Article

Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial MRI late gadolinium enhancement

Università degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan, Italy.
European journal of radiology (Impact Factor: 2.37). 10/2011; 80(1):96-102. DOI: 10.1016/j.ejrad.2010.06.040
Source: PubMed
ABSTRACT
To investigate the time-course of late gadolinium enhancement of infarcted myocardium using gadobenate dimeglumine at different dosages and administration regimens.
After institutional review board approval and informed consent, we studied 13 patients (aged 63±11 years) with chronic myocardial infarction. They underwent two gadobenate dimeglumine-enhanced MR examinations (interval 24-48 h) using short-axis inversion-recovery gradient-echo sequences, with the following two different protocols, in randomized order: 0.05 mmol/kg and imaging at the 2.5th, 5th, 7.5th and 10th minute plus 0.05 mmol/kg and imaging at the 12.5th, 15th, 17.5th and 20th minute; the same as before but using 0.1 mmol/kg for both contrast injections. Contrast-to-noise ratios (CNRs) between infarcted myocardium, non-infarcted myocardium and left ventricle cavity were calculated for each time-point (2.5-min steps). Friedman ANOVA was used for comparing the CNR time-course; Wilcoxon test for comparing CNR at the 10th and the 20th minute.
The CNR between infarcted and non-infarcted myocardium obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than that obtained at the 10th minute with 0.05 mmol/kg (P=0.033) while not significantly different from that obtained at the 10th (0.1mm/kg) or at the 20th minute with 0.1 plus 0.1 mmol/kg. The CNR between infarcted myocardium and the left ventricle cavity obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than all other measured values (P≤0.017).
Using gadobenate dimeglumine, 0.05 plus 0.05 mmol/kg allows for a higher CNR between infarcted myocardium and the left ventricle cavity allowing for reliable assessment of the sub-endocardial infarctions.

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Please cite this article in press as: Secchi F, et al. Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial
MRI late gadolinium enhancement. Eur J Radiol (2010), doi:10.1016/j.ejrad.2010.06.040
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Contents lists available at ScienceDirect
European Journal of Radiology
journal homepage: www.elsevier.com/locate/ejrad
Optimizing dose and administration regimen of a high-relaxivity contrast agent
for myocardial MRI late gadolinium enhancement
Francesco Secchi
a,b,1
, Giovanni Di Leo
a,b,1
, Giacomo D.E. Papini
a,b,1
, Francesca Giacomazzi
c,2
,
Marisa Di Donato
d,3
, Francesco Sardanelli
a,b,
a
Università degli Studi di Milano, Dipartimento di Scienze Medico-Chirurgiche, Milan, Italy
b
IRCCS Policlinico San Donato, Radiology Unit, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy
c
IRCCS Policlinico San Donato, Unit of Cardiac Surgery, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy
d
University of Florence, Department of Critical Care Medicine, IRCCS Policlinico San Donato, Via Morandi 30, 20097 San Donato Milanese, Milan, Italy
article info
Article history:
Received 26 March 2010
Received in revised form 17 June 2010
Accepted 18 June 2010
Keywords:
Cardiac magnetic resonance
Contrast-to-noise ratio
Dose finding
Late gadolinium enhancement
Myocardial infarction
abstract
Objectives: To investigate the time-course of late gadolinium enhancement of infarcted myocardium using
gadobenate dimeglumine at different dosages and administration regimens.
Materials and methods: After institutional review board approval and informed consent, we studied
13 patients (aged 63 ± 11 years) with chronic myocardial infarction. They underwent two gadobe-
nate dimeglumine-enhanced MR examinations (interval 24–48 h) using short-axis inversion-recovery
gradient-echo sequences, with the following two different protocols, in randomized order: 0.05 mmol/kg
and imaging at the 2.5th, 5th, 7.5th and 10th minute plus 0.05 mmol/kg and imaging at the 12.5th, 15th,
17.5th and 20th minute; the same as before but using 0.1 mmol/kg for both contrast injections. Contrast-
to-noise ratios (CNRs) between infarcted myocardium, non-infarcted myocardium and left ventricle
cavity were calculated for each time-point (2.5-min steps). Friedman ANOVA was used for comparing
the CNR time-course; Wilcoxon test for comparing CNR at the 10th and the 20th minute.
Results: The CNR between infarcted and non-infarcted myocardium obtained at the 20th minute with 0.05
plus 0.05 mmol/kg resulted significantly higher than that obtained at the 10th minute with 0.05 mmol/kg
(P = 0.033) while not significantly different from that obtained at the 10th (0.1 mm/kg) or at the 20th
minute with 0.1 plus 0.1 mmol/kg. The CNR between infarcted myocardium and the left ventricle cavity
obtained at the 20th minute with 0.05 plus 0.05 mmol/kg resulted significantly higher than all other
measured values (P 0.017).
Conclusion: Using gadobenate dimeglumine, 0.05 plus 0.05 mmol/kg allows for a higher CNR between
infarcted myocardium and the left ventricle cavity allowing for reliable assessment of the sub-endocardial
infarctions.
© 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Magnetic resonance (MR) imaging of myocardial late
gadolinium enhancement (LGE) after intravenous injection of
a gadolinium-based contrast agent has been widely used to assess
chronic infarcted myocardium and scar extent in humans, with
Corresponding author at: Università degli Studi di Milano, Dipartimento di
Scienze Medico-Chirurgiche, IRCCS Policlinico San Donato, Unità di Radiologia, Via
Morandi 30, 20097 San Donato Milanese, Milan, Italy. Tel.: +39 02 52774468;
fax: +39 02 52774626.
E-mail addresses: francesco.sardanelli@unimi.it,
f.sardanelli@grupposandonato.it (F. Sardanelli).
1
Tel.: +39 02 52774468.
2
Tel.: +39 02 52774300.
3
Tel.: +39 02 52774636.
a high correspondence with pathological standard of reference
in animal models [1,2], with a spatial resolution higher than that
obtained with single-photon emission computed tomography
[3]. Currently, LGE is the noninvasive standard technique for
the evaluation of myocardial viability [4]. Moreover, myocardial
LGE can be found not only after infarction but also in patients
with myocardial inflammatory and infectious disease, cardiomy-
opathies, and congenital or genetic cardiac disease, mainly as a
marker of myocardial fibrosis, as well as in cardiac neoplasms [5].
Myocardial LGE is commonly performed using an inversion-
recovery (IR) T1-weighted gradient-echo sequence, with an
optimized inversion time, 10–20 min after contrast material injec-
tion, when non-viable myocardium appears highly hyperintense
due to local high uptake and slow washout of the contrast material
[5,6]. Conversely, in such a sequence, viable myocardium appears as
strongly hypointense because of the nulling effect of the IR prepara-
0720-048X/$ see front matter © 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.ejrad.2010.06.040
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tion and of its rapid contrast material washout [6]. The time interval
between contrast injection and MR imaging is not so crucial for the
evaluation of the size of the infarction [7].
A key point in detectability of small sub-endocardial myocar-
dial infarctions is the ability to distinguish between infarcted
myocardium and the left ventricle (LV) cavity, where the blood,
containing contrast material, could have signal intensity (SI) as
high as infarcted myocardium. This ability is strongly dependent
on many factors such as the type of contrast agent, the absolute
injected dose, and the administration regimen [8]. A suboptimal
choice of these factors may result in a reduced contrast-to-noise
ratio (CNR) [9,10] with the possibility of overlooking small sub-
endocardial infarctions.
Recently, Wagner et al. [11] assessed “the influence of
time, dose, and inversion time (TI) and their interactions on
myocardial infarction size measurements” in animal and human
models for acute infarctions using gadolinium-diethylenetriamine-
pentaacetate showing that the acute myocardial infarction size
“can be measured with MRI using a contrast dose between 0.1 and
0.2 mmol/kg and a time window of5 to 30 min after contrast admin-
istration, provided that the TI is adjusted”. Moreover, Petersen et
al. [12] compared single (0.1 mmol/kg of bodyweight) and double
(0.2 mmol/kg of bodyweight) dose of gadodiamide in patients with
chronic infarction, showing that there are no statistically signifi-
cant differences in infarcted myocardium size if images were taken
between 10 and 18 min after the contrast injection. However, to
our knowledge, nobody assessed which is the influence of imaging
time and regimen of administration (single or fractionated dose)
of the contrast agent on the CNR for chronic infarctions using a
high-relaxivity contrast agent.
In this study we made the hypothesis that fractionating the
contrast agent total dose in two injections could reinforce the MR
signal coming from the infarcted myocardium without increasing
that coming from the blood inside the LV cavity, finally resulting
in an increased CNR between infarcted myocardium and LV cavity.
Thus, the aim of our study was to investigate the time-course of
the CNR between infarcted myocardium and LV cavity for chronic
infarctions using a high-relaxivity contrast agent such as gadobe-
nate dimeglumine and also to study the effect of fractionating the
contrast agent dose into two separated injections.
2. Materials and methods
2.1. Study design and population
Institutional review board approval was received for this
intraindividual prospective study and patient’s written informed
consent was obtained. From June 2006 to April 2007, 23 consec-
utive in-patients (19 males and 4 females; mean age ± standard
deviation, 63 ± 11 years) met the following inclusion criteria: (1)
presence of a chronic infarction (with at least four weeks from
the acute event) based on electrocardiographic pattern, myocardial
necrosis enzymes and the patient’s clinical history; (2) scheduling
for a surgical revascularization. Exclusion criteria included: Cana-
dian Class III–IV angina, contraindications to MR imaging (e.g.,
pacemaker or other intracardiac devices, ferromagnetic intracra-
nial vascular clips, claustrophobia, etc.) or to gadolinium-based
contrast agents (including, from January 2007, an estimated glob-
ular filtration rate less than 60 ml/min × 1.73 m
2
), and the lack of
written informed consent.
The intraindividual study protocol included two contrast-
enhanced MR examinations of myocardial LGE for each patient:
A. 0.05 mmol/kg of bodyweight of gadobenate dimeglumine (Gd-
BOPTA, MultiHance, Bracco Imaging S.p.A., Milan, Italy) at 2 ml/s
Fig. 1. Regimen of administration of gadobenate dimeglumine for myocardial
delayed enhancement. After the first contrast agent injection late gadolinium
enhancement imaging was performed after 2.5, 5, 7.5 and 10 min. At this time-
point the second contrast agent dose was injected and late gadolinium enhancement
imaging was repeated at 12.5th, 15th, 17.5th, and 20th minute.
followed by a flush of 20 ml of saline solution and LGE imaging
after 2.5, 5, 7.5, and 10 min, followed by a second injection of
0.05 mmol/kg of bodyweight of the same contrast agent at the
same dosage and LGE imaging at the 12.5th, 15th, 17.5th, and
20th minute;
B. 0.1 mmol/kg of bodyweight of gadobenate dimeglumine at
2 ml/s followed by a flush of 20 ml of saline solution and LGE
imaging after 2.5, 5, 7.5, and 10 min, followed by a second injec-
tion of 0.1 mmol/kg of bodyweight of the same contrast agent
at the same dosage and LGE imaging at the 12.5th, 15th, 17.5th,
and 20th minute.
The scheme of administration regimen is shown in Fig. 1.We
have chosen to perform LGE imaging every 2.5 min till the 20th
as a good compromise between the duration of the MR sequence
and the need to obtain an evaluable time-course of the CNR. The
two protocols were randomized for priority order with the aim of
minimizing the possible effect of residual contrast material of the
first protocol.
The second examination was performed 24–48 h after the first
examination. This time delay should be sufficient for a complete
agent washout, thus avoiding a carry-over effect. As showed by
Kim and et al. [13] the Gd-DTPA half-life in infarcted myocardium
is about 30 min. Due to its ability for a weak and transient interac-
tion with serum albumin, gadobenate dimeglumine has a twofold
higher T1-relaxivity compared with gadopentetate dimeglumine;
thus we can speculate a twofold higher half-life in the infarcted
myocardium (about 1 h). As a consequence, 24 h after injection
the contrast concentration should be reduced by a factor equal to
2
24
.
Ten patients (8 males and 2 females; mean age 63 ± 10 years)
underwent only the first examination (6 with the protocol A and 4
with the protocol B) and refused to undergo the second examina-
tion. In order to retain the intraindividual design of the study, data
analysis was performed only on the 13 patients who completed
the study protocol. They were 11 males and 2 females aged 63 ± 11
years; 10 of them had a transmural (>50%) myocardial infarction.
The result of randomization in these 13 patients was as follows: 5
patients began with protocol A and 8 patients began with protocol
B.
2.2. MR imaging
All MR examinations were conducted with a 1.5-T unit with
40-mT/m gradient power (Magnetom Sonata, Siemens, Enlargen,
Germany) using a four-channel cardio-thoracic coil. Whole-LV
images were acquired with an electrocardiographically triggered
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short- and long-axis IR-prepared turbo gradient-echo (fast low-
angle shot) sequence with the following technical parameters:
repetition time depending on the RR interval of the electrocardio-
graphic cycle; echo time, from 1.0 ms to 4.3 ms; flip angle, 10
; slice
thickness, 5 mm; a field of view ranging from 281 mm × 360 mm
to 400 mm × 400 mm and a matrix size ranging from 125 × 192 to
195 × 256 were used, giving a pixel size from 2.05 mm × 1.56 mm
to 2.75 mm × 1.56 mm (the same field of view and matrix size were
used for the two examinations of each patient); the inversion time
was individually optimized between 190 ms and 310 ms. Optimiza-
tion of the inversion time was assessed for each time-point using
a TI scout sequence and choosing the inversion time which cre-
ated the best nulling effect of non-infarcted myocardium, as already
described [5].
2.3. Image analysis
Image analysis was performed with an open-source soft-
ware (Osirix
®
) downloaded from Internet at http://www.osirix-
viewer.com/ [14]. For each patient, we selected the slice in which
the maximal LGE of the infarcted myocardium was subjectively
recognized by a physician with a three-year experience in cardiac
MR imaging (first author). This selection was done firstly choosing
the slices in which the SI of the infarcted myocardium appeared as
maximal; afterwards, among these slices, the slice where LGE was
maximally extended was selected. Then, circular regions of interest
(ROI) were positioned inside the infarcted myocardium in the area
of maximal enhancement, inside the non-infarcted myocardium,
inside the LV cavity, and in an artifact-free area outside the patient
(used as a measure of the noise). Each ROI was positioned carefully
to avoid inhomogeneous signal variations. A measure of SI in arbi-
trary units (a.u.), as mean ± standard deviation, was obtained for
each ROI. We repeated these measurements for each time-point
and for both protocols as shown in Fig. 1. Finally, the radiologist
repeated the measurements twice with a three months delay in
order to estimate the intraobserver reproducibility.
2.4. Statistical analysis
For each patient, we calculated the CNR between infarcted
myocardium and LV cavity and the CNR between infarcted
myocardium and non-infarcted myocardium according to the fol-
lowing formulas:
CNR(
IM
LVC
) =
(SI
IM
SI
LVC
)
SD
noise
= (SNR
IM
SNR
LVC
)
CNR(
IM
NIM
) =
(SI
IM
SI
NIM
)
SD
noise
= (SNR
IM
SNR
NIM
)
where SI stands for signal intensity, SNR for signal-to-noise ratio,
IM for infarcted myocardium, NIM for non-infarcted myocardium,
SD for standard deviation, and LVC for LV cavity.
Intraobserver reproducibility in measuring CNR was estimated
by Bland–Altman method: the mean (bias) and SD of the differences
of the two datasets are reported. The time-course of SI and CNR was
evaluated for both dose protocols. Moreover, we also restricted the
analysis of CNR at 10th and 20th minute; graphs were obtained
using means. When dealing with asymmetric distributions, statis-
tical analyses were conducted with non-parametrical Friedman’s
analysis of variance and Wilcoxon signed rank test. SPSS statistical
software for Windows, release 14.0 (SPSS Inc., Chicago, IL) was used
for analysis. A P < 0.05 was considered as significant.
3. Results
No patient showed atrial fibrillation and all examinations were
assessable. Figs. 2 and 3 show examples of the change in LGE
contrast for both protocols. Mean noise ranged from 2.4 ± 0.7 a.u.
(mean ± SD) to 3.0 ± 0.7 a.u. Data on SI and CNR showed skewed dis-
tributions, as confirmed by substantial differences between means
and medians at several time-points. Intraobserver reproducibility
was good: bias = 1.3 and SD = 4.0 for the CNR between infarcted
myocardium and LV cavity; 0.9 and 13.5 for the CNR between
infarcted and non-infarcted myocardium, respectively.
3.1. Protocol A
The mean SI of infarcted myocardium showed a biphasic time-
course with an initially apparently exponential increase in the first
10 min followed by a linear increase in the second part of the injec-
tion protocol. The difference among these eight values of mean SIs
(one for each time-point) was significant (Friedman, P = 0.010; see
Fig. 4a). The mean SI of LV cavity showed a behavior almost parallel
to that of SI of infarcted myocardium for the first 10 min followed by
a plateau in the second part. As before, the difference among these
eight values of mean SIs was significant (Friedman, P = 0.019; see
Fig. 4a); however, the difference of SI obtained in the last four time-
points (plateau) was not significant (Friedman, P = 0.853). The mean
SI of non-infarcted myocardium showed an almost constant low
level with a low increase at the 7.5th minute (Friedman, P = 0.095;
see Fig. 4a).
The mean CNR between infarcted myocardium and non-
infarcted myocardium after an initial increase in the first 7.5 min
remained almost constant till the 12.5th minute after which, with
the second contrast agent injection, began to linearly increase up
to 44.7 at 20th minute (Friedman, P < 0.001; see Fig. 5a). In the
first 12.5 min, the mean CNR between infarcted myocardium and
LV cavity showed a bell shape curve with a maximum of 4.7 at
7.5th minute and a minimum of 1.1 at 12.5th minute when the sec-
ond contrast agent injection produced a linear increase up to 11.5
(11.5 ± 8.0, mean ± standard deviation; 95% CI 6.6–16.3) at 20th
minute (Friedman, P < 0.001; see Fig. 5a).
3.2. Protocol B
The mean SI of infarcted myocardium was almost constant in
the first 10 min; with the second contrast agent injection it rapidly
reached a maximum of about 55 a.u. between the 12.5th minute
and the 15th minute after which a small decrease was observed
(Friedman, P < 0.001; see Fig. 4b). The time-course of the mean SI of
LV cavity was parallel to that of infarcted myocardium (Friedman,
P < 0.001; see Fig. 4b). The mean SI of non-infarcted myocardium
showed a constant time-course ranging from 4.5 to 6.7 a.u with a
mean of 5.5 a.u. and with non-significant difference among time-
points (Friedman, P = 0.303; see Fig. 4b).
The mean CNR between infarcted myocardium and non-
infarcted myocardium showed an initial apparently exponential
increase in the first 10 min followed by an oscillating behavior with
the second contrast injection, although a global increase could be
observed with an overall significant difference among time-points
(Friedman, P = 0.031; see Fig. 5b). The mean CNR between infarcted
myocardium and LV cavity showed a constant time-course ranging
from 2.1 to 3.2 with a mean of 2.7 and with non-significant sta-
tistically difference among time-points (Friedman, P = 0.363; see
Fig. 5b).
A selection of the measured CNR values (those at the 10th
minute and at the 20th minute) for both protocols is showed in
Fig. 6 while the relative comparisons are listed in Table 1.
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Fig. 2. Short-axis images showing four time-points sampled every 2.5 min after intravenous injection of 0.05 mmol/kg of gadobenate dimeglumine (top row) and four time-
points sampled every 2.5 min after the second injection of 0.05 mmol/kg of gadobenate dimeglumine (bottom row). Note the higher difference between the signal intensity
of the ischemic scar and that of the blood inside the left ventricle cavity after 20 min from the first injection. Note the poor detectability of the ischemic scar due to a high
signal intensity of the blood inside the left ventricle cavity.
Fig. 3. Short-axis images showing four time-points sampled every 2.5 min after intravenous injection of 0.1 mmol/kg of gadobenate dimeglumine (top row) and four
time-points sampled every 2.5 min after the second injection of 0.1 mmol/kg of gadobenate dimeglumine (bottom row).
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Fig. 4. Time-course of mean signal intensity (SI) measured in arbitrary units (a.u.) of non-infarcted myocardium (NIM), infarcted myocardium (IM), and left ventricle cavity
(LVC) for the regimen of administration 0.05 + 0.05 mmol/kg of gadobenate dimeglumine (a) and 0.1 + 0.1 mmol/kg of gadobenate dimeglumine (b). The P-value refers to
the nearest curve and is the result of the Friedman analysis of variance applied to all time-points of the curve. The differences between the last four time-points were not
statistically significant (*, Friedman test). For the sake of clarity error bars are not displayed.
Fig. 5. Time-course of mean contrast-to-noise ratio (CNR) between infarcted myocardium (IM) and left ventricle cavity (LVC) and between IM and non-infarcted myocardium
(NIM), for the regimen of administration 0.05 + 0.05 mmol/kg of gadobenate dimeglumine (a) and 0.1 + 0.1 mmol/kg of gadobenate dimeglumine (b). The P-value refers to the
nearest curve and is the result of the Friedman analysis of variance applied to all time-points. For the sake of clarity error bars are not displayed.
Fig. 6. Contrast-to-noise ratio (CNR) between infarcted myocardium (IM) and left ventricle cavity (LVC) (a) and between IM and non-infarcted myocardium (NIM) at the
10th minute (0.05 and 0.1) and at the 20th minute (0.05 + 0.05 and 0.1 + 0.1) for both protocols. Data are mean and standard deviation.
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Table 1
Statistical analysis restricted at 10th and at 20th minute.
Comparison
a
Wilcoxon, P
CNR
IM-to-LVC IM-to-NIM
0.05 vs 0.05 + 0.05 4.1 vs 11.5 (P = 0.016) 23.3 vs 44.7 (P = 0.033)
0.1 vs 0.1 + 0.1 2.1 vs 2.8 (P = 0.972) 34.7 vs 52.1 (P = 0.028)
0.05 vs 0.1 4.1 vs 2.1 (P = 0.152) 23.3 vs 34.7 (P = 0.064)
0.05 vs 0.1 + 0.1 4.1 vs 2.8 (P = 0.463) 23.3 vs 52.1 (P = 0.013)
0.05 + 0.05 vs 0.1 11.5 vs 2.1 (P = 0.001) 44.7 vs 34.7 (P = 0.382)
0.05 + 0.05 vs 0.1 + 0.1 11.5 vs 2.8 (P = 0.007) 44.7 vs 52.1 (P = 0.249)
Note: Each comparison involves contrast-to-noise ratio (CNR) values measured
at 10th or at 20th minute, depending on the number of injections. IM: infarcted
myocardium. NIM: non-infarcted myocardium. LVC: left ventricle cavity.
a
Contrast agent doses given in mmol/kg of bodyweight.
4. Discussion
The evaluation of myocardial viability is crucial to predict the
ability of the myocardium to recover its contractile function after
revascularization [15,16]. Kim and et al. [1] demonstrated that the
probability of regional contractile recovery is strongly inversely
correlated to the transmural extent of the enhancement prior
revascularization. They studied 50 patients with myocardial LGE
imaging segmenting the left ventricle in twelve circumferential
segments and evaluating the wall motion before and after revascu-
larization. Of all the segments which showed reduced wall motion
before revascularization, contractility increased in 78% (256/329)
of the non-enhancing segments and in 2% (1/58) segments with
transmural extent larger than 75% [1].
The contrast dose used for myocardial LGE commonly ranges
between 0.1 and 0.2 mmol/kg of bodyweight [17]. In their review,
Edelman et al. [17] reported that on a total of 103 contrast-
enhanced MR studies of the myocardium (including perfusion
studies), the contrast agent dose was less than 0.05 mmol/kg of
bodyweight in 10%, 0.05 mmol/kg in 18%, 0.1 mmol/kg in 42%,
0.15 mmol/kg in 2% and 0.2 mmol/kg in 21% of cases. In practice, no
consensus on the optimal dosage for myocardial LGE is available.
In this study we measured the time-course of the CNR between
infarcted myocardium and LV cavity as a key point for the
detectability of small sub-endocardial infarctions [10]. Moreover,
we evaluated the time-course of the CNR between infarcted
myocardium and non-infarcted myocardium in order to better
estimate washin and washout of the contrast material in the
three cardiac compartments: infarcted myocardium, non-infarcted
myocardium and LV cavity. We found that the highest CNR between
infarcted myocardium and LV cavity (equal to 11.5) appears at the
20th minute using the protocol A, that is 10 min after the second
injection of 0.05 mmol/kg of bodyweight of contrast material. As
a matter of fact, this protocol determined the widest change of
the CNR between infarcted myocardium and LV cavity differently
from the constant time-course of the same parameter observed
using protocol B. The latter protocol reached the highest value of
only 3.2, significantly lower (P = 0.003) than that given by proto-
col A (11.5), for which the time-trend suggests a possible higher
value being obtained if the imaging was repeated even later. The
time-course of the CNR between infarcted myocardium and non-
infarcted myocardium for both protocols are quite similar even
though protocol B gave the highest values with the widest sepa-
ration from the curve of the CNR between infarcted myocardium
and LV cavity. These data show that a single dose of 0.1 mmol/kg
of bodyweight of gadobenate dimeglumine results in a highly
enhanced intraventricular blood and infarcted myocardium with
a quite parallel course along the time. Conversely, the use of a
first injection of only 0.05 mmol/kg of bodyweight of the same con-
trast material causes a slightly lower enhancement of the infarcted
myocardium, which can be increased by the second injection of
0.05 mmol/kg of bodyweight, without significant increase of SI of
the LV cavity. Based on this latter fact, we could speculate that a
slow and continuous infusion of the contrast material may result
in an even higher CNR.
In our study, each comparison involving the CNR between
infarcted myocardium and LV cavity for the complete protocol A
is statistically significant, suggesting that the highest detectabil-
ity of sub-endocardial infarctions appears 10 min after the second
injection of 0.05 mmol/kg of bodyweight of gadobenate dimeglu-
mine. The maximum value of 11.5 is about the double than the
mean CNR between infarcted myocardium and LV cavity found by
Schlosser and colleagues [9] using 0.2 mmol/kg of bodyweight of
gadopentetate dimeglumine. On the other hand, Kellman et al. [18]
reported a CNR between infarcted myocardium and LV cavity equal
to 22.5 with multi-contrast delayed enhancement imaging using
0.2 mmol/kg of bodyweight of gadopentetate dimeglumine. Multi-
contrast technique consists in acquiring both T1- and T2-weighted
images with the same resolution and slice prescription, as well as
at the same cardiac and respiratory phases. Combining the two
datasets improves the detectability of sub-endocardial infarctions.
However, the latter result was obtained with an eight-element car-
diac phased array coil and with a phase-sensitive IR method of
image reconstruction that reduce the need for a precise choice of
time of inversion; moreover, this is a time-consuming procedure
[19].
Dose and regimen of administration of contrast material has
particular relevance for high-relaxivity agent such as gadobenate
dimeglumine [20,21]. Several studies have shown the higher per-
formance of this agent if compared to low-relaxivity contrast media
for central nervous system, breast, liver, renal, vasculature imaging
when administered at an equivalent single dose of 0.1 mmol/kg of
bodyweight [20–28]. This creates a limit on the dose to be used in
myocardial LGE imaging. In fact, the presence of residual contrast
material in the ventricular cavity during acquisition could reduce
the contrast between myocardial LGE and intraventricular blood.
A major result of our study is the possibility to reduce the overall
contrast agent dose which may be advantageous for renal failure
patients, given the recent reports of a clear association between
higher doses of contrast material and nephrogenic systemic fibro-
sis in patients with severe renal failure [29,30]. Due to the lack of
unconfounded published cases of nephrogenic systemic fibrosis in
association with the use of gadobenate dimeglumine at the time of
writing, more studies are warranted on this issue.
Another advantage of a fractionated single dose is the possibility
to perform both rest and stress perfusion while waiting for LGE
imaging. This approach reduces the overall examination time and
do not need additional contrast agent.
A limitation of our study is the observer-depending method for
placing the ROI used to calculate the CNR. However, the repro-
ducibility assessment showed that intraobserver variability is quite
small and CNR measurement is well reproducible.
An objective limitation of our study was the use of only a four-
channel radiofrequency coil. Nowadays 32- or 64-channel coils are
commercially available and 128-channel coils are under evalua-
tion. These coils allow a considerable increase in signal-to-noise
ratio and enhance the use of parallel imaging strategies [31–35].
Another limitation of our study is the use of a 1.5-T magnet. Many
recent studies have shown an increase of both signal-to-noise ratio
and CNR between infarcted and non-infarcted myocardium using
3-T scanners [36–38]. However, these studies reported mean CNR
between infarcted myocardium and non-infarcted myocardium
ranging from 12 to 32, less than the value we measured with both
protocol A (44.7) and B (52.1); moreover, the authors have not
assessed the CNR between infarcted myocardium and LV cavity. A
Page 6
Please cite this article in press as: Secchi F, et al. Optimizing dose and administration regimen of a high-relaxivity contrast agent for myocardial
MRI late gadolinium enhancement. Eur J Radiol (2010), doi:10.1016/j.ejrad.2010.06.040
ARTICLE IN PRESS
G Model
EURR-4860; No. of Pages 7
F. Secchi et al. / European Journal of Radiology xxx (2010) xxx–xxx 7
minor limitation of our study was the small number of patients who
resulted in a relatively large 95% CI of the maximum CNR between
infarcted myocardium and LV cavity.
5. Conclusion
In conclusion, our study demonstrate that, for myocardial
LGE at 1.5 T, a gadobenate dimeglumine dosage of 0.05 plus
0.05 mmol/kg separated by 10 min and imaging after other 10 min
produced a high contrast between infarcted myocardium and non-
infarcted myocardium and the highest contrast between infarcted
myocardium and LV cavity. For the combined differentiation of
infarcted myocardium vs the non-infarcted myocardium and vs the
LV cavity, this dosage and regimen of administration should be pre-
ferred to LGE imaging 10 min after injecting only 0.05 mmol/kg of
gadobenate, to LGE imaging 10 min after the unique administration
of 0.1 mmol/kg of gadobenate, and to LGE imaging 10 min after a
double injection of 0.1 mmol/kg plus 0.1 of gadobenate (separated
by 10 min). Finally, studies on LGE imaging at 15 or 20 min after
injection of 0.1 mmol/kg are warranted.
Conflicts of interest
Francesco Sardanelli is a consultant of Bracco Imaging SpA
(Milan, Italy).
Acknowledgement
This study was supported by Bracco Imaging SpA (Milan, Italy).
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