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

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

10.1101/2019.12.17.877514 ◽

2019 ◽

Author(s):

Arsenii Dokuchaev ◽

Svyatoslav Khamzin ◽

Olga Solovyova

Keyword(s):

Experimental Data ◽

Transient Outward Current ◽

Model Parameters ◽

Maximal Velocity ◽

Population Modelling ◽

Individual Parameter ◽

Human Cardiomyocytes ◽

Age Related ◽

Age Related Changes ◽

Modelling Approach

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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Model of geometrical and smooth muscle tone adaptation of carotid artery subject to step change in pressure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.280.6.h2752 ◽

2001 ◽

Vol 280 (6) ◽

pp. H2752-H2760 ◽

Cited By ~ 38

Author(s):

P. Fridez ◽

A. Rachev ◽

J.-J. Meister ◽

K. Hayashi ◽

N. Stergiopulos

Keyword(s):

Experimental Data ◽

Smooth Muscle ◽

Theoretical Model ◽

Arterial Wall ◽

Circumferential Stress ◽

Experimental Studies ◽

Synthetic Activity ◽

Wall Thickening ◽

Model Parameters ◽

Induced Hypertension

Recent experimental studies have shown significant alterations of the vascular smooth muscle (VSM) tone when an artery is subjected to an elevation in pressure. Therefore, the VSM participates in the adaptation process not only by means of its synthetic activity (fibronectins and collagen) or proliferative activity (hypertrophy and hyperplasia) but also by adjusting its contractile properties and its tone level. In previous theoretical models describing the time evolution of the arterial wall adaptation in response to induced hypertension, the contribution of VSM tone has been neglected. In this study, we propose a new biomechanical model for the wall adaptation to induced hypertension, including changes in VSM tone. On the basis of Hill's model, total circumferential stress is separated into its passive and active components, the active part being the stress developed by the VSM. Adaptation rate equations describe the geometrical adaptation (wall thickening) and the adaptation of active stress (VSM tone). The evolution curves that are derived from the theoretical model fit well the experimental data describing the adaptation of the rat common carotid subjected to a step increase in pressure. This leads to the identification of the model parameters and time constants by characterizing the rapidity of the adaptation processes. The agreement between the results of this simple theoretical model and the experimental data suggests that the theoretical approach used here may appropriately account for the biomechanics underlying the arterial wall adaptation.

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Mechanism of atrioventricular nodal facilitation in the rabbit heart: role of the distal AV node

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.6.h2815 ◽

1997 ◽

Vol 272 (6) ◽

pp. H2815-H2825 ◽

Cited By ~ 5

Author(s):

G. J. Fahy ◽

I. Efimov ◽

Y. Cheng ◽

G. A. Kidwell ◽

D. Van Wagoner ◽

...

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Cellular Response ◽

Rabbit Heart ◽

Av Node ◽

Microelectrode Recordings ◽

Bundle Of His ◽

Action Potential Shortening

We investigated whether atrioventricular (AV) nodal facilitation is the result of distal AV nodal action potential shortening. Atrial and bundle of His (H) electrograms and microelectrode recordings from proximal and distal AV nodal cells were analyzed in eight superfused rabbit AV node preparations in response to two pacing protocols. In the facilitation protocol, an atrial extrastimulus (A3) was preceded by an atrial impulse (A2) introduced 300, 200, 150, or 125 ms after 30 basic beats (A1). The preexcitation protocol differed from the facilitation protocol by the addition of a premature His depolarization (h2) such that the H1-h2 interval was shorter than the H1-H2 interval. Conduction curves (A3-H3 vs. H2-A3, h2-A3, and A2-A3 intervals) were constructed. Facilitation was demonstrated in all preparations when H2-A3 was used (P = 0.02) but not in the A2-A3 format. Compared with facilitation at the same A1-A2 intervals, preexcitation, despite shortening the distal cellular action potential duration, resulted in longer A3-H3 delays (P = 0.002), shorter A2-A3 intervals, and depression of the proximal nodal cellular response. Thus facilitation does not result from altered distal AV nodal characteristics and instead is a manifestation of an uncontrolled pacing protocol-dependent modulation of proximal AV nodal function.

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Inhibition of Histone Deacetylases Induces K+ Channel Remodeling and Action Potential Prolongation in HL-1 Atrial Cardiomyocytes

Cellular Physiology and Biochemistry ◽

10.1159/000492840 ◽

2018 ◽

Vol 49 (1) ◽

pp. 65-77 ◽

Cited By ~ 6

Author(s):

Patrick Lugenbiel ◽

Katharina Govorov ◽

Ann-Kathrin Rahm ◽

Teresa Wieder ◽

Dominik Gramlich ◽

...

Keyword(s):

Action Potential ◽

Ion Channel ◽

Action Potential Duration ◽

Histone Deacetylases ◽

Trichostatin A ◽

Class I ◽

K Channel ◽

Hdac Inhibition ◽

Atrial Cardiomyocytes ◽

Channel Expression

Background/Aims: Cardiac arrhythmias are triggered by environmental stimuli that may modulate expression of cardiac ion channels. Underlying epigenetic regulation of cardiac electrophysiology remains incompletely understood. Histone deacetylases (HDACs) control gene expression and cardiac integrity. We hypothesized that class I/II HDACs transcriptionally regulate ion channel expression and determine action potential duration (APD) in cardiac myocytes. Methods: Global class I/II HDAC inhibition was achieved by administration of trichostatin A (TSA). HDAC-mediated effects on K+ channel expression and electrophysiological function were evaluated in murine atrial cardiomyocytes (HL-1 cells) using real-time PCR, Western blot, and patch clamp analyses. Electrical tachypacing was employed to recapitulate arrhythmia-related effects on ion channel remodeling in the absence and presence of HDAC inhibition. Results: Global HDAC inhibition increased histone acetylation and prolonged APD90 in atrial cardiomyocytes compared to untreated control cells. Transcript levels of voltage-gated or inwardly rectifying K+ channels Kcnq1, Kcnj3 and Kcnj5 were significantly reduced, whereas Kcnk2, Kcnj2 and Kcnd3 mRNAs were upregulated. Ion channel remodeling was similarly observed at protein level. Short-term tachypacing did not induce significant transcriptional K+ channel remodeling. Conclusion: The present findings link class I/II HDAC activity to regulation of ion channel expression and action potential duration in atrial cardiomyocytes. Clinical implications for HDAC-based antiarrhythmic therapy and cardiac safety of HDAC inhibitors require further investigation.

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Experimental studies of iron transformations kinetics and autocatalysis during its physicochemical removal from underground water

Water Science & Technology Water Supply ◽

10.2166/ws.2021.428 ◽

2021 ◽

Author(s):

S. Yu Martynov ◽

V. L. Poliakov

Keyword(s):

Experimental Data ◽

Mathematical Model ◽

Experimental Studies ◽

Underground Water ◽

Model Parameters ◽

Kinetic Coefficients ◽

Transfer Equations ◽

The Mathematical Model ◽

Autocatalytic Effect ◽

Forms Of Iron

Abstract The mathematical model of physicochemical iron removal from groundwater was developed. It consists of three interrelated compartments. The results of the experimental research provide information in support of the first two compartments of the mathematical model. The dependencies for the concentrations of the adsorbed ferrous iron and deposited hydroxide concentrations are obtained as a result of the exact solution of the system of the mass transfer equations for two forms of iron in relation to the inlet surface of the bed. An analysis of the experimental data of the dynamics of the deposit accumulation in a small bed sample was made, using a special application that allowed to select the values of the kinetic coefficients and other model parameters based on these dependencies. We evaluated the autocatalytic effect on the dynamics of iron ferrous and ferric forms. The verification of the mathematical model was carried out involving the experimental data obtained under laboratory and industrial conditions.

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Modeling the Excitability of Mammalian Nerve Fibers: Influence of Afterpotentials on the Recovery Cycle

Journal of Neurophysiology ◽

10.1152/jn.00353.2001 ◽

2002 ◽

Vol 87 (2) ◽

pp. 995-1006 ◽

Cited By ~ 397

Author(s):

Cameron C. McIntyre ◽

Andrew G. Richardson ◽

Warren M. Grill

Keyword(s):

Experimental Data ◽

Action Potential ◽

Experimental Studies ◽

Sensory Nerve ◽

Nerve Fibers ◽

Recovery Cycle ◽

Channel Activation ◽

Single Action ◽

Potential Shape ◽

Wide Range

Human nerve fibers exhibit a distinct pattern of threshold fluctuation following a single action potential known as the recovery cycle. We developed geometrically and electrically accurate models of mammalian motor nerve fibers to gain insight into the biophysical mechanisms that underlie the changes in axonal excitability and regulate the recovery cycle. The models developed in this study incorporated a double cable structure, with explicit representation of the nodes of Ranvier, paranodal, and internodal sections of the axon as well as a finite impedance myelin sheath. These models were able to reproduce a wide range of experimental data on the excitation properties of mammalian myelinated nerve fibers. The combination of an accurate representation of the ion channels at the node (based on experimental studies of human, cat, and rat) and matching the geometry of the paranode, internode, and myelin to measured morphology (necessitating the double cable representation) were needed to match the model behavior to the experimental data. Following an action potential, the models generated both depolarizing (DAP) and hyperpolarizing (AHP) afterpotentials. The model results support the hypothesis that both active (persistent Na+ channel activation) and passive (discharging of the internodal axolemma through the paranodal seal) mechanisms contributed to the DAP, while the AHP was generated solely through active (slow K+ channel activation) mechanisms. The recovery cycle of the fiber was dependent on the DAP and AHP, as well as the time constant of activation and inactivation of the fast Na+ conductance. We propose that experimentally documented differences in the action potential shape, strength-duration relationship, and the recovery cycle of motor and sensory nerve fibers can be attributed to kinetic differences in their nodal Na+ conductances.

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