ATX‐II Effects on the Apparent Location of M Cells in a Computational Model of a Human Left Ventricular Wedge
Bibliographic record
Abstract
INTRODUCTION: The apparent location of the myocytes (M cells) with the longest action potential duration (APD) in a canine left ventricular (LV) wedge have been reported to shift after application of a sea anemone toxin, ATX-II. This toxin slows inactivation of I(Na) and thus prolongs APD. Thus, M cells may exhibit dynamic functional states, rather than being a static, anatomically discrete, myocyte population. In this study, we attempted to further define and understand this phenomenon using a mathematical model of the human ventricular myocyte action potential incorporated into an in silico "wedge" preparation. Our simulations demonstrate that even under conditions of a fixed population and ratio of epicardial, M, and endocardial myocytes, the apparent anatomical position (transmural location) of the myocytes with the longest APD can shift following ATX-II treatment. This arises because the ATX-II effect, modeled as a small increase in the late or persistent Na(+) current, and consequent prolongation of APD significantly changes the electrotonic interactions between ventricular myocytes in this LV wedge preparation. METHODS AND RESULTS: This LV wedge model is based on bidomain equations. It corresponds to a rectangular tissue immersed in a passive and isotropic medium that represents the superfusion bath. In this theoretical work, the three known different and discrete populations of myocytes in the human left ventricle have been included: the epicardial, M, and endocardial cells. The effects of ATX-II on I(Na) were simulated by altering the voltage-dependent steady-state inactivation of the parameters h (fast gate) and j (slow gate). As a result, in these ATX-II simulations a persistent late Na(+) current was generated in all three types of ventricular myocytes. However, the APDs were prolonged in a heterogeneous pattern. Our simulations demonstrate that after the ATX-II effects develop, alterations in transmural electrotonic interactions can produce changes in the transmural location of myocytes with the longest APD. CONCLUSIONS: The combination of intercellular electrotonic interactions, which tend to reduce and smooth out the discrete transmural APD variations, and the heterogeneous effects of ATX-II, which preferentially prolong the APD of M cells, can shift the location of the ventricular myocytes. This shift results in significantly altered transmural patterns of action potential durations, which would be expected to change localized refractory period and excitability. These cellular changes give rise to alterations in the corresponding surface electrograms and may change the overall substrates for conduction and rhythm disturbances.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.001 |
| 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".