Session S23.5

Mathematical Models of Human Sinus and Atrioventricular Node Action Potentials

S Inada*, MR Boyett, H Dobrzynski

The University of Manchester
Manchester, UK

There are few models of the human cardiac action potential (AP), because it is difficult to obtain human heart for electrophysiological study. Using qPCR, we have measured the expression of ion channel mRNAs in human sinus and atrioventricular nodes (e.g. Chandler et al., Circulation. 2009;119:1562). Based on the expression data, we have developed models of the APs at the sinus node (1-sinus node; 2-paranodal area) and atrioventricular junction (3-transitional zone; 4-nodal extension; 5-atrioventricular node; 6 His bundle; 7-ventricle). The starting point was the model of the human right atrial AP from Courtemanche et al. (Am J Physiol. 1998;275:H301). For each of the major ionic currents, the sum of relevant mRNAs in each region was calculated and expressed as a percentage of the sum of the same mRNAs in the right atrium. This was assumed to be equal to the conductance of the relevant ionic current in each region expressed as a percentage of the conductance in the right atrium. In human heart, two L-type calcium channel isoforms are expressed: Cav1.2 and 1.3. We assumed the activation curve of Cav1.3-dependent current is shifted by -20 mV compared to the activation curve of Cav1.2-dependent current. Three channels are likely to be responsible for the background inward rectifier: Kir2.1, 2.2 and 2.3. The data for the three channels were scaled to account for the different single channel conductances of the channels. The Courtemanche model does not include T-type calcium and funny currents and yet the nodal tissues express the relevant ion channels. Therefore, equations for these two currents were introduced into the model. The computed APs for the 7 regions had feasible characteristics and shapes. It is predicted that human ventricle has a fast upstroke and a stable resting potential and does not show pacemaker activity. In contrast, it is predicted that human sinus and atrioventricular nodes have a slowly conducting AP with a slow upstroke and diastolic depolarization and do show pacemaker activity. Although function is not necessarily linearly related to mRNA abundance, we suggest this technique is a new form of bioinformatics to explore the consequences of a change in ion channel expression, e.g. in aged or diseased heart.

(Abstract Control Number: 96)