Abstract

Efforts to identify the mechanisms that are responsible for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in one or more elements of the atrial 'substrate'. These correspond to the electrophysiological properties and/or structural elements. We have used experimentally validated mathematical models of the human atrial myocyte action potential, both at baseline in sinus rhythm (SR) and in the setting of chronic AF, to identify significant contributions of the Ca2+-independent transient outward K+ current, Ito, to electrophysiological instability and arrhythmia initiation. Specifically, our initial simulations explored whether changes in the recovery or restitution of the action potential duration (APD), and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified spatial differences in the expression levels of specific K+ channel alpha-subunits that underlie Ito in the left atrium. We observed that following replacement of 50% of the native Ito current, Kv4.3; and its replacement with Kv1.4, significant changes in the stability of human atrial action potential waveform arose. This isoform switch resulted in discontinuities in the initial slope of the APD restitution curve and APD alternans sometimes emerged. Important insights into cellular mechanisms for these changes are based on known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. The emerging pattern of in silico results resemble some of the changes observed in high resolution MAP recordings during clinical electrophysiological studies. The resulting insights provide a basis for considering novel Kv1.4-based pharmacological treatment(s) in management of AF.

View details for PubMedID 30576220