Abstract
AimsGp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility.Methods and resultsNOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype.ConclusionTogether, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
Highlights
Atrial fibrillation (AF) is the most common sustained arrhythmia, mostly occurring in association with aging and cardiovascular risk factors, and leads to thromboembolic complications and premature death.[1]
Data from the more recent and much larger statin therapy in cardiac surgery (STICS) randomized controlled trial showed no significant effect on the incidence of post-operative AF in 1922 patients randomized to rosuvastatin or placebo,[16] raising the question of whether NOX2-derived superoxide production is merely a biomarker of increased AF risk or causal factor in the new onset of AF after cardiac surgery
Left ventricular (LV) systolic and diastolic function and mass assessed by echocardiography did not differ significantly between genotypes (Table 1)
Summary
Atrial fibrillation (AF) is the most common sustained arrhythmia, mostly occurring in association with aging and cardiovascular risk factors, and leads to thromboembolic complications and premature death.[1]. Despite the positive accounts implicating NOX2-derived superoxide in AF, no studies far have assessed whether augmenting myocardial NOX2 activity is sufficient to promote AF induction. We investigated whether myocardial-specific overexpression of the human NOX2 gene generates a substrate for AF in mice and evaluated the efficacy of atorvastatin (ATV) administration for inhibiting atrial NOX2 activity and reducing AF induction
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