Abstract 15442: Pharmacological and Atrial Cardiomyocyte-Specific Inhibition of Tumor Necrosis Factor (TNF) Protects Against Adverse Atrial Remodeling and Valvular Atrial Fibrillation an a Mouse Model of Aortic Regurgitation
Bibliographic record
Abstract
Introduction: Atrial fibrillation (AF) is the most common sustained supraventricular arrhythmia worldwide. Most conditions linked to AF, such as cardiovascular (CVD) and valvular disease, are linked to elevated atrial pressures and atrial cardiomyocyte (CM) stretch, which are powerful stimuli for atrial remodeling. We have shown that the proinflammatory and mechanosensitive cytokine tumor necrosis factor (TNF) is a key mediator of stretch-related atrial remodeling and AF. Hypothesis: As TNF is a critical factor mediating fibrosis, hypertrophy, inflammation, and arrhythmias in CVD, we hypothesized that targeting TNF-dependent signaling may offer a novel therapeutic target in AF patients. Methods: We created an aortic regurgitation (AR) mouse model of volume overload characterized by elevated left ventricular end diastolic (LVEDPs) and atrial pressures. To examine TNF-dependent AF pathogenesis in AR, the impact of Tnf excision in atrial CMs (Cre-recombinase expression controlled by an Nppa promoter) and pharmacological TNF inhibition with Etanercept (twice-weekly, 2.5 mg/kg) beginning 2-days (early) or 1-week (delayed) post-AR in CD1 mice were examined. Cardiac structural, functional, and electrophysiological properties were assessed using echo, pressure telemetry, immunohistochemistry, in vivo intracardiacs, and ex vivo optical mapping of AF. Results: Four weeks of AR resulted in chronically elevated LVEDPs and progressive LV dilatation, functional impairment, and hypertrophy in the absence of ventricular arrhythmias with or without TNF inhibition compared to SHAM mice. In atria, AR resulted in both in vivo (8/11, 73%) and ex vivo (5/8, 63%) AF inducibility, which was associated with hypertrophy, fibrosis, and macrophage infiltration (F4/80 + ) as well as decreased conduction velocity and atrial effective refractory periods. Importantly, atrial CM-specific Tnf excision (n=10) and both early (n=8) and delayed (n=6) pharmacological TNF inhibition attenuated AR-induced adverse atrial remodeling and protected against AF inducibility. Conclusions: AF pathogenesis and vulnerability with AR requires TNF, suggesting TNF is an important therapeutic target for the prevention and treatment of AF linked to elevated atrial pressures.
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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 | 0.000 |
| 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 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".