Abstract 9959: Chronic Administration of Pioglitazone and Pro-Oxidant Effects Within Chronic Hibernating Pig Hearts

Abstract

Background: Glitazones have pleomorphic effects on myocardial metabolism. We hypothesized that the PPAR-gamma agent pioglitazone (PIO) would alter mitochondrial function and induce a pro-oxidant effect on chronically ischemic heart tissue. Methods: Eighteen pigs underwent a thoracotomy with placement of a fixed constrictor around the LAD artery. At 8-weeks post-instrumentation, they were given daily PIO (3 mg/kg) or placebo (P) in the chow for 4 weeks. Regional function by ECHO was measured at baseline and regional blood flows by μspheres were determined at baseline and during high-dose dobutamine (40 μg/kg/min). Using a high-speed drill, tissue was harvested and frozen for enzymatic analysis of high-energy nucleotides. Post-sacrifice, state 3 respiration was measured from isolated mitochondria and tissue levels of glutathionyl 4-oxo-2-nonenal (GS-ONE) were determined by liquid chromatography-tendem mass spectrometry measurement. Results: In all pigs, baseline regional wall thickening (%) was lower in the LAD versus Remote region (42±5% vs 58±5%; P<0.05). LAD blood flow when normalized to the remote region was 83±5% at baseline and 64±7% during dobutamine, demonstrating the presence of chronic ischemic myocardium. The energetic state in the PIO group was more unfavorable than the placebo group, as manifested by lower transmural ATP levels (1.61±0.22 vs 2.35±0.25 μmol/g; P<0.05) and depressed Phosphocreatine to ATP ratios (1.59±0.11 vs 2.11±0.16; P<0.05). As shown by the figure, animals that received chronic PIO had higher levels of oxidant stress, as measured by GS-ONE levels and depressed rates of mitochondrial state 3 respiration. In summary, chronic administration of pioglitazone has a pro-oxidant effect on chronically ischemic hearts and an unfavorable effect on myocardial energetics, potentially by altering activity within the mitochondrial electron transport chain.