Onset of atrial arrhythmias elicited by autonomic modulation of rabbit sinoatrial node activity: a modeling study

Abstract

Neuronal modulation of the sinoatrial node (SAN) plays a crucial role in the initiation and maintenance of atrial arrhythmias (AF), although the exact mechanisms remain unclear. We used a computer model of a rabbit right atrium (RA) with a heterogeneous SAN and detailed ionic current descriptions for atrial and SAN myocytes to explore reentry initiation associated with autonomic activity. Heterogeneous acetylcholine (ACh)-dependent ionic responses along with L-type Ca current (I(Ca,L)) upregulation were incorporated in the SAN only. During control, activation was typical with the leading pacemaker site located close to the superior vena cava or the intercaval region. With cholinergic stimulation, activation patterns frequently included caudal shifts of the leading pacemaker site and occasional double breakouts. The model became increasingly arrhythmogenic for the ACh concentration >20 nM and for large I(Ca,L) conductance. Reentries obtained included counterclockwise rotors in the free wall, clockwise reentry circulating between the SAN and free wall, and typical flutter. The SAN was the cause of reentry with a common leading sequence of events: a bradycardic beat with shifting in the caudal direction, followed by a premature beat or unidirectional block within the SAN. Electrotonic loading, and not just overdrive pacing, squelches competing pacemaker sites in the SAN. Cholinergic stimulation concomitant with I(Ca,L) upregulation shifts leading pacemaker site and can lead to reentry. A heterogeneous response to autonomic innervation, a large myocardial load, and an extensive SAN in the intercaval region are required for neurally induced SAN-triggered reentry.

Fig. 1.

A: right atrium (RA) geometry indicating the sinoatrial node (SAN), septal, and the block zone. B: isolated SAN showing regions used to define gradients in ionic parameters and conductivity. Two different models used for horizontal gradients are shown at left. Color indicates region with numbering beginning with darker colors. Note that not all vertical regions overlap with all horizontal regions.

Fig. 2.

SAN and RA isolated cell action potentials. A: top to bottom: intrinsic action potentials (APs) from the central and peripheral SAN and RA free wall under various ACh concentrations ([ACh]). Note that [ACh] was not introduced into the free wall. B: intrinsic SAN AP properties under 0 (red) and 80 (blue) nM [ACh]. From left to right, cycle length (CL), action potential duration (APD), minimum diastolic potential (MDP), and maximum potential (MP) as functions of position within the SAN. Labels on each group of curves indicate inferior (Inf.) and superior (Sup.) regions. For orientation purposes, the crista terminalis would run along the right side of the SAN from superior vena cava to inferior vena cava. V_m, transmembrane voltage.

Fig. 3.

Activation maps (left), transmembrane voltages (middle), and APD maps (right) for different leading pacemaker sites (LPSs). A: superior LPS. B: central LPS. Voltage traces were obtained at locations labeled in A. Activation and APD maps were computed over yellow windows. The 10-ms isochrones are displayed on activation maps with black indicating inexcitable regions. Arrows in time traces indicate the sequence of propagation within the SAN.

Fig. 4.

Activation maps (top) and transmembrane voltages (bottom) during bath vagal stimulation. A. LPS caudal shift for 80 nM [ACh]. B: double breakout for 40 nM [ACh]. Voltage traces were obtained at locations labeled in A. Activation maps were computed over yellow windows. Arrows in time traces indicate the sequence of propagation within the SAN. 20-ms isochrones are drawn on activation maps.

Fig. 5.

Counterclockwise reentry after vagal stimulation. A: voltage traces were obtained at locations labeled in B upper. An atrial premature beat (APB) occurs leading to conduction block labeled in A1. Arrows indicate direction of propagation. Cycle lengths are indicated in A4 to show the initiation and termination of the reentry. B: activation maps for 2 cycles of reentry over the periods (ms) indicated. C: voltage maps taken at the times indicated in ms since ACh application. 10-mV isopotentials are drawn.

Fig. 6.

Clockwise reentry after vagal stimulation. A: voltage traces were obtained at locations labeled in B. An unidirectional block from 3 to 4 leads to reentry. Arrows show sequence of activation. Cycle lengths in trace 4 (myocardium) show the onset of the reentry. B: activation maps for 2 cycles of reentry over the periods (in ms) indicated. C: voltage maps taken at the times indicated with 10-mV isopotential lines displayed.

Fig. 7.

Comparison of SAN gradient models. A: occurrence of APBs for different maximum [ACh]s and g_Ca,L. B: occurrence of reentry for different [ACh]s and g_Ca,L. C: LPS shifting in control and after 80 nM [ACh]. Distance is measured from the cranial end of the SAN complex.