Abstract 18781: Novel Ryanodine Receptor Mutation Associated With Hypertrophic Cardiomyopathy Induces Cardiac Remodeling and Arrhythmia in Mice
Bibliographic record
Abstract
Introduction: Hypertrophic Cardiomyopathy (HCM) is the most common cardiac genetic disease. We identified a novel mutation in the cardiac Ca 2+ release channel/ryanodine receptor, RyR2-P1124L, in a patient with obstructive HCM and positive family history of HCM. The patient showed a mid-ventricular septal thickness of 24 mm, LVOT obstruction and several episodes of ventricular fibrillation. Here, we use a multi-level approach to determine the pathogenic mechanisms associated with RyR2-P1124L, in order to provide new insights into RyR2-mediated HCM. Results: Using recombinant RyR2-P1124L channels, we determined the Ca 2+ -dependence of [ 3 H]ryanodine binding, an indirect measure of RyR2 activity. RyR2-P1124L requires higher [Ca 2+ ] for activation (EC 50 = 362.9±74.5 vs. 190.6±9.8 nM, p = 0.04) and has lower Bmax than WT (0.44±0.02 vs. 0.60±0.03 pmol/mg of protein, p p = 0.05; and 0.91±0.03 vs. 0.78±0.02 mm, p = 0.01, respectively), recapitulating the human phenotype. At 8 months of age, mice do not display cardiac remodeling but are already more susceptible to epinephrine/caffeine-induced arrhythmias, including bidirectional VT (5/7 vs. 0/7, p 2+ load in the presence of isoproterenol (12.5±0.5 vs. 11.1±0.4 ΔF/F0, p = 0.06), which could provide the basis for cellular Ca 2+ mishandling. Conclusions: RyR2-P1124L is a loss-of-function mutation that alters RyR2 structure and function. To our knowledge, it is the first to induce ventricular remodeling together with arrhythmia. Therefore, it represents a new paradigm for the emerging field of RyR2-mediated cardiac remodeling and Ca 2+ -dependent HCM.
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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 | 0.001 |
| 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 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
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".