HHS Public Access

Author manuscript
JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
Author Manuscript

Published in final edited form as:

JACC Cardiovasc Imaging. 2018 December ; 11(12): 1758–1769. doi:10.1016/j.jcmg.2017.09.021.

Dark-Blood Delayed-Enhancement MRI of Myocardial Infarction

Han W Kim, MD1,2, Wolfgang G Rehwald, PhD4, Elizabeth R Jenista, PhD1,2, David C
Wendell, PhD1,2, Peter Filev, MD1, Lowie van Assche, MD1, Christoph J Jensen, MD1,
Michele A Parker, MS1,2, Enn-ling Chen, PhD1,2, Anna Lisa C Crowley, MD1,2, Igor Klem,
MD1,2, Robert M Judd, PhD1,2,3, and Raymond J Kim, MD1,2,3
1Duke Cardiovascular Magnetic Resonance Center, Duke University Medical Center, Durham,
North Carolina USA
Author Manuscript

2Division of Cardiology, Duke University Medical Center, Durham, North Carolina USA
3Department of Radiology, Duke University Medical Center, Durham, North Carolina USA
4Siemens Medical Solutions, 51 Valley Stream Pkwy, Malvern, Pennsylvania, USA

Abstract
Objective—To introduce and validate a novel flow-independent dark-blood delayed-
enhancement MRI technique (FIDDLE) that depicts hyperenhanced myocardium while
simultaneously suppressing blood-pool signal.

Background—The diagnosis and assessment of myocardial infarction (MI) is crucial in

determining clinical management and prognosis. Although delayed-enhancement-MRI (DE-MRI)
Author Manuscript

is an in-vivo reference standard for imaging MI, an important limitation is poor delineation
between hyperenhanced myocardium and bright LV cavity blood-pool, which may cause many
infarcts to become invisible.

Methods—A canine model with pathology as the reference standard was used for validation
(n=22). Patients with MI and normal controls were studied to ascertain clinical performance
(n=31).

Results—In canines, FIDDLE was superior to conventional DE-MRI for the detection of MI
with higher sensitivity (96% vs 85%, p=0.002) and accuracy (95% vs 87%, p=0.01) with similar
specificity (92% vs 92%, p=1.0). In infarcts that were identified by both techniques, the entire
length of the endocardial border between infarcted myocardium and adjacent blood-pool was
visualized in 33% for DE-MRI compared with 100% for FIDDLE. There was better agreement for
Author Manuscript

FIDDLE-measured infarct size than for DE-MRI infarct size (95% limits-of-agreement, 2.1%

Correspondence, Raymond J. Kim, MD, Duke Cardiovascular Magnetic Resonance Center, DUMC-3934, Durham, NC 27710, (919)
668-3539, (919) 668-3554(FAX), raymond.kim@duke.edu.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may be
discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Disclosures
Drs. R.J. Kim and R.M. Judd are inventors on a US patent on delayed-enhancement MRI owned by Northwestern University. Dr. R.J.
Kim is an inventor on a US patent on flow independent dark-blood delayed enhancement MRI owned by Duke University. Dr. W.
Rehwald is employed by Siemens Medical Solutions. The other authors report no conflicts.
 Kim et al. Page 2

versus 5.5%, p<0.0001). In patients, findings were similar; FIDDLE demonstrated higher accuracy
Author Manuscript

for the diagnosis of MI (100% [95% CI: 89–100%] versus 84% [66–95%], p=0.03).

Conclusions—We introduce and validate a novel MRI technique that improves the
discrimination of the border between infarcted myocardium and adjacent blood-pool. This dark-
blood technique provides superior diagnostic performance than the current in-vivo reference
standard for the imaging diagnosis of MI.

Keywords
myocardial infarction; diagnosis; infarct size; magnetic resonance imaging

INTRODUCTION
Myocardial infarction (MI) is the leading cause of congestive heart failure and death in the
Author Manuscript

industrialized world. Detection of MI is essential, since even small infarcts are associated
with worse prognosis,1 and there are proven therapies that can improve outcome. Even when
the diagnosis of MI is known, assessment of the size, location, and transmural-extent of
infarction is important for patient management decisions, such as whether to undergo
coronary revascularization, resynchronization therapy, or cardioverter-defibrillator
implantation.2

Delayed-enhancement MRI (DE-MRI) is considered to be the in-vivo reference standard for

imaging MI, given its ability to generate high resolution spatial maps of infarcted and viable
myocardium. Accordingly, it is increasingly being used in clinical practice and in
randomized trials evaluating novel MI treatments to provide a measure of therapeutic
efficacy.2
Author Manuscript

One important limitation of DE-MRI, however, is that infarcted myocardium and the LV
blood-pool often hyperenhance to a similar degree following contrast media administration.3
Hence, infarcted myocardium may be hidden when immediately adjacent to the LV cavity
since there is poor delineation between bright tissue and bright blood-pool. This may explain
why a recent multicenter trial evaluating the performance of DE-MRI demonstrated that up
to 21% of infarcts may be missed in select patient cohorts (i.e. those with non-Q-wave
chronic MI).4

Traditional “black-blood” MRI techniques provide improved delineation of tissue by

suppressing signal from adjacent blood-pool.5 However, these techniques depend upon the
long T1 of blood (~2secs at 3T) and sufficient blood flow within this time period to generate
black-blood images. Hence, traditional techniques are not designed to work after contrast
Author Manuscript

administration (which greatly shortens blood T1) and cannot be used to provide contrast-
enhanced, black-blood images of tissues.

In this study, we introduce a novel Flow-Independent Dark-blood DeLayed Enhancement

technique (FIDDLE) that allows visualization of tissue contrast-enhancement while
simultaneously suppressing blood-pool signal. We validate FIDDLE in an animal model of
MI and demonstrate its clinical performance in patients.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 3

METHODS
Author Manuscript

FIDDLE
The pulse sequence timing diagram and evolution of longitudinal magnetization for different
tissue components are shown in Fig 1.6,7 The primary components are: (1) a preparatory
module that affects the magnetization of myocardium differently than blood, (2) an
inversion-recovery pulse (IR), (3) phase-sensitive reconstruction, and (4) an inversion time
(TI) selected such that blood magnetization is less than tissue.

Because the magnetization of blood is made more negative than normal myocardium (i.e.
blood Mz < myocardial Mz, “Black-Blood Condition”), phase-sensitive reconstruction
renders blood in the cardiac chambers darker than myocardium by remapping the
magnetization to positive-only values. As a result, a precise TI is not needed to make the
blood black—rather, a range of TIs can be used, so long as the magnetization of blood is
Author Manuscript

more negative than that of myocardium (Fig 1).

Pilot Study
Theoretically, any pulse that affects the magnetization of myocardium differently than blood
can be used as the initial preparatory module.8 We chose a magnetization-transfer (MT)
module, and performed a pilot study prior to the main investigation in a canine model. The
pilot study involved two parts: first, empiric data were acquired in-vivo to characterize the
effects of the MT-prep module on the magnetization of normal myocardium, infarcted
myocardium, and blood-pool; and second, the data from these in-vivo experiments were
used to simulate the effects of TI on the signal intensity of these tissues.

For the pilot in-vivo experiments, the animal preparation was the same as for the main study
Author Manuscript

(details below) but performed in a separate cohort of canines. Imaging was performed 15
minutes after intravenous gadoversetamide (0.15mmol/kg) administration using an MT-prep
module (a train of gaussian radiofrequency pulses each 5.12ms in duration) that was
immediately followed by a single-shot steady-state free-precession (SSFP) readout. The
effects of MT-prep train length (1–20 repetitions in steps of 1), flip angle (200°–900° in
steps of 50°), and off-resonance frequency (200–1500Hz in steps of 100Hz) on tissue
magnetization were measured.

Simulations were then performed in MATLAB (MathWorks). The effects of readout pulses,
diffusion, and imperfections in the inversion pulse were assumed to be negligible. The
longitudinal magnetization following the MT-prep and IR-pulse for a given tissue species (a)
as a function of time (t) was expressed as:
Author Manuscript

Ma(t) = M0, a − [MTeff + M0, a] exp( − t/T1, a) (1)

where M0,a is the equilibrium magnetization of each tissue species, MTeff is the signal
immediately after the MT-prep (based on the canine data), and T1,a is the T1 of the species.
T1 values of 410ms, 630ms, and 440ms for infarct, normal myocardium (myo), and blood,
respectively, were used assuming typical conditions for delayed-enhancement imaging at 3T.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 4

9 Following phase-sensitive reconstruction, and assuming the black-blood condition

Author Manuscript

(Mblood(t) ≤ minimum {Mmyo(t), Minfarct(t)}), the signal of normal myocardial tissue (or
infarcted tissue) normalized to equilibrium magnetization was calculated as:

FIDDLEmyo (or infarct)(t) = [Mmyo (or infarct)(t) − Mblood(t)]/M0, myo (or infarct) (2)

Canine Protocol Overview and Pathology

Following optimization of the MT-prep module in the pilot study, the diagnostic
performance of FIDDLE was assessed with pathology as the reference standard. For both the
pilot and main investigation, the same canine model of MI was used. MI was produced by
occluding the left anterior descending coronary artery or the left circumflex artery (obtuse
marginal branch) under sterile conditions after a thoracotomy. To investigate a wide range of
Author Manuscript

infarct sizes and transmurality, we employed a range of occlusion times (40—90 minutes)
followed by reperfusion.10 As a point-of-reference, a 40-minute occlusion in the canine
model leads to a subendocardial infarct that averages 38% transmural.11 The care and
treatment of canines followed the Position of the American Heart Association on Research
Animal Use.12 The protocol was approved by the Duke University Institutional Animal Care
and Use Committee.

Following MRI, the heart was removed, and the infarcted region was confirmed using
histochemical staining.13

MRI
MRI was performed at a range of time-points following MI to test if infarct age might affect
Author Manuscript

the performance of FIDDLE. The range was 2 days to 7 months with 14 scanned within the
first 2 weeks, and 8 after two weeks (median 14 weeks). Images were acquired on a 3T
Siemens Verio during ventilated breathholds. DE-MRI and FIDDLE were performed
immediately after one another in random order using matched parameters (e.g. slice
thickness, 7mm; in-plane spatial resolution, 1.2×1.0mm; temporal resolution, 180ms; TR, 2
R-R intervals; breathhold time, 8–10s) 15 minutes after intravenous gadoversetamide
(0.15mmol/kg) administration.

A segmented, inversion-recovery gradient-echo sequence was used for DE-MRI, with TI

manually selected to null signal from normal myocardium.4 FIDDLE consisted of an MT-
prep module and IR-pulse followed by a segmented SSFP readout (TE, 1.36ms; flip angle,
50°; bandwidth 975Hz/pixel; averages, 2). The parameters for the MT-prep module were
selected based on the findings from the pilot study (train length, 19; flip angle, 500°; offset
Author Manuscript

frequency, 800Hz). The TI was manually selected to render blood black and maximize
image contrast between infarcted and normal myocardium. This was performed by selecting
the longest TI (typically 200–280ms) that still resulted in black-blood. A complete short-axis
stack of DE-MRI and FIDDLE images were obtained.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 5

Image Analysis
Author Manuscript

Pathology slices were registered with MR images using myocardial landmarks. Pathology,
FIDDLE, and DE-MRI studies were read separately, blinded to other data. Window and
level for MRI images were preset so that noise was still detectable and infarcted regions
were not over-saturated.14 The presence of MI was determined by visual inspection. Image
were also examined to determine if the entire length of the infarct subendocardial border
could be discriminated from the adjacent blood-pool. Infarct size (%LV mass) was measured
by planimetry of the stack of short-axis pathology and MR images. The transmural-extent of
infarction was expressed as percent myocardial sector area on a slice-by-slice basis.10
Measurements were performed at our core laboratory which undergoes regular audits and
testing for quality assurance (e.g. inter- and intraobserver agreement of infarct size
demonstrates a bias of 1.0% and −0.1%, respectively with a standard deviation of differences
of 2.6% and 0.8%, respectively).
Author Manuscript

Patients
Patients presenting with history of MI were recruited prospectively. The diagnosis of MI was
based on the Universal Definition. Patients <18 years old or with history of multiple infarcts
were excluded. Consecutive patients who underwent coronary angiography during
admission for MI with clear culprit infarct-related-artery, and who agreed to participate were
enrolled. The control group consisted of subjects without known coronary disease and with
low probability for developing disease over the next 10 years (lowest Framingham risk
score: 1% for women, 2% for men).15 All participants gave written informed consent, which
was approved by the Duke University Institutional Review Board.

The MRI protocol was the same as in canines, and the same sequences were used with
Author Manuscript

similar settings. However, to test the generalizability of FIDDLE, half of the patients were
scanned at 3T and half at 1.5T. FIDDLE and DE-MRI were performed using matched
parameters (3T: slice thickness, 6mm; in-plane spatial resolution, 1.7×1.3mm; temporal
resolution, 180ms; TR, 2 R-R intervals. 1.5T: slice thickness, 8mm; in-plane spatial
resolution, 1.9×1.4mm; temporal resolution, 180ms; TR, 2 R-R intervals). FIDDLE
incorporated 2 averages, however, the breathhold time was the same as for DE-MRI (~8–
10sec) since FIDDLE utilized an SSFP readout with twice the k-space lines per segment (59
vs 29). The MT-prep parameters were similar at 3T (train length, 19; flip angle, 500°; offset
frequency, 800Hz) and 1.5T (train length, 19; flip angle, 500°; offset frequency, 600Hz).

Images were obtained 15 minutes after intravenous gadoversetamide (0.15mmol/kg)

administration in multiple short-axis (every 10mm throughout the LV) and 3 long-axis
views. MRI analysis was the same as for canines, and FIDDLE and DE-MRI were
Author Manuscript

interpreted independently, masked to patient identity and clinical information. Additionally,

MR images were scored on a 17-segment model to determine the infarct location. Coronary
angiograms, in patients with MI, were read blinded to all other information and analyzed in
order to localize the perfusion territory of the infarct-related-artery on a 17-segment model.4
MR localization of infarction was categorized as correct or incorrect based upon the match
with the infarct-related-artery perfusion territory on coronary angiography, as previously
described.4

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 6

Specific Absorption Rate (SAR)

Author Manuscript

All scans were performed under strict adherence to FDA guidelines for SAR (<4 W/kg
averaged over the whole body for any 15-minute period). The vendor calculated whole body
SAR was collected from the DICOM header.

Contrast-to-Noise Ratio (CNR)

A separate group of patients—all with a clearly identifiable infarct on conventional DE-MRI
— were recruited in order to measure infarct-to-normal myocardium CNR. Both FIDDLE
and DE-MRI images were obtained and then reconstructed directly in SNR units.16 CNR
was calculated by subtracting the SNR from manually drawn regions-of-interest on the SNR
scaled image reconstructions.

Statistical Analysis
Author Manuscript

Continuous data are presented as mean±SD or as median and interquartile range as

appropriate. McNemar’s test was used to compare the diagnostic performance of methods.
Linear regression analysis was used to compare the relationships between infarct size by
MRI and pathology, accounting for measurements from the same subject. Bland–Altman
analysis was performed to assess the agreement between MRI and pathology measurements
but modified to use the pathology measurements as the reference. Statistical tests were 2-
tailed; P<0.05 was considered significant. SAS (Cary, NC) was used to perform the
analyses.

RESULTS
Pilot Study
Author Manuscript

The effects of the MT-prep parameters on in-vivo tissue signal were measured in 8-canines
with 1-week old MI. Increasing train length, increasing flip angle, and decreasing off-
resonance frequency reduced signal intensity for all tissues (Fig 2a). However, the effect was
substantially increased for myocardium compared with blood. Differences were negligible
between normal and infarcted myocardium.

These data were then used to model the signal behavior of FIDDLE (Fig 2b). These
simulations show: (1) blood-pool signal is nulled (i.e. black-blood condition is met) over a
wide range of MT-prep train lengths and inversion times (red arrows); (2) Infarct signal is
high over a wide range, leading to a large difference in signal between infarcted myocardium
and blood, and (3) when blood-pool signal is nulled, longer inversion times lead to increased
signal differences between normal and infarcted myocardium.
Author Manuscript

Canines
The performance of FIDDLE was assessed in 22 canines. Data from all canines surviving
surgery were included. Examples of in-vivo MRI are shown in Fig 3a. In subjects 1–3,
hyperenhanced regions are visible on DE-MRI and appear to match the infarcted regions by
pathology (blue arrows). In subjects 4–5, the exact border between hyperenhanced
myocardium on DE-MRI and the bright LV cavity blood-pool is not always clear. In
contradistinction, for all 5 subjects, hyperenhanced regions are clearly visible on FIDDLE

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 7

and the complete borders are easily distinguished from adjacent blood-pool and normal
Author Manuscript

myocardium. Moreover, the shape and contour of hyperenhancement on FIDDLE closely

resembles the infarcted regions by pathology.

Fig 3b shows comparisons in one subject at multiple short-axis locations. Pathology

demonstrates a small subendocardial infarct involving the inferoseptum and the
posteromedial papillary muscle, spanning from the base to the apex. The infarct is clearly
depicted by FIDDLE, but it is poorly visualized by DE-MRI on many short-axis locations.

Table 1 summarizes the diagnostic performance of FIDDLE and DE-MRI for the diagnosis
of MI compared to pathology (n=136 slices). Overall, sensitivity and accuracy for FIDDLE
(96% and 95%, respectively) were higher than that for DE-MRI (85% and 87%,
respectively). Specificity was similarly high for both). When only pathology slices with
≤25% transmural infarction were considered (n=87), sensitivity and accuracy remained high
Author Manuscript

for FIDDLE and were again significantly higher than that for DE-MRI (sensitivity: 98% vs
80%; accuracy: 95% vs 85%; p≤0.02 for both). Specificity remained 92% for both.

There was no relationship between infarct age and the diagnostic performance of FIDDLE.
Accuracy was 93% for ≤2-week-old MI and 97% for >2-week-old MI (p=0.35). In infarcts
that were identified by both techniques, the entire length of the endocardial border between
infarcted myocardium and adjacent blood-pool was visualized in 100% for FIDDLE
compared with 33% for DE-MRI. There was no evidence of “slow blood flow” artifacts in
the LV cavity in any of the FIDDLE images.

On a per subject basis, infarct size by FIDDLE (r=0.99) and DE-MRI (r=0.98) were highly
correlated with infarct size by pathology (Fig 4a). Bland-Altman analyses demonstrated that
the level of agreement was high for both comparisons with pathology (Fig 4b). However,
Author Manuscript

DE-MRI showed a small, but significant bias (−1.1%, p=0.001), whereas, FIDDLE showed
no bias (−0.01%, p=0.38). Additionally, 95% limits-of-agreement were larger for DE-MRI
(−3.9%, 1.6%) compared with FIDDLE (−1.1%, 0.9%).

Patients
We enrolled 31 subjects (20 with MI, 11 normal controls), all of whom successfully
completed MRI. No subject was excluded based on poor image quality. The SAR for
FIDDLE was 0.76±0.15W/kg at 1.5T and 1.97±0.27W/kg at 3T, and there were no issues
with exceeding FDA SAR constraints in any patient. Table 2 shows the baseline clinical
characteristics. Among patients with MI, 10 were imaged ≤2-weeks post-MI and 10 were
imaged >2 weeks post-MI (median 24 weeks). In all 20 patients with MI, the infarcted
region on FIDDLE matched the perfusion territory of the infarct-related-artery identified by
Author Manuscript

X-ray coronary angiography. There was no evidence of “slow blood flow” artifacts in the LV
cavity in any of the FIDDLE images.

Fig 5a shows typical images in MI patients in whom both FIDDLE and DE-MRI clearly
depicted infarcted regions. Fig 5b shows images in five patients (3 with MI, 2 controls
without MI) in whom the diagnosis of MI was ambiguous on DE-MRI. With FIDDLE,
patients with MI were easily discriminated from the controls.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 8

Overall, the diagnostic performance in patients was similar to that observed in canines
Author Manuscript

(Table 1), and there were no differences in the findings at 3T (n=15) versus 1.5T (n=16).
Accuracy was higher for FIDDLE than DE-MRI (100% vs 84%). Also there were trends
towards higher sensitivity (100% vs 85%) and higher specificity (100% vs 82%).

The CNR between infarct and normal myocardium was measured in 11 additional patients,
all of whom had a clearly identifiable infarct on DE-MRI. At 1.5T, the mean CNRs for DE-
MRI and FIDDLE were 11.0±5.8 and 9.5±3.5, respectively, reflecting a 14% loss on average
for FIDDLE. At 3T, CNRs were 11.3±4.1 and 10.1±2.6, respectively, representing a 10%
loss on average.

DISCUSSION
In this study, we introduce FIDDLE, a new MRI technique that allows visualization of
Author Manuscript

myocardial tissue contrast-enhancement while simultaneously rendering the blood-pool

black. FIDDLE was characterized in simulations and validated in a canine model of MI with
direct reference to pathology. The clinical performance of FIDDLE was demonstrated in
patients with documented MI and known coronary artery anatomy.

FIDDLE provided superior diagnostic performance compared with conventional DE-MRI,

the current in-vivo reference standard for the imaging diagnosis of MI. In canines, sensitivity
and accuracy were significantly higher for FIDDLE, while specificity was excellent for both
techniques. Findings were similar in patients, where FIDDLE had a diagnostic accuracy of
100% versus 84% for DE-MRI.

FIDDLE overcomes an important intrinsic limitation of conventional DE-MRI. Since

infarcted myocardium and adjacent blood-pool have comparable T1 values following
Author Manuscript

contrast media administration,9 image intensities are often similar on DE-MRI.3 As a result,
distinguishing hyperenhanced infarcted tissue from bright blood-pool may be difficult unless
the infarct is fully transmural or nearly so. This may explain why the diagnostic performance
of DE-MRI is reduced in some cohorts, such as patients with non-Q-wave MI who are more
likely to have infarcts that are subendocardial.4 Consistent with this notion, in the current
study when only subendocardial infarcts were considered, the sensitivity of DE-MRI
dropped to 80% whereas it remained high for FIDDLE at 98%.

Although this may suggest that the primary advantage of FIDDLE is in patients with small
infarcts, we observed that some infarcts missed by DE-MRI can be relatively large. An
example of such a case is shown in Fig 5b (patient 9), who had an infarct size of 14% of LV
mass as measured by FIDDLE. This demonstrates that an infarct can be extensive in the
Author Manuscript

circumferential direction but still be subendocardial and missed by DE-MRI.

Even when infarction was identified by DE-MRI, the data indicate that it was rare to
visualize the entire length of the MI endocardial border, in contradistinction to FIDDLE
images for which the entire border was always visualized. Hence, infarct size measurements
were more robust with FIDDLE than with DE-MRI; in comparison to pathology, there was
reduced bias and smaller 95% limits-of-agreement with FIDDLE.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 9

Several approaches for improving the discrimination of blood-pool and infarcted

Author Manuscript

myocardium have been proposed. Some are dependent on the motion of blood in the LV
cavity, either as bulk flow or diffusion.17 These techniques are limited in that “slow blood
flow” artifacts, which are bright and difficult to distinguish from subendocardial infarction,
are likely to occur in patients with ventricular dysfunction. Unlike these approaches,
FIDDLE employs a novel method which is not dependent on the movement of blood. In the
current study, there was no evidence of “slow blood flow” artifacts in any of the FIDDLE
images, including long-axis views. Nonetheless, it should be noted that inhomogeneities in
B1 and B0 may affect the uniformity of dark-blood preparation, particularly at 3T.

Other techniques have been proposed that are not dependent on blood flow. Liu et al.18
describe a technique that combines T2 and T1 weighting to improve the delineation between
infarcted myocardium and ventricular blood-pool. Peel et al.19 describe a method that uses a
dual IR-prepulse to suppress blood-pool signal. Although contrast between infarcted
Author Manuscript

myocardium and blood-pool may be improved with these techniques, the level of blood
suppression may be minimal. Unlike FIDDLE, none of these methods produce black-blood
images. Specifically, these methods result in images in which blood-pool signal is higher
than viable myocardium, hence, an endocardial layer that is partially infarcted may still be
difficult to distinguish from blood-pool.

FIDDLE was designed to be flexible and modular in order to accommodate different

preparation pulses, execution order, and readout type. Since its first description by our group
in 2011,6 some pilot studies with variants of FIDDLE have been reported.8,16,20 Muscogiuri
et al.20 used a T2-rho-prep variant of FIDDLE and reported that this technique detected more
patients with infarction than DE-MRI in patients with suspected MI. They speculated that
one possible benefit of a T2-rho-prep over an MT-prep is that the latter may have high
Author Manuscript

energy requirements. However, with the sequence described herein, we did not encounter
this problem. There were no issues with exceeding SAR constraints in any of the patients
scanned at 1.5T or 3T.

Kellman et al.16 describe a T2-prep variant of FIDDLE, albeit the order of the T2- and IR-
preparations are reversed. This variant also combines single-shot SSFP readout with motion
correction in order to allow imaging during free-breathing. In a pilot study of 30 patients in
which 1 slice location was imaged per patient with both dark-blood and bright-blood
techniques, they report that the conspicuity of subendocardial fibrosis was improved by
dark-blood imaging. Unfortunately, there was no reference standard for the diagnosis of
fibrosis, hence the diagnostic accuracy of dark-blood imaging was not assessed. In
comparison, the current study is the first to validate dark-blood delayed-enhancement
Author Manuscript

imaging (of any type) directly against a pathology-based reference standard. Additionally,
high diagnostic accuracy was verified in patients, and imaging in patients was performed at
both 1.5T and 3T field strengths to increase the generalizability of the findings.

Recently, our group has compared a T2-prep variant of FIDDLE with MT-prep FIDDLE.8
We observed that T2-prep FIDDLE was more likely to result in artifacts in the left atrial
cavity which appeared to be secondary to non-uniform magnetization preparation,
particularly at 3T. Additionally, T2-prep FIDDLE occasionally resulted in different levels of

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 10

blood-pool suppression in the right versus left-sided cardiac chambers. This is because
Author Manuscript

deoxygenated blood in the right-sided chambers has shorter T2 than the oxygenated blood in
the left-sided chambers. Although these findings suggest potential advantages with MT-prep,
these are only preliminary data; further investigation is needed.

From an efficiency standpoint, FIDDLE is essentially identical to DE-MRI. No additional

post processing or image registration is required and image reconstruction is completed at
the time of image acquisition. The same dose of contrast media is used, and imaging can be
performed at the same time-point after contrast administration. Moreover, spatial resolution,
temporal resolution, and breath-hold duration (8–10secs) were identical in this study. In
other words, the implementation of FIDDLE reported herein was designed to be a ‘drag and
drop’ replacement for conventional DE-MRI.

Additionally, setting the inversion time (TI) for FIDDLE is straightforward. One simply
Author Manuscript

examines the image intensity of the blood-pool: if the blood-pool is not black the TI needs to
be reduced, whereas if the blood-pool is black then the TI should be increased to the
maximum value that still results in black-blood. In general, 1–2 scout images are sufficient
to find the optimal TI, but nonetheless this is a limitation that can lengthen scan time. Given
its diagnostic performance and ease of use, FIDDLE has become a core component of our
clinical cardiac MR exam, and we are currently using it daily at both 1.5 and 3T.

There are several implications of our study. Our data suggest that, even in the modern era,
the imaging diagnosis of MI can be difficult, and that new methods may improve decision
making, risk stratification, and management. Moreover, the data suggest that the most
important source of variability in infarct size measurements by DE-MRI is the uncertainty in
identifying the border between infarction and LV blood-pool. The reduced variability
Author Manuscript

associated with FIDDLE is expected to be important in clinical trials that employ infarct size
as a surrogate endpoint. In the current study, patients with known MI were enrolled in order
to validate FIDDLE. In the future, studies in patients with suspected rather than clinically
confirmed MI will be needed. It should be noted that FIDDLE provides a general approach
to improve contrast-enhanced MRI of tissue pathology by separating parenchymal contrast-
enhancement from blood-pool enhancement. Hence, the technique may have broad
applicability in visualizing other pathologies throughout the heart and cardiovascular system
(e.g. atrial fibrosis, aortopathies, etc). This will need to be evaluated in future investigations.

In summary, our results demonstrate that FIDDLE provides superior diagnostic performance
than the current in-vivo reference standard for the imaging diagnosis of MI.

Acknowledgments
Author Manuscript

Sources of Funding

US National Institute of Health grant NIH-NHLBI R01-HL64726 (R.J. Kim). There was no industry support for
this study.

Abbreviations
CNR contrast-to-noise ratio

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 11

DE-MRI delayed-enhancement magnetic resonance imaging

Author Manuscript

FIDDLE flow-independent dark-blood delayed enhancement

IR inversion-recovery

LV left ventricle

MT-prep magnetization transfer preparation

M0 baseline longitudinal magnetization

Mz blood or tissue magnetization

SAR specific absorption rate

SNR signal-to-noise ratio

Author Manuscript

SSFP steady state free precession

T Tesla

TI inversion time

References
1. Hochholzer W, Buettner HJ, Trenk D, Laule K, et al. New definition of myocardial infarction:
impact on long-term mortality. Am J Med. 2008; 121:399–405. [PubMed: 18456036]
2. Kim HW, Farzaneh-Far A, Kim RJ. Cardiovascular magnetic resonance in patients with myocardial
infarction: current and emerging applications. J Am Coll Cardiol. 2009; 55:1–16. [PubMed:
20117357]
3. Sievers B, Elliott MD, Hurwitz LM, Albert TS, et al. Rapid detection of myocardial infarction by
Author Manuscript

subsecond, free-breathing delayed contrast-enhancement cardiovascular magnetic resonance.

Circulation. 2007; 115:236–44. [PubMed: 17200443]
4. Kim RJ, Albert TS, Wible JH, Elliott MD, et al. Performance of delayed-enhancement magnetic
resonance imaging with gadoversetamide contrast for the detection and assessment of myocardial
infarction: an international, multicenter, double-blinded, randomized trial. Circulation. 2008;
117:629–37. [PubMed: 18212288]
5. Simonetti OP, Finn JP, White RD, Laub G, et al. "Black blood" T2-weighted inversion-recovery MR
imaging of the heart. Radiology. 1996; 199:49–57. [PubMed: 8633172]
6. Kim RJ. Blood signal suppressed enhanced magnetic resonance imaging. US Patent. 9,131,870 B2.
Sep 15, 2015
7. Kim HW, Rehwald W, Wendell DC, Jenista ER. , et al. Black-Blood Contrast-Enhanced MRI:
Validation of a Novel Technique for the Diagnosis of Myocardial Infarction. Proceedings of the
Annual Meeting of ISMRM; Toronto, Ontario, CA #0662. 2015.
8. Jenista E, Wendell DC, Kim HW, Rehwald WG, et al. Comparison of T2-preparation and
Author Manuscript

magnetization-transfer preparation for black blood delayed enhancement. J Cardiovasc Magn

Reson. 2016; 18:1–3. [PubMed: 26732096]
9. Lee JJ, Liu S, Nacif MS, Ugander M, et al. Myocardial T1 and extracellular volume fraction
mapping at 3 tesla. J Cardiovasc Magn Reson. 2011; 13:75. [PubMed: 22123333]
10. Kim HW, Van Assche L, Jennings RB, Wince WB, et al. Relationship of T2-Weighted MRI
Myocardial Hyperintensity and the Ischemic Area-At-Risk. Circ Res. 2015; 117:254–65.
[PubMed: 25972514]

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 12

11. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell
death. 1. Myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;
Author Manuscript

56:786–94. [PubMed: 912839]

12. Position of the American Heart Association on the use of research animals. Circ Res. 1985;
57:330–1. [PubMed: 4017201]
13. Kim RJ, Fieno DS, Parrish TB, Harris K, et al. Relationship of MRI delayed contrast enhancement
to irreversible injury, infarct age, contractile function. Circulation. 1999; 100:1992–2002.
[PubMed: 10556226]
14. Schulz-Menger J, Bluemke DA, Bremerich J, Flamm SD, et al. Standardized image interpretation
and post processing in cardiovascular magnetic resonance. J Cardiovasc Magn Reson. 2013; 15:35.
[PubMed: 23634753]
15. D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, et al. General cardiovascular risk profile for
use in primary care: the Framingham Heart Study. Circulation. 2008; 117:743–53. [PubMed:
18212285]
16. Kellman P, Xue H, Olivieri LJ, Cross RR, et al. Dark blood late enhancement imaging. J
Cardiovasc Magn Reson. 2016; 18:77. [PubMed: 27817748]
Author Manuscript

17. Farrelly C, Rehwald W, Salerno M, Davarpanah A, et al. Improved detection of subendocardial

hyperenhancement in myocardial infarction using dark blood-pool delayed enhancement MRI.
AJR. 2011; 196:339–48. [PubMed: 21257885]
18. Liu CY, Wieben O, Brittain JH, Reeder SB. Improved delayed enhanced myocardial imaging with
T2-Prep inversion recovery magnetization preparation. J Magn Reson Imaging. 2008; 28:1280–6.
[PubMed: 18972338]
19. Peel SA, Morton G, Chiribiri A, Schuster A, et al. Dual inversion-recovery mr imaging sequence
for reduced blood signal on late gadolinium-enhanced images of myocardial scar. Radiology.
2012; 264:242–9. [PubMed: 22589322]
20. Muscogiuri G, Rehwald WG, Schoepf UJ, Suranyi P, et al. T(Rho) and magnetization transfer and
INvErsion recovery (TRAMINER)-prepared imaging: A novel contrast-enhanced flow-
independent dark-blood technique for the evaluation of myocardial late gadolinium enhancement
in patients with myocardial infarction. J Magn Reson Imaging. 2016
Author Manuscript
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 13

Clinical Perspectives
Author Manuscript

COMPETENCY IN MEDICAL KNOWLEDGE

FIDDLE, a novel flow independent dark-blood delayed-enhancement MRI technique, is
described and validated against pathology in an animal model of myocardial infarction.
Comparisons with conventional delayed-enhancement MRI, the current in-vivo reference
standard for imaging myocardial infarction, demonstrate that FIDDLE has higher
diagnostic accuracy and provides more accurate infarct size measurements. Findings
were replicated in patients, where FIDDLE also showed higher accuracy than delayed-
enhancement MRI for the diagnosis of myocardial infarction.

TRANSLATIONAL OUTLOOK
Future studies will further elucidate the role of FIDDLE in identifying infarction,
Author Manuscript

fibrosis, or scarring in patients with coronary artery disease and non-ischemic

cardiomyopathies. FIDDLE may provide a new avenue to explore pathologies involving
the right ventricle, atria, and other tissues where blood pool enhancement may mask
tissue enhancement, as well as improve the quantification of infarct size, which is an
important surrogate endpoint in clinical trials.
Author Manuscript
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 14
Author Manuscript
Author Manuscript

Figure 1. FIDDLE timing diagram

Author Manuscript

Primary components are: (1) preparatory module, (2) inversion recovery pulse, (3) phase-
sensitive reconstruction, and (4) inversion time such that blood magnetization is less than
tissue magnetization (“Black-blood Condition”). Even with inversion times outside the
black-blood condition, blood-pool signal is suppressed compared with DE-MRI, which
improves the conspicuity of infarcted myocardium.
M0=baseline longitudinal magnetization; Mz=blood or tissue magnetization.
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 15
Author Manuscript
Author Manuscript
Author Manuscript

Figure 2. Pilot study

a. In-vivo characterization of MT-prep module in canines. Increasing train length, holding
flip angle and frequency offset constant (600° and 800Hz), reduced signal particularly for
normal (myo) and infarcted myocardium (left panel). Increasing flip angle, holding train
length and frequency offset constant (14 and 800Hz), reduced signal, again especially for
myocardial tissue (middle panel). Increasing frequency offset, holding train length and flip
angle constant (14 and 600°), led to increased signal for myocardium and blood (right
panel).
b. Modeled FIDDLE signal behavior. Top row: Signal of blood, normal myocardium, and
infarcted myocardium as a function of MT-prep train length and inversion time (TI). Bottom
row: Differences in signals when blood-pool signal is nulled.
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 16
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript

Figure 3. Examples of DE-MRI and FIDDLE compared with pathology

Matched DE-MRI and FIDDLE images in 5 subjects (a) and multiple short-axis images in 1
subject (b). See text for details.

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 17
Author Manuscript
Author Manuscript

Figure 4. Comparison of infarct size by FIDDLE and DE-MRI to pathology

Linear regression (a) and Bland-Altman plots (b) demonstrating higher correlation and
better agreement with FIDDLE. See text for details.
Author Manuscript
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 18
Author Manuscript
Author Manuscript
Author Manuscript

Figure 5. Patient examples of FIDDLE and DE-MRI

a. Images in four patients in whom the infarct is clearly delineated on both FIDDLE and
DE-MRI. Of note, there are no “slow flow” artifacts in any of the short or long-axis FIDDLE
images.
Author Manuscript

b. Images from three patients with MI and two controls. In patients 5 and 6, there is possibly
anteroseptal wall hyperenhancement on DE-MRI (red arrows). However, FIDDLE shows no
hyperenhancement and correctly identifies patient 6 as a normal control. In patients 7 and 8,
FIDDLE identifies that patient 8 is a normal control. In patient 9, FIDDLE clearly
demonstrates not only a subendocardial infarct in the anterior wall, but also extension into
the inferoapical wall (blue arrows).

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 19

Table 1

Diagnostic Performance of FIDDLE

Author Manuscript

Sensitivity Specificity Accuracy

Canines
DE-MRI 83/98, 85% (76–91%) 35/38, 92% (79–98%) 118/136, 87% (80–92%)

FIDDLE 94/98, 96% (90–99%) 35/38, 92% (79–98%) 129/136, 95% (90–98%)

p-value 0.002 1.0 0.01

Patients
DE-MRI 17/20, 85% (62–97%) 9/11, 82% (48–98%) 26/31, 84% (66–95%)

FIDDLE 20/20, 100% (83–100%) 11/11, 100% (72–100%) 31/31, 100% (89–100%)

p-value 0.08 0.16 0.03

Author Manuscript

Values in parenthesis represents 95% confidence intervals

Author Manuscript
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.
 Kim et al. Page 20

Table 2

Patient Demographics
Author Manuscript

Characteristics MI patients Normal controls

(n=20) (n=11)
Age, yrs 56±14 32±11

Female Gender 8 (40%) 4 (44%)

Risk Factors

Hypertension 12 (60%) 3 (33%)

Hyperlipidemia 14 (70%) 0 (0%)

Diabetes Mellitus 8 (40%) 0 (0%)

Smoking 8 (40%) 0 (0%)

Family History of CAD 8 (40%) 1 (11%)

ECG at MI admission
Author Manuscript

ST-segment elevation 13 (65%) —

Non-ST-segment elevation 7 (35%) —

Troponin T (ng/ml) 7.6 IQR (4.0, 11.9)* —

Infarct Related Artery

LAD 10 (50%) —

LCx 7 (35%) —

RCA 3 (15%) —

*
Troponin I was used in the diagnosis of acute MI in 4 patients.

CAD, coronary artery disease, IQR, interquartile range; LAD, left anterior descending; LCx, left circumflex; MI, myocardial infarction; RCA, right
coronary artery; yrs, years.
Author Manuscript
Author Manuscript

JACC Cardiovasc Imaging. Author manuscript; available in PMC 2019 December 01.