First-pass contrast-enhanced magnetic resonance angiography in humans using ferumoxytol, a novel ultrasmall superparamagnetic iron oxide (USPIO)-based blood pool agent

PURPOSE: To evaluate the feasibility of first-pass contrast-enhanced 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 micromol Fe/kg (n = 9), or 35.8 micromol Fe/kg (n = 3) was used. Based on a phantom study, the agent with initial concentration of 537.2 micromol Fe/mL was diluted by either four-fold (134.3 micromol Fe/mL) or eight-fold (67.1 micromol Fe/mL) for first-pass MRA. 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.     

Coronary MR angiography using citrate‐coated very small superparamagnetic iron oxide particles as blood‐pool contrast agent: Initial experience in humans

Purpose:

To evaluate very small superparamagnetic iron oxide particles (VSOP‐C184) as blood‐pool contrast agent for coronary MR angiography (CMRA) in humans.

Materials and Methods:

Six healthy volunteers and 14 patients with suspected coronary artery disease underwent CMRA after administration of VSOP‐C184 at the following doses: 20 μmol Fe/kg (4 patients), 40 μmol Fe/kg (5 patients), 45 μmol Fe/kg (6 healthy volunteers), and 60 μmol Fe/kg (5 patients). In healthy volunteers, contrast‐to‐noise ratio (CNR), signal‐to‐noise ratio (SNR), and vessel edge definition (VED) of contrast‐enhanced CMRA were compared with non–contrast‐enhanced CMRA. In patients, a per‐segment intention‐to‐diagnose evaluation of contrast‐enhanced CMRA for detection of significant coronary stenosis (≥50%) was performed.

Results:

Three healthy volunteers (45 μmol Fe/kg VSOP‐C184) and two patients (60 μmol Fe/kg VSOP‐C184) had adverse events of mild or moderate intensity. VSOP‐C184 significantly increased CNR (15.1 ± 4.6 versus 6.9 ± 1.9; P = 0.010), SNR (21.7 ± 5.3 versus 15.4 ± 1.6; P = 0.048), and VED (2.3 ± 0.6 versus 1.2 ± 0.2; P < 0.001) compared with non–contrast‐enhanced CMRA. In patients, contrast‐enhanced CMRA yielded sensitivity, specificity, and diagnostic accuracy for detection of significant coronary stenosis of 86.7%, 71.0%, 73.1%, respectively.

Conclusion:

CMRA using VSOP‐C184 was feasible and yielded moderate diagnostic accuracy for detection of significant coronary stenosis within this proof‐of‐concept setting. J. Magn. Reson. Imaging 2011;. © 2011 Wiley‐Liss, Inc.     

On the dual contrast enhancement mechanism in frequency‐selective inversion‐recovery magnetic resonance angiography (IRON‐MRA)

The susceptibility of blood changes after administration of a paramagnetic contrast agent that shortens T₁. Concomitantly, the resonance frequency of the blood vessels shifts in a geometry‐dependent way. This frequency change may be exploited for incremental contrast generation by applying a frequency‐selective saturation prepulse prior to the imaging sequence. The dual origin of vascular enhancement depending first on off‐resonance and second on T₁ lowering was investigated in vitro, together with the geometry dependence of the signal at 3T. First results obtained in an in vivo rabbit model are presented. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

MR angiography with a new rapid-clearance blood pool agent: Initial experience in rabbits.

The purpose of this study was to assess a new Gd-based macromolecular intravascular contrast agent (P792, Vistarem(R); Laboratoire Guerbet, Aulnay sous Bois, France) for MR angiography (MRA). P792 is a macrocyclic gadolinium compound based on a gadoterate meglumine structure substituted by hydrophilic arms. In vitro imaging of phantoms containing varying concentrations of P792 and gadoterate meglumine (Gd-DOTA) was performed. In rabbits (N = 5), arterial concentrations for P792 and Gd-DOTA were determined, and in vivo 3D MRA was performed. For gadolinium concentrations ranging from 200 to 3000 micromol/l, in vitro imaging showed higher SNR values for P792 compared to Gd-DOTA. Determination of arterial Gd concentration showed comparable bolus phase curves for P792 and Gd-DOTA. With P792, higher concentrations were obtained due to a restricted diffusion into the interstitial space. P792 allowed acquisition of high-quality MR angiograms. Image quality was rated as superior for P792 in the post-bolus phase images. In conclusion, P792 appears to be well suited for high-quality first-pass and equilibrium-phase MRA. The intravascular properties lead to an excellent signal in the vasculature, with limited background enhancement. Since the agent is rapidly renally excreted, it should be well suited for perfusion and permeability imaging.     

MRA of the lower extremities in patients with pulmonary embolism using a blood pool contrast agent: initial experience

PURPOSE: To evaluate the feasibility of blood pool contrast-enhanced magnetic resonance angiography (MRA) to visualize the arterial and venous vessel tree and to detect deep venous thrombosis (DVT) of the lower extremities. MATERIALS AND METHODS: Nine consecutive patients with pulmonary embolism (mean age = 46 +/- 9) were randomized to various doses of NC100150 (between 0.75 and 6 mg of Fe/kg of body weight). A T1-weighted (T1W) 3D gradient recalled echo (GRE) sequence (TE = 2.0 msec, TR = 5.0 msec) was used. Two observers blinded to the dose of contrast agent assessed image quality, contrast attenuation, and appearance of thrombi. RESULTS: Qualitative assessment of overall MRA image quality and semiquantitative vessel scoring revealed good to excellent delineation of venous and arterial vessel segments independent of the dose of NC100150. However, quantitative region of interest analysis revealed a significantly higher signal-to-noise ratio (SNR) in the high-dose group than in the mid- and low-dose groups of NC100150 (P < 0.01). Between dose groups, the SNR was independent of vessel type (artery or vein) and vessel segment localization (proximal or distal). All seven venous thrombi (mean length = 7.2 +/- 0.95 cm) were characterized by a very low signal intensity (SI), which was only 16.6 +/- 7% of the SI in adjacent venous segments (P < 0.0001). CONCLUSION: High-quality MR angiograms of the lower extremities can be obtained using low concentrations of NC100150 in combination with a strong T1W 3D GRE sequence. The obvious delineation of venous thrombi suggests that this technique may be potentially used as a noninvasive "one-stop shopping" tool in the evaluation of thromboembolic disease.     

Pulmonary MR perfusion at 3.0 Tesla using a blood pool contrast agent: Initial results in a swine model

PURPOSE: To prospectively evaluate the technical feasibility of a highly accelerated pulmonary MR perfusion protocol at 3.0T using a blood pool contrast agent in a swine model. MATERIALS AND METHODS: Twelve pigs underwent time-resolved pulmonary MR angiography (MRA) on a 3.0T MR system under anesthesia and controlled mechanical ventilation. After intravenous injection of 0.05 mmol/kg of Gadomer-17 at 4 mL/second, a fast time-resolved MRA sequence with temporal echo-sharing (three segmented k-space) and highly accelerated parallel acquisition was used to acquire 3D data sets with an in-plane resolution of 1 x 1 mm(2) (slice thickness = 6 mm) and temporal resolution of one second. Image quality was evaluated independently by two radiologists, and quantitative analysis of perfusion parameters was performed using pre-released perfusion software. RESULTS: All studies were identified by both readers as having diagnostic image quality (range = 2-3, median = 3) and there was excellent interobserver agreement (kappa = 0.89; 95% CI = 0.83, 0.95). A quantitative analysis of perfusion indices was performed, with excellent overall goodness-of-fit (chi(2) value = 1.4, degree of freedom (DF) = 1). Successfully derived perfusion parameters included the time to peak (TTP, 5.1 +/- 0.7 second), mean transit time (MTT, 6.6 +/- 0.9 second), maximal signal intensity (MSI, 1051.2 +/- 718.9 arbitrary units [A.U.]), and maximal upslope of the curve (MUS, 375.9 +/- 263.4 A.U./second). CONCLUSION: 3.0T pulmonary MR perfusion using a blood pool contrast agent in a swine model is feasible. The higher available signal-to-noise ratio (SNR) at 3.0T and the high T1 relaxivity of Gadomer-17 effectively support highly accelerated parallel acquisition, and improve the performance of time-resolved pulmonary MRA.     

High‐resolution cerebral blood volume imaging in humans using the blood pool contrast agent ferumoxytol

Cerebral blood volume maps are usually acquired using dynamic susceptibility contrast imaging which inherently limits the spatial resolution and signal to noise ratio of the images. In this study, we used ferumoxytol (AMAG Pharmaceuticals, Inc., Cambridge, MA), an FDA‐approved compound, to obtain high‐resolution cerebral blood volume maps with a steady‐state approach in seven healthy volunteers. maps (0.8 × 0.8 × 1 mm³) were acquired before and after injection of ferumoxytol and an intraindividual normalization protocol was used to obtain quantitative values. The results show excellent contrast between white and gray matter as well as fine highly detailed vascular structures. An average blood volume of 4% was found in the brain of all volunteers, consistent with prior literature values. A linear relationship was found between ferumoxytol dose (mg/kg) and (1/s) in gray (R² = 0.98) and white matter (R² = 0.98). A quadratic relationship was found in the sagittal sinus (R² = 0.98). The cerebral blood volume maps compare well with lower resolution dynamic susceptibility contrast‐MRI and their use should improve the evaluation of small and heterogeneous lesions and facilitate intrapatient and interpatient comparisons. Magn Reson Med 70:705–710, 2013. © 2012 Wiley Periodicals, Inc.     

Volume‐targeted and whole‐heart coronary magnetic resonance angiography using an intravascular contrast agent

Purpose

To compare volume‐targeted and whole‐heart coronary magnetic resonance angiography (MRA) after the administration of an intravascular contrast agent.

Materials and Methods

Six healthy adult subjects underwent a navigator‐gated and ‐corrected (NAV) free breathing volume‐targeted cardiac‐triggered inversion recovery (IR) 3D steady‐state free precession (SSFP) coronary MRA sequence (t‐CMRA) (spatial resolution = 1 × 1 × 3 mm³) and high spatial resolution IR 3D SSFP whole‐heart coronary MRA (WH‐CMRA) (spatial resolution = 1 × 1 × 2 mm³) after the administration of an intravascular contrast agent B‐22956. Subjective and objective image quality parameters including maximal visible vessel length, vessel sharpness, and visibility of coronary side branches were evaluated for both t‐CMRA and WH‐CMRA.

Results

No significant differences (P = NS) in image quality were observed between contrast‐enhanced t‐CMRA and WH‐CMRA. However, using an intravascular contrast agent, significantly longer vessel segments were measured on WH‐CMRA vs. t‐CMRA (right coronary artery [RCA] 13.5 ± 0.7 cm vs. 12.5 ± 0.2 cm; P < 0.05; and left circumflex coronary artery [LCX] 11.9 ± 2.2 cm vs. 6.9 ± 2.4 cm; P < 0.05). Significantly more side branches (13.3 ± 1.2 vs. 8.7 ± 1.2; P < 0.05) were visible for the left anterior descending coronary artery (LAD) on WH‐CMRA vs. t‐CMRA. Scanning time and navigator efficiency were similar for both techniques (t‐CMRA: 6.05 min; 49% vs. WH‐CMRA: 5.51 min; 54%, both P = NS).

Conclusion

Both WH‐CMRA and t‐CMRA using SSFP are useful techniques for coronary MRA after the injection of an intravascular blood‐pool agent. However, the vessel conspicuity for high spatial resolution WH‐CMRA is not inferior to t‐CMRA, while visible vessel length and the number of visible smaller‐diameter vessels and side‐branches are improved. J. Magn. Reson. Imaging 2009;30:1191–1196. © 2009 Wiley‐Liss, Inc.     

Optimization of a blood pool contrast agent injection protocol for MR angiography

PURPOSE: To design an ideal first-pass profile for MR angiography (MRA) by optimizing a multiphasic injection protocol based on two experimental animal models. MATERIALS AND METHODS: An equivalent contrast-enhanced (CE) MRA injection protocol was developed with controlled injection modalities (injection rate, volume, and dose) in rabbits and pigs. P792, a blood pool contrast agent, was injected in 17 male New Zealand rabbits and five farm pigs with variable injection schemes (mono- and multiphasic). From the gadolinium (Gd) blood concentration data, a simulation of an MR acquisition was performed to evaluate the impact of such an injection protocol on MR arterial signal and to select the best injection protocol. RESULTS: An empirical relationship between the arterial peak concentration and the injection parameters was found in the rabbits and pigs, allowing precise prediction of the first-pass profile. Of the four injection scheme strategies tested (standard bolus and bi-, tri-, and multiphasic injection protocols), the multiphasic "ramp" injection protocol provided the most optimal contrast agent pharmacokinetics with a durable plateau of concentration. CONCLUSION: Ramp injection protocol provides an optimized first-pass profile for CE-MRA.     

Maximizing contrast-to-noise ratio in ultra-high resolution peripheral MR angiography using a blood pool agent and parallel imaging

PURPOSE: To determine sequence parameters that maximize vascular contrast-to-noise (CNR) for ultra-high resolution equilibrium phase (EP) peripheral imaging for the blood pool agent (BPA) Vasovist. MATERIALS AND METHODS: A model for maximizing CNR in EP MR angiography (MRA) is presented. Tissue relaxation times, coil geometry (g)-factors, and clinical imaging requirements (voxel volume and scan time) were determined from human studies. Using these known values, parameters for TR, TE, bandwidth, flip angle (FA), and sensitivity encoding (SENSE) factor that maximized CNR were derived from the model. CNR was enhanced by using reduction in scan time gained from parallel imaging to increase TR and minimize bandwidth. A total of 10 patients were imaged using model-derived EP CE-MRA parameters. RESULTS: The model closely predicted experimental CNR data measured in two clinical studies (r(2) = 0.85) and demonstrated an increase in CNR by a factor of 2.3 when subjects were imaged using optimal sequence parameters (P < 0.001). Thigh and calf data were acquired with voxel volumes on the order of 0.2 mm(3) using a SENSE factor of 4. CONCLUSION: Recommended imaging parameters for a 12-channel and 18-channel peripheral vascular coil at two doses of Vasovist (0.03 mmol/kg and 0.05 mmol/kg) are presented.     

Magnetic resonance VIBE venography using the blood pool contrast agent gadofosveset trisodium--an interrater reliability study

Purpose

In this study, image quality of leg veins and vena cava inferior was scored by independent raters using the new intravascular magnetic resonance imaging (MRI) contrast agent gadofosveset trisodium using fat-suppressed 3D gradient echo Volume Interpolated Breath-hold Examination.

Material and methods

The leg venous system without clinical signs of deep venous thrombosis (DVT) and sonography-ruled out DVT were imaged using a fat-suppressed 3D gradient echo Volume Interpolated Breath-hold Examination (VIBE FS). Image interpretation was done independently by two experienced radiologists (raters) using a 5-point scoring system.

Results

High diagnostic image quality with an overall mean visibility score of 4.8 ± 0.1 was acquired in patients enrolled in the study using gadofosveset trisodium-enhanced MRI for the venous system of the leg. There were no cases with moderate, poor or nondiagnostic image quality. Additionally, an excellent interrater reliability was observed.

Conclusions

This study shows the feasibility of acquiring high resolution images with excellent image quality of the venous system of the leg using gadofosveset trisodium.     

Value of blood pool contrast agents in magnetic resonance angiography of the pelvis and lower extremities

Our objective was: (1) to determine the appropriate dose of new ultrasmall superparamagnetic iron oxide particles for magnetic resonance angiography (MRA). This agent comprised of a single iron oxide crystal stabilized with a carbohydrate-polyethylene glycol coat (PEG-Ferron/NC 100150 injection); (2) to determine the proper flip angle for PEG-Ferron-enhanced 3 D time-of-flight (TOF) MRA sequence; and (3) to compare the enhancement of peripheral vessels following PEG-Ferron and GdDTPA-BMA. MRA parameters were: TR/TE = 50/2.1 ms, NEX = 1, FOV = 30 × 30 × 1.8 cm, and matrix = 256 × 128 × 64. In anesthetized beagle dogs (n = 10), the effects of PEG-Ferron and GdDTPA-BMA on regional signal were monitored for 45 min and compared. The lowest dose of PEG-Ferron (0.05 mmol/kg) produced the best enhancement of primary, secondary and tertiary vessels. The flip angle 60 ° provided better enhancement than 20 ° on contrast enhanced images. Unlike GdDTPA-BMA, PEG-Ferron allowed prolonged delineation (> 45 min) of the pelvis and lower extremities circulation. PEG-Ferron provided greater Contrast-to-noise ratio CNR (80.2 ± 6.2, P < 0.05) than GdDTPA-BMA (63.5 ± 2.5). It may be possible for blood pool contrast-enhanced 3 D TOF MRA to provide valuable information for visualization of vascular tree including guiding interventions. Received 6 August 1997; Revision received 25 November 1997; Accepted 3 February 1998     

Albumin-binding MR blood pool agents as MRI contrast agents in an intracranial mouse glioma model.

Intravenous MRI contrast agents are commonly used to improve the detection of intracranial tumors and other central nervous system (CNS) lesions for diagnosis and treatment planning. Two small-molecule, albumin-binding blood pool contrast agents (MP-2269 and MS-325) of potential clinical significance were evaluated at 1.5 Tesla in a mouse glioma model and compared with an extracellular contrast agent (OptiMARK). Tumor image contrast was significantly enhanced and long-lived following administration of 30 micromole/kg of the blood pool agents: specifically, contrast enhancement peaked slowly at 25-30 min following administration, remained constant for >3 hr, and returned to baseline within 20 hr. Comparable but "transient" enhancement was achieved using 100 micromole/kg OptiMARK: specifically, contrast enhancement peaked rapidly at 2-5 min following administration and then declined over 40 min. The blood pool contrast agents demonstrated an approximately threefold increased dose-effectiveness and a lengthened window of tumor contrast enhancement in comparison to commonly available extracellular contrast agents. This demonstrates the potential of alternative contrast-enhanced (CE) MRI examination protocols for tumor detection.     

Coronary magnetic resonance angiography: experimental evaluation of the new rapid clearance blood pool contrast medium P792.

The signal-enhancing characteristics of a new monodisperse monogadolinated macromolecular MR contrast medium (P792) were evaluated for magnetic resonance angiography (MRA) of the coronary arteries. A total of 15 cardiac examinations were performed in pigs at 1.5 T using a 3D gradient-echo sequence. Images were acquired during breath-hold before and up to 35 min after IV injection of Gd-DTPA (0.3 mmol Gd/kg), Gd-BOPTA (0.2 mmol Gd/kg), and P792 (13 micromol Gd/kg). An increase in the signal-to-noise ratio (SNR) of 97% +/- 17%, 108% +/- 37%, and 109% +/- 31% in coronary arteries and of 82% +/- 19%, 82% +/- 24%, and 28% +/- 18% in myocardium, respectively, was measured during the first postcontrast acquisition. The blood-to-myocardium signal-difference-to-noise ratio (SDNR) was significantly higher for P792 than for the other Gd compounds (P <.05) for up to 15 min after injection. Qualitative assessment showed that visualization of the coronary arteries and their branches was significantly better for P792 compared to the low-molecular Gd compounds (P <.05). The blood pool contrast medium P792 is well suited for MRA of the coronary arteries.     

High spatial resolution magnetic resonance imaging of experimental cerebral venous thrombosis with a blood pool contrast agent

Purpose

The purpose of this study was to investigate the feasibility of clot visualization in small sinus and cortical veins with contrast enhanced MRA in a cerebral venous thrombosis animal model using a blood pool contrast agent, Gadofosveset, and high spatial resolution imaging.

Material and methods

For induction of cerebral venous thrombosis a recently developed combined interventional and microsurgical model was used. Cerebral sinus and cortical vein thrombosis was induced in six pigs. Two further pigs died during the procedure. Standard structural, time-of-flight- and phase contrast-angiograms were followed by fast time resolved high resolution 3D MRA (4D MRA) and subsequent high spatial resolution 3D MRA in the equilibrium phase with and without addition of parallel imaging. Visualization of the clots using the different sequences was subjectively compared and contrast-to-noise ratio (CNR) was assessed.

Results

In the remaining six animals the procedure and MR-imaging protocol including administration of Gadofosveset was successfully completed. The 3D high resolution MRA in the equilibrium phase without the addition of parallel imaging was superior to all the other applied MR measurement techniques in terms of visualization of the clots. Only applying this sequence bridging vein thromboses were also seen as a small filling defect with a high CNR of >18.

Conclusion

Only the non-accelerated high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset allows for high-contrast visualization of very small clots in the cerebral sinus and cortical veins.

Statement clinical impact

Detection of cortical vein thrombosis is of high clinical impact. Conventional MRI sequences often fail to visualize the clot. We could demonstrate that, in contrast to conventional sequences, with high spatial resolution 3D MRA in the equilibrium in conjunction with the blood pool agent Gadofosveset very small clots in the cerebral sinus and cortical veins could be successfully visualized. We think that with the presented approach cortical vein thrombosis might also be sufficiently visualized in patients.     

4D phase contrast MRI at 3 T: Effect of standard and blood‐pool contrast agents on SNR,PC‐MRA,and blood flow visualization

Time‐resolved phase contrast (PC) MRI with velocity encoding in three directions (flow‐sensitive four‐dimensional MRI) can be employed to assess three‐dimensional blood flow in the entire aortic lumen within a single measurement. These data can be used not only for the visualization of blood flow but also to derive additional information on vascular geometry with three‐dimensional PC MR angiography (MRA). As PC‐MRA is sensitive to available signal‐to‐noise ratio, standard and novel blood pool contrast agents may help to enhance PC‐MRA image quality. In a group of 30 healthy volunteers, the influence of different contrast agents on vascular signal‐to‐noise ratio, PC‐MRA quality, and subsequent three‐dimensional stream‐line visualization in the thoracic aorta was determined. Flow‐sensitive four‐dimensional MRI data acquired with contrast agent provided significantly improved signal‐to‐noise ratio in magnitude data and noise reduction in velocity data compared to measurements without contrast media. The agreement of three‐dimensional PC‐MRA with reference standard contrast‐enhanced MRA was good for both contrast agents, with improved PC‐MRA performance for blood pool contrast agent, particularly for the smaller supra‐aortic branches. For three‐dimensional flow visualization, a trend toward improved results for the data with contrast agent was observed. Magn Reson Med, 2010. © 2009 Wiley‐Liss, Inc.