Mechanisms of spontaneous pacing: sinoatrial nodal cells, neonatal cardiomyocytes, and human stem cell derived cardiomyocytes
Bibliographic record
Abstract
The sinoatrial (SA) node is the primary site from which the mammalian heart is paced, but the mechanisms underlying the pacemaking still remain clouded. It is generally believed that the hyperpolarization-activated current I f , encoded by hyperpolarization-activated cyclic nucleotide–gated (HCN) genes, contributes significantly to pacing, which in tandem with inward current generated by efflux of Ca 2+ via the Na + –Ca 2+ exchanger (NCX), resulting from the released Ca 2+ , mediates the diastolic depolarization. Here, we review the data that implicate I f as the “pacemaker current” and conclude that there is not only a significant discrepancy between the range of diastolic depolarization potential (–60 to –40 mV) and the activation potential of I f (negative to –70 mV), but that also the kinetics of I f and its pharmacology are incompatible with the frequency of a heartbeat in rodents and humans. We propose that I f serves as a functional insulator, which protects the SA-nodal cells against the large negative electrical sink of atrial tissue connected to it with connexins. We also evaluate the role of I f and calcium signaling in mediating the diastolic depolarization in rat neonatal cardiomyocytes (rN-CM), and human induced pluripotent stem-cell derived cardiomyocytes (hiPSC-CM), and provide evidence for a possible involvement of mitochondrial Ca 2+ in initiating the oscillatory events required for the spontaneous pacing.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.004 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".