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.
Highlights
Ageing is one of the dominant risk factors for cardiovascular diseases
We developed a new simulation-based approach to predict the consequences of age-related cellular remodeling
A large experimental data on myocardial remodeling associated with ageing is known, including ionic remodeling affecting the function of cardiomyocytes [1, 2]
Summary
A large body of experimental data has been gathered on cellular remodeling in the ageing myocardium from animals but very few experimental data are available on the age-related changes in the human cardiomyocyte [1, 2]. Populations of human ventricular in silico action potential (AP) models were used to predict the clinical drug-induced arrhythmic risk of Torsade de Pointes (TdP) arrhythmia [3, 4]. A similar approach can be used for assessing the pro-arrhythmic consequences of various interventions affecting the cellular mechanisms of excitation-contraction coupling. The population of models based on a human electro-mechanical cellular model developed by our research group [7] is used here for predicting the pro-arrhythmogenic effects of age-related cellular remodelling
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