ESC Heart Failure (Apr 2021)

Doxorubicin‐induced and trastuzumab‐induced cardiotoxicity in mice is not prevented by metoprolol

  • Martin Nicol,
  • Malha Sadoune,
  • Evelyne Polidano,
  • Jean Marie Launay,
  • Jane Lise Samuel,
  • Feriel Azibani,
  • Alain Cohen‐Solal

DOI
https://doi.org/10.1002/ehf2.13198
Journal volume & issue
Vol. 8, no. 2
pp. 928 – 937

Abstract

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Abstract Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio‐protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast‐treated mice exhibited a 13‐points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six‐fold increase for Dox + Trast‐treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm2 vs. 1.36 ± 0.10 μm2 for control mice, P < 0.001). In addition, Dox + Trast‐treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine‐marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi‐quantitative fibrosis score was three‐fold higher for Dox + Trast‐treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

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