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_m), instability of the intracellular Ca (Ca_i) cycling, or both. V_m dynamics and Ca_i 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_Ks) and the small conductance Ca-activated potassium (SK) current (I_SK). 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_m and Ca_i cycling dynamics (Ca_iV_m 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_Ks and I_SK promote negative Ca_iV_m coupling at the cellular level. Specifically, when alternans is Ca-driven, electromechanically (APD-Ca) concordant alternans becomes electromechanically discordant alternans as I_Ks or I_SK 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 relative strength of these currents becomes larger under pathological conditions or drug administrations.

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