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Online Appendix for the following April 28 JACC article
TITLE: Cardiovascular Magnetic Resonance in Myocarditis: A JACC White Paper
AUTHORS: Matthias G. Friedrich, MD, Udo Sechtem, MD, Jeanette Schulz-Menger,
MD, Godtfred Holmvang, MD, Pauline Alakija, MD, Leslie T. Cooper, James A. White,
MD, Hassan Abdel-Aty, MD, Matthias Gutberlet, MD, Sanjay Prasad, MD, Anthony
Aletras, PHD, Jean-Pierre Laissy, MD, Ian Paterson, MD, Neil G. Filipchuk, MD,
Andreas Kumar, MD, Matthias Pauschinger, MD, Peter Liu, MD, for the International
Consensus Group on Cardiovascular MR in Myocarditis
APPENDIX
CMR Protocol Recommendations
Recommendations are based on the current evidence as published in peer-reviewed
literature as of January 2009.
Steady-State-Free-Precession sequences (SSFP)
Multiple studies have shown that SSFP sequences provide a consistent, good image
quality for cine studies and thus should be used routinely for function, morphology and
assessment of pericardial effusion. Data for normal values are published elsewhere (1–3).
The rectangular field of view (FOV) should be as small as possible and should be
rotated or used with oversampling to avoid wrapping. The matrix ideally should have
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equal to or more than 256  256 pixels, but lower values still may provide sufficient
spatial resolution. At least 25 phases per heartbeat should be acquired. The number of
slices must be sufficient to encompass the entire left ventricle including the left
ventricular outflow tract. Multiple short axis views are recommended. If three to six long
axis views rotating around the anatomical axis of the heart are used (4,5), three additional
short axis views are recommended.
Given the high signal-to-noise ratio, functional imaging can be optimized on
suitable systems by parallel imaging techniques with an acceleration factor of 2 or even
higher.
T2-weighted sequences (edema)
Currently, most of the experience in visualizing myocardial edema has been reported for
a T2-weighted short-TI triple-inversion recovery prepared fast spin echo sequence
(STIR). The body coil (or a signal intensity correction algorithm) should be used to avoid
hardware-derived signal inhomogeneity. A slice thickness of at least 10mm is
recommended to maximize signal-to-noise ratio.
Images obtained in long axis slices (2-, 3-, and 4-chamber views) can be useful in
depicting the full extent of signal abnormality and to confirm the findings in short axis
views. Findings suspicious of regional edema have to be confirmed in at least one
orthogonal plane.
More recently, two new T2-weighted, SSFP-based sequences for cardiac
application have been published, either using T2 preparation (6) or a hybrid approach
with a spin echo pulse (7). Both appear to offer a more robust image quality, with the
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hybrid protocol providing a similarly high contrast-to-noise ratio as STIR. Because of
their T2 properties, these sequences can be used for visualizing regional edema. Due to a
lack of data, however, they cannot be generally recommended at this time for the
normalized quantitative signal intensity evaluation using the published threshold values.
Early myocardial gadolinium enhancement (hyperemia, capillary leakage)
Data on the early phase of gadolinium-DTPA washout have to be obtained over an
extended period within the first 5 minutes after injection. The best way to achieve this is
to start scanning about 10 seconds after injection (i.e. after the first pass) and obtaining
the bulk of (contrast) data during the first 3 minutes after gadolinium injection.
“Snapshots” at any singular time point obtained by breath-held sequences do not provide
reproducible values and thus are not recommended.
For myocardial EGE, a standard fast spin echo sequence should be applied, using
parameters which provide sufficient T1 weighting (see Table 6 of paper). An echo train
length of less than 4 is desirable to maximize T1 weighting. It is of paramount
importance to ensure identical imaging parameters between pre- and post-gadolinium
data acquisition. Thus, auto-shimming and other pre-scan algorithms have to be
deactivated for the post-gadolinium acquisition.
In many patients, localized regions with very high signal intensity can be
observed, indicating focal inflammation (8). Nevertheless, quantitative evaluation of the
global myocardial EGEr of myocardium relative to skeletal muscle should be performed.
An enhancement ratio of 4.0 or higher indicates myocardial inflammation.
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As for T2-weighted imaging, the body coil or effective signal intensity correction
software have to be used. If image quality in short axis views is suboptimal, axial views
with generally lower noise levels can be used instead. Skeletal muscle tissue should be in
the visible field of view for SI normalization.
Late gadolinium enhancement (LGE)
Most centers routinely performing cardiovascular MR imaging have established
experience with inversion-recovery LGE imaging. Various techniques now exist for
image acquisition, including single-shot inversion recovery-SSFP, phase-sensitive
inversion recovery and 3-dimensional acquisition. In this consensus statement we
recommend the use of a conventional 2-dimensional, breath-held, segmented gradientecho inversion recovery pulse sequence.
As for imaging myocardial infarction, the inversion time has to be carefully
selected. Presumably normal myocardium should appear with very low signal intensity to
allow for sensitive detection of areas with increased gadolinium accumulation. Starting at
200-275 ms (range varies between MRI system-specific protocols), the TI may require
small incremental adjustments (i.e., increase of 10 to 20 ms) throughout the course of
imaging due to the washout kinetics of gadolinium. Technologists and physicians should
be aware of the gadolinium washout kinetics and the resulting increase of the optimal TI
over time (for more details we refer to Kim et al. [9]).
Fat saturation pre-pulses may be helpful for discriminating epicardial fat from
subepicardial layers of necrosis or fibrosis.
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The field of view should be reduced and rotated to maximize spatial resolution
while minimizing “wrap” artifact. In addition, the number of segments (lines of k-space)
to be acquired for each TR should be adjusted for extremes in heart rate. At high heart
rates this number should be reduced to minimize motion artifacts, and the trigger should
be increased to every 3rd cardiac cycle to allow for adequate T1 recovery. At lower heart
rates the number of segments can be increased to reduce the duration of breath-holds.
Difficulty nulling the myocardium should prompt the use of a TI scout when this
sequence is available, as it allows selection from a range of images obtained at various TI
times. However, it should be recognized that the optimal TI seen on a SSFP TI scout
sequence might differ from the optimal TI when using a gradient echo sequence.
Alternatively, a segmented phase-sensitive inversion recovery sequence may be used,
eliminating the need for accurate TI prescription.
Findings suspicious of focal/regional injury/fibrosis have to be confirmed in at
least one orthogonal plane.
If patients are unable to hold their breath adequately, three measurements should
be acquired during shallow breathing and averaged. Alternatively, a single-shot IR-SSFP
pulse sequence can be used during free breathing although sensitivity may be reduced.
Regarding quantitative signal intensity evaluation, there is theoretical concern that
results from any such analysis may vary between MRI systems. The threshold values,
however, derive from signal intensity ratios and are normalized to a skeletal muscle
reference region; this would be expected to factor out machine-specific variables (as well
as patient-specific variables related to gadolinium bolus circulation). It is therefore
assumed that the threshold values are generally applicable across different MRI systems.
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If new findings to the contrary should emerge in the future, this information will be
incorporated into future updates.
Detailed CMR protocol implementation
The following recommendations do not necessarily present the exact CMR protocol in all
centers of the Consensus Group. As described in the main text, several pulse sequences
may be available for evaluating each of the three tissue markers. The following is an
explicit outline of a basic protocol that uses widely available pulse sequences in order to
help to set up the sequences and optimize image quality.
Table 9 of the paper summarizes the recommended imaging parameters.
Positioning/setup
When setting up for a myocarditis study, the left arm should be positioned as close to the
left chest wall as possible in order to be able to use the left biceps muscle for a more valid
skeletal muscle reference ROI if necessary in elderly patients where the chest wall /
paraspinal muscles may be substantially atrophied, or in obese patients in whom these
muscles may be co-localized with fat.
If a strip is used to secure an anterior coil element, it should run on the outside of
the arm, and the patient should be asked to shift sideways towards the right as far as
possible inside the scanner to make room to insert a thick padding between the lateral
surface of the left arm and the side-wall of the magnet. This minimizes image and signal
distortion in the left arm by avoiding the extreme edge of the useful field of view along
the sidewall of the magnet bore.
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The patient may ideally be connected to a power injector for efficient remote
administration of the gadolinium infusions.
All images should be acquired using a cardiac phased array surface coil, except
those series where quantification of myocardial signal intensity will be referenced to that
of skeletal muscle (conventional T1 spin echo series for global relative enhancement, and
T2 TSE series for T2 signal intensity ratio). For the latter sequences the body coil should
be used because of its uniform sensitivity profile.
Scanning
Localized shimming is recommended over the heart, particularly for the SSFP-based
sequences, except in the presence of major field inhomogeneity, such as associated with
metallic sternal wires.
Localizers
The initial acquisition is a 3-plane localizer (e.g. SSFP) in sagittal, axial and coronal
planes. The field of view should be sufficiently large (approx. 44 cm) to visualize the full
superior-to-inferior coverage of the coils in the sagittal images, and to include the left
upper arm in the coronal images. The center of the acquisition is shifted towards anterior
and left, so that the coronal stack will include the left upper arm posteriorly, through the
right ventricle anteriorly. A sufficient number of images should be obtained in each
orientation for adequate coverage so that useful landmarks will not be missed. The
localizer images should be acquired during breath-holds at normal end-expiration
(functional residual capacity) to allow these images to be used later for accurate graphic
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prescription of the free-breathing conventional T1 spin echo series. Normally, the scanner
should pause following each of the three scan planes, to allow the patient to breathe in
between data acquisitions. If the sagittal image stack shows that the left ventricle is not
well centered in the range covered by the surface coils, the patient is repositioned in the
superior-to-inferior direction as necessary and the 3-plane localizer is repeated.
Localizer images for standard anatomical axes of the left ventricle can be obtained
by either real-time sequences or SSFP cine localizers. Using an axial view of the left
ventricle, the vertical long axis of the heart is best determined by a parasagittal
midventricular line crossing the center of the mitral ring and the apex. The resulting
image allows for defining the horizontal long axis (again represented by a perpendicular
plane crossing the center of the mitral ring and the apex). On this horizontal long axis a
set of true short axis views is prescribed, which can be used to plan additional long axis
views (3 or more).
Cine series
Typically, a stack of short axis SSFP cines is acquired at 1 cm intervals through the
ventricles for quantitative assessment of ventricular size, morphology and function. Long
axis views can be used if there is no evidence for regional wall motion abnormalities in at
least three short axis views.
One or two slices are added to the stack at the base of the LV as necessary to
include one slice on the atrial side of the mitral annulus (in order to verify that the full
extent of the LV has been covered, and to identify any major degree of mitral
regurgitation). The slice acquisition order is from base to apex in order to include the
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high-flow regions of the LVOT / RVOT, A-V valves and great vessels in the initial
slices, thereby allowing assessment of the severity of any flow-related motion artifacts
and the possible need for center-frequency shifting to “clean up” the images, before the
whole LV function cine data set is acquired. For parallel imaging, a calibration sequence
may be required.
The slice positions for the short axis cines will be copied to the T2 and LGE
series, so that the slice locations for all these series will match.
T2-weighted images
T2-weighted turbo spin echo images are recommended with or without fat suppression in
the short axis view at 1 cm intervals through the left ventricle (body coil acquisition, TE
approximately 65ms,TR 2 R-R intervals, Echo Train Length 24, y-resolution 160 or
higher, slice thickness 8-15 mm with gap 0 to 2 mm). Optionally, a dual echo turbo spin
echo sequence may be used with TE 2 of about 120ms (echo train length 28). Whereas
the first TE = 65ms echo matches the parameters used in the literature for validation of
the T2 ratio, the 2nd TE of 120ms echo provides better T2 weighting for better contrastto-noise ratio between regions with edema and normal myocardium.
The short axis T2-weighted TSE image through the base of the left ventricle is
reviewed for the presence of an adequate cross-section through skeletal muscle for later
placement of a reference ROI. If a satisfactory reference region is not available, the
initial T2 TSE image is used to revise the graphic prescription by shifting the field of
view more off-center towards the left shoulder to include a suitable sample of chest wall /
left shoulder / left upper arm skeletal muscle, adjusting the size of the field of view as
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necessary. All the diagnostic sequences are acquired during breath-holds in either
inspiration or expiration. During the initial acquisition(s) the patient is evaluated for
ability to perform a steady breath-hold, with encouragement to “reach” a bit towards
his/her breath-hold maximum. If it becomes necessary to shorten the acquisition time
due to breath-hold limitations, the number of y-lines may be reduced down to 160,
parallel imaging can be added using a low acceleration factor of 1.25 (higher
accelerations cost signal-to-noise), or the echo train may have to be lengthened.
The initial T2 TSE image(s) are also evaluated for signal-to-noise ratio and
cardiac motion-related image degradation. If the myocardial signal is too low in the 2nd
echo (more likely to occur if the heart rate is fast and TR of 2 R-R intervals is short), the
TE of the 2nd echo can be reduced to 100 ms. With a shorter TE, the echo train can also
be shortened to 24 or even 16 (requires single echo); the resulting shorter acquisition
window in the cardiac cycle will reduce cardiac motion-related image blurring at faster
heart-rates without undue lengthening of the breath-hold duration (the scan finishes more
quickly at faster heart rates). Attention should also be paid to the timing of the echo train
in mid-diastole, in order to limit encroachment onto the P-wave / atrial kick that follows.
Such encroachment is more likely to occur if the heart rate speeds up and the cycle length
shortens during the breath-hold.
The long axis cine images should be reviewed to
determine the earliest moment in diastole at which the early diastolic rapid filling phase is
complete. This time point then defines the trigger delay for the start of the TSE echo
train. At fast heart rates, when there is no mid-diastolic i.e. “quiet” period”, or in the
presence of premature beats or atrial fibrillation, image quality may be improved by
shifting the read-out to systole, so that the echo train finishes at the time of mitral valve
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opening. On some MRI systems, the black blood double-IR inversion time for blood
suppression needs to be set 11 ms shorter than the trigger delay for the echo train.
Adjusting the inversion time to a value that is slightly different from the systemrecommended setting (which is calculated based on the T1 of blood and the patient’s
actual heart rate), has little visible impact on how dark the blood appears in the final
image.
Using a long axis cine, with the inferior A-V groove as the landmark, the
excursion of the mitral annulus can be measured from the point of maximum filling of the
left ventricle at end-diastole after the atrial kick, to the annulus position at the time of the
trigger delay for the TSE read-out at the end of the early diastolic rapid filling period, as
defined above. The width of the slice-selective 180º re-inversion part of the black-blood
double-inversion-recovery prep pulse is adjusted if necessary to be no less than 2 times
this distance. This will prevent artifactual attenuation of myocardial T2 signal intensity
(resulting in an invalid calculated T2 ratio) in the basal short axis slices due to throughplane motion of myocardium which may have received only the initial (non-selective)
180 degree inversion pulse.
After all the above adjustments have been made as
appropriate, the stack of T2 TSE images is resumed and completed, one slice per breathhold.
Early myocardial gadolinium enhancement
The T1-weighted turbo spin echo images (echo train = 2) for quantification of myocardial
EGEr should be acquired during quiet, regular, shallow breathing prior to, and repeated
immediately following IV infusion of 0.1 mmol/kg of gadolinium (recommended
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injection rate 2-4 ml/sec, followed by 15 to 25ml of normal saline). The scan plane may
be prescribed on a coronal localizer image (with cross-reference to a paraseptal long axis
cine), as oblique axial slices that are tipped inferiorly towards the left, into alignment
with the inferior wall of the left ventricle. This will make the overall orientation of the
slices less oblique to the LV wall as compared to straight axial slices, thereby reducing
volume averaging effects when drawing the ROIs, particularly around the apex. The
field of view should be shifted to the left and adjusted in the anterior-posterior dimension
as well, to cover the range from the anterior AV groove out to include the left upper arm.
The short axis view used for the T2-weighted TSE images, with skeletal muscle included
in the pectoral muscle or left shoulder regions, is an alternative scan plane for the T1weighted spin echo images, but tends to be less robust in terms of image quality. The
slice thickness is 7 to 10 mm with gap 1-2 mm. 128 y-lines and 4 signal averages are
recommended, and the acquisition order of the oblique axial slices is from inferior to
superior through the left ventricle.
A double-oblique spatial saturation band is positioned over the atria to saturate the
atrial blood before it flows into the ventricles. The leading edge of this saturation band is
oblique, parallel to the line between the tricuspid annulus at the anterior AV groove and
the mitral annulus at the posterior AV groove, as visualized in a mid-ventricular slice
from the axial localizer series. This edge of the sat band is also tilted so as to be
superimposed on the mitral orifice / annulus in the orthogonal para-septal long axis view,
using a cine frame at end-diastole in order to avoid saturation of myocardium at the base
of the left ventricle. The width of the saturation band is adjusted to cover the atria while
avoiding the paraspinal muscles if possible (to preserve a potential skeletal muscle
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reference region). All the axial, coronal and long axis cine localizers used for planning
the T1 spin echo images should be acquired at end-expiration, for accurate placement of
the oblique axial slices and of the atrial saturation band.
At the completion of the post-gadolinium T1 spin echo series, an additional bolus
of 0.1 mmol/kg of IV gadolinium is infused, followed by 25ml of normal saline for a total
gadolinium dose of 0.2 mmol/kg. This starts the clock for the 5 to 10 min interval before
the LGE images are obtained. For time efficiency reasons, during this interval the cine
acquisition for function can be acquired (see above).
Standard spin echo protocols with respiratory compensation algorithms may be
used for heart rates above 90 beats per min.
Late enhancement
The final image set in the myocarditis protocol is the LGE series. The 2D IR-prepared
gradient echo sequence is currently the most reliable for image quality and is therefore
recommended. The short axis prescription and field of view are copied from the cine
data set, and the slices will therefore match both the cines and the T2-weighted TSE
images. The slice thickness should be 8 to 10 mm, gap 0 to 2 mm, matrix size 256 x 224
or 192 with 12-16 views / segment gated to every 2nd heartbeat. By acquiring the images
in late systole (typically around 300 ms), motion-related artifacts are minimal, image
degradation related to premature beats is minimized, systolic thickening makes it easier
to appreciate transmural detail across the myocardial wall, and the total number of slices
(breath-holds) needed to cover the ventricle may be reduced (due to shortening of the
base-to-apex dimension of the LV during systole). By reviewing the stack of short axis
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cines for the most basal slice that shows LV myocardium in late systole, and by crossreferencing the graphic prescription to a frame with trigger delay close to end-systole in
the paraseptal cine series, the first slice in the delayed enhancement series can be
positioned accurately at the base of the LV myocardium.
A series of LGE test images or a TI scout sequence may be performed at a midventricular slice to identify the optimal inversion time (TI) for nulling normal
myocardium. If the nulling is sub-optimal, TI should be incremented by 20ms steps up or
down and the test image is repeated until complete nulling of the myocardium is
achieved. Acquisition should be gated to every 2nd heartbeat.
The different MRI
manufacturers use slightly different definitions for how the TI is measured, and the
optimal TI for comparable scan parameters may therefore differ slightly from system to
system. As the LGE images are acquired, one slice per breath-hold, it will likely become
necessary to increase TI by at least 10ms but more often by 20ms one or more times
before the image stack is complete, in order to maintain optimal nulling of the
myocardium as the gadolinium washes out and myocardial T1 lengthens.
Late enhancement images can also be obtained as 3D acquisitions during breathholding or during free breathing with respiratory navigator gating, although these images
are more vulnerable to motion-related and other artifacts. In breath-hold mode the basal
and apical ½ of the LV are best acquired separately. In free-breathing mode the scan
times may become lengthy depending on heart rate and the efficiency of the navigator
gating, particularly if the scan needs to be repeated with a different TI. “Single shot”
SSFP acquisitions with an inversion-recovery pre-pulse can be particularly helpful for
LGE imaging in patients who are unable to perform adequate breath-holds, or in whom
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image quality is limited by arrhythmia-related degradation. Any LGE findings in the
short axis view should be confirmed in an orthogonal long axis view through the lesion.
Quantitative Signal Intensity Analysis
Certified software should be used to analyze LV function and tissue characteristics.
Before a quantitative signal intensity analysis of tissue characteristics, the use of a body
coil or of a functional signal intensity coil correction algorithm for image acquisition
should be verified. Contours should include as much tissue as possible, excluding
adjacent areas such as fat, fluid, artifactual areas or intraventricular lumen. Skeletal
muscle signal intensity should be measured in regions as close as possible to the heart to
ensure similar field and reception conditions (Figure 3 of the paper).
For images with less than optimal quality, contours should be copied from other
images in the same slice location, e.g. SSFP-derived cine still frames of the same
contraction phase. Figure 3 shows a screenshot of a T2-weighted image with contours for
skeletal muscle and myocardium.
The T2 ratio is calculated as follows:
T2 ratio = Signal intensitymyocardium/Signal intensityskeletal muscle
T
he Early Enhancement Ratio is calculated by the following formula:
Early gadolinium enhancement ratio = Enhancementmyocardium/Enhancementskeletal muscle
The enhancement of myocardium and skeletal muscle regions of interest for being used
for the formula above are calculated by:
Enhancement= (Signal intensitypost gadolinium - Signal intensitypre gadolinium)/Signal intensitypre gadolinium
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