P5302SCN10A/NaV1.8 channels play a critical role in cellular electrophysiology and arrhythmogenesis of the failing human heart
Bibliographic record
Abstract
In heart failure (HF), persistent current through Na channel (INaL) is enhanced and may lead to arrhythmias. However, the role of neuronal sodium channel NaV1.8 in HF is unknown. Here, we investigated the regulation and electrophysiological contribution of NaV1.8 in the human failing heart. Co-immunocytochemistry showed that NaV1.8 expressed at both T-tubules and intercalated disk and overlapped with Ca/Calmodulin Kinase II (CaMKII) in human and mouse ventricular myocytes. Western blot revealed significant upregulation of NaV1.8 in human HF (n=8), whereas the predominant cardiac isoform NaV1.5 is downregulated compared to non-failing (NF, n=10) myocardium (P<0.05). Co-immunoprecipitation showed a significant interaction between NaV1.8 and CaMKII in HF and NF (n=3 vs. 3). Whole-cell patch clamp showed a potent reduction in both INaL integral and action potential duration (APD) after inhibition with novel Nav1.8 specific blockers either A-803467 (30 nmol/L) or PF-01247324 (1 μmol/L) in ventricular human failing myocytes. Importantly, the incidence of arrhythmias per time presented in the form of delayed afterdepolarizations and spontaneous action potentials were significantly suppressed after addition of PF-01247324 in isoproterenol (ISO, 30 nmol/L) treated ventricular cardiomyocytes isolated from patients with HF. Furthermore, using confocal microscopy (Fluo4 AM), we studied the diastolic Ca spark frequency (CaSpF). In HF, both A-803467 and PF-01247324 resulted in significant decrease of CaSpF (∼43%). Additionally, we measured INaL, APD and CaSpF in mouse ventricular cardiomyocytes lacking Nav1.8 (SCN10A−/−) vs. wild-type (WT). In WT, the addition of ISO resulted in increase of INaL (control:-54.88±3.96 vs. ISO: -78.47±3.85 A*ms*F-1, n=10 vs. 19, P<0.01) and CaSpF (control: 0.2±0.1 vs. ISO: 0.7±0.1 μm–1 s–1, n=87 vs. 65; P<0.0001). Importantly, in SCN10A−/− ISO-dependent increase in INaL was completely abolished, while CaSpF was reduced compare with WT (P<0.05). Furthermore, we observed a significantly abbreviated APD90 in ISO-stimulated cardiomyocytes from SCN10A−/− compared with WT (P<0.05). Preincubation with the both inhibitors significantly reversed the ISO-dependent enhancement of INaL, APD90 and CaSpF in WT myocytes, but not in SCN10A−/−.
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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) | 0.005 | 0.001 |
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".