Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43

Prudat, Yann; Kučera, Jan

doi:10.1016/j.yjmcc.2014.07.019

Cited by 22 publications

(32 citation statements)

References 29 publications

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“…Following our previous approach (Prudat and Kucera, 2014), simulations were based on randomly seeded cellular networks mimicking the irregular layout of the cells in two-dimensional layers of CMCs or CMCs and MFBs. Briefly, the domains to be simulated were partitioned into polygons describing individual cells.…”

Section: Methodsmentioning

confidence: 99%

“…Cytoplasmic resistivity was set to 124 Ωcm (Prudat and Kucera, 2014). This value is in the range of resistivities of physiological electrolyte solutions and matches values used in past computational studies (100–180 Ωcm; Kléber and Riegger, 1987; Shaw and Rudy, 1997; Hubbard and Henriquez, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…As done previously in murine ventricular cell culture models (Prudat and Kucera, 2014), gap junctional conductance between CMCs was adjusted conjointly with the voltage gated sodium current density to replicate the conduction velocity (CV) and the rate of rise of the action potential (dV/dt max ) observed in experiments (Rohr et al, 1998). Intercellular gap junctional conductance was proportional to the contact length between neighboring CMCs and was thus represented by a proportionality constant, γ, representing conductivity (conductance per contact length, see Table 1).…”

Section: Methodsmentioning

confidence: 99%

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Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model

et al. 2016

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Fibrotic myocardial remodeling is typically accompanied by the appearance of myofibroblasts (MFBs). In vitro, MFBs were shown to slow conduction and precipitate ectopic activity following gap junctional coupling to cardiomyocytes (CMCs). To gain further mechanistic insights into this arrhythmogenic MFB-CMC crosstalk, we performed numerical simulations in cell-based high-resolution two-dimensional tissue models that replicated experimental conditions. Cell dimensions were determined using confocal microscopy of single and co-cultured neonatal rat ventricular CMCs and MFBs. Conduction was investigated as a function of MFB density in three distinct cellular tissue architectures: CMC strands with endogenous MFBs, CMC strands with coating MFBs of two different sizes, and CMC strands with MFB inserts. Simulations were performed to identify individual contributions of heterocellular gap junctional coupling and of the specific electrical phenotype of MFBs. With increasing MFB density, both endogenous and coating MFBs slowed conduction. At MFB densities of 5–30%, conduction slowing was most pronounced in strands with endogenous MFBs due to the MFB-dependent increase in axial resistance. At MFB densities >40%, very slow conduction and spontaneous activity was primarily due to MFB-induced CMC depolarization. Coating MFBs caused non-uniformities of resting membrane potential, which were more prominent with large than with small MFBs. In simulations of MFB inserts connecting two CMC strands, conduction delays increased with increasing insert lengths and block appeared for inserts >1.2 mm. Thus, electrophysiological properties of engineered CMC-MFB co-cultures depend on MFB density, MFB size and their specific positioning in respect to CMCs. These factors may influence conduction characteristics in the heterocellular myocardium.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model

et al. 2016

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“…14 In the latter preparations, conduction velocity assessed using optical mapping decreased with the proportion of Cx43-knockout cells and leveled off at a velocity of 2-3 cm/s that was supported by Cx45. 14 Further experiments conducted using microelectrode arrays 46 indicated that the relationship between velocity and Cx43-knockout cell proportion is nonlinear and that conduction in cell strands in which the two cellular genotypes are mixed is susceptible to block.…”

mentioning

confidence: 99%

“…46 In tissue consisting of a random mixture of Cx43-knockout and wild-type cells, conduction was highly discontinuous with patches of myocytes being activated very rapidly while patch-topatch activation was delayed. This heterogeneous pattern was caused by conduction through well-coupled myocytes meandering between irregularly positioned and poorly connected Cx43-knockout regions resulting from the random arrangement of the two cell types.…”

mentioning

confidence: 99%

Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis

Kučera

Rohr

Kléber

2017

Circ: Arrhythmia and Electrophysiology

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Functional Characterization and Comparison of Intercellular Communication in Stem Cell-Derived Cardiomyocytes

Illaste

Heuking

et al. 2015

Stem Cells

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One novel treatment strategy for the diseased heart focuses on the use of pluripotent stem cellderived cardiomyocytes (SC-CMs) to overcome the heart's innate deficiency for self-repair. However, targeted application of SC-CMs requires in-depth characterization of their true cardiogenic potential in terms of excitability and intercellular coupling at cellular level and in multicellular preparations. In this study, we elucidated the electrical characteristics of single SC-CMs and intercellular coupling quality of cell pairs, and concomitantly compared them with well-characterized murine native neonatal and immortalized HL-1 cardiomyocytes. Firstly, we investigated the electrical properties and Ca 21 signaling mechanisms specific to cardiac contraction in single SC-CMs. Despite heterogeneity of the new cardiac cell population, their electrophysiological activity and Ca 21 handling were similar to native cells. Secondly, we investigated the capability of paired SCCMs to form an adequate subunit of a functional syncytium and analyzed gap junctions and signal transmission by dye transfer in cell pairs. We discovered significantly diminished coupling in SCCMs compared with native cells, which could not be enhanced by a coculture approach combining SC-CMs and primary CMs. Moreover, quantitative and structural analysis of gap junctions presented significantly reduced connexin expression levels compared with native CMs. Strong dependence of intercellular coupling on gap junction density was further confirmed by computational simulations. These novel findings demonstrate that despite the cardiogenic electrophysiological profile, SC-CMs present significant limitations in intercellular communication. Inadequate coupling may severely impair functional integration and signal transmission, which needs to be carefully considered for the prospective use of SC-CMs in cardiac repair.

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Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43

Cited by 22 publications

References 29 publications

Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model

Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model

Microstructure, Cell-to-Cell Coupling, and Ion Currents as Determinants of Electrical Propagation and Arrhythmogenesis

Functional Characterization and Comparison of Intercellular Communication in Stem Cell-Derived Cardiomyocytes

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