Publications

August 2022

Jalili MH, Yu T, Hassani C, Prosper AE, Finn JP, Bedayat A.

Vascular imaging can be challenging because of the wide variability of contrast dynamics in different vascular territories and potential safety concerns in patients with renal insufficiency or allergies. Off-label diagnostic use of ferumoxytol, a superparamagnetic iron nanoparticle approved for therapy, is a promising alternative to gadolinium-based contrast agents for MR angiography (MRA). Ferumoxytol has exhibited a reassuring safety profile when used within the dose range recommended for diagnostic imaging. Because of its prolonged and stable intravascular residence, ferumoxytol can be used in its steady-state distribution for a wide variety of imaging indications, including some where conventional MRA is unreliable. In this article, authors discuss some of the major vascular applications of ferumoxytol and highlight how it may be used to provide highly diagnostic images and improve the quality, workflow, and reliability of vascular imaging.

March 2022

Shahrouki P, Khan SN, Yoshida T, Iskander PJ, Ghahremani S, Finn JP.

BACKGROUND: Gadofosveset is a gadolinium-based blood pool contrast agent that was approved by the United States Food and Drug Administration in 2008. Its unanticipated withdrawal from production in 2016 created a void in the blood pool agent inventory and highlighted the need for an alternative agent with comparable imaging properties. OBJECTIVE: The purpose of our study is to compare the diagnostic image quality, vascular contrast-to-noise ratio (CNR) and temporal signal characteristics of gadofosveset trisodium and ferumoxytol at similar molar doses for high-resolution, three-dimensional (3-D) magnetic resonance (MR) venography in children. MATERIALS & METHODS: The medical records and imaging data sets of patients who underwent high-resolution 3-D gadofosveset-enhanced MR venography (GE-MRV) or ferumoxytol-enhanced MR venography (FE-MRV) were retrospectively reviewed. Two groups of 20 pediatric patients (age- and weight-matched with one patient common to both groups; age range: 2 days-15 years) who underwent high-resolution 3-D GE-MRV or FE-MRV at similar molar doses were identified and analyzed. Qualitative analysis of image quality and vessel definition was performed by two blinded pediatric radiologists. Interobserver agreement was assessed with the AC1 (first-order agreement coefficient) statistic. Signal-to-noise ratio (SNR) and CNR of the inferior vena cava and aorta were measured in the steady-state venous phase. Medical records were retrospectively reviewed for any adverse reactions associated with either contrast agent.

July 2021

Colbert CM, Le AH, Shao J, Currier JW, Ajijola OA, Hu P, Nguyen KL.

Myocardial T1 reactivity, defined as the relative change in T1 between rest and vasodilator-induced stress, has been proposed as a magnetic resonance imaging (MRI) biomarker of tissue perfusion. We hypothesize that the superparamagnetic iron-oxide nanoparticle, ferumoxytol, sensitizes T1 to changes in the intramyocardial vascular compartment and improves the sensitivity and specificity of T1 reactivity as an imaging biomarker of tissue perfusion. We aim to assess the diagnostic performance of ferumoxytol-enhanced (FE) myocardial T1 reactivity in swine models of myocardial hypoperfusion. We induced acute myocardial hypoperfusion in 13 swine via percutaneous, transcatheter deployment of a 3D printed intracoronary stenosis implant into the left anterior descending coronary artery. We performed native and FE adenosine stress testing using 5(3)3(3)3 MOLLI and SASHA T1 mapping sequences with bSSFP readout on a clinical 3.0 T magnet. MOLLI T1 maps were fitted using both the conventional MOLLI and the Instantaneous Signal Loss (InSiL) T1-fitting algorithms. Regardless of the MOLLI or SASHA pulse sequence or T1-fitting algorithm, ferumoxytol contrast increased the dynamic range of T1 reactivity in both the remote and ischemic myocardial regions. Relative to remote myocardium, native and FE T1 reactivity were blunted in ischemic myocardium (p < 0.05) with InSiL-MOLLI, MOLLI and SASHA. An InSiL-MOLLI-derived FE T1 reactivity threshold of -4.65% had 73.3% sensitivity and 96.2% specificity for prediction of regional wall motion abnormalities (AUC 0.915, 95% CI 0.786-0.979), whereas a SASHA-derived FE T1 reactivity threshold of -5.25% had 75.0% sensitivity and 95.2% specificity (AUC 0.905, 95% CI 0.751-0.979). Ferumoxytol significantly increased the dynamic range of T1 reactivity as a measure of myocardial hypoperfusion in vasodilator stress T1 mapping studies. FE T1 reactivity maps can be used to quantitatively distinguish ischemic and remote myocardium with high specificity in swine models of acute myocardial hypoperfusion.

July 2021

Nguyen KL, Ghosh RM, Griffin LM, Yoshida T, Bedayat A, Rigsby CK, Fogel MA, Whitehead KK, Hu P, Finn JP.

BACKGROUND: The value of MRI in pediatric congenital heart disease (CHD) is well recognized; however, the requirement for expert oversight impedes its widespread use. Four-dimensional (4D) multiphase steady-state imaging with contrast enhancement (MUSIC) is a cardiovascular MRI technique that uses ferumoxytol and captures all anatomic features dynamically. PURPOSE: To evaluate multicenter feasibility of 4D MUSIC MRI in pediatric CHD. MATERIALS & METHODS: In this prospective study, participants with CHD underwent 4D MUSIC MRI at 3.0 T or 1.5 T between 2014 and 2020. From a pool of 460 total studies, an equal number of MRI studies from three sites (n = 60) was chosen for detailed analysis. With use of a five-point scale, the feasibility of 4D MUSIC was scored on the basis of artifacts, image quality, and diagnostic confidence for intracardiac and vascular connections (n = 780). Respiratory motion suppression was assessed by using the signal intensity profile. Bias between 4D MUSIC and two-dimensional (2D) cine imaging was evaluated by using Bland-Altman analysis; 4D MUSIC examination duration was compared with that of the local standard for CHD.

June 2021

Colbert CM, Thomas MA, Yan R, Radjenovic A, Finn JP, Hu P, Nguyen KL.

Fractional myocardial blood volume (fMBV) estimated using ferumoxytol-enhanced magnetic resonance imaging (MRI) (FE-MRI) has the potential to capture a hemodynamic response to myocardial hypoperfusion during contrast steady state without reliance on gadolinium chelates. Ferumoxytol has a long intravascular half-life and its use for steady-state MRI is off-label. The aim of this prospective study was to optimize and evaluate a two-compartment model for estimation of fMBV based on FE-MRI. Nine healthy swine and one swine with artificially induced single-vessel coronary stenosis underwent MRI on a 3.0 T clinical magnet. Myocardial longitudinal spin-lattice relaxation rate (R1) was measured using the 5(3)3(3)3 modified Look-Locker inversion recovery (MOLLI) sequence before and at contrast steady state following seven ferumoxytol infusions (0.125-4.0 mg/kg). fMBV and water exchange were estimated using a two-compartment model. Model-fitted fMBV was compared to simple fast-exchange fMBV approximation and percent change in pre- and postferumoxytol R1. Dose undersampling schemes were investigated to reduce acquisition duration. Variation in fMBV was assessed using one-way analysis of variance. Fast-exchange fMBV and ferumoxytol dose undersampling were evaluated using Bland-Altman analysis. Healthy normal swine showed a mean mid-ventricular fMBV of 7.2 ± 1.4% and water exchange rate of 11.3 ± 5.1 s-1 . There was intersubject variation in fMBV (p < 0.05) without segmental variation (p = 0.387). fMBV derived from eight-dose and four-dose sampling schemes had no significant bias (mean difference = 0.07, p = 0.541, limits of agreement -1.04% [-1.45, -0.62%] to 1.18% [0.77, 1.59%]). Pixel-wise fMBV in one swine model with coronary artery stenosis showed elevated fMBV in ischemic segments (apical anterior: 11.90 ± 4.00%, apical septum: 16.10 ± 5.71%) relative to remote segments (apical inferior: 9.59 ± 3.35%, apical lateral: 9.38 ± 2.35%). A two-compartment model based on FE-MRI using the MOLLI sequence may enable estimation of fMBV in studies of ischemic heart disease. LEVEL OF EVIDENCE: 2. TECHNICAL EFFICACY STAGE: 2.

May 2020

Yoshida T, Nguyen KL, Shahrouki P, Quinones-Baldrich WJ, Lawrence PF, Finn JP.

OBJECTIVE: The purpose of this study was to establish the feasibility of fusing complementary, high-contrast features from unenhanced computed tomography (CT) and ferumoxytol-enhanced magnetic resonance angiography (FE-MRA) for preprocedural vascular mapping in patients with renal impairment. METHODS: In this Institutional Review Board-approved and Health Insurance Portability and Accountability Act-compliant study, 15 consecutive patients underwent both FE-MRA and unenhanced CT scanning, and the complementary high-contrast features from both modalities were fused to form an integrated, multifeature image. Source images from CT and MRA were segmented and registered. To validate the accuracy, precision, and concordance of fused images to source images, unambiguous landmarks, such as wires from implantable medical devices or indwelling catheters, were marked on three-dimensional (3D) models of the respective modalities, followed by rigid co-registration, interactive fusion, and fine adjustment. We then compared the positional offsets using pacing wires or catheters in the source FE-MRA (defined as points of interest [POIs]) and fused images (n = 5 patients, n = 247 points). Points within 3D image space were referenced to the respective modalities: x (right-left), y (anterior-posterior), and z (cranial-caudal). The respective 3D orthogonal reference axes from both image sets were aligned, such that with perfect registration, a given point would have the same (x, y, z) component values in both sets. The 3D offsets (∆ x mm, ∆y mm, ∆z mm) for each of the corresponding POIs represent nonconcordance between the source FE-MRA and fused images. The offsets were compared using concordance correlation coefficients. Interobserver agreement was assessed using intraclass correlation coefficients and Bland-Altman analyses.

December 2019

Nguyen KL, Yoshida T, Kathuria-Prakash N, Zaki IH, Varallyay CG, Semple SI, Saouaf R, Rigsby CK, Stoumpos S, Whitehead KK, Griffin LM, Saloner D, Hope MD, Prince MR, Fogel MA, Schiebler ML, Roditi GH, Radjenovic A, Newby DE, Neuwelt EA, Bashir MR, Hu P, Finn JP.

Background Ferumoxytol is approved for use in the treatment of iron deficiency anemia, but it can serve as an alternative to gadolinium-based contrast agents. On the basis of postmarketing surveillance data, the Food and Drug Administration issued a black box warning regarding the risks of rare but serious acute hypersensitivity reactions during fast high-dose injection (510 mg iron in 17 seconds) for therapeutic use. Whereas single-center safety data for diagnostic use have been positive, multicenter data are lacking. Purpose To report multicenter safety data for off-label diagnostic ferumoxytol use. Materials and Methods The multicenter ferumoxytol MRI registry was established as an open-label nonrandomized surveillance databank without industry involvement. Each center monitored all ferumoxytol administrations, classified adverse events (AEs) using the National Cancer Institute Common Terminology Criteria for Adverse Events (grade 1-5), and assessed the relationship of AEs to ferumoxytol administration. AEs related to or possibly related to ferumoxytol injection were considered adverse reactions. The core laboratory adjudicated the AEs and classified them with the American College of Radiology (ACR) classification. Analysis of variance was used to compare vital signs.

August 2019

Nguyen KL, Shao J, Ghodrati VK, Ajijola OA, Dharmakumar R, Finn JP, Hu P.

Researchers recently proposed using native myocar-dial T₁ mapping with vasodilator stress testing forevaluation of ischemic heart disease (IHD)(1).Achange of 1.5% in native T₁ between rest and peakstress was able to detect significant epicardial coro-nary stenosis(1). Although this approach is prom-ising, the modest amplitude and narrow dynamicrange for native T₁ reactivity (percentage of change in T₁ at peak vasodilation relative to baseline) may posechallenges in daily clinical practice. We propose toincrease the amplitude and dynamic range of T₁ reactivity through the off-label use of ferumoxytol(Feraheme, AMAG Pharmaceuticals, Waltham, Mas-sachusetts). Ferumoxytol is used for intravenoustreatment of iron deficiency anemia, but it hassuperparamagnetic properties with high r₁ relaxivityand a long intravascular half-life. We posited thatferumoxytol would sensitize the myocardial T₁ to thevasodilator-induced dynamic differences betweenrest and peak stress and significantly boost the T₁ reactivity. Because ferumoxytol shortens the T₁,weexpected the myocardial T₁ to decrease during vaso-dilator stress because of the increased distributionspace of ferumoxytol.

January 2018

Nguyen KL, Moriarty JM, Plotnik AN, Aksoy O, Yoshida T, Shemin RJ, Suh WM, Finn JP.

PURPOSE: To assess the technical feasibility of the use of ferumoxytol-enhanced (FE) magnetic resonance (MR) angiography for vascular mapping before transcatheter aortic valve replacement in patients with renal impairment. MATERIALS AND METHODS: This was an institutional review board-approved and HIPAA-compliant study. FE MR angiography was performed at 3.0 T or 1.5 T. Unenhanced computed tomographic (CT) images were used to overlay vascular calcification on FE MR angiographic images as composite fused three-dimensional data. Image quality of the subclavian and aortoiliofemoral arterial tree and confidence in the assessment of calcification were evaluated by using a four-point scale (4 = excellent vascular definition or strong confidence). Signal intensity nonuniformity as reflected by the heterogeneity index (ratio between the mean standard deviation of luminal signal intensity and the mean luminal signal intensity), signal-to-noise ratio, and consistency of luminal diameter measurements were quantified. Findings at FE MR angiography were compared with pelvic angiograms.

September 2017

Finn JP, Nguyen KL, Hu P.

When gadolinium contrast was first described forhuman use in magnetic resonance imaging (MRI) over three decades ago, many doubted the need for it. Afterall, the promise of MRI was that inherent soft-tissue contrast could be tweaked in limitless ways without the type of pharmaceutical fuel that was essential for computed tomography (CT). As things transpired, the clinical and commercial impact of gadolinium-based contrast agents (GBCAs) has been enormous. Recent estimates put the number of GBCA studies at 30 million annually, fueling a multibilliondollar global market. By the mid 2000s, five extracellular GBCA formulations had been introduced in the United States and for many years these agents enjoyed a blemish-free reputation, even for patients with renal impairment.

August 2017

Han F, Zhou Z, Han E, Gao Y, Nguyen KL, Finn JP, Hu P.

PURPOSE: To develop and validate a cardiac-respiratory self-gating strategy for the recently proposed multiphase steady-state imaging with contrast enhancement (MUSIC) technique. METHODS: The proposed SG strategy uses the ROtating Cartesian K-space (ROCK) sampling, which allows for retrospective k-space binning based on motion surrogates derived from k-space center line. The k-space bins are reconstructed using a compressed sensing algorithm. Ten pediatric patients underwent cardiac MRI for clinical reasons. The original MUSIC and 2D-CINE images were acquired as a part of the clinical protocol, followed by the ROCK-MUSIC acquisition, all under steady-state intravascular distribution of ferumoxytol. Subjective scores and image sharpness were used to compare the images of ROCK-MUSIC and original MUSIC.

March 2017

Nguyen KL, Yoshida T, Han F, Ayad I, Reemtsen BL, Salusky IB, Satou GM, Hu P, Finn JP.

PURPOSE: To summarize our single-center safety experience with the off-label use of ferumoxytol for magnetic resonance imaging (MRI) and to compare the effects of ferumoxytol on monitored physiologic indices in patients under anesthesia with those of gadofosveset trisodium. MATERIALS AND METHODS: Consecutive patients who underwent ferumoxytol-enhanced (FE) MRI exams were included. Adverse events (AEs) were classified according to the Common Terminology Criteria for Adverse Events v4.0. In a subgroup of patients examined under general anesthesia, recording of blood pressure, heart rate, oxygen saturation, and end-tidal CO2 was performed. A comparable group of 23 patients who underwent gadofosveset-enhanced (GE) MRI under anesthesia with similar monitoring was also analyzed.

August 2016

Finn JP, Nguyen KL, Han F, Zhou Z, Salusky I, Ayad I, Hu P.

The practice of contrast-enhanced magnetic resonance angiography (CEMRA) has changed significantly in the span of a decade. Concerns regarding gadolinium (Gd)-associated nephrogenic systemic fibrosis in those with severely impaired renal function spurred developments in low-dose CEMRA and non-contrast MRA as well as efforts to seek alternative MR contrast agents. Originally developed for MR imaging use, ferumoxytol (an ultra-small superparamagnetic iron oxide nanoparticle), is currently approved by the US Food and Drug Administration for the treatment of iron deficiency anaemia in adults with renal disease. Since its clinical availability in 2009, there has been rising interest in the scientific and clinical use of ferumoxytol as an MR contrast agent. The unique physicochemical and pharmacokinetic properties of ferumoxytol, including its long intravascular half-life and high r1 relaxivity, support a spectrum of MRI applications beyond the scope of Gd-based contrast agents. Moreover, whereas Gd is not found in biological systems, iron is essential for normal metabolism, and nutritional iron deficiency poses major public health challenges worldwide. Once the carbohydrate shell of ferumoxytol is degraded, the elemental iron at its core is incorporated into the reticuloendothelial system. These considerations position ferumoxytol as a potential game changer in the field of CEMRA and MRI. In this paper, we aim to summarise our experience with the cardiovascular applications of ferumoxytol and provide a brief synopsis of ongoing investigations on ferumoxytol-enhanced MR applications.

August 2016

Luhar A, Khan S, Finn JP, Ghahremani S, Griggs R, Zaritsky J, Salusky I, Hall TR.

Ferumoxytol is an ultra-small superparamagnetic iron oxide (USPIO) particle that is FDA-approved for parenteral treatment of iron deficiency anemia in adults with chronic kidney disease. Because of the association between gadolinium-based contrast agents and nephrogenic systemic fibrosis in patients with severe chronic kidney disease, we sought to evaluate the diagnostic role of ferumoxytol-enhanced MR venography in children with chronic kidney disease. Twenty children underwent 22 high-resolution ferumoxytol-enhanced MR venography examinations at 3.0 T. High-resolution 3-D contrast-enhanced imaging was performed at a minimum of 3 time points following injection of ferumoxytol at a total dose of 4 mg/kg. Two blinded pediatric radiologists independently scored six named veins on ferumoxytol-enhanced MR venography examinations according to a three-point subjective score, where a score ≥2 was considered diagnostic. Additionally, all relevant venous structures in the included field of view were analyzed for occlusive or non-occlusive thrombosis, compression and presence of collaterals. All patients underwent ferumoxytol-enhanced MR venography successfully and without adverse event. The overall scores of the reviewing radiologists for all venous structures were 2.7-2.9. In all cases, the reviewers were confident basing their diagnoses on the ferumoxytol-enhanced MR venography findings. In 12 of 22 examinations, findings on follow-up imaging or invasive procedures were available to correlate with the findings on ferumoxytol-enhanced MR venography. There was complete concordance between the findings from follow-up imaging and invasive procedures with findings from ferumoxytol-enhanced MR venography. Ferumoxytol holds promise as a powerful alternative to gadolinium-based contrast agents for reliable, high-resolution MR venography in children with chronic kidney disease.

May 2016

Vasanawala SS, Nguyen KL, Hope MD, Bridges MD, Hope TA, Reeder SB, Bashir MR.

Ferumoxytol is an ultrasmall superparamagnetic iron oxide agent marketed for the treatment of anemia. There has been increasing interest in its properties as an MRI contrast agent as well as greater awareness of its adverse event profile. This mini-review summarizes the current state of knowledge of the risks of ferumoxytol and methods of administration.

January 2016

Skelton RJ, Khoja S, Almeida S, Rapacchi S, Han F, Engel J, Zhao P, Hu P, Stanley EG, Elefanty AG, Kwon M, Elliott DA, Ardehali R.

Given the limited regenerative capacity of the heart, cellular therapy with stem cell-derived cardiac cells could be a potential treatment for patients with heart disease. However, reliable imaging techniques to longitudinally assess engraftment of the transplanted cells are scant. To address this issue, we used ferumoxytol as a labeling agent of human embryonic stem cell-derived cardiac progenitor cells (hESC-CPCs) to facilitate tracking by magnetic resonance imaging (MRI) in a large animal model. Differentiating hESCs were exposed to ferumoxytol at different time points and varying concentrations. We determined that treatment with ferumoxytol at 300 μg/ml on day 0 of cardiac differentiation offered adequate cell viability and signal intensity for MRI detection without compromising further differentiation into definitive cardiac lineages. Labeled hESC-CPCs were transplanted by open surgical methods into the left ventricular free wall of uninjured pig hearts and imaged both ex vivo and in vivo. Comprehensive T2*-weighted images were obtained immediately after transplantation and 40 days later before termination. The localization and dispersion of labeled cells could be effectively imaged and tracked at days 0 and 40 by MRI. Thus, under the described conditions, ferumoxytol can be used as a long-term, differentiation-neutral cell-labeling agent to track transplanted hESC-CPCs in vivo using MRI.

October 2015

Han F, Rapacchi S, Khan S, Ayad I, Salusky I, Gabriel S, Plotnik A, Finn JP, Hu P.

PURPOSE: To develop a technique for high resolution, four-dimensional (4D), multiphase, steady-state imaging with contrast enhancement (MUSIC) in children with complex congenital heart disease. METHODS: Eight pediatric patients underwent cardiovascular MRI with controlled mechanical ventilation after ferumoxytol administration. Breath-held contrast-enhanced MRA (CE-MRA) was performed during the first-pass and delayed phases of ferumoxytol, followed by a respiratory gated, 4D MUSIC acquisition during the steady state distribution phase of ferumoxytol. The subjective image quality and image sharpness were evaluated. Assessment of ventricular volumes based on 4D MUSIC was compared with those based on multislice 2D cardiac cine MRI.