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. 2023 Aug 15;5(4):472-485.
doi: 10.1016/j.jaccao.2023.06.003. eCollection 2023 Aug.

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study

Remy Merkx  1 , Jan M Leerink  2 , E Lieke A M Feijen  3 , Esmée C de Baat  3 , Louise Bellersen  4 , Dorine Bresters  3 , Elvira C van Dalen  3 , Eline van Dulmen-den Broeder  5 , Margriet van der Heiden-van der Loo  6 , Marry M van den Heuvel-Eibrink  3   7   8 , Judith L Kok  3 , Marloes Louwerens  9 , Angela H E M Maas  4 , Sebastian J C M M Neggers  10 , Cécile M Ronckers  3   11 , Jop C Teepen  3 , Arco J Teske  12 , Wim J E Tissing  3   13 , Andrica C H de Vries  3   7 , Gert Weijers  1 , Chris L de Korte  1 , Jacqueline Loonen  14 , Annelies M C Mavinkurve-Groothuis  3 , Helena J H van der Pal  3 , Leontien C M Kremer  3   8   15 , Wouter E M Kok  2 , Livia Kapusta  16   17 ; Dutch LATER Study Group
Affiliations

Extensive Cardiac Function Analyses Using Contemporary Echocardiography in Childhood Cancer Survivors: A DCCSS LATER Study

Remy Merkx et al. JACC CardioOncol. .

Abstract

Background: Childhood cancer survivors (CCS) are at risk for cardiotoxicity.

Objectives: We sought to assess how cardiac dysfunction measurements in CCS overlap and are differentially influenced by risk factors.

Methods: This cross-sectional Dutch Childhood Cancer Survivor Study evaluated echocardiograms of 1,397 ≥5-year CCS and 277 siblings. Of CCS, n = 1,254 received cardiotoxic (anthracyclines/mitoxantrone/radiotherapy involving the heart region [RTheart]) and n = 143 received potentially cardiotoxic (cyclophosphamide, ifosfamide, or vincristine) therapy. We assessed demographic, treatment-related, and traditional cardiovascular risk factors for cardiac dysfunction using multivariable logistic regression.

Results: CCS were a median of 26.7 years after diagnosis; 49% were women. Abnormal left ventricular ejection fraction (LVEF) (defined as <52% in men, <54% in women) occurred most commonly in CCS treated with anthracyclines and RTheart combined (38%). Age/sex-specific abnormal global longitudinal strain (GLS) occurred most commonly in CCS treated with RTheart, either with (41%) or without (38%) anthracyclines. Of CCS with normal LVEF, 20.2% showed abnormal GLS. Diastolic dysfunction grade ≥II was rare. Abnormal LVEF was mainly associated with female sex, anthracycline dose, and only in women, RTheart dose. Abnormal GLS was associated with female sex, RTheart dose, diastolic blood pressure, and only in women, anthracycline dose. Cyclophosphamide, ifosfamide, and vincristine were not associated with LVEF or GLS. Compared with siblings, CCS showed higher risk of abnormal LVEF (OR: 2.9; 95% CI: 1.4-6.6) and GLS (OR: 2.1; 95% CI: 1.2-3.7), independent of (potentially) cardiotoxic treatment-related and cardiovascular risk factors.

Conclusions: Abnormal LVEF and GLS constitute complementary measures of systolic dysfunction among long-term CCS. Their diagnostic value may differ according to cardiotoxic exposures. Also, CCS have residual, unexplained risk of cardiac dysfunction. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors, a DCOG LATER study; NTR7481).

Keywords: cancer survivors; cardiotoxicity; child; echocardiography; global longitudinal strain; left ventricular dysfunction.

PubMed Disclaimer

Conflict of interest statement

This work was supported by grant CVON 2015-021 of the Dutch Heart Foundation and grant 171 DCOG LATER program of KiKa and ODAS. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Inclusion Flowchart An asterisk indicates the study arm closed early after exceeding the predefined limit. CCS = childhood cancer survivors; DCCSS = Dutch Childhood Cancer Survivor Study.
Figure 2
Figure 2
Bar Chart of Echocardiographic Abnormalities per Cardiotoxic Exposure Group Single and combined abnormalities are shown in separate bars, for all participants in an exposure group with a complete set of measurements. ANT = anthracyclines; GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; Mitox = mitoxantrone; RT = radiotherapy to the heart region.
Figure 3
Figure 3
Plots of Nonlinear Associations and Interaction Terms for Abnormal LVEF and/or GLS Plots depict nonlinear or interaction ORs for (any) abnormal LVEF (A), (any) GLS (B), and the combination of abnormal LVEF and GLS (C) in CCS in a multivariable logistic regression model. Shaded areas denote 95% CIs. Dots and whiskers indicate risk estimates for categorical risk factor variables and are plotted at the category median value of noncases. Abbreviations as in Figures 1 and 2.
Central Illustration
Central Illustration
The Dutch Childhood Cancer Survivor Study, Echocardiography Substudy The left panel shows prevalence of cardiac abnormalities in childhood cancer survivors compared with sibling control subjects; green arrows denote comparable prevalence, yellow arrows denote slightly elevated prevalence, and red arrows denote markedly elevated prevalence. The right panel shows the residual risk of cardiac abnormalities compared with siblings, after correction for demographics, cardiotoxic therapies, and cardiovascular risk factors. ANT = anthracyclines or mitoxantrone; CCS = childhood cancer survivors; CV = cardiovascular; DD = diastolic dysfunction; GLS = global longitudinal strain; LVEF = left ventricular ejection fraction; RT = radiotherapy to the heart region.
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