The role of the slow component of cardiac delayed rectifier potassium current in ventricular repolarization, fibrillation and proarrythmia
Bibliographic record
Abstract
The contribution of the slow component of the cardiac delayed rectifier K+ current (IKs) to ventricular repolarization, fibrillation and proarrhythmia is not fully understood. We investigated the rate-dependent interactions of IKs with the rapid component of delayed rectifier (IKr), the sodium window current and the inward rectifier K+ current (IK1), and studied the role of IKs activation in ventricular fibrillation and during beta-adrenergic stimulation. Furthermore, we investigated whether IKs block can induce Torsades de Pointes (TdP) during drug-induced action potential (AP) prolongation, and evaluated the relationship between the extent of drug-induced AP prolongation and TdP incidence. IKs is a latent current that contributes little to ventricular repolarization during the basal state, but contributes more significantly during prolongation of the plateau or early phase 3 repolarization; such prolongation was induced by IKr block (where adding IKs block increased reverse rate-dependence) or slowing of sodium channel inactivation, in perfused rabbit hearts. IKs was not activated when the late portion of phase 3 repolarization was prolonged by IK1 block. IKs was activated during beta-adrenergic stimulation by isoproterenol in perfused rabbit hearts, and IKs block by HMR 1556 lowered the defibrillation threshold in rabbits in vivo. In bradycardic perfused rabbit hearts with drug-induced AP prolongation (through combined IKr block by dofetilide and slowing of sodium channel inactivation by veratridine), spontaneous TdP was induced. Despite no further AP prolongation, subsequent addition of IKs block promoted TdP, likely mediated by an increase in dispersion and beat-to-beat variability in ventricular repolarization. When AP duration was prolonged by combining veratridine and increasing concentrations of dofetilide, TdP appeared at moderate AP prolongation but not during extreme prolongation. Subsequent moderate shortening of the AP by isoproterenol (which activates IKs) and pinacidil (which activates ATP-sensitive K + current) re-induced TdP. In summary, IKs is a "reserve current" which protects against TdP development. Although IKs blockers may be antifibrillatory, they may promote TdP when the AP is prolonged by drugs, genetic mutations or heart failure. There is a biphasic relationship between TdP incidence and AP duration---there exists a "Torsadogenic Zone" which defines the AP duration at which TdP occurs.
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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 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".