Downregulation of endocardial nitric oxide synthase expression and nitric oxide production in atrial fibrillation: Potential mechanisms for atrial thrombosis and stroke

Background - In the arterial endothelium, laminar flow and cyclical stretch induce expression of NO synthase (NOS). We hypothesized that atrial fibrillation (AF) causes a downregulation of atrial endocardial NOS expression and NO^. production. Because NO^. has antithrombotic properties, this may contribute to thromboembolism in AF. Methods and Results - In pigs, AF was produced with rapid atrial pacing at 600 bpm for 1 week, whereas controls had atrial pacing at 100 bpm. All animals had catheter ablation of the AV junction and ventricular pacing at 100 bpm. NO^. production from freshly isolated tissue was measured by a NO^.-specific microelectrode. Left atrial basal and stimulated NO^. production was decreased in AF by 73% and 71% (P<0.01). Endocardial NOS expression, determined by Western analysis, was also significantly decreased by 46%. Expression of the prothombotic protein plasminogen activator inhibitor 1 (PAI-1) is known to be regulated by NO^. and was increased in the left atrium by 1.8-fold in AF (P<0.05). NO^. concentration was decreased in the left atrial appendage, although NOS expression was not affected. Neither NOS concentration, NO^. levels, nor PAI-1 expression were altered in the aortas or right atria of animals with AF. Conclusions - AF is associated with a marked decrease in endocardial NOS expression and NO^. bioavailability and an increase in PAI-1 expression in the left atrium. These data suggest that organized atrial contraction is needed to maintain normal endocardial expression of NOS. It is likely that loss of this antithrombotic enzyme contributes to the thromboembolic phenomena commonly observed in AF.