title: Serum cardiac troponin I concentrations transiently increase in rats given rosiglitazone.
abstract: Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist of the thiazolidinedione class, is a major insulin-sensitizing drug widely used to treat type-2 diabetes. Rosiglitazone causes myocardial hypertrophy in rodents and increases the risk of cardiac events in man. To better characterize its cardiac effects, male Wistar rats were orally administered 0, 10 or 80 mg/kg/day rosiglitazone. Myocardial gene expression profiling, hematology, histopathology and clinical chemistry, including measurement of serum cardiac troponin (cTn) I concentration with the ultrasensitive assay, were evaluated after 6 and 24h and 7 and 14 days of dosing. Heart weight was increased 10% after 7 days and 16% after 14 days of dosing at 80 mg/kg/day in the absence of microscopic changes. At the transcriptomic level, the number of differentially expressed probes was small: it was most at 24h in rats given 80 mg/kg rosiglitazone with 356 differentially regulated probes (fold change >1.3 fold, p<0.05). Also, gene categories typically associated with myocardial damage were not over-represented. Most importantly, serum cTnI concentrations in 5/9 rats after 7 days of dosing at 80 mg/kg/day were above the upper limit of serum cTnI concentration. cTnI concentrations after 14 days of dosing were similar between rats given the vehicle and rosiglitazone at 80 mg/kg. This is the first study to detect increases of serum cTnI concentrations in rats administered rosiglitazone. In light of reported cardiac events in patients chronically dosed with PPARγ agonists, our results support serum cTnI concentrations as an early biomarker of cardiac liability.
authors.affiliation: Non-Clinical Safety, Hoffmann-La Roche, Inc., Nutley, NJ 07110, USA. igor.mikaelian@roche.com
authors.forename: I
authors.initials: I
authors.lastname: Mikaelian
authors.forename: A
authors.initials: A
authors.lastname: Buness
authors.forename: G
authors.initials: G
authors.lastname: Hirkaler
authors.forename: R
authors.initials: R
authors.lastname: Fernandes
authors.forename: D
authors.initials: D
authors.lastname: Coluccio
authors.forename: W
authors.initials: W
authors.lastname: Geng
authors.forename: T
authors.initials: T
authors.lastname: Visalli
authors.forename: M O
authors.initials: MO
authors.lastname: Bachynsky
authors.forename: W
authors.initials: W
authors.lastname: Berkofsky-Fessler
authors.forename: C
authors.initials: C
authors.lastname: Kanwal
authors.forename: H
authors.initials: H
authors.lastname: Hilton
authors.forename: R
authors.initials: R
authors.lastname: Nicklaus
authors.forename: J-C
authors.initials: JC
authors.lastname: Hoflack
authors.forename: M
authors.initials: M
authors.lastname: Dunn
authors.forename: M
authors.initials: M
authors.lastname: Sanders
authors.forename: M
authors.initials: M
authors.lastname: Giron
authors.forename: B W
authors.initials: BW
authors.lastname: Boyle
authors.forename: T
authors.initials: T
authors.lastname: Singer
authors.forename: L Suter
authors.initials: LS
authors.lastname: Dick
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D017208:Rats, Wistar; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000633:toxicity*; D019210:Troponin I / Q000097:blood*
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D019210:Troponin I; D000077154:Rosiglitazone