Abstract 16247: Oxidative Stress Initiates Atrial Fibrillation in Fibrotic Hearts by Early Afterdepolarization-Mediated Triggered Activity. The Key Role of Late INa
Introduction: New-onset postoperative atrial fibrillation (PoAF) is a common complication in patients after cardiac surgery, and factors such as oxidative stress activating Ca2+-calmodulin-dependent protein kinase (CaMKII), aging and atrial fibrosis are thought to play important roles.
Hypothesis: Oxidative stress in aged fibrotic hearts leads to AF via CaMKII signaling by enhancing the late sodium current (INa-L) and promoting early afterdepolarizations (EADs), triggered activity & AF & block of INa-L suppresses the AF.
Methods: The hearts of male Fisher344 rats aged (22-24 months) were isolated and perfused in the Langendorff mode. Simultaneous pseudo-ECG, bipolar atrial & ventricular electrograms and left atrial epicardial action potentials (AP) with microelectrode recordings were made before and after arterial perfusion of hydrogen peroxide (H2O2, 0.1 mM). The suppressive and preventive effects of the selective INa-L inhibitors, GS-967 (1 μM) and Ranolazine (R, 10 μM) against AF were then assessed.
Results: H2O2 promoted AF in 18 out of 20 aged hearts. The AF started abruptly during sinus rhythm at mean cycle length (CL) of 420±160 ms. AF was initiated by late phase 3 EADs causing triggered activity (atrial tachycardia) at a mean CL=162±28, that degenerated to AF (CL=65±18 ms) within 2 sec. Pretreatment with the CaMKII inhibitor KN-93 (1 μM) prevented H2O2-induced AF in 6 out of 6 hearts, whereas the inactive form KN-92 (1 μM) had no effect (P<0.01). H2O2-induced AF was terminated by exposure to either GS967 (6/6) or R (4/6), and was prevented by pre-treatment with either drug (N=6). GS967 homogenously shortened the action potential duration (APD) of the atrium, decreased the slope of the APD restitution curve (<1) & prevented rapid pacing-induced AF (4/4 vs. 0/4 (P<0.05, for all three comparisons). However, when the APD was shortened heterogeneously, by activating atrial muscarinic receptors with 1 μM carbachol, AF was not prevented by rapid pacing (N=4). H2O2 (0.1 mM) and rapid atrial pacing failed to induce AF in any of 6 young adult (3-5 months) hearts.
Conclusion: Targeting the late INa-L and CaMKII signaling during oxidative atrial stress may provide therapeutic targets to control spontaneous & inducible AF, even in aged fibrotic hearts.
Author Disclosures: A. Pezhouman: None. H. cao: None. H. Lee: None. L. Belardinelli: Employment; Significant; Gilead Sciences Inc.,. J.N. Weiss: None. H.S. Karagueuzian: Research Grant; Significant; 333 Lakeside Dr Foster City, CA 94404.
- © 2014 by American Heart Association, Inc.