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Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

ABSTRACT: Scar tissue that forms in the heart after cardiac injury, comprises an abundant number of non-excitable fibroblasts in close proximity to excitable myocytes, that are embedded within the matrix of the scar. Electrical coupling of fibroblasts and myocytes is known to occur and in vitro simulation studies have demonstrated that changes in fibroblast membrane potential can lead to myocyte excitability and susceptibility to arrhythmogenesis. However, the physiologic significance of electrical coupling between myocytes and fibroblasts in scar tissue, in the regulation of cardiac excitability and arrhythmogenesis in vivo is hotly debated and has never been demonstrated. Here, we genetically engineer a mouse that expresses the optogenetic cationic channel ChR2 exclusively in cardiac fibroblasts and not in cardiac myocytes. We subject the animal to cardiac injury and demonstrate that optical stimulation of scar tissue elicits cardiac excitability and induces arrhythmias. Connexin 43 (Cx43) is a gap junctional protein that is the most abundant connexin isoform in the heart and thought to mediate electrical coupling of fibroblasts and myocytes. Using genetic loss of function approaches, we show that Cx43 is not necessary for fibroblast-myocyte electrical coupling in vivo. CRISPR/Cas 9 mediated sequential deletion of the other highly expressed connexins also did not affect electrical coupling of fibroblasts and myocytes. Using computational modeling approaches, we show that gap junctional and non-gap junctional coupling mechanisms synergize in a functionally redundant manner to excite myocytes coupled to fibroblasts. These observations demonstrate that cardiac fibroblasts in scar tissue directly regulate cardiac excitability in vivo and can induce arrhythmogenesis. Our findings throw insight into the importance of electrical coupling of fibroblasts and myocytes in the genesis of scar associated cardiac arrhythmias.

ORGANISM(S): Mus musculus

PROVIDER: GSE235434 | GEO | 2023/09/28

REPOSITORIES: GEO

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Project description:This a model from the article: Electrophysiological modeling of fibroblasts and their interaction with myocytes. Sachse FB, Moreno AP, Abildskov JA. Ann Biomed Eng. year volume page 17999190 , Abstract: Experimental studies have shown that cardiac fibroblasts are electrically inexcitable, but can contribute to electrophysiology of myocardium in various manners. The aim of this computational study was to give insights in the electrophysiological role of fibroblasts and their interaction with myocytes. We developed a mathematical model of fibroblasts based on data from whole-cell patch clamp and polymerase chain reaction (PCR) studies. The fibroblast model was applied together with models of ventricular myocytes to assess effects of heterogeneous intercellular electrical coupling. We investigated the modulation of action potentials of a single myocyte varying the number of coupled fibroblasts and intercellular resistance. Coupling to fibroblasts had only a minor impact on the myocyte's resting and peak transmembrane voltage, but led to significant changes of action potential duration and upstroke velocity. We examined the impact of fibroblasts on conduction in one-dimensional strands of myocytes. Coupled fibroblasts reduced conduction and upstroke velocity. We studied electrical bridging between ventricular myocytes via fibroblast insets for various coupling resistors. The simulations showed significant conduction delays up to 20.3 ms. In summary, the simulations support strongly the hypothesis that coupling of fibroblasts to myocytes modulates electrophysiology of cardiac cells and tissues. This model was taken from the CellML repository and automatically converted to SBML. The original model was: sachse, moreno, abildskov.(2008) - version05 The original CellML model was created by: Lloyd, Catherine, May c.lloyd@auckland.ac.nz The University of Auckland Auckland Bioengineering Institute This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2011 The BioModels.net Team. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information. In summary, you are entitled to use this encoded model in absolutely any manner you deem suitable, verbatim, or with modification, alone or embedded it in a larger context, redistribute it, commercially or not, in a restricted way or not.. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Fibroblasts in heart scar tissue directly regulate cardiac excitability and arrhythmogenesis

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