JACC: CARDIOVASCULAR IMAGING
VOL.
-, NO. -, 2019
ª 2019 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER
STATE-OF-THE-ART PAPER
Diffusion Tensor Cardiovascular Magnetic Resonance Imaging A Clinical Perspective Zohya Khalique, MD,a,b Pedro F. Ferreira, PHD,a,b Andrew D. Scott, PHD,a,b Sonia Nielles-Vallespin, PHD,a,b David N. Firmin, PHD,a,b Dudley J. Pennell, MDa,b
ABSTRACT Imaging the heart is central to cardiac phenotyping, but in clinical practice, this has been restricted to macroscopic interrogation. Diffusion tensor cardiovascular magnetic resonance (DT-CMR) is a novel, noninvasive technique that is beginning to unlock details of this microstructure in humans in vivo. DT-CMR demonstrates the helical cardiomyocyte arrangement that drives rotation and torsion. Sheetlets (functional units of cardiomyocytes, separated by shear layers) have been shown to reorientate between diastole and systole, revealing how microstructural function facilitates cardiac thickening. Measures of tissue diffusion can also be made: fractional anisotropy (a measure of myocyte organization) and mean diffusivity (a measure of myocyte packing). Abnormal myocyte orientation and sheetlet function has been demonstrated in congenital heart disease, cardiomyopathy, and after myocardial infarction. It is too early to predict the clinical importance of DT-CMR, but such unique in vivo information will likely prove valuable in early diagnosis and risk prediction of cardiac dysfunction and arrhythmias. (J Am Coll Cardiol Img 2019;-:-–-) © 2019 by the American College of Cardiology Foundation.
M
yocardial phenotyping is crucial to under-
derangements in cardiomyopathy, myocardial infarc-
stand the healthy heart and changes in
tion (MI), and congenital heart disease. Hence, there
disease. It offers insight into the cardiac
is increasing interest in its potential clinical useful-
structurefunction relationship and is key to diag-
ness and the new insight it brings to the pathophysi-
nosis, prognosis, and determining therapeutic inter-
ology
ventions.
current
describes the cardiac microstructure, the DT-CMR
imaging techniques is limited to a scale of millime-
technique, clinical studies performed so far, and the
ters, and it is not possible to assess the microstructure
potential future role of DT-CMR.
However,
phenotyping
with
of
cardiac
disease.
This
clinical
review
of the myocardium without resorting to biopsy. Diffusion tensor cardiovascular magnetic resonance (DT-
THE CARDIAC MICROSTRUCTURE
CMR) is a novel tool that provides noninvasive in vivo microstructural assessment, offering informa-
CARDIOMYOCYTES. Cardiomyocytes measure approx-
tion at the scale of cardiomyocyte organization
imately 150 by 20 mm and intercalate with several
(Central Illustration). Preliminary studies have shown
other cardiomyocytes (1). Although their branching
DT-CMR
nature means that cardiomyocytes do not strictly
can
identify
unknown
microstructural
From the aCMR Unit, Royal Brompton Hospital, London, United Kingdom; and the bNational Heart and Lung Institute, Imperial College, London, United Kingdom. Dr. Scott has received an equipment grant from NVIDIA. Dr. Firmin and Prof. Pennell have received research support from Siemens. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received November 6, 2018; revised manuscript received July 9, 2019, accepted July 11, 2019.
ISSN 1936-878X/$36.00
https://doi.org/10.1016/j.jcmg.2019.07.016
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ABBREVIATIONS
align in fibers, there is a directional grain to
arrangement in systole to facilitate LV wall thick-
AND ACRONYMS
their appearance (Figure 1). This has led to
ening (4,7). However, until the advent of DT-CMR,
variable terminology, when some use “fiber”
there was no way of assessing in vivo microstruc-
to mean cardiomyocytes or groups of car-
tural changes through the cardiac cycle. Recent
“car-
in vivo human and animal work strongly supported
diomyocyte orientation” is used to avoid
the concept of sheetlet reorientation as an important,
cardiovascular magnetic
confusion with the more strictly fiber-like
if not the dominant, myocardial dynamic associated
resonance
skeletal muscle. In the left ventricle (LV),
with radial thickening (8). There is still limited un-
E2A = secondary vector
cardiomyocytes have a left-handed (LH) he-
derstanding of how myocyte shortening translates
angulation
lical course at the epicardium, progressing
into the microstructural rearrangement that causes
EF = ejection fraction
through to a circumferential course in the
wall thickening. However, approaches such as DT-
FA = fractional anisotropy
mesocardium and then a right-handed (RH)
CMR should yield insight into this problem.
HA = helix angle
helical course in the endocardium, as shown
HCM = hypertrophic
in the historical sequential dissection plates
cardiomyopathy
in Figure 1. Recently, histology by Streeter
LH = left-handed
et al. (2) demonstrated the transmural varia-
LV = left ventricular
tion of the fiber angle known as a . This angle,
M2-SE = second-order motion
measured in the plane parallel to the epicar-
compensated spin echo
dium and relative to the LV long axis, is
MD = mean diffusivity
positive at the endocardium and negative at
MI = myocardial infarction
the epicardium, reflecting RH and LH helical
RH = right-handed
orientation, respectively (Figure 2). The near-
STEAM = stimulated echo
zero a in the mesocardium indicates circum-
acquisition mode
ferential cardiomyocytes.
ADC = apparent diffusion coefficient
DCM = dilated cardiomyopathy DT-CMR = diffusion tensor
TA = transverse angle
diomyocytes.
Here,
the
phrase
CMR TECHNIQUE The theory and underlying methods behind diffusion MR were developed in the 1960s by Stejskal and Tanner (9) and advanced in the 1990s (10). The first clinical application of diffusion imaging was in neurology, where it was used for the early diagnosis of stroke (11). Cardiac diffusion imaging is considerably more difficult due to the bulk motion of the heart, but Edelman et al. (12) were able to overcome this by using a stimulated echo acquisition mode (STEAM) technique to produce the first in vivo
SHEETLETS. Cardiomyocytes are aggregated
to form secondary structures, termed “sheetlets” (Figure 3). Each sheetlet is approximately 4 car-
diffusion cardiac image in 1994. DIFFUSION. Diffusion imaging assesses diffusion of
water. Free diffusion, when water molecules may
diomyocytes thick, surrounded and interconnected
diffuse in all directions equally, is known as isotropic
by the collagenous perimysium, allowing shear be-
diffusion. However, in the myocardium where car-
tween neighboring sheetlets during the dynamic
diomyocytes and connective tissues act as barriers,
motion of cardiac contraction (3). It was initially
diffusion is restricted (impermeable barriers) or hin-
believed that sheetlets formed stacked sheets, each
dered (permeable barriers), becoming anisotropic
extending the width of the LV wall (4). It is now
(Figure 4). DT-CMR exploits the effects of the micro-
appreciated that
structure on diffusion to yield information about the
there
are
multiple
local sub-
populations containing counter-sloping sheetlets (5).
underlying myocardial organization.
STRUCTURELFUNCTION RELATIONSHIP. The myocardial
DIFFUSION-WEIGHTED CMR. Diffusion is measured
microstructure is crucial to the dynamics of LV
by assessing the signal loss between 2 images: a
function. The helical arrangement of cardiomyocytes
reference image and a main image with a higher de-
drives myocardial rotation and torsion (6). The
gree of diffusion weighting. The weighting is applied
dominant effect of the larger epicardial radius means
by diffusion encoding gradients and described by the
that cardiomyocyte shortening of the LH epicardial
b-value, which encompasses gradient amplitude,
cardiomyocytes leads to net clockwise rotation
duration, and temporal separation of the gradient
basally and anti-clockwise rotation apically, when
pulses, and is quoted in units of seconds per square
viewed from the apex (6).
millimeter (10). Typically, values of 450 to 600 s/mm 2
However, what is far less well appreciated is the
are used (8,13,14). At higher b-values, the signal in-
contribution of sheetlets to cardiac function. Both
tensity is less easily distinguished from background
Streeter et al. (2) and Spotnitz et al. (7) noted the
noise (15). At lower b-values, other sources of
“wall thickening paradox” in which cardiomyocyte
diffusion-like
thickening of only 8% could not explain wall thick-
including perfusion, confound the signal attenuation
ening of 40%. Histological analysis in rat and dog
(16). The measured diffusion is known as the
myocardium suggested the concept of sheetlet rear-
apparent diffusion coefficient (ADC) to accommodate
rangement from a more LV epicardial wall parallel
factors, such as perfusion and hindered and/or
orientation in diastole to a more wall perpendicular
restricted diffusion that impair accurate measures of
intravoxel
incoherent
motion,
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C ENTR AL I LL U STRA T I O N DT CMR Noninvasively Identifies Microstructures in the Myocardium
Khalique, Z. et al. J Am Coll Cardiol Img. 2019;-(-):-–-.
(Left) Diffusion tensor cardiovascular magnetic resonance (DT-CMR) demonstrates sheetlets of cardiomyocytes that reorient from wall-parallel in diastole to wallperpendicular in systole, facilitating the left ventricular wall thickening that greatly exceeds that of individual cardiomyocytes. In cardiomyopathy, abnormal sheetlet behavior is identified; in hypertrophic cardiomyopathy (HCM), sheetlets fail to relax to the expected diastolic position, and conversely, in dilated cardiomyopathy (DCM) sheetlets fail to rotate to the expected systolic position. (Right) DT-CMR demonstrates the helical arrangement of cardiomyocytes, with a right-handed helix in the endocardium, circumferential in the mesocardium, and left-handed helix in the epicardium. Contraction of these oppositely oriented myocytes drives clockwise rotation basally and anti-clockwise rotation apically, resulting in left ventricular torsion. In congenital conditions, such as situs inversus, this typical pattern is deranged with impaired torsion.
diffusivity (17). The fact that diffusion yields direc-
orientations uses diffusion gradients applied in at
tional information was developed from the obser-
least 6 directions. Information from the diffusion-
vation that ADC was higher when the diffusion
weighted images is used to determine a diffusion
gradient direction was aligned with the axonal di-
tensor, which is a mathematical extension of a
rection in neurological diffusion imaging (18). The
vector, having a 3-dimensional magnitude and di-
modern approach to determining microstructural
rection (19).
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F I G U R E 1 Helical Arrangement of Cardiomyocytes in the Mammalian Heart
Fig . 1 .
Fig . 2 .
Fig . 3 .
Fig . 4 .
Fig . 5 .
Fig . 6 .
Fig . 7 .
Fig . 8 .
Dissection plates showing the transmural evolution of the helical arrangement of cardiomyocytes from (top left) left-handed helix in the epicardium through (bottom left) circumferential in the mesocardium to (bottom right) right-handed helix in the endocardium. Reprinted with permission from Pettigrew et al. (Supplemental Ref. 5).
ACQUIRING DT-CMR DATA. One method to acquire
The key limitation of basic SE is cardiac motion
DT-CMR data is a spin echo (SE) sequence, known as
that occurs during diffusion weighting, which is
the Stejskal-Tanner sequence (9). An excitation pulse
approximately 3 orders of magnitude greater than
is followed by a diffusion gradient that causes spin
the distances diffused by water molecules and leads
dephasing relative to position along the gradient.
to large artefactual signal dropout. This was first
Application of a 180-degree refocusing pulse and a
addressed by bipolar diffusion gradients that offered
second diffusion gradient will realign the spins
first-order motion (constant velocity) compensation
of static tissue to an equal but opposite net magne-
(20). Second- and third- (acceleration and jerk)
tization vector. For spins within a steadily flowing
order motion compensation techniques were then
medium, this pulse sequence will lead to a net phase
developed, although these require high performance
shift. However, in diffusion imaging, the random
gradient systems (Figure 6a) (14,21,22). Third-order
movement of the diffusing spins results in phase
motion compensation addresses the more complex
dispersion within each voxel. The vector sum of the
diastolic motion, but requires longer echo times, so
spins in the presence of phase dispersion leads to
second-order
decreased net magnetization, and thus signal loss
considered optimal. Thus, M2-SE data are typically
(Figure 5). Diffusivity can be calculated from signal
acquired in systole (23,24). Validation using in vivo
loss and diffusion weighting using the Stejskal-
and post-mortem M2-SE DT-CMR in pigs has shown
Tanner equation (9).
good levels of agreement (25). An M2-SE approach is
motion
compensation
(M2-SE)
is
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F I G U R E 2 Transmural Variation in Cardiomyocyte Orientation
DECILE NO.
ENDOCARDIUM
100 a
1 M d c
80
b
2
α(°)
c
60
da M b
3
c d
40
4 20
M a
b d
5
c
M a bd
MIDWALL 6
0 20 LV WALL THICKNESS -%
ca M b d
0 ac 40 M b d
–20
M acd b
60
80 d M cab
100
d
c M ab
d bc
M
7
c
–40
a b
M d
8
b c
M
–60 a
d
9
100 μ
–80
a
10 –100 EPICARDIUM
(Left) Cardiomyocyte orientation smoothly progresses from a positive angle at the endocardium through to a negative angle at the epicardium. (Right) Helix angle through the myocardial wall from epicardium (negative) to endocardium (positive). a to d represent data from 4 samplings. LV ¼ left ventricular; M ¼ mean. Reprinted with permission from Streeter et al. (2).
attractive and growing in popularity because of the
cycles (Figure 6B). Data acquisition is synchronized so
higher
alternative
that the heart is in the same position when both
methods, its suitability for free-breathing acquisi-
diffusion gradients are applied, thus minimizing the
tion, and its more efficient whole heart coverage. It
effects of cardiac motion. STEAM has been the
has been used in several initial human studies
mainstay of recent clinical DT-CMR studies because it
(14,22,26,27). A variation on M2-SE is a diffusion
does not require specialist hardware or motion
prepared method that allows a flexible choice of
compensation. Since its initial success in producing
image acquisition (22).
diffusion-weighted CMR images, STEAM has been
signal-to-noise
ratio
than
A leading alternative sequence type is STEAM, and
readily applied to DT-CMR in both healthy and
this addresses bulk motion artefact by splitting the
diseased hearts (8,12,28–30). However, the wide
180-degree pulse into 2 90-degree pulses, so that the
applicability of STEAM is offset by several disadvan-
time over which diffusion is measured (D ) is an RR
tages. It has low signal-to-noise ratio, requires 2 reg-
interval, and each image is acquired over 2 cardiac
ular RR intervals per image, which necessitates longer
5
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THE
F I G U R E 3 Cardiomyocytes Aggregated into Sheetlets
CONFOUNDING
EFFECTS
OF
STRAIN.
Strain, a measure of myocardial deformation, has been proposed as a confounder of DT-CMR results (28,32). Myocardial deformation occurs during the diffusion time of both sequences, but the longer diffusion time in STEAM make its effects more significant. Reese et al. (32) originally described this phenomenon, explaining how tissue compression, in the direction of and following the initial STEAM gradient phase encoding, would have the effect of increasing the spatial modulation frequency and signal attenuation, and hence, ADC. An alternative simplified visual representation of how strain affects diffusion measures is shown in Figure 7. Diffusion within a medium that is compressed and then stretched back to its original state results in protons that travel further away from the starting point compared with the stationary case, thus over-
Scanning electron micrograph of the transverse cut surface of a left ventricular mid-wall
estimating diffusivity. Several correction methods for
section shows cardiomyocytes aggregated into sheetlets, separated by peri-mysial
STEAM sequences exist, including bipolar gradients
connective tissue. Adapted with permission from Le Grice et al. (3).
(33) or acquiring data at the “sweet spot,” the timepoint where the effects of the strain history over the
breath-holding or a navigator-led approach, and excludes
patients
with
arrhythmias
(31).
Another
disadvantage of STEAM in measuring diffusion is the effect of strain.
cardiac cycle are nulled (34). A post-processing correction technique uses macroscopic strain data (35). However, although strain has been considered a significant confounder to DT-CMR findings for many years (especially systolic secondary vector angulation [E2A] and E2A mobility), 2 recent studies have shown
F I G U R E 4 Diffusion Is Modulated by Its Environment
TISSUE/CELL LEVEL Hindrance Restriction Barriers
strain has only a limited effect and that uncorrected in vivo DT-CMR data are more representative of ex vivo findings (8,36). Consequently, the dynamic, laminar, and semi-permeable nature of the myocardium means strain has a complex, but limited effect on measured diffusion and requires further study (29,36,37). ANALYZING THE DATA.
The eigensystem. The 3-
dimensional diffusion described by a tensor can be
pictorially
diffusion
in
represented.
an
Although
unrestricted
isotropic
environment
is
a
sphere, the restricted diffusion in the heart is an ellipsoid
(Figure
8).
The
lengths
of
the
3-
dimensional axes of the ellipsoid are labeled l1, l 2
l3 (eigenvalues) in order of magnitude of diffusion, and their directions are E1, E2, and E3 (eigenvectors), respectively. Eigenvectors. The eigenvectors can be projected onto cardiac planes (Figure 9), and several validation studies support the correspondence of E1 with average intravoxel cardiomyocyte orientation, E2 Free diffusion is unrestricted, but in the myocardium can be restricted within cells (green), may traverse a permeable cell membrane (red) or take a hindered path within the extracellular space (blue), rendering it anisotropic. Adapted with permission from Le Bihan (Supplemental Ref. 6).
with the predominant sheetlet orientation, and E3 with the sheetlet normal direction (Supplemental Table 1) (5,8,38–43). Helix angle. The primary eigenvector, the long axis of the
diffusion
ellipsoid,
is
projected
onto
the
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F I G U R E 5 Diffusion Is Measured by Signal Loss
90°-Pulse
Echo
180°-Pulse G
G
Fixed
A
Flow
B
Diffusion
C
The diffusion tensor cardiovascular magnetic resonance (DT-CMR) sequence uses an excitation pulse followed by a diffusion gradient, a refocusing pulse, and a second diffusion gradient. Static Hþ spins are subject to (A) equal dephasing and rephasing, whereas flowing spins (B) experience phase shift. (C) With random Hþ displacement, there is incomplete rephasing and signal attenuation. Reproduced with permission from Froeling et al. (Supplemental Ref. 7).
circumferential-longitudinal plane and reflects the
change is called E2A mobility and reflects sheetlet
mean intravoxel cardiomyocyte orientation (8,28,39).
function (8).
The angulation created by the projected primary
Tertiary eigenvector angulation. The tertiary eigen-
eigenvector and the circumferential direction is E1A
vector angulation (E3A) is perpendicular to the
but is often described as the helix angle (HA) or a in
sheetlet plane. E3 is projected onto the longitudinal-
some older published data. HA changes only a little
radial plane and is positive when directed apico-
during cardiac contraction (8).
basally (upward).
Transverse angle. The transverse angle (TA) or imbri-
Mean diffusivity. In DT-CMR, mean diffusivity (MD) is
cation angle reflects the tilt of the mean car-
derived from the tensor (19). It is the mean of l 1, l 2,
diomyocyte orientation toward and/or away from
and l3 and measured in units of square millimetres
the central LV axis. It is derived by projecting E1
per second. MD reflects the packing and integrity of
into
then
the myocytes, with low values indicating tight pack-
calculating the angle with the circumferential di-
ing. MD rises with interstitial abnormality (e.g.,
rection (38,43).
fibrosis) because water has more freedom to diffuse
the
Secondary
circumferential-radial
eigenvector
plane
angulation. The
and
secondary
(26,44). MD is similar to the mean ADC from
eigenvector is projected onto the cross-myocyte
diffusion-weighted CMR.
plane (Figure 9). The angulation between E2 pro-
Fractional anisotropy. Fractional anisotropy (FA) is a
jected into this plane and the myocyte perpendicular
scalar value reflecting the degree, but not direction,
direction is termed E2A and is an index of sheetlet
of anisotropy. Isotropic diffusion has an FA value of
orientation (8). Unlike E1A, E2A orientation changes
0, and diffusion restricted to a single direction has a
substantially between systole and diastole. This
value of 1 (Figure 10). FA reflects the degree of
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F I G U R E 6 Diffusion Tensor Sequences
R
Diffusion gradient
90°(y) water selective
Diffusion gradient
M2-SE
180°(z)
A
TE/2
EPI readout TE/2
Δ
R
TE/2
Diffusion gradient
90°(z)
90°(y)
R
90°(y) water selective
STEAM
Diffusion gradient
B
EPI readout
TE/2
Ttrigger Δ = RR TM
(A) Second-order motion compensated spin echo sequence (M2-SE). The sequence is triggered by the R wave and has excitation and refocusing pulses. D is the “diffusion time” over which the measured diffusion takes place (typically 20 to 30 ms). (B) Stimulated echo acquisition mode (STEAM) DT-CMR sequence. The sequence runs across 2 cardiac cycles; the diffusion time (D) is 1 RR interval, whereas mixing time (TM) reflects the duration of the magnetization storage in the longitudinal plane between the second and third pulses. Modified with permission from Scott et al. (24).
organization of a tissue, such that a higher value is
cardiac and respiratory motion (24). Scan times can
more organized. Thus, a low FA might be expected
be lengthy due to multiple acquisitions in different
with myocyte disarray, should it occur at an appro-
directions.
priate value relative to pixel size.
DT-CMR is limited in both spatial and angular
VISUALIZING DT-CMR FINDINGS. Tractography provides
3-dimensional visualization, typically tracking E1 across voxels into a smooth trajectory. In reality, this is a simplification because the myocardium does not contain serially aligned cardiomyocytes. Another representation uses superquadric glyphs, which are 3-dimensional bricks derived from the tensor that convey pixelwise information about the shape and orientation of the eigensystem (45). The orientation and size of the 3 axes of the glyphs represent
the
eigenvectors
and
eigenvalues,
respectively. LIMITATIONS OF DT-CMR. Acquiring and interpret-
ing DT-CMR data is hampered by technical issues
resolution. Current in vivo spatial resolution is typically 2.7 2.7 mm 2 6 mm for M2-SE and 2.8 2.8 mm2 8 mm for STEAM (8,14). Each DT-CMR image voxel contains millions of cardiomyocytes and many sheetlets. These are not uniformly aligned, and counter-orientated subpopulations exist (5). DTCMR techniques are not able to resolve multiple populations within a single voxel, so the derived values reflect averages. It is also possible that partial volume effects may be responsible. Techniques such as de-noising and different k-space trajectories may aid reducing voxel size but help preserve the signalto-noise ratio.
DT-CMR OF THE HEALTHY HEART
(46). Success rates for image acquisition vary by sequence type and cardiac phase and can be
Clinical applications of DT-CMR are in relative in-
affected by factors such as mis-triggering and
fancy, but the unique ability to provide in vivo
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F I G U R E 7 Effects of Strain in an Isotropic Phantom
time 0
time 1 R-R interval
STATIC
diffusion encoding time = 1 cardiac cycle
FITTED TENSOR ELLIPSOID
free isotropic diffusion elastic medium isotropic
STRETCH > 1
stretching
reduction of diffusion along stretching direction
STRETCH < 1
compressing
enhancement of diffusion along compression direction
Deformation of an isotropic substance over the diffusion time affects the measured diffusion result. In the top panel, a systolic measurement is affected by the intervening diastolic stretch, and in the bottom panel a diastolic measurement is affected by the intervening systolic compression. For both, the diffusion pattern is ovoid in shape, rather than the expected isotropic sphere. Reprinted with permission from Ferreira et al. (36).
microstructural information noninvasively has led to
may relate to the laminar structure of the myocar-
some describing it as “virtual histology.” The tech-
dium, because sheetlets are increasingly prevalent
niques are in constant evolution, and although mea-
toward the endocardium (49).
surement of myocyte and sheetlet orientations are
CARDIOMYOCYTE ORIENTATION. Various DT-CMR
reproducible and stable, the more global measures
studies identify the transmural HA gradient in car-
such as FA and MD show variation with technical
diomyocyte orientation (Supplemental Table 1) and
sequence parameters and acquisition, mostly due to
report only minor changes in cardiomyocyte orien-
the varying diffusion times (24,27).
tation toward a more longitudinal systolic orienta-
DIFFUSIVITY
PARAMETERS. MD
and
FA
are
tion, as shown in Figure 12 (8,35,50). The transverse
commonly reported DT-CMR parameters but vary
angle lies in the region of 20 to þ20 degrees, at both
depending upon sequence type, cardiac phase, and
cardiac phases (43).
b-value (24,47,48). In vivo human studies comparing M2-SE and STEAM report higher MD and lower FA using M2-SE (24,27). This result is expected because with a shorter diffusion time, water molecules encounter fewer restrictive barriers (Figure 11). Re-
F I G U R E 8 Pictorial Representation of Diffusion Tensors
λ1, E1
λ1, E1
ported values for MD and FA are provided in Supplemental Table 2. MD and FA tend to be provided
λ3, E3
as global values, usually across a mid-ventricular slice. However, regional differences
have
been
0.04), compared with the endocardium (0.40 0.04)
λ2, E2
and epicardium (0.39 0.004), possibly due to the relative plateau in HA due to the circumferentially oriented mesocardial cardiomyocytes (48). For MD,
λ3, E3
λ2, E2
described: FA peaks in the mesocardium (0.46
(Left) Isotropic diffusion is shown as a sphere, but restricted diffusion is represented as an (right) ellipsoid shape in DT-CMR. l signifies the eigen-
there is a transmural gradient with an MD of 0.87
value (magnitude of diffusion) and E denotes the eigenvector (direction of
0.07 103 mm 2/s at the epicardium that increases to
diffusion) along the 3 axes.
0.91 0.08 103 mm 2/s in the endocardium. This
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F I G U R E 9 Projections of Eigenvectors on Cardiac Planes
longitudinal di ra al os cr
c yo
m s-
A endo
longitudinal
E2 meso
circumferential epi
E1 B
l
E1 A +T E1
circumferential ra di al
-TA
c yo
circumferential ra di al
yt
e
m s-
os
cr
E2A
l
m s-
ia
E2
ia
Transverse angle
e
circumferential ra d
circumferential ra d
yt
os
cr
longitudinal
-HA
e
E1
+HA circumferential
c yo
yt
E1
cross-myocyte
C Sheetlet planes
Helix angle longitudinal
10
ra d
ia
l
Three myocardial voxels are shown. The primary eigenvector (E1) projected on the circumferential-longitudinal plane gives the helix angle (HA). (A) E1 projected on the circumferential-radial plane gives the transverse angle. (B) The voxels are cut in a cross-myocyte direction, showing the plane perpendicular to E1. (C) Projecting the second eigenvector (E2) onto this sheetlet plane gives E2A. Adapted with permission from Ferreira et al. (29).
SHEETLET ORIENTATION. E2A is used as a DT-CMR
MICROSTRUCTURAL CHANGES IN
index of sheetlet orientation, although E3 is used by
CARDIAC DISEASE
some
investigators.
E2A
changes
substantially
through the cardiac cycle (8). Figure 13 shows how
MI. DT-CMR has been applied in MI, with much in-
sheetlets adopt a wall parallel sheetlet orientation in
terest in acute changes and post-infarct ventricular
diastole (blue), which becomes more wall perpen-
remodeling. Several animal and human studies
dicular in systole (red). This reorientation is inti-
describe increased MD and decreased FA in the
mately linked to the generation of radial strain. A
infarct zone (26,52–55). This accords with myocyte
small movement in the longitudinal direction trans-
swelling and necrosis, extracellular matrix expan-
lates into a larger radial expansion, similar to the
sion, and replacement by less organized collagenous
perpendicular amplification action of a “lazy tong”
fibrosis. Ex vivo porcine DT-CMR 13 weeks after iat-
(Supplemental Ref. 1). This is demonstrated by glyphs
rogenic MI revealed increased mean ADC (1.01
in Figure 13 and shown in Video 1. Biphasic differ-
0.100 103 mm 2/s) compared with control subjects
ences in E2A have been described; a STEAM study of
(0.671 0.106 103 mm 2/s; p < 0.001) in the infarct
healthy humans reported diastolic E2A of 26 6 de-
zone (55). FA was significantly reduced in the infarct
grees and systolic E2A of 54 6 degrees, with E2A
from 0.32 0.01 to 0.20 0.03 (p < 0.001). In the
mobility of 27 8 degrees (51). A different STEAM
human study by the same group 26 days post-MI, DT-
study using E3A reported sheet angles of 65 3.6
CMR detected increased mean ADC, decreased FA,
degrees and 41.6 3.7 degrees in diastole and systole,
and decreased RH and increased LH helical structures
respectively (35).
(cardiomyocytes) compared with the remote zone
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F I G U R E 1 0 Increasing FA
Tensor
Increasing fractional anisotropy
0
1
Increasing microstructural organization
Tissue organization
Fractional anisotropy (FA) in the heart reflects the underlying myocyte organization, such that a value towards zero reflects little organization and a value nearer 1 reflects a more organized structure (packed and anisotropic).
(52). The follow-up human study at a median 191 days
5 patients suggested DT-CMR appeared to detect
after MI described an increased proportion of RH
disarray by reduced FA and lower strain in the
cardiomyocytes in the remote zone, which correlated
septum compared with the free wall of patients with
with increased wall thickness (r ¼ 0.66; p ¼ 0.005)
HCM and 5 healthy control subjects (58). A repro-
and increased wall thickening in the adjacent zone
ducibility study in HCM reported regional differences
(r ¼ 0.61; p ¼ 0.01) (56). The proposed explanation
where FA was lowest and MD highest in the septum,
was that loss of RH cardiomyocytes fit with susceptibility of the endocardium to ischemia and gain of LH cardiomyocytes in the infarct zone and RH cardiomyocytes in the remote zone were both adaptive
F I G U R E 1 1 Expected Diffusion Radii of Free Water
remodeling responses. Recently, a study of MI in mice, sheep, and humans introduced the tractographic propagation angle, defined as the angle between 2 adjacent primary eigenvectors along a given tract and a metric of myofiber curvature, as shown in Figure 14 (57). A propagation angle value of 4 degrees was reported as the
threshold
for
differentiating
normal
from
infarcted myocardium, as correlated to late gadolinium imaging and endocardial voltage mapping. Understanding
microstructural
changes
post-infarct
could offer insight into the pathogenesis and prognostication of negative remodeling and arrhythmias. HCM. A
microscopic
hallmark
of
HCM
is
car-
diomyocyte disarray, detectable currently only by histology. It is hoped that DT-CMR might detect
STEAM has a longer diffusion time (D) than spin echo. The diffusion radii of free water over these timeframes are superimposed upon pig myocardium, cut perpendicular to the
disarray noninvasively, aiding diagnostic differenti-
long axis of the cardiomyocytes. More barriers are encountered during the longer D.
ation from HCM phenocopies and potentially identify
Reproduced with permission from Scott et al (24). Abbreviations as in Figure 6.
those at higher risk of arrhythmias. A study of
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F I G U R E 1 2 Helix Angle in Diastole and Systole
A
End-Diastole
B
End-Systole
Epicardium
60°
C
Base
Apex
D Endocardium
Lateral Wall
12
-60°
Diffusion tensor tractography of the lateral ventricular wall at end-diastole (A and C) and end-systole (B and D). Negative epicardial helix angles are more red and the positive endocardial helix angles are more blue. At end-systole the cardiomyocytes are more longitudinally orientated. Reprinted with permission from Mekkaoui et al. (50).
although only the latter was significant (59). Although
pathophysiology, in which sarcomeric mutations may
this might be related to septal hypertrophy and
result in increased myofilament sensitivity to cal-
expanded extracellular space due to fibrosis and
cium, increasing relative cardiomyocyte tension
disarray, technical factors such as spatial variation in
(Supplemental Ref. 2).
the signal-to-noise ratio might also be responsible;
DILATED CARDIOMYOPATHY. Dilated cardiomyopa-
histological validation was absent. A preliminary
thy DCM has also been studied using DT-CMR. A SE
study suggested FA was focally reduced in patients
study of hamsters with DCM found no change in HA
with HCM compared with control subjects and that
or TA, but elevated MD and reduced FA compared
DT-CMR might be able to detect myocardial disarray
with control hamsters (Supplemental Ref. 3). An
(60).
in vivo STEAM study of 9 patients with nonischemic
Diffusion-weighted CMR can offer another type of
DCM and control subjects found MD was similar be-
myocardial characterization in HCM. In a study of 23
tween groups and cardiac phases (30). FA was lower
patients with HCM, mean ADC was elevated in areas
in patients with DCM compared with control subjects
of fibrosis and correlated with extracellular volume
(diastole 0.56 0.07 vs. 0.63 0.05; p < 0.04, and
(r 2 ¼ 0.72), which suggested that diffusion-weighted
systole 0.58 0.08 vs. 0.62 0.07; p ¼ 0.56). The
CMR might detect the extent of fibrosis without a
transmural HA gradient in diastole was steeper in
contrast agent (Figure 15) (44). However, in vivo DT-
patients with DCM, although this difference seemed
CMR demonstrated an entirely novel abnormality in
to be driven by 2 patients. There was systolic HA
HCM. Diastolic E2A was significantly elevated, and
redistribution in control subjects, with the expected
E2A mobility was reduced (Figure 16) (29). The failure
more longitudinal orientation, but this was not seen in
of sheetlets to return to a more wall parallel orienta-
patients with DCM. E2A findings are shown in
tion in diastole could be described as a failure of
Figure 17. Biphasic E2A changes in control subjects
diastolic relaxation. Interestingly, this microstruc-
(Figures 17A and 17C) showed predominance of low
tural abnormality builds upon our knowledge of HCM
diastolic E2A and a broader systolic distribution.
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F I G U R E 1 3 Secondary Eigenvector E2A Reflects Sheetlet Orientation
A
IN VIVO: DT-CMR AT DIFFERENT TIMES OF THE CARDIAC CYCLE diastole
90 80
|E2A| (Degrees)
80 70 60 50
45
40
systole
30 20 10
10
0 0
0.25 RR
0.5 RR
0.75 RR
RR
Normalized RR Interval
B
HISTOLOGY RELAXED (KCI ARRESTED)
CONTRACTED (BaCI2 ARRESTED)
0 –45
0 +45
–/+90
–45
+/–90
–/+90
–45
+/–90
+45
–45 0
80
10.5 mm
60 1 mm
1 mm
9.9 mm
0
Sheetlet Angle (Degrees)
+45
+45
40 20
ra c
9.0 mm
nt
1 mm
Co
Re l
1 mm
te
ax ed
5.6 mm
d
0
Absolute secondary vector angulation (E2A) changes through the cardiac cycle, rising from diastole (low E2A: blue) to systole (higher E2A: red). (A) Biphasic E2A variation is seen in vivo and corresponds to the (B) histological findings of sheetlet orientation. See Video 1. Adapted with permission from Nielles-Vallespin et al. (8).
However, there was relatively little change in
abnormal in patients with DCM. In control subjects,
the
DCM
median systolic (interquartile range) E2A was 65 (6 ),
(Figures 17B and 17D). The findings of this study must
and in patients with HCM, it was 74 (7 ). In patients
be tempered by its limitations; only 9 patients without
with DCM, systolic E2A was significantly reduced at
LV dilatation and with strain correction, which may
40 degrees (16 degrees), yielding a reduced E2A
E2A
distribution
for
patients
with
have obscured, had altered sheetlet mobility.
mobility and impaired sheetlet mobility (Figure 18).
Nielles-Vallespin et al. (8) studied patients with
Both radial and circumferential strains were signifi-
DCM and HCM, and control subjects and did not use
cantly and similarly reduced in the cardiomyopathy
strain correction. They found similar HA distributions
groups compared with control subjects. However, the
in the 3 cohorts. HA shifted toward more longitudinal
range of E2A (low to low in DCM and high to high in
in systole for all groups. Diastolic E2A was similar
HCM) provided mechanistic insight into these find-
between groups, but systolic E2A findings were
ings. This study was limited by the mean ejection
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F I G U R E 1 4 PA Is Elevated in Areas of Infarction
A
Propagation Angle
B
Normal Human
Base Lateral
C
Infarcted Sheep
C1 Remote Zone PA < 4°
Anterior C2 Infarcted Region PA > 4°
Septum
Apex
0°
Anterior
15°
(A) Propagation angle (PA) is a metric of myofiber curvature, (B) PA in healthy human hearts is uniformly typically <4 , and (C) in a sheep heart with myocardial infarction remote and infarcted areas are delineated by PA #4 , respectively. Reprinted with permission from Mekkaoui et al. (Supplemental Ref. 8).
fraction (EF) in the DCM group of 45 11%, with
difference in the HA histograms among the 3 cohorts,
approximately one-half of the patients having only
but significant findings were present in E2A. Diastolic
mild LV impairment. However, despite this, the
E2A was similar among groups. However systolic E2A
altered sheetlet behavior was statistically significant.
in those with recovered DCM was 59 (14 degrees),
Having established microstructural abnormalities
which was significantly greater than the DCM group
in DCM, the same group studied patients with
(35 degrees [17 degrees]; p < 0.0001), but lower than
recovered DCM and compared them to patients with
the control subjects (65 [8 ]; p ¼ 0.01). When E2A
DCM and healthy control subjects (61). These patients
mobility was plotted against the EF, patients with
were defined by LV size and EF entirely within
recovered DCM and control subjects were indistin-
indexed reference ranges and New York Heart Asso-
guishable by EF but could be discriminated by E2A
ciation functional class I. Again, there was little
(Figure 19).
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F I G U R E 1 5 Diffusivity Is Elevated in Areas of Fibrosis
ECV
LGE
Diffuse
Patch–like
ADC
0
3 µm2/ms
60%
0
2
30%
In hypertrophic cardiomyopathy, the apparent diffusivity coefficient (ADC) is elevated in regions of fibrosis, as detected by late gadolinium enhancement (LGE) and increased extracellular volume (ECV). Reprinted with permission from Nguyen et al. (44)
Together, these 2 studies suggest that DT-CMR can
epicardium and negative HAs in the endocardium,
detect impaired sheetlet behavior in dilated cardio-
whereas toward the apex, the transmural HA distri-
myopathy that appears to persist even when LV size
bution was more similar to situs solitus. There was a
and EF recover to normal by conventional measures.
mid-ventricular transition zone. These findings were
CONGENITAL HEART DISEASE. There is a paucity of
confirmed in the ex vivo hearts. Mid-LV peak radial
DT-CMR data in congenital heart disease. In an adult
and circumferential strain were reduced, and overall
with transposition of the great arteries corrected by
absolute torsion was significantly reduced in situs
arterial switch, DT-CMR showed predominance of
inversus totalis. This was the first in vivo demon-
longitudinal and oblique fibers in the systemic
stration of substantial departure from the typical
right ventricle, which is believed to be an adaptive
mammalian
response
(Figure
to
the
systemic
pressure
and
load
helical
cardiomyocyte
arrangement
20). In addition to the abnormal car-
(Supplemental Ref. 4). A larger study of 12 patients
diomyocyte arrangement in situs inversus totalis,
with situs inversus totalis, 12 healthy situs solitus
there was also impaired sheetlet mobility with fail-
control subjects, and 2 ex vivo situs inversus totalis
ure to achieve the expected systolic orientation.
hearts showed deranged cardiomyocyte orientation,
This might reflect cardiomyocyte derangement that
sheetlet abnormalities, and functional impairment in
affected the transverse shears that were integral to
situs inversus totalis (62). All situs solitus hearts
sheetlet reorientation (6). These findings reinforced
displayed the expected helical arrangement. By
the connection between the microstructure and
contrast, in situs inversus totalis, HAs were more
cardiac mechanics. The abnormal cardiomyocyte
heterogeneous, both intrasubject and intersubject.
structure in situs inversus totalis raises the question
However, the general pattern was an inverted HA
of whether such patients might have a greater sus-
arrangement at the base, with positive HAs in the
ceptibility to heart failure with a “second hit” to
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F I G U R E 1 6 E2A Abnormalities in HCM
Healthy control
HCM patient 80
45
Diastole
10
80
Systole
45
10
90 80 p = 0.026 70 E2 Angle (Degrees)
16
60 50 40 30 20 p < 0.001 10 Diastole-Systole Controls Controls
Diastole-Systole HCM HCM
Quartiles
Example E2A maps of a mid-ventricle slice. The healthy control subject has a blue (low E2A) map in diastole and a red (higher E2A) map is systole. In hypertrophic cardiomyopathy (HCM), maps are predominantly red, displaying elevated E2A at both cardiac phases. The plot below shows that diastolic E2A is significantly elevated compared with the healthy control subjects, as is systolic E2A. Adapted with permission from Ferreira et al. (29). Abbreviation as in Figure 13.
function,
such
as
hypertension,
infarction,
or
applicability and usefulness of the technique. Two
myocarditis.
main streams of future development are needed:
FUTURE DIRECTIONS OF DT-CMR
technical would
and
address
clinical. spatial
Technical and
developments
angular
resolution,
DT-CMR can identify microstructural changes in
scan acceleration, increased coverage, and refining
disease. Further work is required to broaden the
the
understanding
of
strain
effects.
Clinical
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F I G U R E 1 7 E2A Findings in Dilated Cardiomyopathy
B
Control
DCM
0.30
0.30
0.25
0.25
0.20
0.20 Frequency
Frequency
A
0.15
0.15
0.10
0.10
0.05
0.05
0
0
–100 –80
–60
–40
–20
0
20
40
60
80
100
–100 –80
–60
–40
E2A Angles [*] Diastole
C
Systole
Diastole
D
0.20
0.20
0.15
0.15
0.10 0.05 0
–0.10
20
80
100
40
60
80
100
60
80
100
Systole
0
–0.10
0
60
0.05
–0.05
–20
40
0.10
–0.05
–40
20
DCM 0.25
Change in Frequency
Change in Frequency
Control
–60
0
E2A Angles [*]
0.25
–100 –80
–20
–100 –80
–60
–40
–20
0
20
E2A Angles [*]
E2A Angles [*]
Data
Data
Model
40
Model
(A and B) E2A histograms for control subjects and patients with dilated cardiomyopathy. Diastolic and systolic distributions are shown by solid and dashed lines, respectively. (C and D) Change from the expected computer model results. Reprinted with permission from von Deuster et al. (30).
development might see DT-CMR playing a role as a
debate on whether patients with DCM whose EF is
diagnostic and prognostic tool. The ability to detect
improving have achieved recovery or remission. In
microstructural changes before manifest disease
HCM, the ability (if possible in the future) to detect
expression may offer a role for earlier diagnosis of
disarray in vivo could assist risk stratification for
cardiomyopathies. It may also help identify pa-
predicting sudden cardiac death. Similarly, identi-
tients at risk of developing heart failure, not only
fying those at risk of potentially life-threatening
in
and
arrhythmias after infarction is another area in
ischemic heart disease. DT-CMR may inform the
which DT-CMR has the potential to offer novel
cardiomyopathy,
but
also
congenital
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F I G U R E 1 8 Abnormal Sheetlet Reorientation in Dilated Cardiomyopathy
SHEETLET PLANE ORIENTATION E2
CONTROLS - DIASTOLE
CONTROLS - SYSTOLE
HCM – DIASTOLE
HCM – SYSTOLE
DCM – DIASTOLE
DCM – SYSTOLE
E1
(Top-right inset) Sheetlet planes are defined by the primary and secondary eigenvectors (E1 and E2). Septal glyphs are shown, color-coded according to absolute E2A (blue towards wall-parallel and red towards wall-perpendicular). Healthy control subjects show a more wallparallel alignment in diastole and more wall-perpendicular alignment in systole. However, in HCM, sheetlets retain the more wallperpendicular arrangement of systole in both cardiac phases. Conversely, in dilated cardiomyopathy (DCM), the more wall-parallel arrangement of diastole persists in both cardiac phases. Replotted from Nielles-Vallespin et al. (8). Abbreviation as in Figure 16.
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Absolute E2A Mobility (Degrees)
F I G U R E 1 9 E2A mobility and EF Plot in Recovered DCM
60 50 Median p = 0.001
40
Median
30 20 10 0 –10 20
30
40
50
60
70
80
LVEF (%) Controls
Recovered DCM
DCM
Secondary eigenvector (E2A) mobility plotted against left ventricle ejection fraction (LVEF). Patients with DCM patients have low LVEF and low E2A mobility. Both control subjects and recovered DCM groups have normal EF, but the recovered DCM group can be discriminated by their significantly lower E2A mobility. Reprinted with permission from Khalique et al. (61). Abbreviations as in Figures 13 and 18.
F I G U R E 2 0 LV Tractography in SIT
ENDOCARDIUM
SITUS SOLITUS
EPICARDIUM
SIT IN VIVO
Helix angle (degrees) +90 +45 +0 -45
SIT EX VIVO
-90
LV tractography of a situs solitus (SS) and situs inversus (SIT) heart. The contrast between the left-handed helix (blue) in the SS heart, and the right-handed helix (red) in the SIT heart is particularly striking. Modified with permission from Khalique et al. (62).
19
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CONCLUSIONS
HIGHLIGHTS DT-CMR is a unique technique for noninvasive assessment of myocardial microstructure.
DT-CMR is establishing itself as a technique that can
DT-CMR has identified novel cardiomyocyte and sheetlet abnormalities in cardiac disease in vivo.
cardiomyocyte and sheetlet structure and micro-
DT-CMR has the potential to aid clinical diagnosis and risk stratification through microscopic phenotyping.
potential to progress to a clinically useful tool aiding
interrogate the cardiac microstructure and its relation to function. For the first time, it is possible to assess structural dynamics using a noninvasive approach. DT-CMR provides insight into pathological changes in disease, and, with this new understanding, it has the diagnosis and prognosis, as well as guiding patient management.
prognostic information. Expansion to other cardio-
ADDRESS FOR CORRESPONDENCE: Professor Dudley
myopathies and congenital heart disease may offer
Pennell, CMR Unit, Royal Brompton Hospital, London
new
SW3 6NP, United Kingdom. E-mail: Dj.pennell@rbht.
pathophysiological
insight
conditions.
into
these
nhs.uk.
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KEY WORDS cardiomyocytes, diffusion tensor CMR, helix angle, microstructure, sheetlets
A PPE NDI X For supplemental references, a table, and videos, please see the online version of this paper.
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