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First published online September 17, 2007
British Journal of Radiology (2007) 80, 884-892
© 2007 British Institute of Radiology
doi: 10.1259/bjr/34610669
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Full paper

1 M Gd-chelate (gadobutrol) for multislice first-pass magnetic resonance myocardial perfusion imaging

M Fenchel, MD 1 A Franow, MD 1 P Martirosian, PhD 1 M Engels, BS 1 U Kramer, MD 1 N I Stauder, MD 1 U Helber, MD 2 H Vogler, MD 3 C D Claussen, MD 1 and S Miller, MD 1

Departments of 1 Diagnostic Radiology and2 Internal Medicine, Eberhard-Karls-University, Tuebingen and3 Schering AG, Berlin, Germany

Correspondence: Michael Fenchel, Department of Diagnostic Radiology, Eberhard-Karls-University Tuebingen, Hoppe-Seyler-Str 3, 72076 Tuebingen, Germany. E-mail: michael.fenchel{at}med.uni-tuebingen.de


   Abstract
Top
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 References
 
The aim of the study was to evaluate a 1 M gadolinium-chelate (gadobutrol) for first-pass MR myocardial perfusion examinations in patients with suspected coronary artery disease (CAD). In phantom studies, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) values of gadobutrol were compared with gadopentetate (Gd-DTPA). 25 consecutive patients with clinically suspected CAD were examined with dynamic rest/stress MR perfusion examinations using 0.05 mmol kg–1 gadobutrol. Semi-quantitative evaluation of the myocardial perfusion was performed by calculating the myocardial perfusion reserve index (MPRI). Hypoperfused regions were correlated with data from X-ray coronary angiography. In phantom studies, SNR/CNR of gadobutrol-doped blood samples were consistently higher for all applied flip angles at concentrations ≤1.0 mmol L–1 compared with Gd-DTPA. Assessment of 81 stress perfusion series with gadobutrol in 25 patients yielded a sensitivity of 82% and specificity of 91% for significant CAD. Combining the information from all perfusion series of one patient yielded a sensitivity of 89% and specificity of 94% on a per-vessel basis. Gadobutrol exhibited favourable signal properties in phantom studies. Rest/stress myocardial perfusion examinations using 1 M gadobutrol yielded high sensitivity and specificity in detection of malperfused areas (82% and 91%, respectively). This is comparable with recently published perfusion data using 0.5 M Gd-DTPA.


   Introduction
Top
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 References
 
Despite progress in prevention and early diagnosis, coronary artery disease (CAD) constitutes the leading cause of death in both men and women in the Western world [1]. Although invasive X-ray coronary angiography remains the gold standard for the identification of clinically significant CAD, MR first-pass perfusion examinations have gained increasing attention during the past several years. This is mainly a result of the non-invasive nature of MR imaging and substantial recent technical advancements, especially in the field of gradient and sequence technology, which have improved the quality of MR perfusion images [2–6]. Nevertheless, MR perfusion examinations still suffer from relatively low signal-to-noise ratios (SNRs) and contrast-to-noise ratios (CNRs) [7]. In order to increase the depiction of perfusion deficits in MR first-pass perfusion examinations, CNR, i.e. the difference in signal intensity between normally and malperfused myocardium, should be enhanced [7–9].

Increasing the injection dose of a contrast agent in order to increase relative signal intensity (SI) changes is limited by the risk of introducing counteracting T2* effects and concomitant increases in volume, which broadens the bolus profile. The administration of a higher concentrated contrast agent, however, may result in a sharper bolus profile owing to the smaller injection volume and, therefore, improve first-pass perfusion studies [10, 11].

Recently, a new MR contrast agent gadobutrol (GadovistTM 1.0; Schering AG, Berlin, Germany) has become available that combines the favourable safety profile, as well as the osmolality and viscosity, of the traditional extracellular gadolinium chelates with a higher gadolinium concentration. At present, gadobutrol is mainly used for MR angiography and brain examinations [12–14]. Owing to its doubled gadolinium (Gd) concentration compared with other extracellular MR contrast agents, gadobutrol allows for more compact bolus geometries. A previous study has shown promising results in MR cerebral perfusion examinations using gadobutrol [14], as the quality of perfusion data strongly depends on a compact contrast bolus. Therefore, similar to MR angiography and cerebral perfusion, gadobutrol may be advantageous in cardiac T1 weighted dynamic MR perfusion examinations by increasing the SNR, as well as the CNR, between normal and hypoperfused regions.

The aim of this study was to use 1 M gadobutrol in human MR myocardial first-pass perfusion imaging; specifically, 1 M gadobutrol was compared with 0.5 M gadopentetate (Gd-DTPA) in phantom studies. In addition, the study investigated whether the contrast agent 1 M gadobutrol could reliably detect regional hypoperfusion in patients with CAD.


   Methods and materials
Top
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 References
 
Phantom studies
Seven Gd-doped blood samples with identical concentrations (0.0 mmol l–1, 0.1 mmol l–1, 0.2 mmol l–1, 0.5 mmol l–1, 1.0 mmol l–1, 2.0 mmol l–1 and 5.0 mmol l–1) of Gd-DTPA and gadobutrol were prepared. Heparin was used as an anticoagulant. Blood samples were held at 37°C throughout the measurements. Images were acquired with the same phased array surface coil on a 1.5 T MR-scanner (Magnetom Sonata; Siemens Medical Solutions, Erlangen, Germany) equipped with high-performance gradients (maximum amplitude: 40 mT m–1; slew rate: 200 mT m–1 ms–1) that was used in patient studies.

The T1 relaxation time was measured by using an inversion-recovery preparation with variable inversion time (TI) applied before a spin-echo (SE) imaging sequence (repetition time (TR) 8000 ms; echo time (TE) 9.4 ms; matrix 256x256; field-of-view (FOV) 200x200 mm; slice thickness 4 mm; bandwidth (BW) 190 Hz pixel–1). 12 images were acquired with inversion intervals ranging from 25 ms to 5000 ms. For measurement of T2 relaxation times, a variable preparation delay between the 90° excitation pulse and the first refocusing pulse of the SE imaging sequence (TR 3000 ms; TE 10–320 ms; matrix 256x256; FOV 200x200 mm; slice thickness 4 mm; BW 190 Hz pixel–1) was used to vary the SE T2 contrast. 32 images with variable TE were acquired.

Additionally, phantom measurements were performed using the saturation-recovery (SR) fast imaging with steady precession (TrueFISP) perfusion sequence (from patient studies) with different flip angles (10° to 50° in steps of 10°). A commercially available, prospective electrocardiogram (ECG)-triggered SR-TrueFISP-2D perfusion sequence was used for phantom, volunteer and patient studies, which consisted of a non-slice selective 90° saturation pulse and single-shot TrueFISP image acquisition with TR 2.4 ms, TE 1.2 ms, BW 1300 Hz pixel–1, TI 110 ms, and linear cartesian k-space ordering. The matrix was 72x128, FOV was 225x300 mm and trigger delay was 100 ms. This rendered an in-plane resolution of 3.1x2.3 mm2 in all images. Slice thickness was 8 mm.

SI was measured in a region-of-interest (ROI) placed into the interior of the blood samples; ROI size was approximately 0.5 cm2 ({approx}35 pixels). SI from blood samples was normalized with SI from nearby ROIs placed into surrounding water. T1 and T2 relaxation times for imaging data were obtained by fitting the MR signal intensity of a selected ROI in each image using Matlab (The MathWorks, Natick, MA). Estimates of T1 and T2 relaxation times were obtained from a non-linear least squares fit of the SI measured for each TI and TE value, respectively, by using the corresponding measured noise. The model equation for the fit of T1 relaxation was:


Formula 001

having T1, M0 and {alpha} as parameters: {alpha} is the flip angle and M0 the equilibrium magnetization. T2 relaxation times were estimated by fitting to:


Formula 002

having T2, M0 and noise as parameters: M0 represents the equilibrium magnetization.

SNR was calculated from the normalized SI of the Gd-doped blood samples divided by the standard deviation (SD) of background noise (SIROI/{sigma}background). CNR was calculated from the formula [15]:


Formula 003

Volunteer studies
The study protocol was approved by the local ethics committee. Written informed consent was obtained from all volunteers and patients before MR examination and after the nature of the procedure(s) had been fully explained.

Volunteer studies were conducted in order to determine the optimal amount of contrast medium for patient studies. In four healthy volunteers (two male, two female; mean age 29 years, range 24–32 years), first-pass rest perfusion series were acquired after injection of 0.025 mmol kg–1 and 0.05 mmol kg–1 gadobutrol. Examinations were performed using a SR-TrueFISP perfusion sequence. In all volunteers, the bolus injection of 0.025 mmol kg–1 was followed by bolus injection of 0.05 mmol kg–1 while recording perfusion images with the SR-TrueFISP perfusion sequence. Between contrast injections, a delay of 10 min allowed clearance of contrast agent from the myocardium [16]. Furthermore, baseline images were acquired before each successive contrast application.

SNR and SI increases (from baseline to peak SI) were measured in ROIs placed into the left ventricular myocardium. ROIs were placed in representative sections of the septal, anterior, lateral and inferior left ventricular myocardium. SNR values were calculated as described above.

Patient studies
25 consecutive patients with clinically suspected CAD (21 male, 4 female; mean age 64.4±9.8 years, range 40–82 years) who were referred for a diagnostic coronary angiography were examined. Significant CAD was defined as the presence of luminal diameter reduction ≥70% in coronary arteries.

Coronary angiography revealed single-vessel disease in 9 (36%) patients, two-vessel disease in 4 (16%) patients and three-vessel disease in 5 (20%) patients. Significant CAD was absent in 7 (28%) patients, i.e. the patient-based prevalence of CAD found in X-ray angiography in our patient population was 18/25 (72%), whereas the vessel-based prevalence was 32/75 (43%).

Patients with contraindications to MR (e.g. claustrophobia, pacemakers) or dipyridamole (e.g. those with asthma, glaucoma, severe arrhythmia), as well as patients with diabetes mellitus, low cardiac output or high-grade valvular disease, were excluded from the study.

Susceptibility artefacts in perfusion series were rated on a three-point scale: 0 = no artefacts present; 1 = mild artefacts, clearly distinguished from perfusion deficits; 2 = pronounced artefacts, possible misinterpretation as perfusion deficit.

MRI protocol
Examinations were performed at 1.5 T using the same MR scanner as for the phantom studies. An 18-gauge catheter was inserted into an antecubital vein for injection of contrast agent. ECG leads were placed on the subject's chest. Imaging was performed with a phased-array surface coil as a receiver. Perfusion measurements were conducted in 3–5 representative short-axis slices depending upon the patient's heart rate. One image of each slice was obtained on every single heartbeat.

Using the above-described SR-TrueFISP sequence, a series of 40 perfusion images per slice was acquired after injection of 0.05 mmol kg–1 gadobutrol (Gadovist; Schering, Berlin, Germany) during breath-holding. The flip angle was between 45° and 50° depending upon specific absorption rate (SAR) limitations. For myocardial perfusion measurement in patients, the acquisition of images was started simultaneously with peripheral injection of gadobutrol. The bolus injection of gadobutrol (flow rate 5 ml s–1) was followed by a 20 ml flush of 0.9% NaCl (flow rate 5 ml s–1). Perfusion examinations were performed at rest and approximately 10 min later after pharmacologically induced stress. A standard dose of dipyridamole was used for stress induction (0.56 mg kg–1 dipyridamole over 4 min). During dipyridamole injection, the patients' heart rate and blood pressure were continuously monitored. Subsequently, the stress perfusion series was acquired after further injection of 0.05 mmol kg–1 gadobutrol.

Subsequently, an additional 0.05 mmol kg–1 contrast medium was administered, resulting in a total of 0.15 mmol kg–1 contrast medium. After 15 min, "delayed enhancement" images were acquired in several long- and short-axis slices using an inversion recovery (IR) gradient recalled echo (GRE) sequence [17–19]. Sequence parameters of IR-GRE were as follows: FOV 300–340 mm, TR 9.56 ms, TE 4.38 ms, TI 200–260 ms, flip angle 25°, matrix 166x256 and slice thickness 5 mm. The TI was chosen in order to minimize the signal of normal myocardium.

MR image analysis
Matlab-based software (The MathWorks Inc., Natick, MA) was used to semi-quantitatively analyse myocardial perfusion. The myocardium of short-axis views was subdivided into 12 segments, including the complete left ventricular wall, and for each segment SI time curves were calculated separately. Baseline SI measurements before contrast arrival were used to correct for any coil-induced differences in SI in the segments, as well as for differences in SI before contrast agent application:


Formula 004

A linear fit was performed on the upslope of the raw data SI time curve for each segment using five consecutive images. Similar fitting was performed for the blood-pool curve in the left ventricle. Normalization for differences in speed and compactness of the contrast agent bolus was conducted by division of the myocardial upslope by the left ventricular upslope. Segments with hypoperfusion in rest examinations (i.e. upslope values below mean – 2 SD (standard deviation) of all values for one slice) were classified as segments with prior myocardial infarction [19].

Myocardial perfusion reserve index (MPRI) was calculated by dividing the upslope of the stress study by the upslope of the rest study for each segment (Upslopestress/Upsloperest). Segments with MPRI values below 1.5 were classified as having stress-induced hypoperfusion [20].

Coronary arteries (right coronary artery (RCA), left anterior descending (LAD) or ramus circumflex (RCX)) were considered as significantly stenosed if at least one segment in the myocardial region supplied by the respective coronary artery showed hypoperfusion.

Delayed enhancement images were visually assessed by two observers in a consensus reading. The location and extent of delayed enhancement was recorded, as those regions presenting delayed enhancement were excluded from the evaluation in stress perfusion series because of the altered contrast kinetics in myocardial scar tissue, which would falsify perfusion evaluations.

Coronary X-ray angiography
Coronary angiography was performed on a conventional angiography unit (Integris H; Philips Medical Systems, Best, The Netherlands) 1–7 days after the MR examination using 5F high-flow Judkins or Amplatz catheters and filming in multiple projections. Coronary stenoses were filmed in the centre of the field from multiple projections, and, as far as possible, overlap of side branches and foreshortening of relevant coronary arteries were avoided. After selecting the projection showing maximal severity, the luminal diameter of the stenosed artery, along with adjacent reference segments, were measured in the end-diastolic frame. The severity of stenoses was expressed as a percentage reduction of the internal diameter in relation to the estimated diameter interpolated from the diameters at the proximal and distal boundaries of the stenosis. Coronary artery luminal diameter reduction of ≥70% was considered significant. Analysis of the angiograms was performed by an experienced cardiologist who was blinded to the patients' history and MR examination. Coronary artery territories were defined from the angiogram using the American Heart Association guidelines [21].

Statistics
If not stated otherwise, data were given as means ± 1 SD. A p-value of ≤0.05 was regarded as statistically significant.

All data used for statistical calculations were tested for normal distribution using a Kolmogorov–Smirnov test. Statistical difference among SNR values, and also SI values derived from ROI measurements in volunteers, was calculated using a paired Student's t-test.

Statistical evaluation was performed using the software JMP Version 4 (SAS Institute Inc., Cary, NC).


   Results
Top
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 References
 
Phantom studies
Determination of T1 relaxation times at the various concentrations of gadobutrol-doped phantoms yielded a decrease in T1 relaxation time of 0–19% (mean 10.4±7.6%) compared with identical concentrations of Gd-DTPA, i.e. the effect on T1 by gadobutrol was more pronounced (Figure 1aGo). Specifically, T1 relaxivity in blood at 37°C for gadobutrol and Gd-DTPA at 1.5 T was 4.2 l mmol–1 s–1 and 3.5 l mmol–1 s–1, respectively.


Figure 1
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  		Figure 1. (a) T1 relaxation- and (b) T2 relaxation-rate curve for gadopentetate (Gd-DTPA; solid line) and gadobutrol (dashed line). (c) Ratio of signal intensity from phantom measurements using a SR-TrueFISP (repetition time (TR) 2.4 ms, echo time (TE) 1.2 ms, matrix 72x128, field-of-view (FOV) 225x300 mm, slice thickness 8 mm, flip angle 45°, bandwidth (BW) 1300 Hz pixel–1) perfusion sequence (SIgadobutrol/SIGd-DTPA).

 
T2 relaxation times for gadobutrol were increased by 2–13% (mean 7.3±5.8%) at concentrations ≤0.5 mmol L–1 and decreased by 4–21% (mean 11.6±7.4%) at higher concentrations compared with Gd-DTPA (Figure 1bGo). Specifically, T2 relaxivity in blood at 37°C for gadobutrol and Gd-DTPA at 1.5 T was 6.0 l mmol–1 s–1 and 4.4 l mmol–1 s–1, respectively.

Using the SR-TrueFISP perfusion sequence, signal intensities for gadobutrol were consistently increased for all applied flip angles at concentrations ≤1.0 mmol L–1 (e.g. for flip angle = 40°: mean 36.0±32.1%, range 9–82%), whereas for higher concentrations signal intensities for gadobutrol were decreased (e.g. for flip angle = 40°: mean 17.1±12.9%, range 4–30%) compared with Gd-DTPA (Figure 1cGo).

Volunteer studies
Peak SNR after injection of 0.025 mmol kg–1 gadobutrol was 38.8±15.4, whereas after injection of 0.05 mmol kg–1 gadobutrol SNR was 60.4±20.4 (p<0.001).

The mean difference in peak signal intensity ({Delta}SI) between pre- and post-contrast images was 17.7±7.6 after application of 0.025 mmol kg–1 gadobutrol, whereas after injection of 0.05 mmol kg–1 gadobutrol {Delta}SI was 27.7±9.9 in TrueFISP perfusion images (p<0.001).

Statistically significant differences in SNR and {Delta}SI data were evident for contrast injections with 0.025 mmol kg–1 and 0.05 mmol kg–1 gadobutrol (p<0.001).

Patient studies
Owing to the increased heart rate after injection of dipyridamole, the number of acquired slices had to be reduced in six patients in order to fit into the shorter RR interval. Five patients required the administration of aminophylline after injection of dipyridamole and acquisition of stress perfusion images, owing to thoracic discomfort, dyspnoea or significant headache. In all of these patients, the symptoms resolved within 30 min without any additional treatment. The perfusion examinations yielded diagnostic image quality in all patients.

Susceptibility artefacts, originating at the endocardium–blood interface as a result of large differences in contrast agent concentration at the time of contrast agent inflow into the left ventricle, were present in 11 of 25 patients (Figure 2Go). Susceptibility artefacts in these patients were visible for a mean of 6.00±1.34 images in the perfusion series. In eight patients, the artefacts were easily distinguished from perfusion deficits by their transient and circular appearance. However, in three patients, those artefacts were interpreted as perfusion deficits. Two of these three patients had no angiographic evidence of CAD. No other artefacts were present in the perfusion series of patients included in this study.


Figure 2
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  		Figure 2. 59-year-old male patient without evidence of coronary artery disease (CAD). Three early images from a perfusion series of 40 images in short-axis angulations are shown using a SR-TrueFISP sequence (repetition time (TR) 2.4 ms, echo time (TE) 1.2 ms, matrix 72x128, field-of-view (FOV) 225x300 mm, slice thickness 8 mm, flip angle 45°, bandwidth (BW) 1300 Hz pixel–1) after injection of 0.05 mmol kg–1 gadobutrol. Note the circular appearance of the subendocardial susceptibility artefact. Artefacts are significantly shorter and are limited to the endocardium–blood interface compared with perfusion deficits.

 
Evaluation of 87 perfusion series in 25 patients during rest revealed a sensitivity of 66% and specificity of 90% for the detection of myocardial scar formation or high-grade coronary artery stenosis (≥90%) in patients with prior myocardial infarction, having delayed enhancement images as reference.

Assessment of 81 perfusion series after dipyridamole administration yielded a sensitivity of 82% and specificity of 91% for myocardial ischaemia secondary to significant luminal narrowing of epicardial vessels (determined by conventional X-ray coronary angiography). Combination of the information from all perfusion series of one patient yielded a sensitivity of 89% and specificity of 94% on a per-vessel basis.

Furthermore, on a per-patient basis, 11 out of 13 patients with one- or two-vessel CAD were correctly identified (Figure 3Go). In three out of five patients with three-vessel CAD, both coronary arteries exhibiting the highest significant stenosis grade were detected (Figure 4Go) whereas, in one out of four patients with two-vessel CAD, only one hypoperfused area was diagnosed.


Figure 3
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  		Figure 3. 77-year-old male patient with one-vessel coronary artery disease (CAD) (LAD 90%). Rest/stress perfusion series (8 of 40 images) in short-axis angulations are shown using a SR-TrueFISP sequence (see Figure 2Go for parameters) after injection of 0.05 mmol kg–1 gadobutrol. (a) Besides homogeneous enhancement of the left ventricular myocardium, a circumscribed septal perfusion deficit can be observed in rest examinations (arrowheads). (b) An increased stress-induced perfusion deficit (white arrows) is diagnosed in the anterior septal part of the left ventricle. (c) Corresponding coronary angiography depicting the high-grade LAD stenosis.

 

Figure 4
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  		Figure 4. 67-year-old male patient with three-vessel coronary artery disease (CAD) (LAD 50%, RCX 70%, RCA 100%). Rest/stress perfusion series (8 of 40 images) in short-axis angulations are shown using a SR-TrueFISP sequence (see Figure 2Go for parameters) after injection of 0.05 mmol kg–1 gadobutrol. (a) Homogeneous enhancement of the left ventricular myocardium is evident in rest examinations. (b) A stress-induced perfusion deficit (white arrows) is visible in the inferior lateral part of the left ventricle. (c) Corresponding coronary angiography demonstrating the RCA occlusion and high-grade RCX stenosis.

 
Five out of seven patients without angiographic evidence of CAD were correctly diagnosed, i.e. no hypoperfused areas were detected. However, false-positive perfusion deficits (i.e. artefacts) were observed in two of those patients.


   Discussion
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
References
 
Although there are known theoretical advantages of 1 M gadolinium chelates with regard to perfusion examinations, to date no data exist concerning myocardial first-pass T1 weighted perfusion MRI in humans. MR perfusion examinations still suffer from relatively low SNR, which may be improved by new, more highly concentrated contrast media, as more compact bolus profiles have proven advantageous in previous studies assessing cerebral perfusion with T2* weighted sequences [14, 22].

Gadobutrol phantoms exhibited a higher signal using steady-state perfusion sequences at contrast medium concentrations expected in the myocardium during first-pass of the contrast bolus. In patients with CAD, perfusion examinations using gadobutrol yielded a sensitivity and specificity for perfusion defects of 82% and 91%, respectively, having coronary angiography as the standard of reference.

To date, most myocardial perfusion examinations have been performed with 0.5 M extracellular gadolinium chelates. These gadolinium complexes exhibit a favourable safety profile [23–25]. Gadovist 1.0 is the 1 M formulation of a new non-ionic Gd-chelate (gadobutrol) with favorable physico-chemical and pharmacological properties. Despite the higher gadolinium concentration, the osmolality (at 37°C) of 1 M GadovistTM is lower (1.60 Osmol kg–1) than that of 0.5 M MagnevistTM (1.96 Osmol kg–1). T1 relaxivity for gadobutrol at 20 MHz (0.47 T) is 3.6 l mmol–1 s–1 in water and 5.6 l mmol–1 s–1 in plasma, whereas T1 relaxivity for gadopentetate is 3.8 l mmol–1 s–1 in water and 4.8 l mmol–1 s–1 in plasma [26]. Gadobutrol proved to be a safe MR contrast agent even in patients with impaired renal function [27] and those requiring haemodialysis [28]. The rate of adverse events was similar to those recorded for other Gd-containing contrast media.

Previous studies have shown that gadobutrol can be used effectively for the characterization of lesions of the central nervous system at the standard dose of 0.1 mmol kg–1 [29].

The higher gadolinium concentration of GadovistTM 1.0 enables a more compact bolus geometry, and thus is favourable for perfusion examinations. Likewise, previous studies reported promising results using gadobutrol for cerebral perfusion experiments [14, 22]. However, these two studies conducted by Benner et al [14] and Tombach et al [22] assessed cerebral haemodynamics with dynamic susceptibility contrast-enhanced MRI, relying on T2* effects of the contrast media. In contrast, dynamic first-pass myocardial perfusion with Gd-based agents is performed (in most cases) with T1 weighted MR techniques. Goyen et al [13] showed that 1 M gadobutrol leads to improved delineation of blood vessels in whole-body MR examinations using T1 weighted three-dimensional gradient-recalled echo (GRE) sequences. Similarly, in patients with peripheral vascular disease, 1 M gadobutrol improved the delineation of small vessels in the pelvic vascular territory [12]. Here, gadobutrol resulted in a significantly enhanced image quality owing to higher SNR and CNR values of up to 70% for single-station MR angiography. In contrast, performing time-resolved contrast-enhanced MR angiography and pulmonary perfusion MRI, Fink and colleagues [30, 31] reported no relevant advantages of 1 M gadobutrol over 0.5 M Gd-DTPA. Potential explanations were counteracting T2/T2* effects caused by the high intravascular Gd concentration when using high injection rates.

In phantom studies, we found T1 relaxation times for gadobutrol to be about 10% shorter than those for Gd-DTPA. When using the TrueFISP perfusion sequence, as in patient and volunteer examinations, gadobutrol exhibited 53–95% higher SNR values (at 0.2 mmol l–1) for various flip angles compared with phantoms having the same concentration of Gd-DTPA. This may be caused by differences in T2 relaxation times of gadobutrol and Gd-DTPA yielding a higher signal in steady-state perfusion sequences. Specifically, the signal in steady-state sequences is proportional to the ratio of T2/T1, with highest values occurring when T2/T1 ~ 1.

In volunteer studies using a steady-state perfusion sequence, we observed a significantly increased signal enhancement in the left ventricular myocardium after injection of a contrast agent bolus of 0.05 mmol kg–1 gadobutrol compared with injection of 0.025 mmol kg–1 gadobutrol. Similarly, in myocardial perfusion studies at 1.5 T using a T1 weighted fast gradient-echo perfusion sequence, peak profiles of signal intensity time curves for Gd-DTPA were observed following injection of 0.05 mmol kg–1 Gd [32, 33]. Increasing the contrast agent dose above 0.05 mmol kg–1 Gd resulted in counteracting T2* susceptibility effects in one study using a multishot echo-planar-imaging (EPI) sequence [33]. Therefore, in the present study, a contrast agent bolus of 0.05 mmol kg–1 was used for perfusion studies in patients.

Although 1 M gadobutrol enables a more compact bolus profile, Tombach et al [11] reported comparable bolus profiles for gadobutrol and Gd-DTPA in animal first-pass perfusion examinations at the same dose levels. Therefore, they concluded that gadobutrol did not show a significant improvement in cardiac first-pass studies, which was attributed to the small injection volumes of 150 µl used in this study. However, differences in bolus profiles might become apparent using gadobutrol in human perfusion studies applying larger bolus volumes [11].

In a previous study conducted by Schwitter et al [34], myocardial MR perfusion measurements were compared with those from positron emission tomography (PET) and conventional X-ray angiography. The authors reported sensitivity/specificity of 91%/94% relative to PET and 87%/85% relative to X-ray angiography. Another recent study by Nagel et al [35] reported sensitivity and specificity of MR perfusion examinations to be 84–88% and 70–90%, respectively, relative to X-ray angiography, depending upon the chosen evaluation strategy. The present study revealed a sensitivity and specificity for the detection of hypoperfused myocardial regions of 82% and 91%, respectively. Summarizing the results of several previous studies using Gd-DTPA as contrast agent, sensitivities and specificities were in the ranges of 64–91% and 76–94%, respectively, for the detection of perfusion deficits [7, 34–39].

No intra-individual comparison with other contrast media (e.g. Gd-DTPA) was performed in the present study. This was because of ethical concerns with regard to the potentially serious side effects of the stress medication, which would have had to be administered twice to the patient without any additional benefit. Therefore, only a comparison with sensitivity and specificity data from previous studies can be provided, which is, of course, dependent upon the characteristics of the examined patient population as well as technical factors, e.g. the MR protocol. However, the age and gender distribution of our patient group, as well as the prevalence of CAD, was similar to other studies [34, 35].

Although it is not yet clear which technique is best for perfusion examinations (SSFP, GRE or EPI techniques), the TrueFISP (SSFP) sequence used in this study was a commercially available perfusion sequence that has been successfully used for perfusion examinations in previous studies [3, 4, 6].

In conclusion, using a 1 M gadobutrol (GadovistTM 1.0) contrast agent in T1 weighted rest–stress myocardial MR perfusion examinations is feasible. The sensitivity and specificity (per vessel) for the detection of coronary artery stenosis was high: 82% and 91%, respectively. Sensitivity for the detection of CAD in a patient was 89%.

The study was sponsored as an investigator-initiated trial in part by Schering AG, Berlin, Germany

Received for publication August 7, 2006. Revision received December 7, 2006. Accepted for publication January 28, 2007.


   References
Top
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 References
 

  1. American Heart Association. 2004 Heart and stroke statistical update. Dallas: American Heart Association; 2003
  2. Ding S, Wolff SD, Epstein FH. Improved coverage in dynamic contrast enhanced cardiac MRI using interleaved gradient-echo EPI. Magn Reson Med 1998;39:514–9.[Medline]
  3. Schreiber WG, Schmitt M, Kalden P, Mohrs O, Kreitner KF, Thelen M. Dynamic Contrast-enhanced myocardial perfusion imaging using saturation-prepared TrueFISP. J Magn Reson Imaging 2002;16:641–52.[CrossRef][Medline]
  4. Hunold P, Maderwald S, Eggebrecht H, Vogt FM, Barkhausen J. Steady-state free precession sequences in myocardial first-pass perfusion MR imaging: comparison with TurboFLASH imaging. Eur Radiol 2004;14:409–16.[CrossRef][Medline]
  5. Chiu CW, So NMC, Lam WWM, Chan KY, Sanderson JE. Combined first-pass perfusion and viability study at MR imaging in patients with non-ST segment-elevation acute coronary syndromes: feasibility study. Radiology 2003;226:717–22.[Abstract/Free Full Text]
  6. Fenchel M, Helber U, Simonetti OP, Stauder NI, Kramer U, Nguyen CN, et al. Multislice first-pass myocardial perfusion imaging: comparison of saturation recovery (SR)-TrueFISP-two-dimensional (2D) and SR-TurboFLASH-2D pulse sequences. J Magn Reson Imaging 2004;19:555–63.[CrossRef][Medline]
  7. Lauerma K, Virtanen KS, Sipila LM, Hekali P, Aronen HJ. Multislice MRI in assessment of myocardial perfusion in patients with single-vessel proximal left anterior descending coronary artery disease before and after revascularization. Circulation 1997;96:2859–67.[Abstract/Free Full Text]
  8. Kim RJ, Hillenbrand HB, Judd RM. Evaluation of myocardial viability by MRI. Herz 2000;4:417–30.
  9. Mühling OM, Dickson ME, Zenovich A, Huang Y, Wilson BV, Wilson RF, et al. Quantitative magnetic resonance first-pass perfusion analysis: inter- and intraobserver agreement. J Cardiovasc Magn Reson 2001;3:247–56.[CrossRef][Medline]
  10. Mühler A. Assessment of myocardial perfusion using contrast-enhanced MR imaging: current status and future developments. MAGMA 1995;3:21–33.[CrossRef][Medline]
  11. Tombach B, Reimer P, Prümer B, Allkemper T, Bremer C, Mühler A, et al. Does a higher concentration of gadolinium chelates improve first-pass cardiac signal changes? J Magn Reson Imaging 1999;10:806–12.[CrossRef][Medline]
  12. Goyen M, Lauenstein TC, Herborn CU, Debatin JF, Bosk S, Ruehm SG. 0.5 M Gd chelate (Magnevist) versus 1.0 M Gd chelate (Gadovist): dose-independent effect on image quality of pelvic three-dimensional MR-angiography. J Magn Reson Imaging 2001;14:602–7.[CrossRef][Medline]
  13. Goyen M, Herborn CU, Vogt FM, Kröger K, Verhagen R, Yang F, et al. Using a 1M Gd-chelate (Gadobutrol) for total-body three-dimensional MR angiography: preliminary experience. J Magn Reson Imaging 2003;17:565–71.[CrossRef][Medline]
  14. Benner T, Reimer P, Erb G, Schuierer G, Heiland S, Fischer C, et al. Cerebral MR perfusion imaging: first clinical application of a 1 M Gadolinium chelate (Gadovist 1.0) in a double-blinded randomized dose-finding study. J Magn Reson Imaging 2000;12:371–80.[CrossRef][Medline]
  15. Barkhausen J, Ruehm SG, Goyen M, Buck T, Laub G, Debatin JF. MR Evaluation of ventricular function: true fast imaging with steady-state precession versus fast low-angle shot cine MR imaging: feasibility study. Radiology 2001;219:264–9.[Abstract/Free Full Text]
  16. Klocke FJ, Simonetti OP, Judd RM, Kim RJ, Harris KR, Hedjbeli S, et al. Limits of detection of regional differences in vasodilated flow in viable myocardium by first-pass magnetic resonance imaging. Circulation 2001;104:2412–6.[Abstract/Free Full Text]
  17. Higgins CB, Herfkens R, Lipton MJ, Sievers R, Sheldon P, Kaufman L, et al. Nuclear magnetic resonance imaging of acute myocardial infarction in dogs: alterations in magnetic relaxation times. Am J Cardiol 1983;52:184–8.[CrossRef][Medline]
  18. Kim RJ, Chen E, Lima JAC, Judd RM. Myocardial Gd-DPTA kinetics determine MRI contrast enhancement and reflect the extent and severity of myocardial injury after acute reperfused infarction. Circulation 1996;94:3318–26.[Abstract/Free Full Text]
  19. Sandstede JJ, Lipke C, Beer M, Harre K, Pabst T, Kenn W, et al. Analysis of first-pass and delayed contrast-enhancement patterns of dysfunctional myocardium on MR imaging: use in the prediction of myocardial viability. Am J Roentgenol 2000;174:1737–40.[Abstract/Free Full Text]
  20. Al-Saadi N, Nagel E, Gross M, Schnackenburg B, Paetsch I, Klein C, et al. Improvement of myocardial perfusion reserve early after coronary intervention: assessment with cardiac resonance imaging. J Am Coll Cardiol 2000;36:1557–64.[Abstract/Free Full Text]
  21. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the cardiac imaging committee of the council on clinical cardiology of the American Heart Association. Circulation 2002;105:539–42.[Free Full Text]
  22. Tombach B, Benner T, Reimer P, Schuierer G, Fallenberg E, Geens V, et al. Do highly concentrated gadolinium chelates improve MR brain perfusion imaging? Intraindividually controlled randomized crossover concentration comparison study of 0.5 versus 1.0 mol/L gadobutrol. Radiology 2003;226:880–8.[Abstract/Free Full Text]
  23. Niendorf HP, Dinger JC, Haustein J, Cornelius I, Alhassan A, Clauss W. Tolerance data of Gd-DTPA: a review. Eur J Radiol 1991;13:15–20.[CrossRef][Medline]
  24. Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA. Clinical safety of gadopentetate dimeglumine. Radiology 1995;196:439–43.[Abstract/Free Full Text]
  25. Prince MR, Arnoldus C, Frisoli JK. Nephrotoxicity of high-dose gadolinium compared with iodinated contrast. J Magn Reson Imaging 1996. 6:162–166.
  26. Vogler H, Platzek J, Schumann-Giampieri G, Frenzel T, Weinmann HJ, Raduchel B, et al. Pre-clinical evaluation of gadobutrol: a new, neutral, extracellular contrast agent for magnetic resonance imaging. Eur J Radiol 1995;21:1–10.[CrossRef][Medline]
  27. Tombach B, Bremer C, Reimer P, Kisters K, Schaefer RM, Geens V, et al. Renal tolerance of a neutral gadolinium chelate (gadobutrol) in patients with chronic renal failure: results of a randomized study. Radiology 2001;218:651–7.[Abstract/Free Full Text]
  28. Tombach B, Bremer C, Reimer P, Matzkies F, Schaefer RM, Ebert W, et al. Using highly concentrated gadobutrol as an MR contrast agent in patients also requiring hemodialysis: safety and dialysability. Am J Roentgenol 2002;178:105–9.[Abstract/Free Full Text]
  29. Lemke AJ, Sander B, Balzer T, Geens V, Hosten N, Felix R. Safety and use of gadobutrol in patients with brain tumors (phase III trial). Fortschr Röntgenstr 1997;167:591–8.
  30. Fink C, Puderbach M, Ley S, Plathow C, Bock M, Zuna I, et al. Contrast-enhanced three-dimensional pulmonary perfusion magnetic resonance imaging: intraindividual comparison of 1.0 M gadobutrol and 0.5 M Gd-DTPA at three dose levels. Invest Radiol 2004;39:143–8.[CrossRef][Medline]
  31. Fink C, Bock M, Kiessling F, Lichy MP, Krissak R, Zuna I, et al. Time-resolved contrast-enhanced three-dimensional pulmonary MR-angiography: 1.0 M gadobutrol vs. 0.5 M gadopentetate dimeglumine. J Magn Reson Imaging 2004;19:202–8.[CrossRef][Medline]
  32. Atkinson DJ, Burstein D, Edelman RR. First-pass cardiac pPerfusion: pvaluation with ultrafast MR imaging. Radiology 1990;174:757–62.[Abstract/Free Full Text]
  33. Schwitter J, Debatin JF, von Schulthess GK, McKinnon GC. Normal myocardial perfusion assessed with multishot echo-planar imaging. Magn Reson Med 1997;37:140–7.[Medline]
  34. Schwitter J, Nanz D, Kneifel S, Bertschinger KM, Büchi M, Knüsel PR, et al. Assessment of myocardial perfusion in coronary artery disease by magnetic resonance. Circulation 2001;103:2230–5.[Abstract/Free Full Text]
  35. Nagel E, Klein C, Paetsch I, Hettwer S, Schnackenburg B, Wegscheider K, et al. Magnetic resonance perfusion measurements for the noninvasive detection of coronary artery disease. Circulation 2003;108:432–7.[Abstract/Free Full Text]
  36. Keijer JT, van Rossum AC, van Eenige MJ, Bax JJ, Visser FC, Teule JJ, et al. Magnetic resonance imaging of regional myocardial perfusion in patients with single-vessel coronary artery disease: quantitative comparison with 201Thallium-SPECT and coronary angiography. J Magn Reson Imaging 2000;11:607–15.[CrossRef][Medline]
  37. Wilke N, Jerosch-Herold M, Stillman AE, Kroll K, Tsekos N, Merkle H, et al. Concepts of myocardial perfusion imaging in magnetic resonance imaging. Magn Reson Quart 1994;10:249–86.
  38. Eichenberger AC, Schuiki E, Kochli VD, Amann FW, McKinnon GC, von Schulthess GK. Ischemic heart disease: assessment with gadolinium-enhanced ultrafast MR imaging and dipyridamole stress. J Magn Reson Imaging 1994;4:425–31.[Medline]
  39. Panting JR, Gatehouse PD, Yang GZ, Jerosch-Herold M, Wilke N, Firmin DN, et al. Echo-planar magnetic resonance myocardial perfusion imaging: parametric map analysis and comparison with Thallium SPECT. J Magn Reson Imaging 2001;13:192–200.[CrossRef][Medline]




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