Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease

Abstract

Objectives: The goal of this study was to demonstrate that cardiac magnetic resonance could reveal anthracycline-induced early tissue remodeling and its relation to cardiac dysfunction and left ventricular (LV) atrophy.

Background: Serum biomarkers of cardiac dysfunction, although elevated after chemotherapy, lack specificity for the mechanism of myocardial tissue alterations.

Methods: A total of 27 women with breast cancer (mean age 51.8 ± 8.9 years, mean body mass index 26.9 ± 3.6 kg/m2), underwent cardiac magnetic resonance before and up to 3 times after anthracycline therapy. Cardiac magnetic resonance variables were LV ejection fraction, normalized T2-weighted signal intensity for myocardial edema, extracellular volume (ECV), LV cardiomyocyte mass, intracellular water lifetime (τic; a marker of cardiomyocyte size), and late gadolinium enhancement.

Results: At baseline, patients had a relatively low (10-year) Framingham cardiovascular event risk (median 5%), normal LV ejection fractions (mean 69.4 ± 3.6%), and normal LV mass index (51.4 ± 8.0 g/m2), a mean ECV of 0.32 ± 0.038, mean τic of 169 ± 69 ms, and no late gadolinium enhancement. At 351 to 700 days after anthracycline therapy (240 mg/m2), mean LV ejection fraction had declined by 12% to 58 ± 6% (p < 0.001) and mean LV mass index by 19 g/m2 to 36 ± 6 g/m2 (p < 0.001), and mean ECV had increased by 0.037 to 0.36 ± 0.04 (p = 0.004), while mean τic had decreased by 62 ms to 119 ± 54 ms (p = 0.004). Myocardial edema peaked at about 146 to 231 days (p < 0.001). LV mass index was associated with τic (β = 4.1 ± 1.5 g/m2 per 100-ms increase in τic, p = 0.007) but not with ECV. Cardiac troponin T (mean 4.6 ± 1.4 pg/ml at baseline) increased significantly after anthracycline treatment (p < 0.001). Total LV cardiomyocyte mass, estimated as: (1 - ECV) × LV mass, declined more rapidly after anthracycline therapy, with peak cardiac troponin T >10 pg/ml. There was no evidence for any significant interaction between 10-year cardiovascular event risk and the effect of anthracycline therapy.

Conclusions: A decrease in LV mass after anthracycline therapy may result from cardiomyocyte atrophy, demonstrating that mechanisms other than interstitial fibrosis and edema can raise ECV. The loss of LV cardiomyocyte mass increased with the degree of cardiomyocyte injury, assessed by peak cardiac troponin T after anthracycline treatment. (Doxorubicin-Associated Cardiac Remodeling Followed by CMR in Breast Cancer Patients; NCT03000036).

Keywords: T1 mapping techniques; anthracycline; cardiac troponin T; fibrosis; left ventricular remodeling; magnetic resonance imaging.

Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Study Timeline

Timeline for follow-up of patients who were consecutively enrolled if they had received breast cancer diagnoses and had planned adjuvant anthracycline therapy (4 cycles of 60 mg/m2). Clinical assessment and cardiac magnetic resonance (CMR) were performed before and up to 3 times serially after anthracycline treatment. Biomarker collection was performed at the time of each CMR examination and before each anthracycline administration during clinic visits 1, 2, and 3. DOX = doxorubicin.

FIGURE 2. Baseline and Post-Anthracycline Left Ventricular Ejection Fraction, Left Ventricular Mass Index, T2-Weighted, and Left Ventricular Mass-to-Volume Ratio

Left ventricular ejection fraction (LVEF) (A) and left ventricular (LV) mass index (B) were significantly lower in all 4 time intervals (quartiles for follow-up time) after anthracycline therapy (p < 0.0001 for A and B). (C) The T2-weighted signal intensity ratio (myocardium/serratus muscle) was significantly higher in the first (79 to 146 days), second (146 to 231 days), and third (231 to 350 days) quartiles of the follow-up time compared with baseline (p <0.001, p < 0.001, and p < 0.01, respectively). (D) LV mass-to-volume (end-diastole) after anthracycline therapy was less than its baseline level for all time periods shown (p < 0.005). The estimated changes for these cardiac magnetic resonance parameters relative to baseline, and their p values were obtained from linear mixed-effects models and are shown for significant changes above or below the boxes and whiskers. BSA = body surface area; DOX = doxorubicin; EDV = end-diastolic volume.

FIGURE 3. Baseline and Post-Anthracycline Extracellular Volume and Intracellular Lifetime of Water

Extracellular volume (ECV) increased (A) and the intracellular lifetime of water (τic) declined (B) after anthracycline. The p values in A and B are for the fixed effect of follow-up time period (in quartiles) versus baseline in linear mixed-effects models for ECV and τic respectively. (C, D) ECV and τic changed approximately linearly with time. The lines, pink-shaded 95th percentile prediction ranges, and p values in C and D were obtained from linear mixed-effects models for ECV and τic with time (continuous) as single fixed effect. DOX = doxorubicin.

FIGURE 4. Cardiac Troponin T, Left Ventricular Cardiomyocyte Mass, and Left Ventricular Ejection Fraction During the Study

(A) Cardiac troponin T (cTnT) changed significantly (p < 1.00 × 10−10) between the first baseline measurement to the end of the follow-up period, with cTnT peaking at approximately 120 days after anthracycline initiation (~50 days after last anthracycline infusion). The solid lines (pink for patients with Framingham 10-year risk for a cardiovascular disease event [FR] greater than the median and blue for patients with FR less than or equal to the median) represent the predictions from a generalized additive model (GAM) for cTnT with a cubic regression spline for time as a single predictor. The gray-shaded area around the pink and blue lines represents the 95th percentile range for the GAM prediction. (B) The loss of cardiomyocyte mass (CM) after anthracycline therapy was associated with the peak cTnT observed in each patient. The continuous pink and blue lines represent the predicted change of CM, corresponding to patients with peak cTnT >10 pg/ml and ≤10 pg/ml, respectively. The change with time was highly significant in both cases (p < 1.00 × 10−9). With peak cTnT >10 pg/ml (pink line), the loss of CM appears to be accelerated compared with the blue line over a time span of approximately 100 to 400 days after anthracycline initiation. (C) Systolic dysfunction, assessed by left ventricular ejection fraction (LVEF), declined after anthracycline therapy, with a relatively broad minimum for LVEF centered around 300 days post–anthracycline initiation and occurring after cTnT had peaked at about 120 days. The solid line represents the prediction from a GAM for LVEF versus time (p < 0.001), with the 95th percentile range shown in light gray. Peak cTnT had no significant effect on LVEF in (C).

FIGURE 5. Baseline Cardiomyocyte Size and Left Ventricular Systolic Dysfunction Post-Anthracycline

There was a significant decline in left ventricular ejection fraction (LVEF) in both subgroups after anthracyclines (p ≤ 0.001). Patients with intracellular lifetime of water (τic) greater than the median at baseline showed a further 9.3 ± 3.6% decline in LVEF at 231 to 350 days (p = 0.013) and of 8.5 ± 3.5% at 350 to 700 days (p = 0.019) compared with patients with τic at baseline less than or equal to the median. The p values are for coefficient estimates in linear mixed-effects model for LVEF with cardiomyocyte size greater than the median, follow-up time period, and their interaction as predictors. LV = left ventricular.