Monica Sigovan

Rapid-Clearance Iron Nanoparticles for Inflammation Imaging of Atherosclerotic Plaque: Initial Experience in Animal Model

PURPOSE To evaluate the use of a recently developed fast-clearing ultrasmall superparamagnetic iron oxide (USPIO) for detection of vascular inflammation in atherosclerotic plaque. MATERIALS AND METHODS The study protocol was approved by the animal experimentation ethics committee. A recently introduced USPIO, P904, and a reference-standard USPIO, ferumoxtran-10, were tested in a rabbit model of induced aortic atherosclerosis. In vivo magnetic resonance (MR) angiography and T2*-weighted plaque MR imaging were performed at baseline and after administration of P904 and ferumoxtran-10 (administered dose for both, 1000 micromol of iron per kilogram of body weight) in 26 hyperlipidemic New Zealand white rabbits. The variation in vessel wall area over time was evaluated with nonparametric testing. Ex vivo MR imaging findings were compared with iron content at linear regression analysis. RESULTS With in vivo MR imaging, plaque analysis was possible as early as 24 hours after P904 injection. The authors observed a 27.75% increase in vessel wall area due to susceptibility artifacts on day 2 (P = .04) and a 38.81% increase on day 3 (P = .04) after P904 administration compared with a 44.5% increase in vessel wall area on day 7 (P = .04) and a 34.8% increase on day 10 (P = .22) after ferumoxtran-10 administration. These susceptibility artifacts were correlated with intraplaque iron uptake in the corresponding histologic slices. The number of pixels with signal loss on the ex vivo MR images was linearly correlated with the logarithm of the iron concentration (P = .0001; R(2) = 0.93). CONCLUSION Plaque inflammation in rabbits can be detected earlier with P904 than with ferumoxtran-10 owing to the faster blood pharmacokinetics and the early uptake of P904 in the reticuloendothelial system. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/252/2/401/DC1.

Comparison of four-dimensional flow parameters for quantification of flow eccentricity in the ascending aorta

To compare quantitative parameters for assessing the degree of eccentric systolic blood flow in the ascending thoracic aorta (AsAo).

Imaging Biomarkers of Aortic Disease: Increased Growth Rates With Eccentric Systolic Flow

To the Editor: Is the aortic dilation that is commonly seen with bicuspid aortic valve (BAV) related to intrinsic aortic wall fragility or altered systolic hemodynamics? Recent publications on the topic favor the intrinsic fragility hypothesis. But recent advancements in imaging show very abnormal

MRI hemodynamic markers of progressive bicuspid aortic valve-related aortic disease.

To determine the reproducibility of MRI aortic hemodynamic markers and to assess their relationship to aortic growth in a cohort of patients with bicuspid aortic valves (BAV).

Assessment of age modulated vascular inflammation in ApoE-/- mice by USPIO-enhanced magnetic resonance imaging.

Objective:Inflammation within atherosclerotic lesions increases the risk for plaque rupture and thrombosis. A functional approach to plaque analysis is the intravenous administration of ultrasmall superparamagnetic particles of iron oxide (USPIO) that enables visualization of macrophages residing in the plaques. In this study, we sought to characterize the age-related inflammatory status associated with atherosclerosis lesion progression in ApoE−/− mice using USPIO-enhanced magnetic resonance imaging (MRI). Materials and Methods:A total of 24 ApoE −/− mice were divided in 4 groups (N = 6) and were given a high cholesterol diet from 6 weeks of age to the end of the protocol. One group per MR time point was investigated at 10, 16, 24, and 34 weeks of age. Each MR examination was performed on a 4.7 T scanner and consisted of baseline and 48 hours post-USPIO administration imaging sessions. P904, a USPIO contrast agent (Guerbet, Paris, France) with a potential for plaque macrophage targeting, was used.Vessel wall area measurements were performed on high resolution spin echo transverse images. Multi-echo gradient-echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. A one-way analysis of variance was performed to characterize the temporal variation of vessel wall area, susceptibility artifact area, baseline, and post-USPIO T2* values. MR measurements were correlated with the histologic findings. Results:A significant increase was found in the aortic wall area from 1.4 ± 0.2 at 10 weeks to 2.0 ± 0.3 mm2 at 34 weeks of age (P < 0.05). Concerning the post-USPIO MRI, signal loss regions, with patterns spanning from focal to the complete disappearance of the vessel wall, were observed on all postcontrast images. A significant increase in the size of the susceptibility artifact was observed from 0.5 ± 0.2 to 2.4 ± 1.0 at 24 weeks (P < 0.05) and to 2.0 ± 0.9 mm2 at 34 weeks (P < 0.05).The T2* values calculated on the 48 hours post-USPIO images were shorter compared with baseline. The decrease was 34% ± 16% at 10 weeks, 57% ± 11% at 16 weeks, 57% ± 16% at 24 weeks, and 48% ± 13% at 34 weeks.The Pearsons correlation test between measurement of aortic wall area performed on both MR images and histologic analysis showed a statistically significant correlation (r = 0.695 and P < 0.05). A correlation was also obtained between the signal loss area and the macrophages covered area (r = 0.68 and P < 0.05). Conclusions:This study demonstrated the feasibility of USPIO-enhanced MRI in assessing the inflammatory status related to the temporal progression of the atherosclerosis plaque in ApoE−/− transgenic mice model of atherosclerosis. In our experimental conditions, the vascular inflammation peak, for the ApoE−/− mice feeding high-fat/high-cholesterol diet is measured between 16 and 24 weeks of age.

USPIO-enhanced MR Angiography of Arteriovenous Fistulas in Patients with Renal Failure

PURPOSE To determine the feasibility of using ferumoxytol-enhanced magnetic resonance (MR) angiography to depict the vasculature of hemodialysis fistulas and improve image quality compared with nonenhanced time-of-flight (TOF) MR angiography. MATERIALS AND METHODS The study was institutional review board approved and was in compliance with HIPAA regulations. All participants provided written informed consent. TOF and first-pass ferumoxytol-enhanced MR angiography were performed in 10 patients with upper extremity autogenous fistulas. Ferumoxytol was administered as a bolus solution containing 430 μmol of elemental iron. A qualitative comparison was performed on maximum intensity projection images. Lumen depiction was evaluated by using a five-point scale. The uniformity of intraluminal signal intensity was measured as the ratio between the mean signal intensity of the entirety of the imaged fistula and its standard deviation. The contrast-to-noise ratio (CNR) between intraluminal signal and adjacent tissue was evaluated as a function of image acquisition time. Lumen depiction scores, luminal signal heterogeneity, and CNR efficiency were compared between TOF and ferumoxytol-enhanced MR angiography by using a Wilcoxon-Mann-Whitney test. RESULTS Flow artifacts were greatly reduced by the use of ferumoxytol-enhanced MR angiography. Ferumoxytol-enhanced MR angiography had significantly better performance than TOF MR angiography as measured with the following: lumen depiction scores in all segments (mean, 4.7±0.1 [standard error of the mean]; vs 3.0±0.3 for arterial inflow, 4.1±0.3 vs 1.9±0.3 for arterial outflow, 3.7±0.3 vs 1.8±0.2 for anastomosis, and 4.5±0.2 vs 2.1±0.2 for venous outflow; P<.001), intraluminal signal homogeneity (0.3±0.02 vs 0.4±0.06, P=.005), and CNR efficiency in the venous outflow (5.1±0.6 vs 2.5±0.4, P=.01). CONCLUSION This study demonstrates the feasibility of using ferumoxytol-enhanced MR angiography in imaging hemodialysis fistulas with consistently superior image quality compared with nonenhanced TOF MR angiography.

Anti-inflammatory drug evaluation in ApoE-/- mice by ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging.

ObjectivesThe renin-angiotensin system and local phagocytic activity play a major role in atherosclerotic plaque development. Treatment with irbesartan, an antagonist of angiotensin II receptor, can decrease atherosclerotic lesion formation. Iron oxide–enhanced magnetic resonance imaging (MRI) can be successfully used to evaluate the phagocytic activity in the atherosclerotic plaque in mice. In this study, we used 2 iron oxide–enhanced MRI strategies, in vivo labeling by injection of iron oxide particles and injection of in vitro labeled macrophages, to investigate the effect of irbesartan on both atherosclerotic plaque size and macrophage content in apolipoprotein (Apo) E–deficient mice. Materials and MethodsApoE−/− female mice (C57BL/6 background; Charles-River, France) were divided into 2 groups (irbesartan treated [TG] or not treated [NTG]) and started on a high-fat diet (Harlan TD88137 Western Diet, 21% fat, 0.2% cholesterol). Animals underwent magnetic resonance examinations on a 7-T scanner at baseline and at 14 and 28 weeks of treatment. At each time point, 2 MRI sessions were performed, before and 48 hours after administration of an iron oxide agent (P904; Guerbet, France) or magnetically labeled macrophages (MФ&PHgr;). At the end of the follow-up, blood samples were taken for plasma lipid dosing and aorta samples for histology. The study was approved by the animal experimentation ethic committee of our institution.Vessel wall area measurements were performed on high-resolution spin echo transverse images. Multiecho gradient echo images acquired with the same geometry were used to calculate T2* maps of the vessel wall using a pixel-by-pixel monoexponential fit. Irbesartan effect on vessel wall area over time was assessed using a factorial analysis of variance test. T2* values of the vessel wall at pre– and post–ultrasmall superparamagnetic iron oxide (USPIO) administration were analyzed with a 1-way analysis of variance test with Bonferroni post hoc. ResultsIrbesartan treatment resulted in significantly smaller vessel wall areas at 28 weeks of treatment (P = 0.04). Postinjection values varied significantly over time for both the NTG-P904 (P = 0.02) and the TG-P904 (P = 0.01) groups. Furthermore, when comparing the TG-P904 with the NTG-P904 group at 28 weeks of treatment, a significant difference was obtained for both pre– and post–USPIO administration values (P = 0.01). In the labeled-macrophage group, postinjection T2* values were smaller than the preinjection ones for the NTG animals at 14 weeks of treatment. No T2* changes were observed in the TG-M&PHgr; group.The difference between pre– and post–USPIO administration T2* values (&Dgr;T2*) was significantly smaller in the TG-P904 group compared with the NTG-P904 group at 28 weeks of treatment. At this point, a good correlation (R = 0.7, P = 0.03) was found between the &Dgr;T2* values in the P904 imaging group and the macrophage-covered area by immunohistological analysis. ConclusionsThe present study illustrates an MRI follow-up of intraplaque macrophages using in vivo labeling by iron oxide particle injection and macrophage injection after in vitro USPIO labeling in the assessment of a therapeutic effect in a mouse model of atherosclerosis. Even though in vivo labeling is not fully specific of macrophage uptake, it enabled the detection of a treatment-related reduction in the macrophage content of atherosclerotic plaques in ApoE−/− mice.

Systolic flow displacement correlates with future ascending aortic growth in patients with bicuspid aortic valves undergoing magnetic resonance surveillance.

ObjectivesAltered systolic blood flow in the ascending aorta has been correlated with increased aortic growth in patients with bicuspid aortic valves (BAVs). We used conventional, 2-dimensional (2D) phase contrast magnetic resonance imaging (PC-MRI) to assess the relationship between altered flow and future growth in patients with BAV. Materials and MethodsAortic MRI data were reviewed for 17 adult patients with BAV with right-left leaflet fusion undergoing surveillance imaging who had 2D PC-MRI through their ascending aortas on an initial study, follow-up studies more than 1 year later, and an initial maximum aortic diameter of less than 4.5 cm. Diameters were measured at standard levels by 2 blinded reviewers. Normalized systolic flow displacement was calculated at peak systole from the PC-MRI data, and correlation with the interval aortic growth was performed, with adjustment for clinical/demographic factors. ResultsThe average follow-up interval was 2.9 ± 1.3 years. Systolic flow displacement at the initial study strongly correlated with ascending aortic growth rate (r = 0.71, P < 0.005) with moderate, non–significant correlation between initial diameter and growth (r = 0.45, P = 0.214). Aortic growth was 4 times faster in patients with initial flow displacement of 0.2 or greater (n = 9) compared with those (n = 8) with initial flow displacement less than 0.2 (0.8 ± 0.4 vs 0.2 ± 0.3 mm/y; P = 0.002). ConclusionsSystolic flow displacement calculated from conventional 2D PC-MRI in the ascending aorta correlates with future aortic growth in patients undergoing routine surveillance imaging for BAV. With a cutoff valve of 0.2, flow displacement may be used to identify a subset of patients likely to have elevated growth rates and may better risk-stratify patients with BAV for aortic disease progression than vessel diameter alone.

Photon counting spectral CT component analysis of coronary artery atherosclerotic plaque samples

OBJECTIVE To evaluate the capabilities of photon counting spectral CT to differentiate components of coronary atherosclerotic plaque based on differences in spectral attenuation and iodine-based contrast agent concentration. METHODS 10 calcified and 13 lipid-rich non-calcified histologically demonstrated atheromatous plaques from post-mortem human coronary arteries were scanned with a photon counting spectral CT scanner. Individual photons were counted and classified in one of six energy bins from 25 to 70 keV. Based on a maximum likelihood approach, maps of photoelectric absorption (PA), Compton scattering (CS) and iodine concentration (IC) were reconstructed. Intensity measurements were performed on each map in the vessel wall, the surrounding perivascular fat and the lipid-rich and the calcified plaques. PA and CS values are expressed relative to pure water values. A comparison between these different elements was performed using Kruskal-Wallis tests with pairwise post hoc Mann-Whitney U-tests and Sidak p-value adjustments. RESULTS RESULTS for vessel wall, surrounding perivascular fat and lipid-rich and calcified plaques were, respectively, 1.19 ± 0.09, 0.73 ± 0.05, 1.08 ± 0.14 and 17.79 ± 6.70 for PA; 0.96 ± 0.02, 0.83 ± 0.02, 0.91 ± 0.03 and 2.53 ± 0.63 for CS; and 83.3 ± 10.1, 37.6 ± 8.1, 55.2 ± 14.0 and 4.9 ± 20.0 mmol l(-1) for IC, with a significant difference between all tissues for PA, CS and IC (p < 0.012). CONCLUSION This study demonstrates the capability of energy-sensitive photon counting spectral CT to differentiate between calcifications and iodine-infused regions of human coronary artery atherosclerotic plaque samples by analysing differences in spectral attenuation and iodine-based contrast agent concentration. ADVANCES IN KNOWLEDGE Photon counting spectral CT is a promising technique to identify plaque components by analysing differences in iodine-based contrast agent concentration, photoelectric attenuation and Compton scattering.

Ferumoxytol-Enhanced Magnetic Resonance Angiography is a Feasible Method for the Clinical Evaluation of Lower Extremity Arterial Disease

BACKGROUND Renal toxicity from conventional, iodinated, intravenous contrast agents is a common complication in patients with peripheral artery disease (PAD). Similarly, the potential for serious side effects prevents the use of gadolinium-based agents in many patients with depressed renal function. Ferumoxytol-enhanced magnetic resonance angiography (Fe-MRA) is a novel technique that uses an intravenous, ultrasmall, superparamagnetic, iron oxide preparation, currently approved by the Food and Drug Administration for the treatment of iron deficiency anemia in adults with chronic kidney disease. Our objective was to determine the feasibility of Fe-MRA for clinical decision making in PAD patients. METHODS This was a prospective pilot study assessing 10 patients with suspected arterial occlusive disease with contrast-enhanced MRA of the aorta and lower extremities. Of those, 5 had renal insufficiency and were imaged with Fe-MRA, whereas the remainder underwent gadolinium-enhanced MRA. Qualitative and quantitative evaluations of deidentified images at each arterial station were independently performed by 4 blinded vascular surgeons. RESULTS All patients were men, with an average age of 68 ± 4 years. The 2 groups had similar incidences of diabetes, hypertension, hyperlipidemia, and coronary artery disease. Patients undergoing Fe-MRA had significantly decreased renal function (estimated glomerular filtration rate, 35.4 vs. 77.6; P = 0.02). There were no adverse events during contrast administration in either group. No difference was found in the overall quality of the ferumoxytol versus the gadolinium studies (7.1 ± 2.0 vs. 7.4 ± 2.4, P = 0.67). Similarly, reviewers felt comfortable basing clinical decisions on the images 89% of the time with both the ferumoxytol and gadolinium groups (P = 1.00). CONCLUSIONS This is the first report of an important alternative to conventional computed tomography angiography and MRA in PAD patients, particularly in the setting of renal insufficiency. Fe-MRA provides a useful tool in patients with suspected lower extremity PAD without the potential risks of gadolinium.