The high incidence of idiopathic atrial fibrillation (AF) among young subjects highlights the need of identifying potential electrophysiological profiles favoring AF induction. Here, we investigate how specific ionic current distributions can present the electrical restitution properties that facilitate AF inducibility in the absence of structural inhomogeneities.
Action potential duration (APD) and conduction velocity (CV) restitution (APDR and CVR) were evaluated in a population of 22000 atrial electrophysiology models. Every model presenting steep APDR and CVR was included in both chambers of a bi-arial mesh. A population of virtual whole-atria models was developed using always the same bi-atrial mesh and considering a different electrophysiology model each time. The ionic current densities of the models favoring AF inducibility after burst pacing at the pulmonary veins were compared against the remaining population.
Results revealed that cellular models presenting down-regulation of the ultra-rapid potassium current (IKur) and up-regulation of the L-type calcium cur-rent (ICaL), sodium current (INa) and inward rectifier potassium current (IK1) presented higher susceptibility to AF induction. The long plateau resulting from decreased IKur and increased ICaL prompted strong APD modulations in the presence of premature stimuli. Since these electrophysiology models had high cellular excitability, due to INa and IK1 up-regulation, all ectopic beats propagated to the atria. The combination of steep electrical restitution, that favored dynamic heterogeneities in repolarization, and enhanced cellular excitability, that enabled the propagation of rapid firing, was essential for AF inducibility.
This study shed light on how loss-of-function KCNA5 (IKur) and gain-of-function SCN5A (INa), Cav1.2 (ICaL) and KCNJ2 (IK1) might be related to idiopathic AF. Moreover, it provides a mechanistic basis to the recommendations outlined in the current ESC guidelines, which state that pharmacological treatment that attempts to reduce the cellular excitability to cardiovert AF should be the first-line treatment in hemodynamically stable patients without cardiovascular disease.