title: Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs.
abstract: 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 STZ-induced 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.
authors: Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors: Chaoqin
authors: C
authors: Xie
authors: Nora
authors: N
authors: Biary
authors: Carlo G
authors: CG
authors: Tocchetti
authors: Miguel A
authors: MA
authors: Aon
authors: Nazareno
authors: N
authors: Paolocci
authors: Justin
authors: J
authors: Kauffman
authors: Fadi G
authors: FG
authors: Akar
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D003958:Diamide / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D006168:Guinea Pigs; D006321:Heart / Q000503:physiopathology; D006943:Hyperglycemia / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D057216:Propensity Score; D013311:Streptozocin / Q000494:pharmacology; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000378:metabolism*; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D001786:Blood Glucose; D007328:Insulin; D003958:Diamide; D013311:Streptozocin; D005978:Glutathione
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