Background Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with altered nitric oxide (NO)-redox balance. The molecular mechanisms and implications of this phenomenon in the management of patients with AF are poorly understood. Statins improve NO-redox imbalance and decrease the occurrence of postoperative AF but are less effective in the secondary prevention of AF, suggesting that the sources of reactive oxygen species might vary with the substrate and duration of AF.
Methods and Results We investigated atrial tissue from 130 patients undergoing cardiac surgery (26 with permanent AF, 32 who developed AF post-operatively and 72 who were in normal sinus rhythm before and after surgery), and from goats in sinus rhythm (SR, n=19) with or without atrial structural remodelling secondary to surgical AV block (AVB, n=10) or after 2 weeks (2W, n=15) or 6 months (6M, n=10) of pacing-induced AF. Atrial NADPH oxidase activity (chemiluminescence and 2-OH ethidium, Abstract 142 figures 1 and 2), NOX2 & p22phox protein level were increased after 2W-AF and in patients who developed AF post-operatively (n=32). In contrast, the increased superoxide production in atrial tissue from goats with AVB or 6M-AF was exclusively driven by mitochondrial oxidases and uncoupled NOS (secondary to a reduction in atrial BH4 level and an increase in arginase activity). These findings were recapitulated in the right atrial appendage of patients. Increase in basal superoxide production in postoperative AF was associated with an apocynin-reversible increase in NADPH oxidase activity and protein level of the NOX2 and p22phox subunits. NOS activity remained coupled despite the increase in superoxide production. In line with this, atrial BH4 content was unaltered. In contrast, in patients with permanent AF, increased superoxide production was not reversed by apocynin, and was maintained by mitochondrial oxidases and uncoupled NOS (secondary to BH4 deplition). Ex-vivo inhibition of HMG-CoA reductase with atorvastatin (20 μMol/l) inhibited NADPH oxidase activity (via reducing activity of Rac1 and membrane translocation of cytosolic subunit p47phox and p67phox of NADPH oxidase) and caused a mevalonate-reversible reduction in superoxide release in atrial samples of patients with post-operative AF but had no effect in patients with permanent AF. Similarly, atorvastatin did not induce a mevalonate-reversible changes in the atrial BH4 concentration and NOS uncoupling in neither group.
Conclusions Together, these findings indicate that upregulation of NOX2-NADPH oxidases is an early but transient event in the natural history of AF, as mitochondrial oxidases and uncoupled NOS account for the statin-resistant increase in atrial superoxide production in permanent AF. Variation in atrial sources of reactive oxygen species with the duration and substrate of AF may explain the reported variability in the effectiveness of statins in the prevention and management of AF.
- Atrial fibrillation
- nitric oxide-redox balance