Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

Atrial micro-RNAs regulate expression of the TASK-1 potassium channel and are associated with myocardial dilatation in patients with atrial fibrillation
F. Wiedmann1, M. Kraft1, A. Büscher2, S. Kallenberger3, A. Paasche1, P. L. Blochberger1, R. Arif4, J. Kremer4, G. Warnecke4, M. Karck4, N. Frey1, C. Schmidt1
1Klinik für Innere Med. III, Kardiologie, Angiologie u. Pneumologie, Universitätsklinikum Heidelberg, Heidelberg; 2Klinik für Kardiologie II - Rhythmologie, Universitätsklinikum Münster, Münster; 3Digital Health Center, Berlin Institute of Health (BIH), Berlin; 4Klinik für Herzchirurgie, Universitätsklinikum Heidelberg, Heidelberg;
Background/Introduction: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. However, underlying molecular mechanisms are insufficiently understood. Previous studies suggested that microRNA dependent gene regulation plays an important role in the initiation and maintenance of AF. The two-pore-domain potassium channel TASK-1 is an atrial-specific ion channel which is upregulated in AF. Inhibition of TASK-1 current prolongs the atrial action potential duration to similar levels as in patients with sinus rhythm (SR). 
Purpose: Here, we hypothesize that miRNAs might be responsible for the regulation of KCNK3 that encodes for TASK-1. 
Methods and Results: We selected miRNAs potentially regulating KCNK3 and studied their expression in atrial tissue samples obtained from patients with SR, paroxysmal AF or permanent/chronic AF. MiRNAs differentially expressed in AF were further investigated for their ability to regulate KCNK3 mRNA and TASK-1 protein expression in hiPSCs transfected with miRNA mimics or inhibitors. Thereby, we observed that miR-34a increases TASK-1 expression and current, and further decreases the resting membrane potential of Xenopus laevis oocytes, heterologously expressing hTASK-1. Finally, we investigated associations between miRNA expression in atrial tissues and clinical parameters of our patient cohort. A cluster containing AF stage, LV EDD, LV ESD, LA diameter, atrial COL1A2, and TASK-1 protein level was associated with increased expression of miR-25, miR-21, miR-34a, miR-23a, miR-124, miR-1, and miR-29b as well as decreased expression of miR-9 and miR-485. 
Conclusion: These results elucidate the important pathophysiological involvement of miRNAs in regulating the expression of the TASK-1 potassium channel in atria of patients with atrial cardiomyopathy.
 

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