Sorafenib cardiotoxicity increases mortality after myocardial infarction.
BACKGROUND
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.


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.
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Jason M
JM
Duran
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Catherine A
CA
Makarewich
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Danielle
D
Trappanese
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Polina
P
Gross
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Sharmeen
S
Husain
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Jonathan
J
Dunn
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
Hind
H
Lal
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Thomas E
TE
Sharp
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Timothy
T
Starosta
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
Ronald J
RJ
Vagnozzi
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Remus M
RM
Berretta
Department of Anatomy and Cell Biology, Temple University School of Medicine, Philadelphia, PA.
Mary
M
Barbe
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
Daohai
D
Yu
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
Erhe
E
Gao
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Hajime
H
Kubo
Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA.
Thomas
T
Force
Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA.
Steven R
SR
Houser
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002415:Cats; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects / Q000378:metabolism; D000077157:Sorafenib
D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019009:Proto-Oncogene Proteins c-kit; D008790:Metoprolol
cell death; metoprolol; myocardial infarction; sorafenib; stem cells