Introduction: We have previously demonstrated that non-contrast MRI using magnetisation transfer ... more Introduction: We have previously demonstrated that non-contrast MRI using magnetisation transfer rate (MTR), apparent diffusion coefficient (ADC) and T1 mapping can characterise different aspects of organisation in a resolving venous thrombus. We now investigate whether the combination of these non-contrast agent MRI sequences can be used to identify thrombi suitable for lysis in an experimental model, and whether multi-sequence thrombus imaging (MSTI) can be translated to man. Methods: Magnetisation transfer, diffusion weighted images and T1 relaxation times were measured at days 2, 4, 7, 10, 14, 21 and 28 after venous thrombus induction in 8-10wk old male BALB/C mice (n=8/gp). Tissue plasminogen activator (10mg/kg) was administered through tail vein injection immediately after imaging at each time point and mice scanned 24hrs later to evaluate the effect of lysis. This was considered successful if more than 50% of the vein recanalised. Murine imaging sequences were combined and optimised to image the pelvic veins in man using healthy volunteers in order to produce a clinically useable imaging card. MSTI sequences were validated using phantoms before application to patients with iliofemoral deep vein thrombosis (DVT) undergoing lysis. Results: ROC curve analysis shows that the combination of MTR smaller than 2,900(%/cm3), ADC larger than 0.93(x10-3 mm2/s) and T1 shorter than 784ms has a sensitivity of 88% and specificity of 97% to identify experimental thrombi amenable to lysis. MSTI is feasible in man, with optimisation leading to successful characterisation of iliofemoral DVT in under 25mins (Figure 1). Conclusions: Non-contrast MR imaging, using a combination of MTR, ADC and T1 mapping, accurately identifies experimental venous thrombi susceptible to lysis. These MSTI sequences can also be readily translated to man where may find utility in characterising the age and structure of thrombus, and to stratify patients undergoing thrombolysis.
Introduction: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta. Apart from ... more Introduction: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta. Apart from the miR-29 family, miR-195 has been implicated in the regulation of the vascular extracellular matrix (ECM). Our aim was to assess the effect of the miR-15 family in aneurysm formation. Methods and Results: Expression of the miR-15 and miR-29 families was assessed in human aortic tissue. In human aneurysmal tissue, miR-195 expression was reduced to the same extent as miR-29b. In plasma, an inverse correlation of miR-195 was observed with the presence of AAA and aortic diameter. To evaluate the effect of miR-195 in ECM deposition, proteomics analysis was performed on the secretome of murine aortic smooth muscle cells (SMCs) following miRNA manipulation. MiR-195 targeted a cadre of ECM proteins, including collagens, proteoglycans, elastin and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect. Systemic administration of cholesterol bound antagomiRs revea...
Magnetic Resonance Materials in Physics, Biology and Medicine, 2020
Objective To develop a three-dimensional (3D) high-resolution free-breathing magnetization transf... more Objective To develop a three-dimensional (3D) high-resolution free-breathing magnetization transfer ratio (MTR) sequence for contrast-free assessment of myocardial infarct and coronary vein anatomy. Materials and methods Two datasets with and without off-resonance magnetization transfer preparation were sequentially acquired to compute MTR. 2D image navigators enabled beat-to-beat translational and bin-to-bin non-rigid motion correction. Two different imaging sequences were explored. MTR scar localization was compared against 3D late gadolinium enhancement (LGE) in a porcine model of myocardial infarction. MTR variability across the left ventricle and vessel sharpness in the coronary veins were evaluated in healthy human subjects. Results A decrease in MTR was observed in areas with LGE in all pigs (non-infarct: 25.1 ± 1.7% vs infarct: 16.8 ± 1.9%). The average infarct volume overlap on MTR and LGE was 62.5 ± 19.2%. In humans, mean MTR in myocardium was between 37 and 40%. Spatial v...
There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis prog... more There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, since it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression. Netrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNFα either in the presence or absence of aspirin treatment. In vivo experiments were conducted in ApoE(-/-) mice fed a high-fat diet (HFD), receiving either aspirin or clopidogrel. TNFα-induced NF-êB activation up-regulated the nuclear isoform of netrin-1, whilst simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent ac...
Background Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magn... more Background Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging ( MRI ) using an albumin‐binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high‐fat diet ( HFD )–fed ApoE −/− mice. Methods and Results ApoE −/− mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD . HFD ‐fed ApoE −/− mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed‐enhancement MRI and T 1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R 1 , s −1 ) in untreated HFD ‐fed ApoE −/− mice (R 1 =3.8±0.52 s −1 ) compared with controls (R 1 =2.15±0.34 s −1 , P <0.001). Conversely, minocycline‐treated (R 1 =2.7±0.17 s −1 , P <0.001) and ebselen‐treated (R 1 =2...
In this report, we describe the synthesis and use of bifunctional Gd-containing semiconductor pol... more In this report, we describe the synthesis and use of bifunctional Gd-containing semiconductor polymer nanoparticles (SPNs).
Arteriosclerosis, thrombosis, and vascular biology, 2014
Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanal... more Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus' fibrin content in vivo and for the identification of thrombus suitable for thrombolysis. Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus' histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to...
Introduction: We have previously demonstrated that non-contrast MRI using magnetisation transfer ... more Introduction: We have previously demonstrated that non-contrast MRI using magnetisation transfer rate (MTR), apparent diffusion coefficient (ADC) and T1 mapping can characterise different aspects of organisation in a resolving venous thrombus. We now investigate whether the combination of these non-contrast agent MRI sequences can be used to identify thrombi suitable for lysis in an experimental model, and whether multi-sequence thrombus imaging (MSTI) can be translated to man. Methods: Magnetisation transfer, diffusion weighted images and T1 relaxation times were measured at days 2, 4, 7, 10, 14, 21 and 28 after venous thrombus induction in 8-10wk old male BALB/C mice (n=8/gp). Tissue plasminogen activator (10mg/kg) was administered through tail vein injection immediately after imaging at each time point and mice scanned 24hrs later to evaluate the effect of lysis. This was considered successful if more than 50% of the vein recanalised. Murine imaging sequences were combined and optimised to image the pelvic veins in man using healthy volunteers in order to produce a clinically useable imaging card. MSTI sequences were validated using phantoms before application to patients with iliofemoral deep vein thrombosis (DVT) undergoing lysis. Results: ROC curve analysis shows that the combination of MTR smaller than 2,900(%/cm3), ADC larger than 0.93(x10-3 mm2/s) and T1 shorter than 784ms has a sensitivity of 88% and specificity of 97% to identify experimental thrombi amenable to lysis. MSTI is feasible in man, with optimisation leading to successful characterisation of iliofemoral DVT in under 25mins (Figure 1). Conclusions: Non-contrast MR imaging, using a combination of MTR, ADC and T1 mapping, accurately identifies experimental venous thrombi susceptible to lysis. These MSTI sequences can also be readily translated to man where may find utility in characterising the age and structure of thrombus, and to stratify patients undergoing thrombolysis.
Introduction: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta. Apart from ... more Introduction: Abdominal aortic aneurysm (AAA) is a degenerative disease of the aorta. Apart from the miR-29 family, miR-195 has been implicated in the regulation of the vascular extracellular matrix (ECM). Our aim was to assess the effect of the miR-15 family in aneurysm formation. Methods and Results: Expression of the miR-15 and miR-29 families was assessed in human aortic tissue. In human aneurysmal tissue, miR-195 expression was reduced to the same extent as miR-29b. In plasma, an inverse correlation of miR-195 was observed with the presence of AAA and aortic diameter. To evaluate the effect of miR-195 in ECM deposition, proteomics analysis was performed on the secretome of murine aortic smooth muscle cells (SMCs) following miRNA manipulation. MiR-195 targeted a cadre of ECM proteins, including collagens, proteoglycans, elastin and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect. Systemic administration of cholesterol bound antagomiRs revea...
Magnetic Resonance Materials in Physics, Biology and Medicine, 2020
Objective To develop a three-dimensional (3D) high-resolution free-breathing magnetization transf... more Objective To develop a three-dimensional (3D) high-resolution free-breathing magnetization transfer ratio (MTR) sequence for contrast-free assessment of myocardial infarct and coronary vein anatomy. Materials and methods Two datasets with and without off-resonance magnetization transfer preparation were sequentially acquired to compute MTR. 2D image navigators enabled beat-to-beat translational and bin-to-bin non-rigid motion correction. Two different imaging sequences were explored. MTR scar localization was compared against 3D late gadolinium enhancement (LGE) in a porcine model of myocardial infarction. MTR variability across the left ventricle and vessel sharpness in the coronary veins were evaluated in healthy human subjects. Results A decrease in MTR was observed in areas with LGE in all pigs (non-infarct: 25.1 ± 1.7% vs infarct: 16.8 ± 1.9%). The average infarct volume overlap on MTR and LGE was 62.5 ± 19.2%. In humans, mean MTR in myocardium was between 37 and 40%. Spatial v...
There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis prog... more There are conflicting data regarding whether netrin-1 retards or accelerates atherosclerosis progression, since it can lead either to monocyte repulsion from or retention within plaques depending on its cellular source. We investigated the effect of aspirin, which is widely used in cardiovascular prophylaxis, on the synthesis of different isoforms of netrin-1 by endothelial cells under pro-inflammatory conditions, and defined the net effect of aspirin-dependent systemic modulation of netrin-1 on atherosclerosis progression. Netrin-1 synthesis was studied in vitro using human endothelial cells stimulated with TNFα either in the presence or absence of aspirin treatment. In vivo experiments were conducted in ApoE(-/-) mice fed a high-fat diet (HFD), receiving either aspirin or clopidogrel. TNFα-induced NF-êB activation up-regulated the nuclear isoform of netrin-1, whilst simultaneously reducing secreted netrin-1. Down-regulation of the secreted isoform compromised the chemorepellent ac...
Background Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magn... more Background Endothelial dysfunction promotes atherosclerosis. We investigated whether in vivo magnetic resonance imaging ( MRI ) using an albumin‐binding contrast agent, gadofosveset, could monitor the efficacy of minocycline and ebselen in reducing endothelial permeability and atherosclerotic burden in the brachiocephalic artery of high‐fat diet ( HFD )–fed ApoE −/− mice. Methods and Results ApoE −/− mice were scanned 12 weeks after commencement of either a normal diet (controls) or an HFD . HFD ‐fed ApoE −/− mice were either untreated or treated with minocycline or ebselen for 12 weeks. Delayed‐enhancement MRI and T 1 mapping of the brachiocephalic artery, 30 minutes after injection of gadofosveset, showed increased vessel wall enhancement and relaxation rate (R 1 , s −1 ) in untreated HFD ‐fed ApoE −/− mice (R 1 =3.8±0.52 s −1 ) compared with controls (R 1 =2.15±0.34 s −1 , P <0.001). Conversely, minocycline‐treated (R 1 =2.7±0.17 s −1 , P <0.001) and ebselen‐treated (R 1 =2...
In this report, we describe the synthesis and use of bifunctional Gd-containing semiconductor pol... more In this report, we describe the synthesis and use of bifunctional Gd-containing semiconductor polymer nanoparticles (SPNs).
Arteriosclerosis, thrombosis, and vascular biology, 2014
Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanal... more Deep venous thrombosis is a major health problem. Thrombolytic therapies are effective in recanalizing the veins and preventing post-thrombotic complications, but there is no consensus on selection criteria. The aim of this study was to investigate a fibrin-specific MRI contrast agent (EP-2104R) for the accurate quantification of thrombus' fibrin content in vivo and for the identification of thrombus suitable for thrombolysis. Venous thrombosis was induced in the inferior vena cava of 8- to 10-week-old male BALB/C mice and MRI performed 2, 4, 7, 10, 14, and 21 days later. Eighteen mice were scanned at each time point pre and 2 hours post injection of EP-2104R (8.0 μmol/kg) with 12 mice at each time point used to correlate fibrin contrast uptake with thrombus' histological stage and fibrin content. Six mice at each time point were immediately subjected to intravascular thrombolytic therapy (10 mg/kg of tissue-type plasminogen activator). Mice were imaged to assess response to...
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