Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts

[EN] Heart failure (HF) is characterized, among other factors, by a progressive loss of contractile function and by the formation of an arrhythmogenic substrate, both aspects partially related to intracellular Ca2+ cycling disorders. In failing hearts both electrophysiological and structural remodeling, including fibroblast proliferation, contribute to changes in Ca2+ handling which promote the appearance of Ca2+ alternans (Ca-alt). Ca-alt in turn give rise to repolarization alternans, which promote dispersion of repolarization and contribute to reentrant activity. The computational analysis of the incidence of Ca2+ and/or repolarization alternans under HF conditions in the presence of fibroblasts could provide a better understanding of the mechanisms leading to HF arrhythmias and contractile function disorders. Methods and findings The goal of the present study was to investigate in silico the mechanisms leading to the formation of Ca-alt in failing human ventricular myocytes and tissues with disperse fibroblast distributions. The contribution of ionic currents variability to alternans formation at the cellular level was analyzed and the results show that in normal ventricular tissue, altered Ca2+ dynamics lead to Ca-alt, which precede APD alternans and can be aggravated by the presence of fibroblasts. Electrophysiological remodeling of failing tissue alone is sufficient to develop alternans. The incidence of alternans is reduced when fibroblasts are present in failing tissue due to significantly depressed Ca2+ transients. The analysis of the underlying ionic mechanisms suggests that Ca-alt are driven by Ca2+-handling protein and Ca2+ cycling dysfunctions in the junctional sarcoplasmic reticulum and that their contribution to alternans occurrence depends on the cardiac remodeling conditions and on myocyte-fibroblast interactions. Conclusion It can thus be concluded that fibroblasts modulate the formation of Ca-alt in human ventricular tissue subjected to heart failure-related electrophysiological remodeling. Pharmacological therapies should thus consider the extent of both the electrophysiological and structural remodeling present in the failing heart.This work was partially supported by the Plan Estatal de Investigación Científica y Técnica y de Innovación 2013 2016" from the Ministerio de Economía, Industria y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) DPI2016-75799-R (AEI/FEDER, UE), and by the Programa de Ayudas de Investigación y Desarrollo (PAID-01-17) from the Universitat Politècnica de València. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Mora-Fenoll, MT.; Gomez, JF.; Morley, G.; Ferrero De Loma-Osorio, JM.; Trenor Gomis, BA. (2019). Mechanistic investigation of Ca2+ alternans in human heart failure and its modulation by fibroblasts. PLoS ONE. 14(6):1-19. https://doi.org/10.1371/journal.pone.0217993119146Glukhov, A. V., Fedorov, V. V., Kalish, P. W., Ravikumar, V. 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