Abstract 17405: Chronic Treatment of Ibrutinib Reduces PI3K Activation and Causes Increased Mitochondrial Oxidative Stress Leading to Heightened AF in <i> Pitx2c <sup>+/-</sup> </i> Mice
Bibliographic record
Abstract
Background: Ibrutinib, a Bruton’s tyrosine kinase inhibitor which is currently used as first line treatment to various B-cell malignancies is known to cause proarrhythmic effects in patients thus limiting its continual use. Ibrutinib treated patients have been shown to be at a 4-fold increased risk of developing atrial fibrillation (AF), but the underlying molecular mechanisms remain unclear. Studies have shown that Pitx2 , the nearest gene to the 4q25 locus has been implicated in AF pathology and thus can serve as an experimental model for clinical AF. Objective: The goal of this study is to assess the role of the late cardiac Na current (I Na,L ), PI3K activation, and oxidative stress in mediating the increased susceptibility to AF in Pitx2c +/- mice and atrial human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to ibrutinib. Method: Pitx2c +/- mice were administered ibrutinib (30mg/kg/day IP) for 23 days after which their AF burden were assessed using transesophageal rapid pacing (TErP) along with their weight, BP, and plasma glucose. Atrial hiPSC-CMs were exposed to ibrutinib for 48 hrs. ELISA, IHC, Western blotting, cellular patch clamping and, qPCR studies were performed. Results: Pitx2c +/- mice were exposed to ibrutinib showed a graded increase in AF burden. ( Fig. 1A-C ). There was a decreased activation of the PI3K pathway and pAkt leading to overall decrease in SERCA2a expression ( Fig. 1D-F ). There was a significant increase in mitochondrial fragmentation and superoxide production in ibrutinib treated atrial hiPSC-CMs ( Fig G ) and the action potential duration at 90% repolarization and the I Na-L were markedly prolonged after ibrutinib exposure( Fig H ). Conclusion: We showed in Pitx2c +/- mice and atrial hiPSC-CMs that ibrutinib-mediated AF may in part be related to enhanced I Na-L , decreased activation of PI3K and SERCA2a and increased fibrosis leading to mitochondrial fragmentation and increased oxidative stress.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.007 | 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".