Download Impaired right and left ventricular diastolic

European Heart Journal – Cardiovascular Imaging (2012) 13, 905–913
doi:10.1093/ehjci/jes067
Impaired right and left ventricular diastolic
myocardial mechanics and filling
in asymptomatic children and adolescents
after repair of tetralogy of Fallot
Mark K. Friedberg 1*, Fernanda P. Fernandes 1, Susan L. Roche 1,
Lars Grosse-Wortmann 1,2, Cedric Manlhiot 1, Cheryl Fackoury 1, Cameron Slorach 1,
Brian W. McCrindle 1, Luc Mertens1, and Paul F. Kantor 1
1
Division of Paediatric Cardiology, The Labatt Family Heart Center, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada; and 2Division of Cardiology,
Department of Diagnostic Imaging, Hospital for Sick Children and University of Toronto, 555 University Avenue, Toronto, ON, Canada M5G 1X8
Received 23 January 2012; accepted after revision 9 March 2012; online publish-ahead-of-print 30 March 2012
After tetralogy of Fallot (TOF) repair patients have right ventricular (RV) dysfunction and reduced exercise tolerance.
Diastolic dysfunction may be important but is as yet poorly characterized. The early diastolic strain rate (SR) is a
measure of ventricular relaxation, and may be useful to assess diastolic mechanics in TOF. We hypothesized that
children after TOF repair have diastolic dysfunction and dyssynchrony by this measure, and sought to determine
their relationship with pulmonary regurgitation (PR), RV enlargement, and aerobic exercise capacity.
.....................................................................................................................................................................................
Methods
We prospectively recruited asymptomatic children after TOF repair. RV and PR volumes were measured by magnetic
and results
resonance imaging; Doppler and tissue Doppler indices by echocardiography and RV and left ventricular (LV) early
diastolic SR by two-dimensional speckle tracking. Exercise peak oxygen consumption (VO2) was determined using
bicycle ergometry.
Results were compared with healthy controls. We studied 53 TOF patients and 49 age-matched controls. TOF
patients had significant PR (2.05 + 1 L/m2) with moderate RV dilatation (157 + 39 mL/m2), low-normal RV ejection
fraction (49 + 8.8%), and moderate QRS prolongation (141 + 23 ms). The RV outflow gradient was
21.7 + 16.0 mmHg. Patients had RV diastolic dysfunction vs. controls [reduced tricuspid valve (TV) E/A ratio, E′ velocity, and longitudinal diastolic SR; increased right atrial volume and TV E/E′ ratio]. LV early diastolic radial and circumferential SR were lower in TOF patients in association with more PR [parameter estimate (PE) 0.177 standard
error (SE) (0.08) mL/m2, P ¼ 0.02] and higher RV volumes [(PE) 0.005 (0.002) mL/m2, P ¼ 0.01]. Diastolic dyssynchrony was not different in TOF patients vs. controls.
.....................................................................................................................................................................................
Conclusion
TOF patients have RV and LV diastolic dysfunction associated with RV enlargement and reduced early filling. SR
imaging may be useful to quantify early myocardial diastolic dysfunction in these children.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Tetralogy of Fallot † Paediatrics † Diastole † Strain rate † Speckle-tracking echocardiography
Introduction
After surgery for tetralogy of Fallot (TOF), patients may demonstrate progressive pulmonary regurgitation (PR), right ventricular
(RV) enlargement, RV and left ventricular (LV) dysfunction and
exercise intolerance. Ventricular dysfunction, rather than PR or RV
enlargement per se, may predict impaired clinical status1 and diastolic
dysfunction may be an important component. Furthermore, since
diastolic dysfunction may predate clinical symptoms;2 it may be possible to detect ventricular dysfunction early in the disease course.
* Corresponding author. Tel: +1 416 813 7239; Fax: +1 416 813 7547, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]
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Aims
906
Diastolic dysfunction in TOF may stem from impaired myocardial relaxation, decreased recoil attributable to a stiffer ventricle
and dyssynchronous ventricular relaxation.3 – 6 However, assessment of RV diastolic dysfunction is difficult using Doppler flow
parameters.7 Consequently, RV and LV diastolic dysfunction, and
diastolic dyssynchrony have not been well characterized in TOF
patients beyond the phenomenon of restrictive RV physiology.8,9
The early diastolic strain rate (SR) has been proposed as a
measure of myocardial relaxation that is less influenced by
loading conditions than Doppler flow indices.7,10 – 12 This parameter would reflect both impaired recoil and impaired rapid relaxation as it occurs in early diastole. Early diastolic SR directly
measures a global myocardial relaxation parameter less influenced
by annular or valvar pathology.10 Therefore, use of diastolic SR
imaging may enhance assessment of RV and LV diastolic function
in children after repair of TOF. Accordingly, this study aimed to investigate early diastolic RV and LV mechanics and their relation to
PR, RV enlargement, and exercise capacity in young asymptomatic
patients after TOF repair. We hypothesized that early RV and LV
diastolic relaxation is impaired in TOF patients and that this impairment is associated with diastolic dyssynchrony and reduced exercise capacity.
Study population
We prospectively recruited asymptomatic, clinically stable children,
and adolescents after TOF repair scheduled for elective outpatient
evaluation between the years 2007 and 2009. This was a crosssectional study consisting of a single evaluation. To avoid influence of
extraneous factors such as ventricular pacing, TOF variants with distinct pathophysiology, and the influence of severe RV afterload on diastolic function, we excluded patients with an implanted pacemaker,
absent pulmonary valve syndrome, or RV outflow tract gradient
.50 mmHg. The results were compared with those of age-matched
healthy controls. Controls were healthy volunteers or healthy children
being evaluated for an innocent murmur who had normal medical
history, physical examination, and echocardiography.
Echocardiography
Echocardiography followed a standardized protocol. Using probes appropriate for the patient size, images were acquired from the apical
four-, three-, and two-chamber views and para-sternal short-axis
view at the LV basal, mid, and apical levels. Compression and gain
were optimized. Sweep speed was set at 100 cm/s. Image depth and
sector width were optimized for 50 – 90 frames per second (fps) for
two-dimensional speckle-tracking echocardiography (STE).13 Images
were acquired during quiet respiration as breath holding is not consistently feasible in children. Three cardiac cycles were analysed. Images
were transferred to a workstation (Echopac 6.0.1, GE Medical
Systems, Horten, Norway) for offline analysis.
Assessment of RV diastolic function
Tricuspid valve (TV) inflow velocities were recorded from apical or
low para-sternal views. A pulsed wave Doppler sample was placed at
the TV leaflet tips aligning the beam parallel to TV inflow. Peak early
(E) and late (A) diastolic velocities were measured and their ratio
(E/A) and TV E-wave deceleration time measured. Right atrial (RA)
volumes were assessed by the mono-plane Simpson’s method from
the apical four-chamber view and indexed to the body surface area
(BSA). From the apical four-chamber view, optimizing the image to
narrow the insonation angle, pulsed tissue Doppler (TDI) was obtained
at .150 fps at the lateral and septal TV annulus and the TV E/E′ ratio
calculated. RV myocardial diastolic relaxation was assessed from twodimensional STE. The endocardial border was traced in the apical fourchamber view and the region of interest adjusted to wall thickness.
Myocardial tracking by the software was verified visually and retraced
if necessary until adequate tracking was achieved. From the deformation curves, the RV lateral wall longitudinal peak early diastolic SR
(average of basal and mid segments) was measured to reflect RV
early diastolic relaxation (Figure 1A and B). The basal- and
mid-anterior-septal segments were excluded from analysis due to a
ventricular septal defect (VSD) patch in this region.
Assessment of LV diastolic function
LV diastolic function was assessed from mitral valve (MV) inflow, pulmonary vein Doppler, and pulsed TDI of the mitral lateral annulus.14
LV myocardial early diastolic relaxation was assessed in the longitudinal, radial, and circumferential directions using two-dimensional STE. LV
longitudinal, circumferential, and radial SR curves from a TOF patient
are shown in Figure 1C–E.
Assessment of right and left ventricular
diastolic dyssynchrony
RV diastolic dyssynchrony was measured as the delay between time to
peak early diastolic SR between the RV lateral wall and interventricular
septum (Figure 1A).15 LV diastolic dyssynchrony was measured by four
separate indices: delay between time to peak early longitudinal diastolic
SR between the LV lateral wall and interventricular septum; delay from
time to peak early radial diastolic SR between the septum and posterior wall; and by the standard deviation (SD) of time to peak early diastolic SR in six LV mid-ventricular segments in the circumferential and
radial directions. All dyssynchrony measurements were corrected for
the heart rate (yielding a dimensionless index).16,17
Assessment of RV volumes, ejection fraction,
and PR
RV end-diastolic volume indexed for BSA (RVEDVi), ejection fraction
(EF), and PR flow volume indexed for BSA were measured by magnetic
resonance imaging (MRI) on a 1.5 T scanner (‘Avanto’, Siemens Medical
Solutions, Erlangen, Germany). For ventricular volumes, a short-axis
cine stack was acquired during breath-hold, using a steady-state freeprecession gradient echo sequence in a standard fashion. The
in-plane spatial resolution was 1.5 – 2.5 mm, with a slice thickness of
5 – 7 mm, number of slices 10– 12, and the gap adjusted to cover
both ventricles. Temporal resolution was adjusted to accommodate
20 true reconstructed phases per cardiac cycle. For pulmonary flow
volumes, phase-contrast velocity mapping was performed perpendicular to the right and left pulmonary arteries, also in the usual clinical
fashion during free breathing, with a temporal resolution adequate to
achieve 25 true phases per cardiac cycle. A dedicated workstation
(QMass, version 7.2 for volume analysis and QFlow, version 5.2,
Medis Medical Imaging Systems, Leiden, The Netherlands) was used
for volumes and flow analysis. For total pulmonary blood flow and regurgitation volumes, right and left pulmonary artery net forward flow
volumes and reverse flow volumes, respectively, were added.18 MRI
was not used for assessment of myocardial diastolic SR due to relatively
low temporal resolution and the advantage of echocardiography in this
regard.
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Methods
M.K. Friedberg et al.
Diastolic dysfunction in tetralogy of Fallot
907
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Figure 1 Peak early right ventricular longitudinal diastolic SR (white arrow) by two-dimensional speckle tracking in a control (A) and in a
patient after tetralogy of Fallot repair (B). Global SR (average of six-segments) is represented by the dotted white line. The time to peak
early diastolic strain rate is measured from the onset of the QRS complex (double headed arrow). Peak early left ventricular diastolic SR in
patients after tetralogy of Fallot repair are shown in (C ) (LV longitudinal SR); (D) (LV circumferential SR at mid-ventricular level) and (E)
(LV radial SR at mid-ventricular level). RV enlargement is apparent in the reference image.
Statistical analysis
Deformation and mechanical dyssynchrony data were compared
between TOF patients and controls using the non-paired two-tailed
Student’s t-test. Associations between RV mechanics and RV
volumes, PR and exercise capacity (measured as peak oxygen consumption during bicycle ergometry, VO2) were investigated using
908
M.K. Friedberg et al.
univariable linear-regression models with parameter estimates (PE) and
its standard error reported. PEs represent the change in the dependent variable for each increase of 1 unit in the independent variable.
This informs as to the direction of the association (positive or negative) and its strength (how much change was associated with each
unit increase in the independent variable). Intra- and inter-observer reliability were analysed in 10 patients by repeat measurement of peak
early longitudinal and radial diastolic SR and time to peak early longitudinal and radial diastolic SR by the same observer and two different
observers, respectively. For reliability analysis, new SR curves and measurements were generated by each observer on the same cardiac
cycle. Statistical analyses used SAS software v9.2 (The SAS Institute,
Cary, NC, USA). A P-value of ,0.05 was considered statistically significant. The study was approved by the Institutional Research Ethics
Board. Informed consent was given by the patients or guardians as
appropriate.
dyssynchrony was not statistically increased compared with controls (72.5 + 56.5 vs. 61.3 + 43.8 ms, P ¼ 0.3) and was not statistically associated with PR volume. RV longitudinal diastolic SR was
significantly associated with RV relaxation through the tricuspid
inflow Doppler E/A ratio [PE 20.3 (0.15), P ¼ 0.04]. RV longitudinal diastolic SR was not associated with the tricuspid valve E/E′ ratio
(P ¼ 0.49), MRI determined PR flow volume indexed for BSA (P ¼
0.67) or RVEDVi (P ¼ 0.1). RV and LV longitudinal diastolic SR
were not associated with QRS duration. There was no difference
in RV longitudinal diastolic SR between patients who had or had
not undergone a ventriculotomy (22.05 + 0.46 vs. 21.95 +
0.59, P ¼ 0.56). RV longitudinal diastolic SR was not significantly
associated with RV EF (P ¼ 0.56).
Results
TOF patients had LV diastolic dysfunction including lower MV E/A
ratio, lower MV E′ , and higher MV E/E′ ratio (Table 2). LV radial and
LV diastolic relaxation and dyssynchrony
Patient demographics
Conventional and tissue Doppler
measures of RV diastolic function
RV diastolic function assessed by tricuspid inflow and TDI are presented in Table 2. Compared with controls, TOF patients had RV
diastolic dysfunction including lower TV E/A ratio, lower TV
annulus E′ , and higher TV E/E′ ratio. RA volumes were markedly
higher in TOF patients (Table 2).
Table 2 Doppler and tissue Doppler diastolic
measurements
Tetralogy of
Fallot
Controls
P-value
................................................................................
RV diastolic parameters
Tricuspid E/A ratio
Tricuspid E′ wave
(cm/s)
1.5 + 0.58
8.8 + 3.5
2.3 + 0.78
15.8 + 2.5
,0.001
,0.001
Tricuspid E/E′ ratio
10 + 4.6
3.6 + 1.1
,0.001
Right atrial volume
indexed (mL/m2)
25.4 + 13.1
9.7 + 3.0
,0.0001
2.45 + 0.86
2.63 + 0.53
0.24
157 + 33
152 + 22
0.40
211.0 + 20.0
0.12
11.0 + 4.1
19 + 2
,0.001
11.91 + 5.5
5.70 + 0.88
,0.001
LV diastolic parameters
Mitral E/A ratio
Mitral deceleration
time (ms)
PVAD 2 MVAD
(ms)
MV E′ (cm/s)
MV E/E′
5.0 + 38.0
RV early diastolic SR and dyssynchrony
RV longitudinal diastolic SR was significantly reduced in TOF
patients compared with controls (Table 3). RV longitudinal
Table 1
PVAD 2 MVAD, pulmonary venous a-wave duration 2 mitral valve a-wave
duration; E, early diastolic ventricular inflow wave; E′ , early diastolic ventricular
tissue velocity.
TOF patient characteristics
Table 3 Left and right ventricular early diastolic
longitudinal SR
Age (years)
12 (range 5–16)
Age at surgery (months)
Ventriculotomy (%)
17 + 16
54
Previous shunt surgery (%)
13
................................................................................
PR flow indexed (mL/min/m2)
RV end-diastolic volume index (mL/m2)
2.05 + 1
157 + 39
RV lateral wall (s21)
2.00 + 0.58
2.69 + 0.94
,0.001
RV ejection fraction (%)
49 + 8.8
1.93 + 1.02
1.58 + 0.66
1.88 + 0.70
1.68 + 0.44
0.79
0.40
QRS duration (ms)
141 + 23
LV lateral wall (s21)
Interventricular septum
(s21)
Data are reported as mean + SD. PR, pulmonary regurgitation; RV, right ventricle.
Tetralogy of
Fallot
RV, right ventricle, LV, left ventricle.
Controls
P-value
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Fifty-three asymptomatic children and adolescents after TOF
repair and 49 healthy controls were studied. TOF patient demographics are presented in Table 1. On average, TOF patients had
significant PR with moderate RV dilatation, low-normal RV ejection
fraction and moderate QRS prolongation. Six patients had late diastolic antegrade flow in the main pulmonary artery throughout the
respiratory cycle suggestive of restrictive RV physiology.
Twenty-five patients had no or trace tricuspid regurgitation (TR),
25 had mild TR, and 3 had moderate TR, none had severe TR.
The RV outflow gradient was 21.7 + 16.0 mmHg. MRI data were
available in 70% of TOF patients.
909
Diastolic dysfunction in tetralogy of Fallot
Table 4
LV regional early diastolic radial SR
Tetralogy of Fallot
Controls
Table 5 Left ventricular regional early diastolic
circumferential SR
P-value
................................................................................
Basal (s21)
Tetralogy of Fallot
Controls
P-value
................................................................................
Basal (s21)
Antero-septal
Antero-septal
Anterior
—
21.70 + 0.89
—
22.64 + 1.10
0.005
,0.001
—
—
Lateral
21.76 + 0.93
22.85 + 1.10
,0.001
Anterior
1.93 + 1.03
2.15 + 0.92
0.34
Posterior
Inferior
21.72 + 0.87
21.64 + 0.77
22.89 + 1.01
22.48 + 0.90
,0.001
,0.001
Lateral
Posterior
1.86 + 0.91
1.62 + 0.74
2.62 + 1.12
2.63 + 0.86
0.003
,0.001
Infero-septal
21.56 + 0.65
22.10 + 0.84
0.004
1.42 + 0.59
2.03 + 0.69
,0.001
1.95 + 0.71
1.95 + 0.67
0.98
Mid (s21)
Antero-septal
—
—
0.06
Inferior
Infero-septal
Mid (s21)
Anterior
21.52 + 0.92
22.43 + 0.91
,0.001
Antero-septal
—
—
Lateral
Posterior
21.47 + 0.91
21.72 + 0.81
22.61 + 1.04
22.42 + 0.90
,0.001
,0.001
Anterior
Lateral
1.89 + 0.78
1.92 + 1.05
1.73 + 0.76
2.23 + 0.87
0.36
0.16
21.72 + 0.72
22.13 + 0.84
0.02
Posterior
1.58 + 1.14
1.94 + 0.91
0.14
21.63 + 0.64
21.93 + 0.82
0.07
Inferior
Infero-septal
1.48 + 0.71
1.97 + 0.71
1.61 + 0.83
2.11 + 0.63
0.46
0.39
Antero-septal
21.98 + 0.80
22.98 + 1.21
,0.001
Anterior
Lateral
21.97 + 1.01
21.91 + 0.81
22.95 + 0.96
22.75 + 0.87
,0.001
,0.001
2.50 + 0.94
2.03 + 0.88
2.28 + 0.65
2.34 + 0.99
0.25
0.18
Inferior
Infero-septal
Apical (s21)
21.87 + 0.83
22.80 + 0.99
,0.001
21.89 + 0.82
21.87 + 0.92
22.69 + 1.05
22.61 + 1.43
0.001
0.02
circumferential early diastolic SR were lower in multiple LV segments in TOF patients vs. controls (Tables 4 and 5). LV lateral
wall and septal longitudinal diastolic deformation were similar
between TOF and controls (Table 3). LV lateral wall SR was associated with the MV E/E′ ratio [(PE) 20.07 (0.03) cm/s, p ¼ 0.03].
Lower global LV radial diastolic SR was associated with higher
PR volume indexed for BSA [(PE) 0.18 (0.08) mL/m2, P ¼ 0.02]
and with higher RVEDVi [(PE) 0.005 (0.002) mL/m2, P ¼ 0.01].
LV longitudinal (55 + 50 vs.59 + 52, P ¼ 0.75), circumferential
(26.1 + 12.9 vs. 33.1 + 17.6, P ¼ 0.05), and radial (20.5 + 15.2
vs. 25.7 + 15.3, P ¼ 0.13) intra-ventricular diastolic dyssynchrony
were not increased in TOF patients compared with controls.
Each 1 ms increase in radial diastolic LV septal-posterior wall
delay was associated with a 0.43 (0.21) ms increase in MV deceleration time (P ¼ 0.04) and a 2.53 (1.23) increase in the MV E/E′
ratio (P ¼ 0.04).
Association between diastolic SR and
dyssynchrony with exercise capacity
Patients with TOF have moderately decreased exercise capacity.
The peak oxygen consumption during the metabolic exercise
test was 29.7 + 7.1 mL/kg/min (66.3 + 15.2% of predicted).
There were no significant associations between RV or LV diastolic
deformation or dyssynchrony and peak exercise VO2.
Intra- and inter-observer reliability
Owing to the large number of variables, we present the intra- and
inter-observer reliability analysis in a table. As reliability for radial
Antero-septal
Anterior
Lateral
1.91 + 0.94
1.89 + 0.77
0.92
Posterior
Inferior
1.80 + 0.93
2.05 + 1.00
1.88 + 0.77
2.23 + 0.92
0.72
0.44
Infero-septal
2.58 + 0.95
2.29 + 0.91
0.20
diastolic SR has previously been shown to be poor,19 we present
these data as a figure. Accordingly, intra- and inter-observer reliability data for radial diastolic SR and time to peak radial diastolic
SR are presented in Figure 2A–D and for LV and RV lateral wall diastolic SR and time to peak radial diastolic SR in Table 6. Inter- and
intra-observer reliability were acceptable for global early diastolic
SR, but inter-observer reliability was poor for measurement of
time to peak early diastolic SR.
Discussion
The results of this study show that young asymptomatic patients
after repair of TOF have RV and LV diastolic dysfunction with
impaired early diastolic SR. These were associated with abnormal
RV and LV filling, RV dilatation, and markers of increased RV
filling pressures.
Diastolic dysfunction in TOF
Assessment of diastolic dysfunction in TOF, especially early RV relaxation, is challenging. Tricuspid Doppler signals are less defined
than mitral inflow and abnormal loading conditions from pulmonary and TR in some patients complicates assessment of diastolic
dysfunction using TV inflow Doppler. While restrictive RV physiology has been well described in the post-operative TOF population, it predominantly pertains to abnormal RV compliance and
capacitance rather than abnormal early diastolic filling.8,9
RV and LV systolic deformation has previously been shown to be
reduced in TOF patients.5 We now demonstrate myocardial
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Posterior
Inferior
Infero-septal
Apical (s21)
910
M.K. Friedberg et al.
Table 6 Bland –Altman analysis of intra-observer and inter-observer variability for longitudinal diastolic SR and time to
peak longitudinal diastolic SR
Intra-observer variability
......................................................
Inter-observer variability
....................................................
Difference
Difference
..........................
Mean + SD
Mean
SD
.........................
Mean + SD
Mean
SD
...............................................................................................................................................................................
LV long. diastolic SR (s21)
0.01
0.17
1.86 + 0.39
20.02
0.15
Time to peak LV long. diastolic SR (ms)
RV long. diastolic SR (s21)
574.5 + 104.0
2.01 + 0.52
1.86 + 0.36
22.2
0.14
8.55
0.22
574.1 + 108.0
2.01 + 0.54
21.4
0.01
15.27
0.12
Time to peak RV long. diastolic SR (ms)
602.2 + 107.3
218.88
61.97
593.7 + 113.5
23.11
18.58
SD, standard deviation; LV, left ventricular lateral wall; RV, right ventricular lateral wall; long. diastolic SR, longitudinal diastolic SR; s, seconds; ms, milliseconds.
diastolic dysfunction and impaired ventricular filling as well. Diastolic
dysfunction in TOF patients may stem from various factors including
systolic dysfunction, delayed relaxation, and decreased recoil due to
a stiffer ventricle. Indeed, in our study, RV longitudinal diastolic SR
was decreased and markers of filling pressures were higher.
Reduced early diastolic SR and TV E′ suggest impaired myocardial relaxation or decreased recoil and indeed, the RV diastolic SR was
associated with the tricuspid inflow E/A ratio. The markedly enlarged
RA volumes and increased TV E/E′ ratio suggest a stiffer RV. Although RA enlargement may result from TR, there was insufficient
TR to explain the degree of RA enlargement in our cohort. We
could not assess RV radial and circumferential SR, but abnormalities
in RV longitudinal diastolic SR are consistent with the predominant
longitudinal contraction pattern in the RV.20 There are limited data
on RV diastolic SR values in normal children. The values in our
control cohort were lower than those reported previously reported
in healthy children.21 – 23 The reason for this is likely the use of twodimensional speckle tracking vs. Doppler-based techniques used in
previous studies.13 In our study, septal diastolic longitudinal SR
was not significantly different from controls, whereas RV lateral
wall diastolic SR was reduced. These results are similar to a previous
study where the authors suggested that the septum may have a compensatory role for reduced lateral wall function.24 We are unsure
whether this is indeed the case, but the septum may reflect both
RV and LV events. These results, however, do demonstrate the regional heterogeneity found in these hearts.
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Figure 2 Bland – Altman analysis of intra- and inter-observer reliability for LV global early diastolic radial SR and time to peak early radial
diastolic SR. (A) Peak early diastolic SR intra-observer reliability. (B) Peak early diastolic SR inter-observer reliability. (C) Time to peak early
diastolic SR intra-observer reliability. (D) Time to peak early diastolic SR inter-observer reliability.
911
Diastolic dysfunction in tetralogy of Fallot
Clinical implications
We found diastolic abnormalities early in the clinical course. It is
likely that with increasing RV dilatation, these findings would
worsen and our results are consistent with the established role
of PR and RV dilatation in the pathophysiology of TOF.26,28,34 – 40
MRI determined RVEDVi is currently used to determine timing
of intervention for RV outflow dysfunction in the absence of clinical symptoms. Our population had an average RVEDVi of 157 mL/
m2, which in some institutions is used as a cut-off for intervention
(although in our own institution a higher RVEDVi is used). Interestingly, RV longitudinal diastolic SR was not significantly associated
with RVEDVi as we would have expected it to be.41 SR is less influenced by loading conditions than strain, and this may partially
explain this result. In addition, correcting deformation for ventricular volumes needs to be explored and may increase the value of
diastolic SR to predict improvement after pulmonary valve replacement. Our data do not suggest indications for timing of pulmonary
valve replacement and do not inform as to the appropriate cut-off
in terms of RV volume.42 Other factors such as myocardial fibrosis,
VSD patch, coronary artery abnormalities, TR, and intrinsic myocardial properties may also impact diastolic dysfunction in these
children and may have impacted diastolic SR independently of
RV volume.43,44 Likewise, one may hypothesize that a ventriculotomy during repair may influence diastolic properties, although this
did not affect RV diastolic longitudinal SR in our study, possibly
because we analysed diastolic SR in the lateral wall and not the
RVOT.
Our findings of decreased diastolic SR were not significantly
associated with measured exercise capacity. Although we could
not demonstrate a statistical relation between peak oxygen consumption and RV or LV diastolic SR in this study, such a relation
remains credible. Exercise capacity is determined by multiple
factors and given the sample size, variability in exercise capacity,
and variability in diastolic strain measurement, the study may
have lacked power to detect this association. Furthermore, diastolic SR at rest may not be sufficiently sensitive and it likely that the
change in diastolic SR from rest to exercise (diastolic reserve) is a
better parameter to elucidate the relationship between myocardial
diastolic performance and exercise capacity.17,45 This requires
further study. Likewise, serial follow-up over many years and
further study may be necessary to infer clinical significance. It has
become apparent that in this population, clinical symptoms, especially those related to RV dysfunction and exercise intolerance, are
predated by functional changes in the first decades of life. Given
that diastolic dysfunction is commonly an early manifestation of
ventricular dysfunction in other conditions, our findings may implicate early RV dysfunction that warrants closer follow-up and attention to diastolic dysfunction in repaired TOF.2 In any event,
standard metabolic exercise testing remains an important study
in the serial follow-up of these patients. In addition, it would be
of interest to study changes in myocardial diastolic performance
before and after pulmonary valve replacement and perhaps to investigate differences in response between patients with predominant RV outflow tract obstruction vs. those with predominant
pulmonary insufficiency.26 This requires further study. Likewise, it
would be interesting to study the effect of RV scarring on myocardial diastolic deformation as well as association between deformation and brain natiuretic peptide (BNP) levels. These were not
available in our study and require further investigation.
Study limitations
As patients lacked indications for intervention, it was not possible
to obtain invasive reference measurements such as tau or dP/dt
min. Previous investigators have demonstrated that tricuspid E/E′
correlates with RV filling pressures and we assessed RA volumes
as well as E/E′ as surrogates for increased filling pressures in this
study.46 Two-dimensional STE diastolic SR measurements have
relatively low reproducibility.19 We none-the-less measured early
diastolic radial strain in addition to longitudinal and circumferential
strain as we were interested in evaluating all three strain vectors.
The intra- and inter-observer reliability analyses in the current
study were reasonable, except for time to peak radial diastolic
SR. All LV segments were consistently different between groups
in the radial strain results and P-values were highly significant.
Therefore, we believe the results to be valid. At present, TDI
and myocardial deformation imaging are the most direct noninvasive methods to interrogate myocardial relaxation and may
be advantageous when used in conjunction with blood flow parameters as performed in this study. None-the-less we acknowledge
the limitations of STE-derived SR imaging to capture the rapid
events of early diastole. Assessment of function in general, and
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There is increasing emphasis on long-term LV impairment in
TOF and LV systolic deformation has been shown to be decreased
in children.5,25 We now demonstrate that LV diastolic function is
also abnormal, with reduced LV diastolic SR and reduced early diastolic filling. These findings may be important in early detection of
biventricular dysfunction. The mechanism of this biventricular
myocardial dysfunction remains to be elucidated, but our results
suggest possible ventricular interactions as larger RVEDi was associated with reduced LV diastolic SR. This may arise from reduced
preload due to PR or from a LV configuration change from direct
mechanical interaction.26,27
RV early diastolic relaxation is synchronous in healthy children.15
We had hypothesized that diastolic dyssynchrony would be
increased after TOF repair in association with diastolic dysfunction,
as these patients have been found to have systolic electromechanical abnormalities and systolic LV mechanical delay.4,28 – 32
However, our results showed, that in this young cohort, RV and
LV diastolic dyssynchrony were not significantly increased in
TOF patients. In a previous study in a similar (and overlapping)
population, systolic dyssynchrony measured by tissue Doppler
imaging was not present at rest and was evoked only during exercise.17 This may be the case for diastolic dyssynchrony as well and
requires additional investigation. Previous studies, in somewhat
older populations, have found increased RV systolic dyssynchrony
in association with decreased RV systolic longitudinal deformation
and prolonged QRS duration.33 Although we found impaired diastolic myocardial relaxation, this was not associated with QRS duration or diastolic mechanical delay in our cohort. QRS duration
reflects electrical activation more than relaxation and RV diastolic
dyssynchrony was not significantly different in patients vs. controls
in our cohort. However, over time and with advancing age, these
parameters may worsen.
912
especially of diastolic function is more difficult for the RV compared with the LV. Likewise, strain imaging of the RV is more difficult to perform than the LV. None-the-less, while
acknowledging these difficulties, we and others have shown RV
strain measurements to be feasible in children.15,21,47 Previous
studies have found that outflow tract functional abnormalities are
important after TOF repair.31,32,48 We were unable to reliably
obtain RV outflow STE SR measurements. However, as the RV
body generates most RV filling, we are unsure of how much this
is a limitation. None-the-less, in future studies it would be important to study the interaction of the RVOT with other RV regions to
investigate the contribution of the RVOT to diastolic dysfunction.
In general, the diagnosis of diastolic dysfunction is difficult in children, both for the LV and especially for the RV. Likewise, this
study does not define what constitutes diastolic dysfunction in
an individual patient in terms of RV early diastolic SR. This
would require definition of diastolic parameters in a much larger
group of controls. Our results do suggest, that compared with
healthy children, young TOF patients have diastolic dysfunction
that warrants follow-up. Finally, the long-term clinical implications
of these findings are unknown and require further study.
Conclusion
Funding
This research was supported in part by a grant from the Sickkids foundation and the Canadian Institute for Health Research.
Conflict of interest: none declared.
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