ArticleJournal of translational medicine2025
Synergistic antiarrhythmic mechanism of I
Article in Journal of translational medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
1 citing paper in PubMed.
- Predicting recurrence in silent corticotroph adenomas: a habitat analysis and comprehensive nomogram approach.Neuroradiology · 2026Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors.
Funding
Abstract
backgroundArrhythmias represent a leading cause of mortality among individuals with cardiovascular diseases. Considering the failure of antiarrhythmic drugs targeting single-ion channels in clinical trials, this study aims to evaluate the pharmacodynamics of various combinations of single-channel blockers to identify safer and more effective therapeutic regimens.
methodsThe antiarrhythmic effects of inhibitors alone and pairwise combination strategies targeting late sodium current (INa-L), hERG potassium current (IKr), ryanodine receptor 2 (RyR2), and L-type calcium current (ICa-L) inhibitors via a checkerboard dosing approach were evaluated in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Comprehensive evaluation based on synergy scoring, efficacy, and toxicity (SynergyFinder) was performed to identify the preferred combination with high efficacy and low toxicity. The effectiveness of the preferred combination was further validated in isolated perfused guinea pig hearts. In addition, an analysis of the effects of the preferred combination on calcium sparks and Ca2+/calmodulin-dependent protein kinase II (CaMKII) was conducted.
resultsA combination regimen of the INa-L inhibitor GS967 and the RyR2 inhibitor Dantrolene, which exhibited highly effective, low-toxicity synergistic antiarrhythmic properties, was identified through checkerboard high-throughput screening. An alternative combination of the INa-L blocker Eleclazine and the RyR2 inhibitor TMDJ-035 showed similar therapeutic efficacy, indicating that the effectiveness of the preferred combination stems from target-mediated effects. The combination further demonstrated significant efficacy in multiple hiPSC-CM arrhythmia models and an ex vivo guinea pig heart reperfusion arrhythmia model. Mechanistic studies revealed that the dual-target inhibition strategy corrected pathological calcium sparks and calcium cycling dysfunction, downregulated the CaMKII-RyR2 phosphorylation cascade, thereby restoring electrical signaling.
conclusionsThe combination of INa-L and RyR2 inhibitors exerts safer and more effective antiarrhythmic effects. This combinational therapeutic strategy provides a theoretical basis for developing novel antiarrhythmic regimens based on dual-target regulation, demonstrating significant translational medical potential and warranting further clinical evaluation.
Indexed as
Identifiers
What Socratic holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.