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  • Hydrogen peroxide H O is shown to

    2019-04-28

    Hydrogen peroxide (H2O2) is shown to readily promote EADs and triggered activity in isolated rat and rabbit ventricular myocytes by increasing both the L-type Ca channel (ICa-L) and late sodium currents (INa-L) [31–35]. However, this same stress fails to cause EADs in normal non-fibrotic cardiac tissue [10,12]. The discrepancy between non-fibrotic and fibrotic heart tissues in the genesis of EAD-mediated triggered activity either in isolated single myocytes or at the tissue level may result from the “source-to-sink” mismatch [36]. This phenomenon occurs as follows: at a ventricular site, some buy GSK1324726A that become greatly stressed and generate EADs (i.e., “source”) may be electrically well coupled to adjoining cells that do not generate EADs and instead repolarize normally back to the resting potential. In this case, such adjoining cells exert a repolarizing influence on the cells that are prone to generate EADs, i.e., “sink effect,” thus suppressing the EADs. Stated otherwise, EAD as the source becomes incapable of overriding the repolarizing sink effect exerted by the electrically coupled normally repolarizing cells, which results in EAD suppression. The importance of the diffusive electrotonic cellular coupling on the modulation of EADs was systematically studied using simulation. For example, when 2 isolated ventricular myocytes were artificially well coupled via a variable electrical resistor, with 1 cell generating EADs and the other cell devoid of EADs, EADs in the first cell were suppressed if the second cell had normal repolarization. However, if the same cell with EADs was uncoupled from the cell with normal repolarization by applying an infinite electrical resistance between the 2 cells (i.e., complete cellular uncoupling, mimicking an isolated single myocyte) the EADs emerged again [37,38]. These single-cell studies were later expanded in a thorough systematic study using 1-, 2-, and 3-dimensionally arranged (1D, 2D, and 3D) tissues to determine the number of contiguous cells with EADs required to override the sink effect and allow the EAD-mediated triggered beats to propagate to the surrounding tissue. For example, using a realistic cardiac cell model, it was shown that in 3D normally-coupled tissue, one needs approximately 700,000 contiguous cells to synchronously produce EADs in order to overcome the source-to-sink mismatch and allow a triggered premature ventricular contraction (PVC) to propagate [36]. In 2D tissue, this number decreases to approximately 7000, and in a 1D cable to approximately 70. Interestingly, and as expected, the minimum number of cells needed to produce a propagated EAD-induced PVC in 3D tissue decreased by as much as 40-fold when cell-to-cell gap junctional coupling is reduced [36]. Fibrosis, which imposes insulating collagen bands between strands of myocytes (essentially converting 3D tissue into a network of 1D cables), is even more potent at reducing the number of myocytes required for PVC formation [36]. These experimental and simulation studies strongly suggest that the observed discrepancy in EAD production between isolated myocytes and normally coupled cardiac tissue may indeed result from the source-to-sink mismatch. In well-coupled cardiac tissue, the source-to-sink mismatch provides a powerful protective effect for suppression of EAD formation by delinquent cells, preventing the emergence of cardiac arrhythmias. Fig. 2 describes schematically the relationships between fibrosis and repolarization reserve reduction under 3 different conditions: the isolated single myocyte, normal tissue, and fibrotic tissue. Based on the findings above, it could be surmised that cardiac diseases that cause myocyte decoupling should facilitate the emergence of EADs when the repolarization reserve is reduced. A number of factors reduce cellular coupling in diseased heart, including gap junction remodeling and fibrosis. Fibrosis forms insulating barriers between cells and groups of cells through the interstitial tissue deposit of collagenous filaments by the proliferating cardiac myofibroblasts [19,20]. We have shown that aging in rats and rabbits manifests not only increased cardiac fibrosis but also down-regulation of the gap junctional connexins43 (Cx43) [12,39] that effectively reduce the coupling conductance between cardiac myocytes.