title: A multifaceted evaluation of imatinib-induced cardiotoxicity in the rat.
abstract: Cardiotoxicity was an unanticipated side effect elicited by the clinical use of imatinib (Imb). This toxicity has been examined in only a limited number of experimental studies. The present study sought, by a variety of approaches, to identify important characteristics of Imb-induced cardiac alterations. Male spontaneously hypertensive rats (SHRs) received oral doses of 10, 30, or 50 mg/kg Imb or water daily for 10 d. Cardiac lesions, detected at all doses, were characterized by cytoplasmic vacuolization and myofibrillar loss. In a second experiment, cardiac lesions were found in Sprague Dawley (SD) and SHR rats given 50 or 100 mg/kg Imb for 14 d. Mean cardiac lesion scores and serum levels of cardiac troponin I were higher in SHRs than in SD rats. Imb induced myocyte death by necrosis, autophagy, and apoptosis. Dose-related increases in cardiac expression were observed for several genes associated with endoplasmic reticulum stress response, protein folding, and vascular development and remodeling. Imb caused alterations in isolated myocytes (myofibrillar loss, highly disrupted and disorganized sarcomeric α-actinin, apoptosis, and increased lactate dehydrogenase release) at low concentrations (5 mM). The authors conclude that Imb exerts cardiotoxic effects that are manifest through a complex pattern of cellular alterations, the severity of which can be influenced by arterial blood pressure.
authors.affiliation: Food and Drug Administration, Division of Applied Pharmacology Research, Silver Spring, Maryland, USA. eugene.herman@fda.hhs.gov
authors.forename: Eugene H
authors.initials: EH
authors.lastname: Herman
authors.forename: Alan
authors.initials: A
authors.lastname: Knapton
authors.forename: Elliot
authors.initials: E
authors.lastname: Rosen
authors.forename: Karol
authors.initials: K
authors.lastname: Thompson
authors.forename: Barry
authors.initials: B
authors.lastname: Rosenzweig
authors.forename: Joel
authors.initials: J
authors.lastname: Estis
authors.forename: Sara
authors.initials: S
authors.lastname: Agee
authors.forename: Quynh-Anh
authors.initials: QA
authors.lastname: Lu
authors.forename: John A
authors.initials: JA
authors.lastname: Todd
authors.forename: Steven
authors.initials: S
authors.lastname: Lipshultz
authors.forename: Brian
authors.initials: B
authors.lastname: Hasinoff
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides; D054715:Cardiotoxins / Q000008:administration & dosage / Q000633:toxicity*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D000068877:Imatinib Mesylate; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008297:Male; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010084:Oxidation-Reduction / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000633:toxicity*; D011743:Pyrimidines / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011929:Razoxane; D012518:Sarcomeres / Q000187:drug effects; D014336:Troponin / Q000378:metabolism; D015430:Weight Gain
chemical_list: D001549:Benzamides; D054715:Cardiotoxins; D052119:Lysosomal-Associated Membrane Protein 2; D010879:Piperazines; D011743:Pyrimidines; D014336:Troponin; D011929:Razoxane; D000068877:Imatinib Mesylate