Abstract 12678: Thiazolinedione Drugs Alter the Spectral Characteristics and Increase Mortality of Ischemic Ventricular Fibrillation in Pigs
Background: Despite favorable metabolic effects, thiazolidinedione (TZD) drugs have not reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (KATP) channels in pigs. In this study, we investigated if TZDs affect ischemic ventricular fibrillation (VF) and success of defibrillation (DF), and whether such effects are recapitulated by KATP blockade.
Methods: Anesthetized, open-chest pigs were treated with TZDs rosiglitazone (ROSI,n=15), pioglitazone (PIO, n=8), KATP blocker glyburide (GLY, n=7), each 1 mg/kg IV, or vehicle (VEH, n=28). 90 min after treatment, the anterior descending coronary artery was occluded. Conduction velocity in the ischemic zone was measured until onset of ischemic VF. During the initial 30 sec of VF, surface ECG power spectrum was computed by fast Fourier transform. Median and edge (upper 95%;) frequency were determined. After 30 sec VF, DF was attempted with internal shocks of 30J × 2 and 40J × 8, until perfusing rhythm was restored or death.
Results: Out of 58 pigs, 56 developed ischemic VF. TZD treatment did not affect conduction velocity in the absence of ischemia, but attenuated slowing of conduction induced by ischemia (p<0.05). Time to first VF was shorter in TZD-treated pigs than VEH (10 vs 23 min, p=0.01). Total area of power spectra did not differ among groups. However, both ROSI and PIO had higher VF median and edge frequencies (ROSI 10.1±0.4 and 11.4±0.4 Hz; PIO 9.9±0.4 and 11.3±0.4 Hz) than VEH (8.6±0.3 Hz and 10.1± Hz, p<0.05 vs TZDs). Success of DF was lower in TZD-treated than VEH pigs (23% vs. 61%, p=0.01). Each TZD effect was recapitulated by GLY (p<0.05 vs VEH) with median time to VF 13 min, median and edge VF frequencies 10.3±0.2 and 12.1±0.2 Hz, and success of DF 14%.
Conclusions: TZDs prevent slowing of conduction in ischemic tissue, hasten onset of ischemic VF, shift ischemic VF spectrum to higher frequencies, and decrease success of DF. These results are recapitulated by GLY, suggesting they are due to KATP blockade by TZDs. Through off-target effects on KATP, TZDs may have unsuspected potential to alter characteristics of ischemic VF in a manner that may adversely impact cardiovascular mortality.
- © 2010 by American Heart Association, Inc.