Dynamical effects of calcium‐sensitive potassium currents on voltage and calcium alternans

Abstract

Cardiac alternans is a precursor to life-threatening arrhythmias. Alternans can be caused by instability of the membrane voltage (V ), instability of the intracellular Ca ( Ca i2+) cycling, or both. V dynamics and Ca i2+ dynamics are coupled via Ca -sensitive currents. In cardiac myocytes, there are several Ca -sensitive potassium (K ) currents such as the slowly activating delayed rectifier current (I ) and the small conductance Ca -activated potassium (SK) current (I ). However, the role of these currents in the development of arrhythmias is not well understood. In this study, we investigated how these currents affect voltage and Ca alternans using a physiologically detailed computational model of the ventricular myocyte and mathematical analysis. We define the coupling between V and Ca i2+ cycling dynamics ( Ca i2+→V coupling) as positive (negative) when a larger Ca transient at a given beat prolongs (shortens) the action potential duration (APD) of that beat. While positive coupling predominates at baseline, increasing I and I promote negative Ca i2+→V coupling at the cellular level. Specifically, when alternans is Ca -driven, electromechanically (APD-Ca ) concordant alternans becomes electromechanically discordant alternans as I or I increase. These cellular level dynamics lead to different types of spatially discordant alternans in tissue. These findings help to shed light on the underlying mechanisms of cardiac alternans especially when the relative strength of these currents becomes larger under pathological conditions or drug administrations.

Mesenchymal stem cell differentiation: Control by calcium‐activated potassium channels

“…Intracellular Ca 2+ also affected V m oscillations. Thus, in ventricular myocytes, a modeling study indicated that increasing [Ca 2+ ] i would prolong the oscillation period at baseline SK currents but reduce it at higher current levels (Kennedy, Bers, Chiamvimonvat, & Sato, ). Taken together, the spatiotemporal characteristics of intracellular Ca 2+ and V m oscillations, dependent on the tissue specificity of the associated K Ca current(s), could direct the resulting differentiation.…”

“…Intracellular Ca 2+ also affected V m oscillations. Thus, in ventricular myocytes, a modeling study indicated that increasing [Ca 2+ ] i would prolong the oscillation period at baseline SK currents but reduce it at higher current levels (Kennedy, Bers, Chiamvimonvat, & Sato, 2016).…”

Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

“…It is now well recognized that an important component of Na + channel regulation is due to Ca 2+ , calmodulin (CaM) and CaM-dependent protein kinase II (CaMKII) pathway that affects channel function [55]. L-type Ca 2+ (ICaL) and sodium(Na + )-Ca 2+ exchanger currents are Ca 2+ -sensitive, as well as the slowly activating delayed rectifier current IKs, which plays an important role in regulating action potential duration [56]. Although in this work we did not perform electrophysiological measurements on isolated ventricular myocytes, we can speculate on the potential effects of increased SERCA2 activity, based on several findings reported in the present study.…”

From channels to systems: Ca2+‐sensitive K+ currents, alternans and cardiac arrhythmia

“…Either approach seeks to demonstrate arrhythmogenesis at the systems level and then to resolve underlying cellular mechanisms in the corresponding model system. An important computational study in this Journal of Physiology issue (Kennedy et al 2017) investigated effects of the Ca 2+ -activated, slowly activating delayed rectifier and small conductance potassium (SK) channels, respectively carrying I Ks and I SK , on pro-arrhythmic instabilities producing AP duration (APD) alternans. Such alternans can reflect membrane potential (V m (t)) instabilities from steep dependences of APD restitution upon diastolic interval (DI) and are known clinically to presage major ventricular arrhythmias.…”