Abstract
Ischemia in the heart impairs function of the cardiac pacemaker, the sinoatrial node (SAN). However, the ionic mechanisms underlying the ischemia-induced dysfunction of the SAN remain elusive. In order to investigate the ionic mechanisms by which ischemia causes SAN dysfunction, action potential models of rabbit SAN and atrial cells were modified to incorporate extant experimental data of ischemia-induced changes to membrane ion channels and intracellular ion homeostasis. The cell models were incorporated into an anatomically detailed 2D model of the intact SAN-atrium. Using the multi-scale models, the functional impact of ischemia-induced electrical alterations on cardiac pacemaking action potentials (APs) and their conduction was investigated. The effects of vagal tone activity on the regulation of cardiac pacemaker activity in control and ischemic conditions were also investigated. The simulation results showed that at the cellular level ischemia slowed the SAN pacemaking rate, which was mainly attributable to the altered Na+-Ca2+ exchange current and the ATP-sensitive potassium current. In the 2D SAN-atrium tissue model, ischemia slowed down both the pacemaking rate and the conduction velocity of APs into the surrounding atrial tissue. Simulated vagal nerve activity, including the actions of acetylcholine in the model, amplified the effects of ischemia, leading to possible SAN arrest and/or conduction exit block, which are major features of the sick sinus syndrome. In conclusion, this study provides novel insights into understanding the mechanisms by which ischemia alters SAN function, identifying specific conductances as contributors to bradycardia and conduction block.
Highlights
The sinoatrial node (SAN), the pacemaker of the mammalian heart, possesses intrinsic automaticity
This was due to the presence of two leading pacemaking sites in that condition, one of which was at the peripheral region of the SAN that was close to the right atrium (i.e., the leading pacemaker site shifted, see Fig. 6(di), snapshot at 40 ms), the time taken to reach the right atrium was decreased, though the sinoatrial-atrium conduction was slowed down
We modeled the electrophysiological activities of central and peripherial SAN cells during ischemia based on experimental data, and incorporated these models into an electrophysiologically and anatomically detailed 2D intact rabbit SAN-atrium model
Summary
The sinoatrial node (SAN), the pacemaker of the mammalian heart, possesses intrinsic automaticity. Experimental evidence suggests that ischemia can modulate ion channel function in SAN cells, producing an increased L-type calcium channel current (ICaL) and hyperpolarization activated inward current (If), but decreased T-type calcium channel current (ICaT), rapid and slow components of the rectifier potassium channel currents (IKr and IKs), and Naþ-Ca2þ exchanger activity (INaCa).. Experimental evidence suggests that ischemia can modulate ion channel function in SAN cells, producing an increased L-type calcium channel current (ICaL) and hyperpolarization activated inward current (If), but decreased T-type calcium channel current (ICaT), rapid and slow components of the rectifier potassium channel currents (IKr and IKs), and Naþ-Ca2þ exchanger activity (INaCa).6,16,17 It is still unclear if the changes identified at the cellular ion channel level are sufficient to account for the ischemia-induced sinus bradycardia, a nonlinear behaviour arising from the interactions of millions of SAN cells. Using these models we investigated the functional impact of ischemia on the initiation and conduction of SAN action potentials and their conduction into the atrium
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