Ion channel remodeling in response to variations in heart rate
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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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".