Xu Ya, Lu Li, Greyson Clifford, Lee Jenny, Gen Michael, Kinugawa Koichiro, Long Carlin S, Schwartz Gregory G
VA Medical Center and University of Colorado Health Sciences Center, Denver, CO, USA.
Diabetes. 2003 May;52(5):1187-94. doi: 10.2337/diabetes.52.5.1187.
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.
噻唑烷二酮类药物在体外对非心肌细胞具有电生理作用，但迄今为止尚无对心律影响的相关报道。我们之前证明，用噻唑烷二酮类过氧化物酶体增殖物激活受体（PPAR）-γ激动剂曲格列酮进行慢性预处理，可改善缺血再灌注后左心室（LV）功能和底物代谢的恢复，且不会引起心律失常。在本研究中，我们确定急性给予曲格列酮是否能产生类似的有益效果。对麻醉的猪进行90分钟的局部LV缺血和90分钟的再灌注。15只猪在缺血前1小时开始接受曲格列酮治疗（静脉注射负荷剂量10mg/kg，输注剂量5mg·kg⁻¹·h⁻¹）。7只猪接受相应的赋形剂。血浆曲格列酮浓度（平均5μg/ml）与该药物临床使用时达到的浓度相似。在缺血前，急性曲格列酮治疗对LV功能、心电图或底物利用无影响。在缺血或再灌注期间，曲格列酮组有8只猪死于心室颤动，而赋形剂组无猪死亡（P<0.05）。发生心室颤动的猪的QT间期比两组的存活猪短。在存活猪中，两组之间LV功能和底物利用均无差异。急性给予曲格列酮会增加心肌缺血和再灌注期间心室颤动的易感性。噻唑烷二酮类药物在临床使用中是否具有促心律失常潜力需要进一步研究。
