Impaired Cardiac and Skeletal Muscle Energetics Following Anthracycline Therapy for Breast Cancer

Abstract

Background: Anthracycline-related cardiac toxicity is a recognized consequence of cancer therapies. We assess resting cardiac and skeletal muscle energetics and myocyte, sarcomere, and mitochondrial integrity in patients with breast cancer receiving epirubicin.

Methods: In a prospective, mechanistic, observational, longitudinal study, we investigated chemotherapy-naive patients with breast cancer receiving epirubicin versus sex- and age-matched healthy controls. Resting energetic status of cardiac and skeletal muscle (phosphocreatine/gamma ATP and inorganic phosphate [Pi]/phosphocreatine, respectively) was assessed with ³¹P-magnetic resonance spectroscopy. Cardiac function and tissue characterization (magnetic resonance imaging and 2D-echocardiography), cardiac biomarkers (serum NT-pro-BNP and high-sensitivity troponin I), and structural assessments of skeletal muscle biopsies were obtained. All study assessments were performed before and after chemotherapy.

Results: Twenty-five female patients with breast cancer (median age, 53 years) received a mean epirubicin dose of 304 mg/m², and 25 age/sex-matched controls were recruited. Despite comparable baseline cardiac and skeletal muscle energetics with the healthy controls, after chemotherapy, patients with breast cancer showed a reduction in cardiac phosphocreatine/gamma ATP ratio (2.0±0.7 versus 1.1±0.5; P=0.001) and an increase in skeletal muscle Pi/phosphocreatine ratio (0.1±0.1 versus 0.2±0.1; P=0.022). This occurred in the context of increases in left ventricular end-systolic and end-diastolic volumes (P=0.009 and P=0.008, respectively), T1 and T2 mapping (P=0.001 and P=0.028, respectively) but with preserved left ventricular ejection fraction, mass and global longitudinal strain, and no change in cardiac biomarkers. There was preservation of the mitochondrial copy number in skeletal muscle biopsies but a significant increase in areas of skeletal muscle degradation (P=0.001) in patients with breast cancer following chemotherapy. Patients with breast cancer demonstrated a reduction in skeletal muscle sarcomere number from the prechemotherapy stage compared with healthy controls (P=0.013).

Conclusions: Contemporary doses of epirubicin for breast cancer treatment result in a significant reduction of cardiac and skeletal muscle high-energy ³¹P-metabolism alongside structural skeletal muscle changes.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT04467411.

Keywords: anthracycline; breast cancer; cardiac energetics; chemotherapy; skeletal muscle.

Figure 1.

³¹P-magnetic resonance spectroscopy for cardiac and skeletal muscle energetics. Data shown as box plots/error bars and superimposed individual, paired data points with mean line, box for SDs and error bars for minimum and maximum. A, Corrected phosphocreatine (PCr)/gamma ATP (γATP) in the myocardium and (B) inorganic phosphate (Pi)/PCr in the skeletal muscle, for healthy controls and patients with breast cancer before chemotherapy and after chemotherapy. Below are example spectra showing PCr, γ, β, and α ATP, and 2,3-diphosphoglycerate (2,3 DPG) peaks in healthy volunteers (C) and in paired patients with breast cancer before (D) and after (E) chemotherapy; Pi, PCr and γ, β, and α ATP peaks in healthy volunteers (F) and in paired patients with breast cancer before (G) and after (H) chemotherapy.

Figure 2.

Transmission electron microscopy of skeletal muscle showing demarcated (green contours) areas of degradation. Examples from (A) healthy volunteers, (B) patients with breast cancer at baseline, and (C) patients with breast cancer following anthracycline chemotherapy.

Figure 3.

Confocal laser scanning microscopy analysis of skeletal muscle. Immunofluorescence staining was done against TTN-Z (titin; red) and ACTN2 (alpha-actinin-2; green) epitopes and merged (Z-disc); examples from (A) healthy volunteers, (B) patients with breast cancer at baseline, and (C) patients with breast cancer following anthracycline chemotherapy.