Irregularly Appearing Early Afterdepolarizations in Cardiac Myocytes: Random Fluctuations or Dynamical Chaos?

Abstract

Irregularly occurring early afterdepolarizations (EADs) in cardiac myocytes are traditionally hypothesized to be caused by random ion channel fluctuations. In this study, we combined 1), patch-clamp experiments in which action potentials were recorded at different pacing cycle lengths from isolated rabbit ventricular myocytes under several experimental conditions inducing EADs, including oxidative stress with hydrogen peroxide, calcium overload with BayK8644, and ionic stress with hypokalemia; 2), computer simulations using a physiologically detailed rabbit ventricular action potential model, in which repolarization reserve was reduced to generate EADs and random ion channel or path cycle length fluctuations were implemented; and 3), iterated maps with or without noise. By comparing experimental, modeling, and bifurcation analyses, we present evidence that noise-induced transitions between bistable states (i.e., between an action potential with and without an EAD) is not sufficient to account for the large variation in action potential duration fluctuations observed in experimental studies. We conclude that the irregular dynamics of EADs is intrinsically chaotic, with random fluctuations playing a nonessential, auxiliary role potentiating the complex dynamics.

Bifurcation Analysis of a Certain Hodgkin-Huxley Model Depending on Multiple Bifurcation Parameters

“…Further, the membrane capacitance is given by C m = 1 µF/cm 2 , cf. [1,20,27]. As we already mentioned, the gating variables are important for the opening and closing of the different ion channels.…”

“…Later we will give more details on their approach and how it differs from our ansatz, please see Section 3.2. In this paper, the authors chose the model from [20] and considered a modified reduced version, which they final reduced to a two-dimensional model (fast subsystem) for their investigation. Using their approach the authors in [1] have shown that EADs can occur during the transition between stable steady states.…”

Stochastic initiation and termination of calcium-mediated triggered activity in cardiac myocytes

“…During normal activity, both the AP and the Ca 2+ transient are highly reproducible despite a high level of ion channel stochasticity. It is well understood that, except in special cases (6,(50)(51)(52), the noise in the voltage signal is averaged out at the whole-cell level by the fact that there is a very large number of voltage-gated ion channels of any given type and that voltage is spatially uniform on the scale of a myocyte. Similarly, the noise in the Ca 2+ signal in turn is averaged out by the fact that, during normal excitation-contraction coupling, CICR mediated by LCC openings is relatively synchronous, with a very large number of CRUs participating in the whole-cell Ca 2+ release.…”

Effects of Calcium-Channel Noise on Dynamics of Excitation-Contraction Coupling in Paced Cardiac Cells

“…In particular, nowadays there is an increasing interest to take into account the stochastic factors in heart dynamics [17][18][19][20][21][22][23][24]. There are millions of calcium channels distributed in the membrane as well as intracellular space of cardiac cells, leading to random fluctuations in calcium cycling system [21].…”

“…For instance, Tanskanen et al [23] took into account the stochastic gating of L-type calcium channels in their model, and Shuai and Jung [24] studied the stochasticity of intracellular calcium release mechanism due to the random opening and closing of calcium channels. In addition, to study the effects of random fluctuations, Sato et al [17] added Gaussian random variables to APD restitution in their iterated map analysis. Such stochastic factors have been correlated with the beat-to-beat repolarization variability in cardiac cells [20].…”