title: Thiazolidinedione drugs promote onset, alter characteristics, and increase mortality of ischemic ventricular fibrillation in pigs.
abstract: OBJECTIVE
  Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (K(ATP)) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective K(ATP) blocker (glyburide) or a mitochondrial K(ATP) blocker (5-hydroxydecanoate).
  
  
  METHODS
  A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed.
  
  
  RESULTS
  VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11±3 min, p<0.05) or rosiglitazone (14±3 min, p=0.06) than with vehicle (20±2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal K(ATP) channel.
  
  
  CONCLUSIONS
  In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a clinical setting might adversely impact cardiovascular mortality.
authors.affiliation: Cardiology Section, VA Medical Center and University of Colorado, Denver, CO, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Sarraf
authors.forename: Li
authors.initials: L
authors.lastname: Lu
authors.forename: Shuyu
authors.initials: S
authors.lastname: Ye
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Reiter
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Greyson
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D003331:Coronary Vessels / Q000503:physiopathology; D016757:Death, Sudden, Cardiac / Q000209:etiology; D003652:Decanoic Acids / Q000494:pharmacology; D005260:Female; D005905:Glyburide / Q000494:pharmacology; D006880:Hydroxy Acids / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D007511:Ischemia / Q000503:physiopathology*; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D000077205:Pioglitazone; D026902:Potassium Channel Blockers / Q000494:pharmacology; D000077154:Rosiglitazone; D013552:Swine; D045162:Thiazolidinediones / Q000009:adverse effects*; D014693:Ventricular Fibrillation / Q000503:physiopathology*
chemical_list: D000889:Anti-Arrhythmia Agents; D003652:Decanoic Acids; D006880:Hydroxy Acids; D007004:Hypoglycemic Agents; D026902:Potassium Channel Blockers; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C052853:5-hydroxydecanoic acid; D005905:Glyburide; D000077205:Pioglitazone