European Heart Journal – Cardiovascular Imaging (2013) 14, 562–569

doi:10.1093/ehjci/jes217

Myocardial 2D strain echocardiography

and cardiac biomarkers in children during
and shortly after anthracycline therapy for
acute lymphoblastic leukaemia (ALL):
a prospective study
Annelies M.C. Mavinkurve-Groothuis 1*, Karen A. Marcus 2, Milanthy Pourier 1,
Jacqueline Loonen 1, Ton Feuth 3, Peter M. Hoogerbrugge 1, Chris L. de Korte 4,
and Livia Kapusta 2,5
1
Department of Pediatric Hematology and Oncology, Radboud University Nijmegen Medical Centre, PO Box 9101, Huispost 804, 6500 HB Nijmegen, The Netherlands; 2Children’s
Heart Centre, Radboud University Nijmegen Medical Centre, The Netherlands; 3Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University
Nijmegen Medical Centre, The Netherlands; 4Clinical Physics Laboratory, Department of Pediatrics, Radboud University Nijmegen Medical Centre, The Netherlands; and 5Pediatric
Cardiology Unit, Edith Wolfson Medical Center, Holon, Israel

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Received 3 August 2012; accepted after revision 26 September 2012; online publish-ahead-of-print 29 October 2012

Aims The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assess-
ment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with
anthracyclines.
.....................................................................................................................................................................................
Methods Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT)
and results and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardi-
ography before start (T ¼ 0), after 3 months (T ¼ 1), and after 1 year (T ¼ 2), and were compared with 60 healthy
age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening.
Cardiac function decreased significantly during treatment and was significantly decreased compared with normal con-
trols. Cardiac troponin T levels were abnormal in 11% of the patients at T ¼ 1 and were significantly related to
increased time to global peak systolic longitudinal strain at T ¼ 2 (P ¼ 0.003). N-terminal-pro-brain natriuretic
peptide levels were abnormal in 13% of patients at T ¼ 1 and in 20% at T ¼ 2, absolute values increased throughout
treatment in 59%. Predictors for abnormal NT-pro-BNP at T ¼ 2 were abnormal NT-pro-BNP at T ¼ 0 and T ¼ 1,
for abnormal myocardial 2D strain parameters at T ¼ 2 cumulative anthracycline dose and z-score of the diastolic left
ventricular internal diameter at baseline.
.....................................................................................................................................................................................
Conclusion Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthra-
cyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic
peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal
strain at T ¼ 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is im-
portant in the assessment of cardiac function of children with ALL treated with anthracyclines.
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Keywords Myocardial strain imaging † Cardiac biomarkers † Anthracyclines † Early-onset cardiotoxicity † ALL

* Corresponding author. Tel: +31 24 3614430; fax: +31 24 3619348, Email: a.mavinkurve@cukz.umcn.nl
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.com
Myocardial 2D strain echocardiography 563

Introduction groups; standard risk (SR), medium risk (MR), and high risk (HR)
patients largely based on response to treatment.20 The total duration
Cardiotoxicity is a well-known side effect of anthracycline therapy. of treatment is 2 years, but shorter for HR patients who are eligible for
Early-onset anthracycline-induced cardiotoxicity occurs during or stem cell transplantation (SCT). At T ¼ 1, the cumulative anthracycline
within the first year after anthracycline treatment. It is a risk dose of all patients is 120 mg/m2. At T ¼ 2, SR patients have received a
factor for the development of late-onset anthracycline-induced cumulative anthracycline dose of 120 mg/m2, MR patients 300 mg/m2,
and HR patients a maximum cumulative anthracycline dose of
cardiotoxicity, which is known to cause serious cardiac health pro-
240 mg/m2 and an additional 52.5 mg/m2 of mitoxantrone and
blems in a growing number of cancer survivors.1 – 6
18 mg/m2 of idarubicin, depending on (timing of) SCT. All SCT patients
Cardiac biomarkers are increasingly used for the detection of
received total body irradiation.
anthracycline-induced cardiotoxicity.7 – 17 Release of cardiac tropo-
nins is indicative for myocardial necrosis. Natriuretic peptides are
released by the myocardium in response to volume and pressure
Cardiac biomarkers
overload and have shown to be sensitive markers of left ventricular Blood samples were obtained at T ¼ 0, T ¼ 1, and T ¼ 2 from a central
venous line in patients with ALL. Cardiac TnT levels were assessed by
dysfunction.7,8
the Elecsys Troponin T STAT Immunoassay, performed on a Modular
The use of myocardial 2D strain echocardiography in
E immunoassay analyzer (Roche Diagnostics, Mannheim, Germany).21
early-onset anthracycline-induced cardiotoxicity has been studied A level of ≤0.01 ng/mL was defined as normal. N-terminal-pro-brain
by tissue Doppler strain analysis15 and by 2D speckle tracking natriuretic peptide was measured using an electrochemiluminescence
strain analysis.16 – 18 These studies showed decreased myocardial immunoassay, using the NT-pro-BNP kit (Roche Diagnostics).
strain and strain rate during anthracycline therapy15 and years Normal values for children were based on age-dependent reference
after anthracycline therapy,16 – 18 with relatively preserved fraction- values (97.5th percentile).22
al shortening (FS).19
In this prospective study, we aim (i) to document cardiac tropo- Echocardiography
nin T (cTnT) and N-terminal-pro-brain natriuretic peptide Transthoracic echocardiography in left lateral position was performed
(NT-pro-BNP) levels and conventional and myocardial 2D strain at rest, without sedation. Images were obtained with a 3.0 MHz and a
echocardiographic parameters before, during, and shortly after 5.0 MHz transducer, depending on the age and weight of the study

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treatment with anthracyclines in children with newly diagnosed subjects, using a Vivid 7 echographic scanner (GE, Vingmed Ultra-
ALL, (ii) to find predictors for abnormal cardiac function at 1 sound, Horten, Norway). Frame rate was kept between 70 and 100
year after anthracycline treatment, and (iii) to compare cardiac frames per second (fps).23,24 Quantification of cardiac chamber size,
function of children with ALL after 1 year of anthracycline treat- left ventricular mass (LVM) and systolic and diastolic left ventricular
ment to cardiac function of healthy controls. function were measured in accordance with the recommendations
for chamber quantification by the American Society of Echocardiogra-
phy’s Guidelines and Standard Committee and the Chamber Quantifi-
Methods cation Writing Group.25 Z-scores of left ventricular dimensions and
LVM were calculated based on normal values of M mode measure-
Study population ments.26,27 The left ventricular systolic function was indicated using
FS. We did not include left ventricular ejection fraction (Simpson’s
Newly diagnosed patients with childhood ALL and their parents were
method). Left ventricular diastolic function was indicated using the E/
asked informed consent for our study. Exclusion criteria were cardiac
A ratio, E/E′ ratio,28 and the isovolumic relaxation time.29 Left ventricu-
disease prior to therapy and renal failure. As a control group, we
lar mass was calculated according to the formula of Devereux.30
included 60 healthy age-matched controls that were routinely referred
Two-dimensional grey scale images were made in parasternal apical
for echocardiographic evaluation of an asymptomatic, innocent heart
four-chamber and mid-cavity short-axis (at the level of the papillary
murmur or for screening purposes. History, electrocardiogram, and
muscle) views. A sector scan angle of 30 – 60 degrees was chosen to
echocardiogram were not indicative of cardiac disease and no medica-
obtain frame rates of 70 – 100 Hz. Cine loops of three cardiac cycles
tion was used.
triggered by the R wave of the QRS complex were digitally saved.
Cardiac function was assessed by echocardiography for obtaining
Off-line analysis was performed using the software for echocardio-
conventional and myocardial 2D strain parameters. Cardiac TnT and
graphic quantification (EchoPAC 6.1.0, GE Medical Systems, Horten,
NT-pro-BNP were measured in the patient group. The first cardiac
Norway). Separately, timing of aortic valve closure and mitral valve
evaluation was done in the first week of ALL treatment, i.e. before
opening were obtained, using single-gated pulsed Doppler or continu-
the first anthracycline dose (T ¼ 0). The second cardiac evaluation
ous wave Doppler images. These images were acquired just after the
was performed at the end of the induction phase of the ALL treatment,
2D strain grey-scale images and special care was taken that the heart
which is 10 weeks after start of treatment and 5 weeks after the latest
rate was in the same range. Time measurements were expressed as
anthracycline dose (T ¼ 1). The third cardiac evaluation was per-
a percentage of the duration of the complete cardiac cycle.
formed 1 year after start of ALL treatment which is at least 2 weeks
Myocardial segments were named and localized according to the
after the last anthracycline dose (T ¼ 2). The study was approved by
statement of the Cardiac Imaging Committee of the Council on Clin-
the local ethics committee.
ical Cardiology of the American Heart Association.31 Manual tracking
of the endomyocardial borders was performed at the end-systolic
Anthracycline treatment as part of the frame. An automatic generation of the second epicardial tracing was
antileukaemic therapy created by the software. The software automatically divided the
Treatment according to the DCOG-ALL-10 protocol is based on the image into six segments. Quality of the tracking was verified for each
DCOG-ALL-8 protocol. Patients are stratified in three treatment segment and adjusted when needed. Strain curves of three consecutive
564 A.M.C. Mavinkurve-Groothuis et al.

cardiac cycles and values of the manual timing were imported into a acute heart failure) of acute anthracycline-induced cardiotoxicity
custom-made software package for further analysis. Cardiac cycles and none of them used cardiac medication.
with a length more than 10% different from the mean length of the Hyperhydration, i.e. the infusion of 3000 mL/m2/day of glucose
three cardiac cycles were excluded for further analysis. The average 2.5%/NaCl 0.45%, as part of the supportive care to prevent
values of peak systolic longitudinal (SL), radial (SR) and circumferential
tumour lysis syndrome was given in 95% of the patients at T ¼ 0,
(SC) strain and strain rate of the three imported curves were calcu-
but in none at T ¼ 1 and T ¼ 2. Echocardiographic parameters of
lated by the custom-made software. Global strain and strain rate
the patients were compared with 60 healthy controls. The charac-
were calculated by averaging the six segments. For calculating the
global time to reach the peak systolic strain, we used the average of teristics of the study population are shown in Table 1.
the six segments.
We recently showed that myocardial strain imaging with 2D echo-
cardiography can produce scores with high interobserver, intraobser-
Biomarkers
ver, and intrapatient reliability.32 Abnormal global SL, SR, and SC were Table 2 shows the results of the biomarker levels at T ¼ 0, T ¼ 1,
defined as values lower than the fifth percentile of the normal paedi- and T ¼ 2. Levels of cTnT were normal in all patients before start
atric population.33 of anthracycline treatment (T ¼ 0). At T ¼ 1, cTnT levels were ab-
normal in 11% of the patients (5/45) and normalized in all at T ¼ 2.
Statistical analysis In one MR patient, cTnT became abnormal at T ¼ 2 (i.e. after a cu-
Characteristics of the study population and biomarker levels were mulative anthracycline dose of 300 mg/m2).
summarized using median and range. Conventional echocardiographic N-terminal-pro-brain natriuretic peptide levels were abnormal
and 2D strain parameters were summarized by using mean and stand- in 26% of the patients (12/46) at T ¼ 0. Ninety-five percent of
ard deviation (SD). The biomarker levels were studied at T ¼ 1 and the patients received hyperhydration at T ¼ 0, when plasma
T ¼ 2 for available paired observations using the McNemar test for ab- samples of NT-pro-BNP and cTnT were obtained. The median
normal biomarkers levels and the Wilcoxon signed ranks test for the NT-pro-BNP level at T ¼ 0 was 13 pmol/L (range 2–185). Abnor-
absolute biomarker levels. The echocardiographic data in the patient mal NT-pro-BNP levels were not significantly related to, but
group were studied using linear mixed models and generalized estimat- showed a tendency towards lower haemoglobin (Hb) levels,
ing equations (GEE) to account for correlations between different
higher total leucocyte counts (TLC), and hyperhydration (data

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points in time. Echocardiographic parameters of patients and controls
not shown). N-terminal-pro-brain natriuretic peptide levels were
were compared using the independent t-test.
Using logistic regression analysis, we searched for possible predic- abnormal in 13% (6/45) at T ¼ 1 and in 20% of the patients
tors at baseline and T ¼ 1 for abnormal cardiac biomarkers and 2D (8/41) at T ¼ 2. Absolute NT-pro-BNP levels increased during
myocardial global SL, SR, and SC. We refrained from multiple regres- treatment in 59% of the patients.
sion analysis because of the small number of subjects.
Statistical analyses were performed using the Statistical Package for
Social Sciences (SPSS) for Windows, version 16.0 and SAS, version 8.2. Echocardiographic parameters
A P-value less than 0.05 was considered to indicate significance. The echocardiographic parameters during treatment are shown in
Table 3. None of the patients had a FS below 28%. Fractional short-
ening decreased significantly after the first 120 mg/m2 of anthracy-
Results clines (P , 0.0001). In 23% of the patients, a decreased FS of more
than 10% was observed. Z-scores of left ventricular dimensions
Subject characteristics and LVM all changed significantly over time. All myocardial 2D
Seventy children and their parents were asked to give informed strain parameters decreased during anthracycline treatment; a stat-
consent for this study. Parents of four patients refused informed istically significant decrease was observed for global SrL, global SR,
consent. One patient was excluded because of congenital heart and global SC (P ¼ 0.03, 0.004, and 0.01, respectively) and all time
disease (atrial septal defect). Consequently, 65 patients were to peak systolic strain parameters (P , 0.001). Global SL, SrL, and
included in the study. Before T ¼ 1, three patients altered treat- SR were inversely related to cumulative anthracycline dose (P ¼
ment because of treatment-related toxicity and two patients 0.004, P ¼ 0.03, and P ¼ 0.006, respectively). Patients with the ab-
died (progressive disease and sepsis, respectively). Further analysis normal cTnT level at T ¼ 1 had a significant longer time to peak
was done in the remaining 60 patients. Three patients died after global SL at T ¼ 2 (P ¼ 0.003).
T ¼ 1 (one sepsis and two relapses, respectively) and one Table 4 shows the echocardiographic data of patients at T ¼ 2
patient was lost to follow-up by moving abroad. Parents of one compared with that of healthy controls. Conventional echocardio-
SR patient refused echocardiography and biomarker sampling at graphic parameters of patients showed significantly decreased FS,
T ¼ 2. In six patients, the follow-up was not available at T ¼ 2. and increased IVRT compared with healthy controls. Z-scores of
Six patients in the HR group completed T ¼ 2. Four of them left ventricular dimensions and LVM were not significantly different
received the full dose of anthracyclines, two were eligible for from healthy controls. In contrast, all myocardial strain parameters
SCT; one received a cumulative anthracycline dose of 120 mg/ were significantly decreased in patients compared with healthy
m2, and one a cumulative anthracycline dose of 120 mg/m2 plus controls, except for global SR. Time to peak global SL, SR, and
18 mg/m2 of idarubicin and 26.25 mg/m2 of mitoxantrone. None SC were significantly increased in patients compared with
of the patients showed clinical symptoms (e.g. rhythm disorders, healthy controls (P , 0.0001).
Myocardial 2D strain echocardiography 565

Table 1 Characteristics of the study population

Patients Controls P-valuec

...............................................................................................................................................................................
Number (N) 60 60
Male gender (N) 37 (62%) 40 (67%)
Age at diagnosis, (years) 6 (2.2–15.4) 5.8 (2.2– 14.7) 0.09
BSA 0.87 (0.54–1.93) 0.81 (0.50–1.84) 0.07
HR 79 (53– 122) 90 (53–122) 0.04
Hba level at diagnosis (mmol/L) 5.5 (2.2–9.5)
TLCb at diagnosis (*109/L) 10.4 (0.7– 348)
Hyperhydration at T ¼ 0 (N (percentage)) 57 (95%)
Risk stratification
SR (n) 20
MR (n) 30
HR (n) 10
Cumulative anthracycline dose at the different time
points
T¼0 All patients: 0 mg/m2
T¼1 All patients: 120 mg/m2
T¼2 SR-patients: 120 mg/m2
MR-patients: 300 mg/m2
HR-patients (n ¼ 4), no SCT: 240 mg/m2 + 18 mg/m2
idarubicin + 52.5 mg/m2 mitoxantrone
HR-patient (n ¼ 1), SCT: 120 mg/m2

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HR-patient z (n ¼ 1), SCT: 120 mg/m2 + 18 mg/m2 idarubicin +
26.25 mg/m2 mitoxantrone

Values are expressed as median and range.

a
Haemoglobin.
b
Total leucocyte count.
c
Mann – Whitney U-analysis.

Table 2 Cardiac biomarkers in ALL patients during treatment with anthracyclines

T50 T51 T52 P-value

..............................................................................................................................................................................
Number of patients (N) 60 60 49
Number of biomarker samples (N) 46 45 41
Abnormal cTnT (%) [N] 0 [0] 11 [5] 2.5 [1] 0.2a
cTnT (ng/mL), median (range) 0.01 0.01 (0.01–0.04) 0.01 (0.01– 0.02) 0.08b
Abnormal NT-pro-BNP (%) [N] 26 [12] 13 [6] 20 [8] 0.5a
NT-pro-BNP (pmol/L), median (range) 13 (2 –185) 10 (1– 45) 11 (1–68) 0.5b

Values are expressed as median and range.

a
McNemar test based on 37 paired available observations at T ¼ 1 and T ¼ 2.
b
Wilcoxon signed ranks test on 37 paired available observations at T ¼ 1 and T ¼ 2.

Predictors for abnormal biomarkers increase of 100 mg/m2 ¼ 2.25, 95% CI (1.02–4.93)], LVIDd
and strain parameters z-score at baseline [P ¼ 0.03, OR ¼ 1.95, 95% CI (1.05–3.62)],
Cardiac biomarkers and 2D myocardial global SL, SR, and SC were and FS at baseline [P , 0.05, OR ¼ 1.17, 95% CI (1.00– 1.36)]. Pre-
defined as normal and abnormal based on age-dependent refer- dictors for abnormal global SC at the level of the papillary muscle
ence values at T ¼ 2. Predictors for abnormal global SL were cu- were global SL [P ¼ 0.02, OR ¼ 1.33, 95% CI (1.05–1.68)] and
mulative anthracycline dose [P , 0.05, OR associated with an global SrL [P ¼ 0.04, OR ¼ 24.96, 95% CI (1.22–510)] at T ¼ 1.
566 A.M.C. Mavinkurve-Groothuis et al.

Table 3 Echocardiographic parameters in ALL patients during treatment with anthracyclines

T 5 0 (N 5 60) T 5 1 (N 5 60) T 5 2 (N 5 49) P-value*

...............................................................................................................................................................................
Conventional parameters (mean + SD)
FS (%), mean (+SD) 40 + 5 36 + 3 35 + 3 , 0.0001
Z-score LIVD (+SD) 0.14 + 1.15 0.63 + 0.82 0.48 + 0.88 0.005
Z-score LVPWd (+SD) 20.07 + 1.14 20.36 + 0.88 20.59 + 1.28 0.04
Z-score IVSd (+SD) 20.80 + 1.05 20.59 + 0.98 21.09 + 1.05 0.02
Z-score LVM (+SD) 22.23 + 1.58 21.61 + 1.12 22.20 + 1.62 0.007
IVRT (ms) 72 + 12 67 + 9 71 + 10 0.01
E/A ratio 1.8 + 0.6 1.8 + 0.5 1.8 + 0.6 0.8
E/E′ ratio 10.1 + 4.8 12.4 + 3.9 11.6 + 5.7 0.11
Strain (rate) parameters (mean + SD)
Global SL (%) 218.2 + 3.1 217.3 + 3.6 216.7 + 5.2 0.5
Global SrL (1/s) 21.44 + 0.3 21.32 + 0.3 21.20 + 0.4 0.03
Global SR (%) 66.8 + 12 53.5 + 13 55.2 + 16 0.004
Global SrR (1/s) 2.6 + 0.5 2.4 + 0.5 2.3 + 0.6 0.1
Global SC (%) 219.4 + 4.3 217.1 + 3.7 216.9 + 3.1 0.01
Global SrC (1/s) 21.7 + 0.3 21.6 + 0.3 21.5 + 0.2 0.08
Time to peak global SL (%) 43 + 8 51 + 6 48 + 8 ,0.0001
Time to peak global SR (%) 45 + 8 53 + 8 52 + 8 ,0.0001
Time to peak global SC (%) 43 + 8 50 + 7 48 + 7 ,0.0001
Abnormal global SL (%) 45 52 42 0.51 (GEE)
Abnormal global SR (%) 3 15 15 0.01 (GEE)

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Abnormal global SC (%) 15 35 35 0.002 (GEE)

Values are expressed as mean and standard deviation.

*P-values with respect to differences between time points are based on linear mixed model analyses or GEE analysis as indicated. FS, fractional shortening; LIVDd, diastolic left
ventricular internal diameter; LVPWd, diastolic left ventricular posterior wall thickness; IVSd, diastolic intraventricular septum; LVM, left ventricular mass; IVRT, isovolumic
relaxation time; SL, longitudinal strain; SrL, longitudinal strain rate; SR, radial strain; SrR, radial strain rate; SC, circumferential strain; SrC, circumferential strain rate.

Predictors for abnormal NT-pro-BNP were an abnormal 120 mg/m2, which is considered to be a relatively safe dose,34,35
NT-pro-BNP at T ¼ 0 and T ¼ 1 [P ¼ 0.01, OR ¼ 11.0, 95% CI damage of the cardiomyocytes occurs as indicated by the cTnT
(1.6 –73.5)]. Predictors for a decreased FS of more than 10% at levels. The fact that most of the patients had their last anthracycline
T ¼ 2 were FS [P ¼ 0.01, OR ¼ 1.5, 95% CI (1.1 –2.0)], LVM dose 6 months before T ¼ 2 might explain the absence of abnormal
z-score [P ¼ 0.01, OR ¼ 3.8, 95% CI (1.3– 10.7)] and z-scores of cTnT levels in all but one patient at that moment. The absolute levels
the diastolic left ventricular internal diameter [P , 0.01, OR ¼ of the abnormal cTnT measurements in our patients were in the
4.2 95% CI (1.6 –11.1)] and z-score of LVPWd [P ¼ 0.004, OR ¼ lower ranges. Measurement of high-sensitive cTnT is a newer
4.1, 95% CI (1.6 –10.9)] at T ¼ 1. method to detect troponin release at even lower concentrations
than that are detectable now.36 This might be an interesting future
method to evaluate in our patients. We showed that abnormal
Discussion cTnT levels at T ¼ 1 were significantly related to increased time to
Cardiac function of children with ALL, during treatment with a reach the global peak SL strain at T ¼ 2 (P ¼ 0.003). The recent
relatively low dose of cumulative anthracyclines, deteriorated study of Sawaya et al.37 showed a similar relation between cardiac
over time as measured by cardiac biomarkers and conventional troponin I (cTnI) and longitudinal strain. They concluded that abnor-
and myocardial 2D strain echocardiography. Comparison of echo- mal cTnI levels and longitudinal strain were predictive of cardiotoxi-
cardiographic parameters of the patients at 1 year after anthracy- city in patients with breast cancer treated with anthracyclines and
cline therapy with healthy controls showed that mainly strain trastuzumab.
parameters were affected. In our study, an interesting finding was the unexpected high per-
centage of abnormal NT-pro-BNP levels in patients (26%) before re-
Biomarkers ceiving anthracyclines. Our hypothesis is that in children with ALL,
Cardiac TnT levels were all normal before start of treatment (T ¼ 0) release of NT-pro-BNP might be addressed to commonly occurring
and became abnormal in 11% of patients after a cumulative anthracy- symptoms as severe anaemia, leucocytosis, and to hyperhydration to
cline dose of 120 mg/m2 (at T ¼ 1). Release of cTnT during therapy prevent tumour lysis syndrome. A tendency towards lower Hb
or directly after might reflect direct damage to cardiomyocytes. This levels, higher leucocyte counts, and hyperhydration was seen in
study shows that even after a cumulative anthracycline dose of our patients; however, this relation was not statistically significant.
Myocardial 2D strain echocardiography 567

Table 4 Echocardiographic conventional and myocardial 2D parameters in ALL patients at T 5 2 compared with
healthy controls

Controls (N 5 60) Patients T 5 2 (N 5 49) P-value

...............................................................................................................................................................................
Conventional parameters (mean + SD)
FS (%), mean (+SD) 38 + 4 35 + 3 0.002
Z-score LVIDd, mean (+SD) 0.51 + 1.00 0.48 + 0.88 0.86
Z-score LVPWd, mean (+SD) 20.34 + 1.42 20.59 + 1.28 0.40
Z-score IVSd, mean (+SD) 20.92+1.14 21.1 + 1.05 0.42
Z-score LVM, mean (+SD) 22.03 + 1.38 22.20 + 1.62 0.56
IVRT (ms) 47 + 5 71 + 10 ,0.0001
E/A ratio 2.0 + 0.5 1.8 + 0.6 0.03
E/E′ ratio 12.0 + 5.0 11.6 + 5.7 0.6
Strain (rate) parameters (mean + SD)
Global SL (%) 220.9 + 1.3 216.7 + 5.2 ,0.0001
Global SrL (1/s) 21.3 + 0.1 21.20 + 0.4 0.01
Global SR (%) 54.3 + 6 55.2 + 16 0.6
Global SrR (1/s) 3.4 + 0.4 2.3 + 0.6 ,0.0001
Global SC (%) 222.5 + 2.1 216.9 + 3.1 ,0.0001
Global SrC (1/s) 1.9 + 0.2 21.5 + 0.2 ,0.0001
Time to peak global SL (%) 43 + 3 48 + 8 ,0.0001
Time to peak global SR (%) 42 + 4 52 + 8 ,0.0001
Time to peak global SC (%) 43 + 4 48 + 7 ,0.0001

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Values are expressed as mean and standard deviation. Abbreviations as in Table 3.

The number of patients with abnormal NT-pro-BNP levels than 10% in 23% of the patients. Predictors for this decrease
increased throughout treatment from 13% at T ¼ 1 to 20% at were decreased z-scores of left ventricular dimensions and LVM.
T ¼ 2. Absolute values of NT-pro-BNP increased throughout Predictors for abnormal SL were different from the predictors of
treatment in 59% of the patients. We recently showed that in a abnormal SC. Abnormal global SL often precedes abnormalities
large group of asymptomatic long-term survivors of childhood in global SR or SC, which is also described in other studies.41
cancer, none of them had abnormal cTnT levels 15 years after The cumulative anthracycline dose correlated negatively with
anthracycline treatment and concluded that assessment of cTnT global longitudinal strain (P ¼ 0.004) and strain rate (P ¼ 0.03)
levels does not contribute to the detection of subclinical late-onset and global radial strain (P ¼ 0.006), but not with the conventional
anthracyline-induced cardiotoxicity. On the other hand, abnormal echocardiographic parameters, including FS.
levels of NT-pro-BNP were detected in 13% of this group and Myocardial strain imaging with 2D echocardiography can
were related to cumulative anthracycline dose.38 produce scores with high interobserver, intraobserver, and intra-
The predictive role of biomarkers in chemotherapy-induced car- patient reliability, as expressed by ICC’s generally above 0.70 and
diotoxicity has been reviewed before.39 An increase in troponin % of variance between 0 and 5%.32 Changes in deformation para-
levels is related to a high probability of major cardiac events meters in our patient group can therefore be considered clinically
within the first year of follow-up. Patients with a persistent significant. Increasing data suggest that systolic strain and strain rate
normal troponin value would most likely not have cardiac compli- are strong indices of left ventricular contractility.42,43 Although
cations, with a predictive negative value of 99%. The role of natri- strain is more afterload dependent, strain rate is considered a
uretic peptides in the prediction of anthracycline-induced robust measure of contractility.44 An increasing number of
cardiotoxicity seemed less clear.39 Long-term follow-up of our studies report on the usefulness of myocardial 2D strain echocar-
patients might clarify this topic. Biomarkers reflecting fibrosis of diography in monitoring anthracycline-induced cardiotoxicity.15 – 19
the myocardium, such as galectin-3, might be of additional use in In our previous study in long-term survivors of childhood cancer
the assessment of anthracycline-induced cardiotoxicity.40 treated with anthracyclines, we also showed that strain parameters
were lower when compared with healthy controls.45 Similar find-
Myocardial 2D strain ings were reported by Tsai et al.,17 who studied cardiac function in
None of the patients had clinical signs of acute and/or early-onset long-term survivors of Hodgkin’s lymphoma. Interestingly, Cheung
anthracycline-induced cardiotoxicity; all cardiac changes in our et al.19 reported impaired left ventricular myocardial deformation
patients were subclinical. Although FS decreased significantly and mechanical dyssynchrony in ALL patients after more than 1
after 120 mg/m2 of cumulative anthracycline dose, none of the year of treatment when compared with healthy controls. They
patients had abnormal FS. Fractional shortening decreased more showed that synchronicity of myocardial deformation may
568 A.M.C. Mavinkurve-Groothuis et al.

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