title: Myocardial steatosis and necrosis in atria and ventricles of rats given pyruvate dehydrogenase kinase inhibitors.
abstract: Pharmaceutical therapies for non-insulin-dependent diabetes mellitus (NIDDM) include plasma glucose lowering by enhancing glucose utilization. The mitochondrial pyruvate dehydrogenase (PDH) complex is important in controlling the balance between glucose and fatty acid substrate oxidation. Administration of pyruvate dehydrogenase kinase inhibitors (PDHKIs) to rats effectively lowers plasma glucose but results in myocardial steatosis that in some instances is associated primarily with atrial and to a lesser degree with ventricular pathology. Induction of myocardial steatosis is not dose-dependent, varies from minimal to moderate severity, and is either of multifocal or diffuse distribution. Ventricular histopathology was restricted to few myocardial degenerative fibers, while that in the atrium/atria was of either acute or chronic appearance with the former showing myocardial degeneration/necrosis, acute myocarditis, edema, endothelial activation (rounding up), endocarditis, and thrombosis associated with moderate myocardial steatosis and the latter with myocardial loss, replacement fibrosis, and no apparent or minimal association with steatosis. The evidence from these evaluations indicate that excessive intramyocardial accumulation of lipid may be either primarily adverse or represents an indicator of other adversely affected cellular processes.
authors.affiliation: Pathological Sciences, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK huw.jones@astrazeneca.com.
authors.forename: Huw Bowen
authors.initials: HB
authors.lastname: Jones
authors.affiliation: Pathological Sciences, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
authors.forename: Jaimini
authors.initials: J
authors.lastname: Reens
authors.affiliation: Pathological Sciences, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Johnson
authors.affiliation: Pathological Sciences, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Brocklehurst
authors.affiliation: General Toxicology Department, Global Safety Assessment, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Slater
mesh_terms: D000577:Amides / Q000633:toxicity; D000813:Anilides / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects* / Q000473:pathology; D006331:Heart Diseases / Q000139:chemically induced*; D006352:Heart Ventricles / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology; D009336:Necrosis / Q000139:chemically induced* / Q000473:pathology; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D018675:Toxicity Tests
chemical_list: C523124:AZD 7545; D000577:Amides; D000813:Anilides; D004791:Enzyme Inhibitors; D011768:Pyruvate Dehydrogenase Complex
keywords: heart; myocardial steatosis; myocardium; pyruvate dehydrogenase kinase inhibitor.; steatosis