Adaptation of the Calcium-dependent Tension Development in Ventricular Cardiomyocytes

Abstract Today a variety of models describe the physiological behavior of the heart on a cellular level. The intracellular calcium concentration plays an important role, since it is the main driver for the active contraction of the heart. Due to different implementations of the calcium dynamics, simulating cardiac electromechanics can lead to severely different behaviors of the active tension when coupling the same tension model with different electrophysiological models. To handle these variations, we present an optimization tool that adapts the parameters of the most recent, human based tension model. The goal is to generate a physiologically valid tension development when coupled to an electrophysiological cellular model independent of the specifics of that model's calcium transient. In this work, we focus on a ventricular cell model. In order to identify the calcium-sensitive parameters, a sensitivity analysis of the tension model was carried out. In a further step, the cell model was adapted to reproduce the sarcomere length-dependent behavior of troponin C. With a maximum relative deviation of 20.3% per defined characteristic of the tension development, satisfactory results could be obtained for isometric twitch tension. Considering the length-dependent troponin handling, physiological behavior could be reproduced. In conclusion, we propose an algorithm to adapt the tension development model to any calcium transient input to achieve a physiologically valid active contraction on a cellular level. As a proof of concept, the algorithm is successfully applied to one of the most recent human ventricular cell models. This is an important step towards fully coupled electromechanical heart models, which are a valuable tool in personalized health care.

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A SIMPLE MODEL FOR INTERACTION OF VOLTAGE AND CALCIUM DYNAMICS IN VIRTUAL VENTRICULAR TISSUE

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127403008776 ◽

2003 ◽

Vol 13 (12) ◽

pp. 3873-3886

Author(s):

O. V. ASLANIDI ◽

A. V. HOLDEN

Keyword(s):

Intracellular Calcium ◽

Calcium Release ◽

Cell Model ◽

Excitation Threshold ◽

Calcium Dynamics ◽

Variable Model ◽

Ventricular Cell ◽

Calcium Dependent ◽

Intracellular Ca ◽

A Site

A simple two-variable model is used to replace the formulation of calcium dynamics in the Luo–Rudy ventricular cell model. Virtual ventricular cell and tissue are developed and validated to reproduce restitution properties and calcium-dependent voltage patterns present in the original model. Basic interactions between the membrane potential and Ca 2+ dynamics in the virtual cell and a strand of the virtual tissue are studied. Intracellular calcium waves can be linked to both action potentials (APs) and delayed afterdepolarizations (DADs). An intracellular calcium wave propagating from the cell interior can induce an AP upon reaching the cell membrane. The voltage and the intracellular Ca 2+ patterns within the same cell can be highly desynchronized. In a one-dimensional strand of the virtual tissue calcium motion is driven by the AP propagation. However, calcium release can be induced upon certain conditions (e.g. Na + overload of the cells), which results in DADs propagating in the wake of AP. Such propagating DADs can reach the excitation threshold, generating a pair of extrasystolic APs. Collision of a propagating AP with a site of elevated intracellular Ca 2+ concentration does not affect the propagation under the normal conditions. Under Na + overload local elevation of the intracellular Ca 2+ leads to generation of an extrasystolic AP, which destroys the original propagating AP.

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Effects of Serum Calcium Changes on the Cardiac Action Potential and the ECG in a Computational Model

Current Directions in Biomedical Engineering ◽

10.1515/cdbme-2018-0061 ◽

2018 ◽

Vol 4 (1) ◽

pp. 251-254 ◽

Cited By ~ 1

Author(s):

María Hernández Mesa ◽

Nicolas Pilia ◽

Olaf Dössel ◽

Stefano Severi ◽

Axel Loewe

Keyword(s):

Action Potential ◽

Computational Model ◽

Cell Model ◽

Cellular Level ◽

Calcium Dependent ◽

Cardiac Action ◽

Dependent Inactivation ◽

End Stage ◽

Extracellular Sodium ◽

Ventricular Cell Model

AbstractPatients suffering from end stage of chronic kidney disease (CKD) often undergo haemodialysis to normalize the electrolyte concentrations. Moreover, cardiovascular disease (CVD) is the main cause of death in CKD patients. To study the connection between CKD and CVD, we investigated the effects of an electrolyte variation on cardiac signals (action potential and ECG) using a computational model. In a first step, simulations with the Himeno et al. ventricular cell model were performed on cellular level with different extracellular sodium ([Na+]o), calcium ([Ca2+]o) and potassium ([K+]o) concentrations as occurs in CKD patients. [Ca2+]o and [K+]o changes caused variations in different features describing the morphology of the AP. Changes due to a [Na+]o variation were not as prominent. Simulations with [Ca2+]o variations were also carried out on ventricular ECG level and a 12-lead ECG was computed. Thus, a multiscale simulator from ion channel to ECG reproducing the calcium-dependent inactivation of ICaL was achieved. The results on cellular and ventricular level agree with results from literature. Moreover, we suggest novel features representing electrolyte changes that have not been described in literature. These results could be helpful for further studies aiming at the estimation of ionic concentrations based on ECG recordings.

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Rate Dependence and Regulation of Action Potential and Calcium Transient in a Canine Cardiac Ventricular Cell Model

Circulation ◽

10.1161/01.cir.0000147231.69595.d3 ◽

2004 ◽

Vol 110 (20) ◽

pp. 3168-3174 ◽

Cited By ~ 223

Author(s):

Thomas J. Hund ◽

Yoram Rudy

Keyword(s):

Action Potential ◽

Cell Model ◽

Calcium Transient ◽

Rate Dependence ◽

Ventricular Cell ◽

Ventricular Cell Model

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Calcium-dependent resistance to stretch and stress relaxation in resting smooth muscles

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.231.5.1501 ◽

1976 ◽

Vol 231 (5) ◽

pp. 1501-1508 ◽

Cited By ~ 69

Author(s):

MJ Siegman ◽

TM Butler ◽

SU Mooers ◽

RE Davies

Keyword(s):

Stress Relaxation ◽

Smooth Muscles ◽

Muscle Length ◽

Taenia Coli ◽

Tetraacetic Acid ◽

Active Tension ◽

Tension Development ◽

Calcium Dependent ◽

Mechanical Responses ◽

State Force

Mechanical responses to stretch and length-tension relations were examined in rabbit taenia coli, mesenteric vein, aorta, and myometrium and in guinea pig taenia coli made atonic by incubation in Krebs-bicarbonate solution at 20-22 degrees C. When stretched 10% of the length at which maximum active tension is observed (Lo) in 0.5 s, the muscles showed a transient large force (resistance to stretch) that decayed to a new constant level within minutes (stress relaxation). The resistance to stretch decreased markedly in Ca2+-free [disodium ethylene glycolbis-(beta-aminoethylether)-N,N-tetraacetic acid (EGTA)] Krebs but was restored in normal Krebs solution. Calcium removal did not affect the passive length-tension curve. The absence of Ca2+ did not change the steady-state force maintained by the muscle; thus stretch resistance was not due to tone. Blockade of Ca2+ influx associated with electrical activity with 5-[3,4-dimethoxyphenethyl)methylamino]-2-(3,4,5-trimethoxyphenyl-2-isoprop ylvaleronitrile (D-600) and of Ca2+ release from intracellular sites with thymol (1 mM) completely blocked contraction but did not alter the responses to stretch, thus dissociating the responses to stretch from these processes and tension development. The Ca2+-dependent stress relaxation showed a dependence on muscle length similar to that for active tension development. Except at long muscle lengths, where connective tissue markedly affects length-tension relations, most of the "viscoelasticity" of these smooth muscles is dependent on calcium and may be largely due to the straining of crossbridges that are attached, but not generating a net force, in the resting state.

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Iron Supplements Containing Lactobacillus plantarum 299v Increase Ferric Iron and Up-regulate the Ferric Reductase DCYTB in Human Caco-2/HT29 MTX Co-Cultures

Nutrients ◽

10.3390/nu10121949 ◽

2018 ◽

Vol 10 (12) ◽

pp. 1949 ◽

Cited By ~ 3

Author(s):

Ann-Sofie Sandberg ◽

Gunilla Önning ◽

Niklas Engström ◽

Nathalie Scheers

Keyword(s):

Lactobacillus Plantarum ◽

Ferric Iron ◽

Iron Absorption ◽

Cell Model ◽

Goblet Cells ◽

Cellular Level ◽

Intestinal Cell ◽

Ferric Reductase ◽

Iron Supplements ◽

Lactic Fermentation

Several human interventions have indicated that Lactobacillus plantarum 299v (L. plantarum 299v) increases intestinal iron absorption. The aim of the present study was to investigate possible effects of L. plantarum 299v on the mechanisms of iron absorption on the cellular level. We have previously shown that lactic fermentation of vegetables increased iron absorption in humans. It was revealed that the level of ferric iron [Fe (H2O)5]2+ was increased after fermentation. Therefore, we used voltammetry to measure the oxidation state of iron in simulated gastrointestinal digested oat and mango drinks and capsule meals containing L. plantarum 299v. We also exposed human intestinal co-cultures of enterocytes and goblet cells (Caco-2/HT29 MTX) to the supplements in order to study the effect on proteins possibly involved (MUC5AC, DCYTB, DMT1, and ferritin). We detected an increase in ferric iron in the digested meals and drinks containing L. plantarum 299v. In the intestinal cell model, we observed that the ferric reductase DCYTB increased in the presence of L. plantarum 299v, while the production of mucin (MUC5AC) decreased independently of L. plantarum 299v. In conclusion, the data suggest that the effect of L. plantarum 299v on iron metabolism is mediated through driving the Fe3+/DCYTB axis.

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Extracellular Electrophysiology in the Prostate Cancer Cell Model PC-3

Sensors ◽

10.3390/s19010139 ◽

2019 ◽

Vol 19 (1) ◽

pp. 139 ◽

Cited By ~ 9

Author(s):

Miguel Cabello ◽

Haobo Ge ◽

Carmen Aracil ◽

Despina Moschou ◽

Pedro Estrela ◽

...

Keyword(s):

Prostate Cancer ◽

Electrical Activity ◽

Cell Model ◽

Treatment Strategies ◽

Electrode Array ◽

Cellular Level ◽

Low Noise ◽

Cellular Growth ◽

Male Population ◽

Depth Analysis

Although prostate cancer is one of the most common cancers in the male population, its basic biological function at a cellular level remains to be fully understood. This lack of in depth understanding of its physiology significantly hinders the development of new, targeted and more effective treatment strategies. Whilst electrophysiological studies can provide in depth analysis, the possibility of recording electrical activity in large populations of non-neuronal cells remains a significant challenge, even harder to address in the picoAmpere-range, which is typical of cellular level electrical activities. In this paper, we present the measurement and characterization of electrical activity of populations of prostate cancer cells PC-3, demonstrating for the first time a meaningful electrical pattern. The low noise system used comprises a multi-electrode array (MEA) with circular gold electrodes on silicon oxide substrates. The extracellular capacitive currents present two standard patterns: an asynchronous sporadic pattern and a synchronous quasi-periodic biphasic spike pattern. An amplitude of ±150 pA, a width between 50–300 ms and an inter-spike interval around 0.5 Hz characterize the quasi-periodic spikes. Our experiments using treatment of cells with Gd3⁺, known as an inhibitor for the Ca2⁺ exchanges, suggest that the quasi-periodic signals originate from Ca2⁺ channels. After adding the Gd3⁺ to a population of living PC-3 cells, their electrical activity considerably decreased; once the culture was washed, thus eliminating the Gd3⁺ containing medium and addition of fresh cellular growth medium, the PC-3 cells recovered their normal electrical activity. Cellular viability plots have been carried out, demonstrating that the PC-3 cells remain viable after the use of Gd3⁺, on the timescale of this experiment. Hence, this experimental work suggests that Ca2⁺ is significantly affecting the electrophysiological communication pattern among PC-3 cell populations. Our measuring platform opens up new avenues for real time and highly sensitive investigations of prostate cancer signalling pathways.

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