In mammalian hearts, initiation of the heartbeat occurs in a region of specialised pacemaker cells known as the sinoatrial node (SAN). The SAN is a highly complex spatially distributed structure which displays considerable cellular heterogeneity and is subject to complex electrotonic interactions with the surrounding atrial tissue. In this study, biophysically detailed ionic models of central and peripheral SAN pacemaker cells are described. These models are able to accurately reproduce experimental recordings of the membrane potential from central and peripheral SAN tissue. These models are used to investigate frequency synchronisation of electrically coupled cardiac pacemaker cells. Based on simulation results presented, it is proposed that cellular heterogeneity in the SAN plays an important role in achieving rhythm coordination and possibly contributes to the efficient activation of the surrounding atrial myocardium. This represents an important, previously unexplored, mechanism underlying pacemaker synchronisation and cardiac activation in vivo. A spatial-gradient model of action potential heterogeneity within the SAN is then formulated using a large-scale least squares optimisation technique. This model accurately reproduces the smooth spatial variation in action potential characteristics observed in the SAN. One and two dimensional models of the intact SAN are then formulated and three proposed models of SAN heterogeneity are investigated: 1) the discrete-region model, in which the SAN consists of a compact central region surrounded by a region of transitional pacemaker cells, 2) the gradient model, in which cells of the SAN exhibit a smooth variation in properties from the centre to the periphery of the SAN, and 3) the mosaic model, in which SAN and atrial cells are scattered throughout the SAN region with the proportion of atrial cells increasing towards the periphery. Simulation results suggest that the gradient model achieves frequency entrainment more easily than the other models of SAN heterogeneity. The gradient model also reproduces action potential waveshapes and a site of earliest activation consistent with experimental observations in the intact SAN. It is therefore proposed that the gradient model of SAN heterogeneity represents the most plausible model of SAN organisation.
| Identifer | oai:union.ndltd.org:ADTP/235960 |
| Date | January 2005 |
| Creators | Cloherty, Shaun Liam, Graduate School of Biomedical Engineering, Faculty of Engineering, UNSW |
| Publisher | Awarded by:University of New South Wales. Graduate School of Biomedical Engineering |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Shaun Liam Cloherty, http://unsworks.unsw.edu.au/copyright |
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