The sinoatrial node (SAN) is the primary pacemaker in mammalian hearts and is vital to cardiac function. Genetic mutations in SAN can result in lose-of-function of ion channels, consequently arouse sinus node dysfunction (SND), Brugada syndrome (BrS) and progressive cardiac conduction disease (PCCD). The mechanisms underlying the he pathogenesis for cardiac pacemaker dysfunctions associated with genetic mutations has not been defined. In this project, by using computer modeling, mechanisms by which the HCN4 mutations impair cardiac pacemaking and possible pro-arrhythmic effects of ivabradine were investigated. Action potential (AP) models for rabbit sinoatrial node cells were modified to incorporate experimentally reported If changes induced by HCN4 gene mutations. At both the cellular and intact SAN-atrium tissue level, If reduction due to the HCN4 mutations slowed down pacemaking. At the tissue level, these mutations compromised the AP conduction across the SAN-atrium, leading to a possible sinus arrest or SAN exit block. Moreover, vagal nerve activity could amplify the bradycardiac effects of the HCN4 gene mutations, leading to sinus arrest and SAN exit block that was not observed with the mutations or ACh alone. Similarly, SND associated with SCN5A mutations and acquired cardiac conditions were studied. 1) Mathematical models of rabbit SAN cells and 2D tissue models were modified to investigate SAN function and intracardiac conduction in a murine model of long QT syndrome type 3. A prolonged tail current INa,L was introduced and incorporated with a normal INa,T to test the SAN pacemaker function and AP conduction from the SAN to atrial septum. Simulation results showed that a combined reduction in INa,T and introduction of INa,L achieved alterations in both pacemaking rate and conduction. 2) Mathematical models of mouse SAN cells were modified to investigate the mechanisms underlies the SAN associated with SCN5A deficiency and aging. A coupled SAN-atrium cell model was developed to replicate the experimentally observed slowing of SAN conduction with aging and SCN5A-disruption The modelling studies reconstructed the physiological mechanisms by which both aging and SCN5A-disruption lead to SND, thereby drawing parallels between these and similar conduction changes in the ventricle that occur in the possibly related condition of PCCD. At last, a 2D anatomically based model of the SAN-atrium was constructed. This model successfully reproduced the effects of vagal nerve stimulation and SCN5A-E161K gene mutation on spontaneous activity of the SAN and AP conduction across the SAN-atrium.