Sex‐Specific Arrhythmias Caused by Cardiac Sodium Channel Na <sub>v</sub> 1.5 Mutation Alters Cardiomyocyte Metabolism
Bibliographic record
Abstract
Introduction The activation of cardiac Na v 1.5 sodium channels initiates the action potential in the heart to facilitate coordinated contraction. Mutations in Na v 1.5 disrupts the action potential leading to arrhythmic diseases which increases the risk of sudden cardiac arrest. The gain of function Arg222Gln mutation in Na v 1.5 disrupts structural interactions during channel activation, creating an aberrant pore leading to excessive cations entering the cardiomyocyte (CM). The chronic arrhythmia resulting from Arg222Gln places prolonged stress on the heart which can trigger adverse metabolic reprogramming. We have generated a mouse model possessing the human Arg222Gln mutation where the males illustrate a significant arrhythmia burden, whereas females appear to be protected. We hypothesize that sex‐specifc metabolic reprogramming could provide an explanation for the observed difference in phenotype. Methods The human exon containing the Arg222Gln mutation was knocked into the equivalent mouse locus under the endogenous promoter. Shot‐gun proteomics of total heart lysate was performed using LC‐LC mass spectrometry. Significant proteins were identified with at least two unique peptides and a 5% false discovery rate. Clustering and differentially expressed proteins were analyzed using Metaboanalyst and pathway gene ontological analysis was performed with Cytoscape. Cellular metabolism (oxygen consumption) was measured using isolated adult primary CMs with the Seahorse XFe Analyzer. Results After filtering, mass spectrometry yielded 1654 identified protein across all four analyzed groups (wild‐type and Arg222Gln of both sexes). Unsupervised clustering of the data using principal component analysis and hierarchical clustering revealed complete segregation of the four groups. Sex status contributed most significantly to data segregation, with secondary (but clear) segregation based on Arg222Gln mutation. Comparing Arg222Gln male versus females, there were 157 upregulated proteins and 231 down regulated proteins (P<0.05, ±2‐fold change). Pathway analysis of the differentially expressed proteins reveal multiple changes in metabolic pathways including fatty acid metabolism, pyruvate metabolism, and lactate metabolism. Basal respiration of the isolated CMs in all four groups were unchanged, however maximal respiratory capacity of Arg222Gln males were significantly lower (116.9±13.5pmol O 2 /min, P<0.05) compared to the wild‐type males (407.3±16.4pmol O 2 /min). There were no differences between wild‐type females (451.4±22.4pmol O 2 /min) and Arg222Gln females (463.2±33.7pmol O 2 /min). Conclusion We demonstrate sex‐specific proteomic changes in a mouse model of arrhythmia caused by a gain‐of‐function Na v 1.5 mutation. While there were many perturbed pathways in our analysis, metabolic changes featured prominently. Our data suggests that metabolic reprogramming could play a role in the cardioprotection in females or a compensatory detrimental mechanism in males harboring the Arg222Gln mutation. Future experiments will aim to understand how sex affects cardiac metabolism in the context of Arg222Gln, specifically targeting the specific roles of sex hormones.
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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) | 0.000 | 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 | 0.000 | 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".