Session S23.3

Electrophysiologically Detailed Models of the Right and Left Rabbit Atria: Pharmacological Impacts on Propagation and Arrhythmogenesis

OV Aslanidi*, RS Dewey, AR Morgan, MR Boyett, H Zhang

University of Manchester
Manchester, UK

Experimentally observed differences in action potential (AP) properties – and hence, tissue refractoriness – between the left (LA) and right (RA) atria are believed to be important in atrial arrhythmogenesis. However, relationships between underlying ionic differences in the LA and RA cells and their impacts on the tissue refractoriness and susceptibility to arrhythmias are unknown. We quantify such relationships by developing detailed AP models for the LA and RA, studying refractory and vulnerable properties of both tissues, and pharmacological impacts modulating them. The atrial AP model by Lindblad et al. (1996) was modified based on extant voltage-clamp datasets recorded for ionic currents from the rabbit LA and RA. Two major ionic factors determining the AP differences between the LA and RA cells were identified: 1) the fast delayed rectifier current, IKr, was 30% higher in the LA; 2) reactivation time constant of the transient outward current, Ito, was twice longer in the RA. These allowed reproducing experimentally observed differences in AP morphologies and rate-dependence in the LA and RA cells. The single cell models were incorporated into tissue models with an intercellular conductance set to produce the AP propagation velocity of 0.5 m/s. During AP propagation in LA and RA tissues, the refractory period (RP) was 97.0 and 99.5 ms, and the vulnerable window (VW) was 2.2 and 2.1 ms, respectively. Impacts of two anti-arrhythmic drugs, dofetilide and AVE0118 – selective blockers of IKr and Ito – were studied. Dofetilide increased RP to 104.0 and 105.5 ms in the LA and RA, and decreased VW to 2.0 ms in both atria, whereas AVE0118 prolonged PR to 128.9 and 133.0 ms, and decreased VW to 1.5 and 1.4 ms in the LA and RA. Hence, AVE0118 was more effective and relatively safe. Rotation of reentrant spirals waves in control simulations was stable with periods of 118 and 122 ms in the LA and RA. Dofetilide had little impact on stability of reentry – but application of AVE0118 resulted in self-termination of reentry in both tissues. In summary, our electrophysiologically detailed models allowed dissecting ionic mechanisms underlying AP differences between the LA and RA, determining their impacts on refractoriness and vulnerability of atrial tissues, and identifying pharmacological targets for effective and safe anti-arrhythmic drug action.

(Abstract Control Number: 130)