Theoretical Study Of Cardiac Arrhythmia Induced By Ion Channel Mutations

Heart disease, as currently the biggest killer of human beings, has a diversity of incentives. The pathogenic mechanism for different incentives is not explained clearly. Further studies have shown that ion channel structure and its normal function expression is the basis for cells physiological activity, and that site-specific gene mutations lead to channel activation or inactivation, causing functional tissue disorders, resulting in a variety of genetic diseases. It has been confirmed that sick sinus syndrome, QT syndrome, Brugada syndrome and sudden infant death syndrome are associated with gene mutations. The drug therapy for ion channel diseases is still controversial, anti-arrhythmic medications may produce unpredictable effects on patients with channel mutations. Thus, study the mechanism of arrhythmia caused by mutations has became a research front in cardiovascular field.The sinoatrial node (SAN) is the main pacemaker tissue located in the right atrium of the heart, and thus generator of normal sinus rhythm. It is a group of cells positioned on the wall of the right atrium, near the entrance of the superior vena cava. In this paper, from the theory of cell dynamics, we have focused on the effects of sodium channel mutations and relative external stimuli by a mathematical model for rabbit SAN cells. By incorporating the accurate single-cell model of the SAN and the right atrium from intact rabbit tissue, this model was reconstructed as a2D anatomic model. We studied the internal rules and mechanisms of the links between sodium channel mutations and heart beat abnormalities at cell and tissue levels, as well as a combined action with the adjustment by relative ion channels.In the first part of the dissertation, we introduce some fundamental knowledge and concepts associated with this dissertation, including the cardiac system, myocardial cell membrane ion channels, sick sinus syndrome, the sinoatrial node cell model and a series of external environment affect the heart which have reported, such as temperature, acid concentration, acetylcholine, isoprenaline and nicotine. In the second part, by using the intact SA node-atrium model, we study and reconstruct the effects of sodium channel mutations on the cardiac pacemaking. It is found that the SCN5A mutations increase the action potential pacemaking cycle length, decrease the amplitude of action potentials in the SAN cells. The abnormal pacemaking activity is mainly caused by the reduction of sodium current. For this case, combine with the vagal nerves stimulation, addition of Ach amplified the bradycardic effect of the mutation, compromised the ability of the SAN to pace and drive the atrium, leading to a higher probability of SAN exit block and sinus arrest. In part three, when the external environment effects were introduced, the results suggest that not only the relevant currents were changed, but also the sodium current which reduced by gene mutations was increased. Thus, the abnormal pacemaking behavior of sinoatrial node tissue could return to normal state.In briefly, above simulation results imply that the abnormal pacemaking of SAN system may closely relate to the gene mutation of ion channels, the external environment plays a modulatory role. The results may contribute to the understanding about the internal mechanism of the abnormal rhythm in complex cardiac system, and provide a theoretical guidance on the clinical diagnosis and treatment of the sick sinus syndrome.