of inflammation. METHODS AND RESULTS: Microparticles of iron oxide (MPIO; 1 and 4.5 μm diameter) in suspension were visualized and accurately quantified using a clinical optical coherence tomography system. Bound to PECAM-1 on a plane of cultured endothelial cells under static conditions, 1 μm MPIO were also readily detected by OCT. To design a molecular contrast probe that would bind activated endothelium under conditions of shear stress, we quantified the expression (basal vs. TNF-activated; molecules μm(-2)) of VCAM-1 (not detected vs. 16 ± 1); PECAM-1 (132 ± 6 vs. 198 ± 10) and E-selectin (not detected vs. 46 ± 0.6) using quantitative flow cytometry. We then compared the retention of antibody-conjugated MPIO targeting each of these molecules plus a combined VCAM-1 and E-selectin (E+V) probe across a range of physiologically relevant shear stresses. E+V MPIO were consistently retained with highest efficiency (P < 0.001) and at a density that provided conspicuous contrast effects on OCT pullback. CONCLUSION: Microparticles of iron oxide were detectable using a clinical OCT system. Assessment of binding under flow conditions recommended an approach that targeted both E-selectin and VCAM-1. Bound to HUVEC under conditions of flow, targeted 1 μm E+V MPIO were readily identified on OCT pullback. Molecular imaging with OCT may be feasible in vivo using antibody targeted MPIO.

Biasiolli L, Lindsay AC, Choudhury RP, Robson MD. 2011. Loss of fine structure and edge sharpness in fast-spin-echo carotid wall imaging: measurements and comparison with multiple-spin-echo in normal and atherosclerotic subjects. J Magn Reson Imaging, 33 (5), pp. 1136-1143. | Show Abstract | Read more

PURPOSE: To test whether the k-space acquisition strategy used by fast-spin-echo (FSE) is a major source of blurring in carotid wall and plaque imaging, and investigate an alternative acquisition approach. MATERIALS AND METHODS: The effect of echo train length (ETL) and T(2) on the amount of blurring was studied in FSE simulations of vessel images. Edge sharpness was measured in black-blood T(1) W and proton density-weighted (PDW) carotid images acquired from 5 normal volunteers and 19 asymptomatic patients using both FSE and multiple-spin-echo (Multi-SE) sequences at 3 Tesla (T). Plaque images were classified and divided in group α (tissues' average T(2) ∼ 40-70 ms) and group β (plaque components with shorter T(2) ). RESULTS: Simulations predicted 26.9% reduction of vessel edge sharpness from Multi-SE to FSE images (ETL = 9, T(2) = 60 ms). This agreed with in vivo measurements in normal volunteers (27.4%) and in patient group α (26.2%), while in group β the loss was higher (31.6%). CONCLUSION: FSE significantly reduced vessel edge sharpness along the phase-encoding direction in T(1) W and PDW images. Blurring was stronger in the presence of plaque components with short T(2) times. This study shows a limitation of FSE and the potential of Multi-SE to improve the quality of carotid imaging.

Dall'Armellina E, Karia N, Lindsay AC, Karamitsos TD, Ferreira V, Robson MD, Kellman P, Francis JM, Forfar C, Prendergast BD et al. 2011. Dynamic changes of edema and late gadolinium enhancement after acute myocardial infarction and their relationship to functional recovery and salvage index. Circ Cardiovasc Imaging, 4 (3), pp. 228-236. | Show Abstract | Read more

BACKGROUND: Changes in the myocardium in acute ischemia are dynamic and complex, and the characteristics of myocardial tissue on cardiovascular magnetic resonance in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute myocardial infarction, relating these to global and segmental myocardial function at 6 months. METHODS AND RESULTS: Cardiovascular magnetic resonance scans were performed on 30 patients with ST-elevation--myocardial infarction treated by primary percutaneous coronary intervention at each of 4 time points: 12 to 48 hours; 5 to 7 days; 14 to 17 days; and 6 months. All patients showed edema at 24 hours. The mean volume of edema (% left ventricle) was 37±16 at 24 hours and 39±17 at 1 week, with a reduction to 24±13 (P<0.01) by 2 weeks. Myocardial segments with edema also had increased signal on LGE at 24 hours (κ=0.77; P<0.001). The volume of LGE decreased significantly between 24 hours and 6 months (27±15% versus 22±12%; P=0.002). Of segments showing LGE at 24 hours, 50% showed resolution by 6 months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P<0.0001). The area of LGE measured at 6 months correlated more strongly with troponin at 48 hours (r=0.9; P<0.01) than LGE at 24 hours (r=0.7). The difference in LGE between 24 hours and 6 months had profound effects on the calculation of salvage index (26±21% at 24 hours versus 42±23% at 6 months; P=0.02). CONCLUSIONS: Myocardial edema is maximal and constant over the first week after myocardial infarction, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium.

Mankia KS, McAteer MA, Choudhury RP. 2011. Microparticle-Based Molecular MRI of Atherosclerosis, Thrombosis, and Tissue Ischemia Current Cardiovascular Imaging Reports, 4 (1), pp. 17-23. | Show Abstract | Read more

MRI is well suited for imaging vascular disease as it provides excellent soft tissue contrast and spatial resolution of the vessel wall. By generating potent contrast effects, iron oxide particles further enhance the ability of MRI to deliver functional information in a range of vascular syndromes. Larger microparticles of iron oxide (MPIO) generate sufficient contrast to enable detection of low-abundance vascular targets in vivo. Ligand-conjugated MPIO confer molecular specificity, facilitating molecular imaging of a range of specific endovascular targets. This review discusses the application of iron oxide particles in the molecular imaging of a variety of vascular syndromes. In particular, ligand-conjugated MPIO have been used for targeted molecular imaging in experimental models of atherosclerosis, thrombosis, and tissue ischemia syndromes. This provides a platform for vascular molecular imaging that could accelerate diagnosis, characterize disease progression, and measure response to treatment in a clinical setting. © 2010 Springer Science+Business Media, LLC.

Anthony DC, Sibson NR, McAteer MA, Davis B, Choudhury RP. 2011. Detection of brain pathology by magnetic resonance imaging of iron oxide micro-particles. Methods Mol Biol, 686 pp. 213-227. | Show Abstract | Read more

Contrast agents are widely used with magnetic resonance imaging (MRI) to increase the contrast between regions of interest and the background signal, thus providing better quality information. Such agents can work in one of two ways, either to specifically enhance the signal that is produced or to localize in a specific cell type of tissue. Commonly used image contrast agents are typically based on gadolinium complexes or super-paramagnetic iron oxide, the latter of which is used for imaging lymph nodes. When blood-brain barrier (BBB) breakdown is a feature of central nervous system (CNS) pathology, intravenously administered contrast agent enters into the CNS and alters contrast on MR scans. However, BBB breakdown reflects downstream or end-stage pathology. The initial recruitment of leukocytes to sites of disease such as multiple sclerosis (MS), ischemic lesions, or tumours takes place across an intact, but activated, brain endothelium. Molecular imaging affords the ability to obtain a "non-invasive biopsy" to reveal the presence of brain pathology in the absence of significant structural changes. We have developed smart contrast agents that target and reversibly adhere to sites of disease and have been used to reveal activated brain endothelium when images obtained by conventional MRI look normal. Indeed, our selectively targeted micro-particles of iron oxide have revealed the early presence of cerebral malaria pathology and ongoing MS-like plaques in clinically relevant models of disease.

Cited:

89

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Dall'Armellina E, Karia N, Lindsay AC, Karamitsos TD, Ferreira V, Robson MD, Kellman P, Francis JM, Forfar C, Prendergast BD et al. 2011. Dynamic changes of edema and late gadolinium enhancement after acute myocardial infarction and their relationship to functional recovery and salvage index Circulation: Cardiovascular Imaging, 4 (3), pp. 228-236. | Show Abstract | Read more

Background-Changes in the myocardium in acute ischemia are dynamic and complex, and the characteristics of myocardial tissue on cardiovascular magnetic resonance in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute myocardial infarction, relating these to global and segmental myocardial function at 6 months. Methods and Results-Cardiovascular magnetic resonance scans were performed on 30 patients with ST-elevation- myocardial infarction treated by primary percutaneous coronary intervention at each of 4 time points: 12 to 48 hours; 5 to 7 days; 14 to 17 days; and 6 months. All patients showed edema at 24 hours. The mean volume of edema (% left ventricle) was 37±16 at 24 hours and 39±17 at 1 week, with a reduction to 24±13 (P<0.01) by 2 weeks. Myocardial segments with edema also had increased signal on LGE at 24 hours (k=0.77; P<0.001). The volume of LGE decreased significantly between 24 hours and 6 months (27±15% versus 22±12%; P=0.002). Of segments showing LGE at 24 hours, 50% showed resolution by 6 months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P<0.0001). The area of LGE measured at 6 months correlated more strongly with troponin at 48 hours (r=0.9; P<0.01) than LGE at 24 hours (r=0.7). The difference in LGE between 24 hours and 6 months had profound effects on the calculation of salvage index (26±21% at 24 hours versus 42±23% at 6 months; P=0.02). Conclusions-Myocardial edema is maximal and constant over the first week after myocardial infarction, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium. © 2011 American Heart Association, Inc.

Ruparelia N, Digby JE, Choudhury RP. 2011. Effects of niacin on atherosclerosis and vascular function. Curr Opin Cardiol, 26 (1), pp. 66-70. | Show Abstract | Read more

PURPOSE OF REVIEW: Niacin has been used for more than 50 years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently, however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function, both 'lipid-targeted' and 'pleiotropic'. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action. RECENT FINDINGS: The identification of the GPR109A receptor has promoted a greater insight into niacin's mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role. SUMMARY: Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future, however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalize on the benefits more specifically and also more selectively, to avoid troublesome side-effects.

Owen DR, Lindsay AC, Choudhury RP, Fayad ZA. 2011. Imaging of atherosclerosis. Annu Rev Med, 62 (1), pp. 25-40. | Show Abstract | Read more

It is now well recognized that the atherosclerotic plaques responsible for thrombus formation are not necessarily those that impinge most on the lumen of the vessel. Nevertheless, clinical investigations for atherosclerosis still focus on quantifying the degree of stenosis caused by plaques. Many of the features associated with a high-risk plaque, including a thin fibrous cap, large necrotic core, macrophage infiltration, neovascularization, and intraplaque hemorrhage, can now be probed by novel imaging techniques. Each technique has its own strengths and drawbacks. In this article, we review the various imaging modalities used for the evaluation and quantification of atherosclerosis.

Karamitsos TD, Dall'Armellina E, Choudhury RP, Neubauer S. 2011. Ischemic heart disease: comprehensive evaluation by cardiovascular magnetic resonance. Am Heart J, 162 (1), pp. 16-30. | Show Abstract | Read more

Considerable technical advances over the past decade have increased the clinical application of cardiovascular magnetic resonance (CMR) imaging. A comprehensive CMR examination can accurately measure left and right ventricular size and function, identify the presence and extent of reversible versus irreversible myocardial injury, and detect inducible ischemia. Streamlined protocols allow such a CMR examination to be a time-efficient diagnostic tool in patients with coronary artery disease. Moreover, edema imaging with T2-weighted CMR allows the detection of acute coronary syndromes. In this review, we present the relevant CMR methods and discuss practical uses of CMR in acute and chronic ischemic heart disease.

Cited:

27

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Karamitsos TD, Dall'Armellina E, Choudhury RP, Neubauer S. 2011. Ischemic heart disease: Comprehensive evaluation by cardiovascular magnetic resonance American Heart Journal, 162 (1), pp. 16-30. | Show Abstract | Read more

Considerable technical advances over the past decade have increased the clinical application of cardiovascular magnetic resonance (CMR) imaging. A comprehensive CMR examination can accurately measure left and right ventricular size and function, identify the presence and extent of reversible versus irreversible myocardial injury, and detect inducible ischemia. Streamlined protocols allow such a CMR examination to be a time-efficient diagnostic tool in patients with coronary artery disease. Moreover, edema imaging with T2-weighted CMR allows the detection of acute coronary syndromes. In this review, we present the relevant CMR methods and discuss practical uses of CMR in acute and chronic ischemic heart disease. © 2011 Mosby, Inc.

Choudhury RP. 2011. Macrophage detection in aortic aneurysm: the heat is on. Arterioscler Thromb Vasc Biol, 31 (4), pp. 723-724. | Read more

McAteer MA, von Zur Muhlen C, Anthony DC, Sibson NR, Choudhury RP. 2011. Magnetic resonance imaging of brain inflammation using microparticles of iron oxide. Methods Mol Biol, 680 pp. 103-115. | Show Abstract | Read more

For molecular magnetic resonance imaging (mMRI), microparticles of iron oxide (MPIO) create potent hypointense contrast effects that extend a distance far exceeding their physical size. The potency of the contrast effects derive from their high iron content and are significantly greater than that of ultra-small particles of iron oxide (USPIO), commonly used for MRI. Due to their size and incompressible nature, MPIO are less susceptible to nonspecific vascular egress or uptake by endothelial cells. Therefore, MPIO may be useful contrast agents for detection of endovascular molecular targets by MRI. This Chapter describes the methodology of a novel, functional MPIO probe targeting vascular cell adhesion molecule-1 (VCAM-1), for detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Protocols are included for conjugation of MPIO to mouse monoclonal antibodies against VCAM-1 (VCAM-MPIO), the validation of VCAM-MPIO binding specificity to activated endothelial cells in vitro, and the application of VCAM-MPIO for in vivo targeted MRI of acute brain inflammation in mice. This functional molecular imaging tool may potentially accelerate accurate diagnosis of early cerebral vascular inflammation by MRI, and guide specific therapy.

Jefferson A, Wijesurendra RS, McAteer MA, Digby JE, Douglas G, Bannister T, Perez-Balderas F, Bagi Z, Lindsay AC, Choudhury RP. 2011. Molecular imaging with optical coherence tomography using ligand-conjugated microparticles that detect activated endothelial cells: Rational design through target quantification Atherosclerosis,

Sibson NR, Anthony DC, van Kasteren S, Dickens A, Perez-Balderas F, McAteer MA, Choudhury RP, Davis BG. 2011. Molecular MRI approaches to the detection of CNS inflammation. Methods Mol Biol, 711 pp. 379-396. | Show Abstract | Read more

Inflammation is a key component of many neurological diseases, yet our understanding of the contribution of these processes to tissue damage remains poor. For many such diseases, magnetic resonance imaging (MRI) has become the method of choice for clinical diagnosis. However, many of the MRI parameters that enable disease detection, such as passive contrast enhancement across a compromised blood-brain barrier, are weighted towards late-stage disease. Moreover, whilst these methods may report on disease severity, they are not able to provide information on either disease activity or the underlying molecular processes. There is a need, therefore, to develop methods that enable earlier disease detection, potentially long before clinical symptoms become apparent, together with identification of specific molecular processes that may guide specific therapy. This chapter describes the methodology for the synthesis and validation of two novel, functional MRI-detectable probes, based on microparticles of iron oxide (MPIO), which target endothelial adhesion molecules. These contrast agents enable the detection of acute brain inflammation in vivo, at a time when pathology is undetectable by conventional MRI. Such molecular MRI methods are opening new vistas for the acute diagnosis of CNS disease, together with the possibility for individually tailored therapy and earlier, more sensitive assessment of the efficacy of novel therapies.

Dall Armellina E, Choudhury RP. 2011. The role of cardiovascular magnetic resonance in patients with acute coronary syndromes. Prog Cardiovasc Dis, 54 (3), pp. 230-239. | Show Abstract | Read more

Cardiovascular magnetic resonance (CMR) imaging is a recognized technique for characterization of myocardial tissue in stable ischemic heart disease. In addition, CMR is emerging as a noninvasive imaging tool that can provide supporting information to guide treatment in acute coronary syndromes (ACSs). The advantages of using CMR acutely could potentially include triage/differential diagnosis in patients presenting with chest pain and troponin rise but without diagnostic electrocardiogram changes, assessment of severity of myocardial injury (irreversible vs reversible damage) in patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, and risk stratification and assessment of prognosis in patients with ACS. This review evaluates a potential clinical role of CMR in the acute setting, highlighting its advantages and limitations. This critical approach emphasizes areas of uncertainty and ongoing controversies but aims to equip the reader to evaluate the potential clinical application and the practicalities of CMR in patients presenting with ACS.

Jefferson A, Wijesurendra RS, Digby J, McAteer M, Choudhury RP. 2010. Binding Characteristics of Microparticles Targeted to E-Selectin versus VCAM-1 Under Conditions of Shear Stress: Implications for the Rational Design of Targeted Imaging Agents CIRCULATION, 122 (21),

Elkhawad M, Rudd JH, Sarov-Blat L, Marber M, Choudhury RP, Davies LC, Collier DJ, Cai G, Willette RN, Gleeson FV et al. 2010. Inhibition of p38 Mitogen-Activated Protein Kinase Attenuates Vascular and Systemic Inflammation in Patients with Atherosclerosis as Assessed by 18-F Fluorodeoxyglucose PET-CT CIRCULATION, 122 (21),

Lindsay AC, Biasiolli L, Knight S, Cunnington C, Davies R, Robson MD, Neubauer S, Kennedy J, Handa A, Choudhury RP. 2010. Non-Invasive Imaging Of Arterial Restenosis Using 3T Magnetic Resonance Imaging CIRCULATION, 122 (21),

McAteer MA, Mankia K, Hagen R, Stork L-AA, Schneider JE, Choudhury RP. 2010. Noninvasive Molecular Imaging of Differential Endothelial Adhesion Molecule Expression in Early Atherosclerosis Correlates With Plaque Macrophage Content in Apo E Knockout Mice CIRCULATION, 122 (21),

Dall'Armellina E, Karamitsos TD, Neubauer S, Choudhury RP. 2010. CMR for characterization of the myocardium in acute coronary syndromes. Nat Rev Cardiol, 7 (11), pp. 624-636. | Show Abstract | Read more

The utility of cardiac magnetic resonance imaging (CMR) as a diagnostic technique is well established. CMR enables tissue characterization, distinction between myocardial scar tissue and viable tissue, and evaluation of myocardial perfusion and contractile function. To date, CMR has been mostly applied in the assessment of stable disease; however, a role for CMR in the acute setting is also emerging. An accurate appraisal of the myocardium with CMR in the first hours after the onset of chest pain could provide supporting information to standard diagnostic tools, such as electrocardiography and measurement of blood biomarkers, which could help guide the selection of appropriate treatment. The aims of this integrated approach include positive identification of an ischemic syndrome, estimation of downstream areas at risk of damage, evaluation of epicardial artery patency and small vessel integrity, quantification of infarct size, and determination of myocardial function. This Review critically evaluates both established and emerging CMR techniques, and relates the imaging findings to the underlying pathophysiological processes in acute coronary syndromes. A more thorough understanding of CMR techniques will clarify their potential clinical applications and limitations, and assess the practicality of CMR in the setting of acute coronary syndromes, where early intervention is crucial to save myocardium at risk of irreversible injury.

Dall'Armellina E, Cuculi F, Choudhury RP, Neubauer S, Kharbanda RK. 2010. Embolic myocardial infarction in atrial fibrillation: multiple territory injury revealed by cardiac magnetic resonance. Eur Heart J, 31 (21), pp. 2624. | Read more

Taylor J, Choudhury R. 2010. Spotlight: Robin Choudhury, MA, DM, FACC CIRCULATION, 122 (12), pp. F67-F69.

Lee JM, Choudhury RP. 2010. Atherosclerosis regression and high-density lipoproteins. Expert Rev Cardiovasc Ther, 8 (9), pp. 1325-1334. | Show Abstract | Read more

Atherosclerosis regression has been demonstrated clearly in animal experimental models and, to a lesser extent, in human clinical studies. Imaging techniques for study of the arterial wall are playing a key role in promoting our appreciation of regression. LDL lowering remains the mainstay of current lipid treatment, but given the multiple antiatherosclerotic functions of HDL, including reverse cholesterol transport, agents that target HDL may represent the next generation of treatment for atherosclerotic disease. Currently available agents, including nicotinic acid, have documented antiatherosclerotic effects and trials examining clinical outcomes in the context of contemporary LDL treatment are now underway. Future approaches to HDL treatment may include cholesteryl ester transfer protein inhibitors and apolipoprotein A-I mimetics.

Hoyte LC, Brooks KJ, Nagel S, Akhtar A, Chen R, Mardiguian S, McAteer MA, Anthony DC, Choudhury RP, Buchan AM, Sibson NR. 2010. Molecular magnetic resonance imaging of acute vascular cell adhesion molecule-1 expression in a mouse model of cerebral ischemia. J Cereb Blood Flow Metab, 30 (6), pp. 1178-1187. | Show Abstract | Read more

The pathogenesis of stroke is multifactorial, and inflammation is thought to have a critical function in lesion progression at early time points. Detection of inflammatory processes associated with cerebral ischemia would be greatly beneficial in both designing individual therapeutic strategies and monitoring outcome. We have recently developed a new approach to imaging components of the inflammatory response, namely endovascular adhesion molecule expression on the brain endothelium. In this study, we show specific imaging of vascular cell adhesion molecule (VCAM)-1 expression in a mouse model of middle cerebral artery occlusion (MCAO), and a reduction in this inflammatory response, associated with improved behavioral outcome, as a result of preconditioning. The spatial extent of VCAM-1 expression is considerably greater than the detectable lesion using diffusion-weighted imaging (25% versus 3% total brain volume), which is generally taken to reflect the core of the lesion at early time points. Thus, VCAM-1 imaging seems to reveal both core and penumbral regions, and our data implicate VCAM-1 upregulation and associated inflammatory processes in the progression of penumbral tissue to infarction. Our findings indicate that such molecular magnetic resonance imaging (MRI) approaches could be important clinical tools for patient evaluation, acute monitoring of therapy, and design of specific treatment strategies.

Choudhury RP. 2010. Hyperlipidaemia and cardiovascular disease: low HDL-cholesterol as a therapeutic target in statin-treated patients: a role for nicotinic acid (niacin)? Curr Opin Lipidol, 21 (2), pp. 161-162. | Read more

Lee JM, Choudhury RP. 2010. Rheumatoid arthritis: RA--lowering cardiovascular risk with statins. Nat Rev Rheumatol, 6 (3), pp. 123-124. | Read more

MacIntosh BJ, Lindsay AC, Kylintireas I, Kuker W, Günther M, Robson MD, Kennedy J, Choudhury RP, Jezzard P. 2010. Multiple inflow pulsed arterial spin-labeling reveals delays in the arterial arrival time in minor stroke and transient ischemic attack. AJNR Am J Neuroradiol, 31 (10), pp. 1892-1894. | Show Abstract | Read more

Our purpose was to use multiple inflow pulsed ASL to investigate whether hemodynamic AAT information is sensitive to hemispheric asymmetry in acute ischemia. The cohorts included 15 patients with acute minor stroke or TIA and 15 age-matched controls. Patients were scanned by using a stroke MR imaging protocol at a median time of 74 hours. DWI lesion volumes were small and functional impairment was low; however, perfusion abnormalities were evident. Prolonged AAT values were more likely to reside in the affected hemisphere (significant when compared with controls, P < .048). An advantage of this ASL technique is the ability to use AAT information in addition to CBF to characterize ischemia.

McAteer MA, Akhtar AM, von Zur Muhlen C, Choudhury RP. 2010. An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis, 209 (1), pp. 18-27. | Show Abstract | Read more

The rapidly evolving field of molecular imaging promises important advances in the diagnosis, characterization and pharmacological treatment of vascular disease. Magnetic resonance imaging (MRI) provides a modality that is well suited to vascular imaging as it can provide anatomical, structural and functional data on the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specific molecules, cells and biological processes. This article will discuss one such approach, using microparticles of iron oxide (MPIO). MPIO have been shown to create highly conspicuous contrast effects on T(2)(*)-weighted MR images. We have developed a range of novel ligand-conjugated MPIO for molecular MRI of endothelial adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and P-selectin expressed in vascular inflammation, as well as activated platelet thrombosis. This review discusses the application of ligand-targeted MPIO for in vivo molecular MRI in a diverse range of vascular disease models including acute vascular inflammation, atherosclerosis, thrombosis, ischemia-reperfusion injury and ischemic stroke. The exceptionally conspicuous contrast effects of ligand-conjugated MPIO provide a versatile and sensitive tool for quantitative vascular molecular imaging that could refine diagnosis and measure response to treatment. The potential for clinical translation of this new class of molecular contrast agent for clinical imaging of vascular syndromes is discussed.

Lindsay AC, Murray SW, Choudhury RP. 2010. Contemporary coronary imaging from patient to plaque: Part 4 magnetic resonance imaging British Journal of Cardiology, 17 (6), pp. 290-292. | Show Abstract

In recent years a large amount of research has focused on developing both invasive and non-invasive methods of assessing atherosclerosis. In this regard, magnetic resonance imaging (MRI) is safe, noninvasive, requires no ionising radiation, and is capable of giving high-resolution images of atherosclerotic plaque. As a result, MRI has been extensively applied to imaging of the vascular system - in particular, the carotid arteries - where it has been shown to have the ability to not only accurately quantify the extent of atherosclerotic plaque disease, but also to identify several compositional features suggestive of plaque vulnerability. Imaging of the relatively small coronary arteries has, until now, been limited by the problems of cardiac and respiratory motion, however, more recently, technological advancements have allowed more detailed plaque information to be acquired. This article will review the origins of MRI imaging of atherosclerotic disease, its current status, and its potential future applications.

Akhtar AM, Schneider JE, Chapman SJ, Jefferson A, Digby JE, Mankia K, Chen Y, McAteer MA, Wood KJ, Choudhury RP. 2010. In vivo quantification of VCAM-1 expression in renal ischemia reperfusion injury using non-invasive magnetic resonance molecular imaging. PLoS One, 5 (9), pp. e12800. | Show Abstract | Read more

RATIONALE AND OBJECTIVE: Vascular cell adhesion molecule-1 (VCAM-1) is upregulated in ischemia reperfusion injury (IRI), persisting after restoration of blood flow. We hypothesized that microparticles of iron oxide targeting VCAM-1 (VCAM-MPIO) would depict "ischemic memory" and enable in vivo assessment of VCAM-1 expression. METHODOLOGY AND FINDINGS: Mice subject to unilateral, transient (30 minutes) renal ischemia and subsequent reperfusion received intravenous VCAM-MPIO (4.5 mg iron/kg body weight). Contrast agent bound rapidly (<30 minutes) in IRI-kidneys and appeared as intensely low signal areas by MRI in vivo. Automated segmentation and quantification yielded MPIO contrast volumes of 5991±354×10(6) µm(3) in IRI vs. 87±7×10(6) µm(3) in kidneys with no surgical intervention (P<0.001); 90±8×10(6) µm(3) in IRI kidneys exposed to control (IgG-MPIO) and 625±80×10(6) µm(3), in IRI kidneys pre-treated with a blocking dose of VCAM-1 antibody (P<0.001). In keeping with quantitative MRI data, VCAM-1 mRNA expression in IRI was 65-fold higher than in kidneys without surgical intervention (3.06±0.63 vs. 0.05±0.02, P<0.001). Indeed VCAM-1 mRNA expression and VCAM-MPIO contrast volume were highly correlated (R(2)=0.901, P<0.01), indicating that quantification of contrast volume reflected renal VCAM-1 transcription. Serial imaging showed VCAM-MPIO accumulation at target within 30 minutes, persisting for ≥90 minutes, while unbound VCAM-MPIO was cleared rapidly from blood, with sequestration by mac-3 positive Kupffer cells in the liver and monocyte/macrophages in the spleen. CONCLUSIONS: (1) VCAM-MPIO detected VCAM-1 expression and defined its 3-dimensional distribution, revealing "ischemic memory" in renal IRI; (2) automated volumetric quantification of VCAM-MPIO accurately reflected tissue levels of VCAM-1 mRNA; and (3) VCAM-MPIO bound rapidly to target with active sequestration of unbound MPIO in the liver and spleen.

Lee JMS, Choudhury RP. 2010. Rheumatoid arthritis: RA—lowering cardiovascular risk with statins Nature Reviews Rheumatology, 6 (3), pp. 123-124. | Read more

Wijesurendra RS, Jefferson A, Choudhury RP. 2010. Target: ligand interactions of the vascular endothelium. Implications for molecular imaging in inflammation. Integr Biol (Camb), 2 (10), pp. 467-482. | Show Abstract | Read more

Molecular imaging refers to the non-invasive visualisation of biological processes at the molecular and cellular levels within a living organism, and offers a wide range of potential benefits to both clinical medicine and research into novel therapeutic agents. Inflammation plays an important role in a wide variety of pathological processes and imaging the molecular and cellular machinery that underlies chronic inflammation is attractive and feasible. In this review, we present an overview of molecular imaging of inflammation. We start by characterising molecular and cellular events in early inflammation, identifying current and potential future imaging targets. We focus on the imaging of endothelial cells, which mediate the important first steps in inflammation in any tissue, are readily accessible to imaging probes and which present an approach that can be applied across multiple modalities. We then review the generic requirements for imaging contrast agents and focus on the important considerations in respect of ligands, ligand-target interactions and contrast vehicles. We aim to provide an integrated view of current progress with a focus on promising recent developments in experimental and translational molecular imaging.

Jackson CE, Shirodaria CC, Lee JM, Francis JM, Choudhury RP, Channon KM, Noble JA, Neubauer S, Robson MD. 2009. Reproducibility and accuracy of automated measurement for dynamic arterial lumen area by cardiovascular magnetic resonance. Int J Cardiovasc Imaging, 25 (8), pp. 797-808. | Show Abstract | Read more

Bright blood cine images acquired using magnetic resonance imaging contain simple contrast that is tractable to automated analysis, which can be used to derive a measure of arterial compliance that is known to correlate with disease severity. The purpose of this work was to evaluate whether automated methods could be used reliably on a clinically relevant population, and to assess the precision of these measurements so that it could be compared with expert manual assessment. In this paper we apply an algorithm similar to that used by Krug et al., and the exact processing steps are described in detail to allowing easy reproduction of our methods. Phantoms of different sizes have been assessed and the MRI measurements are found to correlate well (r = 0.9998) with physical measurement. Reproducibility assessment was performed on 33 CAD subjects in three anatomical locations along the aorta. Six normal volunteers and ten patients with more severe aortic plaques were investigated to assess reproducibility and sensitivity to pathological changes, respectively. The performance was also assessed on carotid vessels in 40 patients with known arterial plaques. In the human aorta the method is found to be robust (failing in only 7% of cases, all due to clear errors with image acquisition), and to be quantifiably consistent with expert clinical measurement, but showing smaller errors than that approach [<1.21% (5.62 mm(2)) manual vs. <0.58% (2.71 mm(2)) automated, for the aortic area] and with reduced bias, and operated correctly in advanced disease. We have proved over a large number of subjects the superiority of this automated method for evaluating dynamic area changes over the Gold-standard manual approach.

Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, Digby JE, Bannister T, Handa A, Wiesmann F et al. 2009. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol, 54 (19), pp. 1787-1794. | Show Abstract | Read more

OBJECTIVES: Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function. BACKGROUND: NA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment. METHODS: We performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year. RESULTS: NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: -1.64 mm(2) [95% confidence interval: -3.12 to -0.16]; p = 0.03). Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for NA versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = -0.5, p = 0.02 for NA). CONCLUSIONS: In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531).

Kylintireas I, Craig S, Nethononda MR, Kohler M, Francis JM, Choudhury RP, Stradling J, Neubauer S. 2009. Increased obstructive sleep apnoea severity is associated with aortic distensibility reduction and atheroma burden increase EUROPEAN HEART JOURNAL, 30 pp. 744-744.

Kylintireas I, Cunnington C, Lazdam M, Diesch J, Trevitt C, Bechar I, Francis JM, Choudhury RP, Neubauer S, Leeson P, Med DC. 2009. Cardiovascular magnetic resonance of sub-clinical carotid atherosclerosis in young adults at low risk for cardiovascular disease: relation to abdominal adiposity EUROPEAN HEART JOURNAL, 30 pp. 654-654.

Digby JE, McNeill E, Dyar OJ, Lam V, Greaves DR, Choudhury RP. 2010. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. Atherosclerosis, 209 (1), pp. 89-95. | Show Abstract | Read more

OBJECTIVE: A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin. METHODS AND RESULTS: TNF-alpha treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9+/-3.3-fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24+/-1.2-fold, P<0.001), 'regulated upon activation, normal T cell expressed and secreted' (RANTES) (500+/-55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200+/-70-fold, P<0.05). The addition of NA (10(-4)M) to TNF-alpha-treated adipocytes attenuated expression of fractalkine (50+/-12%, P<0.01); MCP-1 (50+/-6%, P<0.01), RANTES (70+/-3%, P<0.01) and iNOS (60+/-16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27+/-3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10(-6)-10(-3)M) increased, in a dose-dependent manner, mRNA of the atheroprotective hormone adiponectin (3-5-fold n=6, P<0.01). CONCLUSIONS: NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new "pleiotropic" role for NA.

Digby JE, Lee JM, Choudhury RP. 2009. Nicotinic acid and the prevention of coronary artery disease. Curr Opin Lipidol, 20 (4), pp. 321-326. | Show Abstract | Read more

PURPOSE OF REVIEW: Nicotinic acid is the most potent treatment clinically available for lowering LDL cholesterol and VLDL cholesterol and raising HDL cholesterol. The strong inverse relationship between coronary heart disease risk and HDL cholesterol at all levels of LDL cholesterol has, therefore, given renewed emphasis on the therapeutic potential of niacin. The purpose of this review is to evaluate advances in the elucidation of mechanisms by which nicotinic acid affects the lipoprotein profile and, more recently, emerging evidence of nonlipid-mediated anti-inflammatory effects. RECENT FINDINGS: Niacin treatment reduces cardiovascular events and the progression of atherosclerosis. Identification of G-protein-coupled receptor 109A as the receptor for nicotinic acid has provided insights into how treatment with this compound leads to a favourable alteration in HDL cholesterol. In addition, evidence of nonlipid-mediated anti-inflammatory effects of nicotinic acid such as direct enhancement of adiponectin secretion demonstrates a novel atheroprotective role. SUMMARY: Whether nicotinic acid use becomes routine in the treatment of atherosclerosis is likely to be determined by the results of two ongoing clinical outcome trials. In addition, further research is required to explore the 'pleiotropic' effects of nicotinic acid and will ultimately provide a platform for the development of newer molecules that are potentially beneficial but without the well known side-effects.

McAteer MA, Choudhury RP. 2009. Chapter 4 - Applications of nanotechnology in molecular imaging of the brain. Prog Brain Res, 180 (C), pp. 72-96. | Show Abstract | Read more

Rapid advances in the field of nanotechnology promise revolutionary improvements in the diagnosis and therapy of neuroinflammatory disorders. An array of iron oxide nano- and microparticle agents have been developed for in vivo molecular magnetic resonance imaging (mMRI) of cerebrovascular endothelial targets, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, and the glycoprotein receptor GP IIb/IIIa expressed on activated platelets. Molecular markers of glioma cells, such as matrix metalloproteinase-2 (MMP-2), and markers for brain tumor angiogenesis, such as alpha (v) beta (3) integrin (alpha(v)beta(3)), have also been successfully targeted using nanoparticle imaging probes. This chapter provides an overview of targeted, iron oxide nano- and microparticles that have been applied for in vivo mMRI of the brain in experimental models of multiple sclerosis (MS), brain ischemia, cerebral malaria (CM), brain cancer, and Alzheimer's disease. The potential of targeted nanoparticle agents for application in clinical imaging is also discussed, including multimodal and therapeutic approaches.

Choudhury RP, Fisher EA. 2009. Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation. Arterioscler Thromb Vasc Biol, 29 (7), pp. 983-991. | Show Abstract | Read more

Appreciation of the molecular and cellular processes of atherosclerosis, thrombosis, and vascular inflammation has identified new targets for imaging. The common goals of molecular imaging approaches are to accelerate and refine diagnosis, provide insights that reveal disease diversity, guide specific therapies, and monitor the effects of those therapies. Here we undertake a comparative analysis of imaging modalities that have been used in this disease area. We consider the elements of contrast agents, emphasizing how an understanding of the biology of atherosclerosis and its complications can inform optimal design. We address the potential and limitations of current contrast approaches in respect of translation to clinically usable agents and speculate on future applications.

von zur Muhlen C, Peter K, Ali ZA, Schneider JE, McAteer MA, Neubauer S, Channon KM, Bode C, Choudhury RP. 2009. Visualization of activated platelets by targeted magnetic resonance imaging utilizing conformation-specific antibodies against glycoprotein IIb/IIIa. J Vasc Res, 46 (1), pp. 6-14. | Show Abstract | Read more

Ruptured atherosclerotic plaques, lined with activated platelets, constitute an attractive target for magnetic resonance imaging (MRI). This study evaluated whether microparticles of iron oxide (MPIO) targeting ligand-induced binding sites (LIBS) on the activated conformation of glycoprotein IIb/IIIa could be used to image platelets. MPIO (size: 1 microm) were conjugated to anti-LIBS or control single-chain antibody. Following guidewire injury to mouse femoral artery, platelet adhesion was present after 24 h. Mice were perfused with anti-LIBS-MPIO (or control MPIO) via the left ventricle and 11.7-tesla MRI was performed on femoral arteries ex vivo. A 3D gradient echo sequence attained an isotropic resolution of 25 microm. MPIO binding, quantified by MRI, was 4-fold higher with anti-LIBS-MPIO in comparison to control MPIO (p < 0.01). In histological sections, low signal zones on MRI and MPIO correlated strongly (R(2) = 0.72; p < 0.001), indicating accurate MR quantification. In conclusion, anti-LIBS-MPIO bind to activated platelets in mouse arteries, providing a basis for the use of function-specific single-chain antibody-MPIO conjugates for molecular MRI, and represent the first molecular imaging of a conformational change in a surface receptor. This presents an opportunity to specifically image activated platelets involved in acute atherothrombosis with MRI.

Lee JM, Lindsay AC, Kylintireas I, Choudhury RP. 2008. Atherosclerosis regression. Curr Treat Options Cardiovasc Med, 10 (3), pp. 187-194. | Show Abstract | Read more

Atherosclerosis follows the deposition, retention, and oxidative modification of lipoproteins, especially low-density lipoprotein (LDL) in the walls of large arteries. Uptake of oxidized LDL results in the formation of macrophage foam cells. Proliferation of vascular smooth muscle cells and secretion of extracellular matrix contribute "fibrous" components of the plaque, whereas ongoing accumulation of lipid and inflammatory cell debris forms the necrotic lipid core of the mature atherosclerotic plaque. Both the size and composition of plaques determine the clinical course. In particular, a large lipid core, thin fibrous cap, dense inflammatory cell infiltrate, and proteolytic enzyme activity are associated with adverse risk. Atherosclerosis has often been considered a relentlessly progressive disease. However, new imaging techniques that can quantify plaque burden and provide insights into some of the specific plaque components have allowed regression to be mapped for the first time. In this article, drugs targeting atherosclerosis that have potential or proven benefit in atherosclerosis regression are discussed.

Lee JM, Wiesmann F, Shirodaria C, Leeson P, Petersen SE, Francis JM, Jackson CE, Robson MD, Neubauer S, Channon KM, Choudhury RP. 2008. Early changes in arterial structure and function following statin initiation: quantification by magnetic resonance imaging. Atherosclerosis, 197 (2), pp. 951-958. | Show Abstract | Read more

Effective LDL-cholesterol (LDL-C) reduction improves vascular function and can bring about regression of atherosclerosis. Alterations in endothelial function can occur rapidly, but changes in atherosclerosis are generally considered to occur more slowly. Vascular magnetic resonance imaging (MRI) is a powerful technique for accurate non-invasive assessment of central and peripheral arteries at multiple anatomical sites. We report the changes in atherosclerosis burden and arterial function in response to open label statin treatment, in 24 statin-naïve newly diagnosed stable coronary artery disease patients. Patients underwent MRI before, and 3 and 12 months after commencing treatment. Mean LDL-C fell by 37% to 70.8 mg/dL (P<0.01). The plaque index (normalised vessel wall area) showed reductions in the aorta (2.3%, P<0.05) and carotid (3.1%, P<0.05) arteries at 3 months. Early reductions in atherosclerosis of aorta and carotid observed at 3 months were significantly correlated with later change at 12 months (R(2)=0.50, P<0.001; R(2)=0.22, P<0.05, respectively). Improvements in aortic distensibility and brachial endothelial function that were apparent after 3 months treatment were sustained at the 12-month time point.

von Zur Muhlen C, von Elverfeldt D, Choudhury RP, Ender J, Ahrens I, Schwarz M, Hennig J, Bode C, Peter K. 2008. Functionalized magnetic resonance contrast agent selectively binds to glycoprotein IIb/IIIa on activated human platelets under flow conditions and is detectable at clinically relevant field strengths. Mol Imaging, 7 (2), pp. 59-67. | Show Abstract | Read more

Recent progress in molecular magnetic resonance imaging (MRI) provides the opportunity to image cells and cellular receptors using microparticles of iron oxide (MPIOs). However, imaging targets on vessel walls remains challenging owing to the quantity of contrast agents delivered to areas of interest under shear stress conditions. We evaluated ex vivo binding characteristics of a functional MRI contrast agent to ligand-induced binding sites (LIBSs) on activated glycoprotein IIb/IIIa receptors of human platelets, which were lining rupture-prone atherosclerotic plaques and could therefore facilitate detection of platelet-mediated pathology in atherothrombotic disease. MPIOs were conjugated to anti-LIBS single-chain antibodies (LIBS-MPIO) or control antibodies (control MPIO). Ex vivo binding to human platelet-rich clots in a dose-dependent manner was confirmed on a 3 T clinical MRI scanner and by histology (p < .05 for LIBS-MPIO vs control MPIO). By using a flow chamber setup, significant binding of LIBS-MPIO to a platelet matrix was observed under venous and arterial flow conditions, but not for control MPIO (p < .001). A newly generated MRI contrast agent detects activated human platelets at clinically relevant magnetic field strengths and binds to platelets under venous and arterial flow conditions, conveying high payloads of contrast to specific molecular targets. This may provide the opportunity to identify vulnerable, rupture-prone atherosclerotic plaques via noninvasive MRI.

von Zur Muhlen C, Sibson NR, Peter K, Campbell SJ, Wilainam P, Grau GE, Bode C, Choudhury RP, Anthony DC. 2008. A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI. J Clin Invest, 118 (3), pp. 1198-1207. | Show Abstract | Read more

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.

Lindsay AC, Choudhury RP. 2008. Form to function: current and future roles for atherosclerosis imaging in drug development. Nat Rev Drug Discov, 7 (6), pp. 517-529. | Show Abstract | Read more

There is a pressing need for robust imaging markers to assist in the development of drugs for the treatment of atherosclerosis. Conventional imaging methods provide quantitative and morphological data but may be inadequate for assessing a new generation of therapies that modify plaque biology directly. Here, we compare the main imaging modalities used to image atherosclerosis in the clinical-trial setting, and assess their ability to predict clinical outcomes for a given sample size. We consider how emerging molecular and cellular imaging techniques could offer the possibility to quantify changes in biological function at the level of the plaque, even without gross structural change.

von zur Muhlen C, von Elverfeldt D, Moeller JA, Choudhury RP, Paul D, Hagemeyer CE, Olschewski M, Becker A, Neudorfer I, Bassler N et al. 2008. Magnetic resonance imaging contrast agent targeted toward activated platelets allows in vivo detection of thrombosis and monitoring of thrombolysis. Circulation, 118 (3), pp. 258-267. | Show Abstract | Read more

BACKGROUND: Platelets are the key to thrombus formation and play a role in the development of atherosclerosis. Noninvasive imaging of activated platelets would be of great clinical interest. Here, we evaluate the ability of a magnetic resonance imaging (MRI) contrast agent consisting of microparticles of iron oxide (MPIOs) and a single-chain antibody targeting ligand-induced binding sites (LIBS) on activated glycoprotein IIb/IIIa to image carotid artery thrombi and atherosclerotic plaques. METHODS AND RESULTS: Anti-LIBS antibody or control antibody was conjugated to 1-microm MPIOs (LIBS MPIO/control MPIO). Nonocclusive mural thrombi were induced in mice with 6% ferric chloride. MRI (at 9.4 T) was performed once before and repeatedly in 12-minute-long sequences after LIBS MPIO/control MPIO injection. After 36 minutes, a significant signal void, corresponding to MPIO accumulation, was observed with LIBS MPIOs but not control MPIOs (P<0.05). After thrombolysis, in LIBS MPIO-injected mice, the signal void subsided, indicating successful thrombolysis. On histology, the MPIO content of the thrombus, as well as thrombus size, correlated significantly with LIBS MPIO-induced signal void (both P<0.01). After ex vivo incubation of symptomatic human carotid plaques, MRI and histology confirmed binding to areas of platelet adhesion/aggregation for LIBS MPIOs but not for control MPIOs. CONCLUSIONS: LIBS MPIOs allow in vivo MRI of activated platelets with excellent contrast properties and monitoring of thrombolytic therapy. Furthermore, activated platelets were detected on the surface of symptomatic human carotid plaques by ex vivo MRI. This approach represents a novel noninvasive technique allowing the detection and quantification of platelet-containing thrombi.

McAteer MA, Schneider JE, Ali ZA, Warrick N, Bursill CA, von zur Muhlen C, Greaves DR, Neubauer S, Channon KM, Choudhury RP. 2008. Magnetic resonance imaging of endothelial adhesion molecules in mouse atherosclerosis using dual-targeted microparticles of iron oxide. Arterioscler Thromb Vasc Biol, 28 (1), pp. 77-83. | Show Abstract | Read more

OBJECTIVE: Microparticles of iron oxide (MPIO) distort magnetic field creating marked contrast effects far exceeding their physical size. We hypothesized that antibody-conjugated MPIO would enable magnetic resonance imaging (MRI) of endothelial cell adhesion molecules in mouse atherosclerosis. METHODS AND RESULTS: MPIO (4.5 microm) were conjugated to monoclonal antibodies against vascular cell adhesion molecule-1 (VCAM-MPIO) or P-selectin (P-selectin-MPIO). In vitro, VCAM-MPIO bound, in dose-dependent manner, to tumor necrosis factor (TNF)-alpha stimulated sEND-1 endothelial cells, as quantified by light microscopy (R2=0.94, P=0.03) and by MRI (R2=0.98, P=0.01). VCAM-MPIO binding was blocked by preincubation with soluble VCAM-1. To mimic leukocyte binding, MPIO targeting both VCAM-1 and P-selectin were administered in apolipoprotein E-/- mice. By light microscopy, dual-targeted MPIO binding to endothelium overlying aortic root atherosclerosis was 5- to 7-fold more than P-selectin-MPIO (P<0.05) or VCAM-MPIO (P<0.01) alone. Dual-targeted MPIO, injected intravenously in vivo bound aortic root endothelium and were quantifiable by MRI ex vivo (3.5-fold increase versus control; P<0.01). MPIO were well-tolerated in vivo, with sequestration in the spleen after 24 hours. CONCLUSIONS: Dual-ligand MPIO bound to endothelium over atherosclerosis in vivo, under flow conditions. MPIO may provide a functional MRI probe for detecting endothelial-specific markers in a range of vascular pathologies.

McAteer MA, Sibson NR, von Zur Muhlen C, Schneider JE, Lowe AS, Warrick N, Channon KM, Anthony DC, Choudhury RP. 2007. In vivo magnetic resonance imaging of acute brain inflammation using microparticles of iron oxide. Nat Med, 13 (10), pp. 1253-1258. | Show Abstract | Read more

Multiple sclerosis is a disease of the central nervous system that is associated with leukocyte recruitment and subsequent inflammation, demyelination and axonal loss. Endothelial vascular cell adhesion molecule-1 (VCAM-1) and its ligand, alpha4beta1 integrin, are key mediators of leukocyte recruitment, and selective inhibitors that bind to the alpha4 subunit of alpha4beta1 substantially reduce clinical relapse in multiple sclerosis. Urgently needed is a molecular imaging technique to accelerate diagnosis, to quantify disease activity and to guide specific therapy. Here we report in vivo detection of VCAM-1 in acute brain inflammation, by magnetic resonance imaging in a mouse model, at a time when pathology is otherwise undetectable. Antibody-conjugated microparticles carrying a large amount of iron oxide provide potent, quantifiable contrast effects that delineate the architecture of activated cerebral blood vessels. Their rapid clearance from blood results in minimal background contrast. This technology is adaptable to monitor the expression of endovascular molecules in vivo in various pathologies.

Cheng ASH, Pegg TJ, Karamitsos TD, Robson MD, Searle N, Jerosch-Herold M, Choudhury RP, Banning AP, Neubauer S, Selvanayagam JB, Reson OCCM. 2007. The utility of cardiovascular magnetic resonance perfusion imaging at 3 Tesla for detection of coronary artery disease: a comparison with 1.5 Tesla EUROPEAN HEART JOURNAL, 28 pp. 275-275.

Cheng AS, Pegg TJ, Karamitsos TD, Searle N, Jerosch-Herold M, Choudhury RP, Banning AP, Neubauer S, Robson MD, Selvanayagam JB. 2007. Cardiovascular magnetic resonance perfusion imaging at 3-tesla for the detection of coronary artery disease: a comparison with 1.5-tesla. J Am Coll Cardiol, 49 (25), pp. 2440-2449. | Show Abstract | Read more

OBJECTIVES: This study was designed to establish the diagnostic accuracy of cardiovascular magnetic resonance (CMR) perfusion imaging at 3-Tesla (T) in suspected coronary artery disease (CAD). BACKGROUND: Myocardial perfusion imaging is considered one of the most compelling applications for CMR at 3-T. The 3-T systems provide increased signal-to-noise ratio and contrast enhancement (compared with 1.5-T), which can potentially improve spatial resolution and image quality. METHODS: Sixty-one patients (age 64 +/- 8 years) referred for elective diagnostic coronary angiography (CA) for investigation of exertional chest pain were studied (before angiogram) with first-pass perfusion CMR at both 1.5- and 3-T and at stress (140 microg/kg/min intravenous adenosine, Adenoscan, Sanofi-Synthelabo, Guildford, United Kingdom) and rest. Four short-axis images were acquired during every heartbeat using a saturation recovery fast-gradient echo sequence and 0.04 mmol/kg Gd-DTPA bolus injection. Quantitative CA served as the reference standard. Perfusion deficits were interpreted visually by 2 blinded observers. We defined CAD angiographically as the presence of > or =1 stenosis of > or =50% diameter in any of the main epicardial coronary arteries or their branches with a diameter of > or =2 mm. RESULTS: The prevalence of CAD was 66%. All perfusion images were found to be visually interpretable for diagnosis. We found that 3-T CMR perfusion imaging provided a higher diagnostic accuracy (90% vs. 82%), sensitivity (98% vs. 90%), specificity (76% vs. 67%), positive predictive value (89% vs. 84%), and negative predictive value (94% vs. 78%) for detection of significant coronary stenoses compared with 1.5-T. The diagnostic performance of 3-T perfusion imaging was significantly greater than that of 1.5-T in identifying both single-vessel disease (area under receiver-operator characteristic [ROC] curve: 0.89 +/- 0.05 vs. 0.70 +/- 0.08; p < 0.05) and multivessel disease (area under ROC curve: 0.95 +/- 0.03 vs. 0.82 +/- 0.06; p < 0.05). There was no difference between field strengths for the overall detection of coronary disease (area under ROC curve: 0.87 +/- 0.05 vs. 0.78 +/- 0.06; p = 0.23). CONCLUSIONS: Our study showed that 3-T CMR perfusion imaging is superior to 1.5-T for prediction of significant single- and multi-vessel coronary disease, and 3-T may become the preferred CMR field strength for myocardial perfusion assessment in clinical practice.

Lee JM, Shirodaria C, Jackson CE, Robson MD, Antoniades C, Francis JM, Wiesmann F, Channon KM, Neubauer S, Choudhury RP. 2007. Multi-modal magnetic resonance imaging quantifies atherosclerosis and vascular dysfunction in patients with type 2 diabetes mellitus. Diab Vasc Dis Res, 4 (1), pp. 44-48. | Show Abstract | Read more

Vascular magnetic resonance imaging (MRI) is emerging as a powerful research tool. We studied 18 patients with type 2 diabetes mellitus and 20 controls (all with coronary artery disease). MRI measured distensibility, pulse wave velocity (PWV) and atherosclerosis in the aorta, and brachial artery flow-mediated dilatation (FMD). Patients with diabetes showed lower aortic distensibility (2.1 x 10(-3) vs . 3.5 x 10(-3) mmHg-1, p<0.01), faster PWV (8.8 vs ., 6.2 m/s, p<0.01) and impaired FMD (8.5% vs . 13.8%, p<0.05). Diabetes was an independent negative predictor of distensibility. Aortic atherosclerosis was similar in the two groups. There was a negative correlation between aortic distensibility and atherosclerosis in control subjects only, suggesting that other factors such as protein cross-linking may explain lower aortic distensibility in diabetes. MRI provides comprehensive vascular phenotyping in patients with type 2 diabetes and is likely to be useful in studies of disease progression and drug therapy.

van Gaal WJ, Choudhury RP, Porto I, Channon K, Banning A, Dzavik V, Ramsamujh R, Bui S, Blackman DJ. 2007. Prediction of distal embolization during percutaneous coronary intervention in saphenous vein grafts. Am J Cardiol, 99 (5), pp. 603-606. | Show Abstract | Read more

Distal protection devices have been proved to decrease distal embolization and improve outcome in unselected patients undergoing percutaneous coronary intervention (PCI) in saphenous vein grafts (SVGs). However, it remains uncertain whether distal protection is necessary in all patients. We investigated whether clinical or angiographic variables can predict distal embolization and, hence, need for a distal protection device. Fifty-eight consecutive SVGs that underwent PCI with a FilterWire distal protection device were studied. After the procedure, the FilterWire was fixed in formalin and photographed, and embolic debris area (square millimeters) was quantified by semi-automated edge-detection analysis. Debris area was correlated with 6 prespecified variables: clinical presentation, SVG age, reference lumen diameter, plaque volume, SVG degeneracy, and presence of a filling defect. Embolic debris was identified in 57 of 58 grafts (98%). Median debris area was 4.0 mm(2) (range 0.0 to 25.1). None of the prespecified variables predicted the occurrence of distal embolization or the amount of captured embolic debris. In conclusion, distal embolization during SVG PCI is universal. Embolic burden cannot be predicted by clinical or angiographic variables, and embolic protection should be used in all patients.

Choudhury RP. 2007. Atherosclerosis and thrombosis: identification of targets for magnetic resonance imaging. Top Magn Reson Imaging, 18 (5), pp. 319-327. | Show Abstract | Read more

Imaging techniques are needed that will allow earlier and more refined diagnosis, guide targeted treatment in individual patients and monitor response to that treatment. Magnetic resonance imaging is well-suited to these tasks as it can provide anatomical, structural, and functional data on the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specific molecules, cells, and biological processes. This article will consider the pathogenesis of atherosclerosis and systematically identify biologically relevant targets for imaging at different stages of disease process.

Lee JM, Choudhury RP. 2007. Prospects for atherosclerosis regression through increase in high-density lipoprotein and other emerging therapeutic targets. Heart, 93 (5), pp. 559-564. | Show Abstract | Read more

In a process often seen as progressive and irreversible, deposition and retention of lipoproteins and the consequent inflammatory reaction result in the accumulation of atherosclerotic plaques from an early age. However, striking effects observed in experimental models support the concept that atherosclerosis can regress. This is often accompanied by changes in plaque composition favouring stability and decreased likelihood of rupture. Large clinical trials have established the value of low-density lipoprotein cholesterol reduction with statin treatment, although this may prevent no more than 30% of all cardiovascular events, and the magnitude of effect on plaque regression seems relatively modest. High-density lipoprotein cholesterol (HDL-C) is well recognised as an important and independent protective factor, although treatment options to increase HDL-C have until now been limited. The recent emergence of new treatments will probably establish increased HDL-C as another important strategy in antiatherosclerosis treatment. Beyond HDL-C increases, further appreciation of mechanisms of cellular lipid homoeostasis and regulation of gene transcription have revealed new targets for atherosclerosis treatment. This review considers emerging approaches to plaque regression together with some of the parallel developments in imaging technology that will improve our appreciation of response to treatment.

Porto I, Choudhury RP, Pillay P, Burzotta F, Trani C, Niccoli G, Blackman DJ, Channon KM, Banning AP. 2006. Filter no reflow during percutaneous coronary interventions using the Filterwire distal protection device. Int J Cardiol, 109 (1), pp. 53-58. | Show Abstract | Read more

BACKGROUND: Distal protection devices are increasingly used to prevent embolization during percutaneous coronary interventions (PCI) in saphenous vein grafts (SVG) and native coronary arteries (NV). During interventions with the Filterwire device we have observed reduced flow that is reversible following removal of the filter (filter no reflow, FNR), which might be erroneously interpreted as true no reflow and might be associated with reduced capture efficiency of the basket. METHODS: We analyzed the incidence of FNR in 58 patients (60 lesions) at high risk of embolization undergoing PCI of either a SVG or a NV using the Filterwire (Boston Scientific, Natick, MA). Qualitative and quantitative angiographic analysis was performed, and the volume of collected debris was estimated using a photographic technique. RESULTS: In our population, about 1/3 of the cases showed FNR, which was associated with angiographically visible filling defects within the basket, indicating macroembolism. However some patients (especially those undergoing vein graft interventions) showed filling defects without FNR, and some others FNR without filling defects. Thus we tried to understand the predictors of FNR: FNR was associated with higher amount of collected debris (36.97 +/- 42.98 mm(3) vs. 11.31 +/- 18.47 mm(3), p = 0.005), was neither prevented by abciximab, nor predicted by high thrombotic burden, increasing stent volume or need for predilatation. When patient with and without angiographically evident macroembolisation were separately analyzed, a linear correlation of FNR with the quantity of debris was only apparent in the macroembolization group. CONCLUSIONS: Interventionalists should be aware of the "Filter No Reflow", a common but reversible angiographic complication when the Filterwire device is used. Reduced flow seen during these procedures should be treated conservatively. Mechanical obstruction of the filter, but also other mechanisms (pharmacologically active debris? platelet aggregates?) play a role in this phenomenon.

Blackman DJ, Choudhury RP, Banning AP, Channon KM. 2005. Failure of the Symbiot PTFE-covered stent to reduce distal embolization during percutaneous coronary intervention in saphenous vein grafts. J Invasive Cardiol, 17 (11), pp. 609-612. | Show Abstract

OBJECTIVES: To examine the effect of the Symbiot PTFE-covered stent on distal embolization during percutaneous coronary intervention (PCI) in saphenous vein grafts (SVGs). BACKGROUND: Covered stents are intended to trap friable debris and reduce distal embolization during vein graft PCI, but have consistently failed to improve clinical outcomes in randomized trials. The reasons for this lack of benefit are unclear. METHODS: Thirty patients undergoing SVG PCI, and eligible for a FilterWire distal protection device, were randomized to Symbiot or to a conventional bare-metal stent. Postprocedure, the FilterWire was removed, fixed in formalin, and photographed under high magnification. The primary end-point was embolic debris area, measured by semi-automated edge-detection analysis of digital images. Secondary end points were no-reflow, "Filter no-reflow", and distal embolization. RESULTS: There was no significant difference between the Symbiot and conventional stent groups in embolic debris area (10.5 +/- 7.2 versus 6.6 +/- 7.8 mm2; p = 0.18). No-reflow occurred in 3/14 Symbiot versus 0/16 conventional (p = 0.09), and final TIMI flow was lower in the Symbiot group (2.7 +/- 0.5 versus 3.0 +/- 0.5; p = 0.01). However, there was no difference in the incidence of Filter no-reflow (7/14 versus 7/16; p = NS) or distal embolization (9/14 versus 8/16; p = NS). Distal embolization in the Symbiot group occurred predominantly after postdilatation (7/9; p = 0.05). CONCLUSIONS: The Symbiot PTFE-covered self-expanding stent does not reduce distal embolization compared to a conventional bare metal stent. Distal embolization with the Symbiot occurs almost exclusively after mandatory postdilatation. These findings may explain the failure of the Symbiot, and of covered stents in general, to improve clinical outcomes during vein graft PCI.

Ali ZA, Bursill CA, Hu Y, Choudhury RP, Xu Q, Greaves DR, Channon KM. 2005. Gene transfer of a broad spectrum CC-chemokine inhibitor reduces vein graft atherosclerosis in apolipoprotein E-knockout mice. Circulation, 112 (9 Suppl), pp. I235-I241. | Show Abstract | Read more

BACKGROUND: Accelerated atherosclerosis is a major cause of vein graft failure after bypass surgery. Several CC-chemokines (CC-CKs) mediate monocyte/macrophage recruitment in native atherosclerotic plaques; we hypothesized that CC-CKs may be critical in the development of accelerated atherosclerosis in vein grafts. METHODS AND RESULTS: Using in vivo gene transfer, we administered a soluble CC-CK binding protein ("35K") to apolipoprotein E-knockout (ApoE-/-) mice that underwent interposition bypass grafting of the vena cava from isogenic donor mice to the common carotid artery. Two days before operation, a recombinant adenovirus encoding either 35K (Ad35K) or green fluorescent protein (AdGFP; control) was injected into recipient mice via the tail vein. 35K greatly reduced CC-CK activity in mouse plasma. After 14 days, vein graft atherosclerotic lesion area, smooth muscle alpha-actin-positive neointimal area, and total vessel wall thickness were strikingly reduced by Ad35K gene transfer compared with AdGFP controls. Furthermore, 35K gene transfer dramatically reduced macrophage content by approximately 90% and cell proliferation by 95%. After 28 days, lesion area and vessel wall thickness remained significantly less in Ad35K mice. CONCLUSIONS: A single intravenous injection of the CC-CK inhibitor 35K significantly reduced atherosclerosis in carotid-caval vein grafts in ApoE-/- mice. This study highlights the importance of the CC-CK class in accelerated atherosclerosis, and its role as a potential target for improving vein graft patency.

Choudhury RP, Lee JM, Greaves DR. 2005. Mechanisms of disease: macrophage-derived foam cells emerging as therapeutic targets in atherosclerosis. Nat Clin Pract Cardiovasc Med, 2 (6), pp. 309-315. | Show Abstract | Read more

The limited efficacy of current treatment strategies for targeting atherosclerosis and its complications requires new therapeutic options to be explored. From early fatty-streak lesions to advanced plaques, macrophage-derived foam cells are integral to the development and progression of atherosclerosis. Elucidation of molecular and cellular processes involving macrophages has led to numerous therapeutic targets being suggested. Potential sites of intervention range from monocyte recruitment, through cholesterol uptake and esterification, to cholesterol evacuation and macrophage egress from plaque. In addition, complex patterns of transcriptional regulation of genes involved in macrophage lipid homeostasis and in the regulation of inflammation have been partly unraveled. Recognition of ATP-binding cassette cholesterol transport mechanisms and cellular interactions with cholesterol-accepting apolipoproteins (or synthetic mimetics) opens up new potential therapies to induce atherosclerosis regression in humans. This review presents a systematic evaluation of actual and potential macrophage-directed pharmacologic interventions. It reflects the timely convergence of three important strands: advances in molecular and cell biology that have suggested therapeutic targets in macrophages; the development of multiple classes of drugs targeting these pathways; and the emergence of sensitive imaging techniques that have enabled identification of changes in plaque size and composition in response to treatment.

Schneider JE, McAteer MA, Tyler DJ, Clarke K, Channon KM, Choudhury RP, Neubauer S. 2004. High-resolution, multicontrast three-dimensional-MRI characterizes atherosclerotic plaque composition in ApoE-/- mice ex vivo. J Magn Reson Imaging, 20 (6), pp. 981-989. | Show Abstract | Read more

PURPOSE: To systematically investigate intrinsic MR contrast mechanisms that would facilitate plaque characterization and quantification in the aortic root and brachiocephalic artery of ApoE-/- mice ex vivo. MATERIALS AND METHODS: To establish unambiguous MR parameters for routinely analyzing atherosclerotic plaque ex vivo at 11.7 T, relaxation times of plaque components were quantitatively assessed. Magnetization transfer and lipid-proton three-dimensional MR imaging was investigated for visualization of collagen- and lipid-rich plaque regions, respectively. A three-dimensional multiecho sequence with a spatial resolution of 47 x 47 x 63 microm was implemented providing a variable degree of T2-weighting. RESULTS: Relaxation time measurements showed clear tissue heterogeneity between atherosclerotic plaque components in the T2-values, but similar T1-values at 11.7 T (T1/T2 mean +/- SD; cellular plaque component: 1.2 +/- 0.3 seconds/26.3 +/- 0.4 msec; fibrofatty plaque component: 1.1 +/- 0.2 seconds/13.7 +/- 2.0 msec). The three-dimensional multiecho sequence allowed the calculation of the intrinsic proton density and T2-maps. The sum of the multiecho data provided strong T2-weighting that facilitated quantification of various components of atherosclerotic plaque in the mouse aortic root and correlated well with histology (P < 0.0001). CONCLUSION: High-resolution MRI allows for accurate classification and quantification of atherosclerotic plaque components in the aortic root of mice.

McAteer MA, Schneider JE, Clarke K, Neubauer S, Channon KM, Choudhury RP. 2004. Quantification and 3D reconstruction of atherosclerotic plaque components in apolipoprotein E knockout mice using ex vivo high-resolution MRI. Arterioscler Thromb Vasc Biol, 24 (12), pp. 2384-2390. | Show Abstract | Read more

OBJECTIVE: To investigate the ability of high-resolution MRI to determine composition and microanatomy of atherosclerosis in mouse aortic root and brachiocephalic artery. METHODS AND RESULTS: Aortic root and brachiocephalic arteries of apolipoprotein E knockout (apoE-/-) mice fed Western diet for 10, 20, or 30 weeks were imaged ex vivo (11.7 T; 3D multiecho sequence; resolution 47x47x62.5 microm). Using semiautomated histogram-based methods, MRI accurately quantified lipid-rich/necrotic areas in the aortic root (r2=0.84; P<0.001) and brachiocephalic artery (r2=0.90; P<0.001) compared with histology. Similarly, cell-rich caps in aortic roots, quantified by MRI and histology, correlated closely (r2=0.74; P<0.001). Reconstruction of segmented brachiocephalic arteries in 3D provided unique insights into plaque microanatomy and enabled volumetric quantification of plaque and lipid-rich/necrotic core. Between 10 and 30 weeks, 3D measurement identified an 11.6-fold increase in plaque volume (versus 4.1-fold for 2D) and a 21.3-fold increase in plaque lipid-rich/necrotic core volume (versus 6.4-fold for 2D), indicating superior power of 3D quantification. CONCLUSIONS: Ex-vivo high-resolution 3D MRI accurately quantified lipid-rich/necrotic core and cell-rich cap areas in atherosclerotic lesions in apoE-/- mice. Reconstruction and volumetric quantification of segmented brachiocephalic arteries demonstrated greater sensitivity in detecting changes in plaque size and lipid composition over time than 2D analysis.

Wiesmann F, Petersen SE, Leeson PM, Francis JM, Robson MD, Wang Q, Choudhury R, Channon KM, Neubauer S. 2004. Global impairment of brachial, carotid, and aortic vascular function in young smokers: direct quantification by high-resolution magnetic resonance imaging. J Am Coll Cardiol, 44 (10), pp. 2056-2064. | Show Abstract | Read more

OBJECTIVES: The purpose of this study was to assess vascular dysfunction in young smokers by high-resolution magnetic resonance imaging (MRI). BACKGROUND: Cigarette smoking is a well-known cause of endothelial dysfunction, reflected by impaired brachial artery reactivity to hyperemia. We hypothesized that smoking induces both peripheral endothelial dysfunction and altered function in central conduit arteries, and that these global changes in vascular function could be directly quantified in a single noninvasive examination using high-resolution MRI. METHODS: A total of 22 healthy young volunteers (mean age 31 +/- 2 years; 12 nonsmokers, 10 smokers: cumulative cigarette consumption 11.9 +/- 6.0 pack-years) underwent noninvasive high-resolution MRI to assess central vascular distensibility and pulse-wave velocity (PWV), and cross-sectional flow-mediated dilation (FMD) of the brachial artery. RESULTS: Brachial artery FMD was significantly reduced in smokers compared with nonsmokers (7.5 +/- 2.7% vs. 15.5 +/- 2.0%; p = 0.03), indicating impaired endothelium-dependant relaxation, whereas endothelium-independent responses to sublingual glyceroltrinitrate(400 mug) were identical in both groups. Impaired peripheral endothelial function in smokers was accompanied by striking decreases in central vascular distensibility in both the common carotid arteries (-45.7%; p = 0.02) and at multiple sites in the aorta (ascending aorta -26.9%, p = 0.04; thoracic descending aorta -25.0%, p = 0.01; abdominal descending aorta -25.5%, p = 0.02). Aortic arch PWV in smokers was increased by 19% (p = 0.02). CONCLUSIONS: Cigarette smoking induces global changes in both peripheral and central vascular function. Direct quantification of multiple parameters of vascular function using high-resolution MRI will provide powerful new approaches to the assessment of vascular disease pathogenesis, diagnosis, and treatment.

Choudhury RP, Fuster V, Fayad ZA. 2004. Molecular, cellular and functional imaging of atherothrombosis. Nat Rev Drug Discov, 3 (11), pp. 913-925. | Show Abstract | Read more

Recent years have seen a dramatic expansion in our knowledge of the events of atherogenesis and in the availability of drugs that can retard the progression - and even induce the regression - of this disease process. Our understanding has been advanced considerably by developments in genetics and molecular biology and by the use of genetically modified mouse models that have provided key mechanistic insights. Increasingly sophisticated imaging techniques will capitalize on these advances by bringing forward diagnosis, enhancing disease characterization and providing more precise evaluation of the effects of treatment. In this review, techniques for imaging atherosclerosis and thrombosis will be discussed. Particular attention will be given to magnetic resonance imaging techniques that enable lesion characterization and allow the targeted imaging of cells, molecules and biological processes. Emphasis is given to the potential contribution of magnetic resonance imaging methods to therapeutic monitoring, drug delivery and drug discovery.

Bursill CA, Choudhury RP, Ali Z, Greaves DR, Channon KM. 2004. Broad-spectrum CC-chemokine blockade by gene transfer inhibits macrophage recruitment and atherosclerotic plaque formation in apolipoprotein E-knockout mice. Circulation, 110 (16), pp. 2460-2466. | Show Abstract | Read more

BACKGROUND: The CC-chemokines (CKs) recruit monocytes/macrophages to sites of inflammation; several different CC-CKs play a role in the pathogenesis of atherosclerosis. The vaccinia virus expresses a 35-kDa soluble protein (35K) that binds to and inactivates nearly all of the CC-CKs, providing a potentially useful therapeutic strategy for broad-spectrum CC-CK inhibition in atherosclerosis. A recombinant adenovirus encoding soluble 35K (Ad35K) was generated to investigate the effect of 35K gene transfer on atherosclerosis in Western diet-fed apolipoprotein E-knockout (ApoE KO) mice. METHODS AND RESULTS: ApoE KO mice received tail-vein injections of phosphate-buffered saline, Ad35K, or control adenovirus AdGFP encoding green fluorescence protein. Two weeks after Ad35K gene transfer, atherosclerotic lesion area was significantly reduced in aortic roots by 55% compared with PBS or AdGFP control mice (P<0.05). Furthermore, 35K gene transfer strikingly reduced the macrophage content in aortic root lesions by 85% (P<0.01) and reduced lipid deposition in descending aortas by more than half (P<0.05). By an in vitro chemotaxis assay, plasma and aortic homogenates from 35K gene transfer mice promoted significantly less CC-CK-induced cell migration than did PBS or AdGFP controls. CONCLUSIONS: These findings show that a single intravenous injection of a recombinant adenovirus encoding the broad-spectrum CC-CK inhibitor 35K can reduce atherosclerosis by inhibiting CC-CK-induced macrophage recruitment in atherosclerotic ApoE KO mice. These experiments suggest that CC-CKs play an important role in atherogenesis and are a rational target for therapeutic intervention.

Choudhury RP, Rong JX, Trogan E, Elmalem VI, Dansky HM, Breslow JL, Witztum JL, Fallon JT, Fisher EA. 2004. High-density lipoproteins retard the progression of atherosclerosis and favorably remodel lesions without suppressing indices of inflammation or oxidation. Arterioscler Thromb Vasc Biol, 24 (10), pp. 1904-1909. | Show Abstract | Read more

OBJECTIVE: Protective properties of high-density lipoproteins (HDL) may include reverse cholesterol transport and suppression of oxidation and inflammation. These were investigated in vivo, as were the effects of HDL on the characteristics of atherosclerotic lesions. METHODS AND RESULTS: Male apolipoprotein E knockout (apoE-/-) and apoE-/- mice expressing human apolipoprotein AI (hAI/apoE-/-) were studied up to 20 weeks after commencing a high-fat diet. Plasma HDL cholesterol was twice as high in hAI/apoE-/- mice. Over time, aortic root lesion area remained less in hAI/apoE-/- mice, although plaques became complex. In advanced lesions, plaque lipid was higher in apoE-/- mice, whereas plaque collagen and alpha actin were increased in hAI/apoE-/- mice. In nonlesional aorta, mRNA abundance for pro-inflammatory proteins (vascular cell adhesion molecule [VCAM]-1, intercellular adhesion molecule-1 [ICAM-1], monocyte chemoattractant protein-1 [MCP-1]) increased between 4 and 16 weeks in apoE-/- (but not wild-type) mice, and were not reduced by elevated HDL. Autoantibodies to malondialdehyde low-density lipoprotein (LDL) increased progressively in apoE-/- mice, with similar results in hAI/apoE-/- mice. CONCLUSIONS: HDL retarded plaque size progression despite greatly elevated plasma cholesterol. This effect was over a wide range of lesion severity. Expression of hAI reduced plaque lipid and increased the proportion of plaque occupied by collagen and smooth muscle cells, but did not affect indicators of inflammation or LDL oxidation.

Fayad ZA, Sirol M, Nikolaou K, Choudhury RP, Fuster V. 2004. Magnetic resonance imaging and computed tomography in assessment of atherosclerotic plaque. Curr Atheroscler Rep, 6 (3), pp. 232-242. | Show Abstract | Read more

The two most promising noninvasive imaging modalities for the study of atherosclerosis are magnetic resonance imaging (MRI) and computed tomography (CT). Both have been shown to be capable of imaging vessel wall structures and differentiating various stages of atherosclerotic wall changes. MRI has been applied in various in vivo human studies to image atherosclerotic plaques in coronary arteries, carotid arteries, and aorta. The latest generation of multidetector row computed tomography (MDCT) systems allows for the noninvasive characterization of different plaque components in various vascular structures. MDCT allows evaluation of the whole arterial vasculature. In addition, MDCT has the ability to visualize the vessel wall and to give a quantitative measurement of calcified and noncalcified plaque. Using either technique, the repeatable, noninvasive study of atherosclerotic disease during its natural history and after therapeutic intervention will enhance our understanding of disease progression and regression. MDCT and MRI, therefore, may help in selecting appropriate treatments.

Alp NJ, McAteer MA, Khoo J, Choudhury RP, Channon KM. 2004. Increased endothelial tetrahydrobiopterin synthesis by targeted transgenic GTP-cyclohydrolase I overexpression reduces endothelial dysfunction and atherosclerosis in ApoE-knockout mice. Arterioscler Thromb Vasc Biol, 24 (3), pp. 445-450. | Show Abstract | Read more

OBJECTIVE: Increased production of reactive oxygen species and loss of endothelial nitric oxide (NO) bioactivity are key features of vascular disease states such as atherosclerosis. Tetrahydrobiopterin (BH4) is a required cofactor for NO synthesis by endothelial nitric oxide synthase (eNOS); pharmacologic studies suggest that reduced BH4 availability may be an important mediator of endothelial dysfunction in atherosclerosis. We aimed to investigate the importance of endothelial BH4 availability in atherosclerosis using a transgenic mouse model with endothelial-targeted overexpression of the rate-limiting enzyme in BH4 synthesis, GTP-cyclohydrolase I (GTPCH). METHODS AND RESULTS: Transgenic mice were crossed into an ApoE knockout (ApoE-KO) background and fed a high-fat diet for 16 weeks. Compared with ApoE-KO controls, transgenic mice (ApoE-KO/GCH-Tg) had higher aortic BH4 levels, reduced endothelial superoxide production and eNOS uncoupling, increased cGMP levels, and preserved NO-mediated endothelium dependent vasorelaxations. Furthermore, aortic root atherosclerotic plaque was significantly reduced in ApoE-KO/GCH-Tg mice compared with ApoE-KO controls. CONCLUSIONS: These findings indicate that BH4 availability is a critical determinant of eNOS regulation in atherosclerosis and is a rational therapeutic target to restore NO-mediated endothelial function and reduce disease progression.

Choudhury RP, Porto I, Banning AP. 2004. Images in cardiovascular medicine. Debris trapped by a distal protection device may mimic no-reflow during percutaneous coronary intervention. Circulation, 109 (6), pp. 803-804. | Read more

Choudhury RP, Porto I, Banning AP. 2004. Debris trapped by a distal protection device may mimic no-reflow during percutaneous coronary intervention CIRCULATION, 109 (6), pp. 803-804. | Read more

Choudhury RP, Carrelli AL, Stern JD, Chereshnev I, Soccio R, Elmalem VI, Fallon JT, Fisher EA, Reis ED. 2004. Effects of simvastatin on plasma lipoproteins and response to arterial injury in wild-type and apolipoprotein-E-deficient mice. J Vasc Res, 41 (1), pp. 75-83. | Show Abstract | Read more

OBJECTIVE: To test the non-lipid-lowering effects of simvastatin on the response to injury in normolipidemic and hyperlipidemic mice. METHODS AND RESULTS: Wild-type (WT) mice (n = 40) and hyperlipidemic apolipoprotein-E-deficient (apoE(-/-)) mice (n = 40) received normal chow or chow containing simvastatin 100 mg/kg/day prior to bilateral femoral artery wire injury. Intimal hyperplasia and plasma cholesterol concentration were quantified after 4 weeks. Plasma cholesterol in WT mice treated or untreated with simvastatin was similar (100.9 +/- 6.6 vs. 94.3 +/- 17.5 mg/dl). Simvastatin did not affect intimal hyperplasia. In apoE(-/-) mice, intimal hyperplasia was increased 2.3-fold relative to WT mice (17090 +/- 4998 vs. 39490 +/- 16190; p < 0.001). In apoE(-/- )mice, simvastatin caused a paradoxical increase in plasma cholesterol (1094 +/- 60.3 vs. 658 +/- 66.8 mg/dl; p < 0.001), confirmed by FPLC. This was associated with a further increase in intimal area (39490 +/- 16190 vs. 55420 +/- 22590 mm(2); p < 0.01). CONCLUSIONS: (1). Simvastatin had no effect on plasma cholesterol or the response to arterial injury in normolipidemic WT mice; (2). hyperlipidemia was associated with markedly increased intimal hyperplasia, and (3). simvastatin treatment of apoE(-/-) mice caused paradoxical hyperlipidemia and increased intimal hyperplasia.

Fayad ZA, Choudhury RP, Fuster V. 2003. Magnetic resonance imaging of coronary atherosclerosis. Curr Atheroscler Rep, 5 (5), pp. 411-417. | Read more

Lin RY, Choudhury RP, Cai W, Lu M, Fallon JT, Fisher EA, Vlassara H. 2003. Dietary glycotoxins promote diabetic atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis, 168 (2), pp. 213-220. | Show Abstract | Read more

Hyperglycemia derived advanced glycation endproducts (AGE) have been implicated in diabetic atherosclerosis (AS) but the role of exogenous (dietary) AGE in the development of this serious complication is not known. This study evaluates the influence of diet-related AGE on AS in genetically hypercholesterolemic apolipoprotein E-deficient (apoE(-/-)), streptozotocin-induced diabetic mice. Diabetic and non-diabetic apoE(-/-) mice (6-8 weeks old) were randomized into either a standard AIN-93G chow (AGE 12,500+/-700 U/mg, termed high-AGE diet, H-AGE), or the same chow having four to fivefold lower AGE level (L-AGE: 2,700+/-830 U/mg) based on ELISA. After 2 months of diabetes, compared to the diabetic mice fed standard (H-AGE) diet, the AS lesions at the aortic root of the L-AGE group were >50% smaller (0.17+/-0.03 vs. 0.31+/-0.05 mm(2), P<0.05). Serum AGE were lower in the diabetic L-AGE than in the H-AGE mice (by approximately 53%) (P<0.00001), as were in the non-diabetic L-AGE vs. H-AGE groups (P<0.05). No diet-related changes were noted in plasma glucose, triglycerides, or plasma cholesterol. Immunohistochemical comparisons showed markedly suppressed tissue AGE, AGE-Receptor-1, -2 and RAGE expression, reduced numbers of inflammatory cells, tissue factor, vascular cell adhesion molecule-1 and MCP-1 in the L-AGE diabetic group. The findings are supportive of an important link between dietary intake of pre-formed glycoxidation products, tissue-incorporated AGE, and diabetes-accelerated AS. The marked anti-atherogenic effects of an AGE-restricted diet in this model may provide the basis for relevant clinical studies.

Choudhury RP. 2003. Clopidogrel and percutaneous coronary interventions. JAMA, 289 (15), pp. 1925. | Read more

Choudhury RP, Fayad ZA, Aguinaldo JG, Itskovich VV, Rong JX, Fallon JT, Fisher EA. 2003. Serial, noninvasive, in vivo magnetic resonance microscopy detects the development of atherosclerosis in apolipoprotein E-deficient mice and its progression by arterial wall remodeling. J Magn Reson Imaging, 17 (2), pp. 184-189. | Show Abstract | Read more

PURPOSE: To test the ability of serial, in vivo magnetic resonance microscopy (MRM) to detect the development of atherosclerosis and quantify its progression in apolipoprotein E-deficient mice. MATERIALS AND METHODS: The abdominal aortae of six ApoE(-/-) and three wild-type (WT) control mice were imaged by MRM at 9.4T. Proton density weighted images were obtained (TR = 2000, TE = 9 msec) using four signal averages. The image resolution was 109 x 109 x 500 microm(3). The six ApoE(-/-) mice underwent serial MRM three to five times over a period < or = 44 weeks. Multiple, anatomically aligned MRM slices (N = 6-11 per time point, total 202) were compared serially in each animal. RESULTS: The abdominal aorta remained free of atherosclerosis until 20 weeks of age but thereafter, atherosclerosis was identified in all ApoE(-/-) mice (P < 0.05 to P < 0.001), but no WT controls. Lesion progression was accompanied by positive remodeling in which atherosclerosis within the aortic wall was accommodated by an increase in total cross sectional area (P < 0.01), while lumen area was unchanged. CONCLUSION: Serial MRM demonstrated the development and progression of atherosclerosis in mouse aorta. Importantly, progression of atherosclerosis could be identified within individual animals. By following the same aortic lesions over time, MRM demonstrated that progression of atherosclerosis in mice is associated with positive arterial remodeling.

Itskovich VV, Choudhury RP, Aguinaldo JG, Fallon JT, Omerhodzic S, Fisher EA, Fayad ZA. 2003. Characterization of aortic root atherosclerosis in ApoE knockout mice: high-resolution in vivo and ex vivo MRM with histological correlation. Magn Reson Med, 49 (2), pp. 381-385. | Show Abstract | Read more

In vivo, cardiac-gated, black-blood, and ex vivo magnetic resonance microscopy (MRM) images of the aortic root, and histopathology data were obtained from 12 transgenic and wild-type (WT) mice. MRM was performed using a black-blood imaging spin-echo sequence with upstream and downstream in-flow saturation pulses to obtain aortic root images in three contrast techniques: proton density-weighted (PDW), T(1)- (T(1)W), and T(2)-weighted (T(2)W). Aortic wall thickness and area were measured and correlated with histopathology data (R > 0.90). Ex vivo lesion components (lipid core, fibrous tissue, and cell tissue) were identified and characterized by differing image contrast in PDW, T(1)W, and T(2)W MRM, and by histopathology. The differences between WT and transgenic mice for maximal wall thickness and area were statistically significant (P < 0.05). This study demonstrates the feasibility of in vivo murine aortic root lesion assessment and ex vivo plaque characterization by MRM.

Bridges JF. 2003. Clopidogrel and percutaneous coronary interventions. JAMA, 289 (15), pp. 1925-1926. | Read more

Choudhury RP, Fayad ZA. 2002. Coronary wall imaging with MRI JOURNAL OF CARDIOVASCULAR RISK, 9 (5), pp. 263-270. | Read more

Choudhury RP, Fayad ZA. 2002. Imaging of atherosclerosis. Coronary wall imaging with MRI. J Cardiovasc Risk, 9 (5), pp. 263-270. | Show Abstract

Contrast arteriography is routinely used in the diagnosis and management of coronary atherosclerosis. However, it is recognized that conventional arteriography can not image plaque directly or provide prognostic information based on plaque characterization. Noninvasive, high-resolution magnetic resonance has the potential to image coronary plaque and to determine its composition and microanatomy. This review summarizes the rationale for coronary plaque imaging, and describes the characteristics of plaque using existing MRI techniques. Current and future applications of MRI, including the development of new contrast agents, targeted molecular imaging and the application of MRI to percutaneous coronary intervention are also discussed.

Choudhury RP, Aguinaldo JG, Rong JX, Kulak JL, Kulak AR, Reis ED, Fallon JT, Fuster V, Fisher EA, Fayad ZA. 2002. Atherosclerotic lesions in genetically modified mice quantified in vivo by non-invasive high-resolution magnetic resonance microscopy. Atherosclerosis, 162 (2), pp. 315-321. | Show Abstract | Read more

We have previously shown that magnetic resonance microscopy (MRM) accurately quantifies atherosclerosis in Apolipoprotein E deficient (ApoE(-/-)) mice aged 36-84 weeks. The present study tests MRM in the quantification of aortic atherosclerosis over a broader range of lesion severity. Younger mice with less advanced disease were imaged in order to evaluate sensitivity, specificity and maximum practical resolution of MRM. Nineteen mice underwent in vivo MRM. Wall area measurements by MRM and light microscopy (LM) (n=43) were highly correlated (r=0.85, slope=0.88, P<0.0001). Wall areas by MRM ranged from 0.114 to 0.934 (median, 0.334) mm(2). A threshold of 0.35 mm(2), for the upper limit of normal, gave MRM positive predictive value (PPV) for detecting abnormally thickened arteries=89.5% and negative predictive value (NPV)=75%, referred to LM. Lesion shape assessed by LM and MRM were also well correlated (r=0.72, P<0.001). Increased wall area in atherosclerosis was found by MRM (P=0.01) and LM (P<0.0001) to be accommodated entirely by 'positive remodeling', confirming the importance of determining plaque size directly. MRM accurately quantifies mouse aortic atherosclerosis and will enhance studies in this important animal model.

Rong JX, Choudhury RP, Trogan E, Fisher EA. 2002. Expression of the macrophage marker CD68 in mouse aortic smooth muscle cells is regulated by cholesterol loading ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22 (5), pp. A14-A14.

Trogan E, Choudhury RP, Dansky HM, Rong JX, Breslow JL, Fisher EA. 2002. Immuno-laser capture microdissection (LCM) enriches macrophage foam cell RNA for the molecular analysis of atherosclerotic lesions ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22 (5), pp. A51-A52.

Grieve SM, Choudhury RP, Schneider JE, Cassidy PJ, Neubauer S, Clarke K. 2002. Magnetic resonance angiography of mouse aorta at 12 tesla ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 22 (5), pp. A12-A12.

Choudhury RP, Carrelli AL, Stern J, Soccio R, Chereshnev I, Elmalem V, Fallon JT, Fisher EA, Reis ED. 2002. Effects of simvastatin on the response to arterial injury in wild-type (WT) and apolipoprotein E-deficient (ApoE0) mice JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 39 (5), pp. 69A-69A.

Trogan E, Choudhury RP, Dansky HM, Rong JX, Breslow JL, Fisher EA. 2002. Laser capture microdissection analysis of gene expression in macrophages from atherosclerotic lesions of apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A, 99 (4), pp. 2234-2239. | Show Abstract | Read more

Macrophage foam cells are integral in the development of atherosclerotic lesions. Gene expression analysis of lesional macrophage foam cells is complicated by the cellular heterogeneity of atherosclerotic plaque and the presence of lesions of various degrees of severity. To overcome these limitations, we tested the ability of laser capture microdissection (LCM) and real-time quantitative reverse transcription PCR to selectively analyze RNA from lesional macrophages of apolipoprotein E (apoE)-deficient mice. Proximal aortic tissue sections were immunostained for macrophagespecific CD68/macrosialin by a rapid (approximately 15-min) protocol. Alternating sections from each animal were used to isolate RNA either from entire sections (analogous to isolation from whole tissue) or by LCM selection of CD68-positive cells. We measured the mRNA levels of CD68, a macrophage-specific marker, alpha-actin, a smooth muscle cell marker, and cyclophilin A, a control gene. Compared with whole sections, CD68 mRNA levels were greatly enriched (33.6-fold) in the laser-captured lesional macrophages. In contrast to whole sections, LCM-derived RNA had undetectable levels of alpha-actin. To illustrate the ability of this method to measure changes in lesional macrophage gene expression, we injected 100 microg of lipopolysaccharide i.p. into apoE-deficient mice and detected in laser-captured lesional macrophages increased mRNA expression for vascular cell adhesion molecule-1, intercellular cell adhesion molecule-1, and monocyte chemoattractant protein-1 (11.9-, 32.5-, and 31.0-fold, respectively). By selectively enriching foam cell RNA, LCM provides a powerful approach to study the in situ expression and regulation of atherosclerosis-related genes. This approach will allow the study of macrophage gene expression under various conditions of plaque formation, regression, and response to genetic and environmental perturbations.

Choudhury RP, Fuster V, Badimon JJ, Fisher EA, Fayad ZA. 2002. MRI and characterization of atherosclerotic plaque: emerging applications and molecular imaging. Arterioscler Thromb Vasc Biol, 22 (7), pp. 1065-1074. | Show Abstract | Read more

Noninvasive high-resolution magnetic resonance has the potential to image atherosclerotic plaque and to determine its composition and microanatomy. This review summarizes the rationale for plaque imaging and describes the characteristics of plaque by use of existing MRI techniques. The use of MRI in human disease and in animal models, particularly in rabbits and mice, is presented. Present and future applications of MRI, including real-time vascular intervention, new contrast agents, and molecular imaging, are also discussed.

Rong JX, Li J, Reis ED, Choudhury RP, Dansky HM, Elmalem VI, Fallon JT, Breslow JL, Fisher EA. 2001. Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content. Circulation, 104 (20), pp. 2447-2452. | Show Abstract | Read more

BACKGROUND: HDL cholesterol levels are inversely correlated with coronary heart disease risk in humans, and in animal studies, HDL elevation decreases formation and progression of foam-cell lesions. The potential for HDL to affect preexisting advanced atherosclerotic lesions is not known. To approach this issue, we used a novel mouse aortic transplantation model. METHODS AND RESULTS: ApoE-deficient (EKO) mice were fed a Western-type diet for 6 months, and thoracic aortic segments containing advanced lesions replaced segments of the abdominal aorta of 4-month-old EKO syngeneic mice not expressing (plasma HDL cholesterol approximately 26 mg/dL) or expressing (HDL approximately 64 mg/dL) a human apoAI (hAI) transgene. Both types of recipients had comparable non-HDL cholesterol levels. Five months after transplantation, mice were killed and grafts analyzed. Compared with lesion area in pretransplant mice (0.14+/-0.04 mm(2), mean+/-SEM), there was progression in the EKO recipients (0.39+/-0.06 mm(2), P<0.01). Compared with EKO recipients, hAI/EKO recipients had retarded progression (0.24+/-0.04 mm(2), P<0.05). Immunostaining for CD68 and other macrophage-associated proteins, monocyte chemoattractant protein-1, acyl coenzyme A:cholesterol acyltransferase, and tissue factor, in lesions of pretransplant and EKO recipient mice showed abundant macrophages. In contrast, compared with any other group, lesional macrophage area in hAI/EKO mice decreased >80% (P<0.003), and smooth muscle cell content (alpha-actin staining) increased >300% (P<0.006). The decrease in macrophages and increase in smooth muscle cells was primarily in the superficial subendothelial layer. CONCLUSIONS: Increasing HDL cholesterol levels in EKO mice retards progression of advanced atherosclerotic lesions and remodels them to a more stable-appearing phenotype.

Rong JX, Li J, Dansky HM, Choudhury RP, Elmalem V, Fallon JT, Reis ED, Breslow JL, Fisher EA. 2001. Apolipoprotein AI overexpression remodels large, complex atherosclerotic lesions to have characteristics of more stable plaques in apoE-deficient mice ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 21 (4), pp. 649-649.

Choudhury RP, Rong JX, Trogan E, Dansky HM, Elmalem V, Yodice C, Fallon JT, Fisher EA. 2001. Human apolipoprotein A-I transgene expression retards the progression of atherosclerosis in apolipoprotein E deficient mice fed Western-type diet (WD) ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 21 (4), pp. 657-657.

Choudhury RP, Aguinaldo JG, Rong JX, Reis ED, Fallon JT, Fayad ZA, Fisher EA. 2001. Plaque remodeling in mouse atherosclerosis identified by high resolution in vivo magnetic resonance imaging (MRM). ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, 21 (4), pp. 716-716.

Choudhury RP, Leyva F. 2001. New insights into the progression of aortic stenosis: implications for secondary prevention. Circulation, 103 (12), pp. E67. | Read more

Choudhury RP, Aguinaldo G, Rong JX, Fallon JT, Fuster V, Fisher EA, Fayad ZA. 2001. Serial, non-invasive, high resolution magnetic resonance microscopy measures progression of atherosclerosis in apolipoprotein E deficient mice JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 37 (2), pp. 380A-380A.

Rong JX, Li J, Dansky HM, Choudhury RP, Yodice C, Fallon JT, Reis E, Fisher EA. 2000. A transplant model to study the long term effects of apoprotein AI overexpression on large, complex atherosclerotic lesions in ApoE-deficient mice CIRCULATION, 102 (18), pp. 253-253.

Aguinaldo JGS, Choudhury RP, Rong JX, Yodice C, Fallon JT, Fisher EA, Fayad ZA. 2000. Severity of atherosclerotic lesions in ApoE-/- mice assessed by noninvasive in vivo high resolution magnetic resonance microscopy CIRCULATION, 102 (18), pp. 459-459.

Beirne P, Taylor P, Choudhury RP, Somerville J. 2000. Cerebellar syndrome complicating Mycoplasma pneumoniae pneumonia. J R Soc Med, 93 (1), pp. 28-29.

Lindsay AC, Biasiolli L, Lee JM, Kylintireas I, MacIntosh BJ, Watt H, Jezzard P, Robson MD, Neubauer S, Handa A et al. 2012. Plaque features associated with increased cerebral infarction after minor stroke and TIA: a prospective, case-control, 3-T carotid artery MR imaging study. JACC Cardiovasc Imaging, 5 (4), pp. 388-396. | Show Abstract | Read more

OBJECTIVES: The goal of this study was to determine whether a 3-T magnetic resonance imaging (MRI) protocol combining carotid atherosclerotic plaque and brain imaging can identify features of high-risk acutely symptomatic plaque that correlate with brain injury. BACKGROUND: It has previously been demonstrated that, in asymptomatic patients, MRI can identify features of carotid plaque that are associated with stroke, such as the presence of a large lipid core. We hypothesized that the early phase (<7 days) after a cerebrovascular event, when risk of recurrence is highest, may be associated with particular plaque characteristics that associate with cerebral injury. METHODS: Eighty-one patients (41 presenting acutely with transient ischemic attack [TIA] or minor stroke and 40 asymptomatic controls) underwent multicontrast carotid artery MRI on 2 separate occasions, each accompanied by diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) imaging of the brain. RESULTS: Complex (American Heart Association [AHA] type VI) plaques were seen in 22 of 41 patients (54%) in the symptomatic group versus 8 of 40 (20%) in the asymptomatic group (p < 0.05). They were caused by intraplaque hemorrhage (34% vs. 18%; p = 0.08), surface rupture (24% vs. 5%; p = 0.03), or luminal thrombus (7% vs. 0%; p = 0.24). Noticeably, 17 of 30 (57%) cases of AHA type VI plaque were in vessels with <70% stenosis. At follow-up scanning (>6 weeks later), only 2 cases of symptomatic AHA type VI plaque showed evidence of full healing. The presence of fibrous cap rupture was associated with higher DWI brain injury at presentation and higher total cerebral FLAIR signal at follow-up (p < 0.05). CONCLUSIONS: Early carotid wall MRI in patients experiencing minor stroke or TIA showed a higher proportion of "complex" plaques compared with asymptomatic controls; a majority were in arteries of <70% stenosis. Fibrous cap rupture was associated with increases in DWI and FLAIR lesions in the brain. Combined carotid plaque and brain MRI may aid risk stratification and treatment selection in acute stroke and TIA.

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McAteer MA, Mankia K, Ruparelia N, Jefferson A, Nugent HB, Stork LA, Channon KM, Schneider JE, Choudhury RP. 2012. A leukocyte-mimetic magnetic resonance imaging contrast agent homes rapidly to activated endothelium and tracks with atherosclerotic lesion macrophage content Arteriosclerosis, Thrombosis, and Vascular Biology, 32 (6), pp. 1427-1435. | Show Abstract | Read more

Objective-Endothelial cell activation is an important mediator of monocyte recruitment to sites of vascular inflammation. We hypothesized that high-affinity dual-ligand microparticles of iron oxide (MPIO), targeted to P-selectin and vascular cell adhesion molecule-1 (PV-MPIO), would identify activated endothelial cells during atherosclerosis progression. Methods and Results-In vivo magnetic resonance imaging in apolipoprotein E-deficient mice showed rapid binding of PV-MPIO to the aortic root, which was maximal 30 minutes post-MPIO injection and maintained at 60 minutes. Minimal binding was observed for control IgG-MPIO. Intensely low magnetic resonance signal areas, corresponding to PV-MPIO binding, were detected early (14 weeks), during foam cell formation. Contrast effects increased at 20 weeks during fibrofatty lesion development (P<0.05), but reduced by 30 weeks (P<0.01). Across all lesion severities, magnetic resonance imaging contrast effects correlated with lesion macrophage area quantified by immunohistochemistry (R=0.53; P<0.01). Near-infrared fluorescently labeled PV-MPIO were shown, by flow cytometry, to bind only activated endothelial cells and not to macrophages. Using en face immunofluorescence, we further demonstrate selective PV-MPIO accumulation at atherosclerosis-susceptible sites, with minimal binding to atherosclerosis- spared regions. Conclusion-This high-affinity leukocyte-mimetic magnetic resonance imaging agent reveals endothelial activation. PV-MPIO demonstrate exceptionally rapid in vivo steady state accumulation, providing conspicuous magnetic resonance contrast effects that can be objectively quantified. In atherosclerosis progression, PV-MPIO tracked closely with the burden and distribution of plaque macrophages, not merely plaque size. On a biocompatible platform, this approach has potential for quantitative magnetic resonance imaging of inflammatory disease activity. © 2012 American Heart Association, Inc.

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Digby JE, Ruparelia N, Choudhury RP. 2012. Niacin in cardiovascular disease: Recent preclinical and clinical developments Arteriosclerosis, Thrombosis, and Vascular Biology, 32 (3), pp. 582-588. | Show Abstract | Read more

Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients. © 2012 American Heart Association, Inc.

Digby JE, Martinez FO, Jefferson A, Ruparelia N, Wamil M, Greaves DR, Choudhury RP. 2011. Anti-inflammatory Effects of Nicotinic Acid: Mechanisms of Action in Human Monocytes CIRCULATION, 124 (21),

Jefferson A, Wijesurendra RS, McAteer MA, Digby JE, Douglas G, Bannister T, Perez-Balderas F, Bagi Z, Lindsay AC, Choudhury RP. 2011. Molecular imaging with optical coherence tomography using ligand-conjugated microparticles that detect activated endothelial cells: rational design through target quantification. Atherosclerosis, 219 (2), pp. 579-587. | Show Abstract | Read more

OBJECTIVES: Optical coherence tomography (OCT) is a high resolution imaging technique used to assess superficial atherosclerotic plaque morphology. Utility of OCT may be enhanced by contrast agents targeting molecular mediators of inflammation. METHODS AND RESULTS: Microparticles of iron oxide (MPIO; 1 and 4.5 μm diameter) in suspension were visualized and accurately quantified using a clinical optical coherence tomography system. Bound to PECAM-1 on a plane of cultured endothelial cells under static conditions, 1 μm MPIO were also readily detected by OCT. To design a molecular contrast probe that would bind activated endothelium under conditions of shear stress, we quantified the expression (basal vs. TNF-activated; molecules μm(-2)) of VCAM-1 (not detected vs. 16 ± 1); PECAM-1 (132 ± 6 vs. 198 ± 10) and E-selectin (not detected vs. 46 ± 0.6) using quantitative flow cytometry. We then compared the retention of antibody-conjugated MPIO targeting each of these molecules plus a combined VCAM-1 and E-selectin (E+V) probe across a range of physiologically relevant shear stresses. E+V MPIO were consistently retained with highest efficiency (P < 0.001) and at a density that provided conspicuous contrast effects on OCT pullback. CONCLUSION: Microparticles of iron oxide were detectable using a clinical OCT system. Assessment of binding under flow conditions recommended an approach that targeted both E-selectin and VCAM-1. Bound to HUVEC under conditions of flow, targeted 1 μm E+V MPIO were readily identified on OCT pullback. Molecular imaging with OCT may be feasible in vivo using antibody targeted MPIO.

Dall'Armellina E, Karia N, Lindsay AC, Karamitsos TD, Ferreira V, Robson MD, Kellman P, Francis JM, Forfar C, Prendergast BD et al. 2011. Dynamic changes of edema and late gadolinium enhancement after acute myocardial infarction and their relationship to functional recovery and salvage index. Circ Cardiovasc Imaging, 4 (3), pp. 228-236. | Show Abstract | Read more

BACKGROUND: Changes in the myocardium in acute ischemia are dynamic and complex, and the characteristics of myocardial tissue on cardiovascular magnetic resonance in the acute setting are not fully defined. We investigated changes in edema and late gadolinium enhancement (LGE) with serial imaging early after acute myocardial infarction, relating these to global and segmental myocardial function at 6 months. METHODS AND RESULTS: Cardiovascular magnetic resonance scans were performed on 30 patients with ST-elevation--myocardial infarction treated by primary percutaneous coronary intervention at each of 4 time points: 12 to 48 hours; 5 to 7 days; 14 to 17 days; and 6 months. All patients showed edema at 24 hours. The mean volume of edema (% left ventricle) was 37±16 at 24 hours and 39±17 at 1 week, with a reduction to 24±13 (P<0.01) by 2 weeks. Myocardial segments with edema also had increased signal on LGE at 24 hours (κ=0.77; P<0.001). The volume of LGE decreased significantly between 24 hours and 6 months (27±15% versus 22±12%; P=0.002). Of segments showing LGE at 24 hours, 50% showed resolution by 6 months. In segments with such a reduction in LGE, 65% also showed improved wall motion (P<0.0001). The area of LGE measured at 6 months correlated more strongly with troponin at 48 hours (r=0.9; P<0.01) than LGE at 24 hours (r=0.7). The difference in LGE between 24 hours and 6 months had profound effects on the calculation of salvage index (26±21% at 24 hours versus 42±23% at 6 months; P=0.02). CONCLUSIONS: Myocardial edema is maximal and constant over the first week after myocardial infarction, providing a stable window for the retrospective evaluation of area at risk. By contrast, myocardial areas with high signal intensity in LGE images recede over time with corresponding recovery of function, indicating that acutely detected LGE does not necessarily equate with irreversible injury and may severely underestimate salvaged myocardium.

Dall'Armellina E, Karamitsos TD, Neubauer S, Choudhury RP. 2010. CMR for characterization of the myocardium in acute coronary syndromes. Nat Rev Cardiol, 7 (11), pp. 624-636. | Show Abstract | Read more

The utility of cardiac magnetic resonance imaging (CMR) as a diagnostic technique is well established. CMR enables tissue characterization, distinction between myocardial scar tissue and viable tissue, and evaluation of myocardial perfusion and contractile function. To date, CMR has been mostly applied in the assessment of stable disease; however, a role for CMR in the acute setting is also emerging. An accurate appraisal of the myocardium with CMR in the first hours after the onset of chest pain could provide supporting information to standard diagnostic tools, such as electrocardiography and measurement of blood biomarkers, which could help guide the selection of appropriate treatment. The aims of this integrated approach include positive identification of an ischemic syndrome, estimation of downstream areas at risk of damage, evaluation of epicardial artery patency and small vessel integrity, quantification of infarct size, and determination of myocardial function. This Review critically evaluates both established and emerging CMR techniques, and relates the imaging findings to the underlying pathophysiological processes in acute coronary syndromes. A more thorough understanding of CMR techniques will clarify their potential clinical applications and limitations, and assess the practicality of CMR in the setting of acute coronary syndromes, where early intervention is crucial to save myocardium at risk of irreversible injury.

McAteer MA, Akhtar AM, von Zur Muhlen C, Choudhury RP. 2010. An approach to molecular imaging of atherosclerosis, thrombosis, and vascular inflammation using microparticles of iron oxide. Atherosclerosis, 209 (1), pp. 18-27. | Show Abstract | Read more

The rapidly evolving field of molecular imaging promises important advances in the diagnosis, characterization and pharmacological treatment of vascular disease. Magnetic resonance imaging (MRI) provides a modality that is well suited to vascular imaging as it can provide anatomical, structural and functional data on the arterial wall. Its capabilities are further enhanced by the use of a range of increasingly sophisticated contrast agents that target specific molecules, cells and biological processes. This article will discuss one such approach, using microparticles of iron oxide (MPIO). MPIO have been shown to create highly conspicuous contrast effects on T(2)(*)-weighted MR images. We have developed a range of novel ligand-conjugated MPIO for molecular MRI of endothelial adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1) and P-selectin expressed in vascular inflammation, as well as activated platelet thrombosis. This review discusses the application of ligand-targeted MPIO for in vivo molecular MRI in a diverse range of vascular disease models including acute vascular inflammation, atherosclerosis, thrombosis, ischemia-reperfusion injury and ischemic stroke. The exceptionally conspicuous contrast effects of ligand-conjugated MPIO provide a versatile and sensitive tool for quantitative vascular molecular imaging that could refine diagnosis and measure response to treatment. The potential for clinical translation of this new class of molecular contrast agent for clinical imaging of vascular syndromes is discussed.

Lee JM, Robson MD, Yu LM, Shirodaria CC, Cunnington C, Kylintireas I, Digby JE, Bannister T, Handa A, Wiesmann F et al. 2009. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function: a randomized, placebo-controlled, magnetic resonance imaging study. J Am Coll Cardiol, 54 (19), pp. 1787-1794. | Show Abstract | Read more

OBJECTIVES: Our aim was to determine the effects of high-dose (2 g) nicotinic acid (NA) on progression of atherosclerosis and measures of vascular function. BACKGROUND: NA raises high-density lipoprotein cholesterol (HDL-C) and reduces low-density lipoprotein cholesterol and is widely used as an adjunct to statin therapy in patients with coronary artery disease. Although changes in plasma lipoproteins suggest potential benefit, there is limited evidence of the effects of NA on disease progression when added to contemporary statin treatment. METHODS: We performed a double-blind, randomized, placebo-controlled study of 2 g daily modified-release NA added to statin therapy in 71 patients with low HDL-C (<40 mg/dl) and either: 1) type 2 diabetes with coronary heart disease; or 2) carotid/peripheral atherosclerosis. The primary end point was the change in carotid artery wall area, quantified by magnetic resonance imaging, after 1 year. RESULTS: NA increased HDL-C by 23% and decreased low-density lipoprotein cholesterol by 19%. At 12 months, NA significantly reduced carotid wall area compared with placebo (adjusted treatment difference: -1.64 mm(2) [95% confidence interval: -3.12 to -0.16]; p = 0.03). Mean change in carotid wall area was -1.1 +/- 2.6 mm(2) for NA versus +1.2 +/- 3.0 mm(2) for placebo. In both the treatment and placebo groups, larger plaques were more prone to changes in size (r = 0.4, p = 0.04 for placebo, and r = -0.5, p = 0.02 for NA). CONCLUSIONS: In statin-treated patients with low HDL-C, high-dose modified-release NA, compared with placebo, significantly reduces carotid atherosclerosis within 12 months. (Oxford Niaspan Study: Effects of Niaspan on Atherosclerosis and Endothelial Function; NCT00232531).

Digby JE, McNeill E, Dyar OJ, Lam V, Greaves DR, Choudhury RP. 2010. Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. Atherosclerosis, 209 (1), pp. 89-95. | Show Abstract | Read more

OBJECTIVE: A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin. METHODS AND RESULTS: TNF-alpha treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9+/-3.3-fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24+/-1.2-fold, P<0.001), 'regulated upon activation, normal T cell expressed and secreted' (RANTES) (500+/-55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200+/-70-fold, P<0.05). The addition of NA (10(-4)M) to TNF-alpha-treated adipocytes attenuated expression of fractalkine (50+/-12%, P<0.01); MCP-1 (50+/-6%, P<0.01), RANTES (70+/-3%, P<0.01) and iNOS (60+/-16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27+/-3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10(-6)-10(-3)M) increased, in a dose-dependent manner, mRNA of the atheroprotective hormone adiponectin (3-5-fold n=6, P<0.01). CONCLUSIONS: NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new "pleiotropic" role for NA.

Choudhury RP, Fisher EA. 2009. Molecular imaging in atherosclerosis, thrombosis, and vascular inflammation. Arterioscler Thromb Vasc Biol, 29 (7), pp. 983-991. | Show Abstract | Read more

Appreciation of the molecular and cellular processes of atherosclerosis, thrombosis, and vascular inflammation has identified new targets for imaging. The common goals of molecular imaging approaches are to accelerate and refine diagnosis, provide insights that reveal disease diversity, guide specific therapies, and monitor the effects of those therapies. Here we undertake a comparative analysis of imaging modalities that have been used in this disease area. We consider the elements of contrast agents, emphasizing how an understanding of the biology of atherosclerosis and its complications can inform optimal design. We address the potential and limitations of current contrast approaches in respect of translation to clinically usable agents and speculate on future applications.

von Zur Muhlen C, Sibson NR, Peter K, Campbell SJ, Wilainam P, Grau GE, Bode C, Choudhury RP, Anthony DC. 2008. A contrast agent recognizing activated platelets reveals murine cerebral malaria pathology undetectable by conventional MRI. J Clin Invest, 118 (3), pp. 1198-1207. | Show Abstract | Read more

Human and murine cerebral malaria are associated with elevated levels of cytokines in the brain and adherence of platelets to the microvasculature. Here we demonstrated that the accumulation of platelets in the brain microvasculature can be detected with MRI, using what we believe to be a novel contrast agent, at a time when the pathology is undetectable by conventional MRI. Ligand-induced binding sites (LIBS) on activated platelet glycoprotein IIb/IIIa receptors were detected in the brains of malaria-infected mice 6 days after inoculation with Plasmodium berghei using microparticles of iron oxide (MPIOs) conjugated to a single-chain antibody specific for the LIBS (LIBS-MPIO). No binding of the LIBS-MPIO contrast agent was detected in uninfected animals. A combination of LIBS-MPIO MRI, confocal microscopy, and transmission electron microscopy revealed that the proinflammatory cytokine TNF-alpha, but not IL-1beta or lymphotoxin-alpha (LT-alpha), induced adherence of platelets to cerebrovascular endothelium. Peak platelet adhesion was found 12 h after TNF-alpha injection and was readily detected with LIBS-MPIO contrast-enhanced MRI. Temporal studies revealed that the level of MPIO-induced contrast was proportional to the number of platelets bound. Thus, the LIBS-MPIO contrast agent enabled noninvasive detection of otherwise undetectable cerebral pathology by in vivo MRI before the appearance of clinical disease, highlighting the potential of targeted contrast agents for diagnostic, mechanistic, and therapeutic studies.

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