Download Left Ventricular Diastolic Mechanical Dyssynchrony and Associated

Left Ventricular Diastolic Mechanical Dyssynchrony and
Associated Clinical Outcomes in Children With
Dilated Cardiomyopathy
Mark K. Friedberg, MD; Susan L. Roche, MD; Arshiya F. Mohammed; Mervin Balasingam;
Eshetu G. Atenafu, MSc; Paul F. Kantor, MBBCh, DCH, FRCPC
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Background—We investigated diastolic mechanical dyssynchrony and its relation to clinical status in pediatric dilated
cardiomyopathy (DCM).
Methods and Results—We calculated a diastolic and systolic dyssynchrony index (standard deviation of time to peak tissue
early diastolic/systolic velocity in 12 left ventricular segments) in 33 children with DCM and 46 control subjects. A
threshold to diagnose diastolic dyssynchrony was determined, and cardiac function and clinical outcomes were
compared between DCM patients with and without diastolic dyssynchrony. Left ventricular wall motion was more
synchronized in diastole than in systole. The diastolic dyssynchrony index was significantly higher in children with
DCM than in control subjects (28.1⫾18.1 versus 9.1⫾3.8 ms, P⬍0.0001). A 17-ms threshold indicated the presence of
diastolic dyssynchrony. Patients who died or underwent transplantation had greater diastolic dyssynchrony (diastolic
dyssynchrony index 37.9⫾20.5 versus 22.1⫾13.8 ms, P⫽0.01), and the rate of transplant-free survival appeared to be
worse for DCM patients with diastolic dyssynchrony than for patients with synchronous DCM (hazard ratio 2.98,
P⫽0.11; hazard ratio adjusted for disease duration 2.95, P⫽0.17).
Conclusions—Left ventricular diastolic mechanical dyssynchrony is common in pediatric DCM, especially in patients who
subsequently experience transplantation or death, and may be associated with a decreased length of transplantation-free
survival. (Circ Cardiovasc Imaging. 2008;1:50-57.)
Key Words: pediatrics 䡲 cardiomyopathy 䡲 dyssynchrony, diastolic mechanical 䡲 echocardiography
䡲 imaging 䡲 survival
M
DCM. We hypothesized that diastolic wall-motion abnormalities are prevalent in pediatric DCM and that their presence is
associated with diastolic ventricular dysfunction and adverse
outcome.
echanical dyssynchrony, the incoordinate wall motion
of different ventricular segments in systole and diastole, is an important contributor to left ventricular (LV) dysfunction in cardiomyopathy both in adults and in children
with dilated cardiomyopathy (DCM).1–3 Although systolic
mechanical dyssynchrony has been studied more than diastolic mechanical dyssynchrony, diastolic dyssynchrony is more
common than systolic dyssynchrony in adults with both
systolic and diastolic heart failure and may be associated with
ventricular dysfunction and poor outcome.4 –10 However,
diastolic wall motion has not been well delineated in children
in general, and diastolic mechanical dyssynchrony has not
been studied in children with DCM. Therefore, the objectives
of the present study were (1) to compare diastolic and systolic
mechanical synchrony in normal control subjects and in
patients with DCM; (2) to investigate the relation between
diastolic dyssynchrony and cardiac function; and (3) to
explore the relation between the presence of diastolic dyssynchrony and clinical status and outcome in patients with
Clinical Perspective see p 57
Methods
Population
Children between 0 and 18 years of age who had undergone
echocardiography between January 2006 and February 2008 were
eligible for inclusion if they were being followed up for clinically
significant DCM with decreased LV systolic function (LV ejection
fraction ⬍55%). Clinical data were obtained retrospectively from the
medical record. Healthy children investigated for an innocent murmur or for screening purposes were used as control subjects for
evaluation of mechanical dyssynchrony. The study was approved by
the institutional ethics board.
Echocardiography
Echocardiography was performed on a Vivid 7 echo system (GE
Corp, Wauwatosa, Wis) with probe frequencies appropriate for
Received March 24, 2008; accepted May 14, 2008.
From the Divisions of Pediatric Cardiology, The Labatt Family Heart Center (M.K.F., S.L.R., A.F.M., M.B., P.F.K.) and Child Health Evaluative
Sciences (E.G.A.), Hospital for Sick Children, Toronto, Ontario, Canada.
Correspondence to Mark K. Friedberg, MD, Division of Cardiology, Hospital for Sick Children, 555 University Ave, Toronto, Ontario M5G 1X8,
Canada. E-mail [email protected]
© 2008 American Heart Association, Inc.
Circ Cardiovasc Imaging is available at http://circimaging.ahajournals.org
50
DOI: 10.1161/CIRCIMAGING.108.782086
Friedberg et al
Diastolic Dyssynchrony in Pediatric Cardiomyopathy
patient size. Tissue Doppler imaging was acquired from equally
rotated apical 4-, 3-, and 2-chamber views. The image position,
depth, and sector width were optimized for frame rate and insonation
angle. Frame rates obtained were 154⫾42 frames per
second (mean⫾SD).
Echocardiography data were transferred to an Echopac workstation (GE Corp) for offline analysis in which tissue Doppler sample
volumes of 5 mm were placed at 12 LV segments (6 basal and 6
mid-LV segments), as well as at the tricuspid valve annulus.
Echocardiographic analysis was blinded to clinical status and outcome; however, because of the obvious echocardiographic differences between DCM and normal conditions, it was not practical to
blind the operator to diagnosis.
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A
Evaluation of Dyssynchrony
LV Intraventricular Systolic Synchrony
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We measured systolic synchrony by 2 methods. First, the LV
intraventricular systolic delay was defined as the delay between time
to peak systolic velocity (S⬘) at the mitral annulus and time to S⬘ at
the basal septum, with the ECG QRS complex onset used as a
reference.1 Next, the standard deviation (SD) of time to peak systolic
velocity between 12 LV basal and mid-LV orthogonal segments was
used as a dyssynchrony index (Figure 1).11,12
B
LV Intraventricular Diastolic Synchrony
Similarly, we measured LV intraventricular diastolic dyssynchrony
by 2 methods: (1) the delay between time to peak early diastolic
velocity (E⬘) at the mitral annulus and time to E⬘ at the basal septum,
with the ECG QRS complex onset used as a reference, and (2) the
SD of time to peak E⬘ of 12 basal and mid-LV orthogonal segments
(Figure 1).9 In instances in which the E⬘ and A⬘ waves were blended,
measurement was made to the peak of the single diastolic wave. The
dyssynchrony index method constituted the primary method to
determine the presence of systolic and diastolic mechanical dyssynchrony and to investigate the relation between dyssynchrony and
clinical status.
Left–Right Interventricular Systolic and
Diastolic Synchrony
Systolic interventricular delay was defined as the delay between time
to peak S⬘ in the mitral annulus and time to peak S⬘ in the tricuspid
annulus. Interventricular diastolic delay was defined as the delay
between time to peak E⬘ in the mitral annulus and time to peak E⬘ in
the tricuspid annulus.
Statistical Analysis
Data were analyzed with commercially available software (SAS
version 9.1, SAS Institute Inc, Cary, NC). The normality assumption
of continuous data was assessed by the Kolmogorov and Smirnov
test. For data for which the normality assumption held, a comparison
of 2 groups was assessed with the 2-tailed Student t test. The Welch
correction was also applied when equality of variance could not be
assumed between groups. A paired t test was used to compare the
systolic and diastolic dyssynchrony indices within the same subject.
For data for which the normality assumption did not hold, nonparametric testing was used (systolic interventricular delay in control
subjects, disease duration, and New York Heart Association class).
Associations between dyssynchrony parameters and echocardiographic parameters of systolic and diastolic function were derived by
linear regression. Pearson correlation coefficient was used when data
were normally distributed, whereas Spearman correlation was used
for bivariate analysis when data were not normally distributed.
z scores for LV end-diastolic dimension were calculated with normal
data obtained from our institution. To assess intraobserver and
interobserver reliability of the systolic and diastolic dyssynchrony
indices, 8 consecutive control studies and 8 consecutive DCM
studies (16 studies in all) were reanalyzed by the same reader and by
a second reader, respectively, on separate occasions for a second
reread. The intraobserver and interobserver reliability are expressed
as the intraclass correlation coefficient with the Cronbach’s ␣-value
Figure 1. Tissue Doppler velocity curves in the 4-chamber view.
Right, Tissue velocity curves. Left, Color tissue Doppler (top)
and corresponding gray-scale images (bottom). Samples (5 mm)
were placed during the same cardiac cycles at the mitral annulus, basal interventricular septum, midlateral LV wall, and midseptum. For clarity, in A, only the mitral annulus (yellow) and
basal septum (cyan) curves are demonstrated. In B, curves from
all 4 points are demonstrated in the same cardiac cycles (yellow, mitral annulus; cyan, basal septum; red, mid lateral wall;
green, midseptum). The time from QRS onset to peak early diastolic velocity (E⬘) was then measured at each of the points
(arrows in A). Similar curves were obtained in the orthogonal 2and 3-chamber views to yield velocity curves in 12 LV segments. The SD of time to peak early diastolic velocity (E⬘)
among the 12 LV segments was used as the diastolic dyssynchrony index. A second method to assess diastolic dyssynchrony, termed the intraventricular diastolic delay, used the
delay between time from QRS onset to peak early diastolic
velocity (E⬘) at the mitral valve (yellow curve) and basal interventricular septum (cyan curve; arrows in A). These curves obtained
from a normal control subject demonstrate near-simultaneous
diastolic motion in these 4 segments. Systolic dyssynchrony
was measured in a similar fashion by use of time from QRS
onset to peak systolic velocity (S⬘) in the same LV segments in
the same cardiac cycles. A similar curve (not demonstrated to
increase clarity) may be obtained for the tricuspid annulus. The
interventricular diastolic delay was defined as the time difference
between time from QRS onset to peak early diastolic velocity
(E⬘) at the mitral annulus and tricuspid valve.
reported. Survival function was analyzed by Kaplan-Meier curves
with log-rank testing for differences in survival. The hazard ratio is
reported after fitting of the proportional hazards model while
adjusting for disease duration and age of the patient at diagnosis.
Follow-up for survival analysis was from time of diagnosis. All
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Circ Cardiovasc Imaging
July 2008
Table 1. Clinical Characteristics of 33 Children With DCM and
46 Control Subjects
Clinical Feature
Age, y
Control Subjects
(n⫽46)
DCM
(n⫽33)
2-Tailed P
10.6⫾5.2
8.0⫾6.3
0.056
Sex, n (%)
0.65
Males
25 (54)
Females
21 (46)
17 (51)
67.2⫾6.3
28.0⫾13.5
Ejection fraction, %
16 (49)
⬍0.0001
probability values are 2 sided and considered statistically significant
if ⬍0.05.
The authors had full access to the data and take full responsibility
for the integrity of the data. All authors have read and agree to the
manuscript as written.
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Results
Figure 2. Point plot depicting the diastolic dyssynchrony index
in 33 children with DCM (f) and 45 control subjects (⽧). The
17-ms cutoff used to determine the presence of diastolic dyssynchrony, based on the mean⫾2 SDs in the control group, is
marked.
General
Thirty-three patients with DCM (16 males [48%]) and 46
control subjects (25 males [54%]) were recruited. Patients
were younger than control subjects, although not significantly
so (8.0⫾6.3 versus 10.6⫾5.2 years, P⫽0.056; Table 1).
subjects (58.5⫾29.5 versus 21.5⫾17.9 ms, P⬍0.0001). The
same trend existed in DCM patients (53.5⫾51.4 versus
32.9⫾23.4 ms, P⫽0.08).
Intraventricular Systolic Versus Diastolic Wall
Motion in Control Subjects and in DCM Patients
Correlation Between Intraventricular and
Interventricular Systolic and Diastolic
Mechanical Dyssynchrony
Table 2 presents interventricular and intraventricular mechanical dyssynchrony in systole and diastole in control subjects
and DCM patients. Diastolic wall motion was more tightly
synchronized than systolic wall motion, both in normal
control subjects and in DCM patients. The mean LV intraventricular systolic delay was significantly longer than the
mean LV intraventricular diastolic delay in control subjects
(27.3⫾24.1 versus 4.5⫾5.6 ms, P⬍0.0001) and in DCM
patients (36.8⫾39.6 versus 15.1⫾17.4 ms, P⫽0.005). Likewise, the average SD of time to peak systole in 12 cardiac
segments (systolic dyssynchrony index) was longer than the
SD of time to peak diastole in 12 cardiac segments (diastolic
dyssynchrony index), both in the control group (26.3⫾11
versus 9.1⫾3.8 ms, P⬍0.0001) and in the DCM group
(42.5⫾22.1 versus 28.1⫾18.1 ms, P⫽0.002).
Interventricular Systolic Versus Diastolic Wall
Motion in Control Subjects and in DCM Patients
The mean interventricular systolic delay was significantly
greater than the interventricular diastolic delay in control
Intraventricular and interventricular systolic wall motion did
not correlate with diastolic wall motion either in control
subjects or in DCM patients. No correlation was found
between the systolic and diastolic intraventricular delay
(control subjects: r⫽0.005, P⫽0.9; DCM: r⫽0.13, P⫽0.46),
between the systolic and diastolic interventricular delay
(control subjects: r⫽0.09, P⫽0.91; DCM: r⫽0.22, P⫽0.29),
or between the SD of time to peak systole and the SD of time
to peak diastole among 12 cardiac segments (control subjects:
r⫽0.14, P⫽0.3; DCM: r⫽0.26, P⫽0.1).
Diastolic Wall Motion in DCM Patients Versus
Control Subjects
The diastolic intraventricular delay was prolonged in children
with DCM compared with control subjects (15.1⫾17.4 versus
4.5⫾5.6 ms, P⫽0.0009), and the SD of time to peak diastole
between 12 LV segments was significantly higher in children
with DCM than in control subjects (28.1⫾18.1 versus
9.1⫾3.8 ms, P⬍0.0001; Figure 2).
Table 2. Systolic and Diastolic Mechanical Dyssynchrony in 33 Children With
DCM and 46 Control Subjects
Control Subjects
DCM
2-Tailed P*
LV intraventricular systolic delay, ms
27.3⫾24.1
36.8⫾39.6
0.20
LV intraventricular diastolic delay, ms
4.5⫾5.6
15.1⫾17.4
0.0009
LV systolic dyssynchrony index, ms
26.3⫾11
42.5⫾22.1
0.0003
LV diastolic dyssynchrony index, ms
9.1⫾3.8
28.1⫾18.1
⬍0.0001
Systolic interventricular delay, ms
58.5⫾29.5
53.5⫾51.4
0.11
Diastolic interventricular delay, ms
21.5⫾17.9
32.9⫾23.4
0.02
LV intraventricular mechanical dyssynchrony
Left-right interventricular mechanical dyssynchrony
Friedberg et al
Diastolic Dyssynchrony in Pediatric Cardiomyopathy
Table 3. Correlation Between Diastolic Dyssynchrony Index
and LV Functional Indices in Children With DCM
Variable Correlated With the Diastolic
Dyssynchrony Index
Correlation
Coefficient (r)
P
LVEDd/BSA, cm/m2
0.36
0.03
LVEDd z score
0.46
0.006
2
LVESd/BSA, cm/m
0.4
0.02
Ejection fraction, %
⫺0.3
0.09
Mitral E⬘, cm/s
⫺0.32
0.06
Mitral E/E⬘ ratio
0.2
0.22
Mitral S⬘, cm/s
⫺0.06
0.74
LVEDd indicates LV end-diastolic dimension; BSA, body surface area; and
LVESd, LV end-systolic dimension.
Determination of a Threshold for the Diagnosis of
Diastolic Dyssynchrony
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We used control results to establish a cutoff for determination
of an abnormal diastolic dyssynchrony index. The diastolic
dyssynchrony index (mean ⫹2 SD) in normal control subjects was 16.6 ms. Using this value, we selected a diastolic
dyssynchrony index of ⬎17 ms as a threshold for determining
the presence of diastolic dyssynchrony. This threshold defined 21 (63.6%) of 33 children with DCM as having diastolic
dyssynchrony, whereas only 1 control subject had a diastolic
dyssynchrony index slightly above the cutoff (19.8 ms).
QRS durations of the DCM group with and without
diastolic dyssynchrony are shown in Table 3; these were not
different between groups. In the DCM group without diastolic
dyssynchrony, 1 patient had left bundle-branch block, and 2
had right bundle-branch block. In the DCM group with
diastolic dyssynchrony, 4 patients had left bundle-branch
block, and 2 had right bundle-branch block.
Relation Between Dyssynchrony and
Echocardiographic Parameters of
Cardiac Function
Table 3 shows correlations between the diastolic dyssynchrony index and LV functional indices in children with
DCM. The diastolic dyssynchrony index correlated modestly
with LV systolic and diastolic dimensions, and there was a
trend toward correlation with ejection fraction. On the other
hand, there was no correlation between the SD of time to peak
systole (systolic dyssynchrony index) among 12 segments
and ejection fraction in DCM (r⫽⫺0.08, P⫽0.66). There was
no correlation between the diastolic dyssynchrony index and
mitral tissue Doppler indices (Table 3). Although in general,
DCM patients without diastolic dyssynchrony had more
favorable diastolic function than DCM patients with diastolic
dyssynchrony, this was not statistically significant (Table 4).
53
determination of the threshold for diastolic dyssynchrony, we
correlated the uncorrected diastolic dyssynchrony index with
the heart rate– corrected diastolic dyssynchrony index. There
was a very strong correlation between these 2 measures
(DCM: r⫽0.98, P⬍0.0001; control subjects r⫽0.96,
P⬍0.0001), which indicates a relatively minor effect of heart
rate on the diastolic dyssynchrony index.
Relation Between Dyssynchrony and
Clinical Status
Patients who were listed for heart transplantation or who died
had more diastolic dyssynchrony than those who were free of
these events (diastolic dyssynchrony index 37.9⫾20.5 versus
22.1⫾13.8 ms, P⫽0.01). The median length of
transplantation-free survival of DCM patients with diastolic
dyssynchrony was 4 years, versus 12 years for those without
diastolic dyssynchrony, and the Kaplan-Meier survival curve
of those with diastolic dyssynchrony was worse than that for
those who did not have diastolic dyssynchrony, although the
log-rank test did not reach statistical significance, likely
because of the relatively small sample size and low event rate
(hazard ratio 2.98, P⫽0.11; Figure 3).We further analyzed
time-related transplantation-free survival between the 2
groups after adjustment for disease duration. This showed a
similar result (hazard ratio 2.96, P⫽0.17). Age at diagnosis
was not significantly associated with length of survival
(hazard ratio 1.04, P⫽0.41). After controlling for age at
diagnosis, the hazard ratio was 3.5 (P⫽0.11). The New York
Heart Association classification of patients below the median
diastolic dyssynchrony index (17 ms) was not significantly
different than that of patients with a diastolic dyssynchrony
index above this median value (2.5⫾0.9 versus 2.3⫾1.3,
respectively, P⫽0.52; Table 5).
Effect of Medications on Diastolic Dyssynchrony
Because all DCM patients were receiving at least 1 kind of
medication (including diuretics, spironolactone, angiotensin
converting enzyme inhibitors, ␤-blockers, and digoxin), it
was difficult to determine the association between effects of
medications and the degree of diastolic dyssynchrony. There
were no significant associations between the proportion of
patients receiving any one class of medication and the
presence or absence of dyssynchrony.
Interobserver and Intraobserver Reliability
Correction of Diastolic Dyssynchrony Index for
Heart Rate
Interobserver reliability of the diastolic dyssynchrony index
was higher than the interobserver reliability for the systolic
dyssynchrony index in normal subjects (Cronbach’s ␣ 0.98
versus 0.69) but was equal in DCM patients (Cronbach’s ␣
0.98 versus 0.98). Intraobserver reliability was higher for the
diastolic dyssynchrony index than for the systolic dyssynchrony
index in normal control subjects (Cronbach’s ␣ 0.99 versus 0.56)
and in DCM patients (Cronbach’s ␣ 0.98 versus 0.8).
Correction of the diastolic dyssynchrony index for heart rate
by the Bazzet method (dyssynchrony index divided by the
square root of the R-R interval) did not alter the results.
Children with DCM still had a significantly higher diastolic
dyssynchrony index than control subjects (1.0⫾0.7 versus
0.3⫾0.1, P⬍0.0001). To evaluate the effect of heart rate on
LV mechanical dyssynchrony, the incoordinate wall motion
of different LV segments, is an important contributor to the
pathophysiology of heart failure and has been linked to worse
functional status and outcomes in adult populations.13 When
Discussion
54
Circ Cardiovasc Imaging
July 2008
Table 4. Echocardiographic Indices of Ventricular Systolic and Diastolic Function in Normal Control
Subjects and in Children With DCM With and Without Diastolic Dyssynchrony as Defined by a Diastolic
Dyssynchrony Index Threshold of 17 ms
Echocardiographic Index
Control
Subjects
DCM With Diastolic
Dyssynchrony
DCM Without Diastolic
Dyssynchrony
2-Tailed
P*
Ejection fraction, %
67.2⫾6.3
24.9⫾11.3
33.3⫾15.8
0.08
LVEDd, cm
4.2⫾0.7
5.2⫾1.1
5.3⫾1.5
0.87
LVEDd/BSA
3.8⫾1.3
8.1⫾4
6.3⫾3.5
0.21
LVEDd z score
6.1⫾1.7
4.8⫾2.5
0.12
LVESd, cm
2.6⫾0.5
4.5⫾0.9
4.4⫾1.5
0.84
LVESd/BSA
2.4⫾0.7
7.1⫾3.8
5.0⫾2.5
0.11
IVRT, ms
58.4⫾12.8
76.9⫾20.0
65.8⫾16.7
0.17
PV A-wave reversal velocity, cm/s
25.8⫾9.6
21.5⫾8.9
23.8⫾9.5
0.51
PV A-wave reversal duration, ms
109.2⫾35.9
97.0⫾14.9
94.3⫾33.6
0.76
PV A/mitral A velocity ratio
0.46⫾0.17
0.43⫾0.22
0.48⫾0.19
0.51
PV A/mitral A duration ratio
0.77⫾0.33
0.97⫾0.36
1.2⫾0.36
0.12
Mitral E velocity, cm/s
96.9⫾16
93.2.⫾26.2
110.7⫾21.9
0.06
Mitral A velocity, cm/s
55.3⫾15.4
52.4⫾18.7
55.1⫾23.1
0.72
Mitral E/A velocity ratio
1.9⫾0.4
2.10⫾1.0
2.3⫾0.8
0.39
158.7⫾46.4
116.7⫾32.2
105.9⫾30.5
0.38
398⫾115
300.2⫾112.9
285.7⫾148.0
0.75
Mitral valve S⬘, cm/s
9.4⫾2.9
5.2⫾2.7
6.0⫾2.1
0.38
Mitral valve E⬘, cm/s
Doppler
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Mitral valve E-wave deceleration time, ms
Mitral valve filling time, ms
Tissue Doppler
16.7⫾4.3
9.3⫾4.4
11.5⫾4.4
0.18
Mitral valve E/E⬘
6.3⫾2.1
12.6⫾8.0
11⫾5.5
0.57
Septal S⬘, cm/s
7.6⫾1.7
4.9⫾1.6
5.9⫾2.4
0.23
Septal E⬘, cm/s
12⫾3.4
7.0⫾2.1
7.9⫾2.6
0.29
Septal E/E⬘
8.2⫾2.6
13.7⫾5.3
15.3⫾5.4
0.42
LVEDd indicates LV end-diastolic dimension; BSA, body surface area; LVESd, LV end-systolic dimension; IVRT, isovolumic relaxation
time; and PV, pulmonary vein.
*P for comparison between DCM patients with and without diastolic dyssynchrony.
tissue Doppler is used to study regional LV wall motion,
mechanical dyssynchrony can be quantified by various techniques, such as the maximal motion delay between different
segments or the variance (expressed as the SD) in time to
Figure 3. Kaplan-Meier curve showing transplantation-free survival among DCM patients with (dashed line) and without (solid
line) diastolic dyssynchrony as defined by a diastolic dyssynchrony index threshold of 17 ms.
peak myocardial tissue velocity between multiple ventricular
segments.13 Although the bulk of research both in
adults1,2,14 –16 and in children3,17 relating to mechanical dyssynchrony has focused on systolic wall motion, recent findings indicate that diastolic wall-motion abnormalities are
prevalent in adults with heart failure, both with and without
systolic dysfunction. 6,8,9 The present study is the first to
investigate diastolic mechanical dyssynchrony in children
with DCM and the first to explore its relation to clinical status
in this group of patients. The major findings of the present
study were as follows: (1) LV diastolic wall motion is highly
synchronized in normal children; (2) LV intraventricular
diastolic mechanical dyssynchrony is common in pediatric
DCM; (3) an intraventricular diastolic dyssynchrony index of
17 ms is a reasonable threshold to define the presence of
diastolic mechanical dyssynchrony in children; and (4) DCM
patients with worse transplant-free survival have more diastolic dyssynchrony and conversely, those with diastolic
dyssynchrony appear to have a worse survival than patients
without diastolic dyssynchrony.
Using our normal control results as a reference, we found
that diastolic mechanical dyssynchrony is common in pediatric DCM and occurs at a rate similar to the 60% rate of
Friedberg et al
Diastolic Dyssynchrony in Pediatric Cardiomyopathy
55
Table 5. Clinical Features of DCM Patients With and Without Diastolic
Dyssynchrony
Clinical Feature
Age, y
DCM With
Diastolic
Dyssynchrony
(n⫽21)
DCM Without
Diastolic
Dyssynchrony
(n⫽11)
2-Tailed
P
7.3⫾5.9
9.5⫾7.0
0.33
QRS duration, ms
87.5⫾15.7
89.3⫾28.4
0.85
Mean NYHA class
2.3⫾1.3
2.5⫾0.9
0.52
% Patients who received transplants or
died
47
27
0.45
% Patients admitted to hospital with
worsening failure
38
36
0.80
1.9⫾2.9
2.9⫾4.5
0.91
Time between diagnosis and
echocardiography (illness duration
at time of evaluation), y
Cause of DCM
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Idiopathic
13
5
ALCAPA
2
0
Myocarditis
1
0
Familial
1
1
Metabolic
1
2
Other systemic disease
1
1
Anthracycline
1
2
Arrhythmogenic
1
0
ALCAPA indicates anomalous left coronary artery from pulmonary artery; DCM, dilated cardiomyopathy.
diastolic dyssynchrony seen in adult patients with systolic
and diastolic heart failure.8 The presence of diastolic wallmotion abnormalities is important because DCM patients
who later died or were listed for heart transplantation had
significantly more diastolic dyssynchrony than did survivors.
The actuarial survival of DCM patients with diastolic dyssynchrony appeared worse than that of patients who had
synchronous diastolic motion, and although this did not reach
the statistical cutoff to determine significance, likely because
of the small sample size and low event rate, we believe that
this is clinically significant and important nonetheless. Statistical significance should be verified with further study on a
larger group of patients. The present findings are in keeping
with diastolic dysfunction being an important prognostic
factor in heart failure4; however, although the present results
indicate a worse clinical outcome for patients with diastolic
dyssynchrony, they do not show whether this is causally
related or a manifestation of overall disease severity. We did
find that the diastolic dyssynchrony index correlated with LV
end-diastolic and end-systolic dimensions. These are important components of ventricular function and remodeling and
are also important prognostic indices. Ventricular reverse
remodeling has also been used as a primary outcome measure
in several trials that have investigated the association between
mechanical dyssynchrony and response to cardiac resynchronization therapy,18,19 and in conjunction with that, the present
results may suggest that in children with decreased systolic
function, there is an important association between diastolic
dyssynchrony, ventricular remodeling, and clinical prognosis.
Conversely, systolic dyssynchrony did not affect these pa-
rameters. Diastolic dyssynchrony may adversely affect ventricular function by adversely affecting filling dynamics,8,20,21
compromising coronary perfusion and ventricular function.22
In DCM, there is a disproportionate shortening of diastolic
time over and above that related to an increase in heart rate,23
and in the present study, even when corrected for heart rate,
diastolic dyssynchrony was significantly higher in DCM than
in control subjects. However, the E/E⬘ ratio and other
echocardiographic parameters of diastolic function were similar between patients with and without diastolic dyssynchrony, and the mechanism whereby diastolic dyssynchrony
impacts ventricular function remains to be further elucidated.
Diastolic Versus Systolic Motion in Normal
Children and in Children With DCM
Measurement of diastolic dyssynchrony was easily achieved
with good interobserver and intraobserver reliability. In the
present study, diastolic wall motion was highly synchronized
as compared with systolic wall motion both in control
subjects and in DCM. These results differ somewhat from
those found in a previous study in the adult population, in
which the diastolic dyssynchrony index was very similar to
the systolic dyssynchrony index both in normal subjects and
in patients with heart failure.9 In addition, the diastolic
dyssynchrony index of 17 ms we determined as a threshold
for diagnosis of diastolic dyssynchrony was lower than that
found in the study by Yu and colleagues.9 Although this may
be the result of shorter cardiac intervals in children, leading to
a smaller SD, it may also be the result of greater diastolic
synchrony in children than in adults, possibly related to the
proportionately shorter diastolic period in children.24
56
Circ Cardiovasc Imaging
July 2008
Consistent with previous findings from studies in adults,9
we found no relation between systolic and diastolic wall
motion either in normal control subjects or in DCM patients.
This implies that the mechanisms that lead to systolic and
diastolic mechanical dyssynchrony are distinct from one
another. We did not investigate the reasons for the lack of
correlation between systolic and diastolic dyssynchrony, and
this requires further study.
2.
3.
4.
Study Limitations
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This was a cross-sectional study of echocardiographic assessment, with inherent limitations. In our institution, children
with DCM do not routinely undergo diagnostic cardiac
catheterization, and therefore, we did not have data relating to
filling pressures or measurements of the time constant of
pressure decay in the LV (␶). None of the patients studied
underwent cardiac resynchronization therapy, and therefore,
it was not possible to study the effect of cardiac resynchronization therapy on diastolic dyssynchrony. Although we
only measured longitudinal motion, it is possible that radial
and circumferential diastolic dyssynchrony is important, and
this requires further study.
Future Implications
Currently, there are no data on the management of diastolic
dyssynchrony in children with DCM. Wang et al8 found that
medical therapy, including diuretics, ␤-blockers, calcium
channel blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, improved diastolic dyssynchrony in adults with cardiomyopathy and decreased
filling pressures, but they did not investigate which of these
medications brought about these changes. Schuster et al6
found in adults that cardiac resynchronization therapy reduced diastolic dyssynchrony, albeit with lesser effect than
systolic dyssynchrony. Others have found that pacing improves diastolic ventricular–ventricular interactions.25,26
Given the present finding that diastolic dyssynchrony is
common in children with DCM, and given that the outcome
of children with symptomatic DCM is poor,27 the effects of
various interventions on diastolic dyssynchrony and function
need to be investigated as an alternative avenue of therapy to
that focused only on improving systolic function.
Conclusions
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
LV intraventricular diastolic mechanical dyssynchrony is
common in children with DCM and is worse in children who
later experience heart transplantation or death. The presence
of diastolic dyssynchrony in pediatric DCM appears to be
associated with a worse clinical outcome.
Acknowledgments
We thank Cameron Slorach and Cheryl Fackoury for their contribution in performing echocardiography.
16.
17.
18.
Disclosures
None.
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CLINICAL PERSPECTIVE
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Left ventricular mechanical dyssynchrony is generally thought of as a systolic phenomenon and appears to be an important
contributor to the pathophysiology of heart failure. It has been associated with worse functional status and outcomes in
adult populations with cardiomyopathy. The significance of diastolic dyssynchrony has not been fully evaluated,
particularly in the pediatric population. This is the first study investigating diastolic mechanical dyssynchrony in children
with dilated cardiomyopathy. This report, using tissue Doppler imaging, establishes normal values for diastolic
dyssynchrony in pediatric patients and shows that diastolic dyssynchrony is relatively common among pediatric patients
with dilated cardiomyopathy. We investigate the relation between diastolic mechanical dyssynchrony, ventricular function,
and clinical outcomes and show that the presence of diastolic dyssynchrony may have implications for length of
transplantation-free survival. These results should stimulate further research into diastolic mechanical dyssynchrony in
children with heart failure and allow investigation of possible treatment modalities to address it.
Left Ventricular Diastolic Mechanical Dyssynchrony and Associated Clinical Outcomes in
Children With Dilated Cardiomyopathy
Mark K. Friedberg, Susan L. Roche, Arshiya F. Mohammed, Mervin Balasingam, Eshetu G.
Atenafu and Paul F. Kantor
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Circ Cardiovasc Imaging. 2008;1:50-57
doi: 10.1161/CIRCIMAGING.108.782086
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