Nonlinear Behavior of Conduction in Cardiac Tissue with Heterogeneous Expression of Connexin 43

Altered cardiac gap junctional coupling is known to potentiate slow conduction and arrhythmias. However, the effects of heterogeneous connexin expression have scarcely been studied. Therefore, our aim was to investigate conduction in tissue consisting of two cardiomyocyte populations expressing different connexin levels.Conduction velocity was measured using microelectrode arrays in cultured strands of fetal murine ventricular myocytes with predefined contents of connexin 43 knock-out (Cx43KO) cells (0 to 100% in steps of 10%) after 1 min of pacing at 3.33 Hz. Corresponding computer simulations of conduction with a subcellular discretization (2.5 µm) were run in randomly generated two-dimensional tissues mimicking the cellular architecture of the strands.In the cultures, the relationship between CV and Cx43KO cell content was highly nonlinear. CV first decreased abruptly from 42.1±2.7 to 7.5±2.3 cm/s when Cx43KO content was increased from 0 to 50% (n=52 and 12, respectively, p<0.001). When the Cx43KO content was ≥60%, CV became comparable to that observed in 100% Cx43KO strands (2.3±0.2 cm/s, n=18). Furthermore, combining Cx43KO and wild-type cells resulted in heterogeneous conduction patterns. The simulations replicated this behavior of conduction. For Cx43KO contents of 10-50%, conduction was slowed due to wavefront meandering between Cx43KO cells. For Cx43KO contents ≥60%, clusters of remaining wild-type cells acted as currents sinks that impaired conduction. For Cx43KO contents of 40-60%, conduction was prone to unidirectional or bidirectional block, while conduction did not block for larger or smaller Cx43KO contents.Thus, conduction velocity and stability behave in a nonlinear manner when cells expressing different connexin amounts are combined. This behavior results from heterogeneous source-sink relationships at the cellular level. In the context of cardiac cellular therapies, such behavior may be arrhythmogenic if transplanted cells and recipient tissue form a heterogeneously coupled substrate.