Abstract 15933: Scn5a Gating Pore Current Causes Cardiac Arrhythmias Associated With Dilated Cardiomyopathy
Bibliographic record
Abstract
Dilated cardiomyopathy (DCM) is a structural heart disease that causes dilatation of cardiac chambers, impairs cardiac contractility and systolic function leading to heart failure. SCN5A gene encodes the cardiac sodium channel (Nav1.5) in which mutations have been identified in patients with arrhythmic disorders associated with DCM. However, it is not understood how a dysfunction in SCN5A may cause very atypical cardiac arrhythmias associated with dilatation remodeling of the heart. We generated control and patient specific human induced pluripotent cells (hiPS) carrying the Nav1.5/R219H mutation. hiPS were differentiated to obtain cardiomyocytes derived from hiPS (hiPS-CM). Molecular dynamic simulations experiments revealed that the R219H mutation opens up a pathway directly through the voltage sensitive domain (VSD) of Nav1.5 channels. We hypothesized that such a proton leak through the VSD caused by the R219H mutation may be responsible for the clinical phenotypes observed in our index patient. We unraveled the underlying mechanism responsible for the association of SCN5A and DCM. Indeed, the data shows the presence of a gating pore or omega current that is responsible of the observed abnormal ionic homeostasis, absent in control hiPS-CM. Action potential recordings showed abnormal electrical activities in both atrial and ventricular hiPS-CM. Myocytes stemmed from the index patient exhibited dilatation. Single cardiomyocytes contractility probed using atomic force microscopy revealed a higher frequency of contractility with reduced force compared to control myocytes. This could be attributed to the observed contractile protein dysfunction uncovered using immunofluorescence. Overall, the results support the hypothesis that the Nav1.5/R219H mutation creates a proton leak. This leak then causes electrical, structural and contractile disturbances that may explain the related cardiac arrhythmias associated with myocytes dilatation. We concluded that gating pore current, a novel cardiac channelopathy is directly related to the association of SCN5A and DCM. We suggest that this aberrant leak current should be investigated to characterize similar SCN5A mutations with similar clinical phenotypes.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.009 | 0.002 |
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".