Natural history of myocardial deformation in children, adolescents, and young adults exposed to anthracyclines: Systematic review and meta-analysis

Abstract

Objective: Anthracyclines are widely used to treat solid and hematologic malignancies, but are known to cause cardiotoxicity. As more childhood cancer survivors reach adulthood due to improvements in oncologic treatments, they become susceptible to late and progressive anthracycline-induced cardiotoxicity. Nonetheless, diagnostic 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 history of the changes in myocardial deformation in CAYA patients after anthracycline therapy.

Methods: We performed a literature review search between 2001 and 2016 using PubMed with the following search terms: strain (or deformation), torsion (or twist), children (or adolescent or young adult), cardiotoxicity (or dysfunction), and anthracyclines (or doxorubicin). A total of 23 articles were reviewed. Fourteen articles were incorporated in the meta-analysis.

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 significant and consistent on long-term follow-up. Although global radial strain and torsional 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 anthracycline therapy acutely and late after treatment. The prognostic value of these strain abnormalities warrants further investigation.

Keywords: cardiac toxicity; myocardial strain; transthoracic echocardiography.

Figure 1.. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram [53]

Figure 2.. Standardized mean difference (SMD) and 95% confidence intervals of global longitudinal strain (GLS) between patients at baseline (prior to anthracyclines) and patients within one year 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<0.001). Level II evidence. There was no statistically significant difference among the findings of the included 6 articles [–31,33] (X² (5)=10.32, p=0.067), 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 papers [–31,33] are moderately heterogeneous. Doses are reported as mean ± SD unless noted otherwise. ^aaverage; ^bmedian.

Figure 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<0.001); Level II evidence). There was a significant difference among the findings of the included 9 articles [20,21,24,29,31,33,44,46,49] (X² (8)=44.06, p<0.001), 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.

Figure 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<0.001); Level II evidence). There was a significant difference among the findings of the included 6 articles [20,24,31,41,44,46] (X² (5)=40.01, p<0.001), 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 al[41].