Transient outward K⁺ current can strongly modulate action potential duration and initiate alternans in the human atrium

Abstract

Efforts to identify the mechanisms for the initiation and maintenance of human atrial fibrillation (AF) often focus on changes in specific elements of the atrial “substrate,” i.e., its electrophysiological properties and/or structural components. We used experimentally validated mathematical models of the human atrial myocyte action potential (AP), 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. First, we explored whether changes in the recovery or restitution of the AP duration (APD) and/or its dynamic stability (alternans) can be modulated by Ito. Recent reports have identified disease-dependent spatial differences in expression levels of the specific K+ channel α-subunits that underlie Ito in the left atrium. Therefore, we studied the functional consequences of this by deletion of 50% of native Ito (Kv4.3) and its replacement with Kv1.4. Interestingly, significant changes in the short-term stability of the human atrial AP waveform were revealed. Specifically, this K+ channel isoform switch produced discontinuities in the initial slope of the APD restitution curve and appearance of APD alternans. This pattern of in silico results resembles some of the changes observed in high-resolution clinical electrophysiological recordings. Important insights into mechanisms for these changes emerged from known biophysical properties (reactivation kinetics) of Kv1.4 versus those of Kv4.3. These results suggest new approaches for pharmacological management of AF, based on molecular properties of specific K+ isoforms and their changed expression during progressive disease. NEW & NOTEWORTHY Clinical studies identify oscillations (alternans) in action potential (AP) duration as a predictor for atrial fibrillation (AF). The abbreviated AP in AF also involves changes in K+ currents and early repolarization of the AP. Our simulations illustrate how substitution of Kv1.4 for the native current, Kv4.3, alters the AP waveform and enhances alternans. Knowledge of this “isoform switch” and related dynamics in the AF substrate may guide new approaches for detection and management of AF. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/k-channel-isoforms-regulate-human-atrial-arrhythmogenesis/ .

Electrical Restitution and Its Modifications by Antiarrhythmic Drugs in Undiseased Human Ventricular Muscle

“…The figure shows that there are marked differences both in the electrical restitution and steady-state frequency dependent curves. The nature and mechanism of the frequency dependent APD changes (Carmeliet, 1977;Elharrar and Surawicz, 1983;Obreztchikova et al, 2006;Qu et al, 2014;Ni et al, 2019) including electrical restitution are not fully resolved yet. A recent study of Schattock et al (2017) suggested that the slope of the restitution curve depends on the APD of the basic heart rate.…”

Cardiac transmembrane ion channels and action potentials: cellular physiology and arrhythmogenic behavior

“…The first hypothesis suggests that the steep slope of APD restitution is the alternans driver (852), and this mechanism of arrhythmia is replicated by the ten Tusscher-Noble-Noble-Panfilov model of human ventricular myocyte (732,733). As mentioned above, the ion channel background of APD alternans is attributed to the incomplete recovery and/or deactivation of different inward (I Na , I Ca ) or outward (I to , I Kr , I Ks , I Cl ) currents based on the gating behavior of these channels (841,842). In addition, intracellular ion concentration changes for Ca 21 and Na 1 rapidly or slowly would activate electrogenic NCX or Na 1 -K 1 pumps.…”

“…Local regional differences in the APD restitution curves (839) may also favor arrhythmogenesis (840). The ion channel background of cycle length-dependent APD changes including APD restitution is attributed to the incomplete recovery and/or deactivation of different inward (I Na , I Ca,L ) or outward (I to , I Kr , I Ks , I Cl ) currents based on the gating behavior of these channels (841,842). In addition, intracellular ion concentration changes for Ca 21 and Na 1 rapidly or slowly would activate electrogenic NCX or Na 1 -K 1 pumps.…”

Electrophysiological Mechanisms Underlying T-Wave Alternans and Their Role in Arrhythmogenesis

“…I to -mediated spike-and-dome AP morphology is linked to Brugada syndrome (BrS). TWA is widely observed in BrS and alternans occurs at normal heart rates in which the DI is still very long ( Ni et al, 2019 ). A possible mechanism of BrS based on experiments and computer simulations ( Miyoshi et al, 2005 ) indicates that dynamical instabilities that can cause alternans and other complex AP dynamics also promote dynamic substrates at the tissue level that, differently from static heterogeneity, can potentiate phase-2 reentry.…”