This thesis studies numerical methods for integrating the master equations describing Markov chain models of cardiac ion channels. Such models describe the time evolution of the probability that ion channels are in a particular state. Numerical simulations of such models are often computationally demanding because many solvers require relatively small time steps to ensure numerical stability. The aim of this project is to analyse selected Markov chains and develop more efficient and accurate solvers. We separate a Markov chain model into fast and slow time-scales based on the speed of transitions between states. Eliminating the fast transitions, we find an asymptotic reduction of zeroth-order and first-order in a small parameter describing the time-scales separation. We apply the theory to a Markov chain model of the fast sodium channel INa. We consider several variants for classifying some transitions as fast in order to find reduced systems that yield a good accuracy. However, the time step size is still restricted by numerical instabilities. We adapt the Rush-Larsen technique originally developed for gate models. Assuming that a transition matrix can be considered constant during each time step, we solve the Markov chain model analytically. The solution provides a recipe for a stable exponential solver, which we call "Matrix Rush-Larsen" (MRL). Using operator splitting we design an even more flexible "hybrid" method that combines the MRL with other solvers. The resulting improvement in stability allows a large increase in the time step size. In some models, we obtain reasonably accurate results 27 times faster using a hybrid method than with the forward Euler method, even with the maximal time step allowed by the stability constraint. Finally, we extend the cardiac simulation package BeatBox by the developed exponential solvers. We upgrade a format of "ionic" modules which describe a cardiac cell, in order to allow for a specific definition of Markov chain models. We also modify a particular integrator for ionic modules to include the MRL and the hybrid method. To test the functionality of the code, we have converted a number of cellular models into the ionic format. The documented code is available in the official BeatBox package distribution.

The heart is one the most important organs in the human body and many other live creatures. The electrical activity in the heart controls the heart function, and many heart diseases are linked to the abnormalities in the electrical activity in the heart. Mathematical equations and computer simulation can be used to model the electrical activity in the heart. The heart models are challenging to solve because of the complexity of the models and the huge size of the problems. Several cell models have been proposed to model the electrical activity in a single heart cell. These models must be coupled with a heart model to model the electrical activity in the entire heart. The bidomain model is a popular model to simulate the propagation of electricity in myocardial tissue. It is a continuum-based model consisting of non-linear ordinary differential equations (ODEs) describing the electrical activity at the cellular scale and a system of partial differential equations (PDEs) describing propagation of electricity at the tissue scale. Because of this multi-scale, ODE/PDE structure of the model, splitting methods that treat the ODEs and PDEs in separate steps are natural candidates as numerical methods. First, we need to solve the problem at the cellular scale using ODE solvers. One of the most popular methods to solve the ODEs is known as the Rush-Larsen (RL) method. Its popularity stems from its improved stability over integrators such as the forward Euler (FE) method along with its easy implementation. The RL method partitions the ODEs into two sets: one for the gating variables, which are treated by an exponential integrator, and another for the remaining equations, which are treated by the FE method. The success of the RL method can be understood in terms of its relatively good stability when treating the gating variables. However, this feature would not be expected to be of benefit on cell models for which the stiffness is not captured by the gating equations. We demonstrate that this is indeed the case on a number of stiff cell models. We further propose a new partitioned method based on the combination of a first-order generalization of the RL method with the FE method. This new method leads to simulations of stiff cell models that are often one or two orders of magnitude faster than the original RL method. After solving the ODEs, we need to use bidomain solvers to solve the bidomain model. Two well-known, first-order time-integration methods for solving the bidomain model are the semi-implicit method and the Godunov operator-splitting method. Both methods decouple the numerical procedure at the cellular scale from that at the tissue scale but in slightly different ways. The methods are analyzed in terms of their accuracy, and their relative performance is compared on one-, two-, and three-dimensional test cases. As suggested by the analysis, the test cases show that the Godunov method is significantly faster than the semi-implicit method for the same level of accuracy, specifically, between 5 and 15 times in the cases presented. Second-order bidomain solvers can generally be expected to be more effective than first-order bidomain solvers under normal accuracy requirements. However, the simplest and the most commonly applied second-order method for the PDE step, the Crank-Nicolson (CN) method, may generate unphysical oscillations. We investigate the performance of a two-stage, L-stable singly diagonally implicit Runge-Kutta method for solving the PDEs of the bidomain model and present a stability analysis. Numerical experiments show that the enhanced stability property of this method leads to more physically realistic numerical simulations compared to both the CN and Backward Euler (BE) methods.