Fig. 9.

Computational modeling study of the three-dimensional (3-D) effect of cardiomyocyte (CM)-cardiac fibroblast (CF) interactions on automaticity. A: schematics of 3-D cube modeling. CMs and CFs were randomly distributed to have 1:1 or 1:2 ratios in a cube of 25 × 2 5 × 25 cells. B: representative activation map of automaticity from the 3-D cube. The activation maps of each layer labeled as L1−L25 in A are shown in 5 × 5 grids, starting the top layer in the top left corner. In this set of CM:CF distribution, automaticity was originated from two sites (open star). C: the number of CFs connected to a single CM in 3-D cube. The parameter set was chosen based on the single CM-CF simulation shown in Fig. 8. The resting membrane potential of a CF (RMP_CF) was set to −20 mV and gap junction coupling conductance between CM-CF (g_gap,CM-CF) was set to 5 nS. With these parameter settings, automaticity was not observed when n = 1 CF was connected (Fig. 8D). A total of 12 randomly generated CM:CF = 1:1 distributions were tested. The black histogram bars indicate the number of CFs connected to CM from all the CMs in the 3-D cube, which shows that the majority of CMs have connections with three CFs on average. The red histogram bars represent the number of CFs connected only to CMs that initiate automaticity. The initiation sites of automaticity showed a larger number of CFs connected to CMs. D: effect of increased CFs on automaticity. RMP_CF was set to −30 mV and showed no automaticity. When the CM:CF ratio was increased from 1:1 to 1:2, automaticity appeared, suggesting that a higher density of CF promotes automaticity as seen experimentally for CM:CF_Gαq (see Fig. 5B). E: effect of g_gap,CM-CF on automaticity. A reduction of g_gap,CM-CF from 5 to 4 nS decreased the frequency of automaticity, which replicates the effect of carbenoxolone we observed experimentally in CM:CF_GαqQL (see Fig. 5E). V_m, membrane potential.