title: Deleterious effects of acute treatment with a peroxisome proliferator-activated receptor-gamma activator in myocardial ischemia and reperfusion in pigs.
abstract: Thiazolidinediones exert electrophysiologic effects in noncardiac cells in vitro, but to date there have been no reports of effects on cardiac rhythm. We previously demonstrated that chronic pretreatment with a thiazolidinedione peroxisome proliferator-activated receptor (PPAR)-gamma activator, troglitazone, improves recovery of left ventricular (LV) function and substrate metabolism after ischemia and reperfusion, without causing arrhythmias. In this study, we determined whether similar salutary effects are achieved with acute treatment with troglitazone. Anesthetized pigs underwent 90 min of regional LV ischemia and 90 min of reperfusion. Fifteen pigs were treated with troglitazone (10 mg/kg load, 5 mg. kg(-1). h(-1) infusion i.v.) beginning 1 h before ischemia. Seven pigs received corresponding vehicle. Plasma troglitazone concentration (mean 5 microg/ml) was similar to that achieved in clinical use of this agent. Before ischemia, acute troglitazone treatment had no effect on LV function, electrocardiogram, or substrate utilization. During ischemia or reperfusion, eight pigs in the troglitazone group died of ventricular fibrillation, compared with no pigs in the vehicle group (P < 0.05). Pigs that developed ventricular fibrillation had shorter QT intervals than survivors of either group. Among survivors, neither LV function nor substrate utilization differed between groups. Acute treatment with troglitazone increases susceptibility to ventricular fibrillation during myocardial ischemia and reperfusion. Whether thiazolidinediones have proarrhythmic potential in clinical use requires further investigation.
authors.affiliation: VA Medical Center and University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Ya
authors.initials: Y
authors.lastname: Xu
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Clifford
authors.initials: C
authors.lastname: Greyson
authors.forename: Jenny
authors.initials: J
authors.lastname: Lee
authors.forename: Michael
authors.initials: M
authors.lastname: Gen
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kinugawa
authors.forename: Carlin S
authors.initials: CS
authors.lastname: Long
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000517:prevention & control; D001794:Blood Pressure; D002839:Chromans / Q000494:pharmacology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006321:Heart / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D013552:Swine; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics* / Q000494:pharmacology*; D000077288:Troglitazone; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077288:Troglitazone