DOI: 10.1111/echo.

13871

O R I G I N A L I N V E S T I G AT I O N

Natural history of myocardial deformation in children,

adolescents, and young adults exposed to anthracyclines:
Systematic review and meta-­analysis

Mirela Tuzovic MD1,2 | Pei-Tzu Wu PhD1,2 | Samuel Kianmahd BS1,2,3 |

Kim-Lien Nguyen MD1,2

1
Division of Cardiology, David Geffen School
of Medicine at UCLA, Los Angeles, CA, USA Objective: Anthracyclines are widely used to treat solid and hematologic malignan-
2
Division of Cardiology, VA Greater Los cies, but are known to cause cardiotoxicity. As more childhood cancer survivors
Angeles Healthcare System, Los Angeles, reach adulthood due to improvements in oncologic treatments, they become suscep-
CA, USA
3 tible to late and progressive anthracycline-­induced cardiotoxicity. Nonetheless, diag-
School of Medicine, Stony Brook University,
New York, NY, USA nostic criteria for early detection of cardiac dysfunction are not well defined in
children, adolescent, and young adults (CAYA, ages 1–40 years). We present a natural
Correspondence
Kim-Lien Nguyen, David Geffen School of history of the changes in myocardial deformation in CAYA patients after anthracy-
Medicine at UCLA, VA Greater Los Angeles
cline therapy.
Healthcare System, Los Angeles, CA, USA.
Email: klnguyen@ucla.edu Methods: We performed a literature review search between 2001 and 2016 using
Funding information PubMed with the following search terms: strain (or deformation), torsion (or twist),
This study was supported by pilot funding children (or adolescent or young adult), cardiotoxicity (or dysfunction), and anthracy-
from the UCLA Jonsson Comprehensive
Cancer Center Foundation and the clines (or doxorubicin). A total of 23 articles were reviewed. Fourteen articles were
infrastructure afforded by UCLA Clinical incorporated in the meta-­analysis.
and Translational Institute (CTSI Grant
#ULTR001881). Results: Strain abnormalities are observed at both short-­term and long-­term follow-
­up. Global longitudinal strain (GLS) abnormalities are common during or early after
chemotherapy, whereas changes in global circumferential strain (GCS) are more sig-
nificant and consistent on long-­term follow-­up. Although global radial strain and tor-
sional parameters are also often abnormal late after chemotherapy, there are few
studies evaluating these parameters.
Conclusion: There are significant abnormalities in GLS and GCS following anthracy-
cline therapy acutely and late after treatment. The prognostic value of these strain
abnormalities warrants further investigation.

KEYWORDS
cardiac toxicity, myocardial strain, transthoracic echocardiography

1 | I NTRO D U C TI O N population, and persists up to 45 years after treatment.5 As in-

creasing numbers of childhood cancer survivors reach adulthood
Anthracyclines have been used since the 1950s to treat many solid due to improved cancer treatments, more of these survivors will be
and hematologic malignancies and are known to cause cardio- affected by the long-­term cardiac consequences of anthracycline
1–3 4
toxicity in a dose-­dependent relationship. The risk of cardio- therapy. As of 2008, there were 619 000 cancer survivors under the
vascular disease-­related morbidity and mortality is 8 times higher age of 40 in the United States, a number which is likely to increase
in anthracycline-­
treated cancer survivors than in the general with improvements in diagnosis and treatment protocols.6,7 Despite

Echocardiography. 2018;1–13. wileyonlinelibrary.com/journal/echo

© 2018 Wiley Periodicals, Inc. | 1
2 | TUZOVIC et al.

the burden of cardiovascular morbidity and mortality in childhood groups based on the duration of anthracycline exposure: during
cancer survivors, especially in the children, adolescent, and young or <1 year after treatment (acute and early-­chronic), 1–10 years
adult group (CAYA, 1 to 40 years of age), sensitive diagnostic tools after treatment (intermediate-­late chronic), and ≥10 years after
for evaluating subclinical dysfunction are not well defined. treatment (late-­chronic). Because studies of anthracycline toxicity
Classification of cardiotoxicity can be based on chronology: acute in the CAYA group described the risk of cardiotoxicity as a func-
(during treatment), early chronic (<1 year after treatment), and late tion of cumulative doxorubicin dosages, the total cumulative an-
chronic (>1 year after treatment). Subclinical myocardial dysfunction thracycline dose was derived by taking the sum of the calculated
can develop during or after anthracycline treatment and is estimated doxorubicin-­isotoxic dose equivalents15: (doxorubicin × 1) + (dau-
8
to occur in 20%–75% of survivors. Acutely, anthracyclines cause norubicin × 0.833) + (epirubicin × 0.67) + (idarubicin × 5) + (mi-
transient electrophysiological changes and mild changes in myocar- toxantrone × 4). Cutoffs for anthracycline cardiotoxicity are as
dial contractility, which may be reversible after treatment.9,10 Early-­ follows: doxorubicin >500 mg/m2 , liposomal doxorubicin >900 mg/
and late-­onset cardiotoxicity are defined by heart failure, pericardial m2 , epirubicin >720 mg/m2 , mitoxantrone >120 mg/m2 , and idaru-
9
effusions, or dilated cardiomyopathy. Children tend to present with bicin >90 mg/m2 . The meta-­analysis portion was used to increase
asymptomatic restrictive and dilated cardiomyopathy.10 population size for two measures of myocardial deformation, GLS
The current paradigm for detection of chemotherapy-­related and GCS, which have been shown to be feasible and reproducible
cardiotoxicity is symptomatology of congestive heart failure or >10% markers of myocardial injury16 in adult patients. A meta-­analysis
11
decline in echo-­derived left ventricular ejection fraction (LVEF). was performed to evaluate the consistency of the change in GLS
This practice has significant limitations because subclinical myo- and GCS after chemotherapy across the available studies in the
cardial damage often occurs in the presence of a stable LVEF. The literature. Studies included in the meta-­analysis were weighted
deterioration in LVEF is frequently only seen late when irreversible based on the inverse of the reported standard error (and therefore
damage has already occurred.12 Myocardial strain (or deformation) indirectly to the sample size). Studies with smaller standard error
imaging has been proposed as a more sensitive surrogate for assess- and larger sample size were given more weight in calculating the
ing myocardial function of cancer survivors. 2 pooled effect size. The heterogeneity among studies was deter-
Because large-­
scale studies to assess the natural history of mined using Cochran’s Q,17 which is based on chi-­s quare test with
anthracycline-­related cardiotoxicity in the CAYA group are lacking, significance defined as P < .10.18 Heterogeneity was also quanti-
we aim to systematically summarize the effect of anthracyclines on fied using I2.19 Low, moderate, and high degree of inconsistency
myocardial deformation in CAYA with cancer or survivors of child- corresponds to I2 values of 25%, 50%, and 75%, respectively. A
hood cancers classified by timing of echocardiographic evaluation. random-­effects model was chosen to assess for standard mean
difference (SMD) of global longitudinal strain (GLS) in two groups
(pre-­vs posttreatment and posttreatment vs normal controls) and
2 | M E TH O DS
global circumferential strain (GCS) in one group (posttreatment vs
normal controls).
2.1 | Data sources and searches
A literature search was performed based on recommendations from
2.3 | Myocardial deformation imaging parameters
the Preferred Reporting Items for Systematic Reviews and Meta-­
Analyses (PRISMA) guidelines for systematic reviews.13 Various Strain, defined as the percentage of change in myocardial wall length,
combinations of the following terms were searched using PubMed: was measured using tissue Doppler imaging (TDI), speckle tracking
strain (or deformation), torsion (or twist), children (or adolescent or echocardiography (STE) in both 2D and 3D, or velocity vector im-
young adult), cardiotoxicity (or dysfunction), and anthracyclines (or aging (VVI).16,20,21 Longitudinal (LS) and circumferential (CS) strain
doxorubicin). The time frame was limited to 2001–2016. The last describe active strain or shortening of the fibers while radial strain
date searched was April 25, 2016. For one article, unpublished data (RS) measures passive strain or thickening of the myocardium.16
were obtained directly from the author.14 Data were estimated from Global strain represents the average strain of the entire myocardium
figures if numerical values were not provided. for each respective direction,16 whereas segmental strain refers to
shortening or lengthening of a specific portion of the myocardium
based on the 16-­or 17-­segment model. 22 Strain rate (Sr) is the rate
2.2 | Data selection, abstraction,
of change in strain (reported as strain per second). Rotational me-
synthesis, and analysis
chanics represent myocardial rotation around the axis of the LV at
The studies were limited to those focusing on the effects of an- the base and apex.16 Twist is the absolute apex-­to-­base difference
thracyclines on myocardial strain in subjects between 1 and in rotation reported in degrees while torsion is the base-­to-­apex dif-
40 years of age, both during and after treatment. Two authors re- ference of the rotation angle divided by the axis of the LV and is
viewed the titles and abstracts for appropriateness. The articles reported in degrees per centimeter. Rotation and twisting velocity,
include observational, cross-­s ectional, and case–control studies. reported in degrees per second, are calculated by dividing by the
Studies of anthracycline exposure in CAYA were divided into three time-­in-­systole.16,23,24
TUZOVIC et al. | 3

F I G U R E 1 Preferred Reporting Items

for Systematic Reviews and Meta-­
Analyses (PRISMA) flow diagram53

3 | R E S U LT S reference ranges for strain25 (mean [95% CIs]): GLS (−20.2 [−20.8 to
−19.6]), global CS (GCS) (−22.3 [−24.6 to −19.9]), global RS (GRS) (45.2
The search returned 131 articles, 23 of which were included in this [38.8–51.7]). Levy et al25 further separated the strain values by age
review (Figure 1). Fourteen papers provided quantitative strain data (0–1, 2–9, 10–13, and 14–21 years of age), and age-­specific values
and were used for the meta-­analysis (Figures 2 and 3). Figure 2 illus- were used as reference when appropriate. For young adults older
trates the standardized mean difference (SMD) and 95% confidence than 21 years of age, adult strain reference values were applied26
intervals (CI) of GLS between patients pre-­and postanthracycline (mean [95% CIs]): GLS (−19.7 [−20.4 to −18.9]), GCS (−23.3 [−24.6 to
therapy. The pooled data in Figure 2 suggest that GLS is a suitable −22.1]), and GRS (46.3 [43.6–51.0]).
biomarker and can detect a change in myocardial function across
a wide spectrum of anthracycline dosages with good agreement
3.2 | Acute and early (<1 year posttreatment)
among the included studies. Figures 3 and 4 illustrate the SMD and
evaluation of strain
95% CI of GLS and GCS, respectively, in patients postanthracy-
cline therapy vs control subjects. Compared to the data in Figure 2, Seven studies27–33 investigated strain during or less than 1 year after
pooled data in Figures 3 and 4 show less agreement because of vari- anthracycline exposure (Table 1). All studies assessed strain at base-
ations in the average anthracycline doses, time-­to-­evaluation, and line and over the course of chemotherapy, 27–31,33 except Pignatelli
technique for strain quantification. et al32 who measured myocardial strain only posttreatment. Several
studies (3 of 7 studies) compared posttreatment patients to healthy
controls31,33 or reference values in healthy children.32 Ganame et al27
3.1 | Reference values for myocardial deformation
used TDI while 2DSTE was used in the other studies. The average
in CAYA
anthracycline dose in the seven studies was below conventional and
Differences in strain between groups are described as absolute established thresholds for high-­risk of cardiotoxicity (normalized to
changes in the strain magnitude with the convention that LS and CS doxorubicin, <500 mg/m2). One study evaluated the relationship be-
are negative and RS is positive. The following values were used as tween changes in strain with respect to patient age.32
4 | TUZOVIC et al.

F I G U R E 2 Standardized mean difference (SMD) and 95% confidence intervals of global longitudinal strain (GLS) between patients at
baseline (prior to anthracyclines) and patients within 1 y of anthracycline treatment. The size of the square marker is proportional to the
weight assigned to each study in the pooled estimate (diamond) using a random effects model. The weighing is related to the inverse of the
standard error (and therefore indirectly to the sample size) reported in the studies. Studies with smaller standard error and larger sample size
are given more weight in calculating the pooled effect size. SMD Total (fixed effects) = −0.714; SMD Total (random effects) = −0.788 (both
P < .001). Level II evidence. There was no statistically significant difference among the findings of the included 6 articles27–31,33 (X2 = 10.32,
P = .067), and the inconsistency among included articles was quantified as I2 = 51.56% (95% CI = 0–80.7). The reported decreases in GLS
after treatment based on the 6 included papers27–31,33 are moderately heterogeneous. Doses are reported as mean ± SD unless noted
otherwise. aaverage; bmedian

F I G U R E 3 Standardized mean difference (SMD) and 95% confidence intervals of global longitudinal strain (GLS) between normal controls
and patients treated with anthracyclines. The size of the square marker is proportional to the weight assigned to the study in the pooled
estimate (diamond) using a random effects model. The weighing is related with the inverse of the standard error (and therefore indirectly to
the sample size) reported in the studies. Studies with smaller standard error and larger sample size are given more weight in calculating the
pooled effect size. The results indicate that GLS is lower in anthracycline-­treated patients as compared to a normal, age-­matched population
(SMD Total [fixed effects] = −0.695; SMD Total [random effects] = −0.810 [both P < .001]; Level II evidence). There was a significant difference
among the findings of the included 9 articles20,21,24,29,31,33,44,46,49 (X2 = 44.06, P < .001), and the inconsistency among included articles was
quantified as I2 = 81.84% (95% CI =66.7–90.1). Doses are reported as mean ± SD unless noted otherwise. amedian; brange; caverage

Posttreatment GLS was 6.7%–20% lower compared to control val-

3.2.1 | Longitudinal strain
ues.31–33 All posttreatment GLS values fall outside the reference
The decrease in GLS during or immediately following treatment range25 except for the 1-­to 4-­year-­old and 10-­to 14-­year-­old groups
27,28,30,31,33
compared to baseline values ranged from 8.2% to 19%. in Pignatelli et al’s paper.32 The majority of segmental LS values were
TUZOVIC et al. | 5

F I G U R E 4 Standardized mean difference (SMD) and 95% confidence intervals of global circumference strain (GCS) between patients and
controls following anthracycline treatment. The size of the square marker is proportional to the weight assigned to the study in the pooled
estimate (diamond) using a random effects model. The weighing is related with the inverse of the standard error (and therefore indirectly to
the sample size) reported in the studies. Studies with smaller standard error and larger sample size are given more weight in calculating the
pooled effect size. The results indicate that GCS is lower in anthracycline-­treated patients as compared to a normal, age-­matched population
(SMD Total [fixed effects] = −1.013; SMD Total [random effects] = −1.010 [both P < .001]; Level II evidence). There was a significant
difference among the findings of the included 6 articles20,24,31,41,44,46 (X2 [5] = 40.01, P < .001), and the inconsistency among included
articles was quantified as I2 = 87.50% (95% CI = 75.2–93.7). Doses are reported as mean ± SD unless noted otherwise. arange. *mid-­papillary
level GCS was used for analysis from the study by Yu et al41

significantly decreased as well. The left-­ventricular (LV) basal LS de- different when compared to healthy controls in one of the stud-
creased by 14%27–16%,33 mid LS decreased by 11%27–12%,33 and ies.31 When compared to reference values, 25 the patients in Ganame
apical LS decreased by 11%. 28 Three papers27,28,31 showed signifi- et al’s27 study had markedly elevated baseline GRS (74 ± 14%) which
28 27
cant changes in GLS rate (GLSr) from 12% –18%, although most decreased after each of the 3 doses of anthracycline administration
posttreatment values remained within the reference range.34 Two (56 ± 11% to 52 ± 12% to 45 ± 11%).
studies29,30 showed that severity of LS abnormalities after chemo-
therapy varies based on the echocardiographic view; the most
3.3 | Evaluation of strain 1–10 years posttreatment
significant reduction was seen in the apical long-­axis view (40% de-
crease) with more modest changes in the apical four-chamber and Ten papers,14,20,21,24,36–41 nine of which were cross-­sectional stud-
apical two-chamber views (8.7%, and 13% decrease, respectively). ies,14,21,24,36–41 assessed changes in strain parameters 1–10 years
after anthracycline treatment in patients aged 6.9–24 years (Table 2).
All studies compared patients treated with anthracyclines to healthy
3.2.2 | Circumferential strain
controls except Ryerson et al.14 Patients were treated with average
All posttreatment values of GCS 31,32 were outside the reference or median doses of anthracyclines (normalized to doxorubicin) rang-
25
range, indicating that GCS in cancer survivors can deteriorate ing from 220 to 401.1 mg/m2. Strain was assessed in images cap-
31
as early as 1 year after treatment. Mavinkurve-­G roothuis et al tured by TDI,37,39 2D-­STE,14,24,36,38,41 3D-­STE,40 and VVI. 20,21
reported a 13% decrease in GCS and a 12% decrease in GCS rate
(GCSr) from baseline to posttreatment in patients. Pignatelli et al32
3.3.1 | Longitudinal strain
compared GCS values 1-­year posttreatment to normal reference
values 35 according to age (1–4, 5–9, 10–14, and 15–19 years of Eight articles14,20,21,24,37–39,41 assessed GLS following anthracycline
age). The reduction in GCS was greater with older age. administration and showed inconsistent findings. Four of the 8 stud-
ies20,24,37,39 found that anthracycline administration was associated
with a significant decrease in GLS. Moon et al20 and Cheung et al24
3.2.3 | Radial strain
reported similar findings where the GLS was on average 7.4% lower
Ganame et al27 and Mavinkurve-­Groothius et al31 compared base- in the patient group compared to controls. Yagci-­Kupeli et al39 did
line and posttreatment GRS, and GRS rate (GRSr) in patients; both not provide numerical data. Ganame et al37 graphically demonstrated
studies showed a significant reduction in GRS (39% and 17%, re- that, while there is a similar pattern of regional variation in the strain
spectively) and GRSr (19% and 12%, respectively) after anthracycline values from base to apex in the septum and lateral LV wall, the abso-
treatment. However, the posttreatment GRS was not significantly lute strain values are approximately 25% lower in patients compared
 6
|

TA B L E 1 Summary of studies evaluating patients during and <1 y following anthracycline therapy

Patient age Timing of measurements Anthracycline dose

Study (years) (years) (mg/m2) Cancer type Software Prechemotherapya Postchemotherapya Controlsa

Agha et al28 9.24 ± 4.14 Baseline and 1 wk after 60.67 ± 9.8 AML, ALL, EchoPAC, GE GLS: −21.58 ± 2.54 GLS: −19.18 ± 3.59 –
last dose HL, nHL
Al-­Biltagi et al29 9.2 ± 2.9 Baseline and within 1 wk 120 (median) ALL EchoPAC, GE GLS: −18.65 ± 4.52 GLS: −15.10 ± 2.45 GLS: −21.5 ± 2.2
after last dose
El-­Shitany et al30 9.5 ± 2.6 Baseline and within 1 wk 120 ALL EchoPAC, GE GLS: −18.65 ± 2.9 GLS: −15.1 ± 1.769 –
after last dose
Ganame et al27 10.7 ± 3.8 Baseline and within 2 h of 141.9 ± 56.57 LY, ALL, OS, Proprietary GLS: −27 ± 5 GLS: −23 ± 6 –
the first 3 doses ES, AML software GRS: 74 ± 14 GRS: 45 ± 11
Mavinkurve-­ 6 (2.2–15.4) Baseline, after induction, 120 mg/m2 after ALL EchoPAC 6.1, GE GLS: −18.2 ± 3.1 GLS: −16.7 ± 5.2 GLS: −20.9 ± 1.3c
Groothuis and 1-­y follow (>2 wk induction; at 1-­y GCS: −19.4 ± 4.3 GCS: −16.9 ± 3.1 GCS: −22.5 ± 2.1
et al31 after last dose) follow-­up; standard
risk = 120, medium GRS: 66.8 ± 12 GRS: 55.2 ± 16 GRS: 54.3 ± 6c
risk = 300, high
risk = 540
Poterucha et al33 15.3 ± 3 0, 4, and 8 mo of treatment 296 ± 103 OS, ES, HL, EchoPAC, GE GLS: −19.9 ± 2.1 GLS: −18.1 ± 2.8 GLS: −20.5 ± 1.5
BCL, RMS,
MPNST,
ALL
Pignatelli et al32,b 9.8 ± 5.8 1-­y follow-­up (>3 wk since 213.33 ± 124.4 ALL, AML, EchoPAC, GE – 1–4 y: 1–4 y:
last dose) NB, OS, ES GLS: −19.31 ± 5.48 GLS: −20.7 ± 1.30 c
GCS: −15.88 ± 3.86 GCS: erroneous value
5–9 y: 5–9 y:
GLS: −18.33 ± 4.02 GLS: −21 ± 1.30 c
GCS: −15.74 ± 2.08 GCS: −20.90 ± 2.00
10–14 y: 10–14 y:
GLS: −19.43 ± 1.4 GLS: −21.8 ± 1.30
GCS: −15.81 ± 1.77 GCS: −21.5 ± 1.70
15–19 y: 15–19 y:
GLS: −18.79 ± 1.4 GLS: −22.5 ± 1.30
GCS: −12.16 ± 2.09 GCS: −21.90 ± 2.10

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; BCL = B-­cell lymphoma; ES = Ewing sarcoma; HL = Hodgkin lymphoma; LY = lymphoma; MPNST = malignant peripheral nerve sheath
tumor; NB = neuroblastoma; nHL = non-­Hodgkin lymphoma; OS = osteosarcoma; RMS = rhabdomyosarcoma;
a
Units, strain (%).
b
Normal reference values were used as controls.
c
No significant difference between control group and patients.
TUZOVIC et al.
TA B L E 2 Summary of studies evaluating patients at 1–10 y following anthracycline therapy

Timing of Anthracycline
Study Patient age (years) ­measurement (years) dose (mg/m2) Cancer type Software Prechemotherapya Postchemotherapya Controlsa
TUZOVIC et al.

Park et al21 9.8 (6.1–17.5) – 90–342 ALL, AML, NB, Syngo US – GLS: −22.89 ± 2.47 GLS:
nHL, HL Workplace 3.0, −23.55 ± 4.19b
Acuson
Moon et al20 10.5 ± 4.7 3.9 ± 4.0 356 ± 106 AML, BL, ES, OS Syngo Velocity GLS: −19.26 ± 3.78 GLS: −18.27 ± 3.35 GLS: −19.74 ± 3.63
Vector GCS: −26.84 ± 5.61 GCS: −24.21 ± 3.74 GCS: −26.48 ± 4.0
Imaging,
Siemens
Ryerson et al14,c Low risk: 16 ± 2.89, Low risk: 8.0 ± 2.73, Low risk: LE, LY, SA, WT, EchoPAC, GE – Low risk: Low risk:
Moderate risk: Moderate risk: 119.6 ± 43.29, NB, Other GLS: −19.2 GLS: −14.26
14.5 ± 3.2, High 9.6 ± 3.43, High Moderate risk:
risk: 16.2 ± 3.64 risk: 8.3 ± 3.03 171 ± 40.01, Moderate risk: Moderate risk:
High risk: GLS: −17.4 GLS: −14.26
344 ± 62.27 High risk: High risk:
GLS: −15.4 GLS: −14.26
36
Cheung et al 15.6 ± 5.5 7.0 (3.1–24.3) 240 (120–470) ALL EchoPAC, GE – Twist: 8.0 ± 4.1 Twist: 11.8 ± 4.5
Twist velocity: Twist velocity:
68.1 ± 20.3 91.0 ± 22.3
Untwisting velocity: Untwisting
−90.1 ± 34.3 velocity:
−109.6 ± 33.4
Cheung et al24 15.3 ± 5.8 6.3 (2.7–19.8) 240 (120–470) ALL EchoPAC, GE – GLS: −17.6 ± 3.0 GLS: −19.0 ± 2.2
GCS: −14.5 ± 2.9 GCS: −17.4 ± 4.3
GRS: 40.1 ± 15.6 GRS: 50.0 ± 16.4
37
Ganame et al 12.7 (4–28) 5.2 (2.0–15.2) 240 (90–300) ALL, AML, LY, Proprietary – GLS: shown GLS: shown
solid tumors software graphically graphically
Toro-­Salazar 22 (12–42) 9.6 (2.5–26.9) 328 (200–600) AML, OS, HL, ES – – GLS: −18.5 ± 2.4 GLS: data not
et al38 provided
GCS: shown GCS: shown
graphically graphically
Yagci-­Kupeli 14 5.8 ± 3.6 350–480 nHL, HL, HB, EchoPAC, GE – No numerical data No numerical data
et al39 WT, LS, NB,
OS, NEDT, NC
Yu et al40,d 18.6 ± 5.1 7.2 (2.4–16.4) 229 (40–644) ALL, AML, OS, Advanced – Twist: 6.6 ± 2.5 Twist: 9.9 ± 3.2
BL, HL, nHL, Cardiology Torsion: 1.3 ± 0.5 Torsion: 1.9 ± 0.7
SS, NB, HB Package,
Toshiba
|

(Continues)
7
 8
|

TA B L E 2 (Continued)

Timing of Anthracycline
Study Patient age (years) ­measurement (years) dose (mg/m2) Cancer type Software Prechemotherapya Postchemotherapya Controlsa

Yu et al41,e 19.3 ± 5.4 6.9 (2.2–14.4) 220 (120–470) ALL, AML, OS, Advanced – Basal level: Basal level:
HL, nHL Cardiology GCS: 12.6 ± 5.0 GCS: 15.6 ± 3.2
Package,
Toshiba Mid-­papillary level: Mid-­papillary level:
GCS: 13.7 ± 1.9 GCS: 15.2 ± 2.7
GRS (inner): GRS (inner):
33.8 ± 4.2 39.7 ± 10.8
GRS (outer): GRS (outer):
23.0 ± 4.0 29.1 ± 6.3
Apical level: Apical level:
GCS: 13.9 ± 2.9 GCS: 15.9 ± 3.1
GRS (inner): GRS (inner):
25.7 ± 4.5 29.1 ± 7.7

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; BL = Burkitt lymphoma; ES = Ewing sarcoma; HB = hepatoblastoma; HL = Hodgkin lymphoma; LE = leukemia; LS = liver sarcoma;
LY = lymphoma; NB = neuroblastoma; NC = nasopharyngeal carcinoma; NEDT = neuroectodermal tumor; nHL = non-­Hodgkin lymphoma; OS = osteosarcoma; RMS = rhabdomyosarcoma; SA = sarcoma;
SS = synovial sarcoma WT = Wilms tumor.
a
Units, strain measurements (%), twist (°), torsion (°/cm), velocity (°/s).
b
No significant difference between control group and patients.
c
Comparison group consists of anthracycline naive cancer survivors.
d
3D measurements.
e
Absolute strain values provided.
TUZOVIC et al.
TUZOVIC et al. | 9

to the control group. In contrast to the studies mentioned above, Park segments of the papillary muscle level were significantly decreased
21
et al showed that GLS was not significantly different in patients com- in patients relative to control by 12%, 15%, 21% in the apical inner
pared to controls; however, patients did have significantly lower LS, layer, mid-­papillary inner level, mid-­papillary outer level, respec-
diastolic Sr, and systolic Sr in the septum when compared to the lateral tively. There was no significant difference in the basal segments or
LV wall. Toro-­Salazar et al38 showed slightly increased GLS in patients the transmural radial strain in patients compared to controls. In con-
vs controls; however, this trend was reversed with MRI-­derived strain trast, Cheung et al24 showed a decrease in GRS of 20% to just above
14
values. In contrast, Ryerson et al showed a nonsignificant improve- reference values in patients compared to controls. The radial strain
ment in GLS in patients who received low-­, moderate-­, or high-­dose difference was present in all segments of myocardium. Statistically
anthracyclines compared to controls (35% increase, 22% increase, and significant differences between patients and controls in both peak
8.0% increase, respectively), but GLS measurements were performed radial systolic Sr and strain in the inferolateral wall were also re-
only in the apical four-­chamber view. The study by Ryerson et al14 was ported (no numerical values provided).37
unique because the control group consisted of 21 anthracycline-­naive
cancer survivors, 15 of whom were overweight or obese which may
3.4.1 | Torsion and twist
account for the baseline lower strain values in the control group.42,43
Lastly, Yu et al41 found similar strain values between patients and con- Three papers examined twist, torsion (twist/LV length), and twisting/
trols; however, no numerical values were provided. untwisting rate.36,40,41 Yu et al40 examined twist and torsion using
Most of the studies also evaluated Sr and similarly found variable 3DSTE and found that both were reduced significantly compared to
14,20,24,37,39 37 39
results. Ganame et al and Yagci-­
Kupeli et al found the healthy cohort (33% and 32% decrease, respectively). Cheung
that GLSr was significantly lower in patients compared to controls et al36 examined peak apical and basal rotation, twisting, and un-
(data shown graphically in Ganame et al’s article, and not provided twisting rates, and LV torsion, systolic twisting velocity, and diastolic
by Yagci-­Kupeli et al). In contrast, Cheung et al24 and Ryerson et al14 untwisting velocity. Peak apical rotation and untwisting rate were
showed that changes in GLSr were similar between patients and significantly reduced (24% and 26% reduction, respectively), while
controls. Moon et al20 found diastolic LSr, but not systolic LSr, to be basal parameters showed no significant change between patients
significantly lower in patients (12% lower than controls). and controls. All three LV parameters in patients were significantly
reduced as compared to controls (peak torsion: 32% reduction, peak
systolic twisting velocity: 25% reduction, peak diastolic untwisting
3.3.2 | Circumferential strain
velocity: 18% reduction). Yu et al41 used 2DSTE to examine trans-
Of the four studies which examined CS, all showed consistently ab- mural rotation, twisting, and untwisting velocity at the base and
normal values in patients 1–10 years postchemotherapy. 20,24,38,41 apex. At the base, both the subendocardial and subepicardial rota-
41
Yu et al examined transmural strain at the basal, papillary mus- tion, twisting velocity, and untwisting velocity were significantly re-
cle, and apical levels. Patients displayed significantly lower trans- duced in patients; hence, there was no significant difference in the
mural CS gradients at all three levels compared to controls (19%, transmural gradient between patients and controls. However, at the
9.9%, and 13% lower at the basal, papillary muscle, and apical apex, only the subendocardial layer showed significant changes in
levels, respectively). Interestingly, the difference in CS between rotation, twisting velocity, and untwisting velocity, which led to a
groups was only observed in the endocardial portion, but not in significantly reduced transmural rotation gradient when compared
the epicardial portion. This finding was attributed to worsened to controls (41% reduction).
subendocardial function with preserved subepicardial function.
Cheung et al24 showed that patients had reduced segmental CS
3.5 | Evaluation of strain >10 years posttreatment
in the anteroseptal, inferoseptal, inferior, and anterior segments
as well as 17% reduction in GCS. Similar reductions in the anter- Six articles examined strain measurements greater than 10 years
oseptal and inferior segments as well as GCS were reported by after treatment44–49 (Table 3). Time of follow-­up ranged from 13.2
Toro-­S alazar et al38; however, no numerical values were provided. to 23.4 years on average. Most studies compared strain measure-
In regard to Sr, Cheung et al24 found that patients’ GCSr was sig- ments between patients treated with anthracyclines to normal con-
nificantly lower than controls by 15%. Moon et al20 similarly re- trols.44–46 One study49 compared patients to anthracycline naive
ported that, compared to controls, GCS was reduced in patients cancer survivors. Yu et al48 and Armstrong et al47 divided patients
by 8.6% while CSr was decreased by 8.8% for systolic CSr and 14% based on whether they received treatment with anthracyclines only
for diastolic CSr. The severity of these abnormalities correlated or anthracyclines and mediastinal radiotherapy (MSRT).
with increasing anthracycline doses.

3.5.1 | Longitudinal strain

3.4 | Radial strain
Cheung et al,44 Mavinkurve-­Groothuis et al,46 and Christiansen et al49
24,37,41 41
Radial strain was evaluated in three studies. In Yu et al’s all showed that GLS was significantly reduced in patients vs controls (be-
article, RS of the inner segment at the apex, and inner and outer tween 6.4% and ~7.6% decrease). Changes in strain rate were variable:
 10

TA B L E 3 Summary of studies evaluating patients at >10 y following anthracycline therapy

|

Patient age Timing of measurements Anthracycline dose

Study (years) (years) (mg/m2) Cancer type Software Post-­chemotherapya Controlsa

Cheung et al44 24.1 ± 4.2 15.3 ± 5.8 218 ± 98 ALL, AML EchoPAC, GE GLS: −16.0 ± 3.1 GLS: −17.1 ± 3.2
GCS: −14.3 ± 3.5 GCS: −16.6 ± 4.7
GRS: 32.9 ± 10.9 GRS: 42.3 ± 12.5
Dietz et al45 27 (18–50) 17 (5–30) 440 (300–645) OS, RMS, ES, SS, LY, WT QLAB quantification, Radial displacement: Radial displacement:
Phillips 5.61 ± 1.16 6.73 ± 1.52
Mavinkurve-­ 20 (5.6–37.4) 13.2 (5–29.2) 180 (50–600) ALL, AML, EP, ES, HB, EchoPAC, GE GLS: −19.8 ± 2.6 GLS: −21.2 ± 1.6
Groothuis et al46 HL, NC, NB, nHL, OS, GCS: −15.9 ± 6.7 GCS: −22.6 ± 2.1
RMS, WT
GRS: 49 ± 12 GRS: 57 ± 5
Yu et al48,b 31 (18–62) 15 (2–39) 300 (27–660) SA, HL, ALL, AML, nHL EchoPAC 12.0, GE Anthracycline alone: –
GLS: 19 (17–20)
GCS: 17.6 (16–19.7)
GRS: 42.0 (31.9–51.4)
Anthracycline and
radiation:
GLS: 18 (16–19.5)
GCS: 16.1 (14.5–19.7)
GRS: 42.1 (26.5–55.2)
47
Armstrong et al 31 (18–65) 22.6 (10.4–48.3) Median not given LE, ALL, AML, LY, nHL, EchoPAC, GE Anthracycline alone: –
(0–600) HL, CNS tumor, bone GLS: −19.3 ± 2.6
tumor, ES, OS, soft
tissue SA, RMS, GCS: −20.2 ± 5.0
nonrhabdo SA, GC, Anthracyclines and
melanoma, NB, RB, WT, radiation:
carcinoma, other GLS: −18.5 ± 2.8
GCS: −20.1 ± 5.0
Christiansen et al49,c 28.6 23.4 (7.4–40) Low dose: ALL EchoPAC 7, GE Low dose: Low dose:
(18.6–46.5) 120 (40–120), GLS: −18.1 ± 2.3 GLS: −19.7 ± 2.4
Mod-­high dose: 240
(173–485) Moderate dose: Moderate dose:
GLS: −18.3 ± 1.9 GLS: −19.7 ± 2.4

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; EP = ependymoma; ES = Ewing sarcoma; GC=germ cell tumor; HB = hepatoblastoma; HL = Hodgkin lymphoma; LE = leukemia; LY = lym-
phoma; NB = neuroblastoma; NC = nasopharyngeal carcinoma; nHL=non-­Hodgkin lymphoma; OS = osteosarcoma; RB = retinoblastoma; RMS = rhabdomyosarcoma; SA = sarcoma; SS = synovial sarcoma;
WT = Wilms tumor.
a
Units, strain measurements (%), radial displacement (mm).
b
Absolute strain values provided.
c
Comparison group consists of anthracycline naive cancer survivors.
TUZOVIC et al.
TUZOVIC et al. | 11

Cheung et al’s44 paper showed no significant change in systolic or dias- the normal range. In the 1–10 years posttreatment, circumferential
46
tolic Sr while Mavinkurve-­Groothuis et al’s showed a significant 13% strain and strain rate are the most consistently abnormal measure-
decrease in GLSr in patients. When comparing patients treated with ments, followed by radial strain measurements. Longitudinal strain
anthracyclines-­only to patients treated with anthracyclines and MSRT, measurements appear to be less reliable in this group, with some
Yu et al48 showed that patients with dual therapy had significantly papers even showing increased absolute strain in patients compared
lower GLS compared to those treated with mono-­therapy; however, to controls. Patients >10 years posttreatment continue to display
GLSr showed no change between the two groups. Armstrong et al47 significant reductions in circumferential strain that are greater than
presented that GLS was abnormal in 27% of anthracycline-­only treated longitudinal strain. Radial strain shows similar reductions in long-­
patients while LVEF was abnormal in only 4.3%. Abnormal GLS was as- term follow-­up.
2
sociated with any dose of MSRT and anthracycline dose >300 mg/m . Previous studies addressing anthracycline therapy and strain
have focused on the effects of anthracyclines in all age groups,50
which includes many breast cancer survivors who are treated with
3.5.2 | Circumferential strain
other cardiotoxic medications (such as trastuzumab) and often re-
Abnormal GCS was common in patients treated with anthracycline ceive mediastinal radiotherapy. In Thavendiranathan’s review,50 for
47 44
therapy alone (23%). Cheung et al and Mavinkurve-­Groothuis example, GLS was determined to be the most consistently affected
et al46 both showed significant reductions of GCS in patients measure during chemotherapy. In this article, where we focus on
compared to controls (14% and 30% decrease, respectively). Both childhood cancer survivors only, we showed that GLS is most consis-
Cheung’s and Mavinkurve-­
Groothius’ papers reported significant tent for acute monitoring, but becomes less consistent >1 year after
decreases in GCSr (11% and 19%, respectively). As with GLS, the therapy. Our meta-­analysis showed only moderate heterogeneity
mean value of GCS and GCSr in patients from Cheung et al’s44 article among the studies when GLS is assessed in the same patient pre-­
was lower than in Mavinkurve-­Groothuis et al’s46 article. Yu et al48 and posttherapy and within 1 year of treatment.
showed that the GCS is abnormal in all patients treated with anthra- Based of the available published data, it remains unclear which
cyclines (average GCS 17.3 [15.2–19.7]); however, unlike the change strain measurement is optimal for late follow-up in CAYA cancer
in GLS, there was no significant difference in the GCS with respect survivors. As mentioned above, GCS was abnormal more often
to radiation treatment. than GLS in patients who were >1 year posttreatment, and hence
may be an important measurement for long-­term follow-­up in
childhood cancer survivors. This is different from the adult liter-
3.5.3 | Radial strain
ature where GLS appears to be a more consistent marker across
Cheung et al44 and Mavinkurve-­Groothuis et al46 both showed signif- many pathologies including restrictive cardiomyopathy, coronary
icant reductions in GRS (22% and 14%, respectively), and GRSr (11% artery disease, and some valvular disease.16,51 We evaluated the
and 49%, respectively) as compared to controls. However, despite consistency of both GLS and GCS abnormalities across studies
the striking change, the GRS values in Mavinkurve-­Groothuis’s 46 in patients posttherapy compared to controls. While there was a
article remained in the normal range likely illustrating lack of stand- difference in the SMD when comparing GLS and GCS values in
45
ardization in measurements among software vendors. Dietz et al patients following treatment and a control cohort, there was high
substituted radial displacement for radial strain due to variability in heterogeneity among studies. The heterogeneity was likely due
strain measurements ultimately finding a significant reduction (17%) to different strain tracking methods and software algorithms, as
between patients and controls. Yu et al48 found minimal, nonsignifi- well as variable time-­to-­evaluation. Lack of standardization in the
cant changes in GRS when comparing anthracycline-­treated patients optimal views used for measuring strain may also explain some of
with and without MSRT; however, the majority of patients in both the observed variability in strain measurements between studies.
groups had GRS values below the reference range. 26 For example, strain data derived from two apical long-­a xis views
that are foreshortened may not be as accurate as those derived
from three apical long-­a xis views (two-chamber, three-chamber,
4 | CO N C LU S I O N four-chamber). In summary, while the findings from our meta-­
analysis are promising, they also suggest that additional studies
Despite a high degree of heterogeneity among studies using GLS and with larger sample sizes and standardized image acquisition will be
GCS to compare patients with normal controls, myocardial strain by helpful for demonstrating value when relating myocardial strain
echocardiography appears to be useful for intra-­individual evalu- changes to clinical outcomes.
ation of subclinical myocardial injury in childhood cancer patients There were limitations encountered in the included studies.
treated with anthracycline therapy. Based on a review of the current Although strain showed good inter-­and intra-­observer reliabil-
body of literature, we found that during and immediately (<1 year) ity, certain measurements did show increased variability and may
after treatment, the GLS, GCS, and strain rate all show significant partly be due to inconsistent techniques, vendor-­specific strain
changes. Radial strain is decreased compared to baseline; however, algorithms, or strain derivation (TDI vs speckle tracking). The
these changes are not necessarily different from controls or below American Society of Echocardiography, the European Association
12 | TUZOVIC et al.

of Cardiovascular Imaging, and industry partners have established cancer-treatment-and-survivorship-facts-and-figures-2016-2017.

a task force to identify sources of variability in strain measure- pdf. Accessed October 3, 2017.
7. Parry C, Kent EE, Mariotto AB, Alfano CM, Rowland JH. Cancer
ments in order to improve standardization. 52 The sample size of
survivors: a booming population. Cancer Epidemiol Biomarkers Prev.
the papers was modest and in some cases images were not analyz- 2011;20:1996–2005.
able due to poor image quality. Some papers did not include data 8. Yeung ST, Yoong C, Spink J, Galbraith A, Smith PJ. Functional myo-
or listed data as figures only. Ganame et al 27,37
and Yagci-­Kupeli cardial impairment in children treated with anthracyclines for can-
cer. Lancet. 1991;337:816–818.
et al39 papers used TDI, which led to generally increased strain
9. Curigliano G, Cardinale D, Suter T, et al. Cardiovascular toxicity in-
values in comparison with other articles. duced by chemotherapy, targeted agents and radiotherapy: ESMO
Strain is more sensitive to myocardial changes than traditional Clinical Practice Guidelines. Ann Oncol 2012;23:vii155–vii166.
echocardiographic measures (LVEF, LV fractional shortening) in both 10. Adams MJ, Lipshultz SE. Pathophysiology of anthracycline-­and
27–31 44–47,49 radiation-­associated cardiomyopathies: implications for screening
early and late-­term follow-­up. Although clinical guidelines
and prevention. Pediatr Blood Cancer. 2005;44:600–606.
recommend obtaining strain measurements in patients who are under-
11. National Cancer Institute. Cancer therapy evaluation program,
going treatment with anthracyclines in order to identify early myocar- common terminology criteria for adverse events version 4.0 (ctcae
dial dysfunction, it is unknown to what extent clinical laboratories are v4.0). 2010. https://ctep.cancer.gov/protocoldevelopment/elec-
equipped with technical training and stringent image acquisition pro- tronic_applications/ctc.htm#ctc_40. Accessed December 3, 2016.
12. Cardinale D, Colombo A, Lamantia G, et al. Anthracycline-­induced
tocols to ensure accurate and reproducible strain assessment. Further,
cardiomyopathy: clinical relevance and response to pharmacologic
clinically significant myocardial strain thresholds are needed for CAYA therapy. J Am Coll Cardiol. 2010;55:213–220.
survivors of childhood cancer, and how these thresholds relate to fu- 13. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for
ture development of cardiomyopathy require additional investigation. systematic review and meta-­analysis protocols (PRISMA-­P) 2015
statement. Syst Rev. 2015;4:1.
Understanding the natural history of myocardial deformation in CAYA
14. Ryerson AB, Border WL, Wasilewski-Masker K, et al. Assessing
survivors of childhood cancer is imperative for testing of preventive anthracycline-­treated childhood cancer survivors with advanced
strategies and treatments. stress echocardiography. Pediatr Blood Cancer. 2015;62:502–508.
15. Children’s Oncology Group. Long-term follow-up guidelines for sur-
vivors of childhood, adolescent and young adult cancers. Version
4.0. [Internet]. 2013. http://www.survivorshipguidelines.org.
AC K N OW L E D G M E N T S Accessed December 3, 2016.
16. Mor-Avi V, Lang RM, Badano LP, et al. Current and evolving echo-
The authors thank Dr. A. Blythe Ryerson for providing additional
cardiographic techniques for the quantitative evaluation of cardiac
strain data needed for the review and analysis (Ryerson AB, Border mechanics: ASE/EAE consensus statement on methodology and in-
WL, Wasilewski-­
Masker K, Goodman M, Meacham L, Austin H, dications endorsed by the Japanese Society of Echocardiography. J
Mertens AC. Assessing anthracycline‐treated childhood cancer sur- Am Soc Echocardiogr. 2011;24:277–313.
17. Cochran W. The combination of estimates from different experi-
vivors with advanced stress echocardiography. Pediatric Blood &
ments. Biometrics. 1954;10:101–129.
Cancer 62.3: 502–508 (2015). 18. Dickersin K, Berlin JA. Meta-­ analysis: state-­of-­
the-­
science.
Epidemiol Rev. 1992;14:154–176.
19. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring incon-
ORCID sistency in meta-­analyses. BMJ. 2003;327:557–560.
20. Moon TJ, Miyamoto SD, Younoszai AK, Landeck BF. Left ventricular
Kim-Lien Nguyen http://orcid.org/0000-0002-8854-2976 strain and strain rates are decreased in children with normal frac-
tional shortening after exposure to anthracycline chemotherapy.
Cardiol Young. 2014;24:854–865.
REFERENCES 21. Park JH, Kim YH, Hyun MC, Kim HS. Cardiac functional eval-
uation using vector velocity imaging after chemotherapy in-
1. Lipshultz SE, Cochran TR, Franco VI, Miller TL. Treatment-­related cluding anthracyclines in children with cancer. Korean Circ J.
cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol. 2009;39:352–358.
2013;10:697–710. 22. Geyer H, Caracciolo G, Abe H, et al. Assessment of myocardial
2. Bijnens B, Cikes M, Butakoff C, Sitges M, Crispi F. Myocardial mo- mechanics using speckle tracking echocardiography: fun-
tion and deformation: what does it tell us and how does it relate to damentals and clinical applications. J Am Soc Echocardiogr.
function? Fetal Diagn Ther. 2012;32:5–16. 2010;23:351–369.
3. Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, 23. Mele D, Rizzo P, Pollina AV, Fiorencis A, Ferrari R. Cancer therapy-­
pathogenesis and treatment. Curr Cardiol Rev. 2011;7:214–220. induced cardiotoxicity: role of ultrasound deformation imaging as
4. Di Marco A, Cassinelli G, Arcamone F. The discovery of daunorubi- an aid to early diagnosis. Ultrasound Med Biol. 2015;41:627–643.
cin. Cancer Treat Rep. 1981;65:3–8. 24. Cheung Y, Hong W, Chan GC, Wong SJ, Ha S. Left ventricular myo-
5. Reulen RC, Winter DL, Frobisher C, et al. Long-­ term cause-­ cardial deformation and mechanical dyssynchrony in children with
specific mortality among survivors of childhood cancer. JAMA. normal ventricular shortening fraction after anthracycline therapy.
2010;304:172–179. Heart. 2010;96:1137–1141.
6. American Cancer Society. Cancer treatment and survi- 25. Levy PT, Machefsky A, Sanchez AA, et al. Reference ranges of left
vorship facts and figures. [Internet]. 2016. https://www. ventricular strain measures by two-­dimensional speckle-­tracking
cancer.org/content/dam/cancer-org/research/cancer-facts-and-sta- echocardiography in children: a systematic review and meta-­
tistics/cancer-treatment-and-survivorship-facts-and-figures/ analysis. J Am Soc Echocardiogr. 2016;29:209–225.
TUZOVIC et al. | 13

26. Yingchoncharoen T, Agarwal S, Popović ZB, Marwick TH. Normal 42. Barbosa MM, Beleigoli AM, de Fatima Diniz M, Freire CV, Ribeiro
ranges of left ventricular strain: a meta-­ analysis. J Am Soc AL, Nunes MC. Strain imaging in morbid obesity: insights into sub-
Echocardiogr. 2013;26:185–191. clinical ventricular dysfunction. Clin Cardiol. 2011;34:288–293.
27. Ganame J, Claus P, Eyskens B, et al. Acute cardiac functional and 43. Kibar AE, Pac FA, Ece İ, et al. . Effect of obesity on left ven-
morphological changes after anthracycline infusions in children. Am tricular longitudinal myocardial strain by speckle tracking
J Cardiol. 2007;99:974–977. echocardiography in children and adolescents. Balkan Med J.
28. Agha H, Shalaby L, Attia W, Abdelmohsen G, Aziz OA, Rahman MY. 2015;32:56–63.
Early ventricular dysfunction after anthracycline chemotherapy in 44. Cheung YF, Yu W, Cheuk DK, et al. Plasma high sensitivity troponin
children. Pediatr Cardiol. 2016;37:537–544. T levels in adult survivors of childhood leukaemias: determinants
29. Al-Biltagi M, Abd Rab Elrasoul Tolba O, El-Shanshory MR, Abd El- and associations with cardiac function. PLoS ONE. 2013;8:e77063.
Aziz El-Shitany N, El-Sayed El-Hawary E. Strain echocardiography 45. Dietz AC, Sivanandam S, Konety S, et al. Evaluation of traditional
in early detection of doxorubicin-­induced left ventricular dysfunc- and novel measures of cardiac function to detect anthracycline-­
tion in children with acute lymphoblastic leukemia. ISRN Pediatr. induced cardiotoxicity in survivors of childhood cancer. J Cancer
2012;2012:870549. Surviv. 2014;8:183–189.
30. El-Shitany NA, Tolba OA, El-Shanshory MR, El-Hawary EE. 46. Mavinkurve-Groothuis AM, Groot-Loonen J, Marcus KA, et al.
Protective effect of carvedilol on adriamycin-­induced left ventric- Myocardial strain and strain rate in monitoring subclinical heart
ular dysfunction in children with acute lymphoblastic leukemia. J failure in asymptomatic long-­term survivors of childhood cancer.
Card Fail 2012;18:607–613. Ultrasound Med Biol. 2010;36:1783–1791.
31. Mavinkurve-Groothuis AM, Marcus KA, Pourier M, et al. Myocardial 47. Armstrong GT, Joshi VM, Ness KK, et al. Comprehensive echocar-
2D strain echocardiography and cardiac biomarkers in children diographic detection of treatment-­related cardiac dysfunction in
during and shortly after anthracycline therapy for acute lympho- adult survivors of childhood cancer: results from the St. Jude life-
blastic leukaemia (ALL): a prospective study. Eur Heart J Cardiovasc time cohort study. J Am Coll Cardiol. 2015;65:2511–2522.
Imaging. 2013;14:562–569. 48. Yu AF, Raikhelkar J, Zabor EC, et al. Two-­dimensional speckle track-
32. Pignatelli RH, Ghazi P, Reddy SCB, et al. Abnormal myocardial strain ing echocardiography detects subclinical left ventricular systolic
indices in children receiving anthracycline chemotherapy. Pediatr dysfunction among adult survivors of childhood, adolescent, and
Cardiol. 2015;36:1610–1616. young adult cancer. Biomed Res Int. 2016;2016:9363951.
33. Poterucha JT, Kutty S, Lindquist RK, Li L, Eidem BW. Changes in 49. Christiansen JR, Kanellopoulos A, Lund MB, et al. Impaired exercise
left ventricular longitudinal strain with anthracycline chemotherapy capacity and left ventricular function in long-­term adult survivors
in adolescents precede subsequent decreased left ventricular ejec- of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer.
tion fraction. J Am Soc Echocardiogr. 2012;25:733–740. 2015;62:1437–1443.
34. Jashari H, Rydberg A, Ibrahimi P, et al. Normal ranges of left ven- 50. Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick
tricular strain in children: a meta-­analysis. Cardiovasc Ultrasound. TH. Use of myocardial strain imaging by echocardiography for
2015;13:37. the early detection of cardiotoxicity in patients during and after
35. Marcus KA, Mavinkurve-Groothuis AM, Barends M, et al. Reference cancer chemotherapy: a systematic review. J Am Coll Cardiol.
values for myocardial two-­dimensional strain echocardiography in 2014;63:2751–2768.
a healthy pediatric and young adult cohort. J Am Soc Echocardiogr. 51. Smedsrud MK1, Pettersen E, Gjesdal O, et al. Detection of left
2011;24:625–636. ventricular dysfunction by global longitudinal systolic strain in
36. Cheung YF, Li SN, Chan GC, Wong SJ, Ha SY. Left ventricular patients with chronic aortic regurgitation. J Am Soc Echocardiogr.
twisting and untwisting motion in childhood cancer survivors. 2011;24:1253–1259.
Echocardiography. 2011;28:738–745. 52. Voigt JU, Pedrizzetti G, Lysyansky P, et al. Definitions for a com-
37. Ganame J, Claus P, Uyttebroeck A, et al. Myocardial dysfunction mon standard for 2D speckle tracking echocardiography: con-
late after low-­dose anthracycline treatment in asymptomatic pedi- sensus document of the EACVI/ASE/Industry Task Force to
atric patients. J Am Soc Echocardiogr. 2007;20:1351–1358. standardize deformation imaging. Eur Heart J Cardiovasc Imaging.
38. Toro-Salazar OH, Gillan E, O’Loughlin MT, et al. Occult cardiotoxic- 2015;16:1–11.
ity in childhood cancer survivors exposed to anthracycline therapy. 53. Moher D, Liberati A, Tetzlaff J, Altman DG, Prisma Group. Preferred
Circ Cardiovasc Imaging. 2013;6:873–880. reporting items for systematic reviews and meta-­ analyses: the
39. Yaǧci-Küpeli B, Varan A, Yorgun H, Kaya B, Büyükpamukçu M. PRISMA statement. PLoS Med. 2009;6:e1000097.
Tissue Doppler and myocardial deformation imaging to de-
tect myocardial dysfunction in pediatric cancer patients
treated with high doses of anthracyclines. Asia Pac J Clin Oncol.
How to cite this article: Tuzovic M, Wu PT, Kianmahd S,
2012;8:368–374.
40. Yu HK, Yu W, Cheuk DK, Wong SJ, Chan GC, Cheung YF. New three-­
Nguyen KL. Natural history of myocardial deformation in
dimensional speckle-­ tracking echocardiography identifies global children, adolescents, and young adults exposed to
impairment of left ventricular mechanics with a high sensitivity in anthracyclines: Systematic review and meta-­analysis.
childhood cancer survivors. J Am Soc Echocardiogr 2013;26:846–852. Echocardiography. 2018;00:1–13. https://doi.org/10.1111/
41. Yu W, Li S, Chan GC, Ha SY, Wong SJ, Cheung YF. Transmural strain
echo.13871
and rotation gradient in survivors of childhood cancers. Eur Heart J
Cardiovasc Imaging. 2013;14:175–182.