Rotor Termination in Cholinergic Paroxysmal Atrial Fibrillation by Small-Conductance Calcium-Activated K+ Channels Inhibition and Isoproterenol: a Computational Study

Chiara Celotto1, Carlos S├ínchez2, Konstantinos Mountris3, Pablo Laguna1, Esther Pueyo1
1University of Zaragoza, 2Centro Universitario de la Defensa de Zaragoza, 3Aragon Institute of Engineering Research, University of Zaragoza, IIS Aragon


Abstract

Hyperactivity of the parasympathetic nervous system has been linked to the onset of paroxysmal atrial fibrillation (AF). Recent investigations have proven inhibition of small-conductance calcium-activated potassium (SK) channels to improve adverse cholinergic effects in the atria. It has also been reported that beta-adrenergic stimulation by Isoproterenol (Iso) can act as a brake to lessen cholinergic effects on atrial tissue. Furthermore, the combination of SK channel block (SKb) and Iso has been suggested to possibly prolong atrial APD in ACh-stimulated myocytes. In this study, computational modeling was used to test individual and combined effects of SKb and Iso in terminating a stable rotor in a cholinergic AF model of human atria. 2D tissues with uniform ACh concentrations of 0.01 or 0.1 muM were simulated. After stable rotors were initiated, 1 muM Iso and/or complete SKb were progressively applied over time following different application kinetics. Both Iso alone and the combination of Iso and SKb were able to terminate rotors for the two ACh concentrations. SKb was only able to terminate the rotor for the lower ACh concentration. In conclusion, the results from this study support beta-adrenergic stimulation and SK channel block, the latter with less efficacy, as potential options to terminate rotors in parasympathetically-stimulated human atria.