Molecular and Functional Relevance of Na V 1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model.
Nico HartmannMaria KnierimWiebke MaurerNataliya DybkovaGerd HasenfußSamuel SossallaKatrin Streckfuß-BömekePublished in: International journal of molecular sciences (2023)
In heart failure and atrial fibrillation, a persistent Na + current (I NaL ) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na V 1.8 contributes to arrhythmogenesis by inducing a I NaL . Genome-wide association studies indicate that mutations in the SCN10A gene (Na V 1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na V 1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A -KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I NaL and action potential duration. Ca 2+ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca 2+ leak. The I NaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na V 1.8. No effects on atrial APD 90 were detected in any groups. Both SCN10A KO and specific blockers of Na V 1.8 led to decreased Ca 2+ spark frequency and a significant reduction of arrhythmogenic Ca 2+ waves. Our experiments demonstrate that Na V 1.8 contributes to I NaL formation in human atrial CMs and that Na V 1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na V 1.8 could be a new target for antiarrhythmic strategies.
Keyphrases
- atrial fibrillation
- catheter ablation
- heart failure
- left atrial
- endothelial cells
- stem cells
- crispr cas
- left ventricular
- induced pluripotent stem cells
- gene expression
- high glucose
- brain injury
- genome editing
- case report
- venous thromboembolism
- climate change
- subarachnoid hemorrhage
- depressive symptoms
- mesenchymal stem cells
- angiotensin ii
- dna methylation
- single molecule