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      Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis

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          Abstract

          Background

          The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR.

          Methods

          Lewis rats were induced to develop autoimmune myocarditis. CMR (3 T, GE Signa) was performed at the early- (day 14, n = 7) and the peak-phase (day 21, n = 8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24 h (6 h- & 24 h-FE-CMR) following the administration of ferumoxytol (300μmolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5 mmol/kg) on day 14 and 21. Healthy rats were used as control ( n = 6).

          Results

          Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7 ± 15.5%; LGE: 8.7 ± 8.7%; both p = ns vs. controls). In contrast, 6 h-FE-CMR detected extensive myocardial signal loss (33.2 ± 15.0%, p = 0.02 vs. EGE and p < 0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4 ± 16.4% vs control: 66.2 ± 6.1%, p < 0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6 h-FE-CMR (41.6 ± 18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6 h R2* = 299 ± 112 s − 1vs control: 125 ± 26 s − 1, p < 0.01) and day 21 (564 ± 562 s − 1, p < 0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27 ± 5 ms vs control: 16 ± 1 ms, p < 0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* ( r = 0.86, p < 0.001).

          Conclusions

          FE-CMR acquired at 6 h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.

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          Most cited references40

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          Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging.

          Superparamagnetic iron oxide MR imaging contrast agents have been the subjects of extensive research over the past decade. The iron oxide particle size of these contrast agents varies widely, and influences their physicochemical and pharmacokinetic properties, and thus clinical application. Superparamagnetic agents enhance both T1 and T2/T2* relaxation. In most situations it is their significant capacity to reduce the T2/T2* relaxation time to be utilized. The T1 relaxivity can be improved (and the T2/T2* effect can be reduced) using small particles and T1-weighted imaging sequences. Large iron oxide particles are used for bowel contrast [AMI-121 (i.e. Lumirem and Gastromark) and OMP (i.e. Abdoscan), mean diameter no less than 300 nm] and liver/spleen imaging [AMI-25 (i.e. Endorem and Feridex IV, diameter 80-150 nm); SHU 555A (i.e. Resovist, mean diameter 60 nm)]. Smaller iron oxide particles are selected for lymph node imaging [AMI-227 (i.e. Sinerem and Combidex, diameter 20-40 nm)], bone marrow imaging (AMI-227), perfusion imaging [NC100150 (i.e. Clariscan, mean diameter 20 nm)] and MR angiography (NC100150). Even smaller monocrystalline iron oxide nanoparticles are under research for receptor-directed MR imaging and magnetically labeled cell probe MR imaging. Iron oxide particles for bowel contrast are coated with insoluble material, and all iron oxide particles for intravenous injection are biodegradable. Superparamagnetic agents open up an important field for research in MR imaging.
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            Emerging applications for ferumoxytol as a contrast agent in MRI.

            Ferumoxytol is an ultrasmall superparamagnetic iron oxide (USPIO) agent initially approved by the Food and Drug Administration (FDA) as an iron replacement therapy for patients with anemia due to chronic renal failure. Recently, ferumoxytol has been investigated extensively as an intravenous contrast agent in magnetic resonance imaging (MRI). Since it causes regional T1 and T2 * shortening in vivo, conventional pulse sequences can be used following ferumoxytol administration to demonstrate signal enhancement or loss. Ferumoxytol can be administered as a rapid bolus and has a long intravascular half-life on the order of 14-15 hours, making it a potentially useful agent for vascular and perfusion-weighted MRI. In comparison to other USPIOs, ferumoxytol is less limited by allergic and idiosyncratic reactions. Furthermore, since ferumoxytol is an iron-based agent with no potential for causing nephrogenic systemic fibrosis, it may be useful as an alternative to gadolinium-based contrast agents in patients with compromised renal function. Ferumoxytol is ultimately taken up by macrophages/the reticuloendothelial system in the liver, spleen, and lymph nodes, and this uptake mechanism is being explored as a novel imaging technique for vascular lesions, tumors, and lymph nodes. This article reviews the properties of ferumoxytol relevant to MRI as well as many of the uses for the agent currently under investigation. © 2014 Wiley Periodicals, Inc.
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              Current and potential imaging applications of ferumoxytol for magnetic resonance imaging

              Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.
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                Author and article information

                Contributors
                ytada@stanford.edu
                atsushimac274@gmail.com
                shahriar40@gmail.com
                phillip@stanford.edu
                mcconnell@stanford.edu
                rhombus@stanford.edu
                Journal
                J Cardiovasc Magn Reson
                J Cardiovasc Magn Reson
                Journal of Cardiovascular Magnetic Resonance
                BioMed Central (London )
                1097-6647
                1532-429X
                16 December 2019
                16 December 2019
                2019
                : 21
                : 77
                Affiliations
                ISNI 0000000419368956, GRID grid.168010.e, Department of Medicine (Cardiovascular Medicine), , Stanford University School of Medicine, ; 300 Pasteur Drive, Stanford, CA 94305 USA
                Author information
                http://orcid.org/0000-0002-2499-6389
                Article
                587
                10.1186/s12968-019-0587-7
                6913003
                31842900
                78361071-b0a3-4403-8095-5df3bbb58a6f
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 31 January 2019
                : 21 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100008880, Kanae Foundation for the Promotion of Medical Science;
                Award ID: N/A
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100005072, Japanese Circulation Society;
                Award ID: N/A
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2019

                Cardiovascular Medicine
                ferumoxytol,cmr,mri,myocarditis,t2* map
                Cardiovascular Medicine
                ferumoxytol, cmr, mri, myocarditis, t2* map

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