The relevance of non‐excitable cells for cardiac pacemaker function

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Abstract
Age-dependent changes in the architecture of the sinus node comprise an increasing ratio between fibroblasts and cardiomyocytes. This change is discussed as a potential mechanism for sinus node disease. The goal of this study was to determine the mechanism through which non-excitable cells influence the spontaneous activity of multicellular cardiomyocyte preparations. Cardiomyocyte monolayers (HL-1 cells) or embryonic stem cell-derived cardiomyocytes were used as two- and three-dimensional cardiac pacemaker models. Spontaneous activity and conduction velocity (theta) were monitored by field potential measurements with microelectrode arrays (MEAs). The influence of fibroblasts (WT-fibs) was determined in heterocellular cultures of different cardiomyocyte and fibroblast ratios. The relevance of heterocellular gap junctional coupling was evaluated by the use of fibroblasts deficient for the expression of Cx43 (Cx43(-/-)-fibs). The beating frequency and of heterocellular cultures depended negatively on the fibroblast concentration. Interspersion of fibroblasts in cardiomyocyte monolayers increased the coefficient of the interbeat interval variability. Whereas Cx43(-/-)-fibs decreased theta significantly less than WT-fibs, their effect on the beating frequency and the beat-to-beat variability seemed largely independent of their ability to establish intercellular coupling. These results suggest that electrically integrated, non-excitable cells modulate the excitability of cardiac pacemaker preparations by two distinct mechanisms, one dependent and the other independent of the heterocellular coupling established. Whereas heterocellular coupling enables the fibroblast to depolarize the cardiomyocytes or to act as a current sink, the mere physical separation of the cardiomyocytes by fibroblasts induces bradycardia through a reduction in frequency entrainment.