Increased Ca <sup>2+</sup> Transient Underlies RyR2-Related Left Ventricular Noncompaction
Bibliographic record
Abstract
Background: A loss-of-function cardiac ryanodine receptor (RyR2) mutation, I4855M +/– , has recently been linked to a new cardiac disorder termed RyR2 Ca 2+ release deficiency syndrome (CRDS) as well as left ventricular noncompaction (LVNC). The mechanism by which RyR2 loss-of-function causes CRDS has been extensively studied, but the mechanism underlying RyR2 loss-of-function-associated LVNC is unknown. Here, we determined the impact of a CRDS-LVNC-associated RyR2-I4855M +/– loss-of-function mutation on cardiac structure and function. Methods: We generated a mouse model expressing the CRDS-LVNC-associated RyR2-I4855M +/– mutation. Histological analysis, echocardiography, ECG recording, and intact heart Ca 2+ imaging were performed to characterize the structural and functional consequences of the RyR2-I4855M +/– mutation. Results: As in humans, RyR2-I4855M +/– mice displayed LVNC characterized by cardiac hypertrabeculation and noncompaction. RyR2-I4855M +/– mice were highly susceptible to electrical stimulation–induced ventricular arrhythmias but protected from stress-induced ventricular arrhythmias. Unexpectedly, the RyR2-I4855M +/– mutation increased the peak Ca 2+ transient but did not alter the L-type Ca 2+ current, suggesting an increase in Ca 2+ -induced Ca 2+ release gain. The RyR2-I4855M +/– mutation abolished sarcoplasmic reticulum store overload–induced Ca 2+ release or Ca 2+ leak, elevated sarcoplasmic reticulum Ca 2+ load, prolonged Ca 2+ transient decay, and elevated end-diastolic Ca 2+ level upon rapid pacing. Immunoblotting revealed increased level of phosphorylated CaMKII (Ca 2+ -calmodulin dependent protein kinases II) but unchanged levels of CaMKII, calcineurin, and other Ca 2+ handling proteins in the RyR2-I4855M +/– mutant compared with wild type. Conclusions: The RyR2-I4855M +/– mutant mice represent the first RyR2-associated LVNC animal model that recapitulates the CRDS-LVNC overlapping phenotype in humans. The RyR2-I4855M +/– mutation increases the peak Ca 2+ transient by increasing the Ca 2+ -induced Ca 2+ release gain and the end-diastolic Ca 2+ level by prolonging Ca 2+ transient decay. Our data suggest that the increased peak-systolic and end-diastolic Ca 2+ levels may underlie RyR2-associated LVNC.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".