Abstract 11919: AMP-Activated Protein Kinase Response to Metabolic Stress: A Novel Determinant of Atrial Fibrillation Progression
Bibliographic record
Abstract
Introduction: Metabolic stress is observed in clinical and experimental atrial fibrillation (AF). Metabolic stress activates AMP-dependent protein kinase (AMPK) via phosphorylation; activated AMPK produces compensatory changes in the determinants of energy balance. Here, we examined AMPK responses in AF and their role in remodeling responses of atrial Ca 2+ handling and contractility. Methods: AMPK and Cav1.2 protein were quantified by immunoblot. Ca 2+ transients (CaTs, Indo1 AM), cell shortening (CS, videometry), L-type Ca 2+ ( I Ca,L ) and NCX ( I NCX ) current (patch clamp) were measured in dog left atrial (LA) cardiomyocytes (CMs) under metabolic stress due to glycolysis inhibition (GI, 10 mM 2-deoxyglucose/10 mM pyruvate). Results: In dogs with 1-wk electrically-maintained AF (n=4), the phosphorylation ratio (PhR) of AMPK (indicating activation) increased in LA by 101%* (*p<0.05) vs. controls (n=4). Metabolic stress due to GI in 2 Hz paced LA CMs increased AMPK PhR by 103%* vs. quiescent CMs. In 2 Hz paced cells, the AMPK inhibitor CompC (10 μM) decreased LA CaT and CS by 58%* and 51%* vs. control, but the AMPK activator AICAR (1 mM) restored CaT and CS by 75%* and 53%* vs. CompC alone, supporting AMPK-dependent regulation. CompC decreased I Ca,L and I Ca,L -triggered CaT by 46%* and 37%*. AMPKα protein coimmunoprecipitated with Ca v 1.2 protein, suggesting that AMPK is physically coupled with the I Ca,L channel α-subunit. CompC also decreased SR Ca 2+ content by 53%* vs. control ( I NCX simultaneously measured with caffeine-induced CaT). AMPK PhR was greater by 61%* in paroxysmal AF (pAF, n=7) patient atria vs. sinus rhythm controls (n=10), whereas AMPK PhR was decreased in chronic AF (cAF) patients (n=9) by 27%*, suggesting that the level of AMPK activation may govern the chronicization of AF. Conclusions: AF activates AMPK. Under AF-induced metabolic stress, AMPK activation limits AF-promoting abnormalities in LA I Ca,L , Ca 2+ handling and contractility. pAF patients have AMPK activation, protecting them against chronicization, whereas cAF patients have reduced AMPK activation. Thus, the response of AMPK to AF-related metabolic stress might be a crucial determinant of AF chronicization, and AMPK-manipulation may be a novel target to prevent AF progression.
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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 | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".