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 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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 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".