Abstract 1516: Role of Oxidative Stress in Atrial Tachycardia Remodelling

Abstract

Atrial tachycardia remodeling (ATR) promotes atrial fibrillation (AF). Oxidant stress (OxS) occurs in atria of AF patients and antioxidants may be beneficial in AF. This study used a previously validated in vitro paced canine cardiomyocyte model to assess the potential role of OxS in ATR. Cultured canine atrial cardiomyocytes were paced at 1 or 3 Hz (P1, P3) for 24 hrs. I CaL was recorded with whole cell voltage clamp. Single cell superoxide production was assessed by dihydroethidium fluorescence (DHEF) imaging. ATR (3 Hz pacing x 24 hrs) decreased I CaL (Fig. A ) and induced OxS (Fig. B ). Short term induction of OxS (H 2 O 2 100 μM x 10 mins) increased I CaL (Fig. C ) and enhanced Ca 2+ loading (Indo-1 AM). 24-Hr H 2 O 2 100 μ M increased DHEF in P1 cells by 250%* (*P<0.05) and mimicked ATR, decreasing I CaL by 51%* (Fig. C ). H 2 O 2 -mediated DHEF changes were suppressed by inhibiting calmodulin (W7) or CaMKII (KN93). H 2 O 2 -induced I CaL suppression at 1 Hz was prevented by: decreasing Ca 2+ i loading by I CaL blockade (nimodipine) or Ca 2+ chelation (BAPTA-AM); W7 or KN93; antioxidants (2-MPG or N-acetylcysteine, NAC); or suppression of free radical generation via NADPH-oxidase (apocynin). 2-MPG, NAC, and apocynin prevented I CaL downregulation by 3-Hz pacing and W7, KN93 and apocynin abolished ATR-induced DHEF increases. H 2 O 2 mimics ATR by causing Ca 2+ i loading and CaMKII activation coupled to NADPH-oxidase stimulation. ATR-induced I CaL -downregulation is mediated in part by OxS generation. These findings provide insights into the pathways by which OxS contributes to ATR and present a mechanistic framework for understanding the effects of antioxidant interventions in AF.