Experimental–geneticChanges in microRNA-1 expression and IK1 up-regulation in human atrial fibrillation
Introduction
Atrial fibrillation (AF) maintenance is importantly related to changes in atrial electrical and structural properties.1 Electrical remodeling occurs early during the course of AF and leads to characteristic changes in action potential shape and duration, whereas structural alterations develop more slowly.2
Up-regulation of inward rectifier currents (IK1 and IKACh,c) is a hallmark of AF-associated electrical remodeling.3 AF-related inward current changes have consistently been shown in animal models4 and in human disease.5, 6 Inward rectifier current up-regulation is an important contributor to stabilization of atrial rotors and thus of AF persistence caused by electrical remodeling.7 In line with these concepts, overexpression of inwardly rectifying potassium channel (Kir)2.1 channels (underlying IK1) generates stable and very fast rotors in mouse ventricles, providing direct evidence for a role of IK1 in reentry stabilization.8
In addition, primary changes in electrical properties (e.g., in genetically determined arrhythmia syndromes) may occasionally create a specific substrate for AF. Such changes include gain-of-function mutations of the Kir2.1-encoding KCNJ2 gene associated with familial AF or the short QT syndrome.9, 10 Affected patients may present with AF at an unusually young age, suggesting that IK1 up-regulation may be a causative factor rather than a (mal-)adaptive response in these cases.
IK1 decrease may similarly be pro-arrhythmic and has been reported in patients with chronic coronary artery disease (CAD).11 Recent evidence suggests a potential regulatory role of microRNA in reduction of human Kir2.1 in this setting.11 Expression of the inhibitory microRNA 1 (miR-1) was increased in patients with CAD and could exacerbate experimental arrhythmogenesis by slowing conduction and depolarizing cell membranes through a post-transcriptional repression of KCNJ2 (encoding Kir2.1) and GJA1 (encoding connexin [Cx] 43).11
Whether miR-1 expression changes with AF is unknown. Furthermore, the role of atrial rate in any AF-related miR-1 changes and any concomitant Kir2.1 expression changes is also unknown. The present study was designed to investigate changes of Kir subunits in relation to alterations in miR-1 expression in human AF, and to use in vitro paced human atrial tissue slices to evaluate the specific role of activation rate.
Section snippets
Patient recruitment
All patients provided written informed consent to participate. Left atrial (LA) tissue samples were collected from patients undergoing mitral valve repair in accordance with the local ethics committee at the Goethe-Universität, Frankfurt (Nr. 54/05). Patients older than 18 years with preserved systolic left ventricular function (ejection fraction >40%) and an indication for surgical repair of mitral valve disease were asked to participate. Exclusion criteria were: paroxysmal AF (as documented
Patient characteristics
Patient characteristics are presented in Table 3. AF patients had greater LA diameters than those with SR. Otherwise, patient characteristics were similar; in particular, mean age, the degree of mitral valve regurgitation, and systolic left ventricular function were comparable.
Electrophysiological recordings
Ionic currents were recorded with a ramp protocol (3-s duration; from −100 to +40 mV) from a holding potential of −40 mV. Inward currents at −100 mV elicited from LA cells of patients with AF (N = 5 cells, 4 patients)
Discussion
The results of our study show increased IK1 in LA cardiomyocytes of AF patients, which was associated with increased Kir2.1 expression and reduced levels of inhibitory miR-1. Similar changes in Kir2.1 and miR-1 expression were reproduced by atrial tachypacing. Reduced levels of miR-1 may play a role in increased expression of Kir2.1. There were no changes in Cx43 expression or localization, suggesting differential regulatory pathways for Kir2.1 and Cx43 expression.
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Dr. Ehrlich received support from Hans und Gertie Fischer–Stiftung and Adolf Messer–Stiftung. Dr Nattel was supported by the Canadian Institutes of Health Research (MOP 44365). Dr. Biliczki was the recipient of a postdoctoral fellowship of the Deutsche Gesellschaft für Kardiologie. Mrs. Girmatsion received an award from the August Scheidel–Stiftung.
Drs. Girmatsion and Biliczki contributed equally to this work.
The authors thank Sabine Harenkamp for expert technical assistance.