Simon P S Howarth

Cambridge University Hospitals NHS Foundation Trust, Cambridge, England, United Kingdom

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Publications (38)127.38 Total impact

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    ABSTRACT: Atherosclerosis is a systemic inflammatory disease that may affect multiple arterial beds simultaneously. Vascular distensibility is increasingly used in the clinical assessment of patients with atherosclerotic disease. In this study, we assess distensibility of symptomatic atherosclerotic carotid artery and of contralateral asymptomatic side. We also investigate the distensibility of bilaterally asymptomatic atherosclerotic carotid arteries using cine phase-contrast carotid magnetic resonance (MR) imaging. Nineteen patients with bilateral carotid artery disease underwent cine phase-contrast carotid imaging on a 1.5 T MR system. Ten patients had ipsilateral symptomatic carotid artery disease and contralateral asymptomatic stenosis. Nine additional patients with bilateral asymptomatic carotid artery disease constituted historical control group. Cine phase-contrast MR imaging acquired at the common carotid artery, maximum luminal stenosis, and internal carotid artery was used to determine carotid distensibility bilaterally for carotid arteries in both patient groups. Symptomatic carotid arteries were found to be significantly less distensible (mean distensibility coefficient [DC] 35.4 ± 6.12 × 10(-3)/kPa) than the contralateral asymptomatic vessels (mean DC 54.4 ± 7.88 × 10(-3)/kPa, P = .03) at the level of the common carotid artery. A similar trend of high distensibility for asymptomatic side in the area of maximum stenosis and the internal carotid artery was seen, but it was not found to be statistically significant. Plaque burden was comparable between the 2 groups at all locations. DC was comparable for patients with bilateral asymptomatic carotid artery stenoses. Distensibility of bilaterally asymptomatic carotid arteries was greater than that of asymptomatic carotid artery contralateral to the symptomatic side. Symptomatic carotid artery is stiffer than the contralateral asymptomatic side, despite comparable plaque burden. Patients with bilateral asymptomatic carotid artery disease have comparable stiffness. Larger studies are warranted to further investigate the findings of this MR study.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 10/2013;
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    ABSTRACT: No abstract available.
    Cerebrovascular Diseases 08/2012; 34(2):169-173. · 2.81 Impact Factor
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    ABSTRACT: Aim: To assess the effect of low-(10 mg) or high-(80 mg) dose atorvastatin on carotid artery distensibility in patients with asymptomatic carotid artery disease using carotid magnetic resonance imaging.Methods: Eighteen patients underwent initial 2-dimensional ECG gated-phase contrast carotid MR imaging and off-line applanation tonometry for distensibility assessment before randomisation to receive low- or high-dose statins and this was repeated at 12 weeks. Phase and magnitude images from the 2-D phase contrast acquisitions were used for quantification of distensibility and compliance coefficients and were compared between the low- and high-dose statin groups.Results: Both groups were comparable with regards to their demographics, co-morbidities and baseline cholesterol levels. After 12 weeks of high-dose statin administration, a significant decrease in LDL (p=0.003) and CRP (p=0.03) was observed. At 12 weeks, the distensibility coefficient of the common and internal carotid artery was found to be significantly higher (with respect to baseline) in the high-dose group (p=0.004 and p=0.007, respectively). The compliance coefficient was likewise found to be raised in the high-dose group when compared with the low-dose group [common carotid (p=0.002), internal carotid (p=0.009)].Conclusions: High-dose atorvastatin tends to reduce carotid arterial stiffness, as suggested by increased distensibility and compliance coefficients; however, these results need validation through large-scale trials to fully establish their possible use in clinical practice.
    Journal of atherosclerosis and thrombosis 08/2012; · 2.93 Impact Factor
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    ABSTRACT: BACKGROUND: Inflammation within atheromatous plaques is a known risk factor for plaque vulnerability. This can be detected in vivo on high-resolution magnetic resonance imaging (MRI) using ultrasmall superparamagnetic iron oxide (USPIO) contrast medium. The purpose of this study was to assess the feasibility of performing sequential USPIO studies over a 1-year period. METHODS: Ten patients with moderate asymptomatic carotid stenosis underwent carotid MRI imaging both before and 36 hours after USPIO infusion at 0, 6, and 12 months. Images were manually segmented into quadrants, and the signal change per quadrant was calculated at these time points. A mixed repeated measures statistical model was used to determine signal change attributable to USPIO uptake over time. RESULTS: All patients remained asymptomatic during the study. The mixed model revealed no statistical difference in USPIO uptake between the 3 time points. Intraclass correlation coefficients revealed a good agreement of quadrant signal pre-USPIO infusion between 0 and 6 months (0.70) and 0 and 12 months (0.70). Good agreement of quadrant signal after USPIO infusion was shown between 0 and 6 months (0.68) and moderate agreement was shown between 0 and 12 months (0.33). CONCLUSIONS: USPIO-enhanced sequential MRI of atheromatous carotid plaques is clinically feasible. This may have important implications for future longitudinal studies involving pharmacologic intervention in large patient cohorts.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 07/2012;
  • European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 10/2009; · 2.92 Impact Factor
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    ABSTRACT: Eleven carotid atherothrombotic plaque samples were harvested from patients. Three samples that were highly calcified were discarded, while eight yielded results. The elastic properties of the material were estimated by fitting the measured indentation response to finite element simulations. The methodology was refined and its accuracy quantified using a synthetic rubber. The neo-Hookean form of the material model gave a good fit to the measured response of the tissue. The inferred shear modulus mu was found to be in the range 7-100 kPa, with a median value of 11 kPa. A review of published materials data showed a wide range of material properties for human atherothrombotic tissue. The effects of anisotropy and time dependency in these published results were highlighted. The present measurements were comparable to the static radial compression tests of Lee et al, 1991 [Structure-dependent dynamic behaviour of fibrous caps from human atherosclerotic plaques. Circulation 83, 1764-1770].
    Journal of biomechanics 06/2009; 42(11):1650-5. · 2.66 Impact Factor
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    ABSTRACT: Both carotid plaque morphology and severity of white matter ischaemia (WMI) have been shown to be independent predictors of stroke risk. This study tests the hypothesis that there is an association between carotid plaque morphology as determined by high-resolution carotid MRI and WMI. Forty patients (80 arteries) with at least 40% stenosis on screening Doppler ultrasound were recruited and underwent high-resolution axial carotid MRI at 1.5 T. In a blinded manner, plaque characteristics such as lipid core, fibrous cap, intraplaque haemorrhage, lumen area, plaque area, and American Heart Association (AHA) classification were qualitatively and quantitatively evaluated. The severity of WMI was independently quantified using a modified Scheltens score based on standard brain Fluid-Attenuated Inversion Recovery. Linear mixed effect models were used to test if carotid plaque characteristics could independently predict severity of WMI. Hypertension (p=0.005) and previous a history of transient ischaemic attack or stroke (p=0.038) were found to be significant predictors of severity of WMI. After accounting for confounding variables, no significant association was found between the modified Scheltens score and lipid core size (p=0.122), fibrous cap status (p=0.991), intraplaque haemorrhage (p=0.708), plaque area (0.835), lumen area (0.371) or an AHA Type VI complex plaque (p=0.195). Carotid plaque morphology as defined by MRI does not independently predict severity of WMI.
    European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 06/2009; 38(2):149-54. · 2.92 Impact Factor
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    ABSTRACT: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (DeltaSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (DeltaSI 0.13; p = 0.0003) and at 12 weeks (DeltaSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).
    Journal of the American College of Cardiology 06/2009; 53(22):2039-50. · 14.09 Impact Factor
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    ABSTRACT: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T1-weighted (T1w), T2*-weighted (T2*w) and quantitative T2* (qT2*) imaging. Six patients with an asymptomatic carotid stenosis underwent high resolution T1w, T2*w and qT2* MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T1w, T2*w and qT2* sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T1w, T2*w and qT2*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. This study showed that a suitable imaging window for T1w, T2*w and qT2* signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients.
    Neuroradiology 04/2009; 51(7):457-65. · 2.70 Impact Factor
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    ABSTRACT: The selection of patients for vascular interventions has been solely based on luminal stenosis and symptomatology. However, histological data from both the coronary and carotid vasculature suggest that other plaque features such as inflammation may be more important in predicting future thromboembolic events. Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans. It has reached the stage of development to have been recently used in an interventional drug study to not only assess inflammatory progression but also select patients at high risk. This article reviews the basic science behind the use of USPIO contrast agents in atheroma MR imaging, experimental work in animals, and how this has led to the emergence of this promising targeted imaging platform for assessment of high risk carotid atherosclerosis in humans.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2009; 29(7):1001-8. · 6.34 Impact Factor
  • British Journal of Surgery 01/2009; 96:4-4. · 4.84 Impact Factor
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    ABSTRACT: PET-FDG and USPIO-enhanced MRI are increasingly being used in depicting carotid atheroma inflammation--a risk factor for the high risk plaque. Their combined use has not been previously reported. Two patients presenting with stroke and identified with 50% carotid stenosis on duplex ultrasonography, underwent PET FDG and USPIO-enhanced MR imaging. Results were concordant and complementary suggesting that both techniques reflect similar metabolic processes. The selection of patients for carotid revascularisation has largely been based on the severity of luminal stenosis alone. The two imaging modalities, which identify inflammatory activity, may be potential surrogate risk markers in the selection of patients eligible for carotid surgery, if plaque inflammation can be correlated with risk of developing clinical symptoms.
    European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 08/2008; 36(1):53-5. · 2.92 Impact Factor
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    ABSTRACT: To prospectively evaluate differences in carotid plaque characteristics in symptomatic and asymptomatic patients using high resolution MRI. 20 symptomatic and 20 asymptomatic patients, with at least 50% carotid stenosis as determined by Doppler ultrasound, underwent preoperative in vivo multispectral MRI of the carotid arteries. Studies were analysed both qualitatively and quantitatively in a randomised manner by two experienced readers in consensus, blinded to clinical status, and plaques were classified according to the modified American Heart Association (AHA) criteria. After exclusion of poor quality images, 109 MRI sections in 18 symptomatic and 19 asymptomatic patients were available for analysis. There were no significant differences in mean luminal stenosis severity (72.9% vs 67.6%; p = 0.09) or plaque burden (median plaque areas 50 mm(2) vs 50 mm(2); p = 0.858) between the symptomatic and asymptomatic groups. However, symptomatic lesions had a higher incidence of ruptured fibrous caps (36.5% vs 8.7%; p = 0.004), haemorrhage or thrombus (46.5% vs 14.0%; p<0.001), large necrotic lipid cores (63.8% vs 28.0%; p = 0.002) and complicated type VI AHA lesions (61.5% vs 28.1%; p = 0.001) compared with asymptomatic lesions. The MRI findings of plaque haemorrhage or thrombus had an odds ratio of 5.25 (95% CI 2.08 to 13.24) while thin or ruptured fibrous cap (as opposed to a thick fibrous cap) had an odds ratio of 7.94 (95% CI 2.93 to 21.51) for prediction of symptomatic clinical status. There are significant differences in plaque characteristics between symptomatic and asymptomatic carotid atheroma and these can be detected in vivo by high resolution MRI.
    Journal of neurology, neurosurgery, and psychiatry 08/2008; 79(8):905-12. · 4.87 Impact Factor
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    ABSTRACT: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The study explores the relationship between the degree of Magnetic Resonance (MR)-defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles and the severity of luminal stenosis in asymptomatic carotid plaques. Seventy-one patients with an asymptomatic carotid stenosis of > or = 40% underwent multi-sequence USPIO-enhanced MR imaging. Stenosis severity was measured according to the NASCET and ECST methods. No demonstrable relationship between inflammation as measured by USPIO-enhanced signal change and the degree of luminal stenosis was found. Inflammation and stenosis are likely to be independent risk factors, although this needs to be further validated.
    Stroke 07/2008; 39(7):2144-7. · 6.16 Impact Factor
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    ABSTRACT: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p<0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p<0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p=0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p<0.001). These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.
    European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 04/2008; 35(4):392-8. · 2.92 Impact Factor
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    ABSTRACT: The authors report an in vivo human examination of carotid atheroma by using the inversion-recovery ON resonance (IRON) sequence, which is able to produce positive contrast after the infusion of an ultrasmall super paramagnetic iron oxide (USPIO) contrast medium. This technique provides a method of potentially identifying inflammatory burden within carotid atheroma. This may be particularly useful in patients who currently do not meet criteria for intervention (ie, moderate symptomatic stenosis or <70% asymptomatic stenosis) to further risk-stratify this important patient cohort. A 63-year-old man was imaged at 1.5 T before and 36 hours after USPIO infusion by using the IRON sequence. Regions of interest showing profound signal loss at T(2)*-weighted imaging corresponded well with regions of positive contrast at IRON imaging after the administration of USPIO. These regions also showed a profound decrease in T(2)* measurements after USPIO infusion, whereas surrounding tissue did not. It has been shown that such strong signal loss on T(2)*-weighted images after USPIO infusion is indicative of USPIO uptake.
    Journal of Vascular and Interventional Radiology 03/2008; 19(3):446-8. · 2.00 Impact Factor
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    ABSTRACT: The aim of this study was to explore whether there is a relationship between the degree of MR-defined inflammation using ultra small super-paramagnetic iron oxide (USPIO) particles, and biomechanical stress using finite element analysis (FEA) techniques, in carotid atheromatous plaques. 18 patients with angiographically proven carotid stenoses underwent multi-sequence MR imaging before and 36 h after USPIO infusion. T(2)(*) weighted images were manually segmented into quadrants and the signal change in each quadrant normalised to adjacent muscle was calculated after USPIO administration. Plaque geometry was obtained from the rest of the multi-sequence dataset and used within a FEA model to predict maximal stress concentration within each slice. Subsequently, a new statistical model was developed to explicitly investigate the form of the relationship between biomechanical stress and signal change. The Spearman's rank correlation coefficient for USPIO enhanced signal change and maximal biomechanical stress was -0.60 (p=0.009). There is an association between biomechanical stress and USPIO enhanced MR-defined inflammation within carotid atheroma, both known risk factors for plaque vulnerability. This underlines the complex interaction between physiological processes and biomechanical mechanisms in the development of carotid atheroma. However, this is preliminary data that will need validation in a larger cohort of patients.
    Atherosclerosis 03/2008; 196(2):879-87. · 3.71 Impact Factor
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    ABSTRACT: Inflammation is a risk factor the vulnerable atheromatous plaque. This can be detected in vivo on high-resolution magnetic resonance (MR) imaging using a contrast agent, Sinerem, an ultra-small super-paramagnetic iron oxide (USPIO). The aim of this study was to explore whether there is a difference in the degree of MR defined inflammation using USPIO particles, between symptomatic and asymptomatic carotid plaques. We report further on its T(1) effect of enhancing the fibrous cap, which may allow dual contrast resolution of carotid atheroma. Twenty patients with carotid stenosis (10 symptomatic and 10 asymptomatic) underwent multi-sequence MR imaging before and 36 h post-USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant was calculated following USPIO administration. Mean signal change across all quadrants were compared between the two groups. Symptomatic patients had significantly more quadrants with a signal drop than asymptomatic individuals (75% vs. 32%, p<0.01). Asymptomatic plaques had more quadrants with signal enhancement than symptomatic ones (68% vs. 25%, p<0.05); their mean signal change was also higher (46% vs. 15%, p<0.01) and this appeared to correlate with a thicker fibrous cap on histology. Symptomatic patients had more quadrants with signal drop suggesting larger inflammatory infiltrates. Asymptomatic individuals showed significantly more enhancement possibly suggesting greater stability as a result of thicker fibrous caps. However, some asymptomatic plaques also had focal areas of signal drop, suggesting an occult macrophage burden. If validated by larger studies, USPIO may be a useful dual contrast agent able to improve risk stratification of patients with carotid stenosis and inform selection for intervention.
    European journal of radiology 03/2008; 70(3):555-60. · 2.65 Impact Factor
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    ABSTRACT: Arterial compliance has been shown to correlate well with overall cardiovascular outcome and it may also be a potential risk factor for the development of atheromatous disease. This study assesses the utility of 2-D phase contrast Magnetic Resonance (MR) imaging with intra-sequence blood pressure measurement to determine carotid compliance and distensibility. 20 patients underwent 2-D phase contrast MR imaging and also ultrasound-based wall tracking measurements. Values for carotid compliance and distensibility were derived from the two different modalities and compared. Linear regression analysis was utilised to determine the extent of correlation between MR and ultrasound derived parameters. In those variables that could be directly compared, an agreement analysis was undertaken. MR measures of compliance showed a good correlation with measures based on ultrasound wall-tracking (r=0.61, 95% CI 0.34 to 0.81 p=0.0003). Vessels that had undergone carotid endarterectomy previously were significantly less compliant than either diseased or normal contralateral vessels (p=0.04). Agreement studies showed a relatively poor intra-class correlation coefficient (ICC) between diameter-based measures of compliance through either MR or ultrasound (ICC=0.14). MRI based assessment of local carotid compliance appears to be both robust and technically feasible in most subjects. Measures of compliance correlate well with ultrasound-based values and correlate best when cross-sectional area change is used rather than derived diameter changes. If validated by further larger studies, 2-D phase contrast imaging with intra-sequence blood pressure monitoring and off-line radial artery tonometry may provide a useful tool in further assessment of patients with carotid atheroma.
    Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2008; 2008:1403-6.
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    Stroke 01/2008; 38(12):e156-7; discussion e158-161. · 6.16 Impact Factor