Abstract 18632: Expression and Function of the Ryanodine Receptor Subtype 3 in Cardiac Purkinje Fibers: Potential Target for Selective Treatment of Purkinje Ectopy?
Bibliographic record
Abstract
BACKGROUND: Focal “discharges” from the Purkinje network were shown to trigger VTs and VFs in ischemic hearts. In dog model of myocardial infarction, this Purkinje ectopy was attributed to abnormal oscillations of Ca 2+ concentration in Purkinje cells (Pcells). The cause of these oscillations is unknown mostly because important features of Ca 2+ handling of normal Pcells remain obscure. It was proposed that distinct forms of Ca 2+ channels participate to Ca 2+ release from endoplasmic reticulum (ER) in canine Pcells, wherein RyR3 was found to co-exist with IP3R and RyR2. Nevertheless, presence of this system of multiple Ca 2+ channels has not been explored in other species and the function of this system in Pcells remains unclear. Here, we examined the hypothesis that a specific region of RyR3 Ca 2+ release exists in Pcells of large size hearts and forms anatomical and functional coupling between membrane and core ER-Ca 2+ releases. METHODS: Purkinje strands were dissected from hearts of 36 Yucatan swine. Enzymatically dispersed Pcells were loaded with Fluo4. Intracellular Ca 2+ dynamics was assessed by 2D confocal imaging (92cells). Function of ER-Ca 2+ channels was investigated through effects of selective inhibitors on intracellular Ca 2+ transients (65cells). mRNA level was measured in Purkinje fibers by RT-PCR for RyR isoforms 1,2,3 and IP3R (11 animals). Protein expression was characterized by immunofluorescence (34 cells). RESULTS: Compared to myocardium, 100fold larger RyR3 mRNA level was detected in Purkinje fibers. 3D distribution of RyR3-Ab revealed a concentric RyR3 layer at the cell periphery. Spark rate-pCarelations showed that Ca 2+ sensitivity of ER-Ca 2+ release at the Pcell periphery was 2fold larger than further in the core. 3 distinct velocities were detected in the typical centripetal Ca 2+ propagation of Pcells. RyR3 inhibitor dantrolene (10µM) immediately reduced the Ca 2+ release event rate by 50% in the periphery only. CONCLUSION: RyR3 is a major component of the specific Ca 2+ signaling of Pcells of large mammalian heart, suggesting that any RyR3 alteration may cause pro-arrhythmic Ca 2+ abnormalities in ischemic heart. Purkinje-specificity of RyR3 highlights a new target for selective treatment of Purkinje-originated dysrhythmia.
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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) | 0.001 | 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) | 0.002 | 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".