CALL FOR PAPERS Mitochondria in Cardiovascular Physiology and Disease Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

Xie C, Biary N, Tocchetti CG, Aon MA, Paolocci N, Kauffman J, Akar FG. Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs. Am J Physiol Heart Circ Physiol 304: H916 –H926, 2013. First published February 1, 2013; doi:10.1152/ajpheart.00026.2012.—Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZinduced hyperglycemia (STZ Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P 0.004) and STZ Ins (P 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early ( 10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P 0.045) and STZ Ins (P 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.