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Quantitative Tissue-Tracking Cardiac Magnetic Resonance (CMR) of
Left Atrial Deformation and the Risk of Stroke in Patients With Atrial
Fibrillation
Yuko Y. Inoue, MD, PhD; Abdullah Alissa, MBBS; Irfan M. Khurram, MD; Kotaro Fukumoto, MD, PhD; Mohammadali Habibi, MD;
Bharath A. Venkatesh, PhD; Stefan L. Zimmerman, MD; Saman Nazarian, MD, PhD; Ronald D. Berger, MD, PhD; Hugh Calkins, MD;
Joao A. Lima, MD; Hiroshi Ashikaga, MD, PhD
Background-—Recent evidence suggests that left atrial (LA) dysfunction may be mechanistically contributing to cerebrovascular
events in patients with atrial fibrillation (AF). We investigated the association between regional LA function and a prior history of
stroke during sinus rhythm in patients referred for catheter ablation of AF.
Methods and Results-—A total of 169 patients (5910 years, 74% male, 29% persistent AF) with a history of AF in sinus rhythm at
the time of pre-ablation cardiac magnetic resonance (CMR) were analyzed. The LA volume, emptying fraction, strain (S), and strain
rate (SR) were assessed by tissue-tracking cardiac magnetic resonance. The patients with a history of stroke or transient ischemic
attack (n=18) had greater LA volumes (V
max
and V
min
;P=0.02 and P<0.001, respectively), lower LA total emptying fraction
(P<0.001), lower LA maximum and pre-atrial contraction strains (S
max
and S
preA
;P<0.001 and P=0.01, respectively), and lower
absolute values of LA SR during left ventricular (LV) systole and early diastole (SR
s
and SR
e
;P=0.005 and 0.03, respectively) than
those without stroke/transient ischemic attack (n=151). Multivariable analysis demonstrated that the LA reservoir function,
including total emptying fraction, S
max
, and SR
s
, was associated with stroke/transient ischemic attack (odds ratio 0.94, 0.91, and
0.17; P=0.03, 0.02, and 0.04, respectively) after adjusting for the CHA
2
DS
2
-VASc score and LA V
min
.
Conclusions-—Depressed LA reservoir function assessed by tissue-tracking cardiac magnetic resonance is significantly associated
with a prior history of stroke/transient ischemic attack in patients with AF. Our findings suggest that assessment of LA reservoir
function can improve the risk stratification of cerebrovascular events in AF patients. (J Am Heart Assoc. 2015;4:e001844 doi:
10.1161/JAHA.115.001844)
Key Words: atrial fibrillation •atrial strain •magnetic resonance imaging •stroke •tracking
Atrial fibrillation (AF)—the most common arrhythmia—
affects 6 million individuals in the United States. AF is
associated with an increased risk of stroke
1,2
that can be
fatal, and survivors are often left permanently disabled.
Mechanistically, cerebrovascular events in AF patients are
thought to result from ineffective contraction during AF and
subsequent intracardiac thrombosis. However, recent evi-
dence suggests that underlying atrial fibrosis and subsequent
atrial dysfunction may also be mechanistically contributing to
cerebrovascular events in AF patients. For example, an
increased left atrial (LA) volume and global LA dysfunction
in individuals without clinically recognized AF are an indepen-
dent predictor of clinical stroke/transient ischemic attack
(TIA)
3–4
as well as subclinical cerebrovascular events detected
by brain magnetic resonance imaging (MRI).
5
Our previous
study demonstrated that the degree of regional LA dysfunc-
tion during sinus rhythm is proportional to the extent of
underlying fibrosis quantified by late gadolinium enhancement
(LGE) on cardiac magnetic resonance (CMR) in AF patients.
6
In addition, regional LA function during AF is significantly
depressed in patients with a prior history of stroke compared
with those without, independent of the CHA
2
DS
2
-VASc
From the Division of Cardiology (Y.Y.I., A.A., I.M.K., K.F., M.H., S.N., R.D.B.,
H.C., J.A.L., H.A.), The Russell H. Morgan Department of Radiology and
Radiological Sciences (B.A.V., S.L.Z.), and Department of Biomedical Engineer-
ing (R.D.B., H.A.), Johns Hopkins University School of Medicine, Baltimore, MD;
Department of Epidemiology, Johns Hopkins University School of Public Health,
Baltimore, MD (S.N.).
Accompanying Videos S1 and S2 are available at http://jaha.ahajour-
nals.org/content/4/4/e001844/suppl/DC1
Correspondence to: Hiroshi Ashikaga, MD, PhD, Cardiac Arrhythmia Service,
Division of Cardiology, Johns Hopkins University School of Medicine, 600 N.
Wolfe St, Carnegie 568, Baltimore, MD 21287. E-mail: hashika1@jhmi.edu
Received February 18, 2015; accepted March 27, 2015.
ª2015 The Authors. Published on behalf of the American Heart Association,
Inc., by Wiley Blackwell. This is an open access article under the terms of the
Creative Commons Attribution-NonCommercial License, which permits use,
distribution and reproduction in any medium, provided the original work is
properly cited and is not used for commercial purposes.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 1
ORIGINAL RESEARCH
score,
7,8
the standard system of risk stratification for stroke
based on age, sex, and comorbidities.
9
To further support the concept that the underlying atrial
fibrosis and subsequent LA dysfunction may be mechanis-
tically contributing to cerebrovascular events in AF patients,
we investigated the association between regional LA func-
tion and a prior history of stroke during sinus rhythm in
patients referred for catheter ablation of AF. We used tissue-
tracking CMR
10,11
to quantify the LA volume and regional LA
function.
Methods
Study Design
To examine the association of LA structure and function as
determined by tissue-tracking CMR with a prior history of
stroke or TIA, a single-center, retrospective, cross-sectional
study was performed within a longitudinal, prospectively
enrolled database for all the patients referred to the Johns
Hopkins Hospital for catheter ablation of AF. Between June
2010 and August 2013, 525 consecutive patients were
referred for AF ablation (Figure 1). Among these, 300 patients
underwent a routine pre-ablation CMR. We excluded patients
who were in AF at the time of CMR (n=92, 31%) because the
CMR image quality is often poor and the measured LA strains
are depressed during AF compared with those in sinus
rhythm.
12
We also excluded patients who had a prior AF
ablation procedure (n=33), severe valvular disease in echo-
cardiography (n=3), or poor-quality CMR images (n=3). Thus,
169 patients were included in the final analysis. The stroke
group (n=18, 11.8%) was identified as those with a prior
history of stroke or TIA at the time of CMR; the remaining
patients were designated as the control group (n=151). The
patients were classified as having either paroxysmal or
persistent AF based on the guidelines,
9
and the thromboem-
bolic risk was assessed using the CHADS
2
and the CHA
2
DS
2
-
VASc scores.
13,14
In general, the patients with persistent AF
were placed on antiarrhythmic medications and referred for
external cardioversion 3 to 4 weeks prior to CMR.
15
All
patients gave an informed consent to be included in the
prospective patient database prior to the pre-ablation CMR,
and the protocol was approved by the Institutional Review
Board of the Johns Hopkins Medicine.
CMR Protocol
CMR was performed with a 1.5-T scanner (Avanto; Siemens
Medical Systems, Erlangen, Germany) and a 6-channel phased
array body coil in combination with a 6-channel spine matrix
coil. All images were ECG gated and acquired with breath-
holding, with the patient in a supine position. Cine CMR
images were scanned in the radial long axis by True Fast
Imaging with Steady-State Precession (TrueFISP) sequence
with a TE/TR and flip angle of 1.2/2.4 ms and 80°, an in-
plane resolution of 1.491.4 mm, a slice thickness of 8 mm,
and a spacing of 2 mm. The images were acquired with 30
frames during the time interval between the R-peak of the
ECG (temporal resolution, 20 to 40 ms). Among the 169
patients included in the final analysis, 85 (n=5 in the stroke
group and n=80 in control group) also underwent late
gadolinium enhancement (LGE) to quantify LA fibrosis. LGE-
MRI scans were acquired within a range of 15 to 25 minutes
after the injection of gadopentetate dimeglumine (0.2 mmol/
kg, Bayer Healthcare Pharmaceuticals, Montville, NJ) using a
fat-saturated 3-dimensional (3-D) inversion recovery-prepared
fast spoiled gradient-recalled echo sequence with the follow-
ing: respiratory navigation and ECG gating with TE/TR and flip
angle of 1.52/3.8 ms and 10°, an in-plane resolution of
1.391.3 mm, and a slice thickness of 2.0 mm. Trigger time
for 3-DLGE-MRI images was optimized to acquire imaging data
during diastole of LA as observed from the cine images. The
optimal inversion time was identified with an inversion time
scout scan (median 270 ms; range 240 to 290 ms) to
maximize nulling of the LA myocardium. A parallel imaging
technique—generalized autocalibrating partially parallel
acquisition (reduction factor 2)—was used. Image processing
was conducted in QMass MR (version 7.2; Leiden University
Medical Center, Leiden, The Netherlands) on multiplanar
reformatted axial images from 3-D axial image data. To define
LA fibrosis, we used the cutoff value of >0.97 for image
intensity ratio, which has been shown to correspond to the
bipolar voltage <0.5 mV.
16
Figure 1. Patient enrollment. AF indicates atrial fibrillation;
CMR, cardiac magnetic resonance.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 2
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
Tissue-Tracking CMR
We used off-line semiautomated multimodality tissue-tracking
software version 6.0 (Toshiba, Tokyo, Japan) to analyze the LA
and left ventricular (LV) structure and function in long-axis 2-
and 4-chamber cine images (Figure 2A and 2B).
1
The endo-
and epicardial borders, excluding pulmonary veins and LA
appendage, were manually traced. The number of pixels that
lay across the LA and LV wall was 2.21.2 and 8.82.7,
respectively. Multimodality tissue-tracking is similar in con-
cept to 2-dimensional (2-D) speckle-tracking imaging. Briefly,
multimodality tissue-tracking reads characteristic pixel pat-
terns in each 10910 mm area as template pieces from the
reference image. The identified area as a template was
searched in the next frame to find the best match according
to the mean squared error of the image pixel intensity. This
was used to accurately track pixel locations between
subsequent image frames. Repeating the algorithm, the LA
wall was automatically tracked through the cardiac cycle
(Videos S1 and S2). With this 2-D displacement field over time
from the reference configuration to the deformed configura-
tion, the differentiation with respect to the reference config-
uration gives the deformation gradient tensor (F), which
depends on position. The Lagrangian Green’s strain tensor (E)
was then calculated as:
E¼1
2ðFTFIÞ(1)
where F
T
is the transpose of Fand Iis the identity matrix. The
strain (S) was defined as a stretch ratio along the longitudinal
A
CDE
B
Figure 2. LA measurements by tissue-tracking CMR in a patient without stroke. A and B, Left atrium (LA) longitudinal strain in the 2- and 4-
chamber views at the end of left ventricular (LV) systole. C, LA volume curve. The pink dotted line is the average of the values of volume in the 2-
and 4-chamber views. The LA maximum volume (V
max
), the pre-atrial contraction volume (V
preA
), and the minimum volume (V
min
) were identified.
The LA emptying fractions (EFs) were calculated using V
max
,V
preA
, and V
min
. D and E, The LA strain and strain rate curve. The LA maximum strain
(S
max
) and pre-atrial contraction strain (S
preA
) were identified from the strain curve. The strain rates during LV systole (SR
s
), LV early diastole
(SR
e
), and atrial contraction (SR
a
) were also analyzed from the strain rate curve. CMR indicates cardiac magnetic resonance.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 3
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
axis that represents the length normalized to its length at the
reference configuration:
S¼100x ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
2Ell þ1
pð%Þ(2)
where E
ll
is the strain with respect to the local longitudinal
axis calculated from the E.
The global longitudinal strain and strain rate were calcu-
lated by averaging all of the strain values obtained in long-axis
2- and 4-chamber views. A positive and negative strain value
indicates stretch and shortening, respectively, with respect to
the reference configuration at the ventricular end-diastole
defined as the peak of R wave on surface ECG. LA maximum
strain (S
max
) and pre-atrial contraction strain (S
preA
) were
identified from the strain curve (Figure 2D); the strain rates in
LV systole (SR
s
), LV early diastole (SR
e
), and LA contraction
(SR
a
) were obtained from the strain rate curve (Figure 2E).
The LA volume curve was generated by the biplane modified
Simpson’s method, which was validated using the area-length
method,
10,17,18
and the maximum LA volume (V
max
), pre-atrial
contraction LA volume (V
preA
), and minimum LA volume (V
min
)
were extracted (Figure 2C). All the LA volumes were indexed by
the body surface area (BSA) according to DuBois’formula (eg,
BSA=0.0071849[weight
0.425
]9[height
0.725
]). From the LA
volumes, the LA emptying fractions (EF) were calculated as
follows
19
: (1) LA total EF=(V
max
V
min
)9100%/V
max
, (2) LA
passive EF=(V
max
V
preA
)9100%/V
max
, and (3) LA active
EF=(V
preA
V
min
)9100%/V
preA
.
Reproducibility
Intra- and interobserver reproducibility for the LA parameters
were examined in a group of 20 randomly selected patients by
1 investigator who made 2 independent measurements, and
by 2 other investigators who were unaware of the other
investigator’s measurements and of the study time point. The
bias (mean difference) and limits of agreement (1.96 SD
of difference) between the first and second measurements
were determined by the Bland-Altman method. Intraclass
correlation coefficients were also assessed to evaluate
reproducibility.
Statistical Analysis
Continuous variables were presented as the meansSD and
categorical variables as frequencies and percentages. The
participants’baseline data and LA parameters were compared
between the stroke and the control groups using Student t
test for continuous variables and v
2
test for categorical
variables. Univariable and multivariable logistic regression
analyses were performed to evaluate the association between
clinical variables and stroke/TIA. Model 1 reflected
(univariable) unadjusted relations of LA and LV measurements
to stroke/TIA. Model 2 was adjusted for the CHA
2
DS
2
-VASc
score prior to stroke/TIA to incorporate a history of Cardiac
failure, Hypertension, Age, Diabetes, Stroke/TIA, Vascular
disease, and Sex. In Model 3, an additional adjustment was
made for the LA V
min
. The incremental value for assessing the
risk of stroke was studied by calculating the improvement in
the global v
2
. Data were analyzed with JMP version 10.0 (SAS
Institute, Inc, Cary, NC) and MedCalc version 13.3 (MedCalc
Software, Inc, Mariakerke, Belgium). A 2-sided P-value of
<0.05 was considered statistically significant.
Results
Patient Demographics
Clinical characteristics of the patients are summarized in
Table 1. A total of 169 patients (5910 years, 74% male, 29%
persistent AF) were included in the analysis. Compared to the
control group, patients in the stroke group were significantly
older (P=0.02). Other clinical characteristics, including the
CHADS
2
score and CHA
2
DS
2
-VASc scores, did not show any
significant difference between the stroke and control groups.
Three of 18 patients (16.7%) in the stroke group and 18 of
Table 1. Patient Demographics
Stroke
(n=18)
Control
(n=151) PValue
Age, y 65.08.2 58.510.6 0.02*
Sex, male 12 (66.7) 113 (74.8) 0.50
Body mass index, kg/m
2
27.82.4 28.05.3 0.94
Type of AF (persistent) 5 (27.8) 44 (29.1) 0.91
Coronary artery disease 4 (22.2) 16 (10.6) 0.14
Hypertension 7 (38.9) 60 (39.7) 0.94
Heart failure 2 (11.1) 12 (7.9) 0.63
Diabetes mellitus 3 (16.7) 18 (11.9) 0.55
CHADS
2
score before stroke 0.940.90 0.740.90 0.20
CHA
2
DS
2
-VASc score
before stroke
2.001.32 1.451.49 0.07
Medications
b-Blockers 10 (55.5) 73 (48.3) 0.70
Ca-channel blockers 6 (33.3) 33 (21.9) 0.44
ACE inhibitors/ARBs 6 (33.3) 49 (32.5) 0.96
Statins 7 (38.9) 62 (41.1) 0.86
Number of antiarrhythmic
drugs
1.40.9 1.60.9 0.60
Data are expressed as the meansSD, or as n (%). ACE indicates angiotensin -converting
enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker.
*P<0.05.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 4
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
151 patients (11.9%) in the control group underwent cardio-
version before pre-ablation CMR (P=0.84). There was no
significant difference in AF duration before cardioversion
(3.33.2 versus 1.21.3 years, P=0.15) and the time from
cardioversion to CMR (59.742.7 versus 52.242.7 days,
P=0.80).
LA Function and Stroke
The time course of LA volume, strain, and strain rate in
representative patients with and without stroke are shown in
Figure 3. The CMR parameters in the stroke and the control
groups are shown in Table 2. In the stroke group, the LA
volumes (V
max
,V
preA
, and V
min
) were significantly higher, the
LA EFs (total, passive, and active) were lower, the LA
longitudinal S
max
and S
preA
were lower, and the absolute
values of the LA SR
s
and SR
e
were lower than in the control
group. There was no significant difference regarding LA wall
LGE between the 2 groups (stroke group versus control group:
29.317.6% versus 27.116.1%, respectively, P=0.75). LV
parameters, including mass index, ejection fraction, end-
diastolic volume index, and longitudinal strain, did not show
any significant difference between the stroke and control
groups.
Univariable and Multivariable Analyses
The univariable and multivariable analyses regarding the
association between the CMR-measured parameters and
stroke are summarized in Table 3. In Model 1, a univariable
analysis identified larger LA volumes (V
max
,V
preA
, and V
min
),
lower EFs (total, active, and passive EF), lower strains (S
max
and S
preA
), and lower absolute values of SR (SR
s
and SR
e
)
as significant contributors to stroke, indicating that all of
the LA parameters that differed significantly between the
stroke and control groups in Table 2 remained significant
and were associated with stroke. In Model 2, larger V
preA
and V
min
, lower EFs (total, active, and passive EF), lower
strains (S
max
and S
preA
), and lower SR
s
were significantly
associated with stroke after adjusting for the CHA
2
DS
2
-
VASc score. In Model 3, only the LA total EF, S
max
, and
SR
s
, which reflect the LA reservoir function (Figures 2 and
3), remained significant after additionally adjusting for the
LA V
min
.
ABC
Figure 3. LA measurements by tissue-tracking CMR in patients with and without stroke. A, The LA volume, (B) LA global longitudinal strain,
and (C) LA strain rate in a patient with stroke (red line) and without stroke (blue line). The patient with stroke has a larger LA volume and smaller
strain and strain rate. The LA serves as a reservoir during LV systole, as a conduit during LV early diastole, and as an active pump during late
diastole. CMR indicates cardiac magnetic resonance; LA, left atrial; LV, left ventricular; S
max
, maximum strain; S
preA
, pre-atrial contraction strain;
SR
a
, strain rate at atrial contraction; SR
e
, strain rate at LV early diastole; SR
s
, maximum strain rate; V
max
, maximum indexed volume; V
min
,
minimum indexed volume; V
preA
, pre-atrial contraction indexed volume.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 5
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
Incremental Value of LA Function as a Marker of
Stroke
Additionally, we found that adding the CMR-measured LA
function significantly improved the statistics of the model on the
basis of the conventional risk stratification of strokes (Figure 4).
The LA V
min
provided incremental value over the CHA
2
DS
2
-VASc
score, and the diagnostic value was further improved by adding
the global LA S
max
(P=0.017 and 0.009, respectively).
Reproducibility of LA Analysis by Tissue-Tracking
CMR
The intra-observer intraclass correlation coefficient was
between 0.88 and 0.99, and the interobserver intraclass
correlation coefficient was between 0.89 and 0.99 for all
measured LA parameters from tissue-tracking CMR (Table 4).
Discussion
Main Findings
We found that greater LA volumes, lower LA EFs, lower strain,
and lower peak SR were associated with a prior history of
stroke. We also found that LA total EF, LA S
max
, and SR
s
,
representing the LA reservoir function, are independently
associated with stroke or TIA after adjusting for potential
confounders and clinical risk factors. These results are
consistent with the previous reports that the reduced LA
reservoir function assessed using transthoracic echocardiog-
raphy in the absence of AF is an independent predictor of
clinical stroke/TIA
4
as well as subclinical cerebrovascular
events detected by brain MRI.
5
Our findings are particularly
important because, to our knowledge, this is the first report to
demonstrate the significant contribution of the LA reservoir
function to stroke in AF patients during sinus rhythm.In
contrast to studies that showed a significant association
between stroke and the LA reservoir function with echocar-
diography during AF,
7,8
the sinus rhythm in our study allowed
us to assess all the LA function components, including the
reservoir function, conduit function, and booster pump
function, and to successfully determine that only the LA
reservoir function is significantly associated with stroke. This
important finding further supports the concept that the
underlying atrial fibrosis and subsequent LA dysfunction is
mechanistically contributing to cerebrovascular events in AF
patients.
Depressed LA Reservoir Function as a
Mechanism of Thromboembolic Events in AF
Patients
The atrial function consists of 3 components: a reservoir
function for pulmonary venous return during LV systole, the
conduit function for pulmonary venous return during LV early
diastole, and the booster pump function that augments LV
filling during LV late diastole (Figure 3). LA total EF, S
max
, and
SR
s
represent LA compliance and reservoir function, reflecting
the passive stretch of the LA during LV systole. The
mechanism as to how the depressed LA reservoir function
leads to thromboembolic events is unclear. It is possible that
the depressed LA reservoir function results in blood flow
stasis in the LA and subsequent thrombus formation. Studies
have also shown that low LA strains are associated with low
flow velocities and thrombi in the LA appendage,
20
which is
the most common site of intracardiac thrombus.
21
Of note,
since none of the LV indices—mass, ejection fraction, end-
diastolic volume, and longitudinal strain—were significantly
associated with stroke/TIA, the role of the LA reservoir
function in the pathogenesis of intracardiac thrombosis is not
due to the indirect consequence of LV function. The possibility
that cardioversion-induced atrial stunning could have con-
founded our findings is low because (1) cardioversion was
performed in only a minority of patients in both groups; (2)
there was no significant difference in the fraction of patients
who underwent cardioversion between both groups; and (3)
Table 2. Comparison of CMR Measurements Between the
Stroke and Control Groups
Stroke
(n=18)
Control
(n=151) PValue
LA V
max
, mL/m
2
52.216.2 44.212.9 0.024*
LA V
preA
, mL/m
2
44.814.5 35.711.7 0.005*
LA V
min
, mL/m
2
35.115.8 24.610.7 <0.001*
LA total EF, % 34.613.5 45.611.8 <0.001*
LA passive EF, % 14.15.6 19.77.8 0.005*
LA active EF, % 23.815.8 32.710.9 0.004*
LA S
max
, % 19.49.2 28.610.6 <0.001*
LA S
preA
, % 10.16.6 15.07.1 0.010*
LA SR
s
, 1/s 0.810.37 1.150.47 0.005*
LA SR
e
, 1/s 0.780.41 1.120.62 0.033*
LA SR
a
, 1/s 1.140.55 1.520.84 0.071
LV mass index, g/m
2
71.016.1 65.614.6 0.177
LV ejection fraction, % 54.414.6 57.39.5 0.281
LV end-diastolic
volume index, mL/m
2
78.726.7 71.712.4 0.292
LV longitudinal strain, % 16.55.2 18.24.4 0.149
Data are expressed as the meansSD. CMR indicates cardiac magnetic resonance; EF,
emptying fraction; LA, left atrial; LV, left ventricular; S
max
, maximum strain; S
preA
, pre-
atrial contraction strain; SR
a
, strain rate at atrial contraction; SR
e
, strain rate at LV early
diastole; SR
s
, maximum strain rate; V
max
, maximum indexed volume; V
min
, minimum
indexed volume; V
preA
, pre-atrial contraction indexed volume.
*P<0.05.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 6
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
CMR was performed 8 weeks after cardioversion on
average, while cardioversion-induced atrial stunning usually
recovers within 4 weeks.
22
In our data set, there was no
significant difference in the extent of the LA fibrosis quantified
by LGE MRI between the stroke group and the control group.
This finding is not consistent with a previous report,
23
but this
may be due to a small sample size since only a small number
of patients underwent LGE (85 out of 169 patients).
LA Measurements by Tissue-Tracking CMR
CMR has been established as a highly accurate and repro-
ducible imaging modality, and is considered a standard
clinical technique for measuring LA dimensions and vol-
umes.
24,25
We analyzed LA volume and function with tissue-
tracking CMR, which has been used to measure multiple LA
parameters with excellent intra- and interobserver reproduc-
ibility in healthy subjects.
10,11
Consistent with these previous
reports, our results showed excellent inter- and intraobserver
reproducibility for LA strain analysis with tissue-tracking CMR,
which is similar or superior to those of speckle-tracking
echocardiography
26
Additionally, tissue-tracking CMR can be
performed with a routine cine CMR examination and does not
require separate image acquisitions (eg, tagged MRI or
displacement encoding with stimulated echoes (DENSE)
27
)
or contrast media, although contrast media might be used in
clinical settings to identify LA wall fibrosis in LGE and LA
appendage thrombus as a sign of possible impending stroke
in CMR angiography before AF ablations.
28
Another strength
of tissue-tracking CMR is that it is user friendly. The images
can be analyzed within minutes per patient by an operator
without prior experience in image analysis, in contrast to LA
Table 3. Univariable and Multivariable Analyses of the Associations Between CMR Measurements and Stroke
Model 1 Model 2 Model 3
OR 95% CI PValue OR 95% CI PValue OR 95% CI PValue
LA V
max
1.04 1.01 to 1.08 0.030* 1.04 0.99 to 1.08 0.062 —
LA V
preA
1.06 1.02 to 1.10 0.008* 1.05 1.01 to 1.10 0.019* —
LA V
min
1.07 1.03 to 1.11 0.002* 1.06 1.02 to 1.11 0.005* —
LA total EF 0.93 0.89 to 0.97 0.002* 0.93 0.89 to 0.97 0.002* 0.94 0.89 to 0.99 0.030*
LA passive EF 0.89 0.81 to 0.96 0.007* 0.89 0.81 to 0.96 0.020* 0.92 0.83 to 1.00 0.063
LA active EF 0.94 0.90 to 0.98 0.006* 0.94 0.90 to 0.98 0.008* 0.96 0.91 to 1.00 0.074
LA S
max
0.90 0.83 to 0.96 0.002* 0.90 0.83 to 0.95 0.002* 0.91 0.84 to 0.97 0.018*
LA S
preA
0.89 0.80 to 0.97 0.012* 0.89 0.80 to 0.97 0.016* 0.92 0.82 to 1.01 0.091
LA SR
s
0.10 0.02 to 0.44 0.006* 0.11 0.02 to 0.50 0.009* 0.17 0.02 to 0.94 0.042*
LA SR
e
3.11 1.14 to 8.72 0.039* 2.88 1.04 to 9.69 0.055 2.21 0.72 to 7.49 0.175
LA SR
a
2.21 1.02 to 5.50 0.066 2.08 0.94 to 5.24 0.095 1.48 0.66 to 3.94 0.391
LV mass index 1.03 0.99 to 1.06 0.189 1.02 0.98 to 1.06 0.224 1.02 0.98 to 1.06 0.321
LV ejection fraction 0.98 0.93 to 1.03 0.301 0.98 0.93 to 1.03 0.347 0.98 0.93 to 1.06 0.547
LV EDVI 1.02 0.99 to 1.05 0.253 0.98 0.95 to 1.01 0.262 0.98 0.95 to 1.01 0.303
LV longitudinal strain 1.08 0.97 to 1.21 0.151 1.07 0.96 to 1.20 0.223 1.05 0.94 to 1.18 0.399
Model 1: unadjusted. Model 2: adjusted for CHA
2
DS
2
-VASc score. Model 3: additionally adjusted for the LA V
min
. CMR indicates cardiac magnetic resonance; EDVI, end-diastolic volume
index; EF, emptying fraction; LA, left atrial; LV, left ventricular; OR, odds ratio; S
max
, maximum strain; S
preA
, pre-atrial contraction strain; SR
a
, strain rate at atrial contraction; SR
e
, strain rate
at LV early diastole; SR
s
, maximum strain rate; V
max
, maximum indexed volume; V
min
, minimum indexed volume; V
preA
, pre-atrial contraction indexed volume.
*P<0.05.
Figure 4. Incremental value of left atrial (LA) strain for diagno-
sis of stroke. The addition of the LA minimum volume (V
min
) to the
model on the basis of the CHA
2
DS
2
-VASc score resulted in
significant improvement in the diagnostic value for stroke. The
value was further increased by adding the LA global longitudinal
maximum strain (S
max
).
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 7
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
fibrosis quantification with LGE that require hours of analysis
per patient in the hands of an expert.
Clinical Implications
The CHADS
2
and CHA
2
DS
2
-VASc scores are the most widely
accepted and validated models to estimate the risk of stroke in
AF patients.
13,14
In addition, an increased LA volume is also
associated with a higher risk of stroke.
29
Our results demon-
strate that the LA reservoir function is significantly associated
with a prior history of stroke/TIA independent of the CHA
2
DS
2
-
VASc score and the LA volume (Table 3). Our results offer a
basis for a prospective study to determine the role of LA
reservoir function by tissue-tracking CMR in predicting stroke
or TIA. This may improve the current risk stratification strategy
for stroke and potentially allow for early identification of
subjects at risk of stroke, with or without a history of AF.
Aggressive clinical management, such as early ablation or
pharmacotherapy for AF to improve LA remodeling
30,31
and
early anticoagulation may reduce the risk of stroke in subjects
with a high risk of stroke. In addition, further studies are
warranted to investigate whether the risk of stroke decreases if
LA function improves by these therapies.
Study Limitations
This study represents a single-center, retrospective, cross-
sectional analysis. Therefore, there is a non-negligible chance
of selection bias. For example, the analysis may be missing
patients who died of stroke. In addition, CMR was not
performed at the time of stroke/TIA, and the time from stroke
to CMR could not be determined from the records. When
evaluating the predictive value of the LA parameters for
stroke, baseline LA strain analysis should ideally be assessed
before stroke. Moreover, the stroke mechanism in each
patient is unclear from the records. For the deformation
analysis, we used only 2- and 4-chamber cine CMR, which was
included in a routine image-acquisition protocol. Therefore, it
is possible that our analysis underestimated the degree of
dysfunction by missing regional dysfunction that was not
covered by those 2 views. Since the strain was 2-D and was
obtained only in the in-plane direction, the strain values may
have been underestimated compared with those in 3-D
strains. In addition, the endo- and epicardial contours included
the ostium of pulmonary veins and the LA appendage in a
small number of patients. This could have led to underesti-
mation of strain values; however, 2 previous studies used the
same approach and validated the results.
10,11
Despite these
potential causes of underestimation, our analysis demon-
strated a significant association between LA dysfunction and
a prior history of stroke with excellent reproducibility
(Table 4). Therefore, we believe that the advantage of our
approach outweighs the disadvantage of including more views
(eg, multiple short-axis LA slices) and of excluding the ostia
area to assess the whole LA deformation, which would
increase the scan time and postprocessing burden.
Conclusions
CMR measurements indicate that lower LA total EF, S
max
, and
SR
s
, representing LA reservoir function, are significantly
Table 4. Reproducibility of the LA Analysis by Tissue-Tracking CMR
Intra-Observer Inter-Observer
Bias
Limits of
Agreement ICC Bias
Limits of
Agreement ICC
LA V
max
, mL/m
2
0.57 4.50 0.96 1.25 4.08 0.99
LA V
preA
, mL/m
2
0.93 3.42 0.97 0.34 4.75 0.99
LA V
min
, mL/m
2
0.83 3.68 0.98 1.61 4.31 0.98
LA total EF, % 1.94 7.75 0.94 1.67 4.78 0.89
LA passive EF, % 0.82 5.41 0.98 0.92 7.81 0.92
LA active EF, % 2.47 10.78 0.88 3.11 0.51 0.90
LA S
max
,% 0.75 3.19 0.94 1.26 2.88 0.90
LA S
preA
,% 1.20 2.99 0.96 1.64 2.17 0.98
LA SR
s
, 1/s 0.10 0.43 0.91 0.11 0.18 0.95
LA SR
e
, 1/s 0.04 0.24 0.98 0.15 0.23 0.94
LA SR
a
, 1/s 0.05 0.28 0.99 0.12 0.27 0.97
CMR indicates cardiac magnetic resonance; EF, emptying fraction; ICC, intraclass correlation coefficient; LA, left atrial; S
max
, maximum strain; S
preA
, pre-atrial contraction strain; SR
a
, strain
rate at atrial contraction; SR
e
, strain rate at LV early diastole; SR
s
, maximum strain rate; V
max
, maximum indexed volume; V
min
, minimum indexed volume; V
preA
, pre-atrial contraction
indexed volume.
DOI: 10.1161/JAHA.115.001844 Journal of the American Heart Association 8
CMR of Left Atrial Deformation and Stroke Inoue et al
ORIGINAL RESEARCH
associated with a prior history of stroke/TIA in patients with
AF. Our results offer a basis for a prospective study to
determine the role of depressed LA reservoir function by
tissue-tracking CMR in predicting stroke or TIA for early
detection of the population at risk of developing stroke.
Acknowledgments
We thank Elzbieta Chamera for excellent technical assistance and
Yoshiaki Ohyama for the valuable advice on statistical analysis.
Sources of Funding
This work was supported by research grants from Philips
Healthcare (to Ashikaga), the Magic That Matters Fund for
Cardiovascular Research (to Ashikaga), the Uehara Memorial
Foundation, Japan (to Inoue), a Boston Scientific Corporation
Fellowship Grant (to Berger), the Grunwald Endowment (to
Calkins), the Roz and Marvin H. Weiner and Family Foundation
(to Calkins), and the Chiaramonte Family Foundation (to
Calkins).
Disclosures
None.
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