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

Autor: Jane Lise Samuel, Evelyne Polidano, Martin Nicol, Alain Cohen-Solal, Feriel Azibani, Jean-Marie Launay, Malha Sadoune
Přispěvatelé: Marqueurs cardiovasculaires en situation de stress (MASCOT (UMR_S_942 / U942)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), leboeuf, Christophe
Rok vydání: 2021
Předmět:
Male
Cardiac function curve
lcsh:Diseases of the circulatory (Cardiovascular) system
medicine.medical_specialty
Necrosis
Cardiac fibrosis
030204 cardiovascular system & hematology
Ventricular Function
Left
Mice
03 medical and health sciences
0302 clinical medicine
Atrophy
[SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Original Research Articles
Internal medicine
medicine
Animals
Original Research Article
030212 general & internal medicine
Metoprolol
Cardiotoxicity
Ejection fraction
business.industry
Stroke Volume
Cardiac atrophy
Trastuzumab
medicine.disease
[SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system
Mice
Inbred C57BL
Endocrinology
lcsh:RC666-701
Doxorubicin
Heart failure
medicine.symptom
Cardiology and Cardiovascular Medicine
business
medicine.drug
Zdroj: ESC Heart Failure
ESC Heart Failure, Vol 8, Iss 2, Pp 928-937 (2021)
ESC Heart Failure, 2021, 8 (2), pp.928-937. ⟨10.1002/ehf2.13198⟩
ISSN: 2055-5822
DOI: 10.1002/ehf2.13198
Popis: International audience; 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 μm 2 vs. 1.36 ± 0.10 μm 2 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 threefold 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.
Databáze: OpenAIRE
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