Atrial Stretch‐Dependent Tumor Necrosis Factor (TNF)‐Mediated Adverse Atrial Remodeling and Atrial Arrhythmia Inducibility in a Mouse Model of Aortic Regurgitation
Bibliographic record
Abstract
Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide, with its incidence linked to cardiovascular (CV) disease and, paradoxically, endurance exercise. Most conditions linked to AF are associated with elevated atrial pressures and stretch, which are powerful stimuli for atrial hypertrophy, fibrosis, and inflammation. We previously established adverse atrial changes and arrhythmogenesis required the pro‐inflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) in intense swim exercised mice. Thus, we hypothesize that stretch‐mediated TNF‐dependent signaling may provide a unifying mechanism linking AF in exercise and disease. We developed a clinically‐relevant mouse model of aortic regurgitation (AR), which is characterized by chronic diastolic volume overload and elevated left ventricular end‐diastolic (LVEDPs) and atrial pressures, to study atrial stretch‐dependent TNF‐mediated AF pathogenesis. AR was induced by retrograde puncture of the aortic valve in 8‐week‐old CD1 wild‐type and whole‐body TNF knockout (TNF‐/‐) mice and cardiac and electrophysiological changes were assessed using echocardiography, invasive hemodynamics, histology, in vivo intracardiacs, and ex vivo optical mapping in isolated atria. Four weeks after regurgitation, AR resulted in volume overload‐mediated progressive LV dilatation, functional impairment, hypertrophy, and elevated LVEDPs in the absence of ventricular arrhythmia inducibility in both groups. In wild‐type mice, AR resulted in adverse atrial remodeling, characterized by atrial hypertrophy and fibrosis, decreased conduction velocity, reduced atrial effective refractory period and action potential duration, and increased in vivo and ex vivo AF susceptibility. By contrast, TNF‐/‐ prevented AR‐induced adverse atrial remodeling and arrhythmia inducibility, independent of ventricular changes. Our results establish that adverse atrial remodeling and AF vulnerability with AR requires TNF, providing a mechanistic link between elevated atrial pressures, adverse atrial remodeling, and AF susceptibility with CV disease and exercise.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".