Résumé
Atrial fibrillation (AF) is the most frequent sustained cardiac arrhythmia worldwide. Several mechanisms have been described in AF pathogenesis and sustainability such as dysregulation of calcium cycling and action potential (AP) duration. Effectors involved in these dysregulations are potential relevant therapeutic targets. Among them, the Exchange Proteins directly Activated by cAMP (EPAC) has been shown to increase arrhythmogenic activity in ventricular cardiomyocytes by lengthening of AP duration. However, the electrophysiological impact of EPAC at the atrial level remains to be established.
To evaluate the propensity of EPAC activation to induce atrial arrhythmogenic activity and by which mechanisms.
Myocytes from human right atrial appendages and wild type (WT) and EPAC1-/- mice atria were dissociated by enzymatic digestion. AP and potassium currents were recorded using the whole cell configuration of the patch clamp technique. EPAC proteins were pharmacologically activated by acute superfusion of 8-CPTAM (10μM), and the selective role of EPAC1 was evaluated by its selective inhibition by superfusion of AM-001 (20μM).
In mouse atrial myocytes, activation of EPAC by 8-CPTAM significantly increases AP duration at 90% of repolarization (APD90). Interestingly, this effect is higher in WT myocytes than in EPAC1-/-. Moreover, AM-001, which fails to correct AP lengthening in EPAC1-/- myocytes, reverses partially but significantly the effect of 8-CPTAM in WT myocytes. In human atrial myocytes, 8-CPTAM treatment lengthens APD90 by 32.3%. Additionally, in both WT mouse and human atrial myocytes, the treatment by 8-CPTAM induces an inhibition of both peak and sustained components of the K+ currents. Finally, effect of 8-CPTAM on K+ currents seems to be weaker in EPAC1-/- myocytes than in WT.
Our results show that EPAC activation lengthens AP duration in mouse and human atrial myocytes. Furthermore, inhibition of K+ currents participates in this AP duration modulation. Thus, these data suggest that EPAC proteins might be involved in atrial arrhythmogenic ectopic activity. Nevertheless, the role of each isoform of EPAC in these modulations and EPAC-induced regulation of other ionic currents remain to be specified.