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Sorafenib Cardiotoxicity Increases Mortality after Myocardial Infarction
- Publication Year :
- 2014
-
Abstract
- Rationale: Sorafenib is an effective treatment for renal cell carcinoma, but recent clinical reports have documented its cardiotoxicity through an unknown mechanism. Objective: Determining the mechanism of sorafenib-mediated cardiotoxicity. Methods and Results: Mice treated with sorafenib or vehicle for 3 weeks underwent induced myocardial infarction (MI) after 1 week of treatment. Sorafenib markedly decreased 2-week survival relative to vehicle-treated controls, but echocardiography at 1 and 2 weeks post MI detected no differences in cardiac function. Sorafenib-treated hearts had significantly smaller diastolic and systolic volumes and reduced heart weights. High doses of sorafenib induced necrotic death of isolated myocytes in vitro, but lower doses did not induce myocyte death or affect inotropy. Histological analysis documented increased myocyte cross-sectional area despite smaller heart sizes after sorafenib treatment, further suggesting myocyte loss. Sorafenib caused apoptotic cell death of cardiac- and bone-derived c-kit+ stem cells in vitro and decreased the number of BrdU+ (5-bromo-2’-deoxyuridine+) myocytes detected at the infarct border zone in fixed tissues. Sorafenib had no effect on infarct size, fibrosis, or post-MI neovascularization. When sorafenib-treated animals received metoprolol treatment post MI, the sorafenib-induced increase in post-MI mortality was eliminated, cardiac function was improved, and myocyte loss was ameliorated. Conclusions: Sorafenib cardiotoxicity results from myocyte necrosis rather than from any direct effect on myocyte function. Surviving myocytes undergo pathological hypertrophy. Inhibition of c-kit+ stem cell proliferation by inducing apoptosis exacerbates damage by decreasing endogenous cardiac repair. In the setting of MI, which also causes large-scale cell loss, sorafenib cardiotoxicity dramatically increases mortality.
- Subjects :
- Sorafenib
Cardiac function curve
Male
Niacinamide
Physiology
Myocardial Infarction
Antineoplastic Agents
Apoptosis
Pharmacology
In Vitro Techniques
Article
Muscle hypertrophy
Mice
Fibrosis
medicine
Myocyte
Animals
Myocytes, Cardiac
Myocardial infarction
Cells, Cultured
Metoprolol
Cell Proliferation
Cardiotoxicity
Dose-Response Relationship, Drug
business.industry
Phenylurea Compounds
Heart
medicine.disease
Mice, Inbred C57BL
Disease Models, Animal
Proto-Oncogene Proteins c-kit
Cats
Cardiology and Cardiovascular Medicine
business
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c4cb26caf04e0a3b66338b56cb9a07f2