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Pathologies that result in early afterdepolarizations (EADs) are a known trigger for tachyarrhythmias, but the conditions that cause surrounding tissue to conduct or suppress EADs are poorly understood. Here we introduce a cell culture model of EAD propagation consisting of monolayers of cultured neonatal rat ventricular myocytes treated with anthopleurin-A (AP-A). AP-A-treated monolayers display a cycle length dependent prolongation of action potential duration (245 ms untreated, vs. 610 ms at 1 Hz and 1200 ms at 0.5 Hz for AP-A-treated monolayers). In contrast, isolated single cells treated with AP-A develop prominent irregular oscillations with a frequency of 2.5 Hz, and a variable prolongation of the action potential duration of up to several seconds. To investigate whether electrotonic interactions between coupled cells modulates EAD formation, cell connectivity was reduced by RNA silencing gap junction Cx43. In contrast to well-connected monolayers, gap junction silenced monolayers display bradycardia-dependent plateau oscillations consistent with EADs. Further, simulations of a cell displaying EADs electrically connected to a cell with normal action potentials show a coupling strength-dependent suppression of EADs consistent with the experimental results. These results suggest that electrotonic effects may play a critical role in EAD-mediated arrhythmogenesis.

Early development of ionic models for cardiac myocytes, from the pioneering modification of the Hodgkin-Huxley giant squid axon model by Noble to the iconic DiFrancesco-Noble model integrating voltage-gated ionic currents, ion pumps and exchangers, Ca(2+) sequestration and Ca(2+)-induced Ca(2+) release, provided a general description for a mammalian Purkinje fibre (PF) and the framework for modern cardiac models. In the past two decades, development has focused on tissue-specific models with an emphasis on the sino-atrial (SA) node, atria and ventricles, while the PFs have largely been neglected. However, achieving the ultimate goal of creating a virtual human heart will require detailed models of all distinctive regions of the cardiac conduction system, including the PFs, which play an important role in conducting cardiac excitation and ensuring the synchronized timing and sequencing of ventricular contraction. In this paper, we present details of our newly developed model for the human PF cell including validation against experimental data. Ionic mechanisms underlying the heterogeneity between the PF and ventricular action potentials in humans and other species are analysed. The newly developed PF cell model adds a new member to the family of human cardiac cell models developed previously for the SA node, atrial and ventricular cells, which can be incorporated into an anatomical model of the human heart with details of its electrophysiological heterogeneity and anatomical complexity.

Cardiac pacemaking in the sinoatrial (SA) node and atrioventricular (AV) node is generated by an interplay of many ionic currents, one of which is the funny pacemaker current (If). To understand the functional role of If in two different pacemakers, comparative studies of spontaneous activity and expression of the HCN channel in mouse SA node and AV node were performed. The intrinsic cycle length (CL) is 179+/-2.7 ms (n=5) in SA node and 258+/-18.7 ms (n=5) in AV node. Blocking of If current by 1 micromol/L ZD7288 increased the CL to 258+/-18.7 ms (n=5) and 447+/-92.4 ms (n=5) in SA node and AV node, respectively. However, the major HCN channel, HCN4 expressed at low level in the AV node compared to the SA node. To clarify the discrepancy between the functional importance of If and expression level of HCN4 channel, a SA node cell model was used. Increasing the If conductance resulted in decreasing in the CL in the model, which explains the high pacemaking rate and high expression of HCN channel in the SA node. Resistance to the blocking of If in the SA node might result from compensating effects from other currents (especially voltage sensitive currents) involved in pacemaking. The computer simulation shows that the difference in the intrinsic CL could explain the difference in response to If blocking in these two cardiac nodes.

A decrease of the transient outward potassium current (Ito) has been observed in cardiac hypertrophy and contributes to the altered shape of the action potential (AP) of hypertrophied ventricular myocytes. Since the shape and duration of the ventricular AP are important determinants of the Ca2+ influx during the AP (QCa), we investigated the effect of ascending aortic stenosis (AS) on QCa in endo- and epicardial myocytes of the left ventricular free wall using the AP voltage-clamp technique. In sham-operated animals, QCa was significantly larger in endocardial compared to epicardial myocytes (803 +/- 65 fC pF(-1), n = 27 vs. 167 +/- 32 fC pF(-1), n = 38, P < 0.001). Ascending aortic stenosis significantly increased QCa in epicardial myocytes (368 +/- 54 fC pF(-1), n = 42, P < 0.05), but did not alter QCa in endocardial myocytes (696 +/- 65 fC pF(-1), n = 26). Peak and current-voltage relation of the AP-induced Ca2+ current were unaffected by AS. However, the time course of the current-voltage relation was significantly prolonged in epicardial myocytes of AS animals. Model calculations revealed that the increase in QCa can be ascribed to a prolonged opening of the activation gate, whereas an increase in inactivation prevents an excessive increase in QCa. In conclusion, AS significantly increased AP-induced Ca2+ influx in epicardial but not in endocardial myocytes of the rat left ventricle.