Investigation of Mechanisms of Age-Related Increase in Atrial Arrhythmia Susceptibility Using Computational Ionic Models of Atrial Cardiomyocytes

The risk of developing atrial fibrillation increases with age. However, the age-related changes in the electrical function of human atrial cardiomyocytes that may trigger atrial fibrillation are poorly understood. This study examined two possible scenarios of age-related modulation of potassium currents, either <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{K1}$</tex> or <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{Kr}$</tex>, and their effects on action potential duration (APD). For both scenarios, based on the physiological data, three ageing groups of ionic cell models were created depending on the severity of age-dependent changes in the particular ionic currents: Adult, Senior I, and Senior II. For each of the two considered aging scenarios we were able to reproduce most of aging dependent features of intracellular calcium dynamics and action potentials. However, both hypotheses have their advantages and disadvantages. In the scenario with <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{Kr}$</tex> change, the resting membrane potential was age independent, which is consistent with the experimental data. Meanwhile, APDs in all age groups in this scenario were close to the lower limit of the acceptable physiologic range. In contrast, in the scenario with <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{K1}$</tex> change, resting potential varied with age, but APDs were closer to the mean values of the physiologic range. Thus, the age-related prolongation of the action potential could be explained by either age-related reduction in <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{K1}$</tex> or in <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{Kr}$</tex>, but neither scenario fully explains the age-related changes. Perhaps a combined age-related inhibition of <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{K1}$</tex> and <tex xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">$\mathrm{I}_{Kr}$</tex> could resolve these discrepancies.