Circ Cardiovasc Imaging 2013

Andreea Dragulescu, Luc Mertens and Mark K.
Friedberg
Echocardiography: Problems and Limitations
Interpretation of Left Ventricular Diastolic Dysfunction in Children with Cardiomyopathy by
Print ISSN: 1941-9651. Online ISSN: 1942-0080
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published online January 23, 2013; Circ Cardiovasc Imaging.
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by guest on November 29, 2013 http://circimaging.ahajournals.org/ Downloaded from by guest on November 29, 2013 http://circimaging.ahajournals.org/ Downloaded from by guest on November 29, 2013 http://circimaging.ahajournals.org/ Downloaded from by guest on November 29, 2013 http://circimaging.ahajournals.org/ Downloaded from
1
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, PhD
1
; Luc Mertens, MD, PhD
1
; Mark K. Friedberg, MD
1

1
Division of Cardiology, The Labatt Family Heart Centre, Hospital for Sick Children, Toronto,
Canada

Correspondence to:
Mark K. Friedberg, MD
Division of Cardiology, The Labatt Family Heart Centre, The Hospital for Sick Children
555, University Avenue, Toronto, Ontario, M5G 1X8, Canada
Tel: 1 416 813 7239
Fax: 1 416 813 5857
E-mail: mark.friedberg@sickkids.ca
DOI: 10.1161/CIRCIMAGING.112.000175
Journal Subject Codes: [31] Echocardiography, [41] Pediatric and congenital heart disease,
including cardiovascular surgery, [11] Other heart failure
:
M
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7
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2
Abstract
BackgroundLeft 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.
Methods and ResultsThree investigators independently classified diastolic function in 4 study
groups: controls; dilated(DCM), hypertrophic(HCM) and restrictive(RCM) cardiomyopathy.
Agreement between investigators, failure to classify DD and the reasons for diagnostic failure
were determined. The usefulness of individual echo parameters to diagnose and classify DD was
assessed. 175 children (0-18yrs) were studied. DD diagnostic criteria were discrepant in the
majority of patients. Delayed relaxation was diagnosed in only 14% of HCM patients and never
in DCM and RCM, with 50% of those patients having co-existing findings of elevated 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).
ConclusionsAssessment 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
re reas as ssssson on on on on on onsssssssfo fo fo fo fo fo for r rrrrr di di di di di di diag ag ag ag ag ag ag
he usefulness f i di id l h diagnose and
e e
t
with % f th p ti havi g isti g findi g of le
heuuuuuse se se se sefu fu fu fu fuln ln ln ln l es es es es ess of individual echo ho ho ho hopparameter es to to to to to diagnose and
en nnnn(((((0-18yrs) s)) wwweeere ssst sudieddd. DDDDD di diag gg ag gno no no no nosstic c cri ite eerrrria aa wer er er ree ddisc sccre
Delayed re eeeela la la la laxa xa xa xa xati ti ti tt on on on on o wwwwwas as as as asdddddiiiiiag ag ag ag agno no no n se se se se sed d d ddin nnooooonl nl nl nl nly yyyy14 14 14 14 14% %%%%of oooo HCM pat
wi with th5550% 0% 0% 0% 0%oooooff fff th th th th thos os os see eepa pa pati ti ti ti tien en ents tts ts t ha ha ha ha havi vi vi vi ving ng ngccco- o- o-ex ex ex ee is is is s isti ti ti ti ting ng ng ng ngfffffin in in in indi di di di dng ng ng nn s ssof of eeele le
3
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-compaction
4
and hypertrophic (HCM) cardiomyopathy
3, 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
provide only partial information on ventricular diastolic properties. Atrial pressures and LV end-
diastolic pressure are generally used as surrogate measures of ventricular stiffness and
compliance but both are influenced by other confounding factors. Ventricular relaxation is even
more difficult to assess invasively as this is a fast event requiring the use of high-fidelity
catheters which are not routinely used in the clinical setting. Apart from methodological
concerns, in many institutions, including our own, pediatric CM patients do not routinely
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 imaging
8
. 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 filling
9-11
. Based on this patho-physiological
paradigm, the American Society of Echocardiography (ASE) has recently published guidelines
for evaluation of DD
8
. 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 patients
1-3, 12
. Consequently, diagnosis and grading of
ntricular stiffne ne ne ne ne ne nes
. VVen en en en en en entr tr tr tr tr tr tric ic ic ic ic ic icul ul ul ul ul ul ular ar ar ar ar ar ar rrrrrrrel e
e h
n o
n r
eeess ss ss ss ss invas sssiv vvvvel eeeey yy y y as as as as asttttthi hi hi hi his ssssis is is is is a aa aafa fa a fa ast st st st s eve veent nt nt nt nt rrrreq eq eq eq equi ui ui ui uiri ri ri r ng ng ng ng ng the he heeeuuuuuse se se se seooooof f ff f hi hi hi hi high gggg
not tttt ro ro ro ro rout ut ut ut utin in in in inel el eeeyyy us us us us u ed eee iiiiinnnn nth th th th the cl cl ccl clin in in in inic ic ic ic ical al aaa sssset et et et ettttttin in in in ingg. ggg AAAAApa pa pa ppart rt rt fffffro ro ro ro rom mmmmme me me me mth th th th thod od od od odo
nnnst st stit it itut ut utio io ions ns ns,,,, in in incl cl clud ud udin in ing g g ou ou our r r ow ow own, n, n,,, ppppped ed edia ia ia aatr tr tric ic icCCCM M M M pa pa pa pp ti ti ti ien en ents ts tsdddooo no no nottt rrr
4
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
Study population
Children and adolescents diagnosed with dilated, hypertrophic or restrictive cardiomyopathy
were identified retrospectively from the institutional database. The study was approved by the
institutional ethics board. We included a group of normal controls consisting of healthy children
with no history of cardiovascular disease and a normal echocardiogram. Children diagnosed with
DCM were included if they had an EF of less than 50% and a LV end diastolic dimension z-
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 EF
14
. 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 thickness
15
.
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
r restrictive ca aaaaaard rd rrrrr
he st sttttttud ud ud ud ud ud udy yy yyyywa wa wa wa wa wa was s s s s ss ap ap ap ap ap aa p
o h
a n
if they had an EF of less than 50% and a LV end diastolic d
oa oa oa oo rrrd rr . We We ee in in in in incl llllud ud ud ud uded ed ed d edaaaaagggggro ro ro ro roup up up upooooof ff no noorm mmmmal al al al al cccccon on on on ontr tr trol ol ol ol olsssscon on on on onsi si si si sist st st stin in in in ing g g g gof of of of of h
ardi di di di diov ov ov ov ovas as as sscu cu ula la la la lar rr di di di di dise sss as as as as seeeaan aaa d ddddaaaaa no no no no norm rm rm rm mal al al al al eeeech ch ch ch choc oc oc oc ocar ar ar r ardi di dddog og ogra ra ra ra ramm. mmm CCCCChi hi hi hiild ld ld ld ldre re re een
if if if ttthe he heyyyha ha haddd an an anEEEFFF of of of llles es ess s s th th than an an5550% 0% 0%aaand nd ndaaaLLLLV VV en en end dddddi di dias as asto to toli li liccc ddd
5
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 (Elat, Emed)), mitral E to mean E
ratio and left atrial volume (by the area length method) indexed to body surface area (LAVi). All
measurements were performed offline from standard views, according to current ASE
recommendations
8
using a commercially available workstation (Syngo Dynamics, Siemens,
Mountain View, California).
Classification of DD
Three investigators independently interpreted the measurements. To assess practical application
and interobserver variability of DD classification by current paradigms, each observer was asked
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 guidelines
8
.
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 age
16-18
. 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
Syngo Dynam mmmmmmic ic iiiii
D
t
r s
DDDDD
nde de de de depe pe pe pe pend nd nd nd nden en en ntl tl tl tl tly yyyyin in in in nterp rp rp rp rpre re re re reted ddddth th th th theeee eme me me me meas as as as sur ur ur ur urem em em em emen en en en ents ts ts ts ts. To To To To Toaaaaass ss sss sses sssssspr pr pr pr prac ac ac cct
ri ri riab ab abil il ilit it ity y y yof of of DDDDDDcl cl clas as assi si sifi fi fica ca cati ti tion on onbbby y y yycu cu curr rr rr rr en en enttt pa pa para ra radi di digm gm gm gg s, s, s,, eeeac ac achhh ob ob obsss
6
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
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 diastolic
parameters were able to discriminate healthy controls from children with CM.
Determination of failure to classify DD
The current ASE guidelines allow diagnosis of normal, constrictive pericarditis or
athletes heart when the LA is dilated (>34 ml/m2) in the presence of a normal E. As none of
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 guidelines
flowchart.
whether indivi vi iiiiidu dddddd
renwwwwwwwit it it it it it ith h hhhhhCM CM CM CM CM CM CM......
l
A
n E
lu uuuurrre rr to cl cl cl c as as as as assi ssssfy fy fy fy fyDDDDDD D D D D
ASSSSSEE EEE gu gu gu gu guid id id id idel el el el ein in in nnes es es ee aaall llllow ow ow ow owdddddia aaaagn gn gn gn gnos os os os osis is is is isooooofffff no no no no norm rm rm rm rmal al al al al, co co c ns ns ns ns nstr tr tr tr tric ic ic ic icttttt fffff iv iv vvve eeepe pe pe pp
nnn th th theeeLA LA LA iiisssdi di dila la late te teddd (> (> (>34 34 34mmml/ l/ l/mmm2) 2) 2) ) iiinnn th th th hheeepr pr pr pp es es esen en ence ce ceooof ff aaa no no norm rm rmal al al EEE
7
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
version
19
.
Results
Characteristics of the study population are presented in Table 1. Overall there were 18 subjects
less than 1 year of age including 1 neonate. The DCM group had higher heart rates and lower EF.
The HCM group was slightly older than the other groups and, as expected, had thicker
ventricular walls and higher EF. The RCM group had normal EF, slightly smaller LV dimensions
compared to controls and significantly dilated atria (mean LAVi: 8038ml/m2 vs. controls
24.86ml/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
Overall there we wwwwww
high gh gh gh ghhher er er er er er er hhhhhhhea ea ea ea ea ea eart rt rt rt rt rt rt rrrrrrrat a
s slightly older than the other groups and, as expected, had th
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s sl sllllightly yyyooooold ld llder er er er er tttttha ha ha ha han n nn n th th th th the ee e eot ooohe he he he her rrr ggrou ou ouuups ps ps ppsaaaaand nd nd nd nd,,, as as as as aseeeexp xppppec ec ec ec ecte te te te ted, d, d, d, d, hhhhhad ad ad ad ad th
d hi hi hi hi high gh gh gh gher er er rr EEEEEF. FFFF TTTTThe he he he h RRRRRCM CM CM CM CM gggggro ro ro ro roup up up up uphhhhhaaadd dddno no no no norm rm rm rm rmal al al al al EEEEEF, FFFF sssli li li iigh gh gh gh ghtl tl tl tl tly yysm sm smmmal al al al alle le le ll
sssaaand nd ndsssig ig ig ggni ni nifi fi fica ca cant nt ntly ly ly yydddil il ilaaate te ted d d at at atri ri riaaa (m (m (m ( ea ea ea aannn LA LA LAVi Vi Vi Vi::: 80 80 803 3 38m 8m 8ml/ l/ l/m2 m2 m2vvv
8
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
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 the normal range; while
11(22%) had 3 or more abnormal criteria using the ASE guidelines flowchart. Nine of these 11
individuals were 7 years of age or younger. This confirms that adult cutoff values would
incorrectly classify normal children as having DD.
Overall, in the study population as a whole and using age appropriate reference values,
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
hin the normal l ra ra rrrrr
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e e
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nor rrrrma ma ma ma mal llll ch ch ch ch chil il il il ildr dr dr dr dren en en en e aaas ha ha ha ha havi vvvv ng ggggDDDDDDDD. DD
hhheeest st stud ud udy y y ypo po po pp pu pu pu p la la lati ti tion on onaaasssaaa wh wh whol ol oleee an an and dd us us us uu in in ing g g ag ag ag ggeee ap ap ap pppr pr pr pp op op opppri ri riat at ateee re re refe fe fe
9
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
characteristics in children with CM. E and LAVi were discordant in 37% of CM patients
overall, most commonly in HCM patients (Table 3). Twenty-five patients had normal tissue
velocities in the presence of a dilated LA. Of these, DT was normal in 8 of 10 HCM, 2 of 5 RCM
and 2 of 10 of DCM patients (5 had blended inflow). A smaller proportion of patients had low E
in the presence of a normal LAVi (18 cases). Most of these were associated with an abnormal
DT: 8 of 10 HCM patients with prolonged DT and 4 of 7 DCM patients with short 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
e patients had no no nnnnn
mal iin n n n n n n8888888of of of of of of of 11111110000000HHHHHC HH
t
n h
a o
pppppaaaat aientssss(5 (5 (5 (5 (5hhhad ad ad ad adbbbbble le le le lend nd nd nd nded ed ed ed ediiinf nf nf nfflo lo loww). AAAAA ssssma ma ma ma mall ll ll ll l er er er e pppppro rrr po po po po port rt rt rt rtio io io io ion nn n n of of of of of pppppat
norrrrrma ma ma ma mal llll LA LA LA LA LAVi Vi Vi Vi Vi ((1118 11 cccccas as as as sees eee ). MMMMMos os os os osttt ooooof ffff th th th th thes es es es esee eeewe we we we were re re re eaaassssssoc oc oc oc o ia ia ia ia iate eeeedd dddwi wi wwwth th th th th ttt
aaati ti tien en ents ts tswwwit it ithhh pr pr pr p ol ol olon on onge ge geddd DT DT DT aaand nd nd444ooof ff 77777DC DC DCM M M M pa pa pa pp ti ti tien en ents ts tswwwit it ithhh sh sh shooo
10
adolescents with HCM.
Tissue velocities and LAVi, which represent the focal point in the ASE classification
flowchart for DD
8
, 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
overlapping or discrepant criteria in individual patients (Table 3). This occurred regardless of
whether adult or pediatric cut-off values were used in the ASE diagnostic flowchart.
Discussion
Diagnosis of DD in children with CM is challenging. Despite the availability of reference values
for individual DF parameters, there is little available guidance for the practicing 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
iagnostic flowwwwwwch ch ccccc
c r
r
chi hi hi hi ild ld ld ld ldre rre re r n nnnnwi wi wwwth th th th th CM CM CM CM C iiiiissss sch ch ch ch chal al al al alle le le le leng ng ng ng ngin in in in ngg. ggg DDDDDes es es es espi pi pi pi pite eeeettttthe he he he heaaavai ai ai ai aila la la la labi bbi bi bili li lll ty ty ty ty tyooofff ff r
ra ra rame me mete te ters rs rs, ,,, th th ther er ereee is is islllit it ittl tl tleee av av avai ai aila la labl bl bleee gu gu gu g id id id ii an an ance ce ceffffor or or ttthhhheee pr pr pr pp ac ac acti ti tici ci cing ng ng
11
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 filling
10
. This
paradigm has not been proven conceptually in infants and children. While the current study
cannot verify of reject this paradigm due to lack of a reference standard and its cross-sectional,
retrospective nature, there are several important observations that can be made from our data that
suggest that this paradigm may not apply to the pediatric population. In our experience, criteria
consistent with delayed relaxation are distinctly uncommon in children. Only 7 HCM patients
(6.4% of all CM patients), presented criteria consistent with delayed relaxation, while no DCM
or RCM patients had sufficiently concordant criteria to classify delayed relaxation or pseudo-
normal 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 expected
19
. 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.
andard and its sssssscccc
t can n n n nnnbe be be be be be bemmmmmmmad ad ad ad ad ad ade e eeeeefr f
a e
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i w
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yeddd ddre re re re rela la la la laxa xa xa xx ti ti ttt on on on nnaaaaare rr dddddis is iis isti ti ti ti tinc cccctttttly ly ly ly lyuuuuunc nc nc nc ncom om om om ommo mo mo mo monn nnnin in in in incccchi hi hi hi hild ld ld ld ldre re re re ren. nnnn OOOOOnl nl nl nl nly yyy7 7777H
iiien en ents ts ts))), ppppre re resssen en ente te teddd cr cr crit it iter er eria ia iacccon on onsi si sist st sten en ent tt wi wi wi wwth th thdddel el el lay ay ay yyed ed ed drrrel el elax ax axat at atio io ionnn, www hhh
12
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 values
16-18
.
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,
both in DCM and in HCM patients, we believe that diastolic dysfunction of some degree must be
present in a substantial proportion of patients. Therefore, our results indicate that current echo
criteria are inadequate to diagnose and classify DD in pediatric CM. Moreover, our results show
that when DD is diagnosed or suspected, discrepancies between diastolic parameters or
diagnostic criteria within individual patients are common. This adversely affects interpretation of
DF, the ability to grade DD and interobserver agreement. These problems are not exclusive to
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 pressures
20
.
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 classification
8
appears to be poorly applicable
in children. This suggests that new diagnostic criteria for diagnosis and grading of DD are
ults indicate tha ha ha ha ha ha hat
CM. MMMMMMMor or or or or or o eo eo eo eo eo eo eove ve ve ve ve ve ver, r, r, r, r, rr o
g e
i
a o
gggggno no no no nosed or or or or sssssus us us us u pe pe pe pe pect ct ct ct cted ed ed ed ed, di di ddi disc ssc sc s re eeepa pa pa pa p ncciiiesssssbe be be be betw tw tw tw twee een nnnndi ddddas ssssto to to to toli li li li lic cccpa pa pa pa para ra ra ra rame mmmm
ith hhhhin in in in iniiind nd nd nd ndiv iv iv iv viidu du du du dual al al al al pppat at at at atie ie ie ie ient nnnns ar ar ar ar aree eeeco co co co comm mm mm mm mmon on on on on. Th Th Th Th This is is is isaaaaadv dv dv dv dver er er er rse se se se sely ly ly ly lyaaaaaff ff ff ff ffec ec ec ee ts ts ts tt
aaade de deDDDDDDan an anddd in in inte te tero ro robs bs bser er erve ve ver r r ag ag ag ggre re reem em emen en en nnttt. TTThe he hese se sepppppro ro robl bl bl bllem em emsss ar ar areee no no no
13
needed in children. Early diastolic tissue velocities, particularly Emed, seemed to differentiate
patients from controls better than Elat or E/mean E ratio (Figure 3) implying decreased recoil
or possibly delayed relaxation
21
. 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
related cutoff values for these parameters should be determined. Conversely, the IVRT does not
appear to be useful in any of the CM patients groups included in this study. Likewise, the E/A
ratio, despite its traditional central position in the assessment of diastolic function, was not useful
in our population, except in a small number of adolescents with HCM.
Agreement between observers for classification of DD
Despite a-priori agreement between investigators on the methodology to classify 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
this study. Lik kkkkkkeeeee
diast sttttttol ol ol ol ol ol lic ic ic ic ic ic cfffffffun un un un un un unct ct ct ct ct ct ctiiiiiiioo
x
n
e y
xccccceeep ee t inaaaasssssma ma ma ma mall ll ll ll ll nnnnnuuuuumb mb mb mb mber er er er e oooof ad ad ad aa olesce eeeent nt nt nt nts sssswi wi wi wwith th th hHHHHHCMMMMM.
n ob ob ob ob obse se se se serv rv rv rv rver er er rsss fo fo fo oorr rrr cl llas as as aa si si si si sifffi f ca ca ca ca cati ti ti ti tion on on on on ooooofff ff DD DD DD DD DD
ee ee eeme me ment nt nt bbbet et etwe we ween en eniiinv nv nves es esti ti tigggggat at ator or orsss on on onttthe he heeemmmet et etho ho hodo do do d lo lo logy gy gy gy gytttooocl cl clas as assi si sify fy fy
14
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
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 when the disease
process actually starts in relation to when the patient becomes symptomatic and is referred for
evaluation. Importantly, our study does not define the prognostic value of individual diastolic
echo parameters. This requires further prospective study.

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.
determine whe he he he he he hen
mpto to oooooma ma ma ma ma ma mti ti ti ti ti ti tic c c c c c can an an an an an anddddd d di
n d
i
ntl tl tl tl tlyyy, y our ssstu tu tu tu tudy dy dy dy dy do do do do does es es es esnnnnnot ot ot ot ot dddddef ef ef ffin in in nne th th he pr pr pr pr prog og og og ogno no no no nost st stic ic ic ic ic val al al al alue ue ue ue ueooooof ffff in in in in indi di di di divi vvvv d
is re re re re requ qu qu qu quir ir ir ir iressssfu fu fu fu furt rt rt rr he he he hh r pr pr pr pproos ooo peeeeect ct ct ct ctiv iv iv iv iveeeeest st st st stud ud ud ud udyyyy.
15
Disclosures
None.

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f left ventricu uuuuula la la la la la lar
wi wi wi wi wi wi with th th th th th thhhhhhhhyp yp yp yp yp yp yper er er er er er ertr tr tr tr tr tr trop op op op op op ophhhhhhh
J , Pignatelli RH, Nagueh SF, LeeVV, Vaughn W, Valdes SO
W e
y g
f
A c
C
3
J , PPPPPig ig ig ig igna na na na nate te ttt ll ll ll ll lli iiii RH, Nagueh SF, LLLLLee eeee VV, Vauggggghn hhhh W, Valdes SO
WWWWWJJJJ , J Den nnnfi fi fi fi fieeeeeld ld ld ld dSSSSSW, W, W, W, W, CCCCClu lu lu lu luni nni nne eeeS, SS, SS Tow owwbi bi bi bi bin nnnnJ A J A J A J A J A, Ei Ei i Ei ide de dde dem m m mBW BW BW BW BW. Le Le Le Le Left ft ft ft ft ve
yo yo yo yo yopa pppp thy in nccchiillldre eeennn: n Chaarrract ct teris is sat tttio io io io ionn nnnof of ccclinnica aaal ll stat at atus uus u uusiinnng
ft ve ve ve ve vent nt nnt nri ri ri ri ricu uuula la la la ar rr di di di di dias aa to to to to toli li li li licc cccre eeeela la la la laxa xa xa xa xati ti ti ti ion on on on on. He He He He Hear ar ar ar art. tttt 2222200 00 00 00 007; 7; 7; 7; 7;93 93 93 93 93:6 :6 :6 :6 :676 76 76 76 76-6 -6 66681 81 81 81 81.
Ackerman MJ MJ MJ MJ MJ , ,, , , Ce Ce Ce Ce Cett tt tt tt a a a aaF, F, F, F, F, OOOOO'LLLLLea ea ea ea eary ry ry yPPPPPWWWWW, Ei Ei Ei Ei Eide de de de dem mm m m BW BW BW BW BW..... Significanc
222000ye ye year ar arsss of of of aaage ge ge gg wwwit it ithhh hy hy hy yype pe pe pp rt rt rtro ro roph ph ph pp ic ic iccccccar ar ardi di diom om omyo yo yo yy pa pa pa pp th th h th hy. y. y. yy AAAmmm JJJ CCC
333
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2004;17:212 22 22 22 22 22 22 22
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graphi hi hi hi hi hi hcccccccst st st st st sttud ud ud ud ud ud udy y y y y y y es es eeeee t
redictors of increased ventricular end-diastolic pressure. May
W o
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red ddddic ic ic ic icto to to to ors rs rs rs rsooooof f f f f increased ventricu uuula la la la lar r end-diasto ooooli li li li lic pressure. May
W,,, LLLi LL ttle WC. CC LLLeeeft vvve v ntricl cl le di ddas sttoli iiiicccccdy ddy dd sffuuuncct tio ooonn nand d d dpr prog gnnno
povic ZB, MMMMMar ar r ar arwi wi wi wi wck ck ck ck ckTTTTTH. H. H. H. H EEEEEff ff ff ff ffec eec eecttt ooooof f fff re re rre r co co comm mm mm mm mmen en en en enda da da ddati ti ti ti tioooon o s oninter t
ol ol olic ic icfffun un unct ct ctio io ionnn ev ev eval al alua ua uati ti tion on on. J A J A J ACC CC CC CCCar ar ardi di di ddov ov ovas as asc c c Im Im Imag ag ag ggin in iing. g. g. gg 22201 01 011; 1; 1;4: 4: 4:
AA Me Me Mert rt rten en ensssLLL FFFri ri iiied ed ddbe be bbb rg rg rgMMMKKK Re Re Rela la ll ti ti iiion on onsssbe be bb tw tw twee ee eennnsy sy syst st stol olic icaaand nd
17
Table 1. General and echo characteristics of the study population by cardiomyopathy type

Controls (n=50) DCM (n=50) RCM (n=16) HCM (n=50)
Age (mean SD) 9.74.8 8.06.1 10.36.2 11.84.1*
BSA (m2) 1.20.45 0.940.53* 1.10.6 1.40.48*
Heart rate (bpm) 85.817.6 10330* 86.511.3 70.813.2
LV EF(%) 58.27.8 2713.6* 5713 76.713.2*
LV EDD z-score -0.081 6.042.4* -0.881.7* -2.231.5*
IVS thickness z-score -0.20.8 -0.171.8 0.61.7* 7.82.7*
Blended mitral inflow 0 9 (6 <1y old) 0 1
*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 in the study population by
cardiomyopathy type according to adult cutoff values and pediatric reference data

% of patients with
normal values
Normal controls
(n=50)
DCM
(n=50)
RCM
(n=16)
HCM
(n=50)
Criterion Adult Pediatric Adult Pediatric Adult Pediatric 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.
thessttttttt ddddddd ppppppop op op op op p la
edat c dut edat lt
of normal individual diastolic parameters in the study popul
e t
m
ric Adult Pediatric t
of normal individual diastolicppppparameters in the study popul
e ac ac ac ac accord ddddiiin ii g ggggto adult cutoff valu ueees and peeeeedi ddddat ttric reference dat
mal al al al l cccccon on on on ontr ttr tr t ol oll ollsss
0)
DC DC DC DC DCMM MMM
(n (n (n nn=5 =5 =5 =5 =50) 0) 0) 0) 0)
RC RC RC RC RCMMMMM
(n (n (n (n (n=1 =1 =1 =1 =16) 6) 6) 6)
lllttt Pe Pe Pe PP di di di di diat at at ttri ii ri ric cc Ad Ad Ad Adul ul ul llttt tt Pe PPe Pe P di di di di diat at at tri ri riccc Ad Add Ad Adul ul ulllt tttt Pe Pe Pe PP di di di di diat at atri ri riccc ttt
18
Table 3. Reasons for failed classification, disagreement or mixed classification criteria
DCM (n=50) RCM (n=16) HCM (n=50)
Adult Pediatric Adult Pediatric Adult Pediatric
Discordant E/LAVi criteria
(E abn-LAVi N/ E N -LAVi abn)
19
12/7
16
7/9
5
1/4
6
1/5
22
9/13
21
11/10
Unclear grading
(grade 1 2/ 2 3/ blended
mitral inflow)
10
1/3/6
15
3/8/4
5
1/4/0
8
2/6/0
11
8/3/0
8
4/3/1
Clear classification (N / abn) 21
7/14
19
12/7
6
0/6
2
0/2
17
13/4
22
11/11
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 and filling pressures by the
three investigators (A, B, C)

DCM (n=50) RCM (n=16) HCM (n=50)
Investigator subjective classification
Agreement(%)
Normal
Abnormal (grade 1/2/3)
23(46%)
10
11 (0/1/10)
10(62.5%)
1
9 (0/0/9)
32(64%)
18
14 (7/7/0)
Disagreement(%) 27(54%) 6(37.5%) 18(36%)
Kappa statistics
A-B
A-C
B-C

0.509
0.549
0.334

0.462
0.647
0.352

0.592
0.812
0.507
Assessment of filling pressures
Agreement(%)
Normal / High
24(48%)
5/17
13 (81.2%)
2/11
37(74%)
26/11
Disagreement(%) 26(52%) 3(18.7%) 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.
ty an an an an an an andd dddddfi fi fi fi fi fi fill ll ll ll ll ll llin in in in in in ing g g g ggg pr pr pr pr pr pr pree
A, B, C)
DCM (n=50) RCM (n=16)
v
A, B, ,, C)
DDDDDCM CM CM CM CM ((((n===50 0)) RC RC RCCMMM (n (n (n (n (n=1111166) 666
ve classifica aaaati ti ti ti t on on on on o
23 23 23 23 23(4 (4 (4446% 6% 6% 6% 6%) ) ) ))
10 10 10 10 10
10 10 10 10 10((6 (6 (6 (62. 22225% 5% 5% 5% 5%)))
11111
19
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
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 in the study population by age and cardiomyopathy type. A:
Mitral valve E to A ratio. B: Mitral valve E wave deceleration time. C: Left atrial volume
indexed to body surface area.

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.
parameters in the study population by age and cardiomyopath
r a
f
par rrrram am am am amet et et et eter eeees s s ssin iiii the study popula aaaati ti ti ti t on ooo by age an nnnnd ddddcardiomyopath
ra aaaati ti ti iio. B: MMitttraaal val al al avvve v E wwwave vee dec ec cel el l el eler er er er erat at aio onnn time me me. C: LLLLLef ftt at triia
face area.
SUPPLEMENTAL MATERIAL
Supplemental Table
Table. Individual diastolic parameters in the study population by cardiomyopathy type.
Criterion
Normal controls
(n=50)
DCM
(n=50)
RCM*
(n=16)
HCM
(n=50)
IVRT (ms) 609.7 5616 6319 74.222.5
PV S/D 0.80.2 0.90.4 10.4 10.4
PV Ar (cm/s) 235.9 24.68 3411 31.612.5
Ar - A (ms) -2318 8.926 36.431 -632
DT (ms) 15328 11334 9427 19743
E/A 20.6 2.31.1 2.61.6 1.80.6
E sep (cm/s) 142.4 7.22.8 7.12.9 83.2
E lat (cm/s) 18.34 105 9.23.8 124.7
E/ mean E 6.61.7 13.24.7 12.36 11.45.4
LAVi score (ml/m
2
) 24.86 47.429 80.438 3914.4
* 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.

Circ Cardiovasc Imaging 2013

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Circ Cardiovasc Imaging 2013

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Andreea Dragulescu, Luc Mertens and Mark K.

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