Differential thermosensitivity in mixed syndrome cardiac sodium channel mutants
Bibliographic record
Abstract
Key points The E1784K mixed syndrome mutant of the cardiac voltage‐gated sodium channel, NaV1.5, responds differently to temperature changes compared to the R1193Q mutant and wild‐type (WT) NaV1.5. In E1784K, elevated temperature causes a larger increase in persistent current; there is also an increase in use‐dependent inactivation at 1 Hz, which is not apparent at 3 Hz. WT NaV1.5 and R1193Q channels respond similarly to temperature changes. Action potential modelling (from extrapolated temperature coefficient (Q10)values) predicts the effects of differential temperature sensitivity on the cardiac action potential: greater attenuation of the epicardial action potential occurs in E1784K as temperature shifts from hypothermic to hyperthermic conditions, and when transient outward potassium currents are increased. The results from the action potential model predict that, at febrile temperatures, E1784K channels results in a larger transmural voltage gradient. Hyperthermia exacerbates the Brugada syndrome 1 (BrS1) phenotype, which may be arrhythmogenic in E1784K mutants. Abstract Cardiac arrhythmias are often associated with mutations in SCN5A the gene that encodes the cardiac paralogue of the voltage‐gated sodium channel, NaV1.5. The NaV1.5 mutants R1193Q and E1784K give rise to both long QT and Brugada syndromes. Various environmental factors, including temperature, may unmask arrhythmia. We sought to determine whether temperature might be an arrhythmogenic trigger in these two mixed syndrome mutants. Whole‐cell patch clamp was used to measure the biophysical properties of NaV1.5 WT, E1784K and R1193Q mutants. Recordings were performed using Chinese hamster ovary (CHOk1) cells transiently transfected with the NaV1.5 α subunit (WT, E1784K, or R1193Q), β1 subunit, and eGFP. The channels’ voltage‐dependent and kinetic properties were measured at three different temperatures: 10ºC, 22ºC, and 34ºC. The E1784K mutant is more thermosensitive than either WT or R1193Q channels. When temperature is elevated from 22°C to 34°C, there is a greater increase in late INa and use‐dependent inactivation in E1784K than in WT or R1193Q. However, when temperature is lowered to 10°C, the two mutants show a decrease in channel availability. Action potential modelling using Q10 fit values, extrapolated to physiological and febrile temperatures, show a larger transmural voltage gradient in E1784K compared to R1193Q and WT with hyperthermia. The E1784K mutant is more thermosensitive than WT or R1193Q channels. This enhanced thermosensitivity may be a mechanism for arrhythmogenesis in patients with E1784K sodium channels.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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 | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".