Ion channel remodeling in response to variations in heart rate
Why this work is in the frame
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Bibliographic record
Abstract
A downregulation of the transient outward K+ current (Ito) is a common finding in hypertrophy; tachypacing induced heart failure, which can lead to lethal arrhythmias and sudden death as a result of action potential prolongation.To better understand how variations in heart rate may affect the electrical properties of the heart, based on an in vitro tachypacing model, we compared frequency-dependent changes in adult epicardial (Epi) versus endocardial (Endo) canine cells. Thus, Ito was recorded with whole-cell patch-clamp in Endo and Epi cardiomyocytes after 24-hr culture under continuous electrical stimulation at either 1-Hz (normal rate) or 3-Hz (tachycardia). Ca2+ transient amplitudes (Indo1-AM) were recorded from En-do and Epi cells at 0hr, 2hr, 4hr, 8hr and 24hr after continuous electrical stimulation at either 1-Hz or 3-Hz. Analysis of inactivation/reactivation kinetics, activation/inactivation voltage dependence properties showed no difference between 1- and 3-Hz paced cells for either cell type. Tachypacing (3Hz pacing) reduced Ito density and Kv4.3 mRNA ex-pression in Epi cells but not in Endo. Ca2+-chelation by BAPTA-AM, prevented rate-dependent Ito downregulation in Epi cells, increasing Ito in tachypaced cells by ~47%. In Endo cells, BAPTA-AM increased Ito by ~200% in a rate-independent way. Con-sistent with the larger Endo response to Ca2+-chelation, Ca2+ transient amplitudes were greater in Endo (85±4 nM) than Epi (46±2 nM) cells. Ca2+ transient amplitude increased at early stages of tachypacing in Epi cells (i.e. 64.2±4.2 from 40.7±3.5 nM), in contrast to Endo cells. Inhibition of the calcineurin/NFAT pathway prevented rate-dependent Ito decrease in tachypaced Epi cells, without affecting Endo Ito.Our findings show that fast firing rate induces a different response in the regulation of Ito in adult Epi and Endo cells, which might be related to differential control by calcium-dependent signaling systems.
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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 | 0.040 | 0.236 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.006 | 0.009 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.002 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| 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 it