Deleterious Effects of Acute Treatment With a Peroxisome Proliferator–Activated Receptor-γ 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)-γ 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 μg/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.