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Published online before print March 24, 2004, 10.1148/radiol.2312021251
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(Radiology 2004;231:474-481.)
© RSNA, 2004

Contrast Media

Myocardial Perfusion and MR Angiography of Chest with SH U 555 C: Results of Placebo-controlled Clinical Phase I Study1

Peter Reimer, MD, Christoph Bremer, MD, Thomas Allkemper, MD, Matthias Engelhardt, MD, Marianne Mahler, MD, Wolfgang Ebert, PhD and Bernd Tombach, MD

1 From the Department of Radiology, Städtisches Klinikum Karlsruhe, Academic Teaching Hospital of University of Freiburg, Moltkestrasse 90, D-76133 Karlsruhe, Germany (P.R., M.E.); Department of Clinical Radiology, University of Muenster, Germany (C.B., T.A., B.T.); and Schering, Berlin, Germany (M.M., W.E.). Received October 8, 2002; revision requested December 12; final revision received October 5, 2003; accepted October 28. Supported in part by Schering, Berlin, Germany. Address correspondence to P.R. (e-mail: p.reimer@web.de).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To evaluate SH U 555 C for contrast material–enhanced three-dimensional magnetic resonance (MR) angiography of the chest and myocardial perfusion.

MATERIALS AND METHODS: For chest MR angiography, SH U 555 C was intravenously injected at four doses (5, 10, 20, and 40 µmol iron [Fe] per kilogram of body weight) into three healthy volunteers per dose group, and placebo (saline) was injected into one additional volunteer per dose group (16 subjects). With a body phased-array coil, serial high-spatial-resolution breath-hold three-dimensional MR angiography of the chest was performed at baseline, first pass, and 6, 12, 18, 24, 30, 36, and 42 minutes after injection. SH U 555 C (40 µmol Fe/kg) was injected into four additional volunteers to evaluate cardiac perfusion. Signal intensity (SI) was measured in vessels, cardiac chambers, and myocardium to calculate relative SI changes during time. Analysis of variance for multiple comparisons was applied for statistical analysis. Two readers assessed image quality. Subjects were monitored for side effects (cardiovascular reactions) for 24 hours.

RESULTS: SH U 555 C showed a dose-dependent increase in SI enhancement during first pass and equilibrium phase. SH U 555 C showed dose-dependent increase (range, 259% ± 160 [SD] at 5 µmol Fe/kg to 907% ± 370 at 40 µmol Fe/kg) for thoracic aorta during first pass. Intravascular SI did not significantly decrease with time during equilibrium phase within arterial and venous vessels. Image quality remained stable and was diagnostic for highest dose group to 30 minutes, with good to excellent contrast even in smaller blood vessels. For cardiac perfusion, SH U 555 C showed peak enhancement during first pass through right and left ventricles, as well as stable SI during equilibrium phase within cardiac chambers and myocardium. Peak enhancement during first pass was limited due to susceptibility effects, which were more pronounced in right ventricle than in left. Contrast agent was well tolerated, and no cardiovascular reactions occurred.

CONCLUSION: SH U 555 C bolus injected at highest dose of 40 µmol Fe/kg has capability for depiction at first-pass MR angiography and for cardiac perfusion.

© RSNA, 2004

Index terms: Iron • Magnetic resonance (MR), contrast enhancement, 56.12142, 56.12143 • Magnetic resonance (MR), perfusion study, 511.12144, 523.12144, 524.12144, 56.12144 • Magnetic resonance (MR), vascular studies, 51.12142, 56.12142 • Thorax, MR, 51.12142, 56.12142


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Extracellular gadolinium chelates diffuse very fast into the interstitium even during first-pass magnetic resonance (MR) angiography (1). Intravascular contrast agents for contrast material–enhanced MR imaging and MR angiography were developed to maintain a high intravascular signal that would provide a broader time window for applications such as high-spatial-resolution imaging and imaging of multiple vascular regions or tumors. Several concepts are currently being evaluated in clinical trials. One approach is to use a reversible protein-binding agent with gadofosveset trisodium, formerly identified with the code name MS-325, as the clinically most advanced agent of this class (2). Another approach is to synthesize large molecules with a prolonged retention in blood based on slow extravasation with different routes of slow renal elimination (1). Whereas these agents are based on paramagnetic gadolinium, the third class is based on small or ultrasmall superparamagnetic iron oxides (USPIO) minimized for susceptibility effects and optimized for blood retention. Frank et al (3) described the application of small iron oxide particles for MR angiography in an experimental study. Furthermore, clinical trials with starch-coated and stabilized iron oxide particles identified with the code name NC 100150 (Clariscan; Amersham Health, Oslo, Norway) have been performed (4).

Our rationale for the evaluation of contrast agents with a prolonged intravascular retention is to overcome the limitations of the short time window and rapid extravasation of low-molecular-weight gadolinium chelates and furthermore to open applications for oncologic imaging, such as permeability and intravascular volume measurements. However, first-pass MR angiography has reached an excellent quality and has become a routine clinical procedure. Intravascular contrast agents enhance the entire vasculature but do not selectively enhance the arterial vessels. Therefore, the ideal vascular contrast agent has to provide the capability for both first-pass MR angiography and equilibrium-phase MR angiography during a certain time, thus allowing visualization of smaller arterial and venous branches by means of high-spatial-resolution imaging.

Early development of superparamagnetic iron oxide particles focused on the use of polydisperse particle formulations as T2* contrast agents for imaging of the reticuloendothelial system. The blood elimination half-life of these particles is relatively short, within the range of several minutes, because of the rapid uptake by macrophages, especially in the liver and spleen (5,6). The inverse relationship of the superparamagnetic iron oxide uptake rate into the reticuloendothelial system to the particle size was the basis for the development of USPIO that provided a prolonged intravascular retention. Furthermore, USPIO show an increased r1/r2 ratio, which is more favorable for T1-weighted MR imaging. On the basis of these properties, USPIO provide the potential for use as an intravascular contrast agent for T1-weighted MR imaging (2,4,7–14).

The purpose of our study was to evaluate the intravascular iron oxide–based contrast agent SH U 555 C for contrast-enhanced three-dimensional MR angiography of the chest and for myocardial perfusion.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Study Drug
SH U 555 C (Schering, Berlin, Germany) is an optimized formulation of carboxydextran-coated ferucarbotran (Resovist; Schering), which was formerly identified as SH U 555 A, with respect to T1-weighted MR imaging (15). SH U 555 C is a sterile bolus-injectable ready-to-use formulation that is provided in a concentration of 0.5 mmol iron (Fe) per milliliter. Electron microscopic studies, x-ray diffraction studies, and dynamic laser light scattering showed a mean core particle size of about 3–5 nm and a mean hydrodynamic diameter of about 20 nm in an aqueous environment. Relaxivity measurements yielded an r1 of 22 sec–1 · (mmol/L)–1 and an r2 of 45 seconds–1 · (mmol/L)–1 at 40°C and 20 MHz in water.

Study Design
In four independent dose groups, SH U 555 C was injected intravenously as a bolus into an antecubital vein at doses of 5, 10, 20, and 40 µmol Fe per kilogram of body weight, which corresponded to 0.28, 0.56, 1.10, and 2.20 mg Fe/kg (three volunteers per dose group) and to injection volumes of 0.01, 0.02, 0.04, and 0.08 mL/kg, respectively. One randomly assigned blinded volunteer per dose group received saline (0.9%, 2 mL) as a placebo. Thus, each dose group included four volunteers (three who received the study agent and one who received the placebo). The mean injection volume ranged from 0.75 mL (SD, 0.11) at 5 µmol Fe/kg, 1.65 mL (SD, 0.26) at 10 µmol Fe/kg, and 2.97 mL (SD, 0.33) at 20 µmol Fe/kg (mean volume) to 6.21 mL (SD, 0.81) at 40 µmol Fe/kg. There was no significant difference in the mean ages of the volunteers in the different groups. The doses were selected on the basis of results in previous experiments in animals (14). Myocardial perfusion was separately assessed in four other volunteers with a dose of 40 µmol Fe/kg. The injection rate of SH U 555 C was 0.5 mL/sec, followed by administration of 20 mL of saline (0.9%) at a flow rate of 3.0 mL/sec with an automatic bolus injector (Spectris; Medrad, Pittsburgh, Pa). A total of 20 male subjects (mean age, 33 years; mean body weight, 78.5 kg) were examined.

The institutional review board at our institution and the ethics committee at the University of Freiburg, Germany, approved the study. Informed signed consents were obtained from the volunteers prior to the study.

MR Imaging
Serial coronal high-spatial-resolution three-dimensional MR angiographic images of the blood vessels of the chest were obtained before injection, during first pass, and during the equilibrium phase (at 6-minute intervals up to 42 minutes) after the injection of the contrast agent. A three-dimensional fast low-angle shot sequence (repetition time msec/echo time msec, 4.6/1.8; flip angle, 30o; matrix, 200 x 512; slab thickness, 108 mm; partitions, 36) with a total acquisition time of 26 seconds was applied to obtain breath-hold MR angiographic images. All studies were performed with a body phased-array coil and a 1.5-T unit (Magnetom Vision; Siemens, Erlangen, Germany). For cardiac perfusion studies, 60 nontriggered dynamic single-section T1-weighted turbo fast low-angle shot MR images through the right and left ventricle were acquired in the short axis with the following parameters: repetition time msec/echo time msec/inversion time msec, 416/1.2/200; time delay, 50 msec; flip angle, 8o; 90 phases x 128 frequency matrix; section thickness, 10 mm; time resolution, one image per second. Data acquisition was initiated immediately following the start of injection. Signal intensity (SI) was measured in the right ventricle, the left ventricle, and the left ventricular myocardium to calculate relative SI enhancement during time.

Since a test bolus was not permitted according to the study protocol, a fixed delay of 8 seconds was used for first-pass MR angiography of blood vessels of the chest on the basis of clinical experience in patients of similar ages.

For safety, during the MR investigation, a nurse closely monitored vital signs (blood pressure, heart rate) for an observation period of 1 hour. Furthermore, all subjects were subsequently hospitalized and monitored by the same nurse for side effects such as cardiovascular reactions for 24 hours after contrast material injection.

Image Analysis and Statistical Evaluation
The original data sets and maximum intensity projection images in the anteroposterior projection were quantitatively and qualitatively analyzed for first pass and at each time of the equilibrium phase of MR angiography separately.

Quantitative analysis of SI in various blood vessels (thoracic aorta, common carotid artery, main pulmonary artery, and superior vena cava), left ventricular myocardium, and myocardial chambers was performed for each data set individually. SI measurements before, designated as SIpre, and after, designated as SIpost, injection of contrast agent were obtained in user-defined regions of interest in the center of the blood vessel separately for each time (before injection of contrast material; at first pass; and at 6, 12, 18, 24, 30, 36, and 42 minutes after injection). The diameter of the regions of interest was chosen according to the diameter of the different structures measured, with care to avoid vessel borders or myocardial borders. To avoid partial-volume and inflow effects and to ensure higher consistency, regions of interest were chosen carefully by only one of the authors (M.E.). Each measurement was performed in three positions, and mean SI and SD were calculated. Intravascular enhancement, or ENH, was defined according to the following equation: ENH (%) = [(SIpost – SIpre)/SIpre] · 100. To test for significant differences of the enhancement at different doses for each time, the analysis of variance test for multiple comparisons was applied. A difference with a P value of less than .05 was considered significant.

For pulmonary arteries, qualitative analysis was performed in consensus by two radiologists who were blinded to the dose. These radiologists rated the visibility of vessel segments in the field of view for each time according to the following five-point scale: score 1, none (no blood vessels visible); score 2, poor (first-order branch blood vessels incompletely visible); score 3, moderate (all first-order branch blood vessels completely visible); score 4, good (second-order branch blood vessels visible); and score 5, excellent (third-order branch blood vessels visible). Furthermore, the presence of artifacts (eg, blurring of blood vessel borders, artifacts due to breathing) and of intravascular signal inhomogeneities was analyzed. The effects of artifacts and inhomogeneities on image quality were graded as follows: grade 4, no effect; grade 3, slight effect; grade 2, strong effect; and grade 1, very strong effect. A grade of 3 or 4 was considered diagnostic.

Parametric images for blood volume, blood flow, and mean transit times were generated to assess whether SH U 555 C-enhanced data sets may be used for this purpose. The software was programmed on a personal computer (Apple G3; Macintosh, Cupertino, Calif) with postprocessing at the downloading of the images.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
Dose Response for Chest MR Angiography
Quantitative analysis of SI within various blood vessels such as the thoracic aorta, carotid artery, pulmonary artery, and superior vena cava during first-pass MR angiography revealed highest enhancement values after the injection of 40 µmol Fe/kg (P < .05). The enhancement increased in a dose-dependent fashion and ranged from 259% ± 160 at a dose of 5 µmol Fe/kg to 907% ± 370 at a dose of 40 µmol Fe/kg for the thoracic aorta (Table 1, Fig 1). The large SDs may be explained by variations in bolus arrival, which could not be measured according to restrictions indicated in the institutional review board–approved protocol.


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  		TABLE 1. Enhancement in Blood Vessels at MR Angiography after SH U 555 C Injection

 


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  		Figure 1. Graph shows dose-dependent enhancement during first pass and equilibrium phase at SH U 555 C-enhanced MR angiography within thoracic aorta. Relative SI enhancement within aorta during first pass (0.1 minute = 12 seconds) and equilibrium phase is displayed as mean value to avoid overlapping error bars (Table 1). SH U 555 C shows statistically significant dose-dependent first-pass effect. Values for each dose do not significantly decrease during observation period. Only the difference between the dose of 10 µmol Fe/kg ({bullet}) and that of 20 µmol Fe/kg (x) was not significant during equilibrium phase. {square} = 5 µmol Fe/kg, {blacksquare} = 40 µmol Fe/kg.

 
During the equilibrium phase, a dose-dependent significant increase in SI resulted for the comparison of 5 µmol Fe/kg and 40 µmol Fe/kg for all times and all blood vessel segments. The difference in SI between 10 and 20 µmol Fe/kg doses was not significant. Highest enhancement values were calculated for the highest investigated dose of 40 µmol Fe/kg. The enhancement in the aorta decreased slightly during time from 819% ± 14 (6 minutes) to 721% ± 19 (42 minutes). Venous enhancement in the superior vena cava also increased in a dose-dependent fashion from 5 to 40 mmol Fe/kg, and enhancement values ranged from 418% ± 18 (6 minutes) to 390% ± 15 (42 minutes) for the highest dose of 40 µmol Fe/kg (Table 1, Fig 2).



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  		Figure 2. SH U 555 C-enhanced coronal three-dimensional MR angiographic images (4.6/1.8; flip angle, 30o) of thoracic aorta. Doses of 20 µmol Fe/kg (top row) and 40 µmol Fe/kg (bottom row) are compared during first pass (left column) and equilibrium phase at 12 (middle column) and 42 (right column) minutes after SH U 555 C injection. SH U 555 C shows dose-dependent first-pass effect. During equilibrium phase, enhancement at 40 µmol Fe/kg is higher.

 
Qualitative analysis for all dose groups confirmed the quantitative results for both first-pass and equilibrium-phase MR angiography (Figs 2, 3). The visibility of pulmonary arteries improved in a dose-dependent fashion, which was similar to the way that intravascular enhancement increased, and was best for the highest dose of 40 µmol Fe/kg (Table 2). This resulted in a visibility score of 5 (excellent, third-order branch blood vessels were visible) for both the first pass and the equilibrium phase to 42 minutes. Intravascular signal inhomogeneities were observed for all doses and decreased with increasing doses. During the first pass, the presence of intravascular SI inhomogeneities resulted in a slight effect on image quality (score of 3) for doses of 10, 20, and 40 µmol Fe/kg, but the images were considered to be diagnostic (Fig 3). Within the equilibrium phase, diagnostic image quality was observed and remained stable for at least 30 minutes for only the highest dose of 40 µmol Fe/kg (Table 2).



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  		Figure 3. SH U 555 C-enhanced coronal three-dimensional MR angiographic image (4.6/1.8; flip angle, 30o) within pulmonary arteries at first pass. Doses of 5, 10, 20, and 40 µmol Fe/kg are compared. Visibility of pulmonary arteries improves with increasing dose and is best for highest dose of 40 µmol Fe/kg.

 

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  		TABLE 2. Visibility of Pulmonary Artery Segments and Effects of Focal Inhomogeneities on Image Quality for SH U 555 C at MR Angiography

 
Cardiac Perfusion
SH U 555 C demonstrated significant enhancement (P < .05) compared with that at baseline within the right ventricle, the left ventricle, and the left ventricular myocardium (Fig 4).



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  		Figure 4a. Images show cardiac enhancement with SH U 555 C and perfusion. (a) Graph shows that short-axis cardiac perfusion images with 40 µmol Fe/kg dose have an early peak at 7 seconds within the right ventricle, followed by an SI decrease at 12 seconds with a second pass and subsequent stable equilibrium phase after 30 seconds. Left ventricle demonstrates first peak at 12 seconds, followed by SI decrease at 19 seconds, second peak at 26 seconds, and subsequent equilibrium phase with continuous (not significant) SI increase during time. Enhancement (ENH) within myocardium of left ventricle shows initial increase during first pass, with maximum at 23 seconds followed by small decrease and subsequent stable equilibrium phase after 30 seconds. Enhancement within left ventricle = A – ENH LV, within right ventricle = B – ENH RV, and within left ventricular myocardium = C – ENH LV Myocard. (b) Short-axis T1-weighted turbo fast low-angle shot MR images (416/1.2/200; delay, 50 msec; flip angle, 8o; time resolution, one image per second) obtained at different times (top left to bottom right) after SH U 555 C (40 µmol Fe/kg) injection show cardiac perfusion. Images show time course with inflow into right and left ventricles and myocardial enhancement. Enhancement within right ventricle with subsequent passage through pulmonary circulation is followed by enhancement within left ventricle and myocardium. pre = precontrast image. (c) Color-coded mean transit time map with homogeneous signal throughout myocardium. Cardiac perfusion data sets obtained at 40 µmol Fe/kg were postprocessed, and parameter maps were generated to test for feasibility of calculation of maps. Images may be used to visualize regional perfusion changes within myocardium.

 


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  		Figure 4b. Images show cardiac enhancement with SH U 555 C and perfusion. (a) Graph shows that short-axis cardiac perfusion images with 40 µmol Fe/kg dose have an early peak at 7 seconds within the right ventricle, followed by an SI decrease at 12 seconds with a second pass and subsequent stable equilibrium phase after 30 seconds. Left ventricle demonstrates first peak at 12 seconds, followed by SI decrease at 19 seconds, second peak at 26 seconds, and subsequent equilibrium phase with continuous (not significant) SI increase during time. Enhancement (ENH) within myocardium of left ventricle shows initial increase during first pass, with maximum at 23 seconds followed by small decrease and subsequent stable equilibrium phase after 30 seconds. Enhancement within left ventricle = A – ENH LV, within right ventricle = B – ENH RV, and within left ventricular myocardium = C – ENH LV Myocard. (b) Short-axis T1-weighted turbo fast low-angle shot MR images (416/1.2/200; delay, 50 msec; flip angle, 8o; time resolution, one image per second) obtained at different times (top left to bottom right) after SH U 555 C (40 µmol Fe/kg) injection show cardiac perfusion. Images show time course with inflow into right and left ventricles and myocardial enhancement. Enhancement within right ventricle with subsequent passage through pulmonary circulation is followed by enhancement within left ventricle and myocardium. pre = precontrast image. (c) Color-coded mean transit time map with homogeneous signal throughout myocardium. Cardiac perfusion data sets obtained at 40 µmol Fe/kg were postprocessed, and parameter maps were generated to test for feasibility of calculation of maps. Images may be used to visualize regional perfusion changes within myocardium.

 


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  		Figure 4c. Images show cardiac enhancement with SH U 555 C and perfusion. (a) Graph shows that short-axis cardiac perfusion images with 40 µmol Fe/kg dose have an early peak at 7 seconds within the right ventricle, followed by an SI decrease at 12 seconds with a second pass and subsequent stable equilibrium phase after 30 seconds. Left ventricle demonstrates first peak at 12 seconds, followed by SI decrease at 19 seconds, second peak at 26 seconds, and subsequent equilibrium phase with continuous (not significant) SI increase during time. Enhancement (ENH) within myocardium of left ventricle shows initial increase during first pass, with maximum at 23 seconds followed by small decrease and subsequent stable equilibrium phase after 30 seconds. Enhancement within left ventricle = A – ENH LV, within right ventricle = B – ENH RV, and within left ventricular myocardium = C – ENH LV Myocard. (b) Short-axis T1-weighted turbo fast low-angle shot MR images (416/1.2/200; delay, 50 msec; flip angle, 8o; time resolution, one image per second) obtained at different times (top left to bottom right) after SH U 555 C (40 µmol Fe/kg) injection show cardiac perfusion. Images show time course with inflow into right and left ventricles and myocardial enhancement. Enhancement within right ventricle with subsequent passage through pulmonary circulation is followed by enhancement within left ventricle and myocardium. pre = precontrast image. (c) Color-coded mean transit time map with homogeneous signal throughout myocardium. Cardiac perfusion data sets obtained at 40 µmol Fe/kg were postprocessed, and parameter maps were generated to test for feasibility of calculation of maps. Images may be used to visualize regional perfusion changes within myocardium.

 
Enhancement within the right ventricle during the first pass (peak for the right ventricle, 57.5% ± 38.8, vs peak for the left ventricle, 115.0% ± 70.6) was significantly (P < .05) lower compared with that within the left ventricle. This finding indicated a susceptibility effect because of the compactness of the bolus within the right ventricle before it passed through the pulmonary circulation. After the second recirculation within the right ventricle, the signal became stable after 30 seconds (enhancement range, 80%–90%). The highest enhancement within the right ventricle was 90.2% ± 55.9 at 50 seconds and was also significantly (P < .05) lower compared with that of 80.0% ± 66.4 at 42 seconds within the left ventricle.

The left ventricle demonstrated a first peak at 12 seconds, which was followed by an SI decrease at 19 seconds. A second peak occurred at 26 seconds, and a subsequent equilibrium phase demonstrated a continuous (not significant) SI increase during time (enhancement range, 140%–180%).

Enhancement within the myocardium of the left ventricle showed an initial increase during the first pass, with a maximum at 23 seconds. This was followed by a small decrease and a subsequent stable equilibrium phase after 30 seconds. Mean enhancement values were between 40% and 60% (Fig 4). The slight increase during time was not significant. Parametric images that displayed blood volume, blood flow, and mean transit time could be computed from all data sets with homogeneous color coding (Fig 4).

Safety and Tolerability
The intravenous injection of a bolus of SH U 555 C was well tolerated by all volunteers. No relevant changes in vital signs (blood pressure, heart rate) occurred during the observation period.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
 
SH U 555 C as an optimized bolus-injectable formulation of ferucarbotran has been proposed for equilibrium-phase MR angiography after encouraging results were found in studies in animals (8,14). Allkemper et al (14) reported an excellent T1 effect for various ferucarbotran formulations of different overall size and best results for a formulation with a mean particle size of 21 nm. A prolonged SI enhancement during time with increasing doses to a 40 µmol Fe/kg dose was demonstrated. We evaluated use of SH U 555 C in humans for first-pass and equilibrium-phase three-dimensional MR angiography of the chest, for cardiac perfusion, and for potential cardiovascular side effects during or after bolus injection.

Quantitative analysis of first-pass MR angiographic images demonstrated enhancement profiles that were comparable with those achieved with experimental data with a preformulation of SH U 555 C (8,14). The intravenous bolus injection of the highest investigated dose of 40 µmol Fe/kg resulted in highest enhancement values during the first pass. Previous data from our group (14) obtained during the first pass showed a comparable enhancement of 1,135.0% ± 58.1 for a dose of 40 µmol Fe/kg in rabbits when comparable imaging parameters (three-dimensional fast low-angle shot sequence with 5.8/1.8 and a flip angle of 30o) were used. The bolus injection in our clinical study was well tolerated by all volunteers, and this injection represented a prerequisite for further trials. To our knowledge, alternative intravascular agents in clinical trials have not been tested with a comparable injection protocol suited for first-pass MR angiography.

Experimental data obtained during the equilibrium phase in rabbits that received optimized ferucarbotran formulations showed an arterial enhancement of 326.0% ± 63.7 during 40 minutes at a dose of 40 µmol Fe/kg (14). We measured an arterial enhancement of 819% ± 14 at 6 minutes and of 721% ± 19 at 42 minutes after injection of 40 µmol Fe/kg. These findings demonstrated a minor decrease during the observation period. Researchers in studies about pulmonary MR angiography with oxidized starch–coated USPIO identified with the code name NC 100150 at 30 mg Fe/mL showed an increased intravascular SI with increasing doses from 1.0 to 4.0 mg Fe/kg (4). Anzai et al (16) reported an increasing signal-to-noise ratio in the aorta with doses to 1.7 mg Fe/kg of dextran-coated USPIO (ferumoxtran-10, Combidex; Advanced Magnetics, Cambridge, Mass) at 20 mg Fe/mL, with no further increase after injection of the highest investigated dose of 2.6 mg Fe/kg. (Ferumoxtran-10 was formerly identified with the code name AMI 227.) We did not observe dose saturations for SH U 555 C within the dose range used in the study for both first-pass and equilibrium-phase MR angiography.

Qualitative analysis of our data demonstrated improved visibility of vessels and decreasing intravascular SI inhomogeneities at increasing doses, according to the increased intravascular enhancement. Artifacts clearly related to the contrast agent injection were not detected at any time for any dose. However, a comparison with human data from the literature is difficult because of different definitions for quality assessment. Anzai and colleagues (16) performed a qualitative analysis of equilibrium-phase MR angiography of the abdomen with visual interpretation by two radiologists in consensus, and they reported increased image quality for the combination of subjective impression and signal-to-noise ratio measurements to the highest investigated dose of 2.6 mg Fe/kg. They suggested that large increases in image quality are not likely to be attained with higher blood concentrations of USPIO because of compromising T2* effects and that visualization was not as good as that at dynamic MR angiography with gadolinium.

Mayo-Smith and colleagues (11) reported that the visualization of arteries and veins in the upper abdomen improved to 45 minutes after the injection of ferumoxtran-10. However, qualitative results were not presented in a dose-dependent fashion for a dose range from 0.8 to 1.7 mg Fe/kg. Furthermore, dose-dependent intravascular SI inhomogeneities or artifacts for a breath-hold T1-weighted gradient-echo sequence (87/2.3; flip angle, 80o) were not discussed. Ahlström and colleagues (4) evaluated the quality of thoracic MR angiography for both delineation of blood vessel branches and overall image quality by using a four-grade scale. Furthermore, they classified focal decreases or increases in SI as artifacts, which were probably due to susceptibility effects. Two readers in consensus graded the effects of artifacts on image quality. Most focal inhomogeneities classified as artifacts were reported for the highest investigated dose of 4.0 mg Fe/kg (NC 100150).

In our study, the highest investigated dose of 2.2 mg Fe/kg (40 µmol Fe/kg) did not affect image quality. However, in the study of Ahlström et al (4), overall image quality and the effect of focal inhomogeneities on image quality were not specified according to blood vessel branch orders, and effects of unsatisfactory or nonmeasurable third- and fourth-branch blood vessel orders could not be extracted. Results of qualitative analysis of first-order pulmonary vessels were comparable with our data. The shorter echo time of 1.8 msec in our study compared with 3.1 msec used by Ahlström and colleagues (4) might further explain the differences in SI inhomogeneities that affect image quality. The need for sequences with short echo time to further increase SI, minimize susceptibility artifacts, and thus improve image quality with use of superparamagnetic iron oxide–based contrast agents has been described previously (17,18).

Absolute and relative SI increase within veins was somewhat lower than it was in most arteries. Previously, it has been reported that the difference in the oxyhemoglobin content and deoxyhemoglobin content accounts for differences in intravascular SI that are based on susceptibility effects (19).

Cardiac perfusion studies indicated susceptibility-induced SI loss for the first pass through the right ventricle, with significantly lower SI than that within the left ventricle. This was most likely caused by the compactness of the bolus within the right ventricle before it became diluted within the pulmonary circulation. The left ventricle demonstrated a first peak, followed by an SI decrease and a small second peak. The myocardium of the left ventricle showed an initial increase during the first pass, followed by a small decrease and a subsequent stable equilibrium phase after 30 seconds, which was also observed for the right and left ventricles. Temporal SI changes within the left ventricular myocardium allowed calculation of parametric images with homogeneous SI for functional parameters such as blood volume, blood flow, and mean transit time.

The application of intravascular contrast agents should allow improved qualitative and quantitative perfusion studies outside the brain (1). More recently, Neyran et al (20) evaluated deconvolution methods to obtain quantitative parameters such as regional myocardial blood flow, regional myocardial blood volume, and regional myocardial mean transit time. The authors concluded that regional myocardial blood volume mapping could be a fast and robust way to detect abnormal myocardial regions. Tian and colleagues (21) experimentally compared a new iron oxide–based intravascular contrast agent, hydroxyethyl-starch-ferrioxamine, which is also known as HES-FO, with gadopentetate dimeglumine for the assessment of myocardial perfusion. The authors found that an intravascular contrast agent such as hydroxyethyl-starch-ferrioxamine provided information regarding myocardial vascular flow that could not be obtained with gadopentetate dimeglumine.

Jerosch-Herold and colleagues (22) published a direct experimental comparison of a gadolinium-based intravascular contrast agent, gadomer-17 (Schering), which is also identified with the code name SH L 643 A, and an extracellular contrast agent (gadopentetate dimeglumine) for quantification of myocardial perfusion. The authors concluded that the use of an intravascular instead of an extracellular contrast agent allowed a reduction in the degrees of freedom for modeling tissue residue curves and therefore yielded improved accuracy of blood flow estimates.

In an angiographically controlled clinical study, Ibrahim and co-workers (23) compared positron emission tomography with MR imaging. They demonstrated that first-pass MR imaging perfusion measurements obtained with gadopentetate dimeglumine demonstrate underestimation of flow reserve values but may represent a promising semiquantitative technique for detection of and assessment of severity of regional coronary artery disease. It has been predicted that the introduction of new intravascular contrast media shall promote the idea that MR imaging should become a clinical tool for assessment of myocardial perfusion imaging in the near future (24).

Kraitchman and co-workers (25) investigated the value of an intravascular albumin-targeted contrast agent, gadofosveset trisodium, in the visualization of myocardial ischemia with MR imaging. A left anterior descending coronary artery stenosis was created in 19 pigs, and myocardial ischemia was detected with first-pass contrast-enhanced MR imaging at peak dipyridamole stress and was compared with technetium 99m sestamibi single photon emission computed tomography (SPECT). Concordance of MR imaging and SPECT for detection of perfusion defects was 85%. Prolonged and persistent MR hypoenhancement of the ischemic myocardial bed with gadofosveset trisodium, which is retained primarily in the vascular bed because of its albumin-binding properties, facilitated the detection of myocardial perfusion defects. Furthermore, the application of blood pool agents to improve coronary MR angiography was investigated by several research groups with various contrast agents (26–31).

Our study had limitations. The approved study protocol allowed the inclusion of only four volunteers per dose group, with one volunteer to receive placebo treatment, and doses only to 40 µmol Fe/kg. Furthermore, sequence parameters might be improved within the near future for the particular contrast agent based on USPIO used in this study, and noise evaluation outside the body was not feasible because of the use of a body phased-array coil. For the second purpose of our study, which was to conduct a preliminary investigation of cardiac perfusion, only four volunteers were permitted for enrollment. Safety data provided were limited; however, extensive safety data were obtained that were not presented but revealed no relevant findings.

However, SH U 555 C was proved to be an intravascular contrast agent with a high T1 effect suitable for both first-pass MR angiography, with avoidance of overlapping vascular structures, and equilibrium-phase MR angiography to 42 minutes; cardiac perfusion demonstrated a first-pass effect within the myocardium and a stable equilibrium phase. The dose of 40 µmol Fe/kg was clearly an overdose for the first-pass effect. The agent was well tolerated, and no cardiovascular side effects occurred during or after bolus injection. Additional clinical studies will be necessary to further evaluate the potential of SH U 555 C use for MR angiography, organ perfusion such as cardiac perfusion, or applications such as tumor imaging.


   FOOTNOTES
 
Abbreviations: SI = signal intensity, USPIO = ultrasmall superparamagnetic iron oxides

Author contributions: Guarantors of integrity of entire study, P.R., M.M., W.E., B.T.; study concepts, P.R., M.M., W.E., B.T.; study design, P.R., M.M., B.T.; literature research, P.R., B.T.; clinical studies, P.R., M.M., C.B., T.A., B.T.; data acquisition, P.R., M.M., C.B., T.A., B.T.; data analysis/interpretation, M.E., M.M., P.R., B.T.; statistical analysis, M.E., M.M., W.E., C.B., P.R., B.T.; manuscript preparation and editing, all authors; manuscript definition of intellectual content and final version approval, P.R., B.T.; manuscript revision/review, P.R., W.E., B.T.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 

  1. Bogdanov AA, Weissleder R, Frank HW, et al. A new macromolecule as a contrast agent for MR angiography: preparation, properties, and animal studies. Radiology 1993; 187:701-706.[Abstract/Free Full Text]
  2. Lauffer RB, Parmelee DJ, Dunham SU, et al. MS-325: albumin-targeted contrast agent for MR angiography. Radiology 1998; 207:529-538.[Abstract/Free Full Text]
  3. Frank H, Loewe R, Loewe C, et al. Efficacy of thrombolytic therapy in pulmonary embolism determined by MION-enhanced MRA: an experimental study in rabbits. Invest Radiol 1998; 33:853-857.[CrossRef][Medline]
  4. Ahlström KH, Johansson LO, Rodenburg JB, Ragnarsson AS, Akeson P, Börseth A. Pulmonary MR angiography with ultrasmall superparamagnetic iron oxide particles as a blood pool agent and a navigator echo for respiratory gating: pilot study. Radiology 1999; 211:865-869.[Abstract/Free Full Text]
  5. Reimer P, Rummeny EJ, Daldrup HE, et al. Clinical results with Resovist: a phase 2 clinical trial. Radiology 1995; 195:489-496.[Abstract/Free Full Text]
  6. Shen T, Weissleder R, Papisov M, Bogdanov A, Brady TJ. Monocrystalline iron oxide nanocompounds (MION): physicochemical properties. Magn Reson Med 1993; 29:599-604.[Medline]
  7. Taylor AM, Panting JR, Keegan J, et al. Safety and preliminary findings with the intravascular contrast agent NC100150 injection for MR coronary angiography. J Magn Reson Imaging 1999; 9:220-227.[CrossRef][Medline]
  8. Knollmann FD, Bock JC, Rautenberg K, Beier J, Ebert W, Felix R. Differences in predominant enhancement mechanisms of superparamagnetic iron oxide and ultrasmall superparamagnetic iron oxide for contrast-enhanced portal magnetic resonance angiography: preliminary results of an animal study original investigation. Invest Radiol 1998; 33:637-643.[CrossRef][Medline]
  9. Wang SC, Wikstrom MG, White DL, et al. Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues. Radiology 1990; 175:483-488.[Abstract/Free Full Text]
  10. Canet E, Revel D, Forrat R, et al. Superparamagnetic iron oxide particles and positive enhancement for myocardial perfusion studies assessed by subsecond T1-weighted MRI. Magn Reson Imaging 1993; 11:1139-1145.[CrossRef][Medline]
  11. 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.[Abstract/Free Full Text]
  12. Pouliquen D, Perroud H, Calza F, Jallet P, Le Jeune JJ. Investigation of the magnetic properties of iron oxide nanoparticles used as a contrast agent. Magn Reson Med 1992; 24:75-84.[Medline]
  13. 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.[CrossRef][Medline]
  14. Allkemper T, Bremer C, Matuszewski L, Ebert W, Reimer P. Contrast-enhanced blood-pool MR angiography with optimized iron oxides: effect of size and dose on vascular contrast enhancement in rabbits. Radiology 2002; 223:432-438.[Abstract/Free Full Text]
  15. Lawaczeck R, Bauer H, Frenzel T, et al. Magnetic iron oxide particles coated with carboxydextran for parenteral administration and liver contrasting: pre-clinical profile of SH U555A. Acta Radiol 1997; 38:584-597.[Medline]
  16. 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.[Medline]
  17. Chambon C, Clement O, Le Blanche A, Schouman-Claeys E, Frija G. Superparamagnetic iron oxides as positive MR contrast agents: in vitro and in vivo evidence. Magn Reson Imaging 1993; 11:509-519.[CrossRef][Medline]
  18. Wikstrom LJ, Johansson LO, Ericsson BA, Borseth A, Akeson PA, Ahlstrom KH. Abdominal vessel enhancement with an ultrasmall, superparamagnetic iron oxide blood pool agent: evaluation of dose and echo time dependence at different field strengths. Acad Radiol 1999; 6:292-298.[CrossRef][Medline]
  19. Boxerman JL, Hamberg LM, Rosen BR, Weisskoff RM. MR contrast due to intravascular magnetic susceptibility perturbations. Magn Reson Med 1995; 34:555-566.[Medline]
  20. Neyran B, Janier MF, Casali C, Revel D, Canet Soulas EP. Mapping myocardial perfusion with an intravascular MR contrast agent: robustness of deconvolution methods at various blood flows. Magn Reson Med 2002; 48:166-179.[CrossRef][Medline]
  21. Tian G, Shen J, Su S, et al. Evaluation of hydroxyethyl-starch-ferrioxamine as an intravascular MR contrast agent for assessment of myocardial perfusion. Acta Radiol Suppl 1997; 412:85-90.[Medline]
  22. Jerosch-Herold M, Wilke N, Wang Y, et al. Direct comparison of an intravascular and an extracellular contrast agent for quantification of myocardial perfusion. Cardiac MRI Group. Int J Card Imaging 1999; 15:453-464.
  23. Ibrahim T, Nekolla SG, Schreiber K, et al. Assessment of coronary flow reserve: comparison between contrast-enhanced magnetic resonance imaging and positron emission tomography. J Am Coll Cardiol 2002; 39:864-870.[Abstract/Free Full Text]
  24. Laddis T, Manning WJ, Danias PG. Cardiac MRI for assessment of myocardial perfusion: current status and future perspectives. J Nucl Cardiol 2001; 8:207- 214.[CrossRef][Medline]
  25. Kraitchman DL, Chin BB, Heldman AW, Solaiyappan M, Bluemke DA. MRI detection of myocardial perfusion defects due to coronary artery stenosis with MS-325. J Magn Reson Imaging 2002; 15:149-158.[CrossRef][Medline]
  26. Duerinckx AJ. MR angiography of the coronary arteries. Top Magn Reson Imaging 1995; 7:267-285.[Medline]
  27. Lorenz CH, Johansson LO. Contrast-enhanced coronary MRA. J Magn Reson Imaging 1999; 10:703-708.[CrossRef][Medline]
  28. Sakuma H, Goto M, Nomura Y, Kato N, Takeda K, Higgins CB. Three-dimensional coronary magnetic resonance angiography with injection of extracellular contrast medium. Invest Radiol 1999; 34:503-508.[CrossRef][Medline]
  29. Stuber M, Botnar RM, Danias PG, et al. Contrast agent-enhanced, free-breathing, three-dimensional coronary magnetic resonance angiography. J Magn Reson Imaging 1999; 10:790-799.[CrossRef][Medline]
  30. 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.[Abstract/Free Full Text]
  31. Taupitz M, Schnorr J, Wagner S, et al. Coronary magnetic resonance angiography: experimental evaluation of the new rapid clearance blood pool contrast medium P792. Magn Reson Med 2001; 46:932-938.[CrossRef][Medline]



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