In-silico study of age-related ionic remodeling in human ventricular cardiomyocytes

Abstract

Ageing is one of the dominant risk factors for cardiovascular diseases. A large number of experimental data is collected on the cellular remodeling in the ageing myocardium from mammals, but very little is known about the human cardiomyocytes. We used a combined electro-mechanical model of human ventricular cardiomyocytes and a population of models approach to investigate the variability in the response of cardiomyocytes to age-related changes in model parameters of the ionic currents. To generate a control model population, we varied 9 ionic parameters and excluded model samples with biomarkers of cellular action potential (AP) and Ca2+ transient (CT) falling outside the physiological ranges. Using the control population of models, we evaluated the response to age-related reduction in the K+ transient outward current, SERCA pump, and an increase in the Na+Ca2+ exchange current and L-type Ca2+ current. Then, we randomly generated 60 age-related sets of the 4 parameters and applied each set to every model in the control population. We showed an increase in the frequency of repolarization anomalies (RA) and critical AP prolongation in the ageing model populations suggesting arrhythmogenic effects of the ionic remodeling. The population based approach allowed us to assess the pro-arrhythmic contribution of the ionic parameters in ageing cardiomyocytes.