JOURNAL OF MAGNETIC RESONANCE IMAGING 21:46 –52 (2005)
Original Research
First-Pass Contrast-Enhanced Magnetic Resonance Angiography in Humans Using Ferumoxytol, a Novel Ultrasmall Superparamagnetic Iron Oxide (USPIO)-Based Blood Pool Agent Wei Li, MD,1* Sean Tutton, MD,1 Anthony T. Vu, PhD,2 Linda Pierchala, BS,1 Belinda S.Y. Li, PhD,3 Jerome M. Lewis, PhD,4 Pottumarthi V. Prasad, PhD,1 and Robert R. Edelman, MD1 Key Words: magnetic resonance imaging; blood pool contrast agent; intravascular contrast agent; ferumoxytol; contrast-enhanced MR angiography; first pass J. Magn. Reson. Imaging 2005;21:46 –52. © 2004 Wiley-Liss, Inc.
Purpose: To evaluate the feasibility of first-pass contrastenhanced magnetic resonance angiography (MRA) using ferumoxytol in humans. Materials and Methods: First-pass and equilibrium phase MRA were performed using ferumoxytol in one healthy volunteer and 11 patients with a fast three-dimensional spoiled gradient recalled (SPGR) pulse sequence. The examined vessels included carotid arteries, thoracic aorta, abdominal aorta, and peripheral arteries. A dose of either 71.6 mol Fe/kg (n ⫽ 9), or 35.8 mol Fe/kg (n ⫽ 3) was used. Based on a phantom study, the agent with initial concentration of 537.2 mol Fe/mL was diluted by either four-fold (134.3 mol Fe/mL) or eight-fold (67.1 mol Fe/ mL) for first-pass MRA.
CONTRAST-ENHANCED magnetic resonance angiography (MRA) is typically performed using extracellular gadolinium chelates, with data acquired during the first pass of the agent through the target vasculature (1,2). Although of great clinical utility, these MRA studies suffer from certain limitations. The limitations include a short time window for data acquisition and soft tissue enhancement that masks blood vessels on maximum intensity projection images. Consequently, there is considerable interest in the use of blood pool (also called intravascular) agents for contrast-enhanced MRA. Various blood pool agents have been tested, including gadolinium-based and ultrasmall superparamagnetic iron oxide (USPIO)-based agents (3–9). Compared with extracellular agents, blood pool agents provide a much longer time window for data acquisition, so that data can be repeatedly acquired over a period of minutes to hours with little loss of intravascular signal intensity. Moreover, true blood pool agents produce only minimal soft tissue enhancement. These features allow for extensive signal averaging to improve the intravascular signal-to-noise ratio (SNR) and thereby permit images with much higher spatial resolution to be obtained than would be feasible using extracellular agents (10 –19). However, equilibrium images acquired over many minutes show both arterial and venous contrast enhancement, which complicates the interpretation of the vasculature (14). It would be ideal to have a contrast agent that can be used for both first-pass and equilibrium MRA in a single exam. Several blood pool agents, both gadoliniumbased and iron oxide-based, are currently being investigated for first-pass MRA in experimental and clinical studies (20 –27). Recently, another blood pool agent,
Results: All subjects completed their studies without adverse events. First-pass MRA showed selective arterial enhancement, with both arterial and venous enhancement on delayed acquisitions. Selective venous enhancement could be obtained by subtraction of arterial phase images from equilibrium phase images. The findings in ferumoxytol MRA were consistent with the results of original vascular tests. Conclusion: Our preliminary experience supports the feasibility of first-pass MRA with ferumoxytol. Satisfactory arterial enhancement during first-pass imaging is obtained with injection of diluted contrast agent. With ferumoxytol, arteries and veins can be selectively depicted in a single exam.
1 Department of Radiology, Evanston Northwestern Healthcare and Northwestern University’s Feinberg School of Medicine, Evanston, Illinois. 2 MR PSD/Applications Engineering, GE Healthcare, Waukesha, Wisconsin. 3 Applied Science Laboratory Central, GE Healthcare, c/o Department of Radiology, Evanston Northwestern Healthcare, Evanston Illinois. 4 Advanced Magnetics, Inc., Cambridge, Massachusetts. Present address for Dr. Li: Department of Radiology/CAI, Walgreen Building, Suite G507, Evanston, IL, 60201. *Address reprint requests to: W.L., MRI Research, Department of Radiology, Rm 5108, Evanston Hospital, 2650 Ridge Ave., Evanston, IL 60201. E-mail:
[email protected] Received April 8, 2004; Accepted September 8, 2004. DOI 10.1002/jmri.20235 Published online in Wiley InterScience (www.interscience.wiley.com).
© 2004 Wiley-Liss, Inc.
46
First-Pass MR Angiography with Ferumoxytol
ferumoxytol (Advanced Magnetics, Cambridge, MA), has been described (28 –31). Because doses up to 4 mg (71.6 mol) Fe per kilogram at a rate of 30 mg (537.2 mol) Fe per second may be administered as a bolus infusion, ferumoxytol provides the possibility to perform first-pass MRA. The purpose of this study was to evaluate the feasibility of first-pass angiography using ferumoxytol in humans, and to determine the technical requirements for optimizing image quality. MATERIALS AND METHODS Contrast Agent Ferumoxytol is a semisynthetic carbohydrate-coated USPIO, currently in phase II clinical trials. The crystal size of the iron oxide core is 6.76 ⫾ 0.41 nm in diameter measured by X-ray diffraction (XRD). The solution particle size is 30.0 ⫾ 2 nm determined by laser light scattering. Ferumoxytol possesses a long intravascular half-life (10 –14 hours) and T1 shortening properties (r1 ⫽ 38 mM–1second–1, r2 ⫽ 83 mM–1second–1, and r2/r1 ⬇ 2.2 at 20 MHz and 39°C in 0.5 % by weight agar gel). The drug is formulated to be isotonic at a concentration of 30 mg (537.2 mol)/mL of iron and 44 mg/mL of mannitol. The product contains no preservatives and the pH is 6 to 9. The highest dose for imaging is 4 mg (71.6 mol) Fe/kg of body weight (bw), and the highest injection rate is 1 mL (537.2 mol) Fe/second (29 –31). For a 70-kg subject, the volume of the ferumoxytol is 9.3 mL. Phantom Experiment to Determine the Dilution Factor It has been reported for MRA using blood pool contrast agents that the T2*-shortening effect dominates at higher concentrations, which can lead to unacceptable signal loss (7,16,18 –19). Minimization of the T2* effect can be achieved by diluting the contrast agent. However, with excessive dilution there may be insufficient shortening of the T1 relaxation time of blood, such that vascular enhancement may be impaired. In order to determine an appropriate dilution factor for ferumoxytol, a phantom experiment was performed. Two contrast agents, gadolinium diethylenetriamine-
47
pentaacide (Gd-DTPA); (Magnevist, Berlex Laboratories, Wayne, NJ) and ferumoxytol, were diluted, respectively, with normal saline, using dilution factors of 1:4, 1:8, 1:16, 1:32, 1:64, 1:128, 1:256, 1:512, 1:1024, and 1:2048. Thus, 20 diluted solutions with different dilution factors were prepared: 10 for Gd-DTPA and another 10 for ferumoxytol. The 20 diluted solutions were scanned together with the same fast three-dimensional spoiled gradient recalled (SPGR) sequence used for human subject MRA (described below). One slice in the center of the three-dimensional volume was used for signal intensity measurement. Regions of interest (ROIs) with size no smaller than 200 mm2 were placed in the center of each tube and in the background by one of the authors (W.L.). SNR of each diluted solution was calculated by dividing the signal intensity by the SD of the background. Based on a plot of SNR against dilution factor of each diluted solution, we selected either 4 or 8 as the dilution factor for first-pass ferumoxytol MRA (see details in Results). Subjects and Data Acquisition A total of 12 subjects, including one healthy volunteer (22-year-old female) and 11 patients (seven men and four women; aged 19 – 86 years; average age 63.5 years) with various vascular disorders were included in this study. All subjects underwent first-pass and equilibrium phase MR angiography with ferumoxytol. The study was approved by our Institutional Review Board, and informed consent was obtained from all subjects. Imaging of the abdominal aorta was performed in the volunteer. One of the 11 patients had a venous malformation of the left calf, as detected by a physical examination. In the other 10 patients, vascular abnormalities were detected by other vascular tests, including conventional catheter angiography (n ⫽ 4), contrast-enhanced MRA (n ⫽ 3), CT angiography (n ⫽ 1), and Doppler ultrasound (n ⫽ 2). Based on the locations of the abnormalities, ferumoxytol MRA was performed in the following vascular territories: extracranial carotid arteries (n ⫽ 2), thoracic aorta (n ⫽ 1), abdominal aorta (including renal arteries) (n ⫽ 4), and peripheral arteries (n ⫽ 4).
Table 1 Subjects, Target Territories of Ferumoxytol MRA, and Dosages and Dilution Factors of Ferumoxytol Subject no.
Abnormalities (detected by)
Territories of ferumoxytol MRA
Dosage (mol Fe/kg)
Dilution factor
1 2 3 4 5 6 7 8 9 10 11 12
Healthy volunteer Aortic/iliac aneurysm (CA) Aortic aneurysm (CA) Aortic aneurysm (CTA) Renal A. stenosis (GMRA) Lung sequestration (GMRA) Narrowing carotids (DUS) Narrowing carotids (DUS) Venous malformation (GMRA) Pain at the left foot (CA) Venous malformation (physical exam) Venous malformation (CA)
Abdominal Abdominal Abdominal Abdominal Abdominal Thoracic Carotid Carotid Calf Mid. leg Calf Calf
71.6 71.6 71.6 71.6 35.8 71.6 71.6 71.6 71.6 71.6 35.8 35.8
4 4 4 4 8 4 4 4 4 4 8 8
CA ⫽ conventional catheter angiography, GMRA ⫽ Gd-DTPA enhanced MR angiography, CTA ⫽ CT angiography, DUS ⫽ Doppler ultrasound.
48
Li et al.
Table 2 MRA Pulse Sequence Parameters Sequences for MRA Three-dimensional SPGR Carotid (N ⫽ 1) Thoracic (N ⫽ 1) Abdominal (N ⫽ 5) Three-dimensional SPGR with TRICKS Calf (N ⫽ 4) Carotid (N ⫽ 1)
TR (msec)
TE (msec)
FA
BW (Hz)
Thickness (mm)
Matrix
FOV (cm)
Frame no./rate
5.0 4.0 3.4–4.2
1.2 1.4 1.2–1.5
45° 30° 30°
⫾31.2 ⫾62.5 ⫾62.5
1.2/⫺0.6 3.0/⫺1.5 3.0/⫺1.5
256*224 256*192 256*192
28 38 30–40
– – –
4.5 4.6
1.7 1.2
40° 45°
⫾83.3 ⫾31.2
3.0/⫺1.5 1.2/⫺0.6
384*256 256*160
40 28
8/8.3 sec 8/9.6 sec
FA ⫽ flip angle, BW ⫽ bandwidth, FOV ⫽ field of view.
Based on the dilution factors determined by the phantom experiment, a full dose of ferumoxytol (71.6 mol Fe/kg bw) with four-fold dilution (i.e., from 537.2 to 134.3 mol Fe/mL) was used in nine subjects. A half dose of ferumoxytol (35.8 mol Fe/kg bw) with eightfold dilution (i.e., from 537.2 to 67.1 mol Fe/mL) was used for first-pass MRA in the other three subjects. These dilutions maintained the total injected volume to be about 30 – 40 mL, comparable to the volumes for contrast-enhanced three-dimensional MRA using double-dose Gd-DTPA. For an infusion rate of 2 mL/second, the duration of infusion was on the order of 15–20 seconds, comparable to the duration of data acquisition. When a half dose of ferumoxytol was given for first-pass MRA, the other half dose was subsequently administered for the rest of the imaging protocol. The vascular abnormalities, target vascular territories for ferumoxytol-enhanced MRA, and dosages and dilution factors of ferumoxytol for each subject are summarized in Table 1. MR exams were performed on a 1.5-T Signa Lx 10.0 TwinSpeed MR scanner equipped with EXCITE technology (GE Healthcare, Waukesha, WI), with a peak gradient strength of 40 mT/m and maximum slew rate of 150 T/m/second. A phased array torso coil (for the scans of the chest or abdomen) or neurovascular array coil (for the scans of the neck or calf areas) were used. The pulse sequences included fast three-dimensional SPGR (n ⫽ 7), or three-dimensional SPGR with time-resolved imaging on contrast kinetics (TRICKS) (32) for time-resolved imaging (n ⫽ 5). The parameters are summarized in Table 2. A 22-gauge intravenous access catheter was placed into a vein in the antecubital fossa or the forearm. The contrast agent was administered with a power injector (Medrad Spectris; Medrad, Indianola, PA) at a rate of 2 mL/second, followed by 15 mL saline at the same injection rate. The infusion rate is the same as that used for gadolinium-enhanced three-dimensional MRA at our institution. Fluoroscopic triggering was used for timing of the non-TRICKS first-pass acquisitions. Equilibrium MR angiograms were then acquired within five minutes post– contrast injection. When using TRICKS three-dimensional SPGR, scans were initiated immediately after starting contrast injection (for carotids) or 16 –20 seconds after starting contrast injection (for calves). The frame immediately before venous enhancement was considered to be the first-pass image, and the last frame was considered to be the equilibrium image.
Vital signs were monitored throughout each study. Blood samples were taken for pharmacokinetic analysis before and 24 hours after contrast injections for all subjects. Data Analysis The SNR of first-pass and equilibrium MRA were determined. For each subject, an individual first-pass image and an equilibrium image at the same slice position were used for evaluation. Selective venous imaging was obtained by subtraction of arterial phase images from equilibrium phase images. ROIs with size no smaller than 16 mm2 were placed (by W.L.) on the artery of interest and the background. SNR was calculated by dividing the signal intensity of the target artery by the SD of the background. The paired Student’s t-test was used to evaluate statistical significance. Overall image quality was graded from 1 to 4 (1 ⫽ nondiagnostic, 2 ⫽ diagnostic, 3 ⫽ good, 4 ⫽ excellent), and scored by an interventional radiologist (S.T.) for all subjects. RESULTS Phantom Experiment A plot of SNR against dilution factor (Fig. 1) shows that Gd-DTPA produces a higher SNR peak than ferumoxytol. Both agents have lower SNR at small dilution fac-
Figure 1. The SNR vs. dilution factor for Gd-DTPA and ferumoxytol in a phantom. The data is from a central slice of the three-dimensional volume obtained with fast three-dimensional SPGR sequence (TR ⫽ 4.0 msec, TE ⫽ 1.4 msec, flip angle ⫽ 30°).
First-Pass MR Angiography with Ferumoxytol
49
Figure 2. MR first-pass thoracic aortograms of a 19-year-old male with history of recurrent left lower lobe pneumonia. a: Image (TR/TE ⫽ 4.0 msec/1.4 msec) was acquired after injection of four-fold diluted ferumoxytol (4 mg Fe/kg). b: Image (TR/TE ⫽ 4.5 msec/1.4 msec) was acquired after injection of Gd-DTPA (0.2 mmol/kg) 33 days earlier. The arrows in both (a) and (b) indicate a prominent vessel arising off the lower left aspect of the descending thoracic aorta (left intralobar bronchopulmonary sequestration). Note that the quality of the first-pass enhancement with ferumoxytol is comparable to that using Gd-DTPA.
tors (higher concentrations) due to the T2*-shortening effect. For ferumoxytol, the curve is relatively flat for dilutions less than 16. Gd-DTPA provides the highest SNR when diluted to approximately 1/16th of the original concentration, whereas ferumoxytol dilutions on the order of 1/64th to 1/128th give the highest SNR. The phantom experiment suggests that, in vivo, the difference in concentration for reaching the highest SNR between the two contrast agents should range from a factor of 4 (64/16) to 8 (128/16). It is well known that original concentration (undiluted) of Gd-DTPA provides good arterial enhancement for first-pass MRA. If we find out the difference in concentration for reaching the highest SNR between Gd-DTPA and ferumoxytol, we would know the proper dilution factor of ferumoxytol for first-pass MRA. Therefore, we selected either 4 or 8 as the dilution factor for first-pass ferumoxytol MRA. Human Subjects All subjects completed their studies without any serious adverse events. One patient had urgent diarrhea approximately 1.5 hours postscan. No undesirable changes were observed in vital signs and clinical labo-
Figure 3. MR carotid angiograms (TR/ TE ⫽ 5.0 msec/1.2 msec) of a 72-year-old man acquired after injection of four-fold diluted ferumoxytol (4 mg Fe/kg). a: First-pass arterial phase image shows bilateral narrowing of carotid arteries (arrowheads). The signal dropout at the base of the right carotid artery is artifact due to incomplete coverage of the three-dimensional volume. b: Equilibrium image shows arterial and venous structures are overlapped. c: A selective venous phase image obtained by subtraction of the arterial phase image from the equilibrium image. Note that the arteries and veins obtained in this way show similar signal intensity.
ratory test results. Good first-pass arterial enhancement with ferumoxytol was obtained in all subjects (Figs. 2–5). Image quality of first-pass MRA was scored as excellent in seven subjects, and good in five subjects. The average SNR of first-pass MRA (42.3 ⫾ 29.1) was comparable to that of equilibrium MRA (48.7 ⫾ 33.3) (Table 3), with no statistically significant difference between the two groups (P ⫽ 0.19). Separation of arteries and veins was feasible by subtraction of first-pass MRA from equilibrium MRA (Fig. 3). In three subjects, the inferior vena cava was also demonstrated during firstpass MRA (Fig. 4). The findings in ferumoxytol MRA were consistent with the results of other vascular tests.
DISCUSSION Several bolus-injectable blood pool agents are currently being investigated for first-pass and equilibrium MRA in experimental and clinical studies (20 –27). Ferumoxytol is another bolus-injectable blood pool contrast agent with potential applications for both first-pass and equilibrium MRA (28 –31). Our preliminary experience demonstrates the feasibility of first-pass MRA using
50
Li et al.
Figure 4. MR abdominal angiograms (TR/TE ⫽ 3.5 msec/1.3 msec) of a 60year-old male acquired after injection of four-fold diluted ferumoxytol (4 mg Fe/ kg). a: First-pass image. b: Equilibrium image. Aortic and left iliac aneurysms (large arrows) are demonstrated. The artery arising from the left iliac artery (arrowhead) supplies a transplanted kidney. The right iliac artery and vein cannot be seen due to metal artifact from right iliac aneurysm stent (small arrows). Note that in the first-pass image, the inferior vena cava is visible. Polycystic kidney disease is also demonstrated.
ferumoxytol in human subjects. Adequate first-pass arterial enhancement was obtained in all subjects and the findings were consistent with the results of other vascular tests. First-pass contrast-enhanced MRA usually uses extracellular agents, typically gadolinium chelates. Extracellular agents provide high arterial SNR, but the enhancement decreases rapidly after the initial pass due to rapid leakage of contrast agent into the extravascular space. Venous imaging can be done but it is not optimal unless very high doses of contrast agent are given. Blood pool contrast agents maintain the signal intensity of arteries and veins over a much longer period, ranging from minutes to hours. Their potential utility for venous imaging is obvious. However, most arterial applications require the ability to distinguish arteries from veins, which is best done by using a combination of first-pass arterial and equilibrium phase imaging. In this study, first-pass ferumoxytol-enhanced MRA not only permitted arteries to be imaged without interference from veins, but also permitted image subtraction for selective venous display. Time-resolved arterial imaging using TRICKS was also feasible. The use of first-pass contrast-enhanced MRA with USPIO-based agents in human subjects has been lim-
ited in the past by the inability to rapidly infuse the contrast agent due to potential toxicity, and by T2*dependent artifacts such as magnetic susceptibility effects that may occur with infusion of the undiluted agent (7,16,18,19). At the high concentrations at which iron oxide agents are typically formulated, the T2* effects predominate even on sequences with ultrashort echo times such as the ones used for first-pass MRA acquisitions (e.g., 1–2 msec). Our initial experience using first-pass MRA during administration of undiluted ferumoxytol at a rate of 1 mL/second showed inhomogeneous arterial enhancement (unpublished data in our department). According to the results of our phantom experiment, 16-fold dilution of Gd-DTPA provides the best SNR, whereas 16fold dilution of ferumoxytol provides poor signal due to T2* effect. Ferumoxytol provides the best SNR in the phantom at dilutions of 64 –128. The difference in concentration for reaching the highest SNR between GdDTPA and ferumoxytol should range from a factor of 4 (16/64) to 8 (16/128). Therefore we used a dilution factor of 4 or 8 to minimize the T2* effect with satisfactory results in vivo. Although first-pass MRA can also be done using undiluted blood pool contrast agent with a lower infusion
Figure 5. Calf MRA (TR/TE ⫽ 4.7 msec/1.7 msec) of a 45-year-old male acquired with TRICKS technique after injection of eight-fold diluted ferumoxytol (2 mg Fe/kg). Six of the eight frames are shown to display the course of enhancement from arterial to equilibrium phase (a–f). Frame (a) demonstrates arterial enhancement, followed by later time frames (b–f) with venous enhancement. Left venous malformation is well demonstrated.
First-Pass MR Angiography with Ferumoxytol
51
Table 3 Individual SNR Measurements at First-Pass and Equilibrium for the Target Arteries Subject no.
Territories of ferumoxytol MRA
Quality of first-pass
SNR of first-pass
SNR of equilibrium
1 2 3 4 5 6 7 8 9 10 11 12
Abdominal Abdominal Abdominal Abdominal Abdominal Thoracic Carotid Carotid Calf Mid leg Calf Calf
Good Good Excellent Good Good Excellent Excellent Good Excellent Excellent Excellent Excellent
47.9 23.6 19.8 53.9 16.3 49.5 18.6 22.3 31.5 80.8 112.2 31.2
46.8 31.3 35.9 63.0 16.1 39.8 17.2 24.6 50.1 127.4 97.8 34.9
rate (24,26,27), our method has the additional benefit of increasing the administered volume, so that the duration of contrast agent infusion can better match the duration of data acquisition. Also, when using a power injector for administration of contrast agent, larger volumes at higher infusion rates (e.g., 2 mL/second) should be more precisely administered than small volumes at very low infusion rates (e.g., 0.25– 0.5 mL/ second). Of course, the appropriate dilution will vary depending on the composition, relaxivity, and concentration of the particular contrast agent, so our results cannot be directly extended to other iron oxide-based agents. One might expect that the SNR for first-pass MRA should be higher than that for equilibrium phase MRA, since the contrast agent is less diluted in the blood and the reduction in T1 relaxation time is greater. However, our measurements showed no significant differences in SNR between first-pass and equilibrium phase MRA. In the case of iron oxide-based agents such as ferumoxytol, the T2* effects are much greater than produced by gadolinium chelates. Although the T1 reduction is greater during the first pass, so is the signal loss due to T2* reduction; this signal loss may occur even with the use of diluted contrast agent. It is also possible that the dilution factor we used is not optimal, since it was based on a phantom study. Additional in vivo studies to determine the optimal dilution factor are warranted. In conclusion, our preliminary experience demonstrates the feasibility of ferumoxytol-enhanced firstpass MRA. Satisfactory arterial enhancement during first-pass imaging is obtained with infusion of diluted contrast agent. The combination of first-pass and equilibrium MRA allows evaluation of arteries and veins in a single exam. REFERENCES 1. Prince MR. Gadolinium-enhanced MR aortography. Radiology 1994;191:155–164. 2. Yucel EK. MR angiography for evaluation of abdominal aortic aneurysm: has the time come? Radiology 1994;192:321–323. 3. McLachlan SJ, Morris MR, Lucas MA, et al. Phase I clinical evaluation of a new iron oxide MR contrast agent. J Magn Reson Imaging 1994;4:301–307. 4. Mitchell DG. MR imaging contrast agent—what’s in a name? J Magn Reson Imaging 1997;7:1– 4.
5. Lauffer R, Parmlee D, Dunham S, et al. MS-325: albumin-targeted contrast agent for MR angiography. Radiology 1998;207:529 –538. 6. Knopp MV, Tengg-Kobligk HV, Floemer F, Schoenberg SO. Contrast agents for MRA: future directions. J Magn Reson Imaging 1999;10: 314 –316. 7. Kroft LJM, Roos AD. Blood pool contrast agent for cardiovascular MR imaging. J Magn Reson Imaging 1999;10:395– 403. 8. Mayo-Smith WW, Saini S, Slater G, Kaufman JA, Sharma P, Hahn PF. MR contrast material for vascular enhancement: value of superparamagnetic iron oxide. AJR Am J Roentgenol 1996;166:73– 77. 9. Reimer P, Allkemper T, Matuszewski L, Balzer T. Contrast-enhanced 3D-MRA of the upper abdomen with a bolus-injectable SPIO (SH U 555). J Magn Reson Imaging 1999;10:65–71. 10. Korosec FR, Turski PA, Carroll TJ, Mistretta CA, Grist TM, Mistretta CA. Contrast-enhanced MR angiography of the carotid bifurcation. J Magn Reson Imaging 1999;10:317–325. 11. Kellar KE, Fujii DK, Gunther WHH, et al. NC100150 injection, a preparation of optimized iron oxide nanoparticles for positive-contrast MR angiography. J Magn Reson Imaging 2000;11:488 – 494. 12. Bunce NH, Moon JC, Bellenger NG, et al. Improved cine cardiovascular magnetic resonance using Clariscan (NC100150 injection). J Cardiovasc Magn Reson 2001;16:217–223. 13. Bunce NH, Keegan J, Gatehouse PD, et al. Initial experience with the intravascular contrast agent NC100150-injection (Clariscan威) for breath-hold and navigator-gated magnetic resonance coronary artery imaging. J Magn Reson Imaging 2002;10:404 – 410. 14. Stillman AE, Wilke N, Li D, Haacke M, McLachlan S. Ultrasmall superparamagnetic iron oxide to enhance MRA of the renal and coronary arteries: studies in human patients. J Comput Assist Tomogr 1996;20:51–55. 15. Anzai Y, Prince MR, Chenevert TL, et al. MR angiography with an ultrasmall superparamagnetic iron oxide blood pool agent. J Magn Reson Imaging 1997;7:209 –214. 16. Loubeyre P, Zhao S, Canet E, et al. Ultrasmall superparamagnetic iron oxide particles (AMI 227) as a blood pool contrast agent for MR angiography: experimental study in rabbits. J Magn Reson Imaging 1997;7:958 –962. 17. Knollmann FD, Bo¨ck JC, Teltenko¨tter S, et al. Evaluation of portal MR angiography using superparamagnetic iron oxide. J Magn Reson Imaging 1997;7:191–196. 18. Zheng J, Carr J, Harris K, et al. Three-dimensional MR pulmonary perfusion imaging and angiography with an injection of a new blood pool contrast agent B-22956/1. J Magn Reson Imaging 2001;14: 425– 432 19. Hoffmann U, Loewe C, Bernhard C, et al. MRA of the lower extremities in patients with pulmonary embolism using a blood pool contrast agent: initial experience. J Magn Reson Imaging 2002;15: 429 – 437. 20. Grist TM, Korosec FR, Peters DC, et al. Steady-state and dynamic MR angiography with MS-325: initial experience in humans. Radiology 1998;207:539 –544. 21. Frank H, Weissleder R, Brandy TJ. Enhancement of MR angiography with iron oxide: preliminary studies in whole blood phantom and in animals. AJR Am J Roentgenol 1994;162:209 –213.
52 22. Taupitz M, Schnorr J, Abramjuk C, et al. New generation of monomer-stabilized very small superparamagnetic iron oxide particles (VSOP) as contrast medium for MR angiography: preclinical results in rats and rabbits. J Magn Reson Imaging 2000;12:905–911. 23. Taupitz M, Schnorr J, Wagner S, et al. Coronary MR angiography: experimental results with a monomer-stabilized blood pool contrast medium. Radiology 2002;222:120 –126 24. Schnorr J, Wagner S, Abramjuk C, et al. Comparison of the ironoxide-based blood-pool contrast medium VSOP-C184 with GdDTPA in first-pass MRA of the aorta and renal arteries in pigs. In: Proceedings of the 11th Annual Meeting of ISMRM, Toronto, Canada, 2003. p 1337. 25. Dirksen MS, Kaandorp TAM, Lamb HJ, Doornbos J, Corot C, Roos AD. Three-dimensional navigator coronary MRA with the aid of a blood pool agent in pigs: improved image quality with inclusion of the contrast agent first-pass. J Magn Reson Imaging 2003;18:502– 506. 26. Tombach B, Reimer P, Mahler M, Ebert W, Pering C, Heindel W. First-pass and equilibrium phase MRA following intravenous bolus injection of SH U 555 C: phase I clinical trial in elderly volunteers with risk factors for arterial vascular disease. Acad Radiol 2002; 9(Suppl 2):S425–S427.
Li et al. 27. Reimer P, Bremer C, Allkemper T, et al. Myocardial perfusion and MR angiography of chest with SH U 555 C: result of placebocontrolled clinical phase I study. Radiology 2004;231:474 – 481. 28. Prasad PV, Pierchala L, Chen Q, Vu A, Li W, Lewis J, Edelman RR. Preliminary evaluation of code 7228 as an iron oxide based blood pool contrast agent for CE-MRA. In: Proceedings of the 11th Annual Meeting of ISMRM, Toronto, Canada, 2003. p 1338. 29. Prince MR, Zhang HL, Chabra SG, Jacobs P, Wang Y. A pilot investigation of new superparamagnetic iron oxide (ferumoxytol) as a contrast agent for cardiovascular MRI. J X-ray sci technol 2003; 11:231–240. 30. Ersoy H, Jacobs P, Kent CK, Prince MR. Blood pool MR Angiography of aortic stent-graft endoleak. AJR Am J Roentgenol 2004;182: 1181–1186. 31. Jacobs P, Shenouda M. A phase 1 pharmacokinetics and safety study of ferumoxytol: a new blood pool and macrophage specific superparamagnetic iron oxide MR contrast agent. In: Proceedings of the 89th Scientific Assembly and Annual Meeting of the Radiological Society of North America, Chicago, 2003. p 249. 32. Korosec FR, Frayne R, Grist TM, Mistretta CA. Time-resolved contrast-enhanced 3D MR angiography. Magn Reson Med 1996;36: 345–351.
