Cell and tissue responses to electric shocks

Europace (2005) 7, S155eS165 Cell and tissue responses to electric shocks Takashi Ashihara a,b, Natalia A. Trayanova a,* a Department of Biomedical Engineering, Tulane University, Boggs Center, Suite 500, New Orleans, LA 70118, USA b Department of Physiology and Biophysics, Kyoto University Graduate School of Medicine, Kyoto, Japan Submitted 22 December 2004, and accepted after revision 18 March 2005 Available online 27 July 2005 KEYWORDS L-type calcium current; virtual electrode polarization; electroporation; simulation; bidomain model; LuoeRudy dynamic model Abstract Aim Existing models of myocardial membrane kinetics have not been able to reproduce the experimentally-observed negative bias in the asymmetry of transmembrane potential changes (DVm) induced by strong electric shocks. The goals of this study are (1) to demonstrate that this negative bias could be reproduced by the addition, to the membrane model, of electroporation and an outward current, Ia, part of the KC flow through the L-type Ca2C-channel, and (2) to determine how such modifications in the membrane model affect shock-induced break excitation in a 2D preparation. Methods and results We conducted simulations of shocks in bidomain fibres and sheets with membrane dynamics represented by the LuoeRudy dynamic model (LRd’2000), to which electroporation (LRdCEP model) and the outward current, Ia, activated upon strong shock-induced depolarization (aLRd model) was added. Assuming Ia is a part of KC flow through the L-type Ca2C-channel enabled us to reproduce both the experimentally observed rectangularly-shaped positive DVm and the value of near 2 of the negative-to-positive DVm ratio. In the sheet, Ia not only contributed to the negative bias in DVm asymmetry at sites polarized by physical and virtual electrodes, but also restricted positive DVm. Electroporation, in its turn, was responsible for the decrease in cathode-break excitation threshold in the aLRd sheet, compared with the other two cases, as well as for the occurrence of the excitation after the shock-end rather than during the shock. Conclusions The incorporation of electroporation and Ia in a membrane model ensures match between simulation results and experimental data. The use of the aLRd model results in a lower threshold for shock-induced break excitation. ª 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. * Corresponding author. Tel.: C1 504 862 8934; fax: C1 504 862 8779. E-mail address: (N.A. Trayanova). 1099-5129/$30 ª 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.eupc.2005.03.020 S156 Introduction Electric shocks are widely used in clinical practice to terminate ventricular tachyarrhythmias. The shock electrodes deliver current into the myocardial extracellular space, resulting in the formation of regions of positive and negative membrane polarization in the tissue [1e5]. These shockinduced changes (DVm) in transmembrane potential (Vm) lead to initiation of post-shock activations that determine shock outcome [6e9]. However, insight into the mechanisms that underlie membrane responses to electric shocks remains incomplete. Understanding the aetiology of these membrane responses, and specifically, the contribution of membrane electroporation [10e13] as well as the changes in ionic currents caused by strong shocks [14e17] to post-shock membrane behaviour is of paramount importance to the rational rather than trial-and-error improvements in defibrillation procedure. Research has demonstrated that the delivery of a strong electric shock during the action potential plateau in cultured myocyte strands [14e16,18,19], papillary muscles [20,21], and three-dimensional myocardial preparations [2,22,23] leads to asymmetrical membrane polarization in the tissue with the negative DVm being nearly twice as large as the positive (phenomenon termed negative bias in DVm asymmetry). Furthermore, both positive and negative DVm exhibit non-linear behaviour as a function of shock strength. Models of ventricular membrane dynamics [24e27] as well as versions of these modified for large changes in transmembrane potential [28e30] have been used to examine the relationship between shocks and the membrane responses they induce [28,30e34]. However, since they were developed to represent the normal action potential behaviour none of these membrane models has been able to reproduce the observed negative bias in the asymmetry of DVm following strong shocks, thus threatening to jeopardize the predictive value of simulations in the study of vulnerability to electric shocks and defibrillation. A recent study from our group, by Ashihara and Trayanova [35] examined which membrane model modifications could bridge the existing gap between simulation and experiment. In this study, we hypothesized that the experimentally-observed negative bias in DVm asymmetry could be reproduced by the addition, to a recent version of the LuoeRudy dynamic (LRd) model [36], of electroporation and an outward current Ia activated upon strong shockinduced depolarization, the latter suggested by the results of a single-myocyte experimental study by T. Ashihara, N.A. Trayanova Cheng et al. [37]. We further hypothesized that Ia is part of the KC flow through the L-type Ca2Cchannel. We presented initial simulation results demonstrating that in multicellular cardiac tissue preparations, Ia and electroporation underlie the negative bias in DVm asymmetry. We achieved this by comparing the behaviour of three models, the original LRd model, the LRd model to which electroporation was added (LRdCEP), and the new augmented LRd (aLRd) model that includes both electroporation and the outward current Ia. This article extends the findings of the original contribution by Ashihara and Trayanova; it presents evidence that the modifications embodied in the aLRd model, but not LRd or LRdCEP models, indeed bridge the gap between simulation and experiment in multicellular preparations, and that these modifications, in turn, affect the threshold and timing of break excitation following the shock. Correct representation of break excitation is particularly important in understanding the mechanisms of defibrillation because its delayed onset and also the propagation pattern that ensues from it are major determinants of post-shock propagation in the heart. Methods Membrane models A recent version [36] of the LuoeRudy dynamic model [26,27,38,39], referred to here as ‘LRd’ was used. To the LRd model, we then added the electroporation current Iep, where the expression developed by DeBruin and Krassowska [40] was used; this membrane model was referred to as ‘LRdCEP’. Finally, to the original ICa,K in the LRd model, we added Ia as formulated by Cheng et al. [37], which, together with the addition of Iep, constituted the ‘augmented’ LRd model, or ‘aLRd’. Protocol for simulating the behaviour of multicellular preparatio (...truncated)