Abstract
The myocardial ischemic border zone is associated with the initiation and sustenance of arrhythmias. The profile of ionic concentrations across the border zone play a significant role in determining cellular electrophysiology and conductivity, yet their spatial-temporal evolution and regulation are not well understood. To investigate the changes in ion concentrations that regulate cellular electrophysiology, a mathematical model of ion movement in the intra and extracellular space in the presence of ionic, potential and material property heterogeneities was developed. The model simulates the spatial and temporal evolution of concentrations of potassium, sodium, chloride, calcium, hydrogen and bicarbonate ions and carbon dioxide across an ischemic border zone. Ischemia was simulated by sodium-potassium pump inhibition, potassium channel activation and respiratory and metabolic acidosis. The model predicted significant disparities in the width of the border zone for each ionic species, with intracellular sodium and extracellular potassium having discordant gradients, facilitating multiple gradients in cellular properties across the border zone. Extracellular potassium was found to have the largest border zone and this was attributed to the voltage dependence of the potassium channels. The model also predicted the efflux of from the ischemic region due to electrogenic drift and diffusion within the intra and extracellular space, respectively, which contributed to depletion in the ischemic region.
Highlights
Myocardial ischemia is caused by reduced perfusion to regions of the heart leading to a localised reduction in supply of metabolites, limited waste removal and compromised ionic homeostasis
The dominant mechanisms for these changes have been attributed to a shift in the ATP/ADP ratio, which inhibits the Sodium-Potassium ATPase pump (NaK) and increases the conductance of ATP-inactivated Kz channels; respiratory acidosis causing an increase in CO2; and metabolic acidosis, where a shift towards anaerobic respiration increases the production of Hz in the cell [5]
These changes in ionic concentrations in the ischemic region lead to gradients in properties across the border zone (BZ), creating electrophysiological heterogeneities that are thought to favour the occurrence of arrhythmias [6,7,8]
Summary
Myocardial ischemia is caused by reduced perfusion to regions of the heart leading to a localised reduction in supply of metabolites, limited waste removal and compromised ionic homeostasis. The dominant mechanisms for these changes have been attributed to a shift in the ATP/ADP ratio, which inhibits the Sodium-Potassium ATPase pump (NaK) and increases the conductance of ATP-inactivated Kz channels; respiratory acidosis causing an increase in CO2; and metabolic acidosis, where a shift towards anaerobic respiration increases the production of Hz in the cell [5]. These changes in ionic concentrations in the ischemic region lead to gradients in properties across the BZ, creating electrophysiological heterogeneities that are thought to favour the occurrence of arrhythmias [6,7,8]. The concentration of free ions were calculated by 1⁄2H z free ~
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