Abstract 1516: Role of Oxidative Stress in Atrial Tachycardia Remodelling
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. ICaL 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 ICaL (Fig. A⇓) and induced OxS (Fig. B⇓). Short term induction of OxS (H2O2 100 μM x 10 mins) increased ICaL (Fig. C⇓) and enhanced Ca2+ loading (Indo-1 AM). 24-Hr H2O2 100 μ M increased DHEF in P1 cells by 250%* (*P<0.05) and mimicked ATR, decreasing ICaL by 51%* (Fig. C⇓). H2O2-mediated DHEF changes were suppressed by inhibiting calmodulin (W7) or CaMKII (KN93). H2O2-induced ICaL suppression at 1 Hz was prevented by: decreasing Ca2+i loading by ICaL blockade (nimodipine) or Ca2+ 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 ICaL downregulation by 3-Hz pacing and W7, KN93 and apocynin abolished ATR-induced DHEF increases. H2O2 mimics ATR by causing Ca2+ i loading and CaMKII activation coupled to NADPH-oxidase stimulation. ATR-induced ICaL-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.