Download Interpretation of Left Ventricular Diastolic Dysfunction in Children

Interpretation of Left Ventricular Diastolic Dysfunction in Children with
Cardiomyopathy by Echocardiography: Problems and Limitations
Dragulescu et al: Classification of Diastolic Function in Children
Andreea Dragulescu, MD, PhD1; Luc Mertens, MD, PhD1; Mark K. Friedberg, MD1
1
Division of Cardiology, The Labatt Family Heart Centre, Hospital for Sick Children, Toronto,
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Canada
Correspondence to::
Mark K. Friedberg, M
MD
D
Division of Cardiology,
ogy
ogy
gy, The Labatt
Laaba
batt
ttt Family
Fam
amilly Heart
H arrt Centre,
He
Ceenttre
re,, The
Thhe Hospital
T
Hoosppittal for
for
o Sick
Sicck Children
C
555, University Avenue,
nue
nue
ue,, Toronto,
To
oro
ront
nto,
nt
o, Ontario,
Onttar
ario
io, M5G
io
M5G 1X8,
1X8, Canada
Can
a ad
adaa
Tel: 1 416 813 7239
Fax: 1 416 813 5857
7
E-mail: [email protected]
e gg@
erg
@ ic
@s
ickkids.ca
ckk
kkid
id
ds.ca
c
DOI: 10.1161/CIRCIMAGING.112.000175
Journal Subject Codes: [31] Echocardiography, [41] Pediatric and congenital heart disease,
including cardiovascular surgery, [11] Other heart failure
1
Abstract
Background—Left ventricular diastolic dysfunction(DD) is a key determinant of outcomes in
pediatric cardiomyopathy(CM), but remains very challenging to diagnose and classify. Adult
paradigms and guidelines relating to DD are currently applied in children. However, it is
unknown whether these are applicable to children with CM. We investigated the assessment of
DD in children with CM using adult and pediatric echocardiographic criteria and tested whether
recent adult guidelines are applicable to this population.
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Methods and Results—Three investigators independently classified diastolic function in 4 study
groups: controls; dilated(DCM), hypertrophic(HCM) and restrictive(RCM) cardiomyopathy.
reas
asson
onss fo
forr di
diag
ag
Agreement between investigators, failure to classify DD and the re
reasons
diagnostic
failure
he usefulness
use
sefu
fuln
fu
l es
ln
ess off individual
i di id l echo
ho
h pparameters
arameter
e s to diagnose and classify DD was
were determined. The
en (0-18yrs)
en
(0-18yrs)
s)) were
were studied.
studiedd. DD
DD diagnostic
diag
di
ag
gno
nossticc criteria
criiteeriaa were
wer
erre discrepant
disc
sccree
assessed. 175 children
in the
reela
laxa
xati
xa
t on
ti
o was
was diagnosed
diag
agno
n se
no
sedd in
n oonly
nlyy 14
nl
14%
% of
o HCM pat
t
majority of patients. Delayed relaxation
patients
and never
with 50%
50%
% of
of th
thos
osse pa
ppatients
pati
tien
ti
ents
en
ts ha
ts
havi
ving
vi
ngg cco-existing
o-ex
oe isti
ex
issti
ting
ngg findi
ffindings
indi
in
d ng
di
ngs of eelevated
le
in DCM and RCM, with
those
having
filling
pressures. Many key parameters, such as mitral and pulmonary venous Doppler were not
informative. Agreement between investigators for grading of diastolic dysfunction was poor
(36% of CM patients).
Conclusions—Assessment of DD in childhood cardiomyopathy seems inadequate using current
guidelines. The large range of normal pediatric reference values allows diagnosis of diastolic
dysfunction in only a small proportion of patients. Key echo parameters to assess DF are not
sufficiently discriminatory in this population and discrepancies between criteria within
individuals prevent further classification and result in poor inter-observer agreement.
Key Words: diastolic dysfunction, pediatric, cardiomyopathy
2
Diastolic dysfunction (DD) is a major determinant of prognosis and survival in several pediatric
cardiomyopathies (CM)1-3. Although left ventricular (LV) ejection fraction (EF) correlates with
patient outcomes in adults and children, echo parameters of DD are most predictive of outcome
in pediatric dilated (DCM)1, 2, non-compaction4 and hypertrophic (HCM) cardiomyopathy3, 5, 6.
Therefore echo diagnosis and grading of DD in childhood CM is important.
The diagnosis of DD is difficult due to a lack of a clinical “gold standard”7. Even
invasive measurements obtained during cardiac catheterization have important shortcomings and
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provide only partial information on ventricular diastolic properties. Atrial pressures and LV endntricular stiffness
stiffne
nes and
ne
diastolic pressure are generally used as surrogate measures of ventricular
entr
en
tric
tr
icul
ic
ular
ul
ar rrelaxation
e
el
compliance but both are influenced by other confounding factors.. V
Ventricular
is even
ess invas
siv
vel
e y as tthis
hiss is a fast
hi
faast
s event
eve
veent rrequiring
equi
eq
uiri
ui
r ng the
ri
hee uuse
se ooff high-fidelity
high
hi
gh
more difficult to assess
invasively
n t ro
rout
utin
ut
inel
in
e y us
el
uused
e iin
ed
n th
the clin
cclinical
cl
lin
inic
ical
ic
a ssetting.
al
etttin
et
ingg. A
part
pa
rt ffrom
rom
ro
m me
m
thod
th
odoo
od
catheters which are not
routinely
Apart
methodological
nst
stit
itut
it
utio
ut
ions
io
ns,, in
ns
incl
clud
cl
udin
ud
ingg ou
in
ourr ow
own,
n,, ppediatric
edia
ed
iaatr
tric
ic C
M pa
ppatients
tiien
ents
ts ddo
o no
nott rroutinely
concerns, in many institutions,
including
CM
undergo diagnostic cardiac catheterization. Therefore, echocardiography serves as the main
imaging modality for evaluation and follow-up of these children. Echocardiographic assessment
is based on integration of information obtained from mitral inflow, pulmonary venous Doppler
and tissue Doppler imaging8. Echocardiographic studies in adult patients describe a progression
of DD along a continuum of increasing severity ranging from normal, through delayed
relaxation, pseudo-normal filling to restrictive filling9-11. Based on this patho-physiological
paradigm, the American Society of Echocardiography (ASE) has recently published guidelines
for evaluation of DD8. However, these guidelines do not inform on their application to children
and adolescents. Moreover, there are very few studies investigating DD in childhood CM and
these involve relatively small numbers of patients1-3, 12. Consequently, diagnosis and grading of
3
DD in childhood CM remains poorly defined.
The aim of this study was to define problems in classification of DD in children with CM
using echocardiography and to assess whether published adult echo guidelines for classification
and grading of DD are applicable to this population. We further investigated the usefulness of
individual echocardiographic diastolic parameters to diagnose and classify DD in children.
Methods
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Study population
Children and adolescents diagnosed with dilated, hypertrophic orr restrictive ca
cardiomyopathy
ard
r
were identified retrospectively from the institutional database. The
study
by the
he st
tud
udyy wa
wass ap
aapproved
p
institutional ethics board.
children
o rd. Wee included
oa
incllud
in
uded
ed
d a group
gro
roup
up of
of normal
noorm
mal controls
con
ontr
trol
tr
olss consisting
ol
con
onsi
on
sist
si
stin
st
ingg of healthy
in
h
with no history of cardiovascular
disease
normal
Children
a di
ardi
diov
ovas
ov
asscu
ula
larr di
dise
s asse aand
nd a no
norm
rm
mal eechocardiogram.
choc
ch
ocar
oc
arrdi
ardi
d og
ogra
ram
ra
m. C
hiild
ldre
reen diagnosed with
DCM were included if they
EF
zthe
heyy ha
hadd an E
F of less
les
esss than
than 550%
0% aand
nd a L
LV
V end
end di
dias
diastolic
asto
as
toli
to
licc dimension
li
d
score >2 (based on institutional z-scores)13. Children diagnosed with HCM were included based
on an increased wall thickness (interventricular septal thickness z score >2) and the presence of a
normal or increased EF14. Children diagnosed with restrictive cardiomyopathy (RCM) were
included if they had clinical symptoms of growth restriction, dyspnea, exercise intolerance,
emesis and/or other symptoms of heart failure with restrictive left ventricular physiology with
dilated atria, normal EF and normal LV dimensions and wall thickness15.
Echocardiography
One echocardiogram was selected for each patient at a time when the patient was clinically
stable, i.e. the first outpatient study or last echocardiogram before discharge from initial
hospitalization depending on availability. Our standardized clinical functional protocol includes
4
a comprehensive diastolic assessment. Diastolic parameters were re-measured from the stored
digital data by a single investigator (AD). These included (Figure 1): mitral inflow early to late
diastolic flow (E/A) ratio, mitral E wave deceleration time (DT), isovolumic relaxation time
(IVRT), pulmonary venous (PV) systolic to diastolic peak velocity ratio (S/D), PV A wave
reversal (Ar) amplitude and duration, time difference between PV Ar and mitral A duration,
mitral lateral and septal peak early diastolic tissue velocities (E’lat, E’med)), mitral E to mean E’
ratio and left atrial volume (by the area length method) indexed to body surface area (LAVi). All
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measurements were performed offline from standard views, according to current ASE
recommendations8 using a commercially available workstation (Syngo
Syngo Dynam
Dynamics,
mic
i Siemens,
Mountain View, California).
Classification of DD
D
Three investigators independently
nde
depe
de
pend
pe
nden
nd
en
ntl
tlyy interpreted
in
nterp
rpre
rp
retedd the
re
the me
meas
measurements.
assur
urem
emen
em
ents
en
ts. To assess
ts
asses
sss ss practical
prac
pr
acct
application
and interobserver variability
current
paradigms,
observer
was asked
r ab
riab
ri
abil
ilit
il
ityy of DD
it
DD classification
clas
cl
assi
as
sifi
si
fica
fi
cati
ca
tion
ti
on bby
y cu
curr
r en
rr
entt pa
para
radi
ra
digm
di
g s,, eeach
gm
achh ob
ac
obs
s
to classify each patient as having either normal diastolic function, delayed relaxation,
pseudonormalization, restrictive physiology or indeterminate DD. Each patient was classified
using three different classification criteria. The first method used the diagnostic flowchart
recently published in the ASE guidelines using adult cut-off values suggested in the guidelines8.
The second method also used the ASE guidelines diagnostic flowchart but adult cut-off values
were substituted with published pediatric reference values by age group. Parameters were
classified as abnormal if outside 2 standard deviations (SD) for age16-18. We did not adjust
parameters for heart rate as published data are presented without heart rate correction. Each
investigator was then asked to classify DF for a third time based on their subjective assessment
of the diastolic parameters. Due to the lack of pediatric guidelines this is likely the method most
5
commonly used in daily clinical practice. In addition, the investigators were asked to assess
whether they thought LV filling pressures were normal or elevated based on the measurements
provided.
In each patient, the agreement in DD classification between investigators for each of the
three classification methods was assessed. Interobserver agreement was also evaluated for the
assessment of LV filling pressures. In addition, we evaluated the percentage of patients defined
by the three observers as having normal diastolic function and those in whom it could not be
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classified. We further defined the reasons for failure to classify DF. In order to assess which
diastolic parameters may be useful to diagnose DF, we assessed whether individual
indivi
viidu
d diastolic
parameters were able to discriminate healthy controls from children
with
ren w
ithh CM
it
CM..
Determination of failure
DD
lure to cl
lu
cclassify
assi
as
s fy D
D
The current AS
ASE
guidelines
A
SE gu
guid
idel
id
e in
el
nes
e aallow
lllow ddiagnosis
iaagn
gnos
osis
os
is ooff ‘‘normal’,
norm
no
rmal
rm
al’,
al
’ ‘‘constrictive
c ns
co
nstr
tric
tr
icttiv
ic
ve pe
ppericarditis’ or
‘athletes heart’ whenn the
ml/m2)
the
normal
E’. As none of
the LA is
is dilated
dila
di
late
la
tedd (>
te
(>34
34 m
l/m
l/
m2)) iin
n th
he pr
ppresence
esen
es
ence
en
ce ooff a no
norm
rmal
rm
al E
the patients in our study were athletes; and all had an obvious CM diagnosis without constriction,
failure to classify DF was determined when there was discordance between the early diastolic
tissue Doppler velocity and the LAVi: i.e. a normal E’ in the presence of a dilated LA or, an
abnormally low E’ in the presence of a normal LAVi. Failure to grade DD was also determined
when diagnostic criteria between two adjoining grades of diastolic dysfunction (based on the
ASE guidelines flowchart) were present. For example when criteria existed for both delayed
relaxation and for pseudonormal filling; or, when criteria existed for both pseudonormal and
restrictive filling. Failure to diagnose DD was also determined when mitral inflow and/ or
diastolic tissue velocities were blended thereby precluding analysis by the ASE guideline’s
flowchart.
6
Statistical analysis
Results are expressed as mean ± SD or percentages as appropriate. An unpaired Student t-test
was used for comparison between the different CM groups and controls. Kappa statistics was
used to assess the interobserver agreement for classification of DF. A p value <0.05 was
considered statistically significant. Analysis was performed using IBM SPSS Statistics software
version19.
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Results
w
Characteristics of the study population are presented in Table 1. Overall there we
were 18 subjects
ghher hheart
eart
ea
rt rrates
a and lower EF.
at
less than 1 year of age including 1 neonate. The DCM group had high
higher
sllightly
y older
old
lder
er than
tha
hann th
thee other
o he
ot
herr groups
grou
ouups
ps and,
and
nd,, as expected,
exppec
ecte
ted,
te
d, had
had th
The HCM group wass slightly
thicker
d hi
high
gher
gh
err E
F T
F.
h R
he
CM ggroup
roup
ro
up hhad
ad no
norm
rmal
rm
al E
F sslightly
F,
liigh
ghtl
tlyy sm
tl
mal
alle
le LV dimensions
le
ventricular walls and
higher
EF.
The
RCM
normal
EF,
smaller
nd ssignificantly
ig
gni
nifi
fica
fi
cant
ca
ntly
nt
ly
y ddilated
ilaate
il
tedd at
atri
riaa (m
ri
((mean
eaan LA
LAVi
Vi:: 80
Vi
80±3
±38m
±3
8ml/
8m
l/m2
l/
m2 vvs. controls
compared to controlss aand
atria
LAVi:
80±38ml/m2
24.8±6ml/m2). The individual diastolic parameters for each of the patient groups are shown in
the supplemental table. Most DCM and RCM patients had one or a combination of heart failure
medication including betablockers (63%), ACE inhibitors (70%), diuretics (70%), digoxin
(13%). Five DCM patients were on milrinone awaiting heart transplantation. In the HCM group,
60% had no medication while the rest were on betablockers, associated with disopyramide in
five.
Interpretation of individual diastolic parameters
We calculated the percentage of each individual diastolic parameter values falling within the
normal range based on published adult and pediatric normal data (Table 2). In all groups,
including the CM groups with overt cardiac dysfunction, a significant proportion of individual
7
diastolic parameter values fell within the normal range.
For the control group, most diastolic parameters fell within normal range according to
pediatric reference data. As expected, some values fell outside the normal control range defined
by +/-2SD. Overall, published pediatric diastolic reference data successfully classified normal
controls as having normal diastolic function, while adult criteria classified 10 to 30% of
individual diastolic parameters as abnormal, mostly in younger children. However, these were
often discrepant in individual patients. For example some controls had short DT and IVRT but
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otherwise normal data, while some had an E/A ratio >2 with or without a short DT. Using adult
definitions of normal, only 12(24%) controls had all criteria within
hin the normall ra
rrange; while
11(22%) had 3 or more abnormal criteria using the ASE guidelines
Nine of these 11
nes fflowchart.
lowc
lo
w ha
wc
hart
rt.. N
rt
individuals were 7 years
age
confirms
that
values
e rs of ag
ea
ge orr yyounger.
oung
ou
nger
ng
er. Th
er
This
is con
on
nfirm
rmss th
rm
hat
a aadult
dultt ccutoff
du
utof
ut
offf va
of
valu
luee would
lu
incorrectly classify nor
nnormal
rma
mall children
chil
ch
ildr
il
dren
dr
e as
en
as having
havi
ha
v ng
g DD.
DD.
Overall, in the
study
whole
age
appropriate
reference
values,
he st
stud
udyy po
ud
ppopulation
p la
pu
lati
tion
ti
on aass a wh
whol
olee an
ol
andd us
uusing
ingg ag
in
ge ap
ppr
p oppri
riat
atee re
at
refe
fe
individual parameters were often not informative. The most consistently abnormal and
discriminating parameter was the mitral DT, which was normal in 90% of controls and abnormal
in ~70% of RCM and DCM patients. The mitral DT was abnormal in a lower percentage of
HCM patients, possibly due to a pseudonormal pattern in some patients (Figure 2). For tissue
Doppler velocities, as a group, CM patients had significantly lower values compared to controls
(p<0.001). Still, up to 50% of values were within the normal range for age (Table 2). Analysis of
the tissue velocity scatter plots showed that a septal peak E’ of 11 cm/s discriminated fairly well
between patients and controls (Figure 3B). LAVi values were abnormal in all RCM patients (by
definition) but also in many DCM and HCM patients, while mild to moderate mitral
regurgitation was present in 14% of patients. Overall, the isovolumic relaxation time, mitral E/A
8
ratio and pulmonary venous velocities were within normal range in most cardiomyopathy
patients by adult and pediatric criteria, limiting the use of these parameters for the interpretation
of diastolic function. (Table 2, Figure 2 and 4).
Discordant parameters within individual patients
Using the recommended guidelines, individual parameters were often discordant in individual
patients, precluding classification of DF. Given that E’, LAVi and DT appeared to be the best
discriminatory parameters to differentiate CM patients from controls, we further analyzed their
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characteristics in children with CM. E’ and LAVi were discordant in 37% of CM patients
overall, most commonly in HCM patients (Table 3). Twenty-fivee patients had normal
tissue
n
no
velocities in the presence of a dilated LA. Of these, DT was normal
mal in
in 8 of 10
10 HCM,
HC 2 of 5 RCM
and 2 of 10 of DCM ppatients
had low E’
atientss (5 hhad
ad bblended
lend
le
nded
nd
ed iinflow).
nfflo
low
w). A smaller
sma
mall
l er
ll
e proportion
pro
r po
port
rtio
rt
ionn of ppatients
io
att
in the presence of a normal
with
n rma
nor
mall LAVi
LAVi (18
(18 cases).
casses). Most
Mos
ostt of
of these
thes
th
esee were
es
weree associated
asssoc
o ia
iateed wi
w
th
h an abnormal
DT: 8 of 10 HCM patients
with
with
short
ati
tien
ents
en
ts w
ithh pr
it
pprolonged
olon
ol
onge
on
gedd DT aand
ge
nd 4 ooff 7 DC
DCM
M pa
ppatients
tien
ti
ents
en
ts w
ithh sh
it
sho
o DT. When
both E’ and LAVi were normal, all HCM patients had a normal DT whereas in the DCM group
there were 6 patients with short DT and 3 who had blended mitral inflow pattern. All 3
parameters were abnormal in 11/50(22%) HCM, 15/50(30%) DCM and 7/16(44%) RCM
patients.
Agreement between investigators for classification of DF and filling pressures
Agreement between investigators was poor for the grading of DD as well as for the estimation of
filling pressures (Table 4). Interobserver agreement was highest in the RCM group (76% for
diastolic grading and 88% for filling pressures), and lowest in the DCM group (<50%).
Interobserver agreement was improved in older patients, those with slower heart rates and those
with higher EF (p<0.05). Only 7 patients had criteria consistent with delayed relaxation, all
9
adolescents with HCM.
Tissue velocities and LAVi, which represent the focal point in the ASE classification
flowchart for DD8, were often discrepant in individual patients by both adult and pediatric
criteria. This led to high failure rate to classify DD (Table 4) and to poor interobserver
agreement. A clear DD grading was assigned in only 37% of CM patients. Of these,
approximately half (23 of 43 patients) were diagnosed by all 3 observers as having normal
diastolic function. Conversely, a DD grade could not be assigned in 27% of patients due to
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
overlapping or discrepant criteria in individual patients (Table 3). This occurred regardless of
iagnostic flow
wch
c
whether adult or pediatric cut-off values were used in the ASE diagnostic
flowchart.
Discussion
Diagnosis of DD in children
chiild
chi
ldre
ren with
re
w th CM
wi
C is
is challenging.
chal
ch
alle
al
leng
le
ngin
ng
in
ng. D
Despite
espi
es
pitee tthe
pi
he aavailability
vai
aila
ai
labi
la
bili
bili
bi
l ty ooff rreference values
for individual DF parameters,
r me
rame
ra
mete
ters
te
rs,, there
rs
ther
th
eree is little
er
lit
ittl
tlee av
tl
avai
available
aila
ai
labl
la
blee gu
bl
gguidance
i an
id
ance
ce ffor
or tthe
he pr
ppracticing
acti
ac
tici
ti
cing
ci
ng clinician on
diagnosis and grading of DD in children with CM. As a consequence, the pediatric cardiologist
has to rely on existing guidelines and recommendations derived from adult studies. In the current
study, we undertook a detailed descriptive analysis of the usefulness of individual
echocardiographic parameters and their application to pediatric CM population, within the
framework of current available guidelines.
The main findings of our study are: 1. There is a high percentage of normal diastolic
parameters in children with overt and often severe cardiac dysfunction. 2. There is frequent
discordance between E’ and LA volume criteria, hindering the use of diagnostic flowcharts
published in the adult recommendations. 3. Discordant and/or overlapping criteria preclude more
precise grading of DD in the majority of patients. 4. These and other factors lead to overall poor
10
agreement between observers, even in a research setting.
Is the adult paradigm of DD progression applicable to children?
The aforementioned problems raise the question whether adult paradigms of DD are applicable
to children, beyond simple differences in age or heart-rate related cut-off values. The
classification of diastolic dysfunction in adults is based on a paradigm of progression of
abnormalities along a continuum of increasing severity from normal, through delayed relaxation,
evolving through a phase of pseudo-normalization to a pattern of restrictive filling10. This
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paradigm has not been proven conceptually in infants and children. While the current study
andard and itss ccross-sectional,
cannot verify of reject this paradigm due to lack of a reference standard
adee fr
ad
ffrom our data that
retrospective nature, there are several important observations thatt cann be m
made
adi
adi
digm m
ay
y no
ot ap
appl
plyy to tthe
pl
hee ppediatric
ed
diaatrric ppopulation.
opul
op
u at
ul
atio
i n.
n IIn
n ou
ourr ex
expe
pe
suggest that this paradigm
may
not
apply
experience,
criteria
y d relaxation
yed
rela
re
laxa
la
x ti
xa
t on
n are
are
r distinctly
disti
isti
is
tincctly uncommon
unc
ncom
ommo
om
monn in children.
mo
chi
hild
ldre
ld
ren.
re
n Only
Onl
nlyy 7 HCM
H
consistent with delayed
patients
ien
ents
ts)), presented
ts
pre
ressen
ente
tedd criteria
te
crit
cr
iter
it
eria
er
ia consistent
con
onsi
sist
si
sten
st
entt with
en
w th
wi
h delayed
dellay
yed
d relaxation,
rel
elax
axat
ax
atio
at
ionn, while
io
w
(6.4% of all CM patients),
no DCM
or RCM patients had sufficiently concordant criteria to classify delayed relaxation or pseudonormal filling. There are several possible explanations for this. One is that children present in
more advanced stages of DD and therefore milder degrees of DD were not diagnosed in our
cohort. However, almost half of the DCM patients where investigators agreed on DD grading
had diastolic parameters within the normal range. These patients demonstrated severe systolic
dysfunction and some degree of diastolic dysfunction would be expected19. Alternatively, it may
be that isolated delayed relaxation is uncommon in children and that decreased compliance exists
in the absence of impaired relaxation; or even without prior development of delayed relaxation.
If this postulate is subsequently confirmed in future studies, it questions the applicability of adult
paradigms and current recommendations to diagnose and grade diastolic dysfunction in children.
11
Difficulties in diagnosing DD in childhood CM
Published normal data for diastolic parameters in children are based on relatively small
populations, especially when sub-divided by age, and present a wide range of normal values16-18.
We found that pediatric reference data successfully defined normal controls, but due to the wide
range of normal values, diastolic dysfunction was classified in only a small proportion of our
cohort of patients with overt CM. Although in the absence of a reference standard we cannot
determine with certainty that these patients had DD, based on the phenotypic disease severity,
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
both in DCM and in HCM patients, we believe that diastolic dysfunction of some degree must be
ults indicate tha
hat current echo
ha
present in a substantial proportion of patients. Therefore, our results
that
o eo
or
eove
ver,
ve
r oour results show
r,
criteria are inadequate to diagnose and classify DD in pediatric CM. M
Moreover,
that when DD is diagnosed
gno
nosed or ssuspected,
u pe
us
pect
cted
ct
ed, disc
ed
ddiscrepancies
di
isc
screepa
p ncciess be
betw
between
tweeen di
tw
ddiastolic
assto
toli
licc pa
li
para
parameters
rame
ra
me
or
i hin individual
ith
ind
ndiv
iv
vidu
dual
al patients
pat
atie
ient
ie
n s ar
aree co
comm
mmon
mm
on. Th
on
This
is aadversely
dver
dv
errse
sely
ly aaffects
ffec
ff
e ts
ec
t interpretation of
diagnostic criteria within
common.
ade D
D and
and interobserver
inte
in
tero
te
robs
ro
bser
bs
erve
er
verr ag
ve
gre
reem
emen
em
en
nt . T
hese
he
se problems
pro
robl
bllem
emss are
are not
no
o exclusive to
DF, the ability to grade
DD
agreement.
These
the pediatric population. A recent study in adults showed important discordance between
investigators in classifying pseudo-normal and restrictive DD, while relative agreement was
noted for normal and delayed relaxation patterns. Agreement was moderate for the estimation of
filling pressures20.
Assessment of DF in children
Our results suggest that among the various DF echo parameters, E’, DT and LAVi are likely to
be the most useful in the evaluation of DF in children with CM. Still, even these parameters were
often discrepant in the individual child. Consequently, the two-level decision tree flowchart
recommended by current ASE guidelines for DD classification8 appears to be poorly applicable
in children. This suggests that new diagnostic criteria for diagnosis and grading of DD are
12
needed in children. Early diastolic tissue velocities, particularly E’med, seemed to differentiate
patients from controls better than E’lat or E/mean E’ ratio (Figure 3) implying decreased recoil
or possibly delayed relaxation21. DT also seemed to differentiate patients from controls, albeit
with considerable overlap, possibly related in part to pseudo-normalization (Figure 2).
Combining septal E’ with DT appears to best differentiate patients from controls (Figure 5).
However, using either of these two parameters alone is inadequate to grade DD. The
discrepancies between E’ and LAVi, especially in the younger group, raises the question if age
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
related cutoff values for these parameters should be determined. Conversely, the IVRT does not
ke
appear to be useful in any of the CM patients groups included in this study. Lik
Likewise,
the E/A
diast
sttollicc function,
fun
unct
ctiio was not useful
ct
ratio, despite its traditional central position in the assessment of diastolic
in our population, except
xcept in a small
xc
sma
mall
ll number
numb
mber
e of
er
of adolescents
a olesceent
ad
ntss wi
w
with
ith
th
hH
HCM.
CM
M.
Agreement between
n observers
obse
ob
serv
se
rver
rv
errs for
fo
or classification
cllas
a si
siffica
cati
tion
ti
on of
of DD
Despite a-priori agreement
e me
eeme
ee
ment
nt bbetween
etwe
et
ween
we
en iinvestigators
nves
nv
esti
es
tiggat
ti
ator
orss on tthe
or
hee m
methodology
etho
et
hodo
ho
d lo
do
logy
gy tto
o cl
clas
classify
assi
as
sify
si
fy
y DD and a
structured research setting, agreement between observers was poor. This further demonstrates the
difficulties in application of current recommended guidelines to the pediatric population and
emphasizes the need for further investigation into whether current paradigms of progression of
DD derived from adult populations are applicable in children. Our data also emphasize the need
for specific pediatric recommendations.
Limitations
As previously mentioned, this is a retrospective study without invasive reference data. CM
patients in our institution do not routinely undergo cardiac catheterization and information such
as filling pressures was not consistently available, even retrospectively. Current
recommendations are based on echo criteria and this study focused on this application. The
13
number of patients is relatively small, especially for the RCM group. In this group, data was
further limited by the lack of tissue Doppler in some patients. There were no missing data other
than the PV Doppler in one HCM patient. The DCM group was relatively younger and some
patients, although stable, were in severe heart failure. This reflects the reality of the patients
encountered in clinical practice. We analyzed a single echocardiogram for each patient. Although
we strictly defined the timing of echocardiography (the discharge echo of initial admission or
first outpatient echo), patients may have been at different time points in the disease process. This
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
is a limitation of a retrospective study and of not knowing at what point in the disease process the
patient presented to the referral center. Likewise, it is difficult to determine whe
when
hen the disease
he
process actually starts in relation to when the patient becomes symptomatic
mpto
to
oma
m ti
ticc and
and is
i referred for
evaluation. Importantly,
the
prognostic
value
individual
ntl
ntl
tlyy, our sstudy
tudy
tu
dy do
does
es nnot
ot ddefine
effin
ne th
he pr
prog
ogno
og
nost
no
stic
st
ic val
alue
al
ue ooff in
indi
divi
di
v d diastolic
echo parameters. This
i requires
is
requ
re
quir
qu
iress further
ir
furt
fu
r he
rt
h r prospective
proospeect
pr
ctiv
ivee study.
iv
stud
st
udyy.
ud
Conclusion
In conclusion, pediatric reference data for echo parameters to assess diastolic function
successfully define normal controls, but due to the large range of normal values, diastolic
dysfunction is classified in only a small proportion of CM patients, even when their disease is
severe. Discrepancies between diagnostic criteria within individual patients are common,
adversely affecting interpretation of diastolic function and inter-observer agreement. Isolated
delayed relaxation is seen in only a minority of HCM patients, and not in DCM or RCM. These
results suggest that pediatric diastolic dysfunction does not follow the progression seen in adult
patients and that new diagnostic criteria are needed in children.
14
Disclosures
None.
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16
Table 1. General and echo characteristics of the study population by cardiomyopathy type
Age (mean ± SD)
Controls (n=50)
9.7±4.8
DCM (n=50)
8.0±6.1
RCM (n=16)
10.3±6.2
HCM (n=50)
11.8±4.1*
BSA (m2)
1.2±0.45
0.94±0.53*
1.1±0.6
1.4±0.48*
Heart rate (bpm)
85.8±17.6
103±30*
86.5±11.3
70.8±13.2
LV EF(%)
58.2±7.8
27±13.6*
57±13
76.7±13.2*
LV EDD z-score
-0.08±1
6.04±2.4*
-0.88±1.7*
-2.23±1.5*
IVS thickness z-score
-0.2±0.8
-0.17±1.8
0.6±1.7*
7.8±2.7*
Blended mitral inflow
0
9 (6 <1y old)
0
1
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
*p<0.05 compared to the control group
BSA – body surface area; DCM – dilated cardiomyopathy; EDD – end diastolic diameter; EF – ejection fraction;
HCM – hypertrophic cardiomyopathy; IVS – interventricular septum; RCM – restrictive cardiomyopathy.
Table 2. Frequency of normal individual diastolic parameters
parameters in the study
st d popul
ppopulation
op
p la
by
cardiomyopathy typee according
accord
ac
ding to adult cutoff values
valu
ues and pediatric
peedi
d attric reference dat
data
t
% of patients with
normal values
Normal
mall ccontrols
mal
ontr
on
trolls
tr
(n=50)
0)
DCM
DC
M
(n
(n=50)
n=5
=50)
0)
RCM
RC
M
(n=16)
(n=1
(n
=16)
=1
6)
HCM
(n=50)
Criterion
Adult
lltt
P
Pe
Pediatric
ed
diat
di
attri
ric
ic
Adul
Ad
Adult
du
ullt
P
Pe
Pediatric
eed
diat
di
attri
ricc
Adult
Adul
Ad
dullt
Pediatric
P
Pe
diat
di
atri
at
ricc
ri
Adult
Pediatric
IVRT(%)
94
100
64
62
62.5
75
52
74
PV S/D ratio(%)
84
100
60
70
50
69
70
70
PV Ar(%)
92
86
86
84
62.5
50
66
62
Ar - A(%)*
92
92
42
42
0
0
48
48
DT(%)
68
90
12
32
0
25
49
60
E/A(%)
58
100
30
86
25
56.2
58
90
E’(%)
100
100
30
46
25
31
52
42
E/E’(%)
90
100
26
44
25
50
40
44
LAVi score(%)
98
98
40
40
0
0
44
44
* a subset of patients in each group had uninterpretable results with abnormal pattern in 22% of DCM, 62.5% of
RCM and 25% of HCM patients.
Ar – A - time difference between pulmonary venous A reversal and mitral A wave duration; DCM – dilated
cardiomyopathy; DT – mitral E wave deceleration time; E/A – mitral inflow peak E to A wave velocities ratio;
E/mean E’ – mitral inflow peak E to mean septal and lateral tissue velocities E’ ratio; E’ lat – peak early diastolic
tissue velocity at lateral mitral annulus; E’ sep - peak early diastolic tissue velocity at medial mitral annulus; HCM
– hypertrophic cardiomyopathy; IVRT – isovolumic relaxation time; LAVi – left atrial volume indexed to body
surface area; PV Ar - pulmonary venous A wave reversal peak velocity; PV S/D - pulmonary venous peak systolic
to diastolic velocity ratio; RCM – restrictive cardiomyopathy.
17
Table 3. Reasons for failed classification, disagreement or mixed classification criteria
DCM (n=50)
Adult
Discordant E’/LAVi criteria
(E’ abn-LAVi N/ E’ N -LAVi abn)
Unclear grading
(grade 1 ļ 2/ 2 ļ 3/ blended
mitral inflow)
Clear classification (N / abn)
Pediatric
RCM (n=16)
Adult
Pediatric
HCM (n=50)
Adult
Pediatric
19
12/7
10
1/3/6
16
7/9
15
3/8/4
5
1/4
5
1/4/0
6
1/5
8
2/6/0
22
9/13
11
8/3/0
21
11/10
8
4/3/1
21
7/14
19
12/7
6
0/6
2
0/2
17
13/4
22
11/11
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
Abn – abnormal; DCM – dilated cardiomyopathy; HCM – hypertrophic cardiomyopathy; LAVi – left atrial volume
index; N – normal; RCM – restrictive cardiomyopathy.
Table 4. Subjective classification of diastolic dysfunction severity
ty an
andd fi
fill
filling
llin
ll
ingg pr
in
pre
pressures
e
by the
three investigators (A,
A, B,, C)
DCM
D
CM ((n=50)
n=
=50
0)
RCM
RC
CM (n=16)
(n=116)
(n
HCM (n=50)
Investigator subjective
v classifica
ve
classification
ati
t on
o
Agreement(%)
23(46%)
23(4
23
(446%
6%))
10
Normal
Abnormal (grade 1/2/3)
11 (0/1/10)
10(
10
10(62.5%)
(62 5%
(62.
(6
5%))
1
9 (0/0/9)
32(64%)
18
14 (7/7/0)
Disagreement(%)
27(54%)
6(37.5%)
18(36%)
0.509
0.549
0.334
0.462
0.647
0.352
0.592
0.812
0.507
Kappa statistics
A-B
A-C
B-C
Assessment of filling pressures
Agreement(%)
Normal / High
Disagreement(%)
24(48%)
5/17
26(52%)
13 (81.2%)
2/11
3(18.7%)
37(74%)
26/11
13(26%)
Kappa statistics
A-B
A-C
B-C
0.464
0.411
0.239
0.823
0.642
0.678
0.714
0.782
0.518
DCM – dilated cardiomyopathy; HCM – hypertrophic cardiomyopathy; ICC - Interclass correlation coefficient;
RCM – restrictive cardiomyopathy.
18
Figure Legends
Figure 1. Assessment of diastolic parameters in a patient with hypertrophic cardiomyopathy. A.
Mitral valve inflow with measurements of the early and late diastolic waves and the E wave
deceleration time. B. Pulmonary venous Doppler with measurement of the systolic, diastolic and
atrial reversal waves amplitude and atrial reversal wave duration. C. Tissue velocities measured
at the base of the interventricular septum. D. Left ventricular inflow and outflow for
Downloaded from http://circimaging.ahajournals.org/ by guest on May 5, 2017
measurement of the isovolumic relaxation time. E - F. Left atrial area and length in apical four
and two chamber views for the estimation of atrial volume.
Figure 2. Diastolic parameters
population
cardiomyopathy type. A:
parram
amet
eter
et
e s in
i the study popula
ati
t on
o by age an
and
nd cardiomyopath
Mitral valve E to A ra
Mitral
valve
wave
deceleration
time.
Left
atrial
rratio.
atiio. B: M
ittraal val
a ve E w
al
ave
vee dec
eccel
eler
ler
erat
a io
at
on time
me. C: L
me
efft at
triia volume
indexed to body surface
area.
f
face
Figure 3. Tissue Doppler diastolic parameters in the study population by age and
cardiomyopathy type. A. Lateral mitral valve early diastolic tissue velocities. B. Medial mitral
valve early diastolic tissue velocities. C. Mitral valve peak early diastolic inflow velocity to
mean early diastolic tissue velocities ratio.
Figure 4. Pulmonary venous (PV) Doppler derived diastolic parameters in the study population.
A: PV systolic to diastolic velocity ratio. B: PV A wave reversal peak velocity (Ar). C: Time
difference between PV Ar duration and mitral A wave duration.
Figure 5. Added value of septal E’ and mitral deceleration time in differentiating patients from
controls.
19
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Interpretation of Left Ventricular Diastolic Dysfunction in Children with Cardiomyopathy by
Echocardiography: Problems and Limitations
Andreea Dragulescu, Luc Mertens and Mark K. Friedberg
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Circ Cardiovasc Imaging. published online January 23, 2013;
Circulation: Cardiovascular Imaging is published by the American Heart Association, 7272 Greenville Avenue, Dallas,
TX 75231
Copyright © 2013 American Heart Association, Inc. All rights reserved.
Print ISSN: 1941-9651. Online ISSN: 1942-0080
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circimaging.ahajournals.org/content/early/2013/01/23/CIRCIMAGING.112.000175
Data Supplement (unedited) at:
http://circimaging.ahajournals.org/content/suppl/2013/01/23/CIRCIMAGING.112.000175.DC1
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SUPPLEMENTAL MATERIAL
Supplemental Table
Table. Individual diastolic parameters in the study population by cardiomyopathy type.
Normal controls
DCM
RCM*
HCM
(n=50)
(n=50)
(n=16)
(n=50)
IVRT (ms)
60±9.7
56±16
63±19
74.2±22.5
PV S/D
0.8±0.2
0.9±0.4
1±0.4
1±0.4
PV Ar (cm/s)
23±5.9
24.6±8
34±11
31.6±12.5
Ar - A (ms)
-23±18
8.9±26
36.4±31
-6±32
DT (ms)
153±28
113±34
94±27
197±43
E/A
2±0.6
2.3±1.1
2.6±1.6
1.8±0.6
E’ sep (cm/s)
14±2.4
7.2±2.8
7.1±2.9
8±3.2
E’ lat (cm/s)
18.3±4
10±5
9.2±3.8
12±4.7
E/ mean E’
6.6±1.7
13.2±4.7
12.3±6
11.4±5.4
LAVi score (ml/m2)
24.8±6
47.4±29
80.4±38
39±14.4
Criterion
* tissue Doppler data available in 16 RCM patients.
Ar – A - time difference between pulmonary venous A reversal and mitral A wave duration; DCM –
dilated cardiomyopathy; DT – mitral E wave deceleration time; E/A – mitral inflow peak E to A wave
velocities ratio; E/mean E’ – mitral inflow peak E to mean septal and lateral tissue velocities E’ ratio; E’
lat – peak early diastolic tissue velocity at lateral mitral annulus; E’ sep - peak early diastolic tissue
velocity at medial mitral annulus; HCM – hypertrophic cardiomyopathy; IVRT – isovolumic relaxation
time; LAVi – left atrial volume indexed to body surface area; PV Ar - pulmonary venous A wave reversal
peak velocity; PV S/D - pulmonary venous peak systolic to diastolic velocity ratio; RCM – restrictive
cardiomyopathy.