154 Myocardial nox2 activity regulates atrial fibrillation susceptibility
Bibliographic record
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 Ca 2+ 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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".