A Population Modelling Approach to Studying Age-Related Effects on Excitation-Contraction Coupling in Human Cardiomyocytes

AbstractAgeing is the dominant risk factor for cardiovascular diseases. A great body of experimental data has been gathered on cellular remodelling in the Ageing myocardium from animals. Very few experimental data are available on age-related changes in the human cardiomyocyte. We have used our combined electromechanical model of the human cardiomyocyte and the population modelling approach to investigate the variability in the response of cardiomyocytes to age-related changes in the model parameters. To generate the model population, we varied nine model parameters and excluded model samples with biomarkers falling outside of the physiological ranges. We evaluated the response to age-related changes in four electrophysiological model parameters reported in the literature: reduction in the density of the K+ transient outward current, maximal velocity of SERCA, and an increase in the density of NaCa exchange current and CaL-type current. The sensitivity of the action potential biomarkers to individual parameter variations was assessed. Each parameter modulation caused an increase in APD, while the sensitivity of the model to changes in GCaL and Vmax_up was much higher than to those in the effects of Gto and KNaCa. Then 60 age-related sets of the four parameters were randomly generated and each set was applied to every model in the control population. We calculated the frequency of model samples with repolarisation anomalies (RA) and the shortening of the electro-mechanical window in the ageing model populations as an arrhythmogenic ageing score. The linear dependence of the score on the deviation of the parameters showed a high determination coefficient with the most significant impact due to the age-related change in the CaL current. The population-based approach allowed us to classify models with low and high risk of age-related RA and to predict risks based on the control biomarkers.

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Electrophysiological Biomarkers for Age-Related Changes in Human Atrial Cardiomyocytes: In Silico Study

ITM Web of Conferences ◽

10.1051/itmconf/20203101004 ◽

2020 ◽

Vol 31 ◽

pp. 01004 ◽

Cited By ~ 2

Author(s):

Tatyana Nesterova ◽

Konstantin Ushenin ◽

Dmitry Shmarko ◽

Olga Solovyova

Keyword(s):

Experimental Data ◽

Action Potential ◽

Action Potential Duration ◽

Cellular Response ◽

Experimental Studies ◽

Model Parameters ◽

Human Cardiomyocytes ◽

Atrial Cardiomyocytes ◽

Age Related ◽

Age Related Changes

Age-related changes in human cardiomyocytes are closely related to cardiac diseases, especially atrial fibrillation. Restricted availability of biological preparations from the human atrial myocardium complicates experimental studies on the aging processes in cardiomyocytes. In this preliminary study, we used available experimental data on the age-related changes in ionic conductances in canine atrial cardiomyocytes to predict possible consequences of similar remodeling in humans using two mathematical models (Courtemanche98 and Maleckar09) of human atrial cardiomyocytes. The study was performed using the model population approach, allowing one to assess variability in the cellular response to different interventions affecting model parameters. Here, this approach was used to evaluate the effects of age-related parameter modulation on action potential biomarkers in the two models. Simulation results show a significant decrease in the action potential duration and membrane potential at 20% of the action potential duration in aging. These model predictions are consistent with experimental data from mammalians. The action potential characteristics are shown to serve as notable biomarkers of age-related electrophysiological remodeling in human atrial cardiomyocytes. A comparison of the two models shows different behavior in the prediction of repolarization abnormalities.

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In-silico analysis of aging mechanisms of action potential remodeling in human atrial cardiomyocites

BIO Web of Conferences ◽

10.1051/bioconf/20202201025 ◽

2020 ◽

Vol 22 ◽

pp. 01025

Author(s):

Tatyana Nesterova ◽

Dmitry Shmarko ◽

Konstantin Ushenin ◽

Olga Solovyova

Keyword(s):

Experimental Data ◽

Atrial Fibrillation ◽

Action Potential ◽

In Silico ◽

Antiarrhythmic Drugs ◽

Model Parameters ◽

Experimental Conditions ◽

Human Cardiomyocytes ◽

Atrial Cardiomyocytes ◽

Age Related

Electrophysiology of cardiomyocytes changes with aging. Agerelated ionic remodeling in cardiomyocytes may increase the incidence and prevalence of atrial fibrillation (AF) in the elderly and affect the efficiency of antiarrhythmic drugs. There is the deep lack of experimental data on an action potential and transmembrane currents recorded in the healthy human cardiomyocytes of different age. Experimental data in mammals is also incomplete and often contradicting depending on the experimental conditions. In this in-silico study, we used a population of ionic models of human atrial cardiomyocytes to transfer data on the age- related ionic remodeling in atrial cardiomyocytes from canines and mice to predict possible consequences for human cardiomyocyte activity. Based on experimental data, we analyzes two hypotheses on the aging effect on the ionic currents using two age-related sets of varied model parameters and evaluated corresponding changes in action potential morphology with aging. Using the two populations of aging models, we analyzed the agedependent sensitivity of atrial cardiomyocytes to Dofetilide which is one of the antiarrhythmic drugs widely used in patients with atrial fibrillation.

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

BIO Web of Conferences ◽

10.1051/bioconf/20202201024 ◽

2020 ◽

Vol 22 ◽

pp. 01024

Author(s):

Arsenii Dokuchaev ◽

Svyatoslav Khamzin ◽

Olga Solovyova

Keyword(s):

Outward Current ◽

Ionic Currents ◽

Population Based ◽

Control Population ◽

Transient Outward Current ◽

Model Parameters ◽

Human Cardiomyocytes ◽

Ventricular Cardiomyocytes ◽

Age Related ◽

Ageing Model

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.

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Comparison of Ito in young and adult human atrial myocytes: evidence for developmental changes

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.268.3.h1335 ◽

1995 ◽

Vol 268 (3) ◽

pp. H1335-H1342 ◽

Cited By ~ 8

Author(s):

W. J. Crumb ◽

J. D. Pigott ◽

C. W. Clarkson

Keyword(s):

Current Density ◽

Outward Current ◽

Inward Rectifier ◽

Developmental Changes ◽

Transient Outward Current ◽

Atrial Myocytes ◽

Patch Clamp Technique ◽

Whole Cell Patch Clamp ◽

Age Related ◽

Age Related Changes

In an effort to understand the ionic basis for the developmental changes that have been reported to occur in the configuration of the human atrial action potential, we characterized the transient outward current (Ito) and the inward rectifier current in atrial myocytes isolated from 20 young (ages 1 day-2.5 yr) and 8 adult (11–68 yr) human hearts using the whole cell patch-clamp technique. We found evidence for statistically significant (P < 0.05) age-related changes in the Ito, including 1) the presence of an Ito in only 67% of the cells isolated from young hearts vs. 100% of the cells isolated from adult hearts, 2) an almost twofold increase in the current density of Ito in adult cells vs. young cells, and 3) recovery kinetics that are approximately twofold slower in young myocytes relative to adult myocytes. In contrast, there were no age-related changes found in the current density of the inward rectifier current or the sustained current measured after the decay of Ito. These results suggest important current-dependent changes that occur with age in human atria.

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Revealing Age-Related Changes of Adult Hippocampal Neurogenesis

10.1101/112128 ◽

2017 ◽

Cited By ~ 1

Author(s):

Frederik Ziebell ◽

Sascha Dehler ◽

Ana Martin-Villalba ◽

Marciniak-Czochra Anna

Keyword(s):

Experimental Data ◽

Mathematical Model ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Cell Dynamics ◽

Cellular Changes ◽

Age Related ◽

Adult Hippocampus ◽

Age Related Changes

In the adult hippocampus, neural stem cells (NSCs) continuously produce new neurons that integrate into the neuronal network to modulate learning and memory. The amount and quality of newly generated neurons decline with age, which can be counteracted by increasing intrinsic Wnt activity in NSCs. However, the precise cellular changes underlying this age-related decline or its rescue through Wnt remain unclear. The present study combines development of a mathematical model and experimental data to address features controlling stem cell dynamics. We show that available experimental data fit a model in which quiescent NSCs can either become activated to divide or undergo depletion events, consisting of astrocytic transformation and apoptosis. Additionally, we demonstrate that aged NSCs remain longer in quiescence and have a higher probability to become re-activated versus being depleted. Finally, our model explains that high NSC-Wnt activity leads to longer time in quiescence while augmenting the probability of activation.

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Adjustment of Muscle Mechanics Model Parameters to Simulate Dynamic Contractions in Older Adults

Journal of Biomechanical Engineering ◽

10.1115/1.1531112 ◽

2003 ◽

Vol 125 (1) ◽

pp. 70-77 ◽

Cited By ~ 293

Author(s):

Darryl G. Thelen

Keyword(s):

Isometric Force ◽

Muscle Mechanics ◽

Muscle Stiffness ◽

Model Parameters ◽

Muscle Properties ◽

Old Adults ◽

Specific Strength ◽

Mechanics Model ◽

Age Related ◽

Age Related Changes

The generation of muscle-actuated simulations that accurately represent the movement of old adults requires a model that accounts for changes in muscle properties that occur with aging. An objective of this study was to adjust the parameters of Hill-type musculo-tendon models to reflect nominal age-related changes in muscle mechanics that have been reported in the literature. A second objective was to determine whether using the parametric adjustments resulted in simulated dynamic ankle torque behavior similar to that seen in healthy old adults. The primary parameter adjustment involved decreasing maximum isometric muscle forces to account for the loss of muscle mass and specific strength with age. A review of the literature suggested the need for other modest adjustments that account for prolonged muscular deactivation, a reduction in maximum contraction velocity, greater passive muscle stiffness and increased normalized force capacity during lengthening contractions. With age-related changes incorporated, a musculo-tendon model was used to simulate isometric and isokinetic contractions of ankle plantarflexor and dorsiflexor muscles. The model predicted that ankle plantarflexion power output during 120 deg/s shortening contractions would be over 40% lower in old adults compared to healthy young adults. These power losses with age exceed the 30% loss in isometric strength assumed in the model but are comparable to 39–44% reductions in ankle power outputs measured in healthy old adults of approximately 70 years of age. Thus, accounting for age-related changes in muscle properties, other than decreased maximum isometric force, may be particularly important when simulating movements that require substantial power development.

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Uncertainty quantification, propagation and characterization by Bayesian analysis combined with global sensitivity analysis applied to dynamical intracellular pathway models

10.1101/294884 ◽

2018 ◽

Cited By ~ 1

Author(s):

Olivia Eriksson ◽

Alexandra Jauhiainen ◽

Sara Maad Sasane ◽

Andrei Kramer ◽

Anu G Nair ◽

...

Keyword(s):

Experimental Data ◽

Sensitivity Analysis ◽

Bayesian Analysis ◽

Uncertainty Quantification ◽

Posterior Distribution ◽

Global Sensitivity Analysis ◽

Parameter Estimates ◽

Model Parameters ◽

Individual Parameter ◽

Global Sensitivity

AbstractMotivationDynamical models describing intracellular phenomena are increasing in size and complexity as more information is obtained from experiments. These models are often over-parameterized with respect to the quantitative data used for parameter estimation, resulting in uncertainty in the individual parameter estimates as well as in the predictions made from the model. Here we combine Bayesian analysis with global sensitivity analysis in order to give better informed predictions; to point out weaker parts of the model that are important targets for further experiments, as well as give guidance on parameters that are essential in distinguishing different qualitative output behaviours.ResultsWe used approximate Bayesian computation (ABC) to estimate the model parameters from experimental data, as well as to quantify the uncertainty in this estimation (inverse uncertainty quantification), resulting in a posterior distribution for the parameters. This parameter uncertainty was next propagated to a corresponding uncertainty in the predictions (forward uncertainty propagation), and a global sensitivity analysis was performed on the prediction using the posterior distribution as the possible values for the parameters. This methodology was applied on a relatively large and complex model relevant for synaptic plasticity, using experimental data from several sources. We could hereby point out those parameters that by themselves have the largest contribution to the uncertainty of the prediction as well as identify parameters important to separate between qualitatively different predictions.This approach is useful both for experimental design as well as model building.

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