Abstract 9398: Dantrolene Prevents Doxorubicin-Induced Cardiac Ryanodine Receptor Dyssynchrony
Bibliographic record
Abstract
Background: Ryanodine receptor 2 (RyR2) is important for cardiac calcium release from the sarcoplasmic reticulum. RyR2 activation triggers a spatio-temporally regulated calcium spark. Synchronous activation of RyR2 clusters creates a steeper slope and shorter systolic rise time in calcium transients. Doxorubicin (Dox) is a commonly used chemotherapy drug that can lead to dyssynchronous RyR2 activation and cardiomyopathy. We therefore sought to investigate the effects of RyR2 stabilizer dantrolene (Dan) on restoring normal RyR2 synchrony of calcium release in a murine model of doxorubicin-induced cardiomyopathy. Hypothesis: We hypothesize that treatment with dantrolene will mitigate RyR2 dyssynchrony induced by doxorubicin. Methods: 22 adult male C57BL/6 mice were randomly divided into four groups: (i) Control, (ii) Dox only (single intraperitoneal injection, 10 mg/kg on day 7), (iii) Dan only (10 mg/kg daily starting on day 0 through day 21), and (iv) Dan + Dox. Two weeks after Dox treatment, the hearts were harvested and perfused in a Langendorff setup. Calcium-sensitive dye Rhod-2AM and mechanical uncoupler Blebbistatin were infused. Each heart was electrically stimulated following a pace-and-pause protocol during optical mapping of the anterior ventricular wall. Dye fluorescence was recorded and analyzed using custom MATLAB codes. Time to rise (TTR), the time duration for Rhod-2AM fluorescence to rise from minimum (10%) to maximum (90%) in each heartbeat, was used as a means of assessing RyR2 synchrony. Results: TTR was prolonged in the Dox group compared to control (11.6±1.3 ms in Dox group vs. 10.1±0.6 ms in control; at 14 Hz). Treatment with Dan prevented this prolongation (11.6±1.3 ms in Dox group vs. 9.8±0.6 ms in Dan+Dox group; at 14 Hz). Conclusions: Our findings suggest that dantrolene is effective in mitigating RyR2 dyssynchrony induced by doxorubicin.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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".