Effect of different chronotropic interventions on the source-sink properties of simulated sinoatrial-atrial cell pairs.

The proper function of cardiac pacemaking depends on both intrinsic excitable properties of sinoatrial (SA) cells and on the structural and electrical interaction among them and between them and the surrounding atrial tissue. Whereas most of the excitable and non excitable cell types forming the SA node have been characterized in literature, the structure of the pacemaker area is still incompletely defined, and so are the source-sink properties of the SA-atrial interface, both in normal condition and during pharmacological interventions. By simulating action potential (AP) conduction between one or more-than-one sino-atrial and one atrial cell, electrically connected via a variable gap junctional resistance, we aimed to study changes in the source-sink balance following different simulated chronotropic interventions. We used the Severi et al and the Lindblad et al rabbit AP models for sinoatrial and atrial simulations respectively. A further aim of our work was to define a numerical safety-factor for pacemaker-to-atrial AP conduction (SASF) based on iterative simulations carried out by varying, in turn, SA/atrial cell-number ratio and the intercellular junctional resistance. We found that antiarrhythmic-like interventions involving down-regulation of calcium channels decrease SASF, whereas a comparable bradycardic effect induced by simulating administration of Ivabradine, an If blocker, does so to a lesser extent. Particularly interesting was also the increase of SASF observed when down-regulating GKr, which simulates the administration of class III antiarrhythmic agents. Exploring the pacemaker source–atrial sink relationship at its most elementary level, i.e. simulated interaction within cell pairs, provides new insights concerning the safety factor for SA-atrial drive under ion channels modulation, which can furthermore better direct pharmacological and clinical antiarrhythmic strategies.