Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

Zhan, Heqing; Xia, Ling; Shou, Guofa; Zang, Yunliang; F, Liu; Crozier, Stuart

doi:10.1631/jzus.b1300156

Cited by 17 publications

(15 citation statements)

References 58 publications

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“…Preliminary experiments [28] showed that hiPSC-CF increase the contraction displacement of the tissue constructs with increasing RFC of up to 50%. This is inconsistent with the computational study of Zhan et al, [23] which suggested that the active stress (and thus the contraction displacement) of ventricular CMs decreases when fibroblasts are added to the tissue. However, it should be noted that their model was not validated with experiments and the results should therefore be treated with caution.…”

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confidence: 89%

Modeling and simulation of human induced pluripotent stem cell‐derived cardiac tissue

Jung

Staat

2019

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Human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) have become a promising in vitro model for human native cardiomyocytes. Cultivated tissue samples beat autonomously and can be used for basic and pharmacological research. For mechanical measurements of these tissue samples, the CellDrum technology has been developed. Measurements are extended by simulations with a multi‐scale electromechanically coupled finite element method based model. This model can be parameterized and validated experimentally. The paper describes the model, its workflow, and preliminary simulations to study the effect of fibroblasts and a selected cardiac drug on the electromechanics of hiPSC‐CMs.

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confidence: 89%

Modeling and simulation of human induced pluripotent stem cell‐derived cardiac tissue

Jung

Staat

2019

GAMM-Mitteilungen

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“…1 for details). In particular, this model was used as the electrical component in electromechanical models combined with different mechanical modules [22,23,33].…”

Section: Tp + M Modelmentioning

confidence: 99%

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

et al. 2020

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Experiments on animal hearts (rat, rabbit, guinea pig, etc.) have demonstrated that mechano-calcium feedback (MCF) and mechano-electric feedback (MEF) are very important for myocardial self-regulation because they adjust the cardiomyocyte contractile function to various mechanical loads and to mechanical interactions between heterogeneous myocardial segments in the ventricle walls. In in vitro experiments on these animals, MCF and MEF manifested themselves in several basic classical phenomena (e.g., load dependence, length dependence of isometric twitches, etc.), and in the respective responses of calcium transients and action potentials. However, it is extremely difficult to study simultaneously the electrical, calcium, and mechanical activities of the human heart muscle in vitro. Mathematical modeling is a useful tool for exploring these phenomena. We have developed a novel model to describe electromechanical coupling and mechano-electric feedbacks in the human cardiomyocyte. It combines the 'ten Tusscher-Panfilov' electrophysiological model of the human cardiomyocyte with our module of myocardium mechanical activity taken from the 'Ekaterinburg-Oxford' model and adjusted to human data. Using it, we simulated isometric and afterloaded twitches and effects of MCF and MEF on excitation-contraction coupling. MCF and MEF were found to affect significantly the duration of the calcium transient and action potential in the human cardiomyocyte model in response to both smaller afterloads as compared to bigger ones and various mechanical interventions applied during isometric and afterloaded twitches.

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“…A tissue-level hallmark of HF is increased fibrosis and proliferation of cardiac fibroblasts. Several in vitro studies and mathematical modeling studies have documented that electrical coupling between myocytes and fibroblasts will lead to changes in APD and intracellular Ca 2+ ( Zhan et al, 2014 ; Li et al, 2017 ). Experimental evidence suggesting the formation of gap junctions between myocytes and fibroblasts in vitro ( Gaudesius et al, 2003 ) has focused researchers attention on the altered electrophysiological properties of myocytes due to this intercellular coupling to explain conduction abnormalities and reentries ( Miragoli et al, 2006 ; Xie et al, 2009a ; Majumder et al, 2012 ).…”

Section: Introductionmentioning

confidence: 99%

Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

et al. 2018

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Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte–fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential (AP) and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+–Ca2+ exchange and SR Ca2+ leak. Changes required to normalize APs in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in HF and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart.

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Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study

Cited by 17 publications

References 58 publications

Modeling and simulation of human induced pluripotent stem cell‐derived cardiac tissue

Modeling and simulation of human induced pluripotent stem cell‐derived cardiac tissue

Mechano-calcium and mechano-electric feedbacks in the human cardiomyocyte analyzed in a mathematical model

Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

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