Small-conductance Ca2+-activated K+ channels promote J-wave syndrome and phase-2 reentry

Background: Small-conductance Ca2+-activated potassium (SK) channels play complex roles in cardiac arrhythmogenesis. SK channels colocalize with L-type Ca2+ channels, yet how this colocalization affects cardiac arrhythmogenesis is unknown. Objective: The purpose of this study was to investigate the role of colocalization of SK channels with L-type Ca2+ channels in promoting J-wave syndrome and ventricular arrhythmias. Methods: We carried out computer simulations of single-cell and tissue models. SK channels in the model were assigned to preferentially sense Ca2+ in the bulk cytosol, subsarcolemmal space, or junctional cleft. Results: When SK channels sense Ca2+ in the bulk cytosol, the SK current (ISK) rises and decays slowly during an action potential, the action potential duration (APD) decreases as the maximum conductance increases, no complex APD dynamics and phase 2 reentry can be induced by ISK. When SK channels sense Ca2+ in the subsarcolemmal space or junctional cleft, ISK can rise and decay rapidly during an action potential in a spike-like pattern because of spiky Ca2+ transients in these compartments, which can cause spike-and-dome action potential morphology, APD alternans, J-wave elevation, and phase 2 reentry. Our results can account for the experimental finding that activation of ISK induced J-wave syndrome and phase 2 reentry in rabbit hearts. Conclusion: Colocalization of SK channels with L-type Ca2+ channels so that they preferentially sense Ca2+ in the subsarcolemmal or junctional space may result in a spiky ISK, which can functionally play a similar role of the transient outward K+ current in promoting J-wave syndrome and ventricular arrhythmias

Cardiac Memory in the Genesis of Arrhythmias

Dynamical instabilities in the heart promote arrhythmias and sudden cardiac death (SCD), one of the most common causes of death in individuals with cardiovascular disease. Beat-to-beat changes in electrophysiological properties at the cellular level can promote arrhythmogenesis at the whole-heart level, yet the precise mechanisms are not well understood. Cardiac cells possess memory, whereby certain physiological properties depend on the prior history. Here, we analyze the effects of short-term cardiac memory from two sources: the slow recovery of ion channels and the slow accumulation of ion concentrations over time. We demonstrate that under diseased conditions, namely early repolarization syndrome and long QT syndrome, action potentials become unstable during fixed pacing due to enhanced effects of memory on action potential duration. We develop new iterated map models that explicitly incorporates the effects of memory on action potential duration, and show that the dynamics of the iterated map models match very closely to the dynamics of detailed action potential models. Using the iterated map models, we propose new techniques of controlling action potential instability under the influence of memory and confirm their efficacy in the detailed action potential models. Finally, we show that action potential instability at the cellular level can generate arrhythmias at tissue-scale levels. In a model of early repolarization syndrome driven by activation of small-conductance Ca2+-activated K+ (SK) channels, action potential instability promotes phase 2 reentry. Spiral wave dynamics become unstable due to early repolarization driven by the transient outward K+ current (Ito), suggesting that action potential instability induced by memory is a mechanism of arrhythmias like ventricular fibrillation

Cardiac Memory in the Genesis of Arrhythmias

Dynamical instabilities in the heart promote arrhythmias and sudden cardiac death (SCD), one of the most common causes of death in individuals with cardiovascular disease. Beat-to-beat changes in electrophysiological properties at the cellular level can promote arrhythmogenesis at the whole-heart level, yet the precise mechanisms are not well understood. Cardiac cells possess memory, whereby certain physiological properties depend on the prior history. Here, we analyze the effects of short-term cardiac memory from two sources: the slow recovery of ion channels and the slow accumulation of ion concentrations over time. We demonstrate that under diseased conditions, namely early repolarization syndrome and long QT syndrome, action potentials become unstable during fixed pacing due to enhanced effects of memory on action potential duration. We develop new iterated map models that explicitly incorporates the effects of memory on action potential duration, and show that the dynamics of the iterated map models match very closely to the dynamics of detailed action potential models. Using the iterated map models, we propose new techniques of controlling action potential instability under the influence of memory and confirm their efficacy in the detailed action potential models. Finally, we show that action potential instability at the cellular level can generate arrhythmias at tissue-scale levels. In a model of early repolarization syndrome driven by activation of small-conductance Ca2+-activated K+ (SK) channels, action potential instability promotes phase 2 reentry. Spiral wave dynamics become unstable due to early repolarization driven by the transient outward K+ current (Ito), suggesting that action potential instability induced by memory is a mechanism of arrhythmias like ventricular fibrillation

Spatially Discordant Repolarization Alternans in the Absence of Conduction Velocity Restitution

Spatially discordant alternans (SDA) of action potential duration (APD) has been widely observed in cardiac tissue and is linked to cardiac arrhythmogenesis. Theoretical studies have shown that conduction velocity restitution (CVR) is required for the formation of SDA. However, this theory is not completely supported by experiments, indicating that other mechanisms may exist. In this study, we carried out computer simulations using mathematical models of action potentials to investigate the mechanisms of SDA in cardiac tissue. We show that when CVR is present and engaged, such as fast pacing from one side of the tissue, the spatial pattern of APD in the tissue undergoes either spatially concordant alternans or SDA, independent of initial conditions or tissue heterogeneities. When CVR is not engaged, such as simultaneous pacing of the whole tissue or under normal/slow heart rates, the spatial pattern of APD in the tissue can have multiple solutions, including spatially concordant alternans and different SDA patterns, depending on heterogeneous initial conditions or pre-existing repolarization heterogeneities. In homogeneous tissue, curved nodal lines are not stable, which either evolve into straight lines or disappear. However, in heterogeneous itssue, curved nodal lines can be stable, depending on their initial locations and shapes relative to the structure of the heterogeneity. Therefore, CVR-induced SDA and non-CVR-induced SDA exhibit different dynamical properties, which may be responsible for the different SDA properties observed in experimental studies and arrhythmogenesis in different clinical settings

Memory-Induced Chaos in Cardiac Excitation.

Excitable systems display memory, but how memory affects the excitation dynamics of such systems remains to be elucidated. Here we use computer simulation of cardiac action potential models to demonstrate that memory can cause dynamical instabilities that result in complex excitation dynamics and chaos. We develop an iterated map model that correctly describes these dynamics and show that memory converts a monotonic first return map of action potential duration into a nonmonotonic one, resulting in a period-doubling bifurcation route to chaos

Memory-Induced Chaos in Cardiac Excitation

Excitable systems display memory, but how memory affects the excitation dynamics of such systems remains to be elucidated. Here we use computer simulation of cardiac action potential models to demonstrate that memory can cause dynamical instabilities that result in complex excitation dynamics and chaos. We develop an iterated map model that correctly describes these dynamics and show that memory converts a monotonic first return map of action potential duration into a nonmonotonic one, resulting in a period-doubling bifurcation route to chaos