Abstract 16651: Generation of Reactive Oxygen Species in a Frequency-Dependent Manner in Atrial Myocytes - Implications for the Emergence of Pulmonary Vein Drivers and the Perpetuation of Atrial Fibrillation Substrate
Background: The precise mechanisms underlying the genesis of AF are not well known. Since reactive oxygen species (ROS) are thought to contribute to AF substrate and since rapidly firing ectopic foci that underlie AF are predominantly located in the posterior left atrium (PLA), we hypothesized that ROS would be preferentially elevated in the PLA of fibrillating atria. We further hypothesized that ‘AF begets AF’ in fibrillating atria in part because ROS generation in atrial myocytes increases in a frequency dependent manner (thereby allowing for perpetuation of AF substrate).
Methods: Isolated left atrial pig myocytes were paced at 1Hz and 2Hz for 6 hours and incubated with a ROS-sensitive dye, CellROX Deep Red. Cell fluorescence was measured with confocal microscopy. In addition, four dogs were subjected to rapid atrial pacing (RAP) at 600 bpm for 3-4 weeks to induce persistent AF. Superoxide production (O2-) was measured by lucigenin-enhanced chemiluminescence assay in RAP and normal (n=5) PLA and left atrial appendage (LAA) tissue homogenates with and without the following ROS inhibitors: apocynin (NADPH oxidase) mito-TEMPO (mitochondrial ROS), L-NMMA (nitric oxide synthase (NOS)) and oxypurinol (xanthine oxidase).
Results: In isolated myocytes, ROS production increased in a frequency dependent manner (Figure 1a, 1b). In tissue homogenates, there was significantly greater O2- production (in relative light units) in RAP dogs compared to normal dogs in the PLA (37.3±4.5 vs. 17.1±4.5, p<0.05), but not in the LAA (24.0±2.7 vs.19±2.5, p=NS); the increase in O2- was primarily due to an increase in NOX and mitochondrial O2- (Figure 2).
Conclusion: Tachychardia-induced atrial remodeling causes significant elevation of ROS in what appears to be a rate dependent phenomenon. Localized ROS formation in the PLA in a frequency dependent manner could participate in establishing AF substrate. Further efforts to block this pathway will identify its role as a therapeutic target.
- © 2013 by American Heart Association, Inc.