Download Prevalence of Left Ventricular Regional Dysfunction in

Manuscript ID: CIRCULATIONAHA/2009/911313
Prevalence of Left Ventricular Regional Dysfunction in
Arrhythmogenic Right Ventricular Dysplasia: a Tagged MRI Study
Running Title: Jain et al. LV Regional Dysfunction in ARVD by Tagged MRI
Aditya Jain, MD, MPH1, Monda L. Shehata, MD1, Matthias Stuber, PhD1,
Seth J. Berkowitz, MD1, Hugh Calkins, MD2, João A. C. Lima, MD1,2,
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David A. Bluemke, MD, PhD1,2,3, Harikrishna Tandri, MD2
1
Department of Radiology, 2Division of Cardiology, Johns Hopkins
ns University
Uniive
v rs
rsit
ityy School
it
Sc
Sc
of Medicine,
MD, USA, 3Radiology
a
adiology
and Imaging Sciences, National Institutes of Health,
Healthh MD, USA
Address for correspondence:
Harikrishna Tandri, MD
Carnegie 565D
The Johns Hopkins Hospital
600 North Wolfe Street
Baltimore, MD, 21287
Phone: 410-903-1182
Fax: 410-502-9148
Email: [email protected]
Journal Subject Codes: [5] Arrhythmias, clinical electrophysiology, drugs; [30] CT and MRI;
[124] Cardiovascular imaging agents/Techniques
1
Abstract:
Background: Although arrhythmogenic right ventricular dysplasia (ARVD) predominantly
affects the right ventricle (RV), genetic/molecular and histological changes are biventricular.
Regional left ventricular (LV) function has not been systematically studied in ARVD.
Methods and Results: The study population included twenty-one patients with suspected
ARVD who underwent evaluation with MRI including tagging. Eleven healthy volunteers served
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as controls. Peak systolic regional circumferential strain (Ecc, %) was calculated by harmonic
phase from tagged MRI based on the 16-segment model. Patients who
ho me
mett AR
ARVD
VD T
Task Force
ositive
ve ffamily
amil
am
ily
il
y hi
hhistory who
criteria were classified as definite ARVD,, whereas ppatients with a ppositive
a or two
had one additional minorr criterion and patients without a family history with one ma
major
s
sified
minor criteria were classified
as probable ARVD.
Of the 21 ARVD subjects, 11 had definite ARVD, and 10 had probable ARVD. Compared with
controls, probable ARVD patients had similar RV ejection fraction (RVEF) (58.9 ± 6.2% vs.
53.5 ± 7.6%, p=0.20), but definite ARVD patients had significantly reduced RVEF (58.9 ± 6.2%
vs. 45.2 ± 6.0%, p=0.001). LVEF was similar in all three groups. Compared to controls, peak
systolic Ecc was significantly less negative in 6/16 (37.5 %) segments in definite ARVD, and
3/16 segments (18.7 %) in probable ARVD (all p<0.05).
Conclusions: ARVD is associated with regional LV dysfunction, which appears to parallel
degree of RV dysfunction. Further large studies are needed to validate this finding and to better
define implications of subclinical segmental LV dysfunction.
Key words: ARVD, LV involvement, MRI tagging, Regional strain
2
Introduction:
Arrhythmogenic right ventricle dysplasia (ARVD) is a familial cardiomyopathy that is
characterized by predominant right ventricular (RV) dysfunction, myocyte loss and fibro-fatty
infiltration of the myocardium 1. Defective cell-to cell adhesion due to mutations in genes
encoding desmosomal proteins have been implicated in the pathogenesis of ARVD. The result is
disruption of the cardiac gap junction apparatus, which has been thought to result both in the
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functional impairment and the failure of impulse transmission with subsequent
arrhythmogenesis. The ultrastructural and molecular consequences are expressed in both
ventr
tric
tr
icul
ic
ular
ul
ar cardiomyopathy,
car
ardi
di
ventricles alike, and this has promoted the notion that ARVD is a biventricular
v
vement
t of the thin-walled RV 1.
with predominant involvement
Patients with advanced or
o end-stage ARVD are observed with clinically obvious biv
biventricular
v
dysfunction that can be readily identified using echocardiography or MRI
MRI. When pre
present, left
ventricular (LV) dysfunction is often associated with significantly more adverse clinical
outcomes such as ventricular arrhythmias and heart failure 2, 3. LV contraction abnormalities
have been demonstrated in ARVD in association with advanced RV disease by previous imaging
studies using radionuclide angiography 4, 5, echocardiography 6, 7 and electron-beam computed
tomography 8. More recently, ARVD with dominant LV involvement has also been reported in
the United Kingdom, 9, 10 but not yet in the United States.
Regional contraction abnormalities often precede global dysfunction but have not previously
been quantified using tagged cardiovascular magnetic resonance imaging (MRI) for the RV or
LV for ARVD. Unfortunately, the thin wall of the RV makes regional motion tracking
3
extremely challenging. However, tagged MRI of the heart provides objective measurements of
regional LV function 11 with great precision and reliability 12. The purpose of this study was to
quantify regional LV function in patients with high clinical suspicion for ARVD using tagged
MRI.
Methods:
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The study population included twenty-one patients who were evaluated for ARVD at the Johns
Hopkins ARVD program following a positive family history (n=13, 62%) or left bundle branch
block morphology ventricular tachycardia (n=8, 38%). Eleven healthy
hy volunteers
volu
lunt
ntee
nt
eers
ee
rs served
sseer
er
as
t
tients
controls. All of these patients
underwent initial non-invasive testing according to a sstandardized
protocol including an electrocardiogram
e
ectrocardiogram
(ECG), signal-averaged electrocardiogram ((SAECG),
c
cardiogram,
w further
Holter monitoring, echocardiogram,
exercise testing, and cardiac MRI. They underw
underwent
invasive testing at the discretion of the cardiologist which included electrophysiologic study, RV
angiography, and endomyocardial biopsy. Diagnosis of ARVD was established based on the
results of non-invasive tests including MRI and invasive tests according to the criteria set by the
Task Force of the Working Group of Myocardial and Pericardial Disease of the European
Society of Cardiology and of the Scientific Council on Cardiomyopathies of the International
Society and Federation of Cardiology 13. Among those who did not meet the Task Force criteria,
patients with a positive family history who had one additional minor criterion and patients
without a family history with one major or two minor criteria were classified as probable ARVD.
MR Imaging Protocol: MR images of study subjects were obtained on 1.5-T scanners (CV/I,
GE Medical Systems, Waukesha, WI or Philips Medical Systems, Best, The Netherlands) at the
4
Johns Hopkins Hospital, and included both fast spin-echo (FSE) and gradient-echo sequences.
Fat-suppressed and non fat-suppressed FSE sequences were acquired in the axial and short-axis
planes with breath-hold double-inversion recovery blood suppression pulses with repetition time
(TR) of 1 or 2 R-R intervals, time to excitation (TE) of 10-20 ms, slice thickness of 5-10 mm and
slice gap of 2-5 mm. The matrix and field of view (FOV) were 256 x 256 and 24-36 cm,
respectively. Cine functional images were obtained in the axial and short-axis planes using
breath-hold steady state free precession (SSFP) imaging. The flip angle was 40-60 degrees and
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TE was set to minimum. For SSFP imaging, the slice thickness was 5-8 mm with a slice gap of
pectively. Inversion
Inve
veers
r
2-6 mm. The matrix and FOV were 256 x 160 and 36-40 cm, respectively.
recovery
ed 200 m
inut
in
utes
ut
es aafter contrast
prepared breath-hold 2D cine gradient-echo images were obtained
minutes
m
mol/kg
of gadodiamide (Omniscan, Amersham Health, Pri
i
agent injection [0.2 mmol/kg
Princeton,
New
m
meters
included TR/TE, 7.2/3.2; inversion time optimized, 150-250 ms;
Jersey)]. Imaging parameters
lice thickness, 8 mm; slice gap, 2 mm; number of excitatio
flip angle, 25 degrees; slice
excitations, 2; matrix,
256 x 192; and FOV, 36 x 27 cm. 2D myocardial delayed enhancement (MDE) MRI scans were
obtained in the short axis and axial planes at 10 mm intervals covering the entire RV and LV. All
studies used a phased array surface coil for signal reception. The temporal resolution of the cine
images was less than or equal to 50 ms.
Tagging Protocol: After completing the standard imaging protocol, three tagged short axis
slices (base to apex) were obtained. Parallel striped tags were prescribed in two orthogonal
orientations (0 and 90 degrees) using ECG-triggered fast gradient-echo sequence with spatial
modulation of magnetization 14, 15. The parameters for tagged MR images were FOV, 40 cm;
slice thickness, 8-10 mm; TR, 3.5-7.2 ms; echo time, 2.0-4.2 ms; flip angle, 10–12 degrees;
matrix size, 256 × 96 to 140; temporal resolution, 20-40 ms and tag spacing, 7 mm.
5
MR Image Analysis: MR images were assessed by experienced cardiac MRI readers at the
Johns Hopkins Hospital who were blinded to all clinical and other diagnostic information. MR
images were transferred to an Advantage windows workstation (GE Medical Systems,
Waukesha, WI) for analysis. Quantitative analysis was performed using dedicated commercially
available MASS software program (Medis, Leiden, The Netherlands). This software was used to
view images using standardized window width and level settings. The first image after the R
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wave trigger represented the end diastolic image. End systolic image was defined visually as the
one with the smallest ventricular cavity size. Quantitative MR parameters included end-diastolic
F) for
fo
or both
both ventricles.
ven
entr
tr
volume (EDV), end-systolic volume (ESV) and ejection fraction (EF)
e
entricular
volume measurements were obtained by summatio
o of
Diastolic and systolic ventricular
summation
ined from serial short axis ima
images.
s. The MR images
im es were qua
a
planimetered areas obtained
qualitatively
e
assessed for ventricular enlargement,
aneurysms, global hypokinesis, regional wall m
motion
abnormalities, intra-myocardial fat, and delayed enhancement.
Strain Analysis: Horizontal and vertical striped tags were superimposed as grid images (Figure
1). Short-axis tagged slices were analyzed for mid-wall regional circumferential strain (Ecc,%)
by the HARP (Figure 1) method (Harmonic Phase, Diagnosoft, Palo Alto, California, USA) 16, 17
based on the 16-segment heart model 18. LV was divided into three circular basal, mid and apical
short-axis slices perpendicular to the long axis of the heart; the basal and mid slices were divided
into 6 circumferential segments of 60 degrees each -- anterior, anteroseptal, inferoseptal,
inferior, inferolateral and anterolateral and the apical slice was divided into 4 segments of 90
degrees each – anterior, septal, inferior and lateral. Since Ecc represents circumferential
shortening, its value during systole is negative. A more negative value (e.g. -25%) reflects
6
greater contraction (healthier), while a relatively less negative value (e.g. -10%) implies weaker
contraction. Peak systolic value of Ecc, which refers to Ecc noted around peak systole, was
considered for the analysis as the contractile effort tends to be at its maximum at this phase
during the cardiac cycle. One of our previous studies has demonstrated excellent inter- and intraobserver agreement for peak systolic mid-wall Ecc (correlation coefficient > 0.8, for both) in
myocardial tagged MRI analysis using the HARP technique 19.
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Statistical Analysis: All continuous variables were reported as mean ± SD. All categorical
variables were reported as frequency (%). The ventricular end-diastolic and end-systolic volumes
nglee Fisher’s
Fis
ishe
her’
he
r’ss exact
r’
ex tests
were indexed to body surface area (BSA, m2). Kruskal-Wallis and single
were utilized for overall comparison of continuous and categorical data respectively among the
three study groups. Wilcoxon-Mann-Whitney
c
coxon-Mann-Whitney
and Fisher’s exact tests were used for post-hoc
o continuous and categorical data respectively, with Bonferr
r
pair-wise comparisons of
Bonferroni
correction of the alpha in order to maintain the overall probability of a type I error at 0.05.
Statistical analyses were performed in STATA statistical software (Version 9.0, College Station,
TX). Two-tailed p-value less than 0.05 was considered statistically significant. The major goal of
this research, as an exploratory study, was hypothesis generation, and no adjustment was made
for examining multiple factors.
Results:
Baseline Characteristics: Table 1 describes the demographics, electrophysiologic and structural
abnormalities of the study population which was composed of 21 patients with ARVD and 11
controls. Out of the 21 patients with ARVD, 11 (52%) were classified as having definite ARVD
7
and 10 (48%) as probable ARVD. Among the definite ARVD group, 45% patients fulfilled 4
Task Force criteria points, and remaining 55% fulfilled more than 4. Among the probable ARVD
group, 20% patients satisfied 2, and remaining 80% patients satisfied 3 points. The mean age of
the definite ARVD and probable ARVD patients was 41.2 ± 14.2 and 34.9 ± 12.1 years, and 7
(64%) and 3 (30%) were men respectively. The mean age of controls was 29.8 ± 6.7 years and 6
(55%) were men. Mean age and gender distribution across all three groups of study participants
were similar (Kruskal-Wallis p=0.14; single Fisher’s exact p=0.37, respectively). The presence
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of greater than 1000 premature ventricular contractions on a 24-hour Holter monitor was
ed to probablee A
significantly more often seen in definite ARVD group as compared
ARVD group
tieent
ntss sh
show
oweed evidence of
ow
(Fisher’s exact p=0.004). None of the definite or probable ARVD pat
patients
showed
r
rmalities
haa any prior
LV wall motion abnormalities
on echocardiography. None of the controls had
r electrical or structural abnormalities consistent with ARVD.
ry,
ARV
V
symptoms, family history,
Characteristics of RV and LV on MRI: Shown in Table 2 are the detailed MRI findings of
subjects included in the study. In general, definite ARVD patients demonstrated a higher degree
of RV structural abnormalities on MRI and showed a significantly higher presence of varying
degrees of dilatation and delayed enhancement of the RV as compared to patients with probable
ARVD (Fisher’s exact p=0.001 and 0.02, respectively). Among the three groups of participants,
definite ARVD patients had significantly higher RVEDV and RVESV, as well as lower RVEF
than controls (Kruskal-Wallis p=0.006, 0.0009 and 0.0007, respectively; post-hoc tests p=0.004,
0.0009 and 0.001, respectively). Definite ARVD patients also showed significantly lower RVEF
than probable ARVD patients (post-hoc test p=0.04). Probable ARVD patients reported higher
global RV volumes and lower RVEF than controls but the differences did not reach statistical
significance (post-hoc tests p=0.12, 0.07 and 0.20, respectively).
8
Among the definite ARVD group, the most commonly seen LV abnormality was intramyocardial fat (3/11, 27%), followed by regional wall motion defects (2/11, 18%), dilatation
(1/11, 9%) and delayed enhancement (1/11, 9%). Similarly, among the probable ARVD group,
the LV abnormalities observed were intra-myocardial fat (1/10, 10%) and delayed enhancement
(1/10, 10%). Quantitatively, LVEDV, LVESV and LVEF were similar across all three groups
(Kruskal-Wallis p=0.29, 0.59 and 0.50, respectively).
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Regional LV Systolic Function: Table 3 shows mean (SD) peak systolic Ecc at the 16
es ffor
or K
Kru
rusk
ru
skal
sk
al-W
al
-W
myocardial segments by study groups, and the corresponding p-values
Kruskal-Wallis
and
R
revealed significantly less negat
post-hoc comparisons. Patients with definite ARVD
negative Ecc (as
i Ecc denotes weaker contraction) than controls in 6/16 (3
ive
stated earlier, less negative
(37.5 %)
r, basal anterolateral, mid inferior, mid inferolateral, mid aant
t
segments - basal inferior,
anterolateral
es 11, 2)
and apical lateral (Figures
2). Ecc was significantly less negative in probable ARV
ARVD compared
to controls in 3/16 (18.7 %) segments - basal anterolateral, mid anterolateral and apical lateral.
Figure 3a shows mean (95% CI) peak systolic Ecc according to the study groups across
myocardial regions along the longitudinal axis of the heart. Definite ARVD patients
demonstrated less negative strain at the basal and mid LV slice levels in contrast to controls
(Kruskal-Wallis p=0.01 and 0.009, respectively; post-hoc tests p=0.01 and 0.01, respectively).
No differences in basal, mid or apical strain were observed between probable ARVD patients
and controls. Figure 3b depicts distribution of mean (95% CI) peak systolic Ecc
circumferentially around the heart in the study population. Of the anterior, septal, inferior and
lateral regions, definite ARVD reported a less negative strain in anterior, inferior and lateral
9
regions compared to controls (Kruskal-Wallis p=0.04, 0.005 and 0.0003, respectively; post-hoc
tests p=0.03, 0.005 and 0.0006, respectively). This is in contrast to probable ARVD which
showed less negative strain in lateral region alone (post-hoc test p=0.006). No differences in
regional strain were found between definite and probable ARVD patients (table 3, figures 3a and
3b).
Discussion:
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To our knowledge, this is the first study to quantitatively assess regional LV function in ARVD
using MRI strain analysis. This approach revealed regional LV systolic
olicc dy
dysf
dysfunction
sfun
sf
unct
un
ctio
ct
ionn despite a
io
preserved global LV function.
n
nction.
Further, the extentt of LV dysfunction appe
appeared
ared to par
parallel
r
RV
dysfunction with definitee ARVD showing worse LV regional dysfunction.
Probable ARVD: Patients
nts with a strong clinical suspicion of ARVD but satisfying less
l than the
required number of Task Force criteria for the definite diagnosis of the disease were considered
to have probable ARVD. Probable ARVD may represent an early spectrum of the disease with
possible progression to diagnostically more overt forms with time. In a high risk population
(such as positive mutation carrier status or positive family history), the classification of probable
ARVD may be particularly relevant. Such patients may not fulfill traditional ARVD criteria, but
may have a higher pre-test probability for disease. In our practice, patients fulfilling several if
not all ARVD criteria frequently mandate closer clinical follow-up.
Left Ventricular Involvement in ARVD: Left-sided involvement in ARVD has been described,
but it is frequently considered a late manifestation of advanced disease 20, 21. However, the recent
10
and important advances in the field of genetic characterization of the disease led to the
hypothesis of a potential LV affliction in ARVD from its early stages 10. Most disease-causing
mutations have been found to involve genes encoding different component proteins of the
cardiac desmosome such as desmoplakin, plakophilin-2, junctional plakoglobin, desmoglein-2
and desmocollin-2 1. Although different mutations may impact ventricles differentially 10, the
spectrum of their phenotypic expression should involve both ventricles concomitantly as right
and left sides of the heart are similar with respect to desmosomal structure and gene expression.
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Our findings are plausible with the purported common genetic substrate between the two
en
nt and favor
ventricles. The findings support the emerging evidence in favor of LV involvemen
involvement
10, 22
ludee L
LV
V de
desc
scri
sc
ripp
ri
.
the need of a contemporaneous revision of Task Force criteria to include
descriptions
With respect to qualitative
v changes, LV functional abnormalities in ARVD have bee
ve
been
e previously
reported 1, 8, 23. However,
r a systematic regional quantification
r,
f
of LV contractile func
function in
context to global function in ARVD has not been previously undertaken. Using myocardial
tagging, we discovered decreased regional LV contraction in probable ARVD that had a higher
prevalence in definite ARVD. Less negative strain noted first in 3/16 myocardial segments in
probable ARVD seemed to progress to 6/16 segments with increase in disease severity to definite
ARVD. Similarly, less negative strain in the basal and mid slice levels of the LV in definite
ARVD was not observed in probable ARVD. The lateral region showed a predilection for less
negative strain in probable ARVD patients while definite disease involved the lateral as well as
anterior and inferior regions. These subclinical reductions in regional LV contractility as
demonstrated by less negative systolic circumferential shortening showed an association with
increasing RV impairment and existed without significant morphological abnormalities of the
LV in the context of normal global LV function. Regional contraction derangement appears to be
11
a more sensitive indicator of LV involvement, and this may be of great relevance in the classic
disease paradigm where the RV is consistently more severely affected than the LV and
conspicuous signs of LV involvement may not set in until later in the course of the disease 9, 10.
Prognostic Significance of LV Involvement: The “left-sidedness” of ARVD is known to
portend an increased likelihood of an eventful clinical course. Prospective and retrospective
studies have highlighted LV involvement to be associated with an increased risk of palpitations,
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syncopal episodes, potentially lethal arrhythmias and heart failure than isolated RV disease
alone, which explains why LV involvement can help in identifying those ARVD patients who
would benefit the most from timely ICD placement 2, 3. In the light off th
the
he af
afor
aforementioned,
orem
or
emen
em
enti
en
ti
the
d
dings
of our study of a possible LV involvement in ARVD in
n the form of
interpretation of the findings
a subclinical reduction in
n myocardial contraction may be critical from the prognosticc stand-point.
Study Strengths and Limitations:
imitations: Strengths of this study include non-subjective an
analysis of
regional LV function by the novel application of myocardial tagging in ARVD, comparative
assessment of probable and definite ARVD patients against normals, and cardiac MRI scanning
for qualitative and quantitative evaluation of ARVD. One of the main limitations of the study is
the small sample size and the study may not have had sufficient power to detect differences in
global LV function between ARVD patients and controls. The results should be interpreted in
context to this important limitation and validated in a large-scale genotyped cohort of ARVD
patients. While the inclusion of individuals who do not fulfill adequate number of Task Force
criteria may imply inclusion of early ARVD patients, it could also lead to a loss of specificity
and admittance of false-positive patients with similar disorders such as idiopathic ventricular
tachycardia and other types of cardiomyopathies. Because of the cross-sectional nature of our
12
study, temporal trends in LV involvement and disease progression in ARVD patients over time
could not be addressed.
Clinical Implications: Although the study is limited by a small sample size, our results for the
first time show regional LV dysfunction in patients with ARVD despite preserved global LV
systolic function. Even patients with probable ARVD had minor LV regional functional
alterations compared to controls. These results support the current molecular/genetic basis of
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ARVD with biventricular disease expression, since early in the course of the disease. Abnormal
strain measurements may be the first indication of an incipient overt LV dysfunction, warranting
re ne
need
eded
ed
ed ttoo vvalidate this
closer clinical follow-up and surveillance. Future longitudinal studiess ar
are
needed
d
derstand
m
of th
h
finding and to better understand
the natural history and prognostic implications
this
asymptomatic segmentall LV dysfunction in ARVD in larger cohorts of patients.
Acknowledgements: We are grateful to the ARVD patients and families who have made this
work possible. More information on the Johns Hopkins ARVD program can be found at
www.arvd.com.
Funding Sources: The authors wish to acknowledge funding from the National Heart, Lung and
Blood Institute (K23HL093350 to Dr. Tandri) and the St. Jude Medical Foundation, Medtronic
Inc., and Boston Scientific Corp. The Johns Hopkins ARVD Program is supported by the Bogle
Foundation, the Healing Hearts Foundation, the Campanella family, and the Wilmerding
Endowments.
Conflict of Interest Disclosures: None
13
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17
Table 1. Demographics of the Study Population
Variable
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Age, years
Men, %
Prior symptoms, %
Presyncope/Syncope
Palpitation
Family history, %
SCD < 35 years of age
ARVD by TFC
ARVD by HP evidence
Depolarization, %
Abnormal SAECG
Epsilon wave
T wave inversions, %
Beyond V1
Beyond V2
Incomplete RBBB
Complete RBBB
Arrhythmia, %
> 1000 PVCs on a 24-hour Holter
monitor*
LBBB type VT
Structural abnormalities on Echo, %
Global RV dilatation
Impaired RV function
RV wall motion abnormalities
Global LV dilatation
Impaired LV function
LV wall motion abnormalities
Criteria points for ARVD diagnosis
4+
4
3
2
1
Definite ARVD
(n=11)
41.2 ± 14.2
63.6
Probable ARVD Controls
(n=10)
(n=11)
34.9 ± 12.1
29.8 ± 6.7
30.0
54.5
4 (36)
5 (45)
6 (60)
7 (70)
0 (0)
0 (0)
1 (9)
2 (18)
4 (36)
3 (33)
4 (40)
(20)
2 (20)
0 (0)
0 (0)
0 (0)
8 (73)
1 (9)
5 (50)
0 (0)
0 (0)
0 (0)
8 (73)
5 (45)
0
0
4 (40)
3 (30)
3 (30)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
7 (64)
4 (36)
0 (0)
3 (30)
0 (0)
0 (0)
8 (73)
4 (50)
0 (0)
6 (55)
1 (9)
1 (9)
0 (0)
0 (0)
1 (13)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
6 (55)
5 (45)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
8 (80)
2 (20)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
18
Values are expressed as n (%) or mean ± SD. Among those who did not meet the Task Force criteria, patients
with a positive family history who had one additional minor criterion and patients without a family history with
1 major or 2 minor criteria were classified as probable ARVD. Criteria points were calculated by adding the
major (2 points each) and minor (1 point each) criteria fulfilled by the individual. The presence of 4 or more points
is indicative of arrhythmogenic right ventricular dysplasia (ARVD) diagnosis by Task Force criteria.
*p<0.05 for comparison between definite ARVD and probable ARVD patients.
SCD, sudden cardiac death; TFC: Task Force criteria; HP: histopathological; SAECG: signal-averaged ECG;
RBBB: right bundle branch block; LBBB: left bundle branch block; VT: ventricular tachycardia
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19
Table 2. Global and Regional Characteristics of the Right and Left Ventricles on MRI
Definite ARVD
(n=11)
Probable ARVD
(n=10)
Controls
(n=11)
11 (100)
2 (18)
6 (55)
8 (73)
4 (36)
3 (30)
2 (20)
2 (20)
3 (30)
1 (10)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
7 (64)
1 (10)
0 (0)
114.5 ± 26.4
1103.1
03 1 ± 330.3
76.6 ± 17.9
End systolic volume
63.1 ± 19.6
49.3 ± 19.8
1
31.3 ± 7.8
Ejection fraction*†
45.2 ± 6.0
53.5 ± 77.6
58.9 ± 6.2
1 (9)
0 (0)
0 (0)
2 (18)
3 (27)
1 (9)
0 (0)
0 (0)
0 (0)
0 (0)
1 (10)
1 (10)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
88.3 ± 25.6
33.9 ± 13.6
62.8 ± 4.6
80.9 ± 20.1
28.7 ± 8.7
64.7 ± 4.3
73.9 ± 15.7
28.1 ± 7.2
61.7 ± 6.6
Variable
Right Ventricle
Qualitative parameters, %
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Dilatation*
Aneurysm
Global hypokinesis
Regional hypokinesis/akinesis/dyskinesis
Intramyocardial fat
Delayed enhancement*
Quantitative parameters, ml/m2
End diastolic volume†
†
Left ventricle
Qualitative parameters, %
Dilatation
Aneurysm
Global hypokinesis
Regional hypokinesis/akinesis/dyskinesis
Intramyocardial fat
Delayed enhancement
Quantitative parameters, ml/m2
End diastolic volume
End systolic volume
Ejection fraction
Values are expressed as n(%) or mean ± SD
*p< 0.05 for comparison between definite ARVD and probable ARVD patients
†
p< 0.05 for comparison between definite ARVD patients and controls
All p-values were Bonferroni-adjusted to account for multiple comparisons, wherever required
20
Table 3. Peak systolic circumferential strain (Ecc,%) at the sixteen myocardial segments by
study groups
P-value
Segment
Probable ARVD
(n=10)
Controls
(n=11)
KruskalWallis
Posthoc*
Posthoc†
Posthoc‡
Basal
Anterior
Anteroseptal
Inferoseptal
Inferior
Inferolateral
Anterolateral
-15.6 ± 1.8
-16.4 ± 2.8
-13.9 ± 3.2
-13.2 ± 3.6
-18.5 ± 2.1
-17.2 ± 3.2
-16.5 ± 5.1
-18.2 ± 2.5
-16.8 ± 2.2
-15.9 ± 3.4
-18.2 ± 4.4
-17.5 ± 3.3
-17.7 ± 3.0
-18.9 ± 2.5
-17.4 ± 3.4
-17.3 ± 3.8
-20.7 ± 2.4
-21.2 ± 2.1
0.35
0.15
0.15
0.04
0.11
0.005
0.31
0.24
0.41
0.04
0.09
0.02
1.0
1.0
1.0
1.0
0.47
0.02
1.0
0.36
0.17
0.37
1.0
1.0
Mid
Anterior
Anteroseptal
Inferoseptal
Inferior
Inferolateral
Anterolateral
.2
2
-17.4 ± 3.2
.9
-18.4 ± 1.9
.2
-17.3 ± 3.2
.9
-13.5 ± 3.9
.4
-19.3 ± 1.4
.3
-19.3 ± 2.3
-17.7 ± 1.8
18
-19.3 ± 2.7
-17.8 ± 4.2
-17.0 ± 4.2
-19.1 ± 4.9
-18.2
18.2 ± 4.0
-19.8
-19
8 ± 2.5
-18.6 ± 1.9
-19.1 ± 3.0
-19.8 ± 2.7
-22.1 ± 1.3
-23.0
23.0 ± 1.9
00.12
12
0.69
0.31
0.01
0.02
0.002
0.31
1.0
0.37
0.02
0.002
0.01
0.21
1.0
1.0
0.49
0.86
0.007
1.0
1.0
1.0
0.16
1.0
1.0
Apical
Anterior
Septal
Inferior
Lateral
-19.4 ± 2.1
-17.7 ± 3.9
-15.6 ± 3.4
-18.8 ± 2.8
-18.6 ± 5.2
-18.3 ± 4.2
-16.7 ± 5.0
-18.2 ± 7.4
-21.5 ± 3.4
-19.2 ± 3.2
-19.1 ± 3.6
-23.4 ± 2.2
0.19
0.63
0.25
0.007
0.23
1.0
0.30
0.02
0.74
1.0
1.0
0.04
1.0
1.0
1.0
0.89
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Definite ARVD
(n=11)
All strain values denote mean ± SD
Kruskal-Wallis test compares the three groups together for an overall difference in strain
*pair-wise comparison between definite ARVD patients and controls
†
pair-wise comparison between probable ARVD patients and controls
‡
pair-wise comparison between definite and probable ARVD patients
All post-hoc pair-wise p-values were Bonferroni-adjusted to account for multiple comparisons
21
Figure Legends
Figure 1. Examples from a healthy control (panel i) and a definite ARVD patient (panel ii)
showing HARP analysis of short-axis tagged MR images at the mid slice level. Circular mesh
(left) is defined by the user to represent the region of measurement in the left ventricular wall
(yellow subendocardial layer, red midwall, green subepicardial layer). The mesh deforms with
the motion of the heart and the changes in the geometry of the mesh can then be measured. By
tracking the motion of different segments of the heart using a mesh, the measured strain can be
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represented numerically in a trajectory by plotting the changes in local strain during the cardiac
n av
aver
erag
er
agee ac
ag
acro
ro
ros
os each
cycle. Circumferential strain at the mid-wall (Ecc) was obtained as an
average
across
me. Panel i shows how individual mesh points comprise six different
segment at each timeframe.
p
ponding
Ecc plots representing the evolution of average stra
a across
segments and the corresponding
strain
th
h peak
each segment with time. The peak (or the most negative) value of each Ecc plot is the
esponding segment as it usually coincides with the height of systole.
systolic Ecc for the corresponding
Note also the generalized less negative peak systolic Ecc peaks in the definite ARVD patient as
compared to the control. Names of the segments: A- anterior, AS- anteroseptal, IS: inferoseptal,
I: inferior, IL: inferolateral, and AL: anterolateral.
Figure 2. Panels a and b show color-coded maps superimposed on tagged MR short-axis
images from a healthy control and a definite ARVD patient respectively. Bar color demonstrates
the spectrum in change of cardiac systolic function: blue color identifies normal contractile state
and red color represents dysfunctional areas. The green-dominant myocardium of the ARVD
patient indicates generalized weaker systolic function in contrast to the blue-dominant
myocardium in the healthy control.
22
Figure 3. Figure a shows the distribution of peak systolic Ecc at basal, mid and apical slice
levels across the study population. Figure b shows peak systolic Ecc in anterior, septal, inferior
and lateral regions. * and † refer to region(s) of the heart in which the mean peak systolic Ecc was
found to be significantly different between definite ARVD patients and controls, and between
probable ARVD patients and controls respectively (all post-hoc p<0.05).
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AL
IS
A
AS
IS
I
IL
AL
ii
IL
I
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AS
A
AS
IS
I
IL
AL
A
i
b
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a
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*
*
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*†
*
*
Prevalence of Left Ventricular Regional Dysfunction in Arrhythmogenic Right Ventricular
Dysplasia: A Tagged MRI Study
Aditya Jain, Monda L. Shehata, Matthias Stuber, Seth J. Berkowitz, Hugh Calkins, João A. Lima,
David A. Bluemke and Harikrishna Tandri
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Circ Cardiovasc Imaging. published online March 2, 2010;
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas,
TX 75231
Copyright © 2010 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-9651. Online ISSN: 1942-0080
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World Wide Web at:
http://circimaging.ahajournals.org/content/early/2010/03/02/CIRCIMAGING.109.911313
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