Longitudinal Changes in Echocardiographic Parameters of Cardiac Function in Pediatric Cancer Survivors

Abstract

Background: Childhood cancer survivors undergo serial echocardiograms to screen for cardiotoxicity. It is not clear whether small longitudinal changes in functional or structural parameters over time have clinical significance.

Objectives: To assess the timing of changes in serial echocardiographic parameters in pediatric age childhood cancer survivors and to evaluate their associations with cardiomyopathy development.

Methods: We performed a multi-center retrospective case-control study of ≥1-year survivors following the end of cancer therapy. Cardiomyopathy cases (fractional shortening (FS) ≤28% or ejection fraction (EF) ≤50% on ≥2 occasions) were matched to controls (FS ≥30%, EF ≥55%, not on cardiac medications) by cumulative anthracycline and chest radiation dose, follow-up duration, and age at diagnosis. Digitally archived clinical surveillance echocardiograms were quantified in a central core lab, blinded to patient characteristics. Using mixed models with interaction terms between time and case status, we estimated the least square mean differences of 2D, M-mode, pulsed wave Doppler and tissue Doppler imaging derived parameters across time between cases and controls.

Results: We identified 50 matched case-control pairs from 5 centers. Analysis of 412 echocardiograms (cases, n=181; controls, n=231) determined that indices of LV systolic function (FS, biplane EF), diastolic function (mitral E/A ratio), and LV size (end diastolic dimension z-scores) were significantly different between cases and controls, even four years prior to the development of cardiomyopathy.

Conclusions: Longitudinal changes in cardiac functional parameters can occur relatively early in pediatric age childhood cancer survivors and are associated with the development of cardiomyopathy.

Keywords: Cancer Survivorship; Cardiomyopathy; Echocardiography.

Graphical abstract

Figure 1

Least Square Means for Echocardiographic Functional Parameters Across Time Periods Prior to Cardiomyopathy Mean estimates (red open circles = cases; black filled circles = control subjects) with 95% confidence intervals (red bars = cases; black bars = control subjects) for categorical time periods prior to cardiomyopathy diagnosis (or index time for control subjects; denoted as time “0”) of (A) left ventricular fractional shortening (LVFS), (B) biplane Simpson’s derived ejection fraction (EF), (C) pulsed wave Doppler mitral E/A ratio, (D) pulsed wave Doppler-derived myocardial performance index (MPI), (E) left ventricular end-diastolic dimension (LVEDD), and (F) left ventricular wall thickness to dimension ratio. Shaded areas represent the same time period included in each category, with estimates and bars placed on the x-axis at the median time within the given period.

Central Illustration

Longitudinal Changes in Echocardiographic Functional Parameters Excluding Data From the 2 Years Prior to Cardiomyopathy Fitted line plots up to 2 years prior to cardiomyopathy, with 95% confidence intervals of (A) left ventricular (LV) fractional shortening, (B) biplane Simpson’s derived ejection fraction, (C) pulsed wave Doppler mitral E/A ratio, (D) pulsed wave Doppler-derived myocardial performance index, (E) LV end-diastolic dimension, and (F) left ventricular wall thickness to dimension ratio. Cardiomyopathy cases denoted by red line and controls denoted by the blue line, both based on a linear model. Time “0” denotes time point when cardiomyopathy was diagnosed.