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Gap junctions are channels in cell membranes allowing ions to pass directly between cells. They are found throughout the body, including heart myocytes, neurons, and astrocytes. In cardiac tissue and throughout the nervous system, an action potential (AP) in one cell can trigger APs in neighboring cells connected by gap junctions. It is known experimentally that there is an ideal gap junction conductance for AP propagation--lower or higher conductance can lead to propagation failure. We explain this phenomenon geometrically in branching networks by analyzing an idealized model that focuses exclusively on gap junction and AP-generating currents. As expected, the gap junction conductance must be high enough for AP propagation to occur. However, if the gap junction conductance is too high, then it dominates the cell's intrinsic firing conductance and disrupts AP generation. We also identify conditions for semiactive propagation, where cells in the network are not individually excitable but still propagate action potentials. [ABSTRACT FROM AUTHOR]

Gap junctions are channels in cell membranes allowing ions to pass directly between cells. They are found throughout the body, including heart myocytes, neurons, and astrocytes. In cardiac tissue and throughout the nervous system, an action potential (AP) in one cell can trigger APs in neighboring cells connected by gap junctions. It is known experimentally that there is an ideal gap junction conductance for AP propagation—lower or higher conductance can lead to propagation failure. We explain this phenomenon geometrically in branching networks by analyzing an idealized model that focuses exclusively on gap junction and AP-generating currents. As expected, the gap junction conductance must be high enough for AP propagation to occur. However, if the gap junction conductance is too high, then it dominates the cell's intrinsic firing conductance and disrupts AP generation. We also identify conditions for semi-active propagation, where cells in the network are not individually excitable but still propagate action potentials.

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.

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. [ABSTRACT FROM AUTHOR]