Computational evaluation of the roles of Na+ current, iNa, and cell death in cardiac pacemaking and driving

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Abstract
Voltage-dependent sodium (Na+) channels are heterogeneously distributed through the pacemaker of the heart, the sinoatrial node (SA node). The measured sodium channel current ( iNa) density is higher in the periphery but low or zero in the center of the SA node. The functional roles of iNa in initiation and conduction of cardiac pacemaker activity remain uncertain. We evaluated the functional roles of iNa by computer modeling. A gradient model of the intact SA node and atrium of the rabbit heart was developed that incorporates both heterogeneities of the SA node electrophysiology and histological structure. Our computations show that a large iNa in the periphery helps the SA node to drive the atrial muscle. Removal iNa from the SA node slows down the pacemaking rate and increases the sinoatrial node-atrium conduction time. In some cases, reduction of the SA node iNa results in impairment of impulse initiation and conduction that leads to the SA node-atrium conduction exit block. Decrease in active SA node cell population has similar effects. Combined actions of reduced cell population and removal of iNa from the SA node have greater impacts on weakening the ability of the SA node to pace and drive the atrium.

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