Computing the Age-Related Dysfunction of Cardiac Pacemaker H Zhang 1 , JH Liu 2 , AV Holden 3 1 The University of Manchester, UK 2 Northeastern University, PR China 3 The University of Leeds, UK Abstract In both human and animal mammals, the pacemaker of the heart, the sinoatrial node (SA node), deteriorates with age. The main features of the aged SA nodes are a slow pacemaking rate and possible SA node-atrium conduction exit block or arrest of SA node pacemaking (i.e., termination of the SA node pacemaker activity). The mechanisms underlying the age-related dysfunction of the heart are unclear. In this study, we developed a detailed computer model of normal and aged SA nodes. Using the model we evaluated the functional roles of age-dependent reduction in SA node i Na current and active cell population in initiation and conduction of pacemaker activity in the aged heart. Simulations have shown that decrease in the SA node i Na or active cell population results in an increase of pacemaking cycle length (equivalent to a decrease of pacemaking rate) and slowing down of SA node-atrium conduction. It also produces the SA node–atrium conduction block in which action potentials originating from the SA node can fail to conduct into the atrium, or termination of the SA node pacemaker activity. When considered together, combined actions have a greater impact on weakening the pacing and driving ability and producing impairment of impulse initiation and conduction that leads to the SA node- atrium conduction exit block. These simulations provide mechanistic insights for understanding the dysfunction of the SA node in aged hearts. 1. Introduction In human and other mammals, the functions of the pacemaker of the heart, the SA node declines with ageing (1, 2, 5, 8). The main features of the aged SA nodes are a slow pacemaking rate (i.e., increase in CL) and possible SA node-atrium conduction exit block or arrest of SA node pacemaking (i.e., termination of the SA node pacemaker activity) (1, 2, 5). There is experimental evidence for the associations between ageing and changes in the electrophysiological and anatomic properties of the SA node. In humans, it was found that there is about 16% reduction in the active SA node cells in the elderly compared to adults (8). In the rabbit heart, several studies suggested a possible reduction of i Na in aged SA nodes (2, 3, 5). It is unclear whether or not such ageing-dependent changes can account for the deterioration of the SA node with ageing. In this study, we used a biophysically detailed computer model of the SA node and surrounding atrium to evaluate how a reduction of i Na or a decrease in active SA node cell population, or both combined, affects the cardiac pacemaker activity. 2. Methods The SA node is a complicated tissue with heterogeneities in cell electrical properties and anatomical structures (5). Based on the measured regional differences of ionic current densities and their relations to cell size, we have developed mathematical models of action potentials of the rabbit central and peripheral SA node cells (10-13). These models generated action potentials having the same characteristics as those recorded experimentally (10). In this study, we used the Zhang et al. models to simulate the electrical action potentials of central and peripheral SA node cells. A 2D model of the intact SA node and surrounding atrium tissue was constructed by incorporating the Zhang et al. single cell models into a 2D coupled ordinary different equation network (13). At each node of the network, electrical action potential is modeled by a set of ordinary differential equations, which can be represented as p NaCa K b Ca b Na b f s K r K sus to T Ca L Ca Na tot tot m i i i i i i i i i i i i i i i C dt dV + + + + + + + + + + + + = - = , , , , , , , 1 (1) ISSN 0276-6547 665 Computers in Cardiology 2006;33:665-668.