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154 Myocardial nox2 activity regulates atrial fibrillation susceptibility
  1. Alexandra Mighiu1,
  2. Alice Recalde2,
  3. Klemen Ziberna1,
  4. Jillian Simon1,
  5. Gil Bub3,
  6. Ajay Shah4,
  7. Barbara Casadei1
  1. 1University of Oxford
  2. 2Universite de Bordeaux
  3. 3McGill University
  4. 4King’s College London

Abstract

Atrial fibrillation, NADPH oxidases, ryanodine receptor

Background Gp91-containing NADPH oxidases (NOX2) are a significant source of reactive oxygen species (ROS) in the human atrial myocardium. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, whether an increase in atrial NOX2 activity is necessary to create a substrate for AF remains to be demonstrated. The purpose of this study is to determine whether an increase in NOX2-derived ROS directly contributes to the development of AF and to identify the molecular changes that occur downstream of NOX2 activation in atrial myocytes.

Methods and Results Mice with myocardial NOX2 overexpression (NOX2-Tg) showed a 2-fold increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in both the left and right atria, without any other electrophysiological or structural abnormalities (assessed by surface ECG and echocardiography); however, AF susceptibility assessed in vivo by transesophageal pacing was significantly higher in NOX2-Tg mice compared with their wild-type (WT) littermate controls (AF probability: 16.9±1.8% vs. 10.2±1.6% respectively, n=25–26/genotype, p<0.01). Moreover, oral supplementation with atorvastatin (30 mg/kg/day), an inhibitor of NOX2 activity, substantially reduced atrial NADPH-stimulated ROS and AF susceptibility in NOX2-Tg mice. Ex vivo high-resolution optical mapping of di-4-ANEPPS-stained atrial preparations revealed no differences in the action potential duration of left and right atria of NOX2-Tg mice compared to controls, suggesting that electrical arrhythmogenic remodelling does not occur with NOX2 overexpression. However, abnormalities in intracellular Ca2+ handling have also been linked to AF; intriguingly, western blot analyses of atrial tissues revealed a 28% reduction (n=11–23/genotype, p=0.0032 with un-paired students t-test) in the phosphorylation status of the ryanodine receptor (RyR) at Ser2814 in the right, but not the left atria of NOX2-Tg mice. Our ongoing experiments are now aimed at determining whether NOX2-derived ROS alters diastolic calcium leak from the sarcoplasmic reticulum in isolated atrial myocytes due to altered RyR gating.

Conclusions Myocardial NOX2 overexpression and related increase in NADPH-stimulated ROS production are associated with increased AF susceptibility in vivo and reduced RyR phosphorylation at Ser2814. These findings suggest increased NOX2 ROS may promote arrhythmogenesis by modulating atrial calcium handling.

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