J. M. U-King-Im

Identifying Inflamed Carotid Plaques Using In Vivo USPIO-Enhanced MR Imaging to Label Plaque Macrophages

Background—Inflammation within atherosclerotic lesions contributes to plaque instability and vulnerability to rupture. We set out to evaluate the use of a macrophage labeling agent to identify carotid plaque inflammation by in vivo magnetic resonance imaging (MRI). Methods and Results—Thirty patients with symptomatic severe carotid stenosis scheduled for carotid endarterectomy underwent multi-sequence MRI of the carotid bifurcation before and after injection of ultrasmall superparamagnetic particles of iron oxide (USPIOs). USPIO particles accumulated in macrophages in 24 of 30 plaques (80%). Areas of signal intensity reduction, corresponding to USPIO/macrophage-positive histological sections, were visualized in 24 of 27 (89%) patients, with an average reduction in signal intensity induced by the USPIO particles of 24% (range, 3.1% to 60.8%). Conclusions—USPIO-enhanced MRI can identify plaque inflammation in vivo by accumulation of USPIO within macrophages in carotid plaques.

In Vivo Detection of Macrophages in Human Carotid Atheroma: Temporal Dependence of Ultrasmall Superparamagnetic Particles of Iron Oxide-Enhanced MRI

Background— It has been suggested that inflammatory cells within vulnerable plaques may be visualized by superpara-magnetic iron oxide particle–enhanced MRI. The purpose of this study was to determine the time course for macrophage visualization with in vivo contrast–enhanced MRI using an ultrasmall superparamagnetic iron oxide (USPIO) agent in symptomatic human carotid disease. Methods— Eight patients scheduled for carotid endarterectomy underwent multisequence MRI of the carotid bifurcation before and 24, 36, 48, and 72 hours after Sinerem (2.6 mg/kg) infusion. Results— USPIO particles accumulated in macrophages in 7 of 8 patients given Sinerem. Areas of signal intensity reduction, corresponding to USPIO/macrophage–positive histological sections, were visualized in all 7 of these patients, optimally between 24 and 36 hours, decreasing after 48 hours, but still evident up to 96 hours after infusion. Conclusions— USPIO-enhanced MRI of carotid atheroma can be used to identify macrophages in vivo. The temporal change in the resultant signal intensity reduction on MRI suggests an optimal time window for the detection of macrophages on postinfusion imaging.

MRI-derived measurements of fibrous-cap and lipid-core thickness: the potential for identifying vulnerable carotid plaques in vivo

Vulnerable plaques have thin fibrous caps overlying large necrotic lipid cores. Recent studies have shown that high-resolution MR imaging can identify these components. We set out to determine whether in vivo high-resolution MRI could quantify this aspect of the vulnerable plaque. Forty consecutive patients scheduled for carotid endarterectomy underwent pre-operative in vivo multi-sequence MR imaging of the carotid artery. Individual plaque constituents were characterised on MR images. Fibrous-cap and lipid-core thickness was measured on MRI and histology images. Bland-Altman plots were generated to determine the level of agreement between the two methods. Multi-sequence MRI identified 133 corresponding MR and histology slices. Plaque calcification or haemorrhage was seen in 47 of these slices. MR and histology derived fibrous cap–lipid-core thickness ratios showed strong agreement with a mean difference between MR and histology ratios of 0.02 (±0.04). The intra-class correlation coefficient between two readers for measurements was 0.87 (95% confidence interval, 0.73 and 0.93). Multi-sequence, high-resolution MR imaging accurately quantified the relative thickness of fibrous-cap and lipid-core components of carotid atheromatous plaques. This may prove to be a useful tool to characterise vulnerable plaques in vivo.

Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous cap: A comparison of symptomatic and asymptomatic individuals

BACKGROUND AND PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Contrast-enhanced MR angiography for carotid disease Diagnostic and potential clinical impact

Objective: To compare contrast-enhanced MR angiography (CEMRA) with intra-arterial digital subtraction angiography (DSA) for evaluating carotid stenosis. Methods: A total of 167 consecutive symptomatic patients, scheduled for DSA following screening duplex ultrasound (DUS), were prospectively recruited to have CEMRA. Three independent readers reported on each examination in a blinded and random manner. Agreement was assessed using the Bland-Altman method. Diagnostic and potential clinical impact of CEMRA was evaluated, singly and in combination with DUS. Results: CEMRA tended to overestimate stenosis by a mean bias ranging from 2.4 to 3.8%. A significant part of the disagreement between CEMRA and DSA was directly caused by interobserver variability. For detection of severe stenosis, CEMRA alone had a sensitivity of 93.0% and specificity of 80.6%, with a diagnostic misclassification rate of 15.0% (n = 30). More importantly, clinical decision-making would, however, have been potentially altered only in 6.0% of cases (n = 12). The combination of concordant DUS and CEMRA reduced diagnostic misclassification rate to 10.1% (n = 19) at the expense of 47 (24.9%) discordant cases needing to proceed to DSA. An intermediate approach of selective DUS review resulted in a marginally worse diagnostic misclassification rate of 11.6% (n = 22) but with only 6.8% of discordant cases (n = 13). Conclusions: DSA remains the gold standard for carotid imaging. The clinical misclassification rate with CEMRA, however, is acceptably low to support its safe use instead of DSA. The appropriateness of combination strategies depends on institutional choice and cost-effectiveness issues.

Noninvasive imaging of carotid plaque inflammation

Ischemic stroke occurs as a result of thromboembolism from ruptured carotid atheromatous plaques.1,2⇓ Histologic data from coronary atherosclerosis has suggested that plaque rupture may be predictable by thinness of fibrous caps that overlie large necrotic lipid cores and by the presence of large numbers of active macrophages.3 Therefore, identification of such “vulnerable” plaques has the potential to offer early aggressive pharmacotherapy, refine patient selection for surgery, and identify asymptomatic subjects thought to be at high risk of atherosclerosis based on risk factor assessment. High-resolution MRI of the carotid bifurcation has demonstrated that the fibrous cap and lipid core components can be identified using a multisequence algorithm4 and that such a technique may form the basis for automated classification of the diseased vessel.5 However, these techniques only provide structural and morphologic plaque characteristics. Invasive studies using …

Correlation of Carotid Atheromatous Plaque Inflammation Using USPIO-Enhanced MR Imaging With Degree of Luminal Stenosis

Background and Purpose— 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. Methods— Seventy-one patients with an asymptomatic carotid stenosis of ≥40% underwent multi-sequence USPIO-enhanced MR imaging. Stenosis severity was measured according to the NASCET and ECST methods. Results— No demonstrable relationship between inflammation as measured by USPIO-enhanced signal change and the degree of luminal stenosis was found. Conclusions— Inflammation and stenosis are likely to be independent risk factors, although this needs to be further validated.

Comparison of the Inflammatory Burden of Truly Asymptomatic Carotid Atheroma with Atherosclerotic Plaques in Patients with Asymptomatic Carotid Stenosis Undergoing Coronary Artery Bypass Grafting: An Ultrasmall Superparamagnetic Iron Oxide Enhanced Magnetic Resonance Study

INTRODUCTION 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). METHODS 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. RESULTS 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). CONCLUSIONS 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.

Correlation of macrophage location and plaque stress distribution using USPIO-enhanced MRI in a patient with symptomatic severe carotid stenosis: a new insight into risk stratification

High resolution, USPIO-enhanced MR imaging can be used to identify inflamed atherosclerotic plaque. We report a case of a 79-year-old man with a symptomatic carotid stenosis of 82%. The plaque was retrieved for histology and finite element analysis (FEA) based on the preoperative MR imaging was used to predict maximal Von Mises stress on the plaque. Macrophage location correlated with maximal predicted stresses on the plaque. This supports the hypothesis that macrophages thin the fibrous cap at points of highest stress, leading to an increased risk of plaque rupture and subsequent stroke.

Non-invasive MR imaging of inflammation in a patient with both asymptomatic carotid atheroma and an abdominal aortic aneurysm: a case report.

Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque.USPIO-enhanced MRI imaging is a promising non-invasive method to identify high-risk atheromatous plaque inflammation in vivo in humans, in which areas of focal signal loss on MR images have been shown to correspond to the location of activated macrophages, typically at the shoulder regions of the plaque. This is the first report in humans describing simultaneous USPIO uptake within atheroma in two different arterial territories and again emphasises that atherosclerosis is a truly systemic disease. With further work, USPIO-enhanced MR imaging may be useful in identifying inflamed vulnerable atheromatous plaques in vivo, so refining patient selection for intervention and allowing appropriate early aggressive pharmacotherapy to prevent plaque rupture.