Reduced gap junction coupling amplifies the effects of cardiomyocyte variability and destabilizes the heartbeat

Cardiomyocytes exhibit significant cell-to-cell variability due to differences in protein expression and post-tra nslational modifications in both the cell membrane and the intracellular machinery. Resulting variability in action potential propagation and configuration have been proposed to promote arrhythmia. However, such effects may be suppressed by tight electrical coupling of cells in the healthy heart, but not during pathological conditions where gap junction function is impaired. To investigate this question, we employed a cell-based mathematical model of cardiac electrophysiology, in which we systematically modified both the properties of individual cells within the array, and inter-cellular electrical connectivity (gap junctions). Despite the inclusion of marked variation in properties between cells, we observed electrical homogeneity across the array when cells were well coupled. In contrast, lower and/or more variable gap junction connectivity resulted in nonhomogeneous action potential configuration, and irregular timing of both the depolarizing and repolarizing electrical wavefronts. Pro-arrhythmic early after-depolarizations also occurred under these conditions, linked to reopening of L-type calcium channels. These effects were effectively dampened in highly coupled cells. Nevertheless, baseline differences in calcium homeostasis were not negated by gap junction coupling, indicating a limit to which electrical connections can ho-mogenize mechanical function. There are also physical limits to electrical convergence, as we observed that action potential differences persisted at the edges and corners of the array where there are fewer electrical contacts with neighbouring cells. This finding may have implications for arrhythmic susceptibility in the border zone neighbouring an infarction. In summary, our findings underscore the critical role of intercellular coupling in maintaining cardiac stability and highlight the importance of studying cardiomyocytes within a syncytium rather than in isolation.