Modelling conduction through the Purkinje ventricular junction and the short-QT syndrome associated with HERG mutation in the rabbit ventricles

Abstract

Remarkable differences in action potential properties between the Purkinje fibre and ventricular cells may lead to abnormalities in excitation conduction through the Purkinje-ventricular junction (PVJ) IntroductionExcitation conducted through the Purkinje fibre (PF) network to the ventricles determines their normal electrical activation and contraction sequence. However, remarkable differences in action potential (AP) properties between the PF and ventricular cells [1,2] may lead to abnormalities in excitation conduction through the Purkinje-ventricular junction (PVJ) and arrhythmogenic behaviour [3][4][5]. Primarily, as action potentials (APs) from PF cells are typically longer than ventricular APs, it has been suggested that dispersion of the action potential duration (APD) at the PVJ can result in unidirectional conduction block [3], triggered activity [4] and reentry [5] under both physiological and pathological conditions.Computer simulations have been used previously in order to reconstruct APs in a single PF cell [6] and AP conduction in the whole fibre [7], as well as characterize electrotonic modulation of the APD dispersion at the PVJ [8]. However, the DiFrancesco-Noble model for a single rabbit PF cell [6] used in the latter simulations has been based on limited experimental data, whereas APs in ventricular cells were simulated using the Luo-Rudy model for a guinea-pig ventricular myocyte [9]. Hence, there is a demand for up-to-date non-chimeric models of the PVJ with realistic APD distributions.The aim of this study is (i) to develop a family of electrophysiologically detailed computer models for rabbit epicardial (epi), midmyocardial (M) and endocardial (endo) ventricular myocytes, (ii) develop a detailed model for the rabbit PF cell, (iii) simulate a realistic APD dispersion due to intercellular electrotonic interactions during conduction through the PVJ under normal conditions, and (iv) explore changes of the APD dispersion under pathological conditions of the short QT syndrome (SQTS) associated with a gain-in-function of I Kr channel due to HERG N588K mutation [10,11]. MethodsDynamics of electrical variables in cardiac tissues can be described by the Hodgkin-Huxley-type nonlinear partial differential equation (PDE) [7,8]:Here V (mV) is the membrane potential, t is time (s), ∇ is a spatial gradient operator defined within the tissue geometry. D is the effective diffusion coefficient (mm 2 ms -1) that characterizes electrotonic spread of voltage via gap junctions. C m (pF) is the cell membrane capacitance, I ion is the total membrane ionic current (pA). Various biophysically detailed mathematical models have been developed to describe the voltage and time dependent current I ion , and hence, action potential (AP) propertiesprimarily in a rabbit ventricular cell [12].The equation (1) is solved for the 1D strand geometry using a finite-difference PDE solver that implements the explicit Euler's method with time and space steps ∆t = 0.005 ms and ∆x = 0.1 mm, respectively. Ventricular modelsT...

Mechanisms of Transition from Normal to Reentrant Electrical Activity in a Model of Rabbit Atrial Tissue: Interaction of Tissue Heterogeneity and Anisotropy

“…This is the first successful incorporation of detailed electrical heterogeneity of the rabbit RA into a mathematical model. The models, along with our previous models for the heterogeneous SA node (36) and ventricular myocytes (53), provide an important step toward our final goal of developing a model for the whole rabbit heart, which will account for details of its electrophysiological heterogeneity and anatomical complexity (54).…”

Effects of electrical heterogeneity on transmural reentry during acute global ischemia

“…Because loop arrangements are abundant in peripheral regions of the conducting system where Purkinje fibers arborize into many branches before interconnecting with muscular fibers, reentry may be easily induced around these areas if the reentrant conditions are satisfied (Elharrar and Zipes 1977). However, because Purkinje and ventricular myocytes are electrically isolated from each other except at Purkinje-ventricular junctions (Aslanidi et al 2007), effects of Purkinje are not taken into account in our study in that what we mostly concerns in this paper is the effects of ischemic heterogeneous distribution in ventricles on electrical vulnerability, not the conduction system through the Purkinje fiber network to the ventricles. In addition, in our tissue model we don't involve in the cardiac interstitium (the space between the cardiomyocytes, containing fibroblasts, blood vessels, lymphatic vessels, adrenergic nerve endings), because our investigations mainly focus on electrical activities among myocytes through gap junctions and the acute ischemia before irreversible cell damages occur, so the role of interstitium in remodeling during myocardial infarction or heart failure (Aslanidi et al 2007) is not obvious in our study.…”