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

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

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dc.contributor.author Mora-Fenoll, María Teresa es_ES
dc.contributor.author Ferrero De Loma-Osorio, José María es_ES
dc.contributor.author Gómez García, Juan Francisco es_ES
dc.contributor.author Sobie, Eric A. es_ES
dc.contributor.author Trenor Gomis, Beatriz Ana es_ES
dc.date.accessioned 2020-06-10T03:32:46Z
dc.date.available 2020-06-10T03:32:46Z
dc.date.issued 2018-08-23 es_ES
dc.identifier.issn 1664-042X es_ES
dc.identifier.uri http://hdl.handle.net/10251/145869
dc.description.abstract [EN] 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 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 action potentials 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 heart failure 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. es_ES
dc.description.sponsorship This work was partially supported by the National Science Foundation (MCB 1615677), the American Heart Association (15GRNT25490006), the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 from the Ministerio de Economia, Industria y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) DPI2016-75799-R (AEI/FEDER, UE)", and the "Programa de Ayudas de Investigacion y Desarrollo (PAID-01-17)" from the Universitat Politecnica de Valencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. es_ES
dc.language Inglés es_ES
dc.publisher Frontiers Media SA es_ES
dc.relation FEDER/DPI2016-75799-R es_ES
dc.relation NSF/MCB 1615677 es_ES
dc.relation AHA/15GRNT25490006 es_ES
dc.relation MINECO/DPI2016-75799-R es_ES
dc.relation UPV/PAID-01-17 es_ES
dc.relation AEI/DPI2016-75799-R es_ES
dc.relation.ispartof Frontiers in Physiology es_ES
dc.rights Reconocimiento (by) es_ES
dc.subject Calcium handling es_ES
dc.subject Heart failure es_ES
dc.subject Fibrosis es_ES
dc.subject Sensitivity analysis es_ES
dc.subject Electrophysiology es_ES
dc.subject.classification TECNOLOGIA ELECTRONICA es_ES
dc.title Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations es_ES
dc.type Artículo es_ES
dc.identifier.doi 10.3389/fphys.2018.01194 es_ES
dc.rights.accessRights Abierto es_ES
dc.contributor.affiliation Universitat Politècnica de València. Departamento de Ingeniería Electrónica - Departament d'Enginyeria Electrònica es_ES
dc.description.bibliographicCitation Mora-Fenoll, MT.; Ferrero De Loma-Osorio, JM.; Gómez García, JF.; Sobie, EA.; Trenor Gomis, BA. (2018). Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01194 es_ES
dc.description.accrualMethod S es_ES
dc.relation.publisherversion https://doi.org/10.3389/fphys.2018.01194 es_ES
dc.type.version info:eu-repo/semantics/publishedVersion es_ES
dc.description.volume 9 es_ES
dc.identifier.pmid 30190684 es_ES
dc.identifier.pmcid PMC6116328 es_ES
dc.relation.pasarela S\370071 es_ES
dc.contributor.funder American Heart Association es_ES
dc.contributor.funder Agencia Estatal de Investigación es_ES
dc.contributor.funder National Science Foundation, EEUU es_ES
dc.contributor.funder European Regional Development Fund es_ES
dc.contributor.funder Universitat Politècnica de València es_ES
dc.contributor.funder Ministerio de Economía, Industria y Competitividad es_ES
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