Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade
Bibliographic record
Abstract
BACKGROUND: The development of effective and safe antiarrhythmic drugs for atrial fibrillation (AF) rhythm control is an unmet clinical need. Multichannel blockers are believed to have advantages over single-channel blockers for AF, but their development has been completely empirical to date. We tested the hypothesis that adding K(+)-channel blockade improves the atrium-selective electrophysiological profile and anti-AF effects of optimized Na(+)-channel blockers. METHODS AND RESULTS: Realistic cardiomyocyte-, tissue-, and state-dependent Na(+)-channel block mathematical models, optical mapping, and action potential recording were used to study the effect of Na(+)-current (INa) blockade with or without concomitant inhibition of the rapid or ultrarapid delayed-rectifier K(+) currents (IKr and IKur, respectively). In the mathematical model, maximal AF selectivity was obtained with an inactivated-state Na(+)-channel blocker. Combining optimized Na(+)-channel blocker with IKr block increased rate-dependent and atrium-selective peak INa reduction, increased AF selectivity, and more effectively terminated AF compared with optimized Na(+)-channel blocker alone. Combining optimized Na(+)-channel blocker with IKur block had similar effects but without IKr block-induced ventricular action potential prolongation. Consistent with the mathematical model, in coronary-perfused canine hearts, the addition of dofetilide (selective IKr blocker) to pilsicainide (selective INa blocker) produced enhanced atrium-selective effects on maximal phase 0 upstroke and conduction velocity. Furthermore, pilsicainide plus dofetilide had higher AF termination efficacy than pilsicainide alone. Pilsicainide alone had no statistically significant effect on AF inducibility, whereas pilsicainide plus dofetilide rendered AF noninducible. CONCLUSIONS: K(+)-channel block potentiates the AF-selective anti-AF effects obtainable with optimized Na(+)-channel blockade. Combining optimized Na(+)-channel block with blockade of atrial K(+) currents is a potentially valuable AF-selective antiarrhythmic drug strategy.
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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 | 0.000 |
| 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".