Loss of Side-to-Side Connections Affects the Relative Contributions of the Sodium and Calcium Current to Transverse Propagation Between Strands of Atrial Myocytes

Jichao Zhao, Ulrich Schotten, Bruce Smaill, Sander Verheule

Background: Atrial fibrillation (AF) leads to a loss of transverse connections between myocyte strands that is associated with an increased complexity and stability of AF. We have explored the interaction between longitudinal and transverse coupling, and the relative contribution of the sodium (INa) and calcium (ICa) current to propagation, both in healthy tissue and under diseased conditions using computer simulations. Methods: Two parallel strands of atrial myocytes were modeled (Courtemanche et al. ionic model). As a control condition, every single cell was connected both transversely and longitudinally. To simulate a loss of transverse connectivity, this number was reduced to 1 in 4, 8, 12, or 16 transversely. To study the interaction with longitudinal coupling, anisotropy ratios of 3, 9, 16, and 25:1 were used. All simulations were repeated for varying degrees of INa and ICa block and the transverse activation delay (TAD) between the paced and non-paced strands was calculated for all cases. Results: The TAD was highly sensitive to the transverse connectivity, increasing from 1 ms at 1 in 1, to 25 ms at 1 in 4, and 100 ms at 1 in 12 connectivity. The TAD also increased when longitudinal coupling was increased. Both decreasing transverse connectivity and increasing longitudinal coupling enhanced the synchronicity of activation of the non-paced strand and increased the propensity for transverse conduction block. Even after long TADs, the action potential upstroke in the non-paced strand was still mainly dependent on the INa. Nevertheless, ICa in the paced strand was essential to provide depolarizing current to the non-paced strand. Loss of transverse connections increased the sensitivity to both INa and ICa block. However, when longitudinal coupling was relatively high, transverse propagation was more sensitive to ICa block than to INa block. Conclusions: Although transverse propagation depends on both INa and ICa, their relative contribution, and sensitivity to channel blockade, depends on the distribution of transverse connections and the axial conductivity. This simple two-strand model helps to explain the nature of atrial discontinuous conduction during structural remodeling and provides an opportunity for more effective drug development.