Session S45.1

Modelling Conduction through the Purkinje-Ventricular Junction and the Short-QT Syndrome Associated with HERG Mutation in the Rabbit Ventricles

OV Aslanidi*, RN Sleiman, H Williamson, MR Boeytt, H Zhang

The University of Manchester
Manchester, UK

Excitation conducted through the Purkinje fibre (PF) network to the ventricles defines their electrical activation pattern. However, remarkable differences in action potential (AP) properties between the PF and ventricular cells may lead to abnormalities in excitation conduction through the Purkinje-ventricular junction (PVJ). The aim of this study is to develop a family of electrophysiologically detailed computer models for rabbit epicardial (epi), midmyocardial (M) and endocardial (endo) ventricular myocytes, as well as the PF cells, in order to explore the effects of AP heterogeneity and intercellular electrotonic interactions on conduction through the PVJ. The LabHeart model of the rabbit ventricular AP was modified to incorporate newly available experimental data on the transmural heterogeneity of the rabbit ventricles. Densities and kinetics of all ionic currents were fitted to respective experimental measurements. The developed models were validated by quantitatively comparing the simulated AP restitution properties to the experimental data for epi, M and endo cells. Similar techniques were used to construct a model for the rabbit PF cells. Finally, all single-cell models were incorporated into a heterogeneous multicellular 1D model, with intercellular electrical coupling conductances chosen to produce AP propagation velocities of 1.5 m/s and 0.3 m/s for the PF and the ventricular tissue, respectively; the values are consistent with experimental measurements in rabbit. Simulations of the 1D model produced transmural action potential duration (APD) dispersion patterns similar to those observed experimentally. Removing voltage-dependent inactivation of the delayed rectified current, IKr, was utilized to simulate short QT syndrome (SQTS) associated with a gain-in-function of IKr channel due to HERG N588K mutation. Such “mutant” IKr resulted in heterogeneous APD shortening among epi, M, endo and PF cells, which augmented transmural APD dispersion in the 1D model and shortened QT interval in pseudo-ECG. This provides the first evidence linking HERG N588K mutation to SQTS. Although under the mutant conditions APD in the Purkinje cells was almost twice longer than in adjacent ventricular cells (~250 ms against 120 ms), the PF cells were not able to drive the ventricular cells repetitively, which shows the importance of intercellular electrotonic interactions in modulating heterogeneity of the PVJ. In summary, the constructed electrophysiologically detailed models of the rabbit PF and ventricle tissue provide a powerful computational tool for non-invasive studies of electrical phenomena within and around the heterogeneous PVJ. Shortening of the QT interval under the defected IKr inactivation conditions substantiates a link between SQTS and the HERG N588K mutation.

(Abstract Control Number: 126)